Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]2[CH2:16][C:12]3[S:13][CH:14]=[CH:15][C:11]=3[C:10]2=O)=O)[CH:2]=1.O.[NH2:19][NH2:20].C(O)(=O)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:9]3[CH2:16][C:12]4[S:13][CH:14]=[CH:15][C:11]=4[C:10]=3[NH:20][N:19]=2)[CH:2]=1
Reactant: NN
Reactant: O=C(c1cccnc1)C1Cc2sccc2C1=O
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: c1cncc(-c2n[nH]c3c2Cc2sccc2-3)c1
Temperature: 25 °C
Yield: 40 %

Procedure:
5-(Pyridine-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.23 g, 5 mmol), hydrazine monohydrate (0.38 mL, 7.5 mmol), glacial acetic acid (0.9 mL) and ethanol (15 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-Pyridin-3-yl-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.5 g, 2 mmol) as white solid in 40% yield.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:15]=O)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1>C(O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:15]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CSC(=S)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Yield: 69.5 %

Procedure:
To a solution of 14.6 g (110 mmol) of rhodanine and 25.7 g (110 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 150 ml of ethanol, 1.08 ml (11.0 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 26.71 g of the desired compound (69.7% yield, pale yellow crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.[C:19](Cl)([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:20])[CH:8]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 20 h
Yield: 56.9 %

Procedure:
A solution of 10 g (58 mmol) 5-chloro-2-nitroaniline in 250 ml dry tetrahydrofuran was added 8.5 ml (62 mmol) dry triethylamine. A solution of 7.0 ml (62.7 mmol) ethoxalylchloride in 50 ml dry tetrahydrofuran was added dropwise. Stirring was continued at 25° C. for 20 h. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with ethanol to give 9.0 g (57%) 4-chloro-2-ethoxalylamino-1-nitrobenzene. M.p. 105.1° C.
Reaction SMILES: [Li]CCCC.[N+:6]([CH2:9][CH2:10][CH3:11])([O-:8])=[O:7].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>C1COCC1.C(Cl)Cl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([CH:19]([OH:20])[CH:9]([N+:6]([O-:8])=[O:7])[CH2:10][CH3:11])=[CH:21][CH:22]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCC[N+](=O)[O-]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC(C(O)c1ccc([N+](=O)[O-])cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.6 %

Procedure:
n-BuLi (1.6 M in hexane, 6.24 mL) was added dropwise with stirring to a solution of nitropropane (0.9mL, 10mmol) in THF (12 mL) at -78° C. After 15 minutes a solution of TiCl3 (OPriso) (5 mmol) in THF (2 mL) and CH2Cl2 (3 mL) solution was added. After a further 15 minutes 4-nitrobenzaldehyde (0.75 mL, 5 mmol) in CH2Cl2 (4 mL) was added and the mixture allowed to warm up to room temperature (~30 min). Stirring was continued for a further 3.5 hours at room temperature and the mixture was quenched with an aqueous slurry of disodium EDTA (1.86 g, 5mmol) and extracted with Et2O (3×75 mL). The combined Et2O fractions were washed with dilute hydrochloric acid (2 M, 75 mL), aqueous sodium bicarbonate (75 mL) and water (75 mL), dried and evaporated in vacuo. Flash column chromatrography [Si2, hexane:Et2O, 3:1 v/v] gave 1-(4-nitrophenyl)-2-nitro-butan-1-ol (0.86 g, 72%) Erythro:threo ratio 7:1.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([S:21][CH2:22][CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:24])[CH:10]=1.[C:31]([O:35][C:36](=[O:50])[CH2:37][CH2:38][S:39][CH2:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45])([CH3:34])([CH3:33])[CH3:32].CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([S:21][CH2:22][CH3:23])[CH:18]=[CH:17][C:16]=2[NH:24][C:44]([C:43]2[CH:42]=[C:41]([CH:49]=[CH:48][CH:47]=2)[CH2:40][S:39][CH2:38][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:50])=[O:45])[CH:10]=1)=[O:25]
Reactant: CCSc1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCSc1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(ethylthio)phenyl)isonicotinamide (200 mg, 0.46 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (200 mg, 0.68 mmol, 1.50 equiv), EDC.HCl (190 mg, 0.99 mmol, 2.00 equiv), and 4-dimethylaminopyridine (60 mg, 0.49 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 300 mg (crude) of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(ethylthio)phenyl)carbamoyl)-benzylthio)propanoate as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5](Cl)[C:6](=O)[CH2:7][CH3:8])[CH3:2].[CH:12]([O-:14])=O.[NH4+:15]>C(O)=O>[CH2:1]([O:3][C:4]([C:5]1[O:14][CH:12]=[N:15][C:6]=1[CH2:7][CH3:8])=[O:11])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C(Cl)C(=O)CC
Reactant: O=C[O-]
Solvent: O=CO
Product: CCOC(=O)c1ocnc1CC
Temperature: 25 °C
Yield: 29.5 %

