Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH2:11]([CH:16]1[O:21][C:20]2[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:19]=2[CH2:18][O:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:26]([C:24]2[CH:23]=[CH:22][C:20]3[O:21][CH:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:17][CH2:18][C:19]=3[CH:25]=2)=[O:27])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCCCC1OCc2cc(C(=O)O)ccc2O1
Reactant: CCCc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC1OCc2cc(C(=O)Oc3ccc(CCC)cc3)ccc2O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
0.1 g of 4-(dimethylamino)pyridine and 1.6 g of p-propylphenol are added to a solution of 2.5 g of 2-pentyl-1,3-benzodioxan-6-carboxylic acid in 50 ml of methylene chloride. The mixture is treated portionwise at 0° C. while stirring with 2.4 g of N,N'-dicyclohexylcarbodiimide. After completion of the addition, the mixture is stirred at 0° C. for a further 10 minutes and then at room temperature for 3 hours. The precipitate is filtered off and the filtrate is evaporated. The residue is taken up in 40 ml of methylene chloride and again filtered. The filtrate is washed with saturated sodium carbonate solution and then with water, dried over sodium sulphate, filtered and evaporated. The crude product is dissolved in boiling hexane, filtered hot with active carbon and crystallized from the filtrate. The crystallizate is recrystallized twice more from hexane. There is obtained pure 2-pentyl-1,3-benzodioxan-6-carboxylic acid p-propylphenyl ester; m.p. 97.5° C., cl.p. 74.5° C. (monotropic).
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.[Cl:48][C:49]1[CH:54]=[C:53]([C:55]([C:57]([F:60])([F:59])[F:58])=[CH2:56])[CH:52]=[C:51]([Cl:61])[CH:50]=1>C1COCC1>[Cl:48][C:49]1[CH:54]=[C:53]([C:55]2([C:57]([F:60])([F:58])[F:59])[O:1][N:2]=[C:3]([C:4]3[C:12]4[N:8]([CH:9]=[CH:10][CH:11]=4)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=3)[CH2:56]2)[CH:52]=[C:51]([Cl:61])[CH:50]=1
Reactant: CCOC(=O)c1ccc(/C=N/O)c2cccn12
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
A solution of crude (E)-ethyl 8-((hydroxyimino)methyl)indolizine-5-carboxylate (0.46 mmol) in THF (5 mL) was added slowly to a stirred solution of iodobenzene diacetate, (PhI(OAc)2, DIB, 296 mg, 0.92 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (222 mg, 0.92 mmol) in THF (10 mL) at rt. The mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and then combiflash to give ethyl 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylate (50 mg, yield 23% over 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 8.66 (t, J=2.0 Hz, 1H), 7.84 (t, J=2.0 Hz, 1H), 7.68-7.71 (m, 3H), 7.25-7.27 (m, 2H), 7.06 (m, 1H), 4.43-4.56 (m, 4H), 1.41 (t, J=2.0 Hz, 3H) ppm; MS: m/z=471.7 (M+1, ESI+).
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.[CH:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(O)CCCCC>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:47]([O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH2:48][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: CCCCCCO
Solvent: O
Product: CCCCCCOC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 100 °C
Yield: 95 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.4 gram of p-toluenesulfonic acid monohydrate in 10 ml of n-hexyl alcohol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 3 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 50 ml of ethyl ether and 50 ml of petroleum ether were added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine-n-hexyl ester di(p-toluenesulfonate) in 95% yield; mp. 190°-193° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)P(=O)(N(C)C)N(C)C.C1OC1C>C(N(CC)CC)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CCCCCCCCBr
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1O
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCOc1c(OC)cc([N+](=O)[O-])c2ncccc12
Yield: 80.2 %

