Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH2:7][CH2:8][C:9](=[O:16])[CH:10]([C:12]([O:14][CH3:15])=[O:13])[O:11][C:5]=2[CH:4]=1.Br[CH2:20][CH2:21][CH2:22][Cl:23].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:23][CH2:22][CH2:21][CH2:20][C:10]1([C:12]([O:14][CH3:15])=[O:13])[C:9](=[O:16])[CH2:8][CH2:7][C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:11]1
Reactant: ClCCCBr
Reactant: COC(=O)C1Oc2cc(OC)ccc2CCC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1(CCCCl)Oc2cc(OC)ccc2CCC1=O
Reaction time: 5 h
Yield: 93.1 %

Procedure:
A solution of 15 g of methyl 3-(4-methoxy-2-methoxy-carbonylmethyloxyphenyl)propionate in 200 ml of toluene is added dropwise to a suspension of 5.6 g of 60% oily sodium hydride in 200 ml of toluene to which 0.4 ml of tert-butanol is added, for a period of 8 hours with heating under refluxing. The reaction mixture is heated under refluxing for 30 minutes and allowed to stand overnight, and then poured into ice water containing 10 ml of acetic acid. The organic layer is separated, washed with water, dried and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=4:1) to give 9.5 g of methyl 8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as a colorless oil. A mixture of 7.4 g of methyl 8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate, 10.9 g of 1-bromo-3-chloropropane, 1.5 g of potassium iodide, 10 g of anhydrous potassium carbonate and 300 ml of acetonitrile is heated under refluxing with stirring for 5 hours. After cooling, the inorganic substances are filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=8:1) to give 9 g of methyl 2-(3-chloropropyl)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as an oil. In 100 ml of methanol is dissolved 9 g of methyl 2-(3-chloropropyl)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate, and 0.6 g of sodium borohydride is added in small portions to the solution under ice-cooling with stirring. The reaction mixture is concentrated under reduced pressure, and the residue is treated with water and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated under reduced pressure, and the residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=3:1) to give 3.3 g of methyl trans-2-(3-chloropropyl)-3-hydroxy-8-methoxy-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as a colorless oil from the first fraction eluted.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[Cl-].[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[C:51]([CH2:59][NH3+:60])[CH:50]=1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:60][CH2:59][C:51]4[CH:50]=[N:49][C:58]5[C:53]([CH:52]=4)=[CH:54][CH:55]=[CH:56][CH:57]=5)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: [NH3+]Cc1cnc2ccccc2c1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: [Cl-]
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnc2ccccc2c1
Yield: 50 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with quinolin-3-ylmethanaminium chloride, the title compound was obtained as a colorless solid in 50% yield: 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.15-8.08 (m, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.74-7.66 (m, 1H), 7.58-7.51 (m, 1H), 7.30-7.22 (m, 2H), 7.07-6.98 (m, 2H), 6.22 (t, J=5.6 Hz, 1H), 6.09 (s, 1 H), 4.74 (d, J=5.6 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.38 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 475.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.O.[C:12]([OH:16])(=[O:15])[CH:13]=O.C(=O)([O-])[O-].[K+:21].[K+]>CO>[C:9]([C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[CH:13][C:12]([O-:16])=[O:15])#[N:10].[K+:21]
Reactant: O=CC(=O)O
Reactant: Cc1cccc(CC#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cccc(C(C#N)=CC(=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (3-methylphenyl)-acetonitrile (21.6 ml, 165 mmol) in methanol (500 ml) were added glyoxylic acid hydrate (22.7 g, 247 mmol) and potassium carbonate (57.0 g, 412 mmol). The reaction mixture was stirred at room temperature for 2 hours followed by 3 hours at reflux. The precipitate was filtered off, washed with methanol (300 ml), dichloromethane (DCM) (300 ml) and then dried under air suction. The desired product was obtained as a white solid which was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[OH:25]>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (4.8 mL, 45.42 mmol), potassium carbonate (13.8 g, 0.1 mol) and 2,4-dichloro-phenol (8.16 g, 50.06 mmol) in dry dimethylformamide (70 mL) was stirred at 100° C. for 2 h. Solids were filtered off, and the filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether and 1N sodium hydroxide, the organic layer was washed with 1N sodium hydroxide, water and brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 11.69 g (91%) of the title compound as a yellowish oil, which solidifies on standing. Mp: 58-59° C. MS (EI) 285.2 (MH+). Lit. [Chem. Heterocycl. Compd. (Engl. Transl.) 