Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8]CC)(=O)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:8][CH2:1][CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: C=CC=CCC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC=CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
A solution of ethyl hexa-3,5-dienoate (4.0 g, 28.6 mmol) in dry tetrahydrofuran (200 mL) was treated with a solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 28.6 mL, 28.6 mmol). The mixture was stirred at room temperature for 2 hours, and then quenched with water. The mixture was acidified with 1.0 N aqueous hydrochloric acid and extracted three times with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated to a yellow oil. 1H NMR (300 MHz, CDCl3) δ6.4-6.1 (m, 2H), 5.67 (m, 1H), 5.13 (d, J=17 Hz, 1H), 5.00 (d, J=11 Hz, 1H), 3.66 (t, J=6.6 Hz, 2H), 2.34 (q, J=6.6 Hz, 2H), 2.13 (broad s, 1H). The oil was dissolved in dichloromethane, cooled to 0° C. and treated with pyridine (10 mL) and p-toluenesulfonyl chloride (5.72 g, 30 mmol). The mixture was stirred for one hour, then warmed to room temperature and stirred for 3 hours. The mixture was then concentrated, and the residue was dissolved in ethyl acetate, washed sequentially with water, 1.0 N aqueous hydrochloric acid, 1.0 N aqueous sodium hydroxide, and saturated aqueous sodium chloride, then was dried over magnesium sulfate and concentrated to provide a yellow oil. This yellow oil was purified by flash column chromatography, eluting with 10% ethyl acetate/hexane, to give a colorless oil (3.84 g, 53%). 1H NMR (300 MHz, CDCl3) δ7.78 (d, J=8 Hz, 2H), 7.33 (d, J=8 Hz, 2H), 6.22 (td, J=17, 10 Hz, 1H), 6.04 (dd, J=11, 10 Hz, 1H), 5.10 (d, J=17 Hz, 1H), 5.02 (d, J=10 Hz, 1H), 4.05 (t, J=7 Hz, 2H), 2.44 (s+m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[N:15][C:16]([F:19])=[CH:17][CH:18]=2)([NH2:12])[C@@H:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](=[O:27])[NH:23][C:22]=1[C:28](O)=O>>[F:20][C:21]1[CH:26]=[CH:25][C:24](=[O:27])[NH:23][C:22]=1[C:28]1[NH:11][C@@H:9]([CH3:10])[C@:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([C:13]2[CH:14]=[N:15][C:16]([F:19])=[CH:17][CH:18]=2)[N:12]=1
Reactant: O=C(O)c1[nH]c(=O)ccc1F
Reactant: C[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)nc1
Product: C[C@@H]1NC(c2[nH]c(=O)ccc2F)=N[C@@]1(c1ccc(F)cc1)c1ccc(F)nc1

Procedure:
According to the method of Example 1, optically active (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine described in Reference Example 5–1 of WO 01/62738 was reacted with 3-fluoro-6-oxo-1,6-dihydro-2-pyridinecarboxylic acid to give the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[NH:19][C:20]([CH:22]=O)=[CH:21][C:13]2=3)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH2:33][C:34](=[O:40])[NH:35]3)[CH:28]=[CH:29][CH:30]=1>N1CCCCC1.C(O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[NH:19][C:20](/[CH:22]=[C:33]4\[C:34](=[O:40])[NH:35][C:36]5[C:32]\4=[C:31]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=4)[CH:39]=[CH:38][CH:37]=5)=[CH:21][C:13]2=3)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]c(C=O)cc32)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=O)N1CCC(C(=O)N2CCCCc3[nH]c(/C=C4\C(=O)Nc5cccc(-c6cccc(F)c6)c54)cc32)CC1
Yield: 53.9 %

