Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[Cl:10][C:11]1[C:12]([C:13]([NH:1][C:2]2[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[O:14])=[CH:16][CH:17]=[CH:18][N:19]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Cc1ccnc(Cl)c1N
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl

Procedure:
3-Amino-2-chloro-4-methylpyridine of Formula A is condensed with 2-chloronicotinoyl chloride of Formula B to give 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of Formula II, which is then reacted with cyclopropylamine to give N-(2-chloro-4-methyl-3-pyridyl)-2 -cyclopropylamino) -3-pyridine carboxamide of Formula III. Then N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide was cyclized in the presence of sodium hydride to give nevirapine of Formula I. The disadvantage of the above process is use of large excess of cyclopropylamine. Further, with the above process undesirable side products are obtained during the reaction, which makes the product impure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29](Cl)[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=2)[N:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=2)[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:24]=1
Reactant: COc1cccc(C(Cl)c2cccc(Br)n2)n1
Reactant: c1cncc(Cc2cccnc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(C(c2cccc(Br)n2)C(c2cccnc2)c2cccnc2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(pyridine-3-ylmethyl)pyridine (2 g, 11.75 mmol) in anhydrous THF (40 mL) @ −78° C. under N2. was added LDA (9.79 mL, 1.8 M) dropwise. The mixture was stirred @ −78° C. for 1 hr and 2-bromo-6-[chloro(6-methoxypyridin-2-yl)methyl]pyridine was added. The mixture was warmed to 0° C. and stirred for 2 hr. The reaction was quenched with saturated aqueous NH4Cl, and extracted 3× with EtOAc. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (1-5% MeOH in CH2Cl2) to give 2-bromo-6-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridine. 1H NMR (500 MHz, CDCl3) δ 8.51 (t, 2H, J=2.7), 8.36-8.28 (m, 2H), 7.69 (dt, 1H, J=8.1, 2.0), 7.58 (dt, 1H, J=8.0, 1.9) 7.50 (d, 1H, J=7.6), 7.38-7.30 (m, 2H), 7.18 (d, 1H, J=7.8), 7.13 (dd, 1H, J=7.9, 4.8), 7.09 (dd, 1H, J=7.8, 4.9), 6.86 (d, 1H, J=7.3), 6.45 (d, 1H, J=8.1), 5.27 (d, 1H, J=12.2), 5.06 (d, 1H, J=12.5), 3.95 (s, 3H), LRMS m/z (M+H) Calcd.: 447.1, found: 447.1. The racemic mixture was separated by ChiralPak AD (40% EtOH in Hexanes+DEA 1 mL/L). The first peak was enantiomer A of 2-bromo-6-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridine, and the second peak was enantiomer B of 2-bromo-6-[1-(6-methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridine.
Reaction SMILES: O.N1(O)C2C=CC=CC=2N=N1.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.[NH2:22][C:23]1[N:27]([C@@H:28]2[CH2:33][CH2:32][C@H:31]([C:34]([NH:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[C:26]2[CH:40]=[C:41]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:42]=[CH:43][C:25]=2[N:24]=1>C(Cl)Cl>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](/[N:22]=[C:23]2\[NH:24][C:25]3[CH:43]=[CH:42][C:41]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[CH:40][C:26]=3[N:27]\2[C@H:28]2[CH2:33][CH2:32][C@@H:31]([C:34](=[O:35])[NH:36][CH:37]([CH3:39])[CH3:38])[CH2:30][CH2:29]2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2c(N)nc3ccc(N4CCOCC4)cc32)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(N4CCOCC4)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of TEA (0.091 mL, 0.654 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (100 mg, 0.654 mmol) in DCM (2 mL) was added 4-fluorobenzoyl chloride (0.064 mL, 0.545 mmol) dropwise, and the reaction was stirred at RT for 30 minutes. After 30 minutes, the suspension was added to a solution of cis-4-(2-amino-6-morpholino-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide (210 mg, 0.545 mmol) in DCM (5 mL). The reaction was stirred at RT. After 3 days, the reaction mixture was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-10% MeOH in DCM, to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a grey powder (95 mg, 34.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.57 (s, 1H), 8.29 (dd, J=6.1, 8.8 Hz, 2H), 7.73 (d, J=7.5 Hz, 1H), 7.44 (s, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.24 (dd, J=8.8 Hz, 8.8 Hz, 2H), 6.87, (d, J=8.8 Hz, 1H), 4.94 (brs, 1H), 3.90-3.99 (m, 1H), 3.78 (t, J=4.7 Hz, 4H), 3.18 (t, J=4.8 Hz, 4H), 2.74-2.84 (m, 2H), 2.55 (brs, 1H), 2.03-2.11 (m, 2H), 1.67-1.78 (m, 2H), 1.54-1.63 (m, 2H), 1.10 (d, J=6.5 Hz, 6H). MS, m/z (C28H34FN5O3): calcd, 507.3. found, 507.9 [M+H].
