Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][CH:11]=2)=[NH:10])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccc(C#N)cc1
Product: CC(C)c1ccc(NC(=N)c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 60 %

Procedure:
The title compound was prepared from 4-methylsulfonylbenzonitrile (5.43 g, 30 mmol) and 4-isopropylaniline (4.05 g, 30 mmol) by following the procedure described in preparation 1 (5.66 g, yield 60%, purity 88% by HPLC). 1H-NMR (CDCl3):δ 1.25-1.27 (d, 6H), 2.9-2.95 (m, 1H), 3.07 (s, 3H), 4.92 (bs, 2H, D2O exchangeable), 6.90-6.92 (d, 2H), 7.23-7.26 (d, 2H), 8.01-8.03 (d, 2H), 8.08-8.1 (d, 2H). MS m/z:317.2 (M+).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)=[CH:6][CH:5]=1.C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[Br:1][C:11]1[C:12]([C:19]([F:22])([F:20])[F:21])=[C:13]([C:15]([F:16])([F:17])[F:18])[NH:14][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)[nH]c1C(F)(F)F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1[nH]c(-c2ccc(Cl)cc2)c(Br)c1C(F)(F)F
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Bromine (0.527 g, 3.3 mmol) is added to a room temperature solution of 5-(p-chlorophenyl)-2,3-bis(trifluoromethyl)pyrrole (0.9 g, 3.0 mmol), acetic acid (5 mL) and sodium acetate (0.492 g, 6 mmol). After stirring for 2 hours the reaction mixture is diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water, sodium metabisulfite solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. Crystallization of the solid from hexanes gives the title product as white crystals (0.77 g, mp 64.5°-65.0° C., 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]=2[CH3:22])=[O:7])=[CH:4][C:3]=1[O:25][CH3:26].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:26][O:25][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:2]=1[NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]=1[CH3:22])=[O:7]
Reactant: CCOC(=O)c1c(C)c(C(=O)c2ccc(N)c(OC)c2)n2ccccc12
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)c1c(C)c(C(=O)c2ccc(NS(C)(=O)=O)c(OC)c2)n2ccccc12

Procedure:
This compound was obtained according to the same procedure as that described in Example 207, by sulphonylation of ethyl 3-(4-amino-3-methoxybenzoyl)-2-methylindolizin-1-ylcarboxylate, a compound of Example 97, with methanesulphonyl chloride. The product is purified by chromatography on a silica column, eluting with a toluene/ethyl acetate (8:2) mixture. A yellow powder is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:27][CH2:26][CH2:25][C:9]32[N:13]([CH3:14])[C:12](=[O:15])[N:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:10]3=[O:24])=[CH:4][CH:3]=1.[C:28]([Cu])#[N:29].C(N)CN>CN1C(=O)CCC1>[Cl:23][C:18]1[CH:17]=[C:16]([N:11]2[C:10](=[O:24])[C@:9]3([CH2:25][CH2:26][CH2:27][C@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([C:28]#[N:29])=[CH:3][CH:4]=3)[N:13]([CH3:14])[C:12]2=[O:15])[CH:21]=[C:20]([Cl:22])[CH:19]=1
Reactant: N#C[Cu]
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)C12CCCC2c1ccc(Br)cc1
Solvent: NCCN
Solvent: CN1CCCC1=O
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(C#N)cc1
Temperature: 180 °C