11 (1975) 1356-1358] Mp: 57-58° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[CH:18]=[CH:17][C:16]([F:20])=[C:15](C(O)=O)[C:14]=4[C:13]([CH3:24])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C.O>[CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][N:11]3[C:19]4[CH:18]=[CH:17][C:16]([F:20])=[C:15]([NH2:39])[C:14]=4[C:13]([CH3:24])=[N:12]3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1nn(Cc2cccc(C3CC3)n2)c2ccc(F)c(C(=O)O)c12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(Cc2cccc(C3CC3)n2)c2ccc(F)c(N)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.3 %

Procedure:
1-((6-Cyclopropylpyridin-2-yl)methyl)-5-fluoro-3-methyl-1H-indazole-4-carboxylic acid (0.205 g, 0.630 mmol) was dissolved in 6 mL of DMF. To this was added diphenylphosphoryl azide (0.260 g, 0.945 mmol) and TEA (0.263 mL, 1.89 mmol) and the mixture was stirred at ambient temperature for 1.5 hours. Water (5 mL) was added and the mixture was warmed to 80° C. for 2 hours, then allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic extracts washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography (1:1 EtOAc:Hexanes) of the crude material afforded 0.107 g (57%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([F:9])[CH:8]=1)#[CH:2].FC1C=CC(P(C2C=CC(F)=CC=2)C2C=CC(F)=CC=2)=CC=1>CN(C=O)C.[Cl-].[Na+].O>[F:9][C:7]1[CH:8]=[C:3]2[CH:1]=[CH:2][NH:10][C:4]2=[N:5][CH:6]=1
Reactant: C#Cc1cc(F)cnc1N
Agent: Fc1ccc(P(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnc2[nH]ccc2c1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A solution of 3-ethynyl-5-fluoro-pyridin-2-ylamine (1.25 g, 9.2 mmol) in DMF (20 mL) is treated with (Rh(cod)2Cl)2 (23 mg, 0.023 mmol) and tris-(4-fluoro-phenyl)-phosphane (115 mg, 0.368 mmol) and stirred at 85° C. for 0.5 h. The mixture is then poured over brine (50 mL), and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 35%-75% EtOAc in heptane to afford 5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.05 g, 84%). MS: 137 (M+H); 1H NMR (300 MHz, CDCl3): δ 9.15 (s, NH, 1H), 7.99 (s, 1H), 7.44 (d, 1H), 7.18 (s, 1H), 6.28 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:18][SH:19].[Na]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[CH:16]=[CH:17][C:3]([CH2:2][S:19][CH3:18])=[CH:4][CH:5]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: CS
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [Na]
Solvent: CO
Product: CSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
4-bromomethyl-4'-chlorobenzophenone (3.1 g) and 15% methylmercaptan-sodium aqueous solution (5.6 g) were added to methanol (150 ml), and the mixture was stirred for 30 minutes under reflux. The reaction mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with n-hexane to obtain the desired product (2.3 g, melting point: 59° to 61° C., yield: 83%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Br[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1>>[Cl:25][C:20]1[CH:19]=[C:18]([C:10]2[CH:9]=[CH:8][C:7]([CH2:15][S:14][C:9]3[C:10]([O:12][CH3:13])=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]([CH3:15])[CH:8]=3)=[CH:6][CH:11]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Reactant: Clc1ccc(Br)cc1Cl
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2ccc(Cl)c(Cl)c2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 5A using 1D and 4-bromo-1,2-dichloro-benzene. MS m/z 479 (M+2).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].[OH-].[Na+]>C1COCC1>[CH3:25][S:26]([NH:11][C:9]1[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(C(=O)O)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 mg (2.0 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 10 ml of THF, 0.56 ml (4.0 mmol) of triethylamine and 230 mg (2.0 mmol) of methanesulfonyl chloride are added. The mixture is stirred overnight at RT, the solvent is removed in vacuo and the crude product is subjected to an aqueous work-up and extracted with dichloromethane. The isolated product is dissolved in 10 ml of DMF, 8 mmol 12.5 mmol of 1M NaOH solution are added and the mixture is stirred overnight at RT. The solvent is removed in vacuo and the crude product subjected to HPLC chromatography. Yield after two steps: 170 mg, 30%
