Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:34]=[CH:33][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br.O>CN(C)C=O>[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:34]=[CH:33][C:15]2[N:16]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: COC(=O)CCCCCBr
Reactant: COc1ccc(-n2c(-c3ccccc3)nc3cc(NS(=O)(=O)c4ccc(Cl)cc4)ccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccc(OC)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
75 mg of 4-chloro-N-[1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-5-yl]benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 6 mg of sodium hydride and stirred for 30 minutes at 20° C. 44 mg of 6-bromohexanoic acid methyl ester was added, allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][C:9]=1[N+:25]([O-:27])=[O:26].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.CN(C)C=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:22][CH:23]=2)(=[O:16])=[O:17])=[CH:10][C:9]=1[N+:25]([O-:27])=[O:26]
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(O)cc2)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OS(=O)(=O)c2ccc(OCc3ccccc3)cc2)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A solution of cesium carbonate (156 mg) in water (0.3 ml) was added to a solution of 4-hydroxy-benzenesulfonic acid 4-amino-3-nitro-phenyl ester (150 mg) and benzyl bromide (58 μl) in dimethylformamide (3 ml). The reaction mixture was heated at 80° C. for 3 hours then allowed to cool to ambient temperature, poured into water (25 ml) and extracted three times with ethyl acetate (30 ml). The combined extracts were dried over magnesium sulfate then evaporated to give 189 mg of crude 4-benzyloxy-benzenesulfonic acid 4-amino-3-nitrophenyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:16][OH:17].C(N(CC)CC)C>CCO>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10]1
Reactant: NO
Reactant: O=C1CCC(c2ccc(O)cc2O)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: ON=C1CCC(c2ccc(O)cc2O)C1

Procedure:
(±)-3-(2,4-Dihydroxyphenyl)cyclopentanone (5 mg), hydroxylamine hydrochloride (2.7 mg) and triethylamine (5.4 uM) were heated in EtOH (4 ml) under reflux for 3 hr. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 4:1 v/v) to furnish the title compound as a white solid and a mixture of isomers (3.8 mg, 71%). δH (d4-MeOH) 1.80-1.93 (1H, overlapping m), 2.05-2.20 (0.5H, m), 2.39-2.55 (3H, overlapping m), 2.68-2.74 (1H, overlapping m), 2.94 (0.5H, br dd), 6.26-6.33 (2H, overlapping m), 6.94 (0.5H, d), 6.96 (0.5H, d); m/z (ES−) 266 ((M+60)−1)−.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:28])([C:18]([CH3:27])([CH3:26])[CH:19](OS(C)(=O)=O)[CH3:20])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[C:18]([CH3:26])([CH3:27])[CH:19]([CH3:20])[O:28]1
Reactant: CC(OS(C)(=O)=O)C(C)(C)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1OC(Cn2cncn2)(c2ccc(Cl)cc2Cl)C1(C)C
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
84 mg (2.1 mmole) of sodium hydride (as a 60% w/w suspension in mineral oil) were added to a solution of 400 mg (0.95 mmole) of 2-(2,4-dichlorophenyl)-3,3-dimethyl-4-mesyloxy-1-(1H-1,2,4-triazol-1-yl)-2-pentanol in 5 ml of N,N-dimethylformamide, and then the mixture was stirred at 90° C. for 2 hours. At the end of this time, the reaction mixture was allowed to cool, after which it was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was washed with hexane to give 262.4 mg of a crude product, which was then purified by column chromatography through silica gel, eluted with a 1:1 by volume mixture of hexane and ethyl acetate, to afford 220.7 mg (yield 71.4%) of the title compound, melting at 118°-125° C. This compound is a steroisomer, isomeric at the C4 position, of the compound obtained in Example 42.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([O:16][CH2:17][CH3:18])[CH:4]=3)[CH2:8][CH2:9]2)=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C(C)(C)C)cc3)CC2)ccc1Cl
Yield: 30 %

