Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[S:23])=[CH:3][CH:2]=1.Cl[CH2:25][CH2:26][CH2:27][CH2:28][S:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[N:33]1[CH:34]=[CH:35][C:30]([S:29][CH2:28][CH2:27][CH2:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[S:23])=[CH:31][CH:32]=1
Reactant: ClCCCCSc1ccncc1
Reactant: O=c1c2ccccc2[nH]c(=S)n1CCCCSc1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccccc2n(CCCCSc2ccncc2)c(=S)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a solution of 515 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2(1H)-thion-4(3H)-one and 332 mg (1.65 mmol) of 4-(4-chlorobutylthio)pyridine in 15 ml of dimethylformamide, 0.25 ml (1.65 mmol) of 1,8-diazabicyclo-[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent: ethyl acetate/ethanol=25:1 to 10:1) to give 0.694 mg of the desired product (97.1% yield; colorless oil).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>O1CCCC1.ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 90 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide in 5 mL of tetrahydrofuran are added dropwise 50 μL of 2-fluoro-5-(trifluoromethyl)phenyl isocyanate. The reaction mixture is stirred for 16 hours at room temperature under an argon atmosphere and then concentrated under reduced pressure. The residue obtained is stirred for 30 minutes in 2 mL of dichloromethane. The suspended solid is filtered off and drained by suction. After drying under vacuum, at 40° C., 115 mg of 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]-pyridine-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:10]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:44]1[C:48]2([CH2:52][CH2:51][NH:50][CH2:49]2)[CH2:47][N:46]([C:53](=[O:56])[CH2:54][CH3:55])[CH2:45]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:9]1[C:10]([C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[N:11][C:12]([N:50]2[CH2:51][CH2:52][C:48]3([CH2:44][CH2:45][N:46]([C:53](=[O:56])[CH2:54][CH3:55])[CH2:47]3)[CH2:49]2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)N1CCC2(CCNC2)C1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)N1CCC2(CCN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccc(CN(C)C(=O)OC(C)(C)C)cc5)o4)n3)C2)C1
Temperature: 90 °C
Yield: 75.8 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (153 mg, 0.23 mmol) and 1-(3,7-diazaspiro[4.4]nonan-3-yl)propan-1-one (101 mg, 0.46 mmol) in DMF (2 mL) was added Et3N (70 mg, 97 μL, 0.70 mmol). The reaction vessel was sealed and heated at 90° C. for 40 minutes. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with brine (2×). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 0-60% EtOAc in DCM to yield tert-butyl N-[[4-[5-[3[bis(tert-butoxycarbonyl)amino]-6-(3-propanoyl-3,7-diazaspiro[4.4]nonan-7-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (133 mg, 75%). LC/MS m/z 763.9 [M+H]+.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:15][C:16]12[CH2:23][CH2:22][C:19]([C:24]([NH2:26])=O)([CH2:20][CH2:21]1)[CH2:18][CH2:17]2)[C:5]([CH3:14])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6])#[N:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([N:3]=[C:4]([NH:15][C:16]12[CH2:21][CH2:20][C:19]([C:24]#[N:26])([CH2:18][CH2:17]1)[CH2:22][CH2:23]2)[C:5]([CH3:14])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6])#[N:2]
Reactant: CC(C)(Oc1ccccc1)C(=NC#N)NC12CCC(C(N)=O)(CC1)CC2
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Oc1ccccc1)C(=NC#N)NC12CCC(C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 82 (70 mg, 0.2 mmol) and triethylamine (120 mg, 1.2 mmol) in dichloromethane cooled in an ice bath was added trifluoroacetic anhydride (125 mg, 0.6 mmol) dropwise. After addition was complete, the mixture was stirred overnight at room temperature. After removal of the solvent, the residue was purified by preparative reverse phase HPLC [Waters 2767; Benetnach 10-C18 20×250 mm, 10 μm; 35-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/minute; detection at 214 and 254 nm] to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (t, J=7.85 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.01 (s, 1H), 6.91 (d, J=7.6 Hz, 2H), 2.01˜2.08 (m, 12H), 1.69 (s, 6H); LCMS (ESI+) m/z 337.7 (M+H)+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([CH2:12][O:13][CH3:14])[CH:5]=1)[NH2:3].[CH:15]1([CH:20]=[C:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([C:31]([O:33][CH3:34])=[O:32])[CH:25]=[CH:24][C:23]=3[C:22]2=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:36](O)C>>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([N:2]2[CH:20]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:21]3[C:22]([C:23]4[CH:24]=[CH:25][C:26]([C:31]([O:33][CH2:34][CH3:36])=[O:32])=[CH:27][C:28]=4[CH2:29][CH2:30]3)=[N:3]2)=[CH:5][C:6]=1[CH2:12][O:13][CH3:14])#[N:9]
