Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:17])[CH:13]2[O:14][CH:12]2[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1.[NH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=[O:24].N1C=CC=CC=1>C(O)C>[CH3:1][O:2][CH2:3][C:4]1([CH3:17])[CH:13]([OH:14])[CH:12]([N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=[O:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1
Reactant: O=c1cccc[nH]1
Reactant: COCC1(C)Oc2ccc(C#N)cc2C2OC21
Solvent: c1ccncc1
Solvent: CCO
Product: COCC1(C)Oc2ccc(C#N)cc2C(n2ccccc2=O)C1O
Reaction time: 72 h

Procedure:
A mixture of 23.1 g of 2-methoxymethyl-2-methyl3,4-epoxy-6-cyanochroman, 9.5 g of 1H-2-pyridone, 12 ml of pyridine and 600 ml of ethanol is boiled for 72 hours. About 300 ml are removed by distillation, the mixture is cooled and filtered, the solution is evaporated and the residue is worked up in the customary manner. 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano3-chromanol, stereoisomer mixture ("A") is obtained, which can be separated into isomer "Al" (CH3 and OH in the cis-position; m.p. 216°-218° C.) and isomer "A2" (CH3 and OH in the trans-position; m.p. 210°-212° C.) by chromatography (silica gel; ethyl acetate/methanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])([O-:21])=[O:20].C(OCC)(=O)C>CN1C(=O)CCC1.CCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([O:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N+:19]([O-:21])=[O:20])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccccc1Oc1nc(Cl)ncc1Cl
Temperature: 100 °C

Procedure:
To a stirred solution of 2,4,5-trichloropyrimidine (1.3 g, 7.19 mmol) in NMP (3 mL), DIPEA (1.85 g, 14.3 mmol) and 2-nitrophenol (1 g, 7.19 mmol) were added and heated to 100° C. for 1 h. TLC showed completion of starting material (TLC system: 20% ethyl acetate in hexane (Rf): 0.3). The reaction mixture was poured into crushed ice (50 mL). The obtained solid was filtered, washed with water (50 mL) and dried to obtain 2,5-dichloro-4-(2-nitrophenoxy)pyrimidine as an off-white solid. (Yield: 1.7 g, 85%). 1H NMR (400 MHz, D6-DMSO) δ 8.98 (s, 1H), 8.25 (d, 1H), 7.92 (t, 1H), 7.70 (m, 2H).
Reaction SMILES: C([O:5][C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)C(O)=O)(C)(C)C.[C:29]([O:33][C@@H:34]([C:37]1[C:46]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)=[C:45]2[C:40]([CH:41]=[CH:42][CH:43]=[N:44]2)=[CH:39][C:38]=1[CH3:54])[CH2:35][OH:36])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C@@H:34]([C:37]1[C:46]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)=[C:45]2[C:40]([CH:41]=[CH:42][CH:43]=[N:44]2)=[CH:39][C:38]=1[CH3:54])[C:35]([OH:5])=[O:36])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](OC(C)(C)C)C(=O)O)c(Cl)cc2n1
Product: Cc1cc2cccnc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)acetic acid (4J) was prepared following the procedure used to prepare compound 1L of Example 1, except that (S)-2-tert-butoxy-2-(8-(4-chlorophenyl)-6-methylquinolin-7-yl)ethanol (4I) was used instead of compound 1K. 1H-NMR 300 MHz, (CD3OD) δ 8.97-8.91 (m, 1H), 8.86-8.82 (m, 1H), 8.11 (s, 1H), 7.95-7.90 (m, 1H), 7.72-7.65 (m, 3H), 7.50-7.45 (m, 1H), 5.23 (s, 1H), 2.73 (s, 3H), 0.99 (s, 9H); LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23ClNO3: 384.9. Found: 384.1, 386.1.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]=1[CH3:9].[K].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>[Cl-].C[N+](C)(C)C>[CH2:11]([N:6]1[C:7](=[O:8])[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]1=[O:5])[CH:13]1[O:15][CH2:14]1
Reactant: CC1=C(C)C(=O)NC1=O
Reactant: ClCC1CO1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K]
Product: CC1=C(C)C(=O)N(CC2CO2)C1=O