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:35]1([N:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)N)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:33][CH:2]([CH3:1])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:36]4[C:35](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc([N+](=O)[O-])c4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 601.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]([OH:23])[C:20](O)=[O:21])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][NH2:42]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH:19]([OH:23])[C:20](=[O:21])[NH:42][CH2:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Reactant: NCc1ccccn1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCc1ccccn1)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with pyridin-2-ylmethylamine; ESI-MS [M+H]+: 551.5
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17](=S)[CH2:18][C:19](=O)[CH3:20])[C@H:14]([C:23]([O:25][CH3:26])=[O:24])[CH2:13]1)(=[O:11])=[O:10].Cl.[O:28]1[CH2:33][CH2:32][CH:31]([NH:34][NH2:35])[CH2:30][CH2:29]1>>[CH3:26][O:25][C:23]([C@@H:14]1[CH2:13][C@@H:12]([S:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:11])[CH2:16][N:15]1[C:17]1[N:34]([CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)[N:35]=[C:19]([CH3:20])[CH:18]=1)=[O:24]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=S)CC(C)=O
Reactant: NNC1CCOCC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1c1cc(C)nn1C1CCOCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chloro-4-fluorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate was reacted with (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (CAS Reg. No. 116312-69-7) to give the title compound as yellow solid. MS (ESI): m/z=486.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:38][C:39]([F:49])([F:48])[C:40]1[CH:47]=[CH:46][C:43]([CH2:44]O)=[CH:42][CH:41]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:38][C:39]([F:48])([F:49])[C:40]1[CH:47]=[CH:46][C:43]([CH2:44][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)=[CH:42][CH:41]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: CN1CCN(c2cccc3ccc(O)cc23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(c2cccc3ccc(OCc4ccc(C(F)(F)F)cc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a mixture of 7-hydroxy-1-(4-methyl-1-piperazinyl)-naphthalene (0.20 g, 0.83 mmol), triphenylphosphine (0.32 g, 1.22 mmol), and 4-trifluoromethylbenzyl alcohol (0.17 mL, 1.26 mmol)in dry THF (4 mL) was added diethyl azodicarboxylate in THF (1 mL). The mixture was stirred overnight at ambient temperature; then it was concentrated at reduced pressure. The residue was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with water and brine; then it was dried over magnesium sulfate and concentrated onto silica gel for flash chromatographic purification (1×6 inches). Elution with 75% ethyl acetate/hexane gave 0.24 g (72%) of the title compound as a nearly colorless oil. The oil was treated with HCl in ether to form the hydrochloride salt (0.23 g) which was recrystallized from chloroform/ether to give 0.14 g of a white solid thereof: mp 205°-206° C. Analysis calculated for C23H23F3N2O·HCl·0.25 H2O: C, 62.58; H, 5.59; N, 6.35. Found: C, 62.59; H, 5.63; N, 6.40.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCCCCCBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCBr)cc1

Procedure:
A solution of 30 g. 11-bromoundecyl alcohol and 25.0 g. 4-toluenesulfonyl chloride in 250 ml. dry ether is cooled with stirring in an ice-water bath. To this is added dropwise 13.2 g. triethylamine in 50 ml. ether. After addition, the solution is stirred in the cold for 1 hour and filtered. The ether is washed with 100 ml. 10% hydrochloric acid solution, 100 ml. brine, dried and evaporated to yield the title compound as an oily solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.S=[C:19]1[CH2:23][S:22][C:21](=[O:24])[NH:20]1>C(O)C>[O:24]=[C:21]1[N:20]=[C:19]([NH:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:23][S:22]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