Procedure:
A mixture of 6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-1,3-diazaspiro[4.4]nonane-2,4-dione (1 g, 2.1 mmol) (Example 1) and CuCN (0.45 g, 5 mmol) in NMP was heated to 180° C. for 6 h. After cooling, the reaction mixture was poured on a mixture of ice and ethylene diamine and extracted twice with DCM. The brown residue was chromatographed over silica gel to yield 4-[(5R*,6S*)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3-diazaspiro[4.4] non-6-yl]benzonitrile as a beige solid. 1H NMR (CDCl3): 7.62 (2H, d, J=8.1 Hz), 7.25–7.3 (3H, m), 6.67 (2H, br s), 3.45 (1H, dd, J1=12.8 Hz, J2=6.4 Hz), 3.16 (3H, s), 2.4–2.7 (1H, m), 1.8–2.4 (5H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].CC(C)=O.C(Cl)Cl>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([Cl:23])=[CH:16][CH:17]=[CH:18][C:19]=2[NH2:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(N)cccc2Cl)CC1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of 342 mg (1 mmol) of 4-(2-chloro-6-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 5.0 mL of MeOH was treated with 630 mg (10 mmol, 10 eq) of ammonium formate and a catalytic amount of 10% Pd—C (34 mg). The reaction mixture was stirred at 65° C. for 30 min. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. TLC (silica, 5% acetone/CH2Cl2): Rf=0.40. MS (electrospray): exact mass calculated for C15H22ClN3O2, 311.14; m/z found, 312.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][CH:12]3[CH:8]2[CH2:9][NH:10][CH2:11]3)[CH:2]=1.[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18]>CO.C(OC(=O)C)(C)C>[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][C@@H:12]3[C@H:8]2[CH2:9][NH:10][CH2:11]3)[CH:2]=1
Reactant: c1cncc(N2CC3CNCC32)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(=O)OC(C)C
Solvent: CO
Product: c1cncc(N2C[C@H]3CNC[C@H]32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
The product of Example 40C (65 mg, 0.37 mmol) was treated with fumaric acid (46.4 mg, 0.4 mmol) in methanol/isopropylacetate (1:10 v/v, 20 mL). The mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried under reduced pressure at 40-50° C. to provide the title compound (47 mg, 44% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.18 (dd, J=12.6, 3.4 Hz, 1H), 3.35 (m, 1H), 3.46 (m, 1H), 3.75 (m, 3 H), 4.04 (t, J=7.5 Hz, 1H), 4.90 (m, 1H), 6.58 (s, 2H), 7.04 (ddd, J=8.2, 2.7, 1.3 Hz, 1H), 7.27 (dd, J=8.2, 4.8 Hz, 1H), 7.87 (d, 2.7 Hz, 1H), 7.95 (dd, J=4.8, 1.1 Hz, 1H); m/z 176 (M+H)+; Anal. calculated for C10H13N3.1.25C4H4O4.0.6H2O: C, 54.41; H, 5.84; N, 12.69. Found: C, 54.96; H, 5.50; N, 12.10.
Reaction SMILES: CO.[CH2:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21](=[O:31])[CH2:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[C].[Pd].C(OCC)(=O)C>[CH2:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]=1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(C/C=C/c1ccccc1)Nc1cc(CCc2ccccc2)ccc1C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCCc1ccccc1)Nc1cc(CCc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 mg of 10% palladium-carbon was added to a mixed solution of 0.50 mL of methanol and 0.50 mL ethyl acetate containing 8.0 mg of 4-phenethyl-2-((E)-4-phenyl-3-butenamido)benzoic acid and stirred under hydrogen atmosphere at room temperature for 1 hour and 30 minutes. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified with silica gel column chromatography [Flash Tube 2003 manufactured by Trikonex Company, eluent; ethyl acetate] to obtain 4.6 mg of 4-phenethyl-2-(4-phenylbutanamido)benzoic acid as white solid.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:18])=[O:2])=[CH:9][CH:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
4-Benzyloxy-benzoic acid methyl ester (8.0 g, 0.033 mol) was dissolved in THF:methanol:water (3:2:1, 80 ml) and NaOH (1.98 g, 0.05 mol) was added to the reaction mixture and stirred at 50-55° C. for 3 hours. Solvents were removed and residue was diluted with water, washed with hexane and acidified with dil HCl to obtain 4-benzyloxy-benzoic acid (7.0 g, 92%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl-].[NH4+].CO>[Zn].O>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a mixture of of N-[(1,1-dimethylethoxy)carbonyl]-4-nitro-L-phenylalanine methyl ester (222 mmol, 72 g), zinc dust (˜325 mesh, 2.2 mol, 145.2 g, 10 equiv) and ammonium chloride (3.3 mol, 178.1 g, 15 equiv) was added methanol (1 L) and water (500 mL) at room temperature. After addition of water, an exothermic reaction ensued and the internal temperature rose to 45 to 50° C. The suspension was stirred for 30 min to 1 h at room temperature, at which time TLC analysis of the mixture indicated the absence of starting material, and the reaction mixture was filtered through a pad of celite and the filtered cake was washed with methanol (1 L) and water (500 mL). Concentration to remove most of the methanol afforded white solid which was collected by filtration and washed with water. After air drying, 65.5 g of a white solid, mp 86-89° C. was obtained. 1H-NMR (DMSO-d6) (400 MHz) δ 6.9 (d, 2H, J=20 Hz), 6.62 (d, 2H, J=20 Hz), 7.39 (d, 1H, J=22 Hz), 4.26-4.28 (m, 1H), 3.68 (s, 3H), 2.96-3.19 (m, 2H), 1.25 (s, 9H). HR MS: Obs. mass, 294.1614. Calcd. mass, 294.1621 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][O:31]C5CCCCO5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:10]=1.C(Cl)(=O)C>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:10]=1
Reactant: CS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCOC5CCCCO5)c4)ccc32)c1
Solvent: CO
Solvent: CC(=O)Cl
Product: CS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCO)c4)ccc32)c1
Yield: 49.1 %