Procedure:
30 g (0.184 mol) of potassium dimethylmaleimide are suspended in 175 g (1.89 mols) of epichlorohydrin. After adding 0.05 g of tetramethylammonium chloride, the mixture is heated, whilst stirring, and boiled under reflux for 18 hours and is then filtered. After removing the unconverted chlorohydrin by distillation under a waterpump vacuum, about 30 g of a viscous, pale brown liquid which has an epoxide content of 4.9 equivalents/kg (calculated: 5.5 equivalents/kg) remain. The NMR spectrum of the product corresponds to N-glycidyl-dimethylmaleimide of the formula ##STR30##
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]=[CH:8][C:7]3[N:13]=[N:14][N:15]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:6]=3[C:5]=2[N:4]=1.[C:22]([O:25][C@@H:26]([CH3:30])[C:27](Cl)=[O:28])(=[O:24])[CH3:23].CCN(CC)CC>C(Cl)Cl>[C:22]([O:25][C@@H:26]([CH3:30])[C:27]([N:19]1[CH2:20][CH2:21][CH:16]([N:15]2[C:6]3[C:5]4[N:4]=[C:3]([Cl:2])[CH:12]=[CH:11][C:10]=4[N:9]=[CH:8][C:7]=3[N:13]=[N:14]2)[CH2:17][CH2:18]1)=[O:28])(=[O:24])[CH3:23]
Reactant: Clc1ccc2ncc3nnn(C4CCNCC4)c3c2n1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H](C)C(=O)N1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a solution of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine hydrochloride (1 g, 3.08 mmol) in 10 mL of CH2Cl2 was added (S)-1-chloro-1-oxopropan-2-yl acetate (1.4 g, 9.23 mmol) and Et3N (2.2 mL). After the mixture was stirred at room temperature for 2 h, it was quenched with water (10 mL). The resulting mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layer was dried over anhydrous Na2SO4, and then was concentrated in vacuo to afford the (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-1-oxopropan-2-yl acetate (1.2 g). MS (m/z): 403 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][N:5](C(OC(C)(C)C)=O)[C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(Cl)Cl.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[O-][Mn](=O)(=O)=O.[K+]>CCOC(C)=O>[OH:26][C:24]([C:23]([F:28])([F:27])[F:22])=[O:25].[CH3:17][O:16][C:14]([C@@H:4]1[CH2:3][C:2]([F:18])([F:1])[CH2:6][NH:5]1)=[O:15]
Reactant: COC(=O)[C@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CC(F)(F)CN1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A round-bottom flask was charged with (R)-1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate (675 mg, 2545 μmol), 10.2 mL DCM and trifluoroacetic acid (980 μl, 12724 μmol). The mixture was stirred at RT. After 6 h, TLC (50% hex/EtOAc, KMnO4 stain) indicated complete conversion. The mixture was concentrated, and the crude (5)-methyl-4,4-difluoropyrrolidine-2-carboxylate TFA salt was use as is.
Reaction SMILES: [O:1]=[C:2]1[C@@H:6](OS(C)(=O)=O)[CH2:5][CH2:4][NH:3]1.Cl.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([CH:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)O[C@H]1CCNC1=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(C2CCNC2=O)CC1
Temperature: 85 °C
Yield: 7.8 %

Procedure:
To a 10 mL microwave vial was added methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (4.97 mmol, 890 mg) and (4-fluoro-phenyl)-piperidin-4-yl-methanone hydrochloride (4.97 mmol, 1.21 g) in DIEA (24.8 mmol, 5 mL) was heated to 85° C. for 105 min. The DIEA was decanted and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (112 mg, 7.8% yield). MS (ESI) m/e 291.2 (M+H+), calculated 290.33; HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.303 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1.[CH3:31][NH:32][CH3:33]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([N:32]([CH3:33])[CH3:31])=[O:22])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]=1
Reactant: CNC
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Product: CN(C)C(=O)c1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1

