Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[CH:15]([NH2:16])[C@H:12]2[S:11][CH2:10][C:9]=1[C:18]([CH2:28][PH:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:47])([F:46])[CH2:38][S:39]([CH2:42][C:43](O)=[O:44])(=[O:41])=[O:40].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[N:13]2[C:14](=[O:17])[C@@H:15]([NH:16][C:43](=[O:44])[CH2:42][S:39]([CH2:38][C:37]([F:46])([F:36])[F:47])(=[O:40])=[O:41])[C@H:12]2[S:11][CH2:10][C:9]=1[C:18]([CH2:28][PH:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])([S:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1)[O:19][CH2:20][CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCOC(C[PH](=O)OC(C)(C)C)(Sc1nnn[nH]1)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)CS(=O)(=O)CC(F)(F)F)[C@H]2SC1
Reaction time: 12 h

Procedure:
To a solution of 10.42 g (0.019 mol) of 7-amino-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester and 3.9 g (0.019 mol) of 2,2,2-trifluoroethylsulfonylacetic acid in tetrahydrofuran is added dropwise a solution of 3.9 g (0.019 mol) of dicyclohexylcarbodiimide in 100 ml of tetrahydrofuran. The reaction mixture is stirred at 25° for 12 hours, then filtered and concentrated to about 10 ml. The residue is filtered and evaporated to dryness to give 7β-(2,2,2-trifluoroethylsulfonylacetamido)-3-(1-ethoxy-t-butoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid t-butyl ester.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Product: CC(C)(C)C(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 104.6 %

Procedure:
Following the general method as outlined in Example 89, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 200 mg; 0.47 mmol) and pivaloyl chloride (0.12 mL; 0.98 mmol), 250 mg (>100%) of the title compound was obtained as a yellow solid, which was used directly without further purification.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:51][CH2:52][C:53]([F:56])([F:55])[F:54])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[O:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[F:67][C:68]1[C:77]([F:78])=[CH:76][C:71]2[N:72]=[C:73]([SH:75])[NH:74][C:70]=2[CH:69]=1>>[F:78][C:77]1[C:68]([F:67])=[CH:69][C:70]2[N:74]=[C:73]([S:75][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]4[C:39]([O:51][CH2:52][C:53]([F:56])([F:54])[F:55])=[N:40][C:41]([CH3:50])=[CH:42][C:43]=4[O:44][CH2:45][C:46]([F:47])([F:48])[F:49])=[O:36])[CH2:30][CH2:29]3)[NH:72][C:71]=2[CH:76]=1
Reactant: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCO)CC2)c(OCC(F)(F)F)n1
Reactant: Fc1cc2nc(S)[nH]c2cc1F
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CN2CCN(CCSc3nc4cc(F)c(F)cc4[nH]3)CC2)c(OCC(F)(F)F)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 5,6-difluoro-2-mercaptobenzimidazole, to thereby yield the title compound as a colorless foamed substance.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[NH:14][C:15](=[O:22])[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[N:18][CH:17]=4)[CH:5]=1.Cl[CH2:24][C:25]1[N:26]=[N:27][N:28]([CH3:30])[CH:29]=1.O>CN(C=O)C>[CH3:3][C:4]1[O:8][N:7]=[C:6]([C:9]2[N:13]3[N:14]=[C:15]([O:22][CH2:24][C:25]4[N:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[N:18][CH:17]=4)[CH:5]=1
Reactant: Cc1cc(-c2nnc3c4ccncc4c(=O)[nH]n23)no1
Reactant: Cn1cc(CCl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2nnc3c4ccncc4c(OCc4cn(C)nn4)nn23)no1
Temperature: 60 °C
Yield: 14.3 %

