Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CC1(C)[O:26][C@@H:25]([CH2:27][CH2:28][O:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][C:34]([C:39](O)=[O:40])=[CH:33]3)[CH2:24][O:23]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CCOC(C)=O>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:39]([C:34]2[NH:35][C:36]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:29][CH2:28][CH2:27][C@H:25]([OH:26])[CH2:24][OH:23])=[CH:38][CH:37]=3)=[O:40])=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CC1(C)OC[C@H](CCOc2ccc3[nH]c(C(=O)O)cc3c2)O1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(OCC[C@H](O)CO)ccc4[nH]3)c2F)c1
Yield: 42.5 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25.0 mg, 0.080 mmol), 5-({2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl}oxy)-1H-indole-2-carboxylic acid (24.53 mg, 0.080 mmol) and DIPEA (0.014 mL, 0.080 mmol) in DMF (1 mL) was added HATU (30.6 mg, 0.080 mmol). After 2 h the reaction mixture was poured into EtOAc and water. The organic layer was separated, dried over MgSO4 and the solvent evaporated. The residue was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.019 g, 42%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 10.67 (br. s., 1H), 8.31 (t, 1H), 7.60 (t, 1H), 7.46 (d, 1H), 7.40-7.42 (m, 1H), 7.38-7.40 (m, 1H), 7.34-7.38 (m, 2H), 7.07 (d, 1H), 7.04 (d, 1H), 6.88 (dd, 1H), 4.67 (d, 2H), 4.04-4.17 (m, 2H), 3.82-3.91 (m, 1H), 3.51-3.58 (m, 1H), 3.43-3.50 (m, 1H), 1.92-2.01 (m, 1H), 1.73-1.84 (m, 1H). LCMS m/z 558.0 (M+1).
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:38]1[CH:42]=[CH:41][NH:40][N:39]=1>N1C=CC=CC=1>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:38]1[CH:42]=[CH:41][N:40]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:39]=1
Reactant: Fc1ccc(-c2cc[nH]n2)c(F)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Fc1ccc(-c2ccn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c(F)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
Add triphenylmethylchloride (4.78 g, 17.2 mmol)) and dimethylaminopyridine (0.350 g, 2.86 mmol) to a stirred solution of 3-(2,4-difluorophenyl)-1H-pyrazole (2.58 g, 14.33 mmol) in dry pyridine (30 mL). Stir at 80° C. for about 18 hours. Cool to RT, concentrate and purify (silica gel chromatography, eluting with a gradient of hexane dichloromethane 25:75 to 0:100) to give the desired compound (43%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[CH3:26][O:27][CH2:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:32]3[CH2:33][CH2:34][CH:29]([CH2:28][O:27][CH3:26])[CH2:30][CH2:31]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: COCC1CCNCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: COCC1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-(methoxymethyl)piperidine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.10 (qd, J=12.3, 4.0 Hz, 2H) 1.59 (br. s., 1H) 1.67 (br. s., 1H) 1.70-1.85 (m, 1H) 2.36 (s, 3H) 2.74 (br. s., 1H) 3.14 (d, J=6.3 Hz, 2H) 3.17 (s, 3H) 3.57 (br. s., 1H) 4.41 (br. s., 1H) 7.57 (dd, J=8.0, 1.4 Hz, 1H) 7.64 (s, 1H) 7.74 (d, J=8.1 Hz, 1H) 7.96 (dd, J=8.6, 2.3 Hz, 1H) 8.03-8.09 (m, 1H) 8.31 (d, J=8.3 Hz, 1H) 8.42-8.47 (m, 1H) 13.03 (br. s., 1H). MS m/z [M+H]+ 432.5.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>O1CCCC1>[CH3:10][O:9][C:4]1[N:3]=[C:2]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: c1nc[nH]n1
Reactant: COc1nc(C)cc(Cl)n1
Solvent: C1CCOC1
Product: COc1nc(C)cc(-n2cncn2)n1
Yield: 22.5 %