Procedure:
4-(1-Acetyl-piperidine-4-carbonyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde (56 mg) was condensed with 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (40 mg) and piperidine (2 drops) in ethanol (1 mL) at rt for overnight. The solvent was concentrated and the residue was purified on a silica gel column to give 50 mg of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH:28]([CH3:30])[CH3:29]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Reactant: CC(C)CI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and 1-iodo-2-methylpropane.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=1[C:13]([O:15]C)=O)=O>C(O)(=O)C>[CH3:12][C:9]1[N:8]=[C:7]2[C:13](=[O:15])[NH:2][NH:3][CH:4]=[C:6]2[C:10]=1[CH3:11]
Reactant: NN
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c(=O)[nH][nH]cc-2c1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
1.50 g (0.030 mole) of hydrazine monohydrate were dropwised added slowly to a solution of 4.00 g (0.022 mole) of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate in 80 ml of acetic acid at room temperature and the resulting mixture was stirred at 110° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into ice-water. The resulting precipitates were collected by filtration and washed well with water. The precipitates were dissolved in dichloromethane and the solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 3.40 g of 2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-one as a grayish-white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:22])[CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:22][C:4]1[CH:3]=[C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 1) was reacted with 3-trifluoromethyl-phenyl boronic acid to give the title compound as off-white amorphous solid. MS: 431.4 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:17]=[CH:18][C:19]=1[OH:20].[OH-].[Na+]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:17]=[CH:18][C:19]=1[O:20][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1

Procedure:
The title compound is prepared in analogy to the procedure of Example XIV from 5.3 g (0.03 mol) of 2-chloromethylquinoline, 6 g (0.03 mol) of methyl 3-chloro-4-hydroxyphenylacetate and 1.2 g (0.03 mol) of sodium hydroxide.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]3[N:15]=[CH:16][N:17]=[C:18]4[C:25]=3[C:24]3[C@@H:23]([CH2:26][C:27]#[N:28])[CH2:22][CH2:21][C:20]=3[S:19]4)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:29]O>CO.C(Cl)Cl>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:14]3[N:15]=[CH:16][N:17]=[C:18]4[C:25]=3[C:24]3[C@@H:23]([CH2:26][C:27]([NH2:28])=[O:29])[CH2:22][CH2:21][C:20]=3[S:19]4)[CH2:11][CH2:12]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: N#CC[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Solvent: CO
Solvent: ClCCl
Product: NC(=O)C[C@H]1CCc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (120 mg, 0.30 mmol, 1.00 equiv) in methanol (8 mL) was added LiOR.H2O (37.8 mg, 0.90 mmol, 3.00 equiv) and H2O2 (30%, 0.5 mL) in an ice-water bath. The resulting solution was stirred for 2 h at room temperature and diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (20:1) to give 100 mg (80%) of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]amino]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide as a white solid. MS (ES): m/z 416 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.23 (s, 1H), 4.11-4.20 (m, 1H), 3.82-3.89 (m, 1H), 3.72 (s, 4H), 3.09-3.17 (m, 1H), 2.93-2.99 (m, 1H), 2.70-2.82 (m, 1H), 2.65 (s, 4H), 2.47 (s, 2H), 2.27-2.35 (m, 2H), 2.11-2.19 (m, 2H), 2.05-2.10 (m, 2H), 1.40-1.67 (m, 4H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[CH3:9][SH:10].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH3:9][S:10][CH2:2][CH2:1][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: C=Cc1cnccn1
Reactant: CS
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CSCCc1cnccn1

Procedure:
h. 2-Pyrazinyl-ethyl methyl sulfide was prepared by reacting vinylpyrazine [c.f. J.Org.Chem. 27, 1363 (1962)] with methylmercaptan by the action of ultra-violet light and in the presence of benzoyl peroxide by the method described in Acta Chem. Scand. 8, 295 (1954). The product was identified by mass spectrometry. It has a b.p. of 57°-69° C. at 0.05 mm. Hg.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:11]>>[NH2:11][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cccnc1Cl
Reactant: [NH4+]
Agent: [OH-]
Product: N#Cc1cccnc1N
Temperature: 120 °C

Procedure:
Add 100 mL ammonium hydroxide to a sealed tube containing 12.5 gm (90.21 mMol) 2-chloro-3-cyanopyridine. Seal the tube and heat the suspension at 120° C. for 6 hours. Cool the reaction mixture to room temperature and partition between ethyl acetate and saturated aqueous sodium bicarbonate. Extract the aqueous phase with ethyl acetate (3×100 mL) followed by 70:30 ethyl acetate:n-butanol (2×100 mL). Combine organic phases and concentrate under reduced pressure to provide 2-amino-3-cyanopyridine.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: S=C(NN=Cc1ccccc1)NC1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.4 %