Reactant: CCO
Reactant: COCc1cc(NN)ccc1C#N
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1CCCC1)C2=O
Agent: Cl
Product: CCOC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(COC)c2)C1C1CCCC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4-hydrazinyl-2-(methoxymethyl)benzonitrile hydrochloride, Methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 18 (209 mg, 0.73 mmol) and ethanol (4 mL) was stirred under argon at 80° C. for four hours. The mixture was cooled to room temperature and concentrated to give ethyl 2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate as a yellow solid. The ester was suspended in tetrahydrofuran (4 mL), methanol (1 mL) and treated with 2.5 N sodium hydroxide (1 mL) at room temperature. After four hours the mixture was concentrated to half the original volume, treated with 6 N Hydrogen chloride (2 mL), dimethylsulfoxide (24 mL) and purified by reversed-phase HPLC (acetonitrile/water/0.05% trifluoroacetic acid) to give 2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (yellow/orange solid, 65 mg, 0.015 mmol, 18% yield). The title compound was largely present as (±)-(3RS,3aSR)-2-(4-cyano-3-(methoxymethyl)phenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (s, 1H), 8.07 (d, J=8.06 Hz, 1H), 7.80-7.87 (m, 2H), 7.60 (d, J=8.86 Hz, 1H), 7.35 (d, J=2.15 Hz, 1H), 7.18 (dd, J=8.86, 2.15 Hz, 1H), 4.92 (dd, J=9.80, 5.51 Hz, 1H), 4.50 (s, 2H), 3.59 (ddd, J=13.83, 9.40, 4.70 Hz, 1H), 3.36 (s, 3H), 3.06-3.15 (m, 1H), 2.82-2.96 (m, 1H), 2.19-2.29 (m, 1H), 2.00-2.13 (m, 1H), 1.65-1.89 (m, 2H), 1.14-1.54 (m, 7H). ES-MS m/z 430 (M+H)
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([F:8])([F:7])[F:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][O:16][CH2:17][C:18]1[S:22][C:21]2=[N:23][C:24]([C:28]([F:31])([F:30])[F:29])=[C:25]([CH2:26][NH2:27])[N:20]2[N:19]=1>CN(C)C=O>[F:6][C:5]([F:8])([F:7])[CH:4]=[CH:3][CH2:2][NH:27][CH2:26][C:25]1[N:20]2[C:21]([S:22][C:18]([CH2:17][O:16][CH3:15])=[N:19]2)=[N:23][C:24]=1[C:28]([F:29])([F:31])[F:30]
Reactant: COCc1nn2c(CN)c(C(F)(F)F)nc2s1
Reactant: FC(F)(F)C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1nn2c(CNCC=CC(F)(F)F)c(C(F)(F)F)nc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-bromo-1,1,1-trifluorobut-2-ene (0.782 g, 4.14 mmol, 1.4 eq) and sodium carbonate (0.376 g, 3.55 mmol, 1.2 eq) are added to suspension of 1-[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine a19 in N,N-dimethylformamide (15 ml). The mixture is stirred overnight at room temperature to afford crude 4,4,4-trifluoro-N-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}but-2-en-1-amine a20. Ethoxycarbonyl isocyanate (0.51 g, 4.43 mmol, 1.5 eq) is added to the reaction mixture. After 4 h, the reaction is not complete and ethoxycarbonyl isocyanate (0.5 eq) is added again. The reaction mixture is stirred overnight to afford crude ethyl ({[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}[(4,4,4-trifluorobut-2-en-1-yl]carbamoyl)carbamate a21. Potassium tert-butoxide is added and the reaction mixture is heated at 75° C. for 4 h. After cooling, the reaction mixture is extracted with toluene (2×80 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by chromatography over silicagel (eluent: CH2Cl2/MeOH 99/1) to afford 602 mg of a mixture of ethyl 5-(2,2-difluoroethenyl)-3-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-2-oxoimidazolidine-1-carboxylate a22 (as the major compound) and ethyl 3-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-2-oxo-5-(2,2,2-trifluoroethyl)imidazolidine-1-carboxylate a23.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.O>CN(C)C(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Clc1ccc(N2CCNCC2)nc1
Yield: 50.2 %

Procedure:
Following the general procedure of Example 33, Step 1, and making non-critical variations, 2,5-dichloropyridine (Aldrich; 5.10 g), piperazine (14.8 g), water (50 mL), and N,N-dimethylacetamide (2 mL) give 3.42 g of 1-(5-chloropyridin-2-yl)piperazine; mp 92-107° C.; IR 1480, 1244, 1390, 1589 815 cm-1 ; 1H NMR (CDCl3) δ2.98, 3.47, 6.58, 7.42, 8.11.
