Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17](O)=[O:18])=[C:12]2[N:11]=[CH:10][C:9]=1[C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:18])=[C:12]2[N:11]=[CH:10][C:9]=1[C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: CS(N)(=O)=O
Reactant: COc1cccc(CNc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: COc1cccc(CNc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)NS(C)(=O)=O)cnn23)c1
Yield: 88.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-methoxybenzylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.06 g, 0.12 mmol) obtained in step 2 and methanesulfonamide (0.06 g, 0.62 mmol), the title compound (0.06 g, 69%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:16][CH2:17][CH2:18]Cl)=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=1.[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:16][CH2:17][CH2:18][NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:20][C:21]1[C:26]([CH3:27])=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][N:22]=1
Reactant: CC(C)CN
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NCCCl)C3)c1C
Solvent: C1COCCO1
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NCCNCC(C)C)C3)c1C
Yield: 28 %

Procedure:
A mixture composed of 4-amino-N-(2-chloroethyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carboxamide of Example 16 (20 mg), isobutylamine (0.8 mL) and dioxane (3 mL) was heated under reflux for 16 hours, and then the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reversed phase liquid chromatography to obtain the title compound (6 mg, 28%) as a solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:14][CH2:13][C:5]2[S:6][C:7]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:8][C:4]=2[CH2:3]1.[BH4-].[Na+].O.Cl>C(O)C>[OH:1][CH:2]1[CH2:14][CH2:13][C:5]2[S:6][C:7]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:8][C:4]=2[CH2:3]1
Reactant: NS(=O)(=O)c1cc2c(s1)CCC(=O)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1cc2c(s1)CCC(O)C2
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a suspension of 5-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-2-sulfonamide (1.0 g, 0.0043 mole) in ethanol (30 ml) was added sodium borohydride (160 mg, 0.004 mole). The suspended solid dissolved within 10 minutes in a slightly exothermic reaction. Stirring was continued overnight at room temperature. After dilution with water (15 ml), the ethanol was stripped in vacuo. The residual aqueous solution was cooled in an ice bath and acidified with 6N HCl. The precipitate was collected, washed with water, and dried to yield 0.7 g (70%) of product as an off-white crystalline solid, mp 176°-179° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[CH:10][C:9]2=[O:20])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[CH:10][C:9]2=[O:20]
Reactant: O=c1cc(-c2ccncc2)[nH]c2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2c(=O)cc(-c3ccncc3)[nH]c12

Procedure:
8-Nitro-2-(4-pyridinyl)-4(1H)-quinolinone (KN-352) was hydrogenated using Pd/C in ethanol to afford the title compound: MS-ES m/e 238 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]2[O:22][CH2:21]2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[CH3:23][O:24][C:25](=[O:33])[C:26]1C=CC(O)=[CH:28][CH:27]=1.[Na].C[O:36][C:37](=O)[C:38]1C=CC(O)=C[CH:39]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:2]([CH3:11])([CH3:1])[CH2:3][O:4][CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][O:6]3)=[CH:17][CH:16]=2)=[CH:19][C:20]=1[O:22][CH2:21][CH:37]([OH:36])[CH2:38][CH3:39]
Reactant: CC(C)(COC1CCCCO1)c1ccc(CCC2CO2)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCC(O)COc1cc(-c2ccc(C(C)(C)COC3CCCCO3)cc2)ccc1C(=O)OC

Procedure:
30.4 g (0.100 Mol) 4-{4'-[1,1-dimethyl-2-(tetrahydropyran-2-yl)oxyethyl]phenyl}-1,2-epoxy butane, 15.2 g (0.100 Mol) 4-hydroxybenzoic acid methyl ester and 1.74 g (0.010 Mol) 4-hydroxy benzoic acid methyl ester sodium salt are heated in 100 ml dimethyl formamide for 23 hours while stirring to 100°-110° C. The cooled reaction mixture is poured into water, the precipitating product taken up in ethyl acetate and the organic phase washed with water. After drying over sodium sulfate the solvent is removed in vacuum and the residue chromatographed on silica with dichloromethane/methanol 99/1. A highly viscous oil is obtained; yield 32.5 g (71%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[C:11](Cl)[C:10]=2[Cl:17])=[C:4]([CH2:18][O:19][CH3:20])[N:3]=1.[Cl:21]C1C=CC=C(Cl)C=1CC#N>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[C:14]([Cl:21])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:17])=[C:4]([CH2:18][O:19][CH3:20])[N:3]=1
Reactant: COCc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Reactant: N#CCc1c(Cl)cccc1Cl
Product: COCc1nc(N)nc(N)c1-c1c(Cl)cccc1Cl