Procedure:
A stirred mixture of 5-hydroxy-6-methoxy-8-nitroquinoline, (6.6 g, 0.03 mole), n-octylbromide (6.7 g, 0.035 mole) and hexamethylphosphoric triamide (10 ml) was maintained at 125°-130°, under N2, while a mixture of triethylamine (1 ml) and propylene oxide (6 ml) was added in small portions during 3 hr. The mixture was cooled and extracted with petroleum ether (bp 20°-40°) (3×100 ml). The extracts were discarded. The petroleum ether-insoluble, semi-solid residue was dissolved in 300 ml of diethyl ether and washed with water, dilute sodium hydroxide and water. The ethereal solution was dried and concentrated in vacuo to leave 8 g of pale brown solid. Crystallization from boiling petroleum ether (20°-40°) (carbon) gave 7.5 g (75%) of the 5-octoxyquinoline derivative, mp 52°-54°. An additional crystallization from petroleum ether did not change the melting point.
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:17])(=[O:16])[C:8]2=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=[CH:15][C:6](=[C:7]23)[NH:5][CH2:4]1.Br[CH2:19][C:20]([NH2:22])=[O:21]>CN(C)C=O>[O:17]=[S:3]1(=[O:16])[C:8]2=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=[CH:15][C:6](=[C:7]23)[NH:5][CH:4]1[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: O=S1(=O)CNc2cccc3cccc1c23
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)CC1Nc2cccc3cccc(c23)S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.011 g of sodium hydride is suspended in 0.5 mL of dimethylformamide, and 0.06 g of 2,3-dihydronaphtho[1,8-de][1,3]thiazine-1,1-dioxide in 1 mL of dimethylformamide is added. The mixture is stirred for 1 hour at ambient temperature and then 0.042 g of 2-bromoacetamide are added batchwise. Then the mixture is stirred for 18 hours at ambient temperature. The reaction mixture is poured onto ice water and extracted with dichloromethane. The organic extracts collected are dried with sodium sulfate and, after evaporation in vacuo, purified by chromatography. Yield: 0.043 g; m.p.: 195° C.–196° C.
Reaction SMILES: C([O:8][C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=[C:11]2[O:19][C@H:20]3[CH2:48][N:23]([C:24](=[O:47])[C@H:25]([CH:38]4[CH2:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH2:39]4)[NH:26][C:27](=[O:37])[O:28][C@@H:29]4[CH2:36][C@H:30]4[CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:10]=12)[C@H:22]([C:49]([O:51][CH3:52])=[O:50])[CH2:21]3)C1C=CC=CC=1>CO.C1COCC1.[Pd].C(OCC)(=O)C>[CH2:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46][CH:38]1[C@H:25]1[C:24](=[O:47])[N:23]2[CH2:48][C@@H:20]([CH2:21][C@H:22]2[C:49]([O:51][CH3:52])=[O:50])[O:19][C:11]2=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]([OH:8])=[C:10]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]2[CH2:36][C@H:29]2[O:28][C:27](=[O:37])[NH:26]1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1Cc3ccccc3C1)NC(=O)O[C@@H]1C[C@H]1CCCC#Cc1c(nc3ccccc3c1OCc1ccccc1)O2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1Cc3ccccc3C1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of the product of step 4 (480 mg, 0.686 mmol) in MeOH (9146 μl) and THF (4573 μl) was treated with a catalytic amount of 10% palladium on carbon (36 mg). The mixture was hydrogenated at 20 psi. After 2 hours LCMS showed >70% conversion. Hydrogenation was continued for another 2 h. LCMS showed >90% conversion. The mixture was diluted with ethyl acetate (50 mL) and the solids were removed by filtration. The filtrate was concentrated in rotavap and the residue was purified on a RediSep® (80 g) silica gel column (gradient: 0 to 50% ethyl acetate in hexanes) to give the title compound (420 mg, 0.684 mmol, 100% yield) as a white powder.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].C([O:11][C:12]([N:14]=[C:15]=[O:16])=O)C>C(OCC)C>[OH:11][C:12]1[N:14]=[C:15]([OH:16])[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:8])[N:1]=1
Reactant: CCOC(=O)N=C=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CCOCC
Product: COC(=O)c1c(C)nc(O)nc1O
Reaction time: 4 h
Yield: 49.7 %