Procedure:
The title compound (13 mg, 30%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 4-tert-butylbenzoic acid. MS: 429.5 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:23]([C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1)(=[O:25])=[O:24])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccnc2)c1CN(C)C
Temperature: 25 °C
Yield: 3.9 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (30 mg, 0.15 mmol; Intermediate 97) and pyridine-3-sulfonyl chloride hydrochloride (43 mg, 0.20 mmol) in DCM (1 mL) 5 M NaOH (2 mL) was added. The reaction mixture was stirred at rt over night. The organic phase was collected and the solvent was removed under reduced pressure. Purification by preparative HPLC/UV (System B) afforded the title product (2 mg, 4%) as a white solid. MS (ESI+) for C17H19N3O3S m/z 346 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][C:21]=2[F:28])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1F
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4F)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (55 mg, 61%), MS (ISP) m/z=363.4 [(M+H)+], mp 251.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH3:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1>C(#N)C>[CH:38]1([N:30]2[C:31]3[C:26](=[C:25]([CH3:24])[C:34]([F:35])=[C:33]([N:9]4[CH2:10][CH2:11][CH2:12][CH:7]([N:2]5[CH:6]=[CH:5][N:4]=[N:3]5)[CH2:8]4)[C:32]=3[F:37])[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29]2)[CH2:39][CH2:40]1
Reactant: c1cn(C2CCCNC2)nn1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1c(F)c(N2CCCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reaction time: 66 h
Yield: 47.9 %

Procedure:
3-(1,2,3-triazol-1-yl)piperidine hydrochloride (63 mg, 0.33 mmol) and DBU (77 mg, 0.5 mmol) were added to a suspension of 5-methyl-1-cyclopropyl-6,7,8-trifluoro -1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed under stirring for 66 hrs and then concentrated. The residue was diluted with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 35 mg of desired product. m.p. 227°-228.5° C.; 1H NMR (TFA) δ: 9.35 (s, 1H), 8.53 (s, 1H), 8.65 (s, 1H), 5.30 (m, 1H), 4.60 (m, 1H), 3.55-4.35 (m, 4H), 2.90 (s, 3H), 2.08-2.75 (m, 4H), 1.30-1.55 (m, 4H).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[N:5][C:6]([Cl:19])=[CH:7][CH:8]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[N:26]=[CH:27][N:28]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)CCC>C1(C)C=CC=CC=1.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>[Cl:19][C:6]1[N:5]=[C:4]2[CH:3]=[C:2]([C:25]3[N:26]=[CH:27][N:28]([C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:29]=3)[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]2=[CH:8][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Clc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1cccc(Cn2c(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc3nc(Cl)ccc32)c1
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-5-chloro-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine (0.59 g, 1.7 mmol, prepared as in Example 103, Step 2) and 4-(tributylstannyl)-1-trityl-1H-imidazole (1.0 g, 1.7 mmol, Synthonix) in toluene (32 mL) was degassed. Tetrakis(triphenylphosphine)palladium(0) (0.19 g, 0.17 mmol, Strem) was added, and the mixture was heated at 110° C. for 17 hours. Solvent was removed in vacuo, and the product was purified by flash chromatography, eluting with a gradient from 0-35% EtOAc in hexanes. Yield: (0.61 g, 62%).
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)c1
Product: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-(2-cyclopropylmethoxy-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c6) the title compound is obtained as off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[NH2:17].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>C(Cl)Cl>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[S:26]([NH:17][C:3]1[CH:4]=[CH:5][C:6]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:7][C:2]=1[F:1])(=[O:28])=[O:27]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)OC1(C)C