Procedure:
In anhydrous tetrahydrofuran, 159 mg of 4-chloro-2-methoxy-6-methylpyrimidine was substituted with 69 mg of 1,2,4-triazole. The reaction mixture was treated according to the procedure of Example 5 to yield 43 mg of 2-methoxy-6-methyl-4-(1,2,4-triazol-1-yl)pyrimidine, recrystallized from n-hexane, having a melting point of 98°-98.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[C:10]1([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.Cl.[CH3:21][C:22]1[N:23]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=2)[CH:24]=[CH:25][N:26]=1>>[F:1][C:2]1[C:7]([O:8][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH3:21])=[CH:34][CH:33]=2)=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[C:10]1([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: COC(=O)C1(c2cc(F)cc(O)c2F)CCOCC1
Agent: Cl
Product: COC(=O)C1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2F)CCOCC1
Yield: 49 %

Procedure:
Methyl 4-(2,5-difluoro-3-hydroxyphenyl)-3,4,5,6-tetrahydropyran-4-carboxylate was reacted with 4-(2-methylimidazol-1-yl)benzyl chloride hydrochloride according to the procedure described in Example 2H to give the titled compound in 49% yield as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH2:13][CH2:14][Cl:15].[Na+].[Br-]>O>[Cl:15][CH2:14][CH2:13][CH2:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCOc1ccc(Cl)cc1
Temperature: 100 °C
Yield: 83 %

Procedure:
A 1 L flask provided with a stirrer was charged with 128.6 g (1.0 mol) of p-chlorophenol (available from Tokyo Chemical Industry Co., Ltd.), 52.0 g (1.3 mols) of sodium hydroxide (available from Wako Pure Chemical Industries Ltd.), 188.9 g (1.2 mols) of 1-bromo-3-chloropropane (available from Tokyo Chemical Industry Co., Ltd.) and 300 g of water. The content was maintained at 100° C. for 6 hours. Then the reaction liquid was cooled to room temperature, and deposited NaBr, produced by side reaction, was filtered off. The organic phase was separated and subjected to distillation under reduced pressure to give 179.2 g of the target p-(3-chloropropoxy)chlorobenzene (yield: 83%, purity: 95%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:21][CH2:22][C:23]1[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:29][C:28]1[CH:27]=[C:26]([CH3:30])[NH:25][C:24](=[O:31])[C:23]=1[CH2:22][NH:21][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[C:10]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH:11]=1)=[O:15]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccsc3)nc21
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccsc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-(3-thienyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.244 mmol), DMSO (2 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (68.9 mg, 0.365 mmol) HCl salt, N-methylmorpholine (0.107 mL, 0.974 mmol), 1-hydroxy-7-azabenzotriazole (33.2 mg, 0.244 mmol) and EDC (93 mg, 0.487 mmol). The final product was collected as 75 mg (73%). LCMS E-S (M+H)=422.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=6.8 Hz, 6H), 2.13 (s, 3H), 2.23 (s, 3H), 4.41 (d, J=4.8 Hz, 2H), 5.30 (quin, J=6.6 Hz, 1H), 5.91 (s, 1H), 7.71 (dd, J=5.0, 3.0 Hz, 1H), 7.92 (d, J=5.0 Hz, 1H), 8.09 (s, 1H), 8.34 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.79-8.95 (m, 1H), 11.58 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[N:37]1(C2C=CC(C(=O)C)=CC=2)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([N:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:4][CH:5]=2)[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(N5CCNCC5)cc4)ccc3c1)n2C1CCCCC1
Yield: 91 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-piperazin-1-yl-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (120 mg, 91% yield). MS: 532.21 (M+H+); HPLC Procedure A, retention time=7.78 min.
Reaction SMILES: C(OC(N1C[CH2:12][CH2:11][CH:10]([C:14]2[N:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[O:16][N:15]=2)[CH2:9]1)=O)(C)(C)C.[C:25]([O:29][C:30]([N:32]1CCCC[CH:33]1C1N=C(CCC(OC)=O)ON=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(OC(N1CCCC1C1N=C(CCC(OC)=O)ON=1)=O)(C)(C)C.C(OC(NC1SC=C(C2N=C(CCC(OC)=O)ON=2)C=1)=O)(C)(C)C.C(OC(NC1SC(C2N=C(CCC(OC)=O)ON=2)=CC=1)=O)(C)(C)C.C(OC(NC1N(C)N=CC=1C1N=C(CCC(OC)=O)ON=1)=O)(C)(C)C.N1C=CC=C1C1N=C(CCC(OC)=O)ON=1.CN1C=CC=C1C1N=C(CCC(OC)=O)ON=1.C([Si](C(C)C)(C(C)C)OCC1C=C(C2N=C(CCC(OC)=O)ON=2)C=CC=1)(C)C.C([Si](C(C)C)(C(C)C)OCC1C=CC(C2N=C(CCC(OC)=O)ON=2)=CC=1)(C)C.COC(=O)CCC1ON=C(C2C=C(NS(CC)(=O)=O)SC=2)N=1.COC(=O)CCC1ON=C(CCl)N=1>>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:9][CH:10]([C:14]2[N:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[O:16][N:15]=2)[CH2:11][CH2:12]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)CCc1nc(C2CCCN(C(=O)OC(C)(C)C)C2)no1
Reactant: COC(=O)CCc1nc(C2CCCCN2C(=O)OC(C)(C)C)no1
Agent: CCS(=O)(=O)Nc1cc(-c2noc(CCC(=O)OC)n2)cs1
Agent: COC(=O)CCc1nc(-c2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc2)no1
Agent: COC(=O)CCc1nc(-c2ccc(NC(=O)OC(C)(C)C)s2)no1
Product: COC(=O)CCc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)no1