Procedure:
This material is prepared by a method analogous to that described for Example 21, starting from 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carboxylic acid and dimethylamine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][CH2:14][CH2:15][OH:16]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:16][CH2:15][CH2:14][O:13][CH3:12])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: COCCO
Solvent: CN(C)C=O
Product: COCCOc1cccc(F)c1[N+](=O)[O-]
Yield: 49.9 %

Procedure:
A solution of 1,3-difluoro-2-nitro-benzene (1.0 g), 2-methoxyethanol (480 mg), and CsCO3 (3.6 g) in DMF (20 mL) was heated at 60° C. for 16 hours. The reaction mixture was filtered, concentrated, and purified by silica gel chromatography to afford 675 mg of 1-fluoro-3-(2-methoxy-ethoxy)-2-nitro-benzene: 1H NMR (300 MHz, CDCl3) δ 7.4 (dd, 1H), 6.8 (m, 2H), 4.2 (t, 2H), 3.7 (t, 2H), 3.4 (s, 3H).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6]2.C1C2C(=CC=CC=2)CC1N[S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24]>>[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH:12][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH2:6]2
Reactant: CC(C)S(=O)(=O)NC1Cc2ccccc2C1
Reactant: NC1Cc2ccc(Br)cc2C1
Agent: Br
Product: CC(C)S(=O)(=O)NC1Cc2ccc(Br)cc2C1

Procedure:
The title compound was prepared from 5-bromo-2-aminoindane hydrobromide (Prashad et al, Adv. Synth. Catal. 2001, 343, No. 5, pp 461-472) by a similar process to the preparation of Intermediate 1.
Reaction SMILES: [NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:10]([O:12]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[NH2:1][C@@H:2]1[C:26](=[O:27])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cl)CS[C@H]12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reaction time: 0.25 h
Yield: 34.1 %

Procedure:
1.59 g (4 mmols) of diphenylmethyl 7β-amino-3-chloro-3-cephem-4-carboxylate are dissolved in 5 ml of trifluoroacetic acid at 0° and the solution is stirred for 15 minutes. The clear, pale yellow solution is diluted with 20 ml of toluene and then freed from excess trifluoroacetic acid and toluene under reduced pressure. The residue is dissolved in about 20 ml of water/ethyl acetate (1:1), the organic phase is separated off and the acid aqueous phase is brought to a pH of 3.0 with 20% strength triethylamine in methanol. The pale yellow precipitate is filtered off, washed with ethyl acetate and diethyl ether and dried under a high vacuum. 320 mg of 7β-amino-3-chloro-3-cephem-4-carboxylic acid are isolated as a pale yellow amorphous powder; thin layer chromatogram: Rf = 0.08 (silica gel, n-butanol/acetic acid/water, 67:10:23).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH3:12][CH2:13]O.CS(O)(=O)=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][CH3:13])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: CCO
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: CS(=O)(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(Br)c(O)c1
Yield: 90 %

Procedure:
To a mixture containing 4-bromo-3-hydroxybenzoic acid (5.0 g, 0.023 mol) and 5 ml of EtOH in 150 ml of benzene was added 1 ml of MeSO3H. The mixture was heated at reflux for 10 h using a Dean-Stark trap to collect water, then concentrated. The residue was dissolved in CH2Cl2, washed (water, 5% NaHCO3, and brine), dried (Na2SO4), and concentrated. The crude product was chromatographed (EtOAc/hexane) to gave a white solid (5.1 g, 90%): 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=7.2 Hz, 3 H), 4.37 (q, J=7.2 Hz, 2 H), 5.75 (s, 1 H), 7.48 (d, J=8.1 Hz, 1 H), 7.55 (d, J=8.1 Hz, 1 H), 7.68 ppm (s, 1 H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:14]2=[C:15]3[C:10](=[CH:11][CH:12]=[CH:13]2)[CH2:9][CH2:8][CH2:7][N:6]3[C:5]=1[CH3:16].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[Br:1][CH2:2][CH2:3][C:4]1[C:14]2=[C:15]3[C:10](=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[CH:13]2)[CH2:9][CH2:8][CH2:7][N:6]3[C:5]=1[CH3:16]
Reactant: Cc1c(CCBr)c2cccc3c2n1CCC3
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(CCBr)c2cc([N+](=O)[O-])cc3c2n1CCC3
Temperature: 0 °C