Procedure:
To a solution of N-(2′,4′-difluoro-5-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)-ethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)methanesulfonamide (0.15 g, 0.252 mmol) in methanol (5 ml) was added acetyl chloride (1 ml) at 0° C. as in Example 1(d). The solvent was distilled off to afford the product (0.063 g). 1H NMR (300 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.22 (s, 1H), 8.00-7.97 (d, 2H), 7.80-7.69 (m, 2H), 7.67-7.61 (m, 1H), 7.59-7.60 (d, 1H), 7.53 (s, 2H), 7.47-7.41 (m, 2H), 7.29-7.25 (t, 1H), 4.97-4.95 (t, 1H), 4.18-4.15 (m, 2H), 3.80-3.78 (m, 2H), 3.14 (s, 3H) Calculated mass: 509.1; Observed mass: 510.3 [M+H]+ (rt: 1.18 min).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].C[O-].[Na+].[CH3:10][N:11](C=NC=[N+](C)C)[CH3:12].[Cl-]>C(COC)OC>[C:1]([C:3]1[C:4]([SH:5])=[N:6][CH:10]=[N:11][CH:12]=1)#[N:2]
Reactant: N#CCC(N)=S
Reactant: CN(C)C=NC=[N+](C)C
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cncnc1S
Temperature: 25 °C
Reaction time: 5 h

Procedure:
At room temperature, 2-cyanothioacetamide (4.5 g, 0.045 mol) was added to an initial charge of sodium methoxide (24.3 g, 0.1.35 mol, 29% in methanol). 100 ml of dimethoxyethane were added. The Gold's reagent prepared as in Example 1 (8.1 g, 0.050 mol) was then added, and the reaction mixture was stirred at room temperature for about 5 hours. The mixture was then heated briefly to 50° C. and left to stand at room temperature overnight. The dimethoxyethane was stripped off on a rotary evaporator, 20 ml of water were added, and then the reaction mixture was cooled in an ice bath. 30 ml of 2N eq. HCl solution were used to adjust the pH to 5.5. After renewed cooling, the solid which had precipitated out was filtered off, then washed with a small amount of cold water and dried at 40° C. in a vacuum drying cabinet to give the title product in a yield of 5.57 g (90.4%) in the form of an orange solid.
Reaction SMILES: [C:1]([C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C#N)c2CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2cccc(C(=N)NO)c2CC1
Yield: 39.2 %

Procedure:
1,1-dimethylethyl 6-cyano-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 14) (1.15 g), hydroxylamine hydrochloride (1.18 g) and sodium bicarbonate (1.76 g) were heated at 60° C. in ethanol (100 ml) for 18 hours under argon. The cooled reaction was evaporated to dryness, partitioned between DCM (100 ml) and water (100 ml). The DCM layer was collected and the water layer washed with DCM (50 ml). The combined DCM layers were dried and evaporated. The title compound (506 mg) was isolated by chromatography eluting with 5% methanol in DCM. δH (400 MHz, CDCl3) 7.27 (1H, s) 7.16-7.13 (2H, m), 5.38 (1H, br. s), 3.58-3.55 (4H, m), 3.05 (2H, br. s), 2.89 (2H, br. s) 1.46 (2H br. s), 1.12 (9H, br. s); MS (ES) C16H23N3O3 requires 305; found 306 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1>C(Cl)Cl>[C:1]([O:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
Acetylchloride (1.5 mL, 21 mmol) is added to a solution of 4-(4-hydroxyphenoxy)benzoic acid (2.3 g, 10 mmol) and TEA (2.9 mL, 21 mmol) in CH2Cl2 (50 mL). The reaction is stirred for 16 hours at room temperature. The reaction mixture is diluted with CH2Cl2 and washed three times with saturated NaHCO3. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The resulting material is dissolved in dioxane (6 mL). Aqueous LiOH (1N, 930 μL) is added, and the reaction is allowed to stir for one hour at room temperature. The reaction mixture is poured into CH2Cl2 and washed twice with KHSO4. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the desired acid (1.5 g, 87%). 1H NMR (300 MHz, DMSO) δ12.80, 7.96, 7.23-7.13, 7.04, 2.29.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:23]([NH2:25])[CH3:24].O>CS(C)=O>[CH2:23]([NH:25][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH3:24]
Reactant: CCN
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Solvent: O
Product: CCNc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), 70% v/v ethanamine in water (26.1 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(3-(ethylamino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 12.23 (br. s, 1H), 7.84-7.89 (m, 1H), 7.50-7.56 (m, 1H), 7.26-7.33 (m, 2H), 7.06-7.11 (m, 1H), 6.93 (br. s, 1H), 3.48-3.58 (m, 2H), 3.38-3.45 (m, 2H), 2.82-2.89 (m, 2H), 2.50 (s, 3H), 1.30 (t, J=1.0 Hz, 3H). m/z (ESI, +ve) 322.1 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#N)=[N:11][CH:12]=1.C(=O)([O-])[OH:16].[Na+].[CH2:20]([OH:22])[CH3:21]>>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:22][CH2:20][CH3:21])=[O:16])=[N:11][CH:12]=1
Reactant: Cc1ccc(C#N)nc1
Reactant: CCO
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(C)cn1