Procedure:
Methyl 3-[3-(1-tert-Butyloxycarbonylpiperidin-3-yl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(1-tert-Butyloxycarbonylpiperidin-2-yl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(1-tert-Butyloxycarbonylpyrrolidin-2-yl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(2-tert-Butyloxycarbonylaminothiophen-4-yl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(2-tert-Butyloxycarbonylaminothiophen-5-yl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(3-tert-Butyloxycarbonylamino-2-methyl-2H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(3-tert-Butyloxycarbonylamino-1-(2-trimethylsilyl)ethoxymethyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(4-tert-Butyloxycarbonylamino-1-(2-trimethylsilyl)ethoxymethyl-1H-imidazol-5-yl)-1,2,4-oxadizaol-5-yl]propionate; Methyl 3-[3-(5-tert-Butyloxycarbonylamino-1-(2-trimethylsilyl)ethoxymethyl-1H-imidazol-4-yl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(1H-Pyrrol-2-yl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(1-Methyl-1H-pyrrol-2-yl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(3-Triisopropylsilyloxymethylphenyl)-1,2,4-oxadiazol-5-yl]propionate; Methyl 3-[3-(4-Triisopropylsilyloxymethylphenyl)-1,2,4-oxadiazol-5-yl]propionate; 3-{4-[(5-(2-Carbomethyoxy)ethyl)-1,2,4-oxadiazol-3-yl]thiophen-2-yl}-1-isobutylurea; Methyl-3-(2-Ethanesulfonylaminothiophene-4-yl-1,2,4-oxadiazol-5-yl)propionate; Methyl-3-(3-Chloromethyl-1,2,4-oxadiazol-5-yl)propionate; and Methyl-3-[3-(5-tert-Butyloxycarbonylamino-3-methylisoxazol-4-yl)-1,2,4-oxadizol-5-yl]propionate.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[C:12](=[O:13])[C:4]=2[CH:3]=1.[C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35](B(O)O)[CH:36]=1)#[N:30].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.O>O.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:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=4[O:40][CH3:41])[C:29]#[N:30])[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:19]=1
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Reactant: COc1ccc(C#N)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C#N)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: 100 °C