Procedure:
5 g 1-(2-bromoethyl)-2-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline were added to 10 ml of concentrated sulfuric acid cooled to 0° C. The reaction mixture was kept at a temperature of about 0° C., and a mixture of 1.15 ml of concentrated sulfuric acid and 0.84 ml of nitric acid was added dropwise as a nitrating agent. The reaction mixture was kept for a further hour at 0° C. and one more hour at room temperature. To work up the reaction mixture it was poured onto 30 g of ice and extracted with dichloromethane. The organic phase was dried and concentrated. The residue which remained was heated in 10 of ethanol, and the resulting yellowish precipitate was filtered out. 2.26 g of 1-(2-bromoethyl)-2-methyl-8-nitro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline were obtained as an ochre-colored powder.
Reaction SMILES: CN(C)[C:3]([CH3:17])=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.C([O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=1)(C)(C)C.C(OC(=O)C1C=CC=C(C(=N)N)C=1)(C)(C)C.[H-].[Na+]>C(O)C>[CH3:17][C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=2)[N:32]=[C:31]([C:28]2[CH:27]=[CH:26][C:25]([C:24]([OH:23])=[O:34])=[CH:30][CH:29]=2)[N:33]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=N)N)cc1
Reactant: CC(=CC(=O)c1ccc(C(F)(F)F)cc1)N(C)C
Agent: CC(C)(C)OC(=O)c1cccc(C(=N)N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(C(=O)O)cc2)n1
Yield: 2.7 %

Procedure:
Part B. To a mixture of 3-dimethylamino-1-(4-trifluoromethyl-phenyl)-but-2-en-1-one (290.1 mg, 1.13 mmol), 4-carbamimidoyl-benzoic acid tert-butyl ester (220.3 mg, 1.00 mmol, prepared by the same manner as 3-carbamimidoyl-benzoic acid tert-butyl ester) and sodium hydride (79.9 mg, 2.00 mmol, 60% in hexanes) is added dry ethanol (5.0 mL). The resulting mixture is stirred at refluxing for 14 h until complete consumption of the starting material is determined by TLC. The solvent is removed, and the residue is neutralized with 1N HCl until pH <7 to precipitate a white solid, which is collected by filtration followed by washing with water and ethyl ether/hexanes (1:1). The obtained solid is further purified by flash column chromatography, eluting with methanol/methylene chloride (1:40), to give the title product (10.7 mg, 2.7% yield), m.p. 272-275° C. 1H NMR (300 MHz, CDCl3+2 drops DMSO-d6): δ 8.54 (2H, d, J=8.3 Hz), 8.23 (2H, d, J=8.6 Hz), 8.09 (2H, d, J=8.3 Hz), 7.71 (2H, d, J=8.6 Hz), 7.48 (1H, s), 2.61 (3H, s). MS (ES+): m/e 359.27.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([C:11](Cl)=[O:12])[S:7][C:6]=2[CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([Cl:10])=[C:8]([CH2:11][OH:12])[S:7][C:6]=2[CH:14]=1
Reactant: O=C(Cl)c1sc2cc(Br)ccc2c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1sc2cc(Br)ccc2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 6-bromo-3-chlorobenzo[b]thiophene-2-carboxylic acid chloride (6.20 g) in dry ether (50 ml) and dry tetrahydrofuran (50 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.58 g) in dry ether (250 ml) at 0° under an atmosphere of dry nitrogen. The mixture was stirred at room temperature for 30 minutes and then at reflux for 21/2 hours before being cooled and allowed to stand for 18 hours. It was then cooled and the excess of lithium aluminium hydride was decomposed by the cautious addition of water (1.0 ml) followed by 5N sodium hydroxide (1.0 ml) followed by water (2.0 ml) with vigorous stirring. The mixture was filtered and the filtrate was evaporated to give a solid which was chromatographed on silica gel. Elution with chloroform first gave some impurity followed by pure product. The product containing fractions were combined and evaporated to give a solid which was crystallised from chloroform to give 6-bromo-3-chloro-2-hydroxymethylbenzo[ b]thiophene (2.22 g), m.p. 117°-118°.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.CC(C)([O-])C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:29][CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCOCC1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc(NC3CCOCC3)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 100 °C