Reaction SMILES: [CH3:1][C:2]([S:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:7])[C:3](=[O:6])[CH2:4][CH3:5].[Br-:13].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>C(Cl)Cl>[Br:13][CH:4]([CH3:5])[C:3](=[O:6])[C:2]([S:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:1])[CH3:7]
Reactant: [Br-]
Reactant: CCC(=O)C(C)(C)SCC(=O)O
Agent: C[N+](C)(C)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(Br)C(=O)C(C)(C)SCC(=O)O
Reaction time: 0.25 h

Procedure:
To a solution of [(1,1-dimethyl-2-oxobutyl)thio]acetic acid (0.3 g, 1.58 mmol) in CH2Cl2 (10 ml) was added phenyltrimethylammonium tribromide (0.62 g, 1.65 mmol) at 0° C. After stirring for 15 min, the solution was allowed to come to room temperature and stirring was continued for 1 h. Water (30 ml) was added and the aqueous layer was extracted with diethyl ether (15 ml). The combined organic layers were washed with brine (25 ml), dried over Na2SO4, filtered and concentrated in vacuo. The remaining oil was purified by flash chromatography (ethyl acetate-petroleum ether 1:1 containing 0.1% glacial acetic acid). Yield: 0.39 mg (91%). 1H-NMR (400 MHz, CDCl3): δ=1.15, 1.64 (2×s, 6H, C(CH3)2), 1.81 (d, 3H, J=7.0 Hz), 3.14, 3.21 (2×d, 2H, J=6.8 Hz), 5.07 (q, 1H, J=7.0 Hz) ppm. C8H13BrO3S (269.16, 267.98), HRMS: calcd (M+Na)+ 290.9661, found 290.9669.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=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.O[NH:49][C:50]([C:52]1[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][C:58]=2[CH:59]=[CH:60][CH:61]=1)=[NH:51]>CN(C=O)C>[F:13][C:2]([F:1])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:10][N:51]=[C:50]([C:52]3[CH:61]=[CH:60][CH:59]=[C:58]4[C:53]=3[CH:54]=[CH:55][N:56]=[CH:57]4)[N:49]=2)=[CH:11][CH:12]=1
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1
Temperature: 120 °C
Yield: 46 %

Procedure:
4-[(Trifluoromethyl)oxy]benzoic acid (Aldrich; 132 mg, 0.642 mmol) was stirred in DMF (1 ml) with HATU (244 mg, 0.642 mmol) and DIPEA (0.28 ml, 1.605 mmol) at room temperature for 30 mins before adding a solution of N-hydroxy-5-isoquinolinecarboximidamide (D1, 100 mg, 0.535 mmol) in DMF (1 ml). The resulting mixture was heated to 120° C. for 30 mins in a Biotage Initiator microwave. The solvent was removed under vacuum and the residue was purified by column chromatography on silica, eluting with 0-80% ethyl acetate in cyclohexane. The relevant fractions were combined and concentrated under vacuum to give the title compound as a white solid (88 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1([CH2:64]O)[CH2:63][O:62][CH2:61]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:59][C:60]2([CH3:64])[CH2:63][O:62][CH2:61]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(CO)COC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2(C)COC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.44 g), tributylphosphine (1.78 mL), (3-methyloxetan-3-yl)methanol (0.44 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 62%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][S:7][C:8]=1/[CH:9]=[CH:10]\[S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:3])=O.C(C(C(C(O)=O)O)O)(O)=O.[OH:41][CH:42]1[CH2:45][NH:44][CH2:43]1>>[OH:41][CH:42]1[CH2:45][N:44]([C:1]([C:4]2[N:5]=[CH:6][S:7][C:8]=2/[CH:9]=[CH:10]\[S:11][C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:3])[CH2:43]1
Reactant: OC1CNC1
Reactant: O=C(O)c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Product: O=C(c1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC(O)C1
Yield: 68.7 %

Procedure:
In the same manner as in step c) in Example 3, 0.742 g of the title compound was prepared from 0.957 g of 4-carboxy-5-((Z)-2-tritylthioethen-1-yl)thiazole and 0.757 g of 3-hydroxyazetidine tartrate.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]([CH2:14][OH:15])[CH:11]([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[CH3:12][CH:11]([CH3:13])[C@H:10]([N:9]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14][OH:15]
Reactant: O=Cc1ccccc1
Reactant: CC(C)[C@H](N)CO
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](CO)N=Cc1ccccc1

Procedure:
2.64 ml (2.78 g, 26.16 mmol) of benzaldehyde were added to a stirred solution of 2.57 g (24.91 mmol) of L-valinol in 28 ml of toluene, and the mixture was heated under reflux with a water trap for one hour. Cooling was followed by concentration and recrystallization from heptane. The colorless solid was filtered off with suction and dried under reduced pressure (3.74 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:17]([CH:21]=2)[C:18]([OH:20])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:17]([CH:21]=2)[C:18]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[O:20])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3OC)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3OC)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(2-methoxyphenyl) benzoic acid (66 mg, 0.1563 mmol) was dissolved in methylene chloride (5 ml), then p-anisidine (38 mg, 0.3089 mmol), triethylamine (47 mg, 0.4653 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (53 mg, 0.3136 mmol) were added thereto at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:1) to give the title compound (38 mg, 0.0721 mmol, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:59]1([CH2:62][C:63](O)=O)[CH2:61][CH2:60]1>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:63]([CH2:62][CH:59]5[CH2:60][CH2:61]5)[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)CC1CC1
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
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: CN(C)C=O
Product: Cn1c(CC2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (101 mg), N,N-diisopropylethylamine (0.130 ml), cyclopropylacetic acid (0.024 ml) and DMF (2 ml) was stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (2.00 ml), and the mixture was stirred at 90° C. for 2 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (56.3 mg) as an off-white solid.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=[O:18])=[CH:8][CH:7]=1)([O-])=O>O.CO.C1COCC1.[Zn]>[NH2:3][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=[O:18])=[CH:8][CH:7]=1
Reactant: O=c1ccccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(-n2ccccc2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Ammonium chloride (4.45 g, 83.26 mmol) in water (10 mL) and methanol (20 mL) was added to a stirred solution of 1-(4-nitro-phenyl)-1H-pyridin-2-one (1.8 g, 8.3 mmol) in THF (20 mL). Zinc powder (4.3 g, 66.6 mmol) was then added portion wise and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was filtered over celite and the filtrate was concentrated and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 1.23 g (79%) of 1-(4-amino-phenyl)-1H-pyridin-2-one. 1H NMR: (DMSO-d6): δ 7.6-7.4 (m, 2H), 7.0 (d, 2H), 6.7 (d, 2H), 6.45 (d, 1H), 6.3 (t, 1H), 5.4 (s, 2H).
Reaction SMILES: [C:1]([CH:3]([OH:18])[CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)#[N:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:1]([CH:3]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CC(O)C#N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC(C#N)OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of tert-butyl 4-(2-cyano-2-hydroxyethyl)piperidine-1-carboxylate (67.0 g) and triethylamine (35.0 g) in dichloromethane (500 mL) was slowly added a solution of methanesulfonyl chloride (36.3 g) in dichloromethane (200 mL). The reaction system was stirred at room temperature for 2 hr, and added to ice water (300 mL). The organic layer was dried over anhydrous sodium sulfate, insoluble material was removed by filtration, and the filtrate was concentrated to give the title compound (80.0 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:27](=[O:28])[C:26]3[S:29][C:30]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)=[CH:31][C:25]=3[N:24]=[CH:23]2)=[CH:18][C:17]=1[O:39][CH3:40])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:41][NH:42][CH3:43]>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:30]2[S:29][C:26]3[C:27](=[O:28])[N:22]([C:19]4[CH:20]=[CH:21][C:16]([N:5]([CH2:4][CH2:3][CH2:2][N:42]([CH3:43])[CH3:41])[S:6]([C:9]5[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=5)(=[O:8])=[O:7])=[C:17]([O:39][CH3:40])[CH:18]=4)[CH:23]=[N:24][C:25]=3[CH:31]=2)=[CH:33][CH:34]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N(CCCBr)S(=O)(=O)c1ccc(C)cc1
Reactant: CNC
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N(CCCN(C)C)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared by reaction of N-(3-bromopropyl)-N{4-[6-(4-chlorophenyl)4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]-2-methoxyphenyl}4-methylbenzenesulfonamide (the title compound from Example K15) and dimethylamine. LCMS m/z 623 (MH+).