Procedure:
This compound was prepared in an analogous manner to the compound of Example 2 from 2,6-dichlorophenylacetonitrile (Aldrich), mp. 204°-207° C.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([N:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH3:8])=[O:6].[SH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[Cl-].[NH4+]>O1CCCC1>[CH2:9]([N:7]([CH3:8])[C:5](=[O:6])[CH2:4][S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCN(C)C(=O)CBr
Reactant: OCCCCCS
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)CSCCCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
1.4 g of sodium hydride at 50% in oil and 6 g of bromo N-butyl-N-methyl acetamide of Step A of Preparation B of Example 78 were added to a solution of 3.36 g of the product of Step A in 45 ml of tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred for 2 hours at ambient temperature and poured into an ammonium chloride solution and extracted with ethyl acetate. The extracts were washed and evaporated to dryness under reduced pressure. The 10 g of residue were chromatographed on silica (eluant: cyclohexane-ethyl acetate 2-8) to obtain 5.27 g of the expected product.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([OH:17])[C:9]2[C:8](=[O:18])[CH2:7][C:6]3([CH2:21][CH2:20][CH2:19]3)[CH2:5][C:4]=2[N:3]=1.[C:22](=[O:25])([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[O:25]1[CH2:22][CH:5]=[C:4]([C:2]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([OH:17])[C:9]3[C:8](=[O:18])[CH2:7][C:6]4([CH2:21][CH2:20][CH2:19]4)[CH2:5][C:4]=3[N:3]=2)[CH2:9][CH2:8]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(Cl)nc2c(c1O)C(=O)CC1(CCC1)C2
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C2=CCOCC2)nc2c(c1O)C(=O)CC1(CCC1)C2

Procedure:
Obtained by starting from ethyl 2′-chloro-4′-hydroxy-5′-oxo-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carboxylate. 1,4-Dioxane is used instead of tetrahydrofurane and caesium carbonate instead of sodium carbonate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:29][CH:30]([F:41])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38](O)[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:38]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH:30]([F:29])[F:41])[CH3:39])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Reactant: CC(O)c1ccccc1OC(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1OC(F)F

Procedure:
In a similar manner as described for example B31, 2.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.41 g of 1-[2-(difluoromethoxy)phenyl]ethanol, 3.33 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 2.3 g of di-tert-butyl azodicarboxylate in 60 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([CH3:47])=[CH:44][CH:45]=[CH:46][C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cc1cccc(F)c1B(O)O
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cc1cccc(F)c1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@@H](F)CO2)c(N)s1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 88), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-6-methylphenyl)boronic acid gave 273. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.74 (s, 1H), 7.45-7.33 (m, 3H), 7.26-7.14 (m, 2H), 5.02-4.77 (m, 2H), 4.10-3.85 (m, 2H), 3.75 (s, 3H), 3.37 (s, 3H), 2.15-2.04 (m, 1H), 1.98-1.75 (m, 2H), 1.72-1.63 (m, 1H). LCMS (ES+) m/z 463 (M+1).
Reaction SMILES: [NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:38](OCC1C=CC=CC=1)=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:58][NH2:59]>CN(C=O)C>[NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:49])[C@H:2]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][C@H:33]([C:38]([NH:58][NH2:59])=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])=[O:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: NN
Solvent: CN(C)C=O
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NN