Procedure:
A degassed mixture of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25.0 mg, 0.0804 mmol, Example 228, Step 7), tetrahydro-2H-pyran-4-amine (32 mg, 0.32 mmol, CombiBlocks), sodium tert-butoxide (23 mg, 0.24 mmol, Aldrich), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (9.3 mg, 0.016 mmol, Aldrich) and tris(dibenzylideneacetone)dipalladium(0) (7.4 mg, 0.0080 mmol, Aldrich) in toluene (1.2 mL) was heated at 100° C. overnight. Toluene was removed in vacuo and the crude mixture was dissolved in MeOH/H2O/MeCN and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (3 mg, 10%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=1)[O:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)#[N:2].Cl>C(O)C>[CH3:24][O:23][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: COc1ccc(C#N)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C#N)cc1OC1CCNCC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-(5-cyano-2-methoxyphenoxy)piperidine-1-carboxylate (2, 39.31 g, 118.26 mmoles) was suspended in ethanol (155.53 g) and heated to 40° C. To this slurry was slowly added HCl (46.61 g, 573.04 mmoles). The mixture was heated to 60° C. and held for 3 hours. The reaction mixture was cooled to 20° C. and seed was charged initiating crystallisation. The resulting solid was isolated by filtration at 0° C., washed twice with ethanol (62.21 g) and then dried to give the title compound as the hydrochloride salt (29.84 g, 77% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 (m, 2H) 2.09 (m, 2H) 3.02 (ddd, J=12.7, 8.9, 3.4 Hz, 2H) 3.20 (m, 2H) 3.84 (s, 3H) 4.63 (tt, J=7.7, 3.6 Hz, 1H) 7.15 (d, J=8.5 Hz, 1H) 7.45 (dd, J=8.5, 1.9 Hz, 1H) 7.56 (d, J=1.9 Hz, 1H) 9.16 (br. s, 2H); Mass Spectrum: m/z (M+H)+ 233.2.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[C:35]5[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=5[CH:29]=[CH:28][CH:27]=4)=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A solution of (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (43 mg, 0.08 mmol) in methanol (1 mL) at 25° C. was treated with p-toluenesulfonic acid monohydrate (4 mg, 0.02 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was diluted with dichloromethane (25 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL), water (1×25 mL) and a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (8 g, 1-10% methanol/dichloromethane) afforded (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (28 mg, 71%) as a white solid: HR-ES-MS m/z calculated for C26H34N4O5 [M+H]+ 483.2602, observed 483.2603; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H), 1.46 (br. s., 1H), 1.53-1.65 (m, 1H), 1.65-1.85 (m, 5H), 2.57 (br. s., 2H), 2.76 (br. s., 2H), 3.21-3.31 (m, 2H), 3.72-3.82 (m, 1H), 3.87 (dd, J=13.4, 7.5 Hz, 1H), 4.09 (dd, J=13.6, 4.0 Hz, 1H), 4.18 (d, J=18.3 Hz, 1H), 4.56 (d, J=18.3 Hz, 1H), 4.65 (s, 1H), 4.71 (t, J=5.4 Hz, 1H), 4.87 (dd, J=10.7, 4.9 Hz, 1H), 4.93 (d, J=5.1 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.04 (d, J=7.7 Hz, 2H), 7.18 (t, J=7.7 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[F:22].Cl.[NH:24]1[CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[N:24]1([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]3[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=2[F:22])[CH2:27][CH2:26][CH2:25]1
Reactant: C1CNC1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(F)cc2c1=O
Reaction time: 1 h

Procedure:
A solution of Example 7C (13.26 g), azetidine hydrochloride (9.58 g) and triethylamine (17.2 mL) in dichloromethane (650 mL) was stirred for 2 hours, treated with triethylamine (900 mg), stirred for 1 hour, diluted with dichloromethane, washed with water and brine, dried (MgSO4), filtered, and concentrated; and the concentrate was triturated with refluxing dichloromethane, treated with diethyl ether and hexanes, and filtered.