Procedure:
To a suspension of methyl 3-aminocrotonate (2.0 g) in diethyl ether (15 mL) was added a solution of ethoxycarbonylisocyanate (2 g) in diethyl ether (5 mL) in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 4 hours. The insoluble material was collected by filtration, and the collected material was washed with diethyl ether, and dried under reduced pressure. To this material was added 25% aqueous triethylamine solution (20 mL), and the mixture was stirred at 50° C. overnight, and then stirred at 60° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The residual crystals were suspended in methylene chloride, and collected by filtration. The collected crystals were washed with methylene chloride, and dried under reduced pressure to give the title compound (1.59 g).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([NH:25][O:26][CH3:27])[CH:22]([NH2:24])[CH3:23].C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([NH:25][O:26][CH3:27])[CH:22]([NH:24][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:23]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(c1ccc(Cl)cc1Cl)C(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(c1ccc(Cl)cc1Cl)C(C)NC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (86 mg, 0.44 mmol) in dichloromethane (1 ml) was added dropwise to a stirred solution of (110 mg, 0.44 mmol) 2-(2,4-dichloro-phenyl)-2-methoxyamino-1-methyl-ethylamine, which was prepared as described in example P4, and triethylamine (50 mg, 0.50 mmol) in dichloromethane (3 ml) at 0° C. The reaction mixture was stirred for 1 hr at ambient temperature then allowed to stand for 1 h. After removal of the solvent the residue was purified by flash chromatography over silica gel (eluant:hexane/ethyl acetate 3:7). 115 mg (64.1% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-2-methoxyamino-1-methyl-ethyl]-amide was obtained in the form of a resin as a mixture of diastereomeres.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[H-].[Na+].[CH2:13]([O:15][CH2:16]Cl)[CH3:14].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][O:15][CH2:13][CH3:14])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCOc1ccc(Br)cc1CC
Reaction time: 0.5 h

Procedure:
24.5 g (121 mmol) of 4-bromo-2-ethylphenol are dissolved in 150 ml of DMF, and this solution is slowly added to a suspension of 5.3 g (133 mmol) of sodium hydride in 50 ml of DMF. The medium is stirred for 30 minutes, and then 12.4 ml (133 mmol) of ethoxymethyl chloride are added. The reaction medium is stirred for 4 hours at room temperature, and then poured into water and extracted with ethyl acetate. The organic phases are washed with water, and the residue obtained after drying and concentration is purified by chromatography on a silica column (eluent ethyl acetate 10/heptane 90). A yellow oil is obtained (m=25 g, y=80%)
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:12])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].C1COCC1.[OH-].[K+]>O>[CH3:9][Si:8]([CH3:11])([CH3:10])[CH2:7]/[CH:6]=[CH:5]\[CH2:4][C@@H:3]1[CH2:2][O:12]1
Reactant: C[Si](C)(C)C/C=C\C[C@@H](O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C/C=C\C[C@@H]1CO1
Reaction time: 24 h
Yield: 98.3 %

Procedure:
12.97 g (62.7 mmol) of (Z)-(R)-1-Chloro-6-trimethylsilanyl-hex-4en-2-ol was dissolved in 215 ml of abs. THF. A solution of 60.34 g (1.08 mol) of KOH in 61 g of water was added ant the heterogeneous mixture stirred at 30° for 24 h, until GC analysis indicated the disappearance of the starting chlorohydrine. The reaction mixture was then poured onto crushed ice/NH4Cl, extracted with ether, dried over sodium sulfate, and the solvents removed i.V. Thereby, 10.5 g of (Z)-(R)-trimethyl-(4-oxiranyl-but-2-enyl)silane was isolated, 93% pure according to GC, which was used as such for the next step.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C([O:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[NH:11][C:10]=1[CH:16]=O)=O)C.S(=O)(=O)(O)O>C(O)C>[CH3:15][C:12]1[NH:11][C:10]2[CH:16]=[N:3][N:2]([CH3:1])[C:7](=[O:6])[C:9]=2[C:13]=1[CH3:14]
Reactant: CNN
Reactant: CCOC(=O)c1c(C=O)[nH]c(C)c1C
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1[nH]c2cnn(C)c(=O)c2c1C
Temperature: 25 °C
Yield: 104.2 %

Procedure:
A solution of methylhydrazine (1.82 g) and 3-ethoxycarbonyl-4,5-dimethyl-2-formylpyrrole (3.85 g) in ethanol (40 ml) was refluxed for 2 hours. After cooling to room temperature, concentrated sulfuric acid (0.7 ml) was added and the mixture was further refluxed for 13 hours. The mixture was cooled to room temperature and the resulting precipitate was collected by filtration, washed with ethanol and ether, and dried under reduced pressure to provide the title compound as light-yellow powder (3.64 g; yield 100%). 1H-NMR (DMSO-d6) δ: 2.26(6H,s), 3.62(3H,s), 7.98(1H,s), 11.6-11.7(1H,m).
Reaction SMILES: [O:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=[CH2:12])=[CH:6][CH:5]=1)[C:2]#[N:3].[CH3:13][O:14][SiH:15]([O:18][CH3:19])[O:16][CH3:17]>C1(C)C(C)=CC=CC=1>[O:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Si:15]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:13])=[CH:6][CH:5]=1)[C:2]#[N:3]
Reactant: C=CCc1ccc(OC#N)cc1
Reactant: CO[SiH](OC)OC
Solvent: Cc1ccccc1C
Product: CO[Si](CCCc1ccc(OC#N)cc1)(OC)OC
Yield: 42 %