Procedure:
Compound I, Z-Tyr-Gly-Gly-Phe-Met-OBzl (0.85 g, 1.07 mmol) was dissolved in DMF (10 ml, purged with Argon for 15 min) and treated with 0.34 ml of H2NNH2 for 72 hr. at 25° C. The solvent was removed under reduced pressure to yield a crystalline residue which was triturated with H2O to form a crystalline product, yield 0.65g (84.2%). Recrystallized from DMF and ethanol to give colorless needles; mp 209°-213° C.; [α]D25 -27.6° (c 1, DMF). Anal. Calcd for C35H43N7O8S1 (721.84): C, 58.24; H, 6.00; N, 13.58; S, 4.44. Found: C, 57.50; H, 6.04; N, 13.75; S, 4.67.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15](O)=[O:16])(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[OH:36][CH:37]([CH:40]1[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]1)[CH2:38][NH2:39]>C(OCC)(=O)C>[OH:36][CH:37]([CH:40]1[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41]1)[CH2:38][NH:39][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][CH:20]=[C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:21]([F:22])([F:23])[F:24])[CH:13]=1
Reactant: CC1(C)OCC(C(O)CN)O1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)OCC(C(O)CNC(=O)c2cccc(S(=O)(=O)Nc3ccc(F)cc3C(F)(F)F)c2)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.63 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]-benzoic acid is suspended in 36 ml of ethyl acetate, 2.38 g (20 mmol) of thionylchloride is added and the suspension is heated to boiling temperature. After 15 minutes, a clear solution is present, after 1 hour the formation of the acid chloride is complete. The solution is evaporated to dryness under reduce pressure, the residue is concentrated by evaporation in a vacuum twice with 50 ml of dichloromethane each and then dissolved in 36 ml of dioxane. 1.21 g (12 mmol) of triethylamine and 1.93 g (12 mmol) of 2-hydroxy-2-(2,2-dimethyl-I,3-dioxolan-4-yl)-ethylamine are added to this solution and it is stirred for 5 hours at room temperature. The reaction mixture is then evaporated to dryness in a vacuum, the residue is extracted with ethyl acetate, the ethyl acetate extract is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 3.42 g (6.75 mmol) =67.5% of the theoretical yield of the product is obtained as an amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:4]=1[O:5][CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCCOc1cc([N+](=O)[O-])ccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc([N+](=O)[O-])cc1OCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To an ice-cold solution of tert-butyl (2-(2-cyano-5-nitrophenoxy)ethyl)carbamate (4 g, 13.02 mmol) in DCM (20 mL) was added TFA (10 mL). The reaction mixture was stirred at rt for 60 min. The solvent was removed under reduced pressure and treated with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to get 2-(2-aminoethoxy)-4-nitrobenzonitrile (2.4 g, 89%) as a yellow solid. LC-MS (M+H)+=208.0. 1H NMR (400 MHz, CDCl3) δ ppm 7.89 (1H, d, J=8.4 Hz), 7.83 (1H, s), 7.76 (1H, d, J=8.4 Hz), 4.23 (2H, t, J=5.2 Hz), 3.22 (2H, t, J=5.2 Hz).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[N+:20]([C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N+:20]([C:23]1[CH:24]=[N:25][N:26]([CH2:6][C@H:7]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)[CH:27]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc([N+](=O)[O-])cn2)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 107.7 %

Procedure:
To a solution of (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (2.8 g, 9.5 mmol) and 4-nitro-1H-pyrazole (715 mg, 6.3 mmol) in acetonitrile (100 mL) was added cesium carbonate (6.2 g, 19.0 mmol). The reaction mixture was stirred at 55° C. overnight and then concentrated. The residue was dissolved in ethyl acetate (100 mL), washed with water (50 mL), dried over sodium sulfate, filtered and concentrated. The crude sample was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate=8:1, to afford (S)-tert-butyl 2-((4-nitro-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate as a yellow oil (2.12 g, 71%). MS (ES+) C13H20N4O5 requires: 312, found: 257 [M+H-56]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([OH:28])=[O:27].C(N(C(C)C)CC)(C)C>C(O)(C)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=2[C:26]([OH:28])=[O:27])[C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1cccc(F)c1C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Nc4cccc(F)c4C(=O)O)nc(Cl)nc32)cc1
Temperature: 85 °C
Yield: 66 %