Procedure:
Sodium hydride (42 mg of a 60% dispersion on oil, 1.1 mmol) was added to a stirred solution of 3-(5-methylisoxazol-3-yl)-1,2,3a,4,7-pentaazacyclopenta[a]naphthalen-5(4H)-one (200 mg, 0.75 mmol) in DMF (6 ml) at room temperature under nitrogen, and the mixture was heated at 60° C. for 0.5 h. The reaction mixture was allowed to cool to room temperature, treated with 4-chloromethyl-1-methyl-1,2,3-triazole (108 mg, 0.82 mmol) and heated at 60° C. for 1.5 h. On cooling to room, water was added. The mixture was extracted with ethyl acetate, the organics separated, dried (MgSO4), and evaporated in vacuo. The residue was recrystallised from methanol to afford the title product as a white solid (39 mg, 14%), 1H NMR (360 MHz, d6 DMSO) δ 2.60 (3H, s, Ar—CH3), 4.08 (3H, s, N—CH3), 5.73 (2H, s, OCH2), 7.21 (1H, d, J=0.8 Hz, Ar—H), 8.45 (2H, m, Ar—H), 9.15 (1H, d, J=5.3 Hz, Ar—H)), 9.41 (1H, s, Ar—H); MS (ES+) m/e 364 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][CH2:17][NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:28]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][CH2:17][NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:28]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CCNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Solvent: CC(C)O
Solvent: CCCCCC
Product: O=C1Nc2ccc(Cl)cc2[C@](CCNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
N-{2-[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]ethyl}-4-fluorobenzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=3:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:8]#[N:9])[CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18]>>[C:8]([C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:18][CH2:17][C:16]#[N:19])#[N:9]
Reactant: C=CC#N
Reactant: N#CC(c1cccnc1)N1CCOCC1
Product: N#CCCC(C#N)(c1cccnc1)N1CCOCC1

Procedure:
Leete et al. [J. Org. Chem. 37, 4465-6 (1972)] shows the reaction of 2-(3-pyridinyl)-2-(4-morpholinyl)ethanenitrile with acrylonitrile to produce 4-cyano-4-(3-pyridinyl)-4-(4-morpholinyl)butanenitrile and its conversion by heating it with acetic acid, water and tetrahydrofuran to 4-oxo-4-(3-pyridinyl)butanenitrile.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([C:10]([N:12]3[CH2:17][CH2:16][N:15](CC4C=CC=CC=4)[CH2:14][CH2:13]3)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(O)C.[Pd].O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[O:11])=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(c1ccc(-n2ccnc2)cc1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(-n2ccnc2)cc1)N1CCNCC1
Temperature: 50 °C
Reaction time: 30 h

Procedure:
1-[4-(1H-Imidazol-1-yl)benzoyl]-4-(phenylmethyl)piperazine (26.65 g, 76.9 mmol) is dissolved in ethanol (500 mL) and 10% palladium on carbon (2.00 g) as a slurry in water (10 mL) is added to the solution. The mixture is shaken under an atmosphere of hydrogen on a Parr apparatus at 50 psi and 50° C. for 30 hr. The mixture is filtered through Celite, the solvent is evaporated, and the residue is triturated with ether and crystallized from ethyl acetate-hexane to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:5]=2[N:6]=1.CO.S(OC)(O[CH3:23])(=O)=O>[OH-].[Na+]>[CH3:23][N:6]1[C:5]2[CH:7]=[C:8]([N+:14]([O-:16])=[O:15])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=[C:2]1[CH3:1]
Reactant: COS(=O)(=O)OC
Reactant: Cc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2n1C
Temperature: 92.5 °C