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][CH:62]=[CH:63][C:64]1[CH:69]=[CH:68][C:67]([Br:70])=[CH:66][CH:65]=1.FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][CH:62]=[CH:63][C:64]3[CH:69]=[CH:68][C:67]([Br:70])=[CH:66][CH:65]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: N=C(OCC=Cc1ccc(Br)cc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(Br)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg in 6 ml 33% methylene chloride in cyclohexane), p-bromocinnamyl trichloroacetimidate (135 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (7 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 1 hour the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×20 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (19 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[Na+].C(O)(=O)C.CN([CH:20]=[N:21][C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)C>O1CCOCC1>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:22]([C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[N:21][CH:20]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)C=NC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2ncnn2-c2ccc(Br)cc2)cc1

Procedure:
To a solution of 12.1 g. of 4-bromophenylhydrazine hydrochloride in a mixture of 10.9 ml. of 5 N sodium hydroxide, 100 ml. of 30% aqueous acetic acid and 50 ml. of p-dioxane is added 10.0 g. of N-(dimethylaminomethylene)-p-nitrobenzamide. The procedure of Example 2 is followed, giving 12.7 g. of the desired product as tan crystals, mp. 142°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([CH:14]=[O:15])[N:13]=1
Reactant: OCc1csc(-c2c(Cl)cccc2Cl)n1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: O=Cc1csc(-c2c(Cl)cccc2Cl)n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 102.1 %

Procedure:
To a stirred solution of (2-(2,6-dichlorophenyl)thiazol-4-yl)methanol (5.8 g, 22 mmol) in EtOAc (200 mL) at room temperature was added 2-iodoxybenzoic acid (12.5 g, 44.6 mmol). The resulting mixture was warmed to 70° C. and stirred for 18 hours. The solid was removed via filtration, and the filtrate concentrated under reduced pressure to afford the desired product as a white solid (5.8 g, ˜100% yield), which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[C:6]2[CH:12]=[CH:11][S:10][C:7]=2[NH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]2[S:10][CH:11]=[CH:12][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c([N+](=O)[O-])c[nH]c2sccc12
Product: O=[N+]([O-])c1cnc2sccc2c1Cl
Temperature: 115 °C
Yield: 94 %

Procedure:
A mixture of 3.4 g of 5-nitrothieno[2,3-b]pyridin-4(7H)-one 6 and 34 ml of phosphorus oxychloride is heated at 115° C. (bath temperature) for 1 hour and evaporated to dryness in vacuo. The residue is taken up in chloroform and washed with water. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel. Elution with dichloromethane-ether (50:1 v/v) affords 3.51 g (94%) of Compound 7 as crystals melting at 110°-113° C.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([O:19][CH3:20])=[O:18])[N:14]=2)[CH2:7]1)(=O)=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+]>CN(C)C=O>[C:21]([S:23][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([O:19][CH3:20])=[O:18])[N:14]=2)[CH2:9]1)(=[O:24])[CH3:22]
Reactant: COC(=O)NCc1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCc1csc(N2CC(SC(C)=O)C2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 105.3 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(methoxycarbonylamino-methyl)-1,3-thiazol-2-yl]azetidine (448 mg, 1.39 mmol) (obtained as described in Reference Example 63(3)) in dimethylformamide (13 ml) was added potassium thioacetate (952 mg, 8.34 mmol) at room temperature, and the mixture was stirred in an oil bath (90° C.) for 6 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 3-acetylthio-1-[4-(methoxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (441 mg, yield 100%) as a pale brown solid.
