Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1C[CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([CH2:29][CH:30]4[CH2:34][CH2:33][N:32]([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[C:31]4=[O:41])=[C:24]([Cl:42])[CH:23]=3)=[CH:18][CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.Cl.[O-]C#[N:47].[K+]>O1CCOCC1>[Cl:28][C:26]1[CH:27]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:14]([N:10]3[CH2:9][CH2:8][N:7]([C:6]([NH2:47])=[O:5])[CH2:12][CH2:11]3)=[O:15])=[CH:21][CH:20]=2)[CH:23]=[C:24]([Cl:42])[C:25]=1[CH2:29][CH:30]1[CH2:34][CH2:33][N:32]([CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[C:31]1=[O:41]
Reactant: N#C[O-]
Reactant: CC(C)(C)OC(=O)NC1CCCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)C1
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Product: NC(=O)N1CCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)CC1
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
Dissolve racemic 4-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.40, 0.65 mmol) in dioxane (20 mL), add 4N hydrochloric acid in dioxane (10 mL) and stir 30 min to obtain an orange residue in reaction vessel. Concentrate under vacuum, dilute residue with water (10 mL) and add potassium cyanate (0.55 g, 0.68 mmol). Stir the reaction at room temperature to obtain a white precipitate. Filter off solid and wash with water. Dissolve the solid in dichloromethane and concentrate under vacuum to yield a clear foam. Use resin bound solid phase acidic media (SCX) to remove residual starting material and obtain 0.168 g (46%) of product as a white solid: MS (m/z): 557 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:35][C:34](=[O:36])[N:33]([CH3:37])[N:32]=2)=[CH:27][CH:26]=1>C(O)C>[NH2:14][C:13]1[O:36][C:34]2[N:33]([CH3:37])[N:32]=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:35]=2[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:12]=1[C:11]#[N:15]
Reactant: N#CCC#N
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc(C2=NN(C)C(=O)C2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2nn(C)c3c2C(c2ccc(OC)cc2)C(C#N)=C(N)O3)cc1
Reaction time: 0.02 h
Yield: 62 %

Procedure:
A mixture of anisaldehyde (350 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 3-(4-methoxyphenyl)-1-methyl-1H-pyrazol-5(4H)-one (689 mg, 2.87 mmol, 1 equiv.). The reaction mixture was concentrated after 24 h and the precipitate was washed with ethanol and hexanes, and then re-crystallized from ethanol to give 6-amino-3,4-bis(4-methoxyphenyl)-1-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (690 mg, 1.78 mmol, 62%) as a white solid. 1H-NMR (400 MHz) DMSO: 7.42-7.40 (d, 2H), 7.05-7.03 (d, 2H), 7.00 (s, 2H), 6.78-6.75 (dd, 4H), 4.86 (s, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.66 (s, 3H), 13C-NMR (100 MHz) DMSO: 159.0, 158.9, 158.3, 145.9, 144.5, 136.9, 128.9, 127.7, 125.9, 120.6, 114.1, 113.9, 95.3, 60.3, 55.4, 55.3, 37.5, 34.3; LC/MS-MS: 389.2→323.0 m/z; GS1 and GS2 at 30, DP=66, CE=29, CXP=22, tR=3.94 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:20]1([CH2:26][CH2:27][CH:28]=[CH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][CH:17]([CH3:19])[CH2:16][N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([CH:29]=[CH:28][CH2:27][CH2:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1
Reactant: C=CCCc1ccccc1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Product: CC(C)Cn1cnc2c(N)nc3ccc(C=CCCc4ccccc4)cc3c21
Yield: 51.7 %