Procedure:
To a solution of 2-methyl-5,6-dinitro-benzimidazole in 5% NaOH was added methanol and dimethyl sulfate. The reaction mixture was heated for 30 min at 90-95° C. and then cooled to room temperature. The precipitate which formed was filtered, washed with 10% NaOH and then water, and dried overnight at 40° C. to yield 1,2-dimethyl-5,6-dinitrobenzimidazole.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:19]([CH:30]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=3)[CH3:31])[CH2:18]2)=[O:16])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][N:17]([C:15]([CH:12]3[CH2:13][CH2:14][CH:9]([NH:7][CH3:6])[CH2:10][CH2:11]3)=[O:16])[CH2:18][CH:19]2[CH:30]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=2)[CH3:31])[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCC(N(C)C(=O)OC(C)(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(C(C)Oc3ccc(C#N)cn3)C2)CC1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a stirred solution of {4-[(3RS,4SR)-3-[(SR)-1-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-cyclohexyl}-methyl-carbamic acid tert-butyl ester described herein above (30 mg, 0.050 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL). After 1 hour, aqueous NaHCO3 was added until ph=8, the product was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 to give the title product as a colorless oil (25 mg, 98%). ES-MS m/e: 500.9 (M+H+).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C@H:7]([C:18]2[CH:26]=[CH:25][C:21]3[O:22][CH2:23][O:24][C:20]=3[CH:19]=2)[N:6]1[C:27](=[O:30])[CH2:28]Cl)=O.[CH3:31][NH2:32]>CO>[O:22]1[C:21]2[CH:25]=[CH:26][C:18]([C@@H:7]3[C:8]4[NH:9][C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=5[C:16]=4[CH2:17][C@@H:5]4[C:3](=[O:2])[N:32]([CH3:31])[CH2:28][C:27](=[O:30])[N:6]34)=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccc3c(c2)OCO3)N1C(=O)CCl
Reactant: CN
Solvent: CO
Product: CN1CC(=O)N2[C@H](c3ccc4c(c3)OCO4)c3[nH]c4ccccc4c3C[C@@H]2C1=O
Reaction time: 5 h

Procedure:
Cis-1-benzo[1,3]dioxol-5-yl-2-(2-chloro-acetyl)-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester of Step 3 (30 g) was taken in methanol (450 ml). The resultant mixture was heated to 35° C. to 40° C. and aqueous methyl amine (27 ml; 40%) was added. The reaction mixture was stirred at 50° C. to 55° C. for 5 hours and then cooled to 10° C. to 15° C. with continuous stirring for 0.5 hours. The solid so obtained was filtered and dried to afford (6R,12 aR)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[N:15]1([CH2:21][CH2:22][NH2:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:23][CH2:22][CH2:21][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13]
Reactant: NCCN1CCCCC1
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCCN1CCCCC1)CCCC2=O
Yield: 85.7 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 2-(piperidin-1-yl)ethanamine 0.27 g (2.1 mmol) was reacted to give 0.26 g (86%) of the titled compound as a white solid.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][OH:10])[CH2:4]1.[CH2:11](Br)[CH2:12][CH2:13][CH3:14]>C(O)C>[CH2:11]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][OH:10])[CH2:4]1)[CH2:12][CH2:13][CH3:14]
Reactant: OCC1CCCNC1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN1CCCC(CO)C1
Yield: 79 %

Procedure:
A] A 1N solution of sodium hydroxide (174 ml, 0.17 mole) was added to a mixture of 3-piperidinemethanol (20 g, 0.17 mole) and butyl bromide (23 ml, 0.2 mole) in ethanol (200 ml). The reaction mixture was refluxed for 4 hours, then the solvent was evaporated under vacuum. The aqueous solution was acidified with HCl and washed with ethyl ether, then treated with a 32% solution of sodium hydroxide to pH-12 and extracted with ethyl ether. The combined organic phases were anhydrified over sodium sulfate and the solvent was evaporated under vacuum. The crude was purified by distillation yielding 23 g of N-butyl-3-piperidinemethanol (b.p.: 115-117/6 mmHg) (yield: 79%).
Reaction SMILES: [CH:1](=[N:8][N:9]([C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20](OC)=[O:21])[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+].O.Cl>C(O)C>[OH:21][C:20]1[C:19]2[C:18](=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([N:8]=[CH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10](=[O:17])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)N(N=Cc1ccccc1)c1ccccc1C(=O)OC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(O)c2ccccc2n(N=Cc2ccccc2)c1=O
Temperature: 50 °C
Yield: 91.9 %