Procedure:
To a suspension of 2,4-dichloro-6-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.40 mmol) and 2-amino-6-fluorobenzoic acid (218 mg, 1.40 mmol) in isopropanol (15 mL) was added diisopropylethylamine (907 mg, 7.02 mmol) and the mixture was heated at 85° C. for ˜72 h. The reaction was diluted with EtOAc (100 ml) and washed with a solution of 1N HCl, a saturated solution of sodium bicarbonate and a saturated solution of NaCl. Solid began to crash out on addition of brine. Ether was added to force everything out of solution and also water was added to ensure NaCl was all in solution. The solids were filtered and dried under reduced pressure to afford 2-({2-chloro-6-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid (439 mg, 0.924 mmol) as a pale yellow solid. ESIMS (M+H)+=475.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][N:17]3[C:22](=[O:25])[NH:23][CH3:24])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:26][C:27]([OH:29])=[O:28])[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][N:17]3[C:22](=[O:25])[NH:23][CH3:24])(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CNC(=O)N1CCc2c1cccc2N(CC(=O)OC(C)(C)C)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)N1CCc2c1cccc2N(CC(=O)O)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg tert.butyl [(3,5-dichloro-phenylsulphonyl)-(1-methylcarbamoyl-2,3-dihydro-1H-indol-4-yl)-amino]-acetate are dissolved in 4 ml of a 4 N solution of HCl in dioxane. The mixture is stirred overnight at RT and the solvents are then eliminated in vacuo. The residue is extracted from dichloromethane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.[C:22](#[N:26])[CH2:23][C:24]#[N:25]>O1CCOCC1.C1(C)C=CC=CC=1.[Cl-].[Na+].O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:23]([C:22]#[N:26])[C:24]#[N:25])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCC#N
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
p-Nitro-acetophenone (165 g/mole; 4.0 g; 24 mmoles), ammonium acetate (0.50 g) and glacial acetic acid (0.80 mL) were added to a round-bottom flask containing 20 mL toluene, and heated to reflux using a Dean-Stark trap and a reflux condenser. Separately, malononitrile (66 g/mole; 2.0 g; 30.3 mmoles) was dissolved in 5 mL dioxane and 20 mL toluene, transferred to an addition funnel and added dropwise to the heated solution of ketone. Upon completion of the addition, the system was heated for 2 hours and then cooled to room temperature. The reaction mixture was poured into 150 mL brine and 100 mL ethyl acetate. The aqueous layer was separated and washed with 50 mL ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the crude product 2-[1-(4-nitrophenyl)-ethylidene]-malononitrile (213 g/mole) was used as such in Intermediate Example 11.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:34][C:35]1[S:39][C:38]([S:40](Cl)(=[O:42])=[O:41])=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:13][N:12]([S:40]([C:38]2[S:39][C:35]([Br:34])=[CH:36][CH:37]=2)(=[O:42])=[O:41])[CH2:11][CH2:10][N:9]1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC(O)(c1ccc(N2CCNC[C@@H]2Cc2ccccc2)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3ccc(Br)s3)C[C@@H]2Cc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
The 2-(4-((2S)-2-benzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (147 mg, 0.404 mmol) was dissolved in CH2Cl2 (10 mL) was cooled to 0° C. To this solution was added triethylamine (124 μL, 0.889 mmol) followed by 5-bromothiophene-2-sulfonyl chloride (127 mg, 0.485 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was allowed to slowly warm to room temperature and stirred for 2 h. The mixture was concentrated and absorbed onto silica gel. The crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(4-((2S)-2-benzyl-4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (105 mg).
Reaction SMILES: [Li+].[BH4-].[Br:3][C:4]1[C:13]([F:14])=[CH:12][C:11]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34](=[O:37])[NH:35][CH3:36])=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][C:5]=1[C:6](OC)=[O:7].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[Br:3][C:4]1[C:5]([CH2:6][OH:7])=[CH:10][C:11]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:35][CH3:36])=[O:37])=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:13]=1[F:14]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of LiBH4 (1.018 mL, 2M) in THF was added dropwise to a solution of methyl 2-bromo-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate (430 mg, 0.679 mmol) in MeOH (0.5 mL) and THF (5.0 mL) at 0° C. After 0.5 h, citric acid (4.0 mL, 5% wt) was added to the mixture. The organic solvent was then removed under reduced pressure. The residue was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give 6-(N-(4-bromo-3-fluoro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (400 mg, 97% yield) as white solid. The crude was used for next step without more purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.57 (br. s., 1H), 0.71-0.88 (m, 2H), 0.93-1.06 (m, 1H), 1.96-2.02 (m, 1H), 2.63 (t, J=6.1 Hz, 1H), 2.96 (d, J=4.8 Hz, 3H), 3.25 (s, 3H), 4.67 (d, J=5.6 Hz, 2H), 5.96 (d, J=4.8 Hz, 1H), 7.08-7.21 (m, 3H), 7.31 (s, 1H), 7.42 (s, 1H), 7.56 (s, 1H), 7.82 (dd, J=8.7, 5.3 Hz, 2H). LCMS (m/z, ES+)=605, 607 (M+H+).