Procedure:
Intermediate 25 was prepared in analogy to GP 4 from 1.78 g 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (7.5 mmol) and 2.03 g 2,3-dichloro-benzenesulfonyl chloride (8.25 mmol, 1.1 eq.) in 20 mL DCM and in the presence of 0.66 mL pyridine (8.25 mmol, 1.1. eq.) yielding after trituration 2.42 g of the target compound (72% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[O:26])=[O:18]
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Reactant: CC(C)NNC(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2cccs2)C(C)C)c1C
Yield: 50.8 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (207 mg, 0.81 mmoles) and thiophene-2-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.81 mmoles) in DMF (8 mL) was treated with triethylamine (0.34 mL, 2.44 mmoles), HOBT (132 mg, 0.98 mmoles) and EDCI (156 mg, 0.98 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (173 mg, 51%). LC-MS m/e 421.46 (M+H+)
Reaction SMILES: CS(C)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13](Br)[CH:12]=1.[OH-].[K+]>C(OC(=O)C)C>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH:12]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(C)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(C)cc1-n1ccnc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
To a degassed DMSO (20 mL) solution of imidazole (1.0 g, 15 mmol) was added 4-methyl-2-bromoanisole (1.25 mL, 10 mmol), KOH (1.12 g, 20 mmol) and Cu2O (280 mg, 2 mmol) under nitrogen. The resulting mixture was stirred at 140° C. for 24 hrs under N2. After cooling to room temperature, the mixture was poured into ethylacetate (EA) (50 mL) and filtered. The filtrate was washed with water (50 mL×3) and dried over anhydrous magnesium sulfate. After rotary evaporation, the crude oil was purified via column chromatography on silica gel with eluent of EA/MeOH (9/1, v/v), affording a light yellow solid (57%). 1H-NMR (300 MHz, CDCl3) δ(ppm) 7.78 (s, 1H), 7.16 (m, 3H), 7.09 (d, J=1.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.81 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:16])[O:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[O:9]1>>[C:1]1(=[C:11]2[C:12](=[O:14])[O:13][C:8]([CH3:16])([CH3:7])[O:9][C:10]2=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C1CCCC1
Product: CC1(C)OC(=O)C(=C2CCCC2)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 1 starting from cyclopentanone and 2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: Cl.[CH2:2]([S:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)[C@@H:13]([NH2:15])[CH3:14])=[CH:8][CH:7]=1)[CH3:3].C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH2:2]([S:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:21]=[CH:20]3)[C@@H:13]([NH:15][C:37](=[O:36])[CH2:38][OH:39])[CH3:14])=[CH:10][CH:11]=1)[CH3:3]
Reactant: CCSCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: CCSCc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CO)cc1

Procedure:
The title compound was prepared analogous to the method described in Example 21 starting from (1R,2S)-1-(4-(ethylthiomethyl)phenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine hydrochloride (25a) (50 mg, 0.11 mmol), and acetoxyacetyl chloride (13 μL, 0.12 mmol). Yield 33 mg (63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:6]=[CH:7][CH:8]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].CC(O)C>C1(C)C=CC=CC=1>[OH:20][C@H:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])[CH3:11]
Reactant: COc1cccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: COc1cccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A mixture of tert-butyl [(1S)-2-(3-methoxyphenyl)-1-methyl-2-oxoethyl]carbamate (13.6 g, 48.7 mmol), aluminum isopropoxide (1.99 g, 9.70 mmol), 2-propanol (41 mL, 535 mmol) in toluene (63 mL) was stirred under an atmosphere of argon at 50° C. overnight. LC/MS showed complete conversion into the alcohol. The mixture was partitioned between ethyl acetate (200 mL) and hydrochloric acid (1M, 200 mL). The organic phase was washed with water (200 mL), dried over magnesium sulfate and concentrated to give the subtitle compound as a syrup (13.5 g). The compound was used in the next step without further purification.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:11])[S:4]([NH:7][CH2:8][CH2:9][NH2:10])(=[O:6])=[O:5].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC=CC=1>[ClH:1].[CH:12](=[N:10][CH2:9][CH2:8][NH:7][S:4]([N:3]([CH3:11])[CH3:2])(=[O:6])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)S(=O)(=O)NCCN
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)NCCN=Cc1ccccc1
Yield: 41.1 %