Procedure:
Methyl 2-[2-benzylidene-1-(3-ethoxy-3-oxopropanoyl)hydrazino]benzoate (5.17 g, 14.59 mmol) in ethanol (100 mL) was reacted with sodium ethoxide (21% by weight in ethanol, 5.50 mL, 14.60 mmol) at 25° C. then heated at 50° C. for 1 hour. After cooling to 25° C., the reaction mixture was poured into water, acidified to pH 4 with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to give ethyl 4-hydroxy-2-oxo-1-{[phenylmethylene]amino}-1,2-dihydroquinoline-3-carboxylate (4.51 g, 96%). MS (DCI) m/z 323 (M+H)+. 1H NMR (300 MHz, DMSO-d6) ppm 3.73 (s, 3 H) 7.21 (m, 1 H) 7.56 (m, 5 H) 7.95 (m, 2 H) 8.03 (d, J=7.72 Hz, 1 H) 9.08 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH2:18]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH:33]=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCO.N1CCCCC1>[C:15]([C:3]1[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:33][CH:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])(=[O:16])[NH2:17]
Reactant: O=CC1CCCN1C(=O)OCc1ccccc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=CC1CCCN1C(=O)OCc1ccccc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and benzyl-2-formylpyrrolidine-1-carboxylate (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>C(O)C>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[N:17]1[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]1=[O:11]
Reactant: COc1ccccc1N
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: COc1ccccc1N1CCC(C(=O)O)C1=O
Yield: 101.2 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 2-methoxyaniline (0.495 mL; 4.41 mmol) in ethanol (3 mL). 1-(2-methoxyphenyl)-2-oxopyrrolidine-3-carboxylic acid 0.350 g (quantitative) was obtained as a grey solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[CH3:20][C:21]1[S:35][C:24]2[NH:25][C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[N:28]=[C:29](N)[C:23]=2[CH:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:29]2[C:23]3[CH:22]=[C:21]([CH3:20])[S:35][C:24]=3[NH:25][C:26]3[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=3[N:28]=2)[CH2:4][CH:3]1[CH2:8][N:9]1[C:10](=[O:19])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]1=[O:18]
Reactant: CN1CCNCC1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)C(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
A solution of 2-((1-methylpiperazin-2-yl)methyl)isoindoline-1,3-dione, prepared as described in step D, (100 mg, 0.38 mmol), 2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-amine, prepared as described in step G, (150 mg, 0.52 mmol) and diisopropylethylamine (0.49 g, 3.8 mmol) in dimethylsulfoxide (0.5 mL) was stirred at 170° C. for 2 hrs. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was concentrated and the residue purified by column to give 15 mg of 2-((1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-2-yl)methyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ 7.76-7.73 (m, 1H), 7.45-7.35 (m, 3H), 7.18-7.17 (m, 1H), 6.98-6.95 (m, 2H), 6.75-6.73 (m, 1H), 6.46 (s, 1H), 4.28-4.25 (m, 1H), 3.96-6.92 (m, 1H), 3.71-3.64 (m, 3H), 3.47-3.41 (m, 1H), 3.29-3.28 (m, 1H), 3.12-3.09 (m, 1H), 2.87-2.86 (m, 1H), 2.67-2.53 (m, 3H), 2.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6](Br)([F:12])[CH2:5]2.[NH2:14][C:15]([NH2:17])=[S:16].C(N(CC)CC)C>CS(C)=O>[NH2:17][C:15]1[S:16][C:6]2([F:12])[CH2:5][C:4]3[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=3[C:7]2([OH:11])[N:14]=1
Reactant: NC(N)=S
Reactant: O=C1c2ccc(Cl)cc2CC1(F)Br
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: NC1=NC2(O)c3ccc(Cl)cc3CC2(F)S1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
263 mg of 5-chloro-2-bromo-2-fluoroindan-1-one and 152 mg of thiourea are dissolved in 2.5 ml of dry dimethyl sulfoxide and stirred at 50° C. for 8 h. Excess triethylamine is added to the reaction mixture, which is then concentrated in vacuo. The residue is purified by chromatography on silica gel with ethyl acetate as eluent. 2-Amino-6-chloro-8a-fluoro-8 ,8a-dihydroindeno[1,2-d]thiazol-3a-ol is obtained with a melting point of 159° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23]([F:28])[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34]C1C=C(C2C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=2)C=CC=1F.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:34])=[C:23]([F:28])[CH:22]=3)[C:19]=2[CH3:20])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CC(C)Cn1nc(-c2ccc(F)c(F)c2)cc(COS(C)(=O)=O)c1=O
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1c(-c2ccc(F)c(F)c2)nn(CC(C)C)c(=O)c1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 85.5 %