To a solution of tert-butyl glycinate hydrochloride (4.00 g) and triethylamine (3.33 mL) in ethanol (20 mL) was added 4-thioxo-1,3-thiazolidin-2-one (2.65 g), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.70 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[N:23]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(C=O)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1ccc(C=O)cc1

Procedure:
A solution of 5.0 g (15.61 mmol) of the compound from Example 35A and 2.03 g (31.22 mmol) of sodium azide in 100 ml of dry DMF is stirred at RT for 12 h. The reaction mixture is concentrated using a rotary evaporator, and the residue is suspended in about 20 ml of water. After three extractions with in each case 30 ml of diethyl ether, the combined organic phases are washed twice with in each case 10 ml of water and once with 10 ml of saturated sodium chloride solution. After drying over sodium sulphate, the solvent is removed on a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21]Cl)[C:9]2=[O:23])[CH:7]=1.C(#N)C.[C:30]([OH:34])(=[O:33])[CH2:31][OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:34][C:30](=[O:33])[CH2:31][OH:32])[C:9]2=[O:23])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Reactant: O=C(O)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)CO)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 57.5 %

Procedure:
To a 10 mL flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-1-chloromethyl-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-V) (0.200 g, 0.489 mmol) was added 3 mL anhydrous acetonitrile, glycolic acid (0.045 g, 0.588 mmol) and cesium carbonate (0.079 g, 0.245 mmol). The reaction was stirred for 36 hours at room temperature, then the organic layer was diluted with 5 mL diethyl ether and the organic solution was decanted away from the solid cesium chloride. The solvent was evaporated in vacuo and the resulting white foam was purified by flash chromatography (silica gel 4:1 hexanes:acetone) producing the title compound (0.126 g, 58%) as a white powder. 1H NMR (CDCl3 400 MHz): δ=7.79 (s, 1H), 7.38-7.33 (m, 3H), 7.26 (d, 1H, J=7 Hz), 6.75 (d, 1H, J=7 Hz), 5.99 (d, 1H, J=12 Hz), 5.91 (d, 1H, J=12 Hz), 4.26 (s, 2H), 3.49 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2=[N:10][C:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=4)[N:16]([CH3:27])[N:15]=3)=[CH:12][N:13]=[C:8]2[N:7](COC(=O)C(C)(C)C)[CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.O>[CH3:26][S:23]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:27])[N:15]=[C:14]2[C:11]1[N:10]=[C:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7][C:8]2=[N:13][CH:12]=1)(=[O:25])=[O:24]
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4ccc(S(C)(=O)=O)cc34)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2cc(S(C)(=O)=O)ccc21
Temperature: 85 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a suspension of methyl2-(1-methyl-5-(methylsulfonyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (80 mg, 0.16 mmol) in dioxane/water (6 mL/4 mL) was added NaOH (100 mg, 2.5 mmol), the reaction mixture was heated to 85° C. with stirring for 4 hours, the dioxane was removed under reduced pressure, the aqueous layer was adjusted to pH=4 with 2 N HCl. The formed precipitate was collected by filtration, washed with water (3 mL) and dried to afford 2-(5-methanesulfonyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (40 mg, 67.7%) as an orange solid. LCMS: (M+H)+=372; 1H NMR (300 MHz, DMSO): δ 12.89 (d, 1H, J=2.7 Hz), 12.49 (brs, 1H), 9.47 (s, 1H), 9.08 (s, 1H), 8.50 (d, 2H, J=3.3 Hz), 8.01-7.95 (m, 1H), 4.23 (s, 3H), 3.27 (s, 3H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][NH2:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:1]1([NH:18][CH2:17][CH2:16][NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNC1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1.04 mL (1.0 mmol) of cyclohexanone and 1.6 g (1.0 mmol) of N-(2-t-butoxycarbonylaminoeth-1-yl)amine in 24 mL of tetrahydrofuran were added 0.71 mL (1.2 mmol) of acetic acid and 2.97 g (1.4 mmol) of sodium triacetoxyborohydride. The reaction stirred at room temperature for 20 hr then saturated sodium bicarbonate (12 mL) was added and the mixture extracted with ethyl acetate (12 mL). The organic phase was washed with more saturated sodium bicarbonate (12 mL) and brine (12 mL). At this point a crystalline precipitate formed which was filtered off and washed with water and ethyl acetate to leave the title compound.