Procedure:
200 ml of ethanol and 100 ml (1.88 mol) of concentrated sulfuric acid were added to 55.5 g of 5-methylpyridine-2-carbonitrile to form a homogeneous solution, followed by heating under reflux for 2 days. The reaction liquid was gradually poured into a saturated aqueous solution of sodium hydrogencarbonate under cooling with ice to neutralize the sulfuric acid, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in a reduced pressure to give 78.1 g of a brown oil of the title compound as the crude product.
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.Cl[C:29]1[C:30]([O:43][CH2:44][C@H:45]2[CH2:50][CH2:49][C@@H:48]([C:51]([F:54])([F:53])[F:52])[CH2:47][CH2:46]2)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=1)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35]>>[CH:10]1([C:29]2[C:30]([O:43][CH2:44][C@H:45]3[CH2:50][CH2:49][C@@H:48]([C:51]([F:54])([F:53])[F:52])[CH2:47][CH2:46]3)=[CH:31][C:32]([F:42])=[C:33]([CH:41]=2)[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[O:35])[CH2:1][CH2:2]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(OC[C@H]2CC[C@@H](C(F)(F)F)CC2)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OC[C@H]2CC[C@@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with cis-5-chloro-2-fluoro-N-(methylsulfonyl)-4-((4-(trifluoromethyl)cyclohexyl)methoxy)benzamide, the title compound was obtained as colorless solid (0.12 g, 24%): 1H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.04 (d, J=13.1 Hz, 1H), 4.06 (d, J=7.1 Hz, 2H), 3.34 (s, 3H), 2.36-2.28 (m, 1H), 2.13-1.97 (m, 2H), 1.74-1.56 (m, 8H), 0.91-0.85 (m, 2H), 0.70-0.65 (m, 2H); MS (ES+) m/z 438.1 (M+1); MS (ES−) m/z 436.2 (M−1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)([OH:3])=[O:2].[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)([OH:3])=[O:2].[N:23]1([CH2:22][CH2:21][NH:20][C:1]([C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:3])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NCCN1CCOCC1
Agent: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Product: O=C(NCCN1CCOCC1)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1

Procedure:
Entry 61: 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 4-(2-aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4,4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline to afford the urea.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH:25]3[CH2:27][O:26]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[CH:34][N:35]2[CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:31][CH:30]=1>CCO>[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[CH:34][N:35]2[CH:38]2[CH2:43][CH2:42][N:41]([CH2:27][CH:25]([OH:26])[CH2:24][N:11]3[C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]=4[C:13]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=4)=[N:12]3)[CH2:40][CH2:39]2)=[CH:31][CH:30]=1
Reactant: Clc1ccc2ccn(C3CCNCC3)c2c1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: CCO
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(n3ccc4ccc(Cl)cc43)CC2)C1
Temperature: 60 °C
Yield: 47.9 %

Procedure:
To a stirred solution of 86 mg (0.21 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine in 4 mL of EtOH was added 50 mg (0.39 mmol) of 6-chloro-1-piperidin-4-yl-1H-indole. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, gradient elution from 0-5% 2 N NH3/MeOH in CH2Cl2) to afford 64 mg (48%) of a white solid. MS (electrospray), exact mass calculated for C30H33ClF3N5O3S: 635.19; m/z found, 636.2 [M+H]+. HPLC (reverse phase conditions 10-90%), tR=4.88 min. 1H NMR (CDCl3, 400 MHz): 7.72 and 7.67 (A and B of AB quartet, J=8.80 Hz, 4H), 7.52 (d, J=8.41, 1H), 7.34 (s, 1H), 7.18 (d, J=3.33 Hz,1H), 7.07 (dd, J=8.41, 1.76 Hz, 1H), 6.50 (d, J=3.33 Hz, 1H), 4.59 and 4.54 (A and B of AB quartet, J=14.48 Hz, 2H), 4.24 (dd, J=13.69, 2.39 Hz, 1H), 4.21-4.14 (m, 2H), 4.05 (dd, J=13.69, 6.46 Hz, 1H), 3.69 (m, 2H), 3.15 (brd, J=11.54 Hz, 1H), 3.11-2.91 (m, 3H), 2.60-2.48 (m, 3H), 2.28 (dt, J=11.74, 2.15 Hz, 1H), 2.13-1.93 (m, 4H).