Reaction SMILES: O.[CH2:2]([O:4][C:5](=[O:27])[CH2:6][CH:7]1[O:11][B:10]([OH:12])[C:9]2[CH:13]=[C:14]([O:18][C:19]3[S:20][C:21]([N+:24]([O-])=O)=[N:22][N:23]=3)[CH:15]=[C:16]([CH3:17])[C:8]1=2)[CH3:3]>Cl.C(O)C.[Fe]>[CH2:2]([O:4][C:5](=[O:27])[CH2:6][CH:7]1[O:11][B:10]([OH:12])[C:9]2[CH:13]=[C:14]([O:18][C:19]3[S:20][C:21]([NH2:24])=[N:22][N:23]=3)[CH:15]=[C:16]([CH3:17])[C:8]1=2)[CH3:3]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 108.9 %

Procedure:
Concentrated HCl (10 drops) and water (12 ml) were added to a mixture of [6-(5-nitro-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.65 g, 1.71 mmol) and iron powder (0.479 g; 8.55 mmol) in ethanol (30 mL) at room temperature. The resulting mixture was stirred at 85° C. for 1.5 hours, cooled to room temperature and filtered through a pad of celite. The filtrate was evaporated and the residue dissolved in EtOAc (300 mL), washed with brine, dried over Na2SO4 and concentrated to give [6-(5-amino-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.650 g, 100%) which was used without further purification. 1HNMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.33 (d, J=12.4 Hz, 1H), 7.18 (d, J=16.8 Hz, 1H), 5.51 (d, J=6.0 Hz, 1H), 4.02 (q, J=7.2 Hz, 2H), 3.10 (d, J=14.4 Hz, 1H), 2.33-2.31 (m, 1H), 2.30 (s, 3H), 1.10 (t, J=7.6 Hz, 3H). MS (ESI) m/z=350 [M+H]+.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[CH:42][CH:43]3[CH2:45][CH2:44]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C=CCCC)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:41][CH2:42][CH:43]3[CH2:45][CH2:44]3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=CC3CC3)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Agent: CCCC=Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: C[Si](C)(C)CCOCn1ncc2c(c(CCC3CC3)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Yield: 93.6 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 68-(b) except for using 0.47 g (0.71 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-cyclopropylvinyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 70-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(1-pentenyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 0.44 g of the title compound was obtained as a colorless oil. (Yield: 94%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:26]([C:23]4[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=4)(=[O:28])=[O:27])=[CH:3][CH:4]=3)[N:9]=[CH:10][C:11]=12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)Nc2ccc(-n3ncc4c(N)ncnc43)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.7 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (36 mg, 1.1 eq, 0.16 mmol), 4-methoxybenzenesulphonylchloride (30 mg, 1.0 eq, 0.15 mmol) and diisopropylethylamine (25 μl, 1.0 eq, 0.15 mmol) were added to DMF (1 ml) and the mixture was stirred for 15 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant solid was purified by semi-preparative HPLC to yield the title compound as a white solid (40 mg, 0.10 mmol, 70%). LCMS: [M+H]+=397, Rt=1.66 min, 100% purity.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH:14]=O)=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:14][C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=4)=[N:10][NH:11][CH:12]=3)[CH2:31][CH2:30]2)[CH:24]=1)=[O:21]
Reactant: O=Cc1c[nH]nc1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]nc3-c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 471.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH:23]1([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[C@H:27]([CH3:26])[CH2:31][O:30][C:29]5=[O:32])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[CH:18][CH:19]=2)[CH2:25][CH2:24]1
Reactant: O=C(c1ccc(Br)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Reactant: C[C@@H]1COC(=O)N1
Product: C[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(Oc3ccc(C4CC4)cc3)CC2)cn1
Yield: 59.8 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(4-cyclopropylphenoxy)piperidin-1-yl]methanone (401 mg) described in Preparation Example 152 and (R)-4-methyloxazolidin-2-one (111 mg) described in Preparation Example 25, the title compound (252 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[NH:19]1[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]1>>[O:25]=[S:22]1(=[O:26])[CH2:23][CH2:24][N:19]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)N3CCS(=O)(=O)CC3)s2)noc1C(F)(F)F
Yield: 80 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and thiomopholine 1,1-dioxide by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (157 mg, 80%). 1H NMR (DMSO-d6) 2.34 (d, J=1.7, 3 H), 3.27 (obs m, 4 H), 4.00 (m, 4 H), 7.58 (d, J=3.5, 1 H), 7.68 (d, J=4.0, 1 H). 13C NMR (incomplete, F-coupled carbons obscured by baseline noise due to poor solubility) 8.0, ˜44 (br), 51.5, 116.6, 128.0, 130.0, 130.8, 139.6, 158.5, 162.7. 19F NMR −62.2. LC/MS 5.80 min, [M+1]+ 395.