Procedure:
To 3.94 g (24.75 mmol) of purified 1-cyanato-4-(2-propenyl)benzene, prepared as described above, at 65° C. was added 10 μL of a 3% solution of Karstedt's™ catalyst (platinum-divinyltetramethyldisiloxane complex) in xylene (United Chemical Technologies, Bristol, Pa.). Trimethoxysilane (Aldrich) was added in 500 μL increments followed by 10 μL increments of the catalyst solution until NMR showed that the reaction was more than 80% complete. The product was distilled twice to yield 2.94 g (42%) of 3-(4-cyanatophenyl)propyltrimethoxysilane. The structure of the product was verified by IR and NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](O)=[O:27])=[CH:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:26]([C:19]4[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[NH:17][CH:18]=4)=[O:27])[CH2:14][CH2:15]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccc(Br)cc2C12CCNCC2
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: O=C(c1c[nH]c2ccccc12)N1CCC2(CC1)C(=O)Nc1ccc(Br)cc12

Procedure:
Following the general procedure I as described above, the acylation of 5-bromospiro[indole-3,4′-piperidin]-2(1H)-one with 1H-indole-3-carboxylic acid (commercially available), gave the title compound. ES-MS m/e (%): 424.3 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:7])[NH:5][NH2:6])[CH3:2].[F:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=O)[CH2:14][Cl:15])=[CH:11][CH:10]=1>CO>[ClH:15].[CH2:1]([NH:3][C:4]1[S:7][CH2:14][C:13]([C:12]2[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=2)=[N:6][N:5]=1)[CH3:2]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CCNC(=S)NN
Solvent: CO
Product: CCNC1=NN=C(c2ccc(F)cc2)CS1
Product: Cl
Temperature: 25 °C

Procedure:
11.19 g of 4-ethyl-thiosemicarbazide and 17.6 g of 4-fluorophenacyl chloride are heated and stirred under reflux (65° C.) in 400 ml of methanol for 30 minutes in a one liter round bottom flask equipped with a magnetic stirring bar and a condenser protected by a CaCl2 drying tube. The solution is allowed to cool to room temperature and is then concentrated to a yellow solid residue. The residue is recrystallized from methanol/butanone yielding 21.0 g (75.5%) of N-ethyl-5-(4-fluorophenyl)-6H-1,3,4-thiadiazin-2-amine hydrochloride. m.p. 192°-193° C. The fluffy, yellowish white solid is dried under high vacuum at 65° C.
Reaction SMILES: [CH2:1]1[C@@H:11]2[C@H:5]([CH:6]=[CH:7][C:8]3[C:9]4[N:10]2[C:12]2[CH:21]=[CH:20][N:19]=[CH:18][C:13]=2[C:14]=4[CH2:15][CH2:16][CH:17]=3)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:30][CH:31]=[C:32]([Cl:34])[CH3:33].O>CN(C)C=O>[Cl:34][C:32]([CH3:33])=[CH:31][CH2:30][CH:3]1[CH2:4][CH:5]2[CH:6]=[CH:7][C:8]3[C:9]4[N:10]([C:12]5[CH:21]=[CH:20][N:19]=[CH:18][C:13]=5[C:14]=4[CH2:15][CH2:16][CH:17]=3)[CH:11]2[CH2:1][CH2:2]1
Reactant: C1=C[C@@H]2CCCC[C@H]2n2c3c(c4cnccc42)CCC=C13
Reactant: CC(Cl)=CCCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cl)=CCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
A suspension of 2.76 g of (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3';2,3]indolo[1,7-ab][1]benzazepine in 20 ml of dimethylformamide (DMF) containing 2.3 ml triethylamine was treated with 1.25 g of 1,3-dichloro-2-butene. Solution resulted immediately. The solution was stirred at room temperature for 4 hours, by which time some white precipitate had formed. The reaction mixture was poured into 150 ml of cold water, a gummy solid was separated and washed by decantation with cold water. Recrystallization from ethanol gave 2.93 g of the title compound, m.p. 130°-132° C.
Reaction SMILES: [Si:1]([N:8]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:10]([CH2:18][C:19]([CH2:21]O)=[CH2:20])[C:9]1=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Li+].[Cl-].CS([Cl:38])(=O)=O.N#N>CN(C=O)C.O>[Si:1]([N:8]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:10]([CH2:18][C:19]([CH2:21][Cl:38])=[CH2:20])[C:9]1=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(CO)C[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: N#N
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: C=C(CCl)C[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1c1ccccc1
Reaction time: 0.33 h
Yield: 107 %