Procedure:
A degassed mixture of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate B) (0.337 mmol), 5-cyano-2-methoxyphenylboronic acid [612833-37-1] (0.675 mmol), Pd(PPh3)4 (0.067 mmol) and K3PO4 (1.350 mmol) in 2:1 dioxane/H2O (4.5 mL) was heated at 100° C. for 4 h. After cooling to rt, the reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4) and concentrated. The residue was dissolved in CH2Cl2 and filtered through a PL-thiol MP SPE cartridge (StratoSpheres), washing through with additional CH2Cl2. The filtrate was re-concentrated and the residue purified using a RediSep® silica gel column to afford the title compound as a yellow solid. tR: 5.43 min (HPLC 1); ESI-MS: tR=1.37 min, [M+H]+ 530/532/534 (LC-MS 1); TLC: Rf=0.29 (1:1 EtOAc/heptanes); 1H-NMR (d6-DMSO, 600 MHz): 8.15 (br s, 1H), 7.95 (m, 1H), 7.77 (m, 2H), 7.37 (m, 2H), 7.31 (d, 1H), 7.24 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 3.85 (m, 1H), 3.85 (s, 3H), 1.91 (s, 3H), 1.29 (m, 3H), 0.46 (m, 3H).
Reaction SMILES: O=[C:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH3:19])[CH2:17][OH:18])[CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.I>>[CH:14]1[C:15]2[CH2:2][C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:9][C:10]=2[CH:11]=[CH:12][C:13]=1[CH:16]([CH3:19])[CH2:17][OH:18]
Reactant: CC(CO)c1ccc2oc3ccccc3c(=O)c2c1
Agent: I
Product: CC(CO)c1ccc2c(c1)Cc1ccccc1O2

Procedure:
10 g. of 2-(9-oxo-2-xanthenyl)-propanol is refluxed with 1 g. of red phosphorus in 50 ml. of hydriodic acid (b.p. 127°) for 4 hours. After the excess hydrogen iodide has been distilled off, 2-(2-xanthenyl)-propanol is obtained, m.p. 86°-89°.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:39]=[CH:38][C:31]([C:32](N(OC)C)=[O:33])=[CH:30][CH:29]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:32](=[O:33])[C:31]3[CH:38]=[CH:39][C:28]([Cl:27])=[CH:29][CH:30]=3)=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)(=[O:10])=[O:11])=[CH:13][C:14]=1[C:19]([F:21])([F:22])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Product: O=C(c1ccc(Cl)cc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by procedure analogous to that described in Example 29 using N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide and 4-chloro-N-methoxy-N-methyl-benzamide 1H NMR (400 MHz, CDCl3) δ10.61 (s, 1 H), 8.37 (m, 1 H), 8.16 (m, 1 H), 8.09 (m, 1 H), 7.84 (m, 1 H), 7.77-7.75 (m, 2 H), 7.53 (m, 1 H), 742-7.40 (m, 2 H), 7.23 (m, 1 H) MS: (M+H)/z=509.0.
Reaction SMILES: C[Mg]Br.O1CCC[CH2:5]1.[CH:9]([C:11]1[CH:29]=[C:14]2[C:15]([C:21]3[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[N:13]2[N:12]=1)=[O:10]>C1COCC1>[OH:10][CH:9]([C:11]1[CH:29]=[C:14]2[C:15]([C:21]3[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=3)=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[N:13]2[N:12]=1)[CH3:5]
Reactant: C1CCOC1
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C=O)nn12
Agent: C[Mg]Br
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)O)nn12
Temperature: 25 °C

Procedure:
A 0.90 mol/L methyl magnesium bromide-tetrahydrofuran solution (0.878 mL) was added dropwise to a solution of the compound of Example 237 (90.6 mg) in THF (15 mL) at −78° C. in an argon atmosphere. The mixture was allowed to gradually warm to room temperature. The reaction was quenched by adding a saturated aqueous solution of ammonium chloride and the mixture was extracted with THF (100 mL). The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The dried extract was concentrated and purified by recrystallization (methanol-ethyl acetate-hexane) to afford the title compound as a pale yellow powder (38.0 mg).
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15](C)=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].[C:38]([O-])([O-])=O.[K+].[K+]>CO.O>[F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH3:38])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(C)cn3S(=O)(=O)c2ccccc2)c1F
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C)cc3c2)c1F