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)\[CH2:8][CH2:9][CH3:10].[OH-].[Na+]>CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[C:7](/[CH2:8][CH2:9][CH3:10])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1
Reactant: CCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Yield: 76.5 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4-octadienoic acid methyl ester (6.7 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 3 hours reaction was worked up in the usual way and the crude acid crystallized from 2-propanol-hexane to provide 4.85 g of (E,E)-5-(4-methoxyphenyl)-2,4-octadienoic acid, mp 151°-152.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[CH:5][C:6]2[N:10]([C:11]3[CH:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[NH:13][N:12]=3)[CH:9]=[N:8][C:7]=2[CH:19]=1.[C:30](O)(=[O:32])[CH3:31]>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([N:10]3[C:6]4[CH:5]=[C:4]([NH:20][C@H:21]([C:23]5[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=5)[CH3:22])[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])=[CH:19][C:7]=4[N:8]=[CH:9]3)[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1cc2c(cc1CN)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCc1cc2ncn(-c3cc(C4CC4)[nH]n3)c2cc1N[C@@H](C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A round bottom flask was charged with 6-(aminomethyl)-3-(5-cyclopropyl-1H-pyrazol-3-yl)-N-((S)-1-(4-fluorophenyl)ethyl)-3H-benzo[d]imidazol-5-amine (Example 42; 0.10 g, 0.256 mmol) and acetic acid loaded TFP resin (1.0 mmol/g loading, 0.256 g, 0.256 mmol) in mixture of THF-DCM (1:1, 3 ml) at 0° C. The resulting solution was stirred vigorously at 0° C. for 1 hour and filtered through a Jones tube. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml). After removal of solvent, the residue was purified by column chromatography (EtOAc-MeOH=20:1) to give the title compound as an off-white solid (0.083 g, 75%). 1H NMR (400 MHz) 12.67 (s, 1H), 8.50 (m, 1H), 8.18 (s, 1H), 7.39 (m, 3H), 7.11 (m, 2H), 6.73 (s, 1H), 6.09 (d, J=6.0 Hz, 1H), 5.96 (s, 1H), 4.53 (m, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 1.93 (m, 1H), 1.93 (s, 3 h), 1.47 (d, J=6.4 Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 432; Found: [M+H]+ 433.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](Br)[CH:26]=1.CC([O-])=O.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[CH:24]=[N:23][CH:22]=[C:21]([Br:20])[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1c(-c2cncc(Br)c2)cc2ccccc21
Temperature: 80 °C
Yield: 24.5 %

Procedure:
1-(tert-Butoxycarbonyl)indole-2-boronic acid (900 mg, 3.5 mmol), 3,5-dibromo-pyridine (810 mg, 3.5 mmol), KOAc (1.01 g, 10.4 mmol) and Pd(dppf)Cl2 (252 mg, 0.35 mmol) are mixed in 1,4-dioxane (70 mL) and heated to 80° C. for 2 hours. The mixture is filtered and the filtrate is concentrated. The residue is dissolved in DCM and washed with water. The organic layer is separated, dried over Na2SO4, filtered and concentrated to afford the crude product which is purified by column chromatography to give 320 mg of 2-(5-bromo-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:8][CH2:9][CH:10]=[N:11][OH:12])[CH2:5][CH:6]=[CH2:7].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[N:11]1[O:12][CH2:7][CH:6]2[CH2:5][CH2:4][O:8][CH2:9][C:10]=12
Reactant: C=CCCOCC=NO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: C1CC2CON=C2CO1
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A 5% sodium hypochlorite solution (122 ml) was added dropwise to a solution of 3-butenyloxyacetaldehyde oxime (5.30 g) in dichloromethane (530 ml) under ice-cooling. After stirring at the same temperature for two hours, sodium thiosulfate was added. The aqueous layer was extracted with dichloromethane. The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (4.15 g).