Procedure:
A mixture of 4.0 g (0.02 mole) of 2-[N-[(dimethylamino)sulfonyl]-amino]ethylamine hydrochloride and 2.0 g (0.02 mole) of benzaldehyde was stirred and treated immediately with 2.0 g (0.02 mole) of triethylamine, followed by the addition of 200 ml of dry benzene. The solution was heated to reflux employing a Dean-Stark apparatus. After 2 hr at reflux, the benzene solution was cooled and washed twice with 100 ml portions of water. The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure to an oil, which was dissolved in ether and treated with HCl gas to precipitate a yellowish solid. The product was collected by filtration, washed with ether and air dried to provide 2.4 g (50%) of product. The NMR spectrum was consistent with the assigned structure and the solid was used without additional purification.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:19]([OH:25])([CH2:23][CH3:24])[C:20]([OH:22])=[O:21])[CH:15]=[C:16]([F:18])[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C>[CH2:4]([O:11][C:12]1[CH:13]=[C:14]([C:19]([OH:25])([CH2:23][CH3:24])[C:20]([O:22][CH3:3])=[O:21])[CH:15]=[C:16]([F:18])[CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: CCC(O)(C(=O)O)c1cc(F)cc(OCc2ccccc2)c1
Solvent: CCOCC
Product: CCC(O)(C(=O)OC)c1cc(F)cc(OCc2ccccc2)c1

Procedure:
A solution of diazomethane in diethyl ether was added to a solution of (-)-2-(3-benzyloxy-5-fluorophenyl)-2-hydroxybutyric acid (2.24 g) in diethyl ether (35 ml) until the reaction mixture retained a yellow colouration. The mixture was evaporated to give optically active methyl 2-(3-benzyloxy-5-fluorophenyl)-2-hydroxybutyrate (2.27 g).
Reaction SMILES: [NH3:1].[CH2:2]([N:9]1[CH:14]=[CH:13][C:12](OCC2C=CC=CC=2)=[C:11]([N+:23]([O-:25])=[O:24])[C:10]1=[O:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>ClCCl>[NH2:1][C:12]1[CH:13]=[CH:14][N:9]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10](=[O:26])[C:11]=1[N+:23]([O-:25])=[O:24]
Reactant: O=c1c([N+](=O)[O-])c(OCc2ccccc2)ccn1Cc1ccccc1
Reactant: N
Solvent: ClCCl
Product: Nc1ccn(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
20 ml of a saturated ethanolic ammonia solution were added to a solution of 5.5 g (16.3 mmol) of 1-benzyl-4-benzyloxy-3-nitro-pyridin-2-one in 50 ml dichloromethane and stirred for 3 days at ambient temperature in the sealed flask. The solution was evaporated to dryness, the residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH:11]1[C:10]1[C:9]([OH:13])=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>CN(C)C=O>[CH3:1][C:2]12[CH2:12][CH:11]1[C:10]1[C:9]([O:13][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=3)=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][CH2:3]2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC12COc3cccc(O)c3C1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC12COc3cccc(Oc4ccc([N+](=O)[O-])cn4)c3C1C2
Temperature: 110 °C
Yield: 77.7 %

Procedure:
To a solution of 1a-methyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-ol (Intermediate 125, 190 mg) in dry N,N-dimethylformamide (10 ml) were added K2CO3 (447 mg, 3.23 mmol) and 2-chloro-5-nitropyridine (171 mg, 1.078 mmol) to give a light brown solution. The reaction was heated at 110° C. for 1 hour and then quenched with water, extracted with ethyl acetate, washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, with a gradient from pure Cyclohexane to cyclohexane/ethyl acetate 5/1) to give the title compound as a light brown solid (250 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([C:27]1[N:31]=[C:30]([CH3:32])[O:29][N:28]=1)([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:19][C:20]([C:27]3[N:31]=[C:30]([CH3:32])[O:29][N:28]=3)([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CCOC(=O)C(C)(N)c1noc(C)n1
Product: CCOC(=O)C(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1noc(C)n1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 48c) and ethyl 2-amino-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate (example 147a) as starting materials and isolated (508 mg, 86%); MS (ESI, m/z): 443.5 (M+H+).