Procedure:
To a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.55 mmol) and benzaldehyde (56 μl, 0.55 mmol) in ethanol (5 mL) was added a solution of sodium acetate (45 mg, 0.55 mmol) in water (1 mL) and the mixture was stirred at room temperature for 24 h. The mixture was diluted with water (1.5 mL) and the resultant precipitate was collected by filtration and isolated as a white solid (14 mg, 9%). 1H NMR (CDCl3): 9.84 (s, 1H), 7.88 (s, 1H), 7.64-7.61 (m, 2H), 7.50 (d, J=7.5 Hz, 1H), 7.42-7.40 (m, 3H), 6.24-6.14 (m, 2H), 4.314.26 (m, 1H), 3.06 (s, 1H), 2.96 (s, 1H), 1.94-1.86 (m, 1H), 1.67 (d, J=9.3 Hz, 1H), 1.52 (d, J=9.0 Hz, 1H), 1.46-1.39 (m, 1H).
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25]>>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[S:22][C:23]1[C:24](=[O:25])[O:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:27]=1[OH:28]
Reactant: Cc1cccc(C)c1SC(C(=O)O)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: Cc1cccc(C)c1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2,6-dimethylphenyl)thio]propanedioic acid (2.0 g, 6.8 mmol). m.p. 248°-249° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 6H), 6.75 (s, 1H), 7.08 (m, 3H), 7.39 (m, 3H), 7.78 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH2:27][C:28]1[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:27][C:28]1[S:29][C:30]([C:34]([NH:13][C:10]2[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]3[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[C:3]([O:2][CH3:1])[C:12]=3[N:11]=2)=[O:35])=[C:31]([CH3:33])[N:32]=1
Reactant: Cc1nc(N)sc1C(=O)O
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1sc(N)nc1C)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (100 mg, 0.28 mol) was dissolved in DMF (3 mL), and 2-amino-4-methylthiazole-5-carboxylic acid (44 mg, 0.28 mmol) was added. PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (0.15 mL, 0.83 mmol) were subsequently added, and the mixture was stirred at rt overnight. The mixture was purified by HPLC to give the title compound (6 mg, 4%): LC MS RT=1.06 min, MH+=500.1; 1H NMR (DMSO-d6) δ: 12.59 (1H, s), 7.55 (1H, d), 7.47 (1H, s), 6.98 (1H, d), 4.13 (2H, t), 3.93 (4H, m), 3.86 (3H, s), 3.55 (4H, t), 2.47 (3H, s), 2.45 (2H, t), 2.33 (4H, m), 1.93 (2H, m).
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[CH:12]=2)=[CH:7][CH:6]=1>C1COCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24][CH2:25][C:26]([OH:28])([CH3:1])[CH3:27])[CH:12]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(-n2nc(CCC(C)=O)cc2-c2ccc(Cl)cc2)cc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CCC(C)(C)O)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1 h

Procedure:
To a solution of MeMgBr (1.32 ml of 3.2M, 4.23 mM) in THF (15 ml) at 0° C., was added a solution of the ketone 23, (1.00 g, 2.82 mM) in THF (25 ml) dropwise over a 20 minute period. After stirring for 1 hour, the reaction mixture was quenched with a saturated NH4Cl solution, diluted to a 100 ml volume with Et2O, washed with H2O, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography of the residue (Baker silica gel, 45 g) with Et2O as eluent, afforded 27, (0.68 g, 80% corrected for recovered starting material) as a colorless oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[C:35]([OH:39])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: Nc1cccc(O)c1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2cccc(O)c2)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 19.6 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 15, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (28.8 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 20% (24 mg, 0.047 mmol) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[N+:16]([C:19]1[CH:30]=[CH:29][C:22]([CH2:23][C@@H:24]([C:26]([OH:28])=[O:27])[NH2:25])=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[C:26]([C@@H:24]([NH:25][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:23][C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:30][CH:29]=1)([OH:28])=[O:27]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Yield: 61 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 4-nitro-L-phenylalanine to provide the title compound in 61% yield as yellow needles (recrystallization from MeOH/water).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N1CCCC1
Yield: 48 %

Procedure:
N-Cyclopropyl-N-[1-(3-pyrrolidin-1-ylhexanoyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide (43) was prepared by reacting N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethyl-benzenesulfonamide (30) (250 mg, 0.56 mmol) and pyrrolidine (2 mL) as described in Example 26 above. The residue was chromatographed over flash silica eluting with ethyl acetate:methanol:ammonia (100:10:1) to give the title compound 43 as a white solid (140 mg, 48%). LC: 98.9%. m/z=516.3, 517.3 (M+H). 1H NMR (400 MHz, CDCl3): (1:1 mixture of rotamers) δ 8.14 (1H, s), 8.05 (1H, d, J=7.5 Hz), 7.86 (1H, d, J=7.5 Hz), 7.70 (1H, t, J=7.5 Hz), 4.75 (1H, d, J=15 Hz), 4.10 (1H, m), 3.97 (1H, d, J=15 Hz), 3.05 (2H, m), 2.65-2.45 (6H, m), 2.35 (1H, m), 1.96 (1H, m), 1.85-1.30 (16H, m), 0.98 (1H, m), 0.92-0.70 (6H, m).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[Cl:9]N1C(=O)CCC1=O>C1C=CC=CC=1>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([S:7][Cl:9])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: c1ccccc1
Product: Cc1ccc(SCl)cc1
Yield: 88.2 %

Procedure:
By the method of Preparation 5, 6.2 g. of p-toluenethiol (6.2 g., 50 mmoles) was reacted with N-chlorosuccinimide (6.67 g., 50 mmoles) in 100 ml. of benzene to yield p-toluenesulfenyl chloride (7.0 g.) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:41][C:40]([NH2:42])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH3:32])[CH3:31]>>[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:41][C:40]([NH:42][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:19])([F:21])[F:20])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])=[N:39][C:38]=1[CH3:43])(=[O:36])=[O:35])([CH3:32])[CH3:31]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 655.1 [(M−H)−]; mp 274° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][CH:9]([NH2:11])[CH2:8][CH:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([C:21]([NH2:23])=[O:22])=[CH:16][N:15]=1.O>CO>[Cl:13][C:14]1[N:19]=[C:18]([NH:11][CH:9]2[CH2:8][CH:7]3[N:3]([CH2:4][CH2:5][CH2:6]3)[C:2]([CH3:12])([CH3:1])[CH2:10]2)[C:17]([C:21]([NH2:23])=[O:22])=[CH:16][N:15]=1
Reactant: CC1(C)CC(N)CC2CCCN21
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: CC1(C)CC(Nc2nc(Cl)ncc2C(N)=O)CC2CCCN21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (±)-octahydro-5,5-dimethylindolizin-7-amine (0.65 g, 3.9 mmol) in MeOH (10 ml) was added to a stirred solution of 2,4-dichloropyrimidine-5-carboxamide (0.75 g, 3.9 mmol; prepared according to the procedure set forth in US patent application publication US20110130415, page 41) in MeOH (30 ml) and H2O (4 ml) at 0° C. under nitrogen. After complete addition, the mixture was slowly warmed to room temperature and stirred at room temperature overnight. The mixture was then concentrated in vacuo and the residue partitioned between EtOAc (150 ml) and 1N NaOH (100 ml). The aqueous layer was extracted with EtOAc (1×100 ml) and the combined organic extracts were dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was dry-loaded on to basic alumina (Brockmann grade IV) and then purified by column chromatography on basic alumina (Brockmann grade IV) using CH2Cl2/MeOH (1:0 to 95:5) as eluent to give the product (550 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](C3CCC3)=[O:18])[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[CH3:40][O:41]C(Cl)=O>>[CH3:40][O:41][C:17](=[O:18])[NH:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:12]([OH:24])[C@@H:13]1[OH:23]
Reactant: COC(=O)Cl
Reactant: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Product: COC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to cyclobutanecarboxylic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-amide (Intermediate K) by replacing cyclobutanecarboxylic acid chloride with methylchloroformate.