Procedure:
2-Chloro-3-oxo-pentanoic acid ethyl ester (13.5 g) was dissolved in 75 ml of 95% formic acid. Ammonium formate (27.6 g) was added and the reaction heated at reflux under nitrogen for 6 hours. After cooling to room temperature the reaction mixture was evaporated and the residue extracted with ether (3×50 ml). Combined ether extracts were washed with water and brine, dried (MgSO4), filtered and evaporated to give a crude oil (9 g). The oil was purified by chromatography on silica gel, eluting with CH2Cl2/MeOH 99:1, providing the title compound (3.77 g) as a pale brown oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([C:20](O)=[O:21])[C:11]3=[O:23])=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:27])=O.CN(C)C=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([C:20]([Cl:27])=[O:21])[C:11]3=[O:23])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1nc2ccccc2n(-c2ccc3c(c2)OCO3)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1nc2ccccc2n(-c2ccc3c(c2)OCO3)c1=O

Procedure:
5.7 g (19 mmol) of 1-(benzo[d][1,3]dioxol-5-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid and 3.1 g (24 mmol) of oxalyl chloride were dissolved in dichloromethane (10 mL), and 0.026 g (0.35 mmol) of dimethylformamide was added thereto. The mixture was heated to reflux for 2 hours while stirring. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 1-(benzo[d][1,3]dioxol-5-yl)-2-oxo-1,2-dihydroquinoxaline-3-carbonyl chloride as yellow crystals (Compound No. of Production Intermediate: IX-73).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:22])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccccc3)c2c1O
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc(F)cc2)c2snc(-c3ccccc3)c2c1O
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 50.3 %

Procedure:
A mixture of 7-bromo-4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (53 mg, 0.139 mmol), Pd(PPh3)4 (16.1 mg, 0.0139 mmol), 4-fluorophenylboronic acid (29.3 mg, 0.209 mmol), K2CO3 (57.8 mg, 0.418 mmol), and 1,4-dioxane (1.39 mL) was heated at 140° C. in a microwave oven with stirring for 5 min. After cooling to r. t., the mixture was filtered and the filter cake was washed with CH2Cl2. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the title compound as a white solid (27.6 mg): MS (m/z) 395.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1.CCN(CC)CC.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C1COCC1.CN(C1C=CN=CC=1)C.CCOCC>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:1]2[CH2:5][CH:4]=[CH:3][CH2:2]2)=[O:19])=[CH:16][CH:15]=1
Reactant: C1=CNCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)N1CC=CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Pyrroline (4 mL, 54 mmol) was dissolved in THF (100 mL), Et3N (14 mL, 100 mmol) was added. The mixture was cooled to 0° C. 4-chloro-benzoyl chloride (7.6 mL, 60 mmol) was added very slowly at 0° C. Catalytic amount of DMAP was added too. Finally the reaction mixture was stirred at 0° C. to RT for overnight. The reaction mixture was diluted with ether and filtered to remove white solid of Et3N.HCl. Then evaporated to remove solvent and triturated with hexane/ether to give white solid 10.3 g with ratio of unsaturated/saturated about 3/1 by NMR. Then triturated with hexane/ether again to give 6.68 g white solid with ratio of unsaturated/saturated about 3.7/1 by NMR. 1H-NMR (300 MHz, CDCl3): δ 4.3 (4H, d), 5.80 (2H, d), 7.40 (4H, dd)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH:7]=[C:8]([C:13]([CH3:15])=O)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].[CH2:19]([C:23]1[O:27][N:26]=[C:25]([CH2:28][N:29]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:30])[N:24]=1)[C:20]([CH3:22])=O.O.[NH3:39]>C(O)(C)C>[CH3:22][C:20]1[NH:39][C:13]([CH3:15])=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]([C:6]2[CH:16]=[CH:17][CH:18]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:19]=1[C:23]1[O:27][N:26]=[C:25]([CH2:28][N:29]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:30])[N:24]=1
Reactant: N
Reactant: CC(=O)Cc1nc(CN(C)Cc2ccccc2)no1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 250 mg of methyl 2-(3-nitrobenzylidene)acetoacetate, 260 mg of 5-acetonyl-3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazole, 3 ml of isopropyl alcohol and 40 mg of 29% ammonia water was reacted and worked up as described in Example 104 to give methyl 1,4-dihydro-2,6-dimetyl-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-4-(3-nitrophenyl)pyridine-5-carboxylate, m.p. 126°-127° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([F:9])[F:8])=[N+]=[N-].[ClH:18].CCOCC>CCO.[OH-].[Pd+2].[OH-]>[ClH:18].[NH2:1][CH2:4][CH2:5][CH2:6][C:7]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([F:8])[F:9]
Reactant: CCOP(=O)(OCC)C(F)(F)CCCN=[N+]=[N-]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCOP(=O)(OCC)C(F)(F)CCCN
Reaction time: 8 h