Procedure:
2,6-Difluoro-N-(3-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.654 g, 1.19 mmol) was dissolved in MeOH (9 mL) and water (3 mL). K2CO3 (3.295 g, 23.84 mmol) was added, and the reaction mixture was stirred at reflux overnight. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to a solid. The solid was triturated with DCM to provide 2,6-difluoro-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide as a solid (148 mg, 30% for three steps). 1H NMR (400 MHz, DMSO-d6) δ 11.31 (br s, 1H), 10.85 (s, 1H), 9.79 (br s, 1H), 8.31 (br s, 2H), 7.51-7.57 (m, 1H), 7.24-7.29 (m, 2H), 3.11-3.15 (m, 2H), 2.26 (br s, 3H), 1.75-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-neg) M−1=407.2.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[C:21]([N+:27]([O-])=O)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[Pt]>[NH2:27][C:21]1[CH:20]=[C:19]([C:17]2[S:18][C:14]3[C:13]([C:33]4[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=4)=[C:12]([C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:31]([CH3:32])=[CH:30][C:15]=3[N:16]=2)[CH:24]=[CH:23][C:22]=1[NH:25][CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(NC)c([N+](=O)[O-])c3)sc2c1-c1ccc(Cl)cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(NC)c(N)c3)sc2c1-c1ccc(Cl)cc1

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-(methylamino)-3-nitrophenyl)benzo[d]thiazol-6-yl)acetate (510 mg) in EtOH (4 mL) and EtOAc (2 mL) was added 5% Pt/C (150 mg). The reaction mixture was flushed with hydrogen gas and stirred under hydrogen atmosphere (using a balloon) for 1.5 h. The mixture was filtered through celite and concentrated in vacuo and (S)-ethyl 2-(2-(3-amino-4-(methylamino)phenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate was used without further purification. LCMS-ESI+: calc'd for C29H33ClN3O3S: 538.2 (M+H+); Found: 538.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1([N:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#N.C[Mg+].[Br-].C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[OH:22][CH:19]1[CH2:20][CH2:21][N:16]([C:3]2([CH3:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(N2CCC(O)CC2)CC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
To a stirred solution of tert-butyl 4-cyano-4-(4-hydroxy-1-piperidyl)piperidine-1-carboxylate (5.8 g, 18.74 mmol) in THF (40 mL) was added a 1.4 M solution of MeMgBr in toluene/THF (26.8 mL, 37.48 mmol) at 0° C., and the mixture was stirred at room temperature for 12 h. The reaction was then quenched with saturated aqueous ammonium chloride and the mixture was extracted with dichloromethane (2×30 mL). The combined extracts were concentrated in vacuo to afford (5.42 g, 97%) the title compound, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:40])=[O:32]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C(Cl)Oc1ccccc1Cl
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Oc1ccccc1Cl

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-chlorophenyl chloroformate according to the procedure of Example 65. MS (ES) m/z 546.9.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[C:11]([NH:13][C:14](=[N:17]CCSCC1C=CNN=1)SC)#[N:12]>C(O)C>[C:11]([NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[NH:17])#[N:12]
Reactant: CSC(=NCCSCc1cc[nH]n1)NC#N
Reactant: NCCSCc1cc[nH]n1
Solvent: CCO
Product: N#CNC(=N)NCCSCc1cc[nH]n1

Procedure:
By the procedure of Example 18, reacting 3-[(2-aminoethyl)thiomethyl]pyrazole with dimethyl-N-cyanoimidodithiocarbonate and reacting the resulting N-cyano-N'-[2-(3-pyrazolylmethylthio)ethyl]-S-methylisothiourea with ammoniacal ethanol gives N-cyano-N'-[2-(3-pyrazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7](=[CH:11][O:12]C)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:14]#[N:15].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH:11]=[O:12])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:14]#[N:15]
Reactant: COC=C1CCc2c1ccc(F)c2C#N
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1c(F)ccc2c1CCC2C=O
Reaction time: 0.25 h

Procedure:
A solution of 5-Fluoro-1-(methoxymethylidene)-2,3-dihydro-1H-indene-4-carbonitrile (10 mg, 0.049 mmol) in DCM was cooled to −78° C. To this solution was dropped BBr3 (0.492 ml, 0.492 mmol). The mixture was allowed to stir for 15 minutes, and then it was diluted with DCM (10 mL), washed with NaHCO3, dried over Na2SO4, and concentrated. The residue was used directly in the next step.