Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=O.[N+:18](CC)([O-])=O.C(O)(=O)C>O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[C:6]([OH:17])[C:3]=1[C:4]#[N:18]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1c(O)cc(OCc2ccsc2)cc1F
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(O)cc(OCc2ccsc2)cc1F
Temperature: 25 °C
Yield: 25.3 %

Procedure:
A mixture of 2-fluoro-6-hydroxy-4-(3-thienylmethoxy)benzaldehyde (1 g), nitroethane (0.6 g) sodium acetate (0.66 g) and glacial acetic acid (1 mL) is heated at reflux for 2 hours. The reaction mixture is cooled to ambient temperature, water (50 mL) is added and the mixture is extracted three times with ethyl acetate (50 mL). The combined organic phases are washed with saturated brine (50 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a brown oil. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give 2-fluoro-6-hydroxy-4-(3-thienylmethoxy)benzonitrile (250 mg), as a yellow solid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][CH:10]([CH3:25])[CH2:11][N:12]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2>>[Br:8][C:16]1[CH:15]=[CH:14][C:13]2[N:12]([CH2:11][CH:10]([CH3:25])[CH3:9])[C:24]3[C:19]([C:18]=2[CH:17]=1)=[CH:20][CH:21]=[CH:22][CH:23]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Cn1c2ccccc2c2ccccc21
Product: CC(C)Cn1c2ccccc2c2cc(Br)ccc21
Yield: 84 %

Procedure:
The procedure for the synthesis of 2 was followed (1 eq. NBS was used) to prepare 3 from 1 as white crystals in an 84% yield. 1H NMR (400 MHz, CDCl3, 298 K): δ(ppm) 8.20-8.19 (d, 1H), 8.05-8.03 (d, 1H), 7.53-7.38 (m, 3H), 7.28-7.21 (m, 2H), 4.04-4.02 (d, 2H), 2.32-2.30 (m, 1H), 0.97-0.94 (d, 6H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:24]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1C(O)=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:23])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)=[O:7])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc(F)cc1
Yield: 75 %

Procedure:
By the same procedure as in Example 26-D), while using (2S)-1-(tert-butoxycarbonyl)-2-[2-(4-fluorophenoxy)-1-hydroxyethyl]pyrrolidine (1.90 g) and N-(tert-butoxycarbonyl)-L-proline (1.38 g), there was obtained 1.85 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[C:10]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:11]1[C:10]([CH3:17])=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Cc1c(Oc2ccnc(Cl)c2)ccc(N)c1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(Oc2ccnc(-c3cnn(C)c3)c2)ccc(N)c1F
Yield: 75.2 %

Procedure:
4-(2-Chloropyridin-4-yloxy)-2-fluoro-3-methylbenzenamine (1.0 g, 3.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g, 4.8 mmol), Na2CO3 (0.84 g, 6.6 mmol) and Pd(PPh3)4 (0.25 g, 0.2 mmol) were combined in DME (75 mL) and water (25 mL). The mixture was sparged with nitrogen for 15 min and was heated to reflux overnight. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were washed with brine, concentrated in vacuo and purified by silica gel chromatography to give 2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (0.74 g, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J=6.0 Hz, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.07 (s, 1H), 6.63 (m, 2H), 6.45 (dd, J=5.6, 2.4 Hz, 1H), 5.06 (s, 2H), 3.82 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z: 299.2 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[C:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:41])[C@:34]([OH:40])([CH3:39])[C:35]([F:38])([F:37])[F:36].[CH2:42]([CH2:44][NH2:45])[OH:43]>CN(C=O)C.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29](=[O:31])[NH:45][CH2:44][CH2:42][OH:43])=[CH:27][CH:28]=2)(=[O:21])=[O:22])[CH:17]=[CH:16][C:15]=1[NH:32][C:33](=[O:41])[C@:34]([OH:40])([CH3:39])[C:35]([F:37])([F:36])[F:38]
Reactant: NCCO
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)O)cc2)cc1Cl)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)c2ccc(C(=O)NCCO)cc2)cc1Cl)C(F)(F)F
Reaction time: 17 h

Procedure:
A solution of 1,1′-carbonyldiimidazole (0.169 g) and (R)-N-[2-chloro4-(4-carboxyphenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 121) (0.30 g) in DMF (1 ml)/ethyl acetate (9 ml) was heated at 50° C. for 30 minutes. Ethanolamine (0.055 ml) was added and the mixture was heated and stirred a further 17 hours. The mixture was cooled, diluted with ethyl acetate (50 ml), washed with dilute aqueous hydrochloric acid (25 ml), water (25 ml), saturated aqueous sodium hydrogen carbonate solution (25 ml) and brine, then dried. Volatile material was removed by evaporation and the residue was purified by chromatography, eluting with 2.5% ethanol/ethyl acetate to give the title compound (0.25 g) as a solid. NMR (CDCl3+DMSO-δ6):1.58 (s, 3H), 3.44 (m, 2H), 3.62 (m, 2H), 4.26 (t, 1H), 7.05 (s, 1H), 7.76 (dd, 1H), 7.83-8.01 (m, 6H), 8.56 (d, 1H), 9.73 (brs, 1H); MS (ESP−): 495.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[Br:52][C:53]1[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1>>[Br:52][C:53]1[CH:58]=[CH:57][C:56]([S:59]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:16])(=[O:61])=[O:60])=[CH:55][CH:54]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 65 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-bromobenzenesulfonyl chloride as described in example 2, affording the title compound in 65% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH3:9])[O:3]1.[Br:11][CH:12]([CH2:16][Br:17])[C:13](Cl)=[O:14].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[N:6]([C:13](=[O:14])[CH:12]([Br:11])[CH2:16][Br:17])[CH2:5][CH:4]([CH2:7][O:8][CH3:9])[O:3]1
Reactant: COCC1CNC(C)(C)O1
Reactant: O=C(Cl)C(Br)CBr
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COCC1CN(C(=O)C(Br)CBr)C(C)(C)O1

Procedure:
To 11.6 milliliters of 25 percent w/v, 2,2-dimethyl-5-methoxymethyl oxazolidine solution in 50 milliliters of benzene with 5.0 grams of 2,3-dibromopropionyl chloride was added dropwise 2.1 grams of triethylamine. After the reaction was complete the mixture was washed with water, separated, dried and the organic solvent removed in vacuo. There was obtained 2.7 grams of the title compound, nD30 1.4887. Analytical data supports the structure.
Reaction SMILES: [C:1]([OH:10])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:11][O:12][C:13](=[O:20])[C@@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15]>>[CH3:18][CH:17]([CH3:19])[CH2:16][C@@H:14]([NH:15][C:1](=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:13]([O:12][CH3:11])=[O:20]
Reactant: CCCCC/C=C/C(=O)O
Reactant: COC(=O)[C@H](N)CC(C)C
Product: CCCCC/C=C/C(=O)N[C@H](CC(C)C)C(=O)OC

Procedure:
Prepared in a similar manner as described in example 4 from (E)-oct-2-enoic acid and D-leucine methyl ester. MS (M+H, 270).
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: F[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7])([OH:3])=O.Cl.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH3:33])[C:1](=[O:3])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7]
Reactant: CNC
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Agent: Cl
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)N(C)C

Procedure:
The carboxylic acid from Example 33 (0.07 g, 0.18 mmol) was reacted with dimethylamine hydrochloride (0.072 g, 0.88 mmol) according to the procedure in Example 7. The product was purified by flash chromatography on silica (eluant chloroform:methanol:acetic acid 98:1:1) to give a white solid; yield 0.08 g (11%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=NN)[CH2:11][CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:16]([N:22]1[C:26](=[O:27])[CH:25]=[CH:24][C:23]1=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CO>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:16]([N:22]1[C:23](=[O:28])[CH:24]2[CH:25]([C:10]2([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:11][CH2:12][CH3:13])[C:26]1=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCN1C(=O)C=CC1=O
Reactant: CCCC(=NN)c1cccc([N+](=O)[O-])c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCN1C(=O)C2C(C1=O)C2(CCC)c1cccc([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
1-(3-Nitrophenyl)-1-butanone hydrazone (Preparation 63, 1.0 g, 4.8 mmol) was dissolved in dioxan (20 ml) and cooled to 10° C., manganese dioxide (grade CMD-1 from Sumitomo, 10 g, 117 mmol) was added portionwise. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. This suspension was filtered over a pad of Celite® directly into a solution of 1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 0.88 g, 4.5 mmol) in dioxan (20 ml). The Celite® pad was washed with dioxan (125 ml) and then stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo to give a crude orange oil. Methanol (8 ml) was added and the mixture was cooled to 0° C. and upon scratching a white solid precipitated. The solid was filtered off and washed with cold methanol to give the pure product, the mother liquors were concentrated in vacuo and treated again with methanol under the procedure described above to give further product. The title compound was obtained as a white solid (0.28 g, 16%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Cl:19][C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][NH:21]1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1cc(I)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)C1(Cl)C=CC=CN1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)c1

Procedure:
The title compound was prepared from 2-iodo-4-methyl-6-(4-trifluoromethyl-phenyl)pyridine (example A.58) (5.45 g, 15 mmol) and commercially available 2-chloropyridine boronic acid (2.48 g, 15.75 mmol) according to the general procedure IVb. Obtained as an off-white solid (3.82 g, 73%). MS (ISP) 349.2 [(M+H)+] and 351 [(M+2+H)+].
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[F:36])[NH:32][N:31]=[CH:30]2.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:32]3[C:33]4[C:29](=[CH:28][C:27]([F:26])=[C:35]([F:36])[CH:34]=4)[CH:30]=[N:31]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Fc1cc2cn[nH]c2cc1F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(F)c(F)cc43)nc12
Temperature: 125 °C
Yield: 68.3 %

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol) and 5,6-difluoro-1H-indazole (54.1 mg, 351 μmol) in dioxane (5.25 mL) was added sodium tert-butoxide (74.2 mg, 772 μmol) and bis(tri-tert-butylphosphine)palladium(0) (17.9 mg, 35.1 μmol). The mixture was degassed then heated in sealed tube at 125° C. for 15 h. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave N-tert-butyl-2-(5,6-difluoro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 68%). 1H NMR (CDCl3) δ: 9.17 (s, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.44 (dd, J=10.0, 6.8 Hz, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 8.24 (d, J=0.8 Hz, 1H), 5.72 (s, 2H), 3.55-3.61 (m, 2H), 1.61 (s, 9H), 0.93-0.96 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17]NCC(C1C=CC(OC)=CC=1)C>>[Cl:14][C:15]1[C:33]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17][NH:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CC(CN)c1ccccc1
Reactant: COc1ccc(C(C)CNCc2cccc(C(F)(F)F)c2Cl)cc1
Product: CC(C)CC(CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Yield: 77 %

Procedure:
The titled compound was prepared from 2-Phenyl-4-methylpentylamine in 77% yield in the same manner as the preparation of N-(2-Chloro-3-trifluoromethylbenzyl)-2-(4-methoxyphenyl)propylamine in Example 188d. MS (ESI) 370 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=O)[NH:11][CH2:10][CH:9]2[CH2:15]CC(O)=O)=[CH:4][CH:3]=1.B.[O:21]1CCCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:15][OH:21])=[CH:6][CH:7]=1
Reactant: O=C(O)CCC1CNC(=O)CC1c1ccc(F)cc1
Reactant: C1CCOC1
Agent: B
Product: OCC1CNCCC1c1ccc(F)cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
Borane-tetrahydrofuran complex (1.0 molar solution in tetrahydrofuran (10.8 ml, 10.8 mmol) was added over 20 hours in 3 stages (in 3.6 mmol portions) at a rate of 7 ml/hour by means of a syringe pump to a solution of 4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one (0.53 g, 2 mmol, trans/cis˜1:1) in tetrahydrofuran (3 ml) at 26° C. The reaction mixture was stirred for 1 hour after addition of the last portion of the borane solution. then quenched with 3.5 ml 30% aqueous potassium carbonate solution. The phases were separated and the aqueous phase extracted with diethyl ether (25 ml). The organic phases were combined and evaporated to yield 0.43 g of the title compound. Yield 80%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([F:15])=[CH:9][CH:8]=3.[OH-].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br>CN(C)C=O>[F:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH:20]3[CH2:21][O:22]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([F:1])=[CH:3][CH:4]=3
Reactant: BrCC1CO1
Reactant: Fc1ccc2[nH]c3ccc(F)cc3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)c1cc(F)ccc1n2CC1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a stirred solution of 3,6-difluoro-9H-carbazole (0.500 g, 2.5 mmol) in N,N-dimethylformamide (5 mL) at 0° C. was added 85% potassium hydroxide (0.195 g, 3.0 mmol) and the mixture was stirred for 1 hr. Epibromohydrin (0.407 mL, 4.9 mmol) was added and the mixture was slowly warmed to room temperature and stirred for 16 hrs. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10-50% methylene chloride/hexanes) to afford the desired product as a white solid (0.575 g, 90%). 1H NMR (300 MHz, CDCl3) δ 7.69 (dd, 2H, J=8.7, 2.7 Hz), 7.39 (dd, 2H, J=9.0, 3.9 Hz), 7.24 (td, 2H, J=9.0, 2.7 Hz), 4.68 (dd, 1H, J=15.9, 3.0 Hz), 4.33 (dd, 1H, J=15.9, 5.1 Hz), 3.35 (m, 1H), 2.84 (t, 1H, J=4.5 Hz), 2.55 (dd, 1H, J=4.8, 2.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:7](=[O:17])[CH2:6][CH2:5]2.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.CCOCC>[CH3:16][N:14]([CH3:15])[CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:17]
Reactant: CN(C)CCN1C(=O)CCc2cc(N)ccc21
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21
Reaction time: 18 h

Procedure:
A solution of 6-amino-1-(2-(dimethylamino)ethyl)-3,4-dihydroquinolin-2(1H)-one (0.045 g, 0.182 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.103 g, 0.361 mmol) at room temperature and the resulting mixture was stirred over night (18 h). The reaction was diluted with ether (45 mL) and the precipitate collected by vacuum filtration. The precipitate was washed from the filter with methanol and the solvent was evaporated. The residue was diluted with 1N sodium hydroxide solution (5 mL) and product was extracted into ethyl acetate (3×10 mL). The combined ethyl acetate layer was washed with brine and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 1:19). Product was dried under high vacuum. Yield: 40 mg of yellow oil 4 (58%) 1H NMR (CDCl3) δ 7.44 (dd, J=1, 5.4 Hz, 1H), 7.41 (d, J=3.3 Hz, 1H), 7.09 (t, J=4.2 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.88 (dd, J=2.1, 8.4 Hz, 1H), 6.83 (d, J=2.1 Hz, 1H), 4.87 (br s, 2H), 3.98 (t, J=7.2 Hz, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 2.25 (s, 6H), 1.89-1.79 (m, 2H). MS (ESI): 357.2 (M+1). ESI-HRMS calculated for C19H25N4SO (MH+): 357.1743, Observed: 357.1752.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Na].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(OCC)(=O)C>CN(C)C=O>[N:10]1([C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: c1nc[nH]n1
Reactant: Brc1ccc(Br)nc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(-n2cncn2)nc1
Yield: 92.6 %

Procedure:
In 20 ml of dimethylformamide, 1 g of 2,5-dibromopyridin was reacted with 0.58 g of 1,2,4-triazole sodium at 80° C. for 10 hours with stirring. Following the addition of ethyl acetate, the organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo to give 880 mg of 2-(1,2,4-triazol-1-yl)-5-bromopyridine. This compound was dissolved, along with 1.4 g of (S)-[N-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide, in 50 ml of dimethylformamide and then added with 1.2 ml of triethyl amine and 1.1 g of dichlorobistriphenylphosphine palladium (II) at room temperature. Reaction was conducted at 100° C. for 3 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo. Purification of the concentrate with column chromatography provided the title compound. 320 mg. Yield 23%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:17][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([NH2:1])[CH:10]=1)[OH:11]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1O

Procedure:
A solution of 20.0 g of 5-aminosalicylic acid, 250 ml of methanol and 10 ml of concentrated sulfuric acid is refluxed overnight. The reaction mixture is cooled, made alkaline with dilute aqueous sodium carbonate solution and concentrated. The resulting solid is separated and washed with water. The solid is then washed with ether, and the ether is evaporated to dryness yielding a brown solid. The aqueous filtrate above is extracted with ether, the extract is dried over anhydrous sodium sulfate, and evaporated yielding a brown solid. The solids are combined and recrystallized from ether to afford 10.7 g of 5-aminosalicylic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:23](=[O:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Ca+2].[H-].[CH3:29][N:30]=[C:31]=[O:32]>C1C=CC=CC=1>[C:23]([N:10]1[CH:11]([CH3:22])[CH2:12][C:13]2[CH:18]=[C:17]3[O:19][CH2:20][O:21][C:16]3=[CH:15][C:14]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:31]([NH:30][CH3:29])=[O:32])=[CH:3][CH:4]=2)=[N:9]1)(=[O:25])[CH3:24]
Reactant: CN=C=O
Reactant: CC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1C)OCO3
Agent: [Ca+2]
Agent: [H-]
Solvent: c1ccccc1
Product: CNC(=O)Nc1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
0.70 g (2 mmol) of the product of Example 15 was dissolved in benzene dehydrated over calcium hydride, 0.3 ml (5 mmol) of methyl isocyanate was added and the reaction mixture was stirred at 50° C. for 4 hours. The crystals formed after coling were filtered, washed with 3×3 ml of benzene, then triturated with 20 ml of hot benzene. The hot mixture was filtered, the precipitate was washed with 3×3 ml of benzene and dried to give 0.65 g (79.6%) of the aimed product, m.p.: 168°-170° C. (decomp.).