Procedure:
To a solution of diethyl 4-azido-1,1-difluorobutylphosphonate (1 eq) in EtOH (2 M) was added palladium hydroxide (0.05 eq) and 2 M HCl in ether (1.1 eq). The reaction mixture was stirred under hydrogen (1 atm) overnight. The palladium was filtered off and the filtrate was concentrated en vaccuo. The crude mixture was used for the next reaction without further purification.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]=1[CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=1)=[NH:11]>CO.[OH-].[OH-].[Pd+2]>[ClH:5].[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10]([NH:9][CH2:8][C:7]2[CH:6]=[CH:23][CH:22]=[CH:21][C:20]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[NH:11])=[N:14][CH:15]=1
Reactant: Cc1ccc(NC(=N)NCc2c(Cl)cccc2Oc2ccccc2)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(NC(=N)NCc2ccccc2Oc2ccccc2)nc1
Product: Cl
Reaction time: 12 h

Procedure:
0.111 g (0.261 mmol) N-(2-chloro-6-phenoxybenzyl)-N′-(5-methylpyridin-2-yl)guanidine acetate was dissolved in 10 mL methanol, and 10 mg Pearlman's catalyst (palladium hydroxide, 20% by weight Pd on C) was added. After evacuation and flushing of the reaction vessel with nitrogen, the reaction flask was re-evacuated and then filled with hydrogen. The reaction mixture was hydrogenated for 12 hr at room temperature. The catalyst was then separated via a membrane filter, and the resulting solution was removed from the solvent under vacuum. The viscous, clear residue was combined with diethyl ether, and after 2 hr crystallization 0.071 mg (0.192 mmol, 73%) purified N-(5-methylpyridin-2-yl)-N-(2-phenoxybenzyl) guanidine hydrochloride was isolated.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=O)[CH2:8][CH2:7]1)=[O:5].Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1>C(O)C>[CH2:2]([O:3][C:4]([CH:6]1[CH2:12][C:11]2[C:19]3[C:18](=[CH:17][CH:16]=[C:15]([F:14])[CH:20]=3)[NH:21][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Yield: 98.2 %

Procedure:
4-Cyclohexanonecarboxylic acid ethyl ester (25 g, 0.14 m) and 4-fluorophenyhydrazine hydrochloride (22.5 g, 0.13 m) were dissolved in ethanol (450 mL) and heated under reflux for 16 hrs. After cooling, the white solid was filtered off and the solvent removed under reduced pressure. After partitioning the residue between water and ethyl acetate, the organic portion was separated, dried (MgSO4), and evaporated under reduced pressure to give compound III (35.5 g, 0.13 m). The crude product was recrystallized from heptane. mp: 115-117° C. MS: [M+H]+ @m/e=262. [Lit. ref.: Block, M. H., et al. J. Med. Chem. 2002, 45, 3509].
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])(C)C[C:4]([CH3:10])=[CH:3]1.[CH:11]12C[CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2>ClCCl>[CH3:8][CH2:6][CH2:9][C:2](=[O:1])[CH2:3][CH2:4][CH2:10][CH2:15][CH2:16][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C1=CC2CCC1C2
Reactant: CC1=CC(=O)CC(C)(C)C1
Solvent: ClCCl
Product: CCCCCCCCCC(=O)CCC

Procedure:
To a Pyrex photoreactor equipped with a quartz immersion well and nitrogen bubbler was added, under nitrogen, 103.6 g. (0.75 mol.) of isophorone and 400 g. (4.25 mol) of freshly distilled bicyclo [2.2.1] hept-2-ene. The vessel was filled to its internal volume of 1200 ml. with dichloromethane. The solution was bubbled with nitrogen for 1 hour and irradiated through a Pyrex filter for 18.5 hours with an Hanovia 450 watt medium pressure mercury arc. After the lamp was turned off, the solution was concentrated in vacuo to obtain an oil which was distilled through a 90 cm. Vigreux-column to yield 143.6 g. (0.62 mol., 82%) of the desired product having b.p. 90°-94° C./0.5 mm.Hg. Glpc showed the product to be a 1:1 mixture of two main isomers (180 cm. × 0.3 cm. 1% OV-225 on Chrom G, 150° C. initially for 3 min. and then programmed 10° C./min. to 250° C.) IR: 1692 cm-1NMR: (CCl4) singlets at 1.35δ, 1.10δ, 1.00δ, 0.92δ, 0.87δ with the singlet at 1.00δ having an integral area of 6H while the others integrated to 3H. The rest of the NMR spectrum was a set of complicated multiplets.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[N:23](C(C)(C)C)[C:22](=[O:31])[CH2:21]2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.[CH:32](N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[C:65]1([CH2:71][CH2:72][CH2:73][CH2:74][NH2:75])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>CN(C)C=O>[C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:31])[CH2:21]2)=[CH:16][CH:15]=1)[C:10]([NH:75][CH2:74][CH2:73][CH2:72][CH2:71][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:12])(=[O:7])[CH3:32]
Reactant: NCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)NC(Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)C(=O)NCCCCc1ccccc1
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[4-(2-tert-butyl-1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (12 mg, 0.035 mmol) in N,N-dimethylformamide (1.0 mL) was added N,N-diisopropylethylamine (0.018 mL, 0.10 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (16 mg, 0.042 mmol) and premixed for 5 minutes. 4-phenylbutan-1-amine (6.3 mg, 0.042 mmol) was added and the mixture was stirred for 2 h. The product was purified by preparative LCMS to afford the final product (6.8 mg, 41%). 1H NMR (500 MHz, CD3OD): δ 7.41 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.25–7.27 (m, 2H), 7.15–7.20 (m, 4H), 5.08–5.12 (m, 1H), 4.54–4.58 (m, 1H), 3.18–3.31 (m, 1H), 3.07–3.17 (m, 3H), 2.93–2.97 (m, 1H), 2.59–2.68 (m, 2H), 1.94 (s, 3H), 1.51–1.59 (m, 2H), 1.41–1.46 (m, 2H); LCMS found for C24H30N3O5S (M+H)+: m/z=472.2
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:22][CH2:23][CH3:24])=[C:16]([N+:19]([O-])=O)[CH:17]=2)[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=S)=[S:26].C(N(CC)CC)C.O>C(O)C>[CH2:1]([NH:8][C:9]1[C:18]2[CH:17]=[C:16]3[NH:19][C:25](=[S:26])[N:22]([CH2:23][CH3:24])[C:15]3=[CH:14][C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: CCNc1cc2ncnc(NCc3ccccc3)c2cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCn1c(=S)[nH]c2cc3c(NCc4ccccc4)ncnc3cc21
Yield: 60.6 %

Procedure:
6-Amino-4-benzylamino-7-ethylaminoquinazoline (4.5 g, 15.4 mmol) obtained, according to the procedures in Example 1, from 4-benzylamino-7-ethylamino-6-nitroquinazoline obtained in Reference Example 3 was suspended in ethanol (300 ml). To the suspension were added carbon disulfide (25 ml) and triethylamine (9.3 ml, 66.4 mmol), followed by heating under reflux for 6.5 hours. Water was added to the reaction mixture and the resulting crystals were filtered and recrystallized from a mixed solvent of dimethylformamide and ethanol to give the title compound (3.54 g, 60.6%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.OC(C(F)(F)F)=O.[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:57](OC(C)(C)C)=[O:58])=[CH:31][C:32]=3[N:33]3[CH2:39][C:38]([C:40]([N:42]4[CH:47]5[CH2:48][CH2:49][CH:43]4[CH2:44][N:45]([CH3:50])[CH2:46]5)=[O:41])=[CH:37][C:36]4[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:35]=4[C:34]=23)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[CH2:64]([C:66]1([S:69]([NH2:72])(=[O:71])=[O:70])[CH2:68][CH2:67]1)[CH3:65].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:20]1([C:26]2[C:27]3[CH:28]=[CH:29][C:30]([C:57]([NH:72][S:69]([C:66]4([CH2:64][CH3:65])[CH2:68][CH2:67]4)(=[O:71])=[O:70])=[O:58])=[CH:31][C:32]=3[N:33]3[CH2:39][C:38]([C:40]([N:42]4[CH:43]5[CH2:49][CH2:48][CH:47]4[CH2:46][N:45]([CH3:50])[CH2:44]5)=[O:41])=[CH:37][C:36]4[CH:51]=[C:52]([O:55][CH3:56])[CH:53]=[CH:54][C:35]=4[C:34]=23)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCC1(S(N)(=O)=O)CC1
Reactant: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(S(=O)(=O)NC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)CC(C(=O)N2C3CCC2CN(C)C3)=Cc2cc(OC)ccc2-4)CC1
Temperature: 60 °C
Yield: 17 %

Procedure:
CDI (80 mg, 0.49 mmol) was added to a solution of tert-butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate TFA (200 mg, 0.30 mmol) in THF (1.5 mL) and the reaction mixture was heated at 60° C. for 2 h. The reaction was cooled to rt and then ⅓ (˜0.55 mL) of the reaction solution was added to a stirring solution of 1-ethylcyclopropane-1-sulfonamide (40 mg, 0.27 mmol) in DBU (0.20 mL, 1.3 mmol) and THF (0.20 mL). The reaