Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[S:2]1(=[O:14])=[O:13].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>CN(C)C=O.O.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[S:2]1(=[O:13])=[O:14]
Reactant: O=S1(=O)Nc2cccc3c2N1CCC3
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S1(=O)N(CCCCl)c2cccc3c2N1CCC3
Reaction time: 0.5 h
Yield: 77 %

Procedure:
1-(3-Chloropropyl)-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide can be obtained as follows: a solution of 5,6-dihydro-(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (4 g) in dry N,N-dimethylformamide (30 cc) is added dropwise to a suspension of sodium hydride (0.69 g, 80% suspension in oil) in N,N-dimethylformamide (20 cc). After 30 minutes' stirring, a solution of 1-bromo-3-chloropropane (3.25 g) in N,N-dimethylformamdide (20 cc) is added. The reaction mixture is stirred at 25° C. for 2 hours and is then diluted in a mixture of water (300 cc) and ethyl acetate (300 cc). The organic phase is washed with water (3×200 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 4-cm diameter, 50-cm height), and eluted at a pressure of 0.7 bars of nitrogen with a mixture of cyclohexane and ethyl acetate (80-20 by volume), 125-cc fractions being collected. Fractions 4 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 1-(3-chloropropyl)-5,6-dihydro-(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (4.2 g) in the form of a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:19]([N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[C:8](=[O:10])[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:13]([OH:14])=[C:12]([C:15]([CH3:16])([CH3:18])[CH3:17])[CH:11]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCNCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
To a stirred solution of 25 grams (0.1 mole) of 3,5-di-t-butyl-4-hydroxybenzoic acid and 12.9 grams (0.1 mole) of di-n-butylamine in 100 milliliters of dry tetrahydrofuran was added dropwise a solution of 20.6 grams (0.1 mole) of dicyclohexylcarbodiimide in 75 milliliters of dry tetrahydrofuran. The mixture was stirred for several hours and the white solid (dicyclohexyl urea) was filtered off and discarded. Evaporation of the filtrate gave a white solid, which was recrystallized from 1:1 benzene-hexane to give N,N-di-n-butyl-3,5-di-t-butyl-4-hydroxybenzamide; melting point 94°-95°C. When tested by the procedure of Example 2, the sample containing this compound lasted 1000 hours, about 3.3 times as long as the control.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:19]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 4-(dibenzylamino)benzoate (52 mg, 0.16 mmol) in a 2:1 mixture of THF/dH2O was added LiOH (10 mg, 0.48 mmol). Tetra-butyl ammonium hydroxide (2 mL, 0.1N solution in toluene/MeOH) was added to the reaction and allowed to stir at room temperature for 6 hours. The solvent was concentrated in vacuo and the reaction mixture was azeotroped with MeOH several times then placed on the high vacuum for 2 hours to dry to provide the desired 4-(dibenzylamino)benzoic acid which was confirmed by MS: cal'd 318.1 (MH+), exp 318.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH:26]([CH2:30][CH3:31])[CH2:27][O:28][CH3:29]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:25][CH:26]([CH2:27][O:28][CH3:29])[CH2:30][CH3:31])=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=1
Reactant: CCC(N)COC
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: CCC(COC)NC(=O)c1ccc(OC)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 2-amino-1-methoxybutane in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=3)=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH2:53][C:54]([O:56]CC)=[O:55])[N:10]=2)[N:5]=1)[CH3:3].[OH-].[Na+]>C(O)C.O>[ClH:1].[C:54]([CH2:53][O:52][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH2:2][CH3:3])[CH:13]=[C:12]2[O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:20][CH:21]=1)([OH:56])=[O:55]
Reactant: CCOC(=O)COc1ccc2nc(CC)cc(OCc3ccc(-c4ccccc4-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2nc(OCC(=O)O)ccc2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (2.7 ml) was added to a solution of 2-ethyl-6-(ethoxycarbonylmethoxy)-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (1.0 g) in ethanol (16 ml). The solution was heated at 50° C. for 2 hours and then cooled. 4M Sodium hydroxide solution (10 ml) was added and the solution was heated at 50° C. for 30 minutes and then diluted with water (50 ml). The solution was washed with ether (25 ml) and the aqueous phase was concentrated by evaporation. Water (10 ml) was added to the residue and the suspension was stirred for 1 hour. The insoluble solid was collected by filtration and dissolved in ethanol (7 ml). Concentrated hydrochloric acid was added and the resultant precipitate was collected by filtration to give 6-(carboxymethoxy)-2-ethyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine hydrochloride, m.p. 223°-225° C.; NMR (d6 -DMSO): 1.4(t, 3H), 3.1(q, 2H), 5.0(s, 2H), 5.6(s, 2H), 7.2(d, 2H), 7.4-7.8(m, 8H), 8.7(d, 1H); mass spectrum (+ve FAB, DMSO/NBA): 527 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[N:28]([Sn](CCCC)(CCCC)CCCC)=[N+:29]=[N-:30]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:27]=[CH:26][C:23]([C:24]5[NH:30][N:29]=[N:28][N:25]=5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Nc2nccc(-c3c[nH]nc3-c3ccc(Cl)cc3)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: Clc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(-c4nnn[nH]4)cc3)n2)cc1
Temperature: 160 °C
Reaction time: 117 h

Procedure:
The title compound is prepared starting from 4-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzonitrile. 4-{4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-benzonitrile (0.932 g; 2.5 mMol) is suspended in o-xylene (10 mL) and treated at rt with azidotributyltin (1.66 g; 1.37 mL; 5 mMol). After stirring the yellow suspension at 160° C. for 117 h the reaction mixture is filtered off without cooling and the crystals are washed with o-xylene. Since the reaction is still incomplete, the crude product is resuspended in o-xylene (20 mL) and treated at rt with azidotributyltin (1.37 mL; 5 mMol). After stirring the yellow suspension at 160° C. for 117 h the reaction mixture is filtered off without cooling and the crystals are washed with o-xylene. The crude product is suspended in methanol (1.00 mL), refluxed and filtered without cooling. The crude product is acidified with 4N HCL/methanol and extracted with ethyl acetate. The aqueous layer is basified with 4N NaOH (ca. pH 12) and extracted with ethyl acetate. Upon this treatment, the product precipitates from the aqueous layer and is filtered off to obtain the title compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:26])[CH:11]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2]2.C(#N)C.[Br:30][CH2:31][C:32]([C:34]1[O:38][N:37]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:35]=1)=[O:33]>C(OCC)(=O)C>[Br-:30].[CH2:19]([NH:18][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:10]([O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N+:1]([CH2:31][C:32]([C:34]3[O:38][N:37]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:35]=3)=[O:33])([CH2:8][CH2:7]2)[CH2:2]1)=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(NCc1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc(C(=O)CBr)on1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C(NCc2ccccc2)c2ccccc2)C3)on1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
Benzylamino-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (C80) (100 mg, 0.28 mmol) is dissolved in ethyl acetate (1.90 mL) and acetonitrile (0.95 mL) and ethyl 5-(2-bromoacetyl)isoxazole-3-carboxylate (82.0 mg, 0.31 mmol) is added. The orange solution is stirred at RT overnight. The suspension is evaporated and the crude is purified by flash chromatography (DCM/EtOH=93/7) to obtain the title compound as a pale brown solid (61 mg, 35% yield, bromide salt, mixture of diastereoisomers).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:16])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[OH:8].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:16][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]([O:8][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CN(C)CCC(O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCC(Oc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 116.1 %

Procedure:
2.85 g of sodium hydride in a 50% oil suspension were added at 20° C. to a solution of 6.32 g of α-[2-dimethylamino-ethyl]-4-chlorobenzene methanol in 60 ml of dimethylformamide and 5.1 g of p-chloronitrobenzene were added thereto under nitrogen. The mixture was stirred for 45 minutes and 100 ml of water were added thereto at 25° C. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness to obtain 11.5 g of N,N-dimethyl-γ-(4-nitrophenoxy)-4-chlorobenzene-propanamine in the form of an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[C:14]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:13]([CH3:27])[O:12][N:11]=1>N1C=CC=CC=1>[CH3:9][C:10]1[C:14]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[C:13]([CH3:27])[O:12][N:11]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(N)nc1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylpyridin-2-amine (54 mg, 0.5 mmol) in pyridine (5 mL) stirred at room temperature, was added 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (0.151 g, 0.5 mmol). The reaction was stirred at room temperature overnight. The solvent was then removed under a stream of nitrogen to give the crude product, which was used directly in the next reaction with no purification. LCMS (2 min, formic) Rt 0.84 min, m/z (ES+) 374 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:33][CH2:32][C:12]3([CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:13]3)[CH2:11][CH2:10]2)[N:3]=1.[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH2:44][NH2:45].CCN(CC)CC>C(O)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:45][CH2:44][C:35]2[CH:36]=[CH:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:34]=2)[N:5]=[C:4]([N:9]2[CH2:33][CH2:32][C:12]3([CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:13]3)[CH2:11][CH2:10]2)[N:3]=1
Reactant: CCOC(=O)C1CC2(CCN(c3nc(N)nc(Cl)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: NCc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)C1CC2(CCN(c3nc(N)nc(NCc4ccc5ccccc5c4)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-benzyl 3-ethyl 8-(4-amino-6-chloro-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (265 mg, 0.56 mmol) in isopropanol (3 mL) were added naphthalen-2-ylmethanamine (105 mg, 0.67 mmol) and Et3N (1.4 mL). The reaction mixture was heated to reflux for 12 h, then cooled to RT, and concentrated in vacuo. Purification by normal phase chromatography (CH2Cl2/MeOH) provided 2-benzyl 3-ethyl 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[S:20][CH:21]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:23]=2)[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[CH2:3]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[S:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[CH:23]=2)[CH2:17][CH2:18]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1csc(C2CCN(C(=O)OCc3ccccc3)CC2)c1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
Potassium hydroxide (0.52 g, 9.0 mmol) in water (2 mL) was added to a solution of 4-(4-ethoxycarbonyl-thiophen-2-yl)-piperidine-1-carboxylic acid benzyl ester (3.0 mmol) in IMS (6 mL). The reaction was stirred for 1 hour then partitioned between diethyl ether and water. The aqueous layer was acidified to pH 7 and further extracted with diethyl ether. The organic solution was dried over magnesium sulphate, filtered and the solvent removed to give the title compound (0.92 g). LCMS m/z 346 [M+H]+ RT=3.43 min (Analytical Method 4).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:9]([SnH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].CC(N=NC(C#N)(C)C)(C#N)C>C1COCC1>[CH2:18]([Sn:13]([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:14][CH2:15][CH2:16][CH3:17])/[CH:2]=[CH:1]/[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#Cc1cccnc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C/c1cccnc1)(CCCC)CCCC
Yield: 53 %

Procedure:
3-Ethynyl-pyridine (1.03 g, 10 mmol) and tributyltin hydride (3.2 mL, 12 mmol) were stirred in dry THF (10 mL) with a catalytic amount of AIBN at 50° C. for 18 h. The solution was concentrated in vacuo and purified by silica gel chromatography (10% EOAc/hexanes) to give 2.09 g (53%) of the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ8.61 (s, 1H), 8.45 (d, 1H, J=3.2 Hz), 7.75 (d, 1H, J=7.6 Hz), 7.25-7.29 (m, 1H), 6.93 (AB q, 2 H, J=57.2, 19.6 Hz), 1.49-1.59 (m, 6H), 1.28-1.39 (m, 6H), 0.87-1.00 (m, 15H).
Reaction SMILES: [NH:1]([CH2:7][CH2:8][CH2:9][C:10]#[N:11])[CH2:2][CH2:3][CH2:4][C:5]#[N:6].C(N(CC)CC)C.[CH2:19]([O:21][P:22](Cl)([O:24][CH2:25][CH3:26])=[O:23])[CH3:20]>ClCCl>[CH2:19]([O:21][P:22]([N:1]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:7][CH2:8][CH2:9][C:10]#[N:11])([O:24][CH2:25][CH3:26])=[O:23])[CH3:20]
Reactant: N#CCCCNCCCC#N
Reactant: CCOP(=O)(Cl)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)N(CCCC#N)CCCC#N
Yield: 75 %