Procedure:
To a stirred and ice-cooled slurry of (3S*,4R*)-1-tert-Butyldimethylsilyl-3-(2-hydroxymethyl-2-propenyl)-4-phenyl-2-azetidinone (13.66 g, 41.0 mmol), 2,6-lutidine (15.3 ml, d0.920, 123 mmol), and LiCl (anhydros, 4.37 g, 103 mmol) in DMF (103 ml) was added MeSO2Cl (MsCl, 7.93 ml, d1.480, 103 mmol) dropwise under an atmosphere of N2. After the reaction mixture was stirred with ice-cooling for 5 hours and 50 minutes, H2O (40 ml) was added. The stirring was continued at room temperature for additional 20 minutes to destroy the excess MsCl. The resultant dark red mixture was poured into H2O (70 ml). The mixture was extracted with Et2O (70 ml×5). The combined Et2O extracts were washed with H2O (×3), sat. NaHCO3 aq. solution (×1), and sat. NaCl aq. solution (×1), dried (MgSO4), treated with activated charcoal, and concentrated in vacuo to give practically pure title compound (15.36 g, quantitative) as a pale yellow oil. IRmax (film): 1735(v.s), 1650(w), 1175(s), 825(s), 750(s), 700(s) cm-1 ; 1H-NMR δ: 7.43-7.25(m, 5H), 5.14(br.s, 1H), 4.87(br.s, 1H), 4.22(d, J=2.6 Hz, 1H), 3.99(s, 2H), 3.25(ddd, J=10.1, 5.1, 2.6 Hz, 1H), 2.78(dd, J=16.1, 5.1 Hz, 1H), 2.60(dd, J=16.1, 10.1 Hz, 1H), 0.92(s, 9H), 0.22(s, 3H), -0.20(s, 3H) ppm. This was employed in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:3]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:31]=O)=[C:27]([CH3:30])[CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1.[SH:33][CH2:34][C:35](O)=[O:36]>O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:31]4[S:33][CH2:34][C:35](=[O:36])[NH:7][C:6]5[N:2]([CH3:1])[N:3]=[C:4]([C:8]6[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=6)[C:5]4=5)=[C:27]([CH3:30])[CH:28]=3)[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: O=C(O)CS
Reactant: Cn1nc(-c2ccccn2)cc1N
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1C=O
Solvent: O
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1C1SCC(=O)Nc2c1c(-c1ccccn1)nn2C
Temperature: 110 °C
Reaction time: 0.02 h
Yield: 30.8 %

Procedure:
A reaction vial was charged with 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (0.07 g, 0.39 mmol, Example #2, step B), 1-(4-fluorophenyl)-6-methyl-1H-indazole-5-carbaldehyde (0.10 g, 0.39 mmol) and water (0.4 mL). The mixture was stirred for about 1 min then 2-mercaptoacetic acid (0.03 mL, 0.39 mmol) was added and the vial was sealed and warmed in a preheated bath to about 110° C. After stirring for 30 min, 2-mercaptoacetic acid (0.014 mL, 0.20 mmol) was added and continued heating for about 90 min. The vial was cooled to ambient temperature and the water was decanted. The solid was sonicated in Et2O (30 mL) and collected by vacuum filtration. The solid was then rinsed with heptane (30 mL) then dissolve in DCM and purified by column chromatography (EtOAc/heptane 100:0 to 0:100) to afford rac-4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-methyl-3-(pyridin-2-yl)-6,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7(4H)-one (0.06 g, 0.12 mmol, 29%). LC-MS (Table 1, Method g) Rt=2.32 min, m/z 485 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ 10.11 (s, 1H), 8.36-8.30 (m, 1H), 8.10 (s, 1H), 7.79-7.69 (m, 3H), 7.64-7.60 (m, 1H), 7.54 (s, 1H), 7.40-7.36 (m, 2H), 7.27 (s, 1H), 7.12-7.04 (m, 1H), 6.74 (s, 1H), 3.90 (s, 3H), 3.42-3.38 (m, 1H), 3.18-3.14 (m, 1H), 2.70 (s, 3H).