Procedure:
Following the procedure of Example 1 (10), 6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 85.5%).
Reaction SMILES: C(Br)(Br)(Br)Br.[P:6]([O:11]C)([O:9][CH3:10])[O:7][CH3:8].[C:13]([O:17][C:18]([NH:20][C@@:21]([CH3:45])([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=2[O:40][CH2:41][O:42][CH3:43])=[CH:28][C:27]=1[Cl:44])[CH2:22][OH:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].O>N1C=CC=CC=1>[C:13]([O:17][C:18]([NH:20][C@@:21]([CH3:45])([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=2[O:40][CH2:41][O:42][CH3:43])=[CH:28][C:27]=1[Cl:44])[CH2:22][O:23][P:6]([O:9][CH3:10])([O:7][CH3:8])=[O:11])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COCOc1ccc(C)cc1Sc1ccc(CC[C@@](C)(CO)NC(=O)OC(C)(C)C)c(Cl)c1
Reactant: COP(OC)OC
Agent: BrC(Br)(Br)Br
Solvent: c1ccncc1
Solvent: O
Product: COCOc1ccc(C)cc1Sc1ccc(CC[C@@](C)(COP(=O)(OC)OC)NC(=O)OC(C)(C)C)c(Cl)c1
Reaction time: 2 h

Procedure:
Carbon tetrabromide (130 mg) and trimethyl phosphite (46 μL) were added under ice cooling to a solution of the compound of Example 20 (97 mg) in pyridine (0.5 mL) to form a reaction solution. This reaction solution was stirred for 2 hours under ice cooling. Then, water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the target product (84 mg) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:26]=[C:15]3[C:16]4[C:21]([CH2:22][CH2:23][N:14]3[C:13](=[O:27])[N:12]=2)=[CH:20][C:19]([O:24][CH3:25])=[CH:18][CH:17]=4)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO>CC(O)=O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:26]=[C:15]3[C:16]4[C:21]([CH2:22][CH2:23][N:14]3[C:13](=[O:27])[N:12]=2)=[CH:20][C:19]([O:24][CH3:25])=[CH:18][CH:17]=4)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc([N+](=O)[O-])c2)nc1=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(N)c2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.9 %

Procedure:
To a solution of 2-(3-nitro-phenylamino)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (5) (525.4 mg, 1.4 mmol) in AcOH (40 mL), Zn powder (ca. 300 mg) was added and stirred at room temperature for 3 hrs, then at 40° C. overnight. After cooling, MeOH was added to the mixture and insoluble materials were removed by filtration. The MeOH solution was purified on BondElut® SCX (Varian Incorporated) then passed through BondElut® NH2 (Variant Incorporated). Result solid was washed with MeOH to give the title compound (215.1 mg, 46%). MS (ESI) (M+H)+ 335.