Procedure:
3,3′-Iminodipropyl cyanide (50 mmol) was dissolved in dichloromethane (100 ml). To the system was added triethylamine (10 ml), and then dropwise added at room temperature diethoxyphosphoryl chloride (50 mmol) in dicholormethane (60 ml) solution. The mixture was allowed to react at room temperature over night. The resultant was concentrated and performed to column chromatography (eluant: dichloromethane/methanol system) to obtain 9.7 g of a colorless transparent oily substance, yield 75%, MS[M]+=259.2 m/e.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:17]1(=O)CCCCC1>>[CH3:17][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][C:11]1([CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:9][C:8]2=[O:10]
Reactant: O=C1CCCC1
Reactant: O=C1CCCCC1
Reactant: CC(=O)c1ccccc1O
Product: Cc1ccc2c(c1)C(=O)CC1(CCCC1)O2

Procedure:
The title compound was prepared using the procedure as described in Example 1A, substituting 2′-hydroxy-5′-methylacetophenone (Aldrich, CAS#1450-72-2) for 2′-hydroxyacetophenone and cyclopentanone for cyclohexanone. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.51 (m, 1H), 7.35 (m, 1H), 6.87 (d, J=8.5 Hz, 1H), 2.85 (s, 2H), 2.26 (s, 3H), 1.89-1.95 (m, 2H), 1.59-1.79 (m, 6H). MS (DCI+) m/z 217 (M+H), 234 (M+NH4).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f13) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]([C:12]1([CH2:25][CH2:26][CH2:27]Br)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])[CH3:8].O>O1CCCC1>[CH2:7]([O:9][C:10]([C:12]1([CH2:25][CH2:26][CH2:27][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: C1CCNCC1
Reactant: CCOC(=O)C1(CCCBr)CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(CCCN2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 62.5 °C

Procedure:
Piperidine (0.13 mL, 0.00132 mol) is added to a solution of 4-(3-bromopropyl)piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (0.1 gm, 0.00026 mol) in tetrahydrofuran (5 mL). The reaction mixture is heated at 60-65° C. for 3 hours. It is then cooled to room temperature, treated with demineralized water (12 mL) and extracted with ethyl acetate (2×20 mL). Combined extract is dried over sodium sulphate and concentrated under reduced pressure to get a crude residue which is purified by column chromatography (silica gel 230-400 mesh, methanol:dichloromethane, 1:9) to yield 4-(3-piperidin-1-yl propyl)piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:31]=[CH:30][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:10]=3[OH:29])[N:8]=[C:4]2[CH:3]=1.[OH-].[K+].[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN1CCCC1=O>[C:34]1([S:40][C:2]2[CH:31]=[CH:30][C:5]3=[N:6][N:7]([C:9]4[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:10]=4[OH:29])[N:8]=[C:4]3[CH:3]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)CC(C)(C)c1cc(-c2ccccc2)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC(C)(C)CC(C)(C)c1cc(-c2ccccc2)c(O)c(-n2nc3ccc(Sc4ccccc4)cc3n2)c1

Procedure:
The tide compound is prepared according to the procedure of Example 4 from 20 g of the compound of Example 8, 20.4 g of 45% aqueous potassium hydroxide, 10.3 g of thiophenol and 100 g of N-methylpyrrolidone. The title compound is an oil purified by chromatography on silica gel using toluene as eluent
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].N1C=CC=CC=1O[C:17](=[S:25])OC1C=CC=CN=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:17]=[S:25]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Nc1c(F)cccc1Cl
Solvent: C1CCOC1
Product: Fc1cccc(Cl)c1N=C=S
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-6-fluoro-phenylamine (400 mg, 2.8 mmol), thiocarbonic acid O,O-dipyridin-2-yl ester (650 mg, 2.8 mmol) and TEA (840 μL, 6.0 mmol) in 5 mL THF was stirred overnight at 50° C. The mixture was heated to 65° C. and stirred for further 5 h. The mixture was concentrated i.vac. The residue was purified by chromatography on HPLC (C-18 Symmetry, eluent gradient: water+0.15% HCOOH+15-100% acetonitrile).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][O:19][C:18]=2[CH3:22])(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.C(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][O:19][C:18]=2[CH3:22])(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1occc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccoc2C)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methyl-3-furyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (187 mg) was dissolved in ethyl acetate (1 mL) and ethanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. The mixture was stirred at room temperature for 2 hr, and the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=3:1 to give the title compound as colorless crystals (yield 125 mg, 78%).