Procedure:
8-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 9.4 mmol) was treated with 4-phenyl butene (4.2 mL, 28.2 mmol) according to the method described in Part B of Example 425. The reaction was heated overnight. Following chromatographic purification (eluting with 95:5 chloroform:methanol), 1.8 g of 1-(2-methylpropyl)-8-(4-phenylbut-1-enyl)-1H-imidazo[4,5-c]quinolin-4-amine were obtained as an off-white solid.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([N:12](COC)[S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[S:10][CH:11]=2)[CH:2]=1.Cl.O>O1CCCC1>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[S:10][CH:11]=2)[CH:2]=1
Reactant: COCN(c1nc(-c2cccc(-c3ccccc3)c2)cs1)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(-c4ccccc4)c3)cs2)cc1
Yield: 45.9 %

Procedure:
A solution of 0.29 g of N-(4-biphenyl-3-yl-thiazol-2-yl)-N-methoxymethyl-4-methyl-benzenesulfonamide in 6 ml of tetrahydrofuran was stirred at room temperature for 6 hours after the addition of 1.5 ml of 6N hydrochloric acid. The reaction mixture was added to 40 ml of water and extracted with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and concentrated. Recrystallization from 10 ml of 50% ethanol yielded 120 mg of N-(4-biphenyl-3-yl-thiazol-2-yl)-4-methyl-benzenesulfonamide as colorless crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:17][OH:18]>>[Si:1]([O:8][CH2:9][C:10]1[O:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)o1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)o1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1d) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-2-furonitrile (7.5 g, 32 mmol) that was obtained in Example 2 (2a) and a 40% aqueous solution of hydroxylamine (4.0 ml). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1) as the eluent to afford the title compound (8.1 g) in a yield of 95% as a white crystalline solid.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)=[O:17])C(=O)C=1)C1C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][NH:39][C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1.BrCC(C1C=CC(CO)=CC=1)=O>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][N:39]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)=[O:17])[C:38](=[O:42])[CH:37]=2)=[N:32][CH:33]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cn[nH]1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Agent: O=C(CBr)c1ccc(CO)cc1
Product: O=C(Cn1ncc(OCc2ccc(Cl)cn2)cc1=O)c1ccc(CO)cc1

Procedure:
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 15b from 450 mg (1.89 mmol) 5-(5-chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 18b) and 477 mg (2.08 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 15a).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].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>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:17]#[N:18])[C:10]=2[N:9]=[CH:8]1
Reactant: Brc1cccc2c1ncn2C1CCCCO1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2c1ncn2C1CCCCO1
Temperature: 85 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
A mixture of 54 (1.30 g, 4.62 mmol), Zn(CN)2 (1.08 g, 9.24 mmol), Pd(PPh3)4 (0.53 g, 0.46 mmol) and NMP (15 mL) was stirred under nitrogen at 85° C. for 14 h. The mixture was filtered and the filtrate was purified by reverse phase chromatography eluting with 35% MeCN/H2O (containing 0.5% ammonia) to afford 0.75 g (70%) 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-4-carbonitrile (56) as brown solid: MS (ESI) m/z=228.3 [M+l]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=1[NH2:22]>C(O)(C)C>[ClH:1].[F:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc(N)c(F)c1
Solvent: CC(C)O
Product: COCCOc1cc2ncnc(Nc3ccc(C)cc3F)c2cc1OC
Product: Cl
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture of 4chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (107 mg, 0.4 mmol), (prepared as described for the starting material in Example 14), and 2-fluoro4-methylaniline (50 mg, 0.4 mmol) in isopropanol (7 ml) was heated at reflux for 2 hours. The mixture was allowed to cool to ambient temperature, the precipitated solid was collected by filtration, washed with isopropanol add ether and dried to give 4-(2-fluoro-4-methylanilino)-6-methoxy-7(2-methoxyethoxy)quinazoline hydrochloride (95 mg, 60%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[O:7].[CH3:18][NH:19][NH:20][C:21](=[O:25])[CH:22]([F:24])[F:23]>C1(C)C=CC=CC=1>[F:23][CH:22]([F:24])[C:21]([NH:20][N:19]([CH3:18])[C:6]([NH:5][CH2:4][C:3]1[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:7])=[O:25]
Reactant: CNNC(=O)C(F)F
Reactant: Cc1ccc(-c2ccccc2)cc1CN=C=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)cc1CNC(=O)N(C)NC(=O)C(F)F
Temperature: 60 °C

Procedure:
1.00 g of crude 2-methyl-5-phenylbenzyl isocyanate is added to 5 ml of toluene, and to the resulted suspension is added 556 mg of N′-methyl-difluoroacetohydrazide, and the mixture is stirred at 60° C. The reaction solution is concentrated, and the residue is subjected to silica gel column chromatography, to obtain 1-difluoroacetyl-2-methyl-4-(2-methyl-5-phenylbenzyl) semicarbazide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C>[CH3:34][S:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.40 mmol of methanesulfonyl chloride in 3 ml of DMF were added. The reaction solution was then stirred at room temperature for a further 6 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([O:7][C:8]2[C:16]3[C:15]4[CH:17]=[C:18]([C:21]#[N:22])[N:19]=[CH:20][C:14]=4[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:12]=3[N:11]=[CH:10][CH:9]=2)[CH2:2]1.I[CH2:32][CH3:33]>C(#N)C.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH2:32]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([O:7][C:8]2[C:16]3[C:15]4[CH:17]=[C:18]([C:21]#[N:22])[N:19]=[CH:20][C:14]=4[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:12]=3[N:11]=[CH:10][CH:9]=2)[CH2:2]1)[CH3:33]
Reactant: CCI
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(O[C@@H]3CCCNC3)ccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCN1CCC[C@@H](Oc2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 50 °C

Procedure:
To a solution of (R)-4-(piperidin-3-oxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (84 mg, 0.20 mmol) in acetonitrile (1.0 mL) was added iodoethane (24 uL, 0.30 mmol), and the mixture was heated at 50° C. for 18 hours. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 4 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as a yellow oil, which was used in the next step without any further purification (46 mg, 51%).
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[C:36]2=[O:47])[S:28][C:29]=1[C:30]([O:32]CC)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[C:36]2=[O:47])[S:28][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1sc(N2CCN(CC3CCCCO3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(CC3CCCCO3)C2=O)sc1C(=O)O
Yield: 84 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-((tetrahydro-2H-pyran-2-yl)methyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 84% yield: 1H NMR (300 MHz, DMSO-d6) δ 3.96-3.91 (m, 2H), 3.85-3.78 (m, 1H), 3.65-3.54 (m, 2H), 3.46-3.34 (m, 1H), 3.32-3.24 (m, 1H), 3.17-3.09 (m, 2H), 2.47 (s, 3H), 1.86-1.70 (m, 1H), 1.49-1.37 (m, 4H), 1.18-1.04 (m, 1H); MS (ES+) m/z 326.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[C:34]1([S:40]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([N:17]4[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]5[CH2:25][CH2:26][CH2:27][CH:18]45)(=[O:16])=[O:15])=[CH:12][CH:13]=3)=[CH:4][CH:3]=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)C1CC2CCCC2N1S(=O)(=O)c1ccc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.5 mmol of benzenesulfonyl chloride in 6 ml of DMF were added. The reaction solution was then stirred at RT for a further 12 h. The crude product was purified using chromatographic methods.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Br:19][C:20]1[N:21]=[C:22]([CH3:25])[NH:23][CH:24]=1>>[Br:19][C:20]1[N:21]=[C:22]([CH3:25])[N:23]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:24]=1
Reactant: Cc1nc(Br)c[nH]1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cc(Br)nc2C)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)pyrimidine (example A.12) (0.4 g, 1.47 mmol) and commercially available 4-bromo-2-methylimidazole (0.35 g, 2.17 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.41 g, 70%). MS (ISP) 399.0 [(M+H)+]; mp 180° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:65]([O:67][C:68]([C:70]1[N:71]=[C:72]([NH2:75])[S:73][CH:74]=1)=[O:69])[CH3:66]>C(Cl)Cl>[CH2:65]([O:67][C:68]([C:70]1[N:71]=[C:72]([NH:75][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[S:73][CH:74]=1)=[O:69])[CH3:66]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CCOC(=O)c1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1csc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.22 mmol) in methylene chloride (10 mL), HATU (Aldrich, 83 mg, 0.25 mmol) was added followed by the addition of DIPEA (100 uL) and 2-amino-thiazole-4-carboxylic acid ethyl ester (Oakwood, 43 mg, 0.25 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 40-80% EtOAc/hexanes) to give a solid. 32 mg.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:21][C:22]([C:25]1[CH:26]=[CH:27][C:28]([O:33][C:34]([F:37])([F:36])[F:35])=[C:29]([CH:32]=1)[CH:30]=O)([F:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:30][C:29]2[CH:32]=[C:25]([C:22]([F:24])([F:21])[CH3:23])[CH:26]=[CH:27][C:28]=2[O:33][C:34]([F:35])([F:37])[F:36])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Reactant: CC(F)(F)c1ccc(OC(F)(F)F)c(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 156.8 %

Procedure:
To a stirred solution of Compound 12 (500 mg, 1.81 mmol) and Compound 25 (552 mg, 2.17 mmol) in dry CH2Cl2 (10 ml) was added sodium triacetoxyborohydride (1.15 g, 5.43 mmol) portionwise at room temperature. Then to this was added acetic acid (109 mg, 1.81 mmol) at same temperature. The reaction mixture was stirred at room temperature for 66 h. The reaction mixture was basified to pH10-11 with 10% NaOH aq. with ice-cooling. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with brine, dried (MgSO4), and concentrated in vacuo to give crude product (1.46g) as a pale yellow oil. This was employed for the next step without further purification.
Reaction SMILES: N/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].Cl.[CH:8]1([NH:12][NH2:13])[CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([N:12]2[C:4]([NH2:5])=[CH:3][C:2]([CH3:6])=[N:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: NNC1CCC1
Reactant: C/C(N)=C/C#N
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)n(C2CCC2)n1
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
(2Z)-3-Amino-2-butenenitrile (1.339 g, 16.31 mmol) and cyclobutylhydrazine HCl (2 g, 16.31 mmol) were added to ethanol (20 mL) and heated at 75° C. for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude residue was suspended in saturated NaHCO3 (30 mL) and EtOAc (50 mL), and stirred for 10 min. The phases were separated and the aq. phase extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0 to 5% EtOAc:DCM, then gradient to 100% EtOAc). The final product was collected as 0.4 g (16%). LCMS E-S (M+H)═:152.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-2.00 (m, 2H) 2.21 (s, 3H) 2.32-2.43 (m, 2H) 2.69 (ddd, J=10.55, 9.41, 2.53 Hz, 2H) 3.26-3.55 (br s, 2H) 4.48-4.59 (m, 1H) 5.36 (s, 1H)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: IC1CCOCC1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC3CCOCC3)cc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8) and 4-iodotetrahydro-2H-pyran (Maybridge) by General Procedure N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:15](=[O:27])[CH:16]([C:18]3[CH:23]=[CH:22]C(C#N)=[C:20]([F:26])[CH:19]=3)[CH3:17])=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:32].[Na+].Cl.[CH3:35][CH2:36][OH:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][NH:14][C:15](=[O:27])[CH:16]([C:18]3[CH:23]=[CH:22][C:35]([C:36]([OH:32])=[O:37])=[C:20]([F:26])[CH:19]=3)[CH3:17])=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(C#N)c(F)c1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(C(=O)O)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution compound N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(4-cyano-3-fluorophenyl)propanamide (870 mg, 1.930 mmol) in EtOH was added 2N NaOH (9.7 ml, 19.300 mmol). The reaction mixture was stirred overnight at 100° C. and then was cooled to room temperature. The mixture was acidified with 10% HCl solution and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure compound 4-(1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylamino)-1-oxopropan-2-yl)-2-fluorobenzoic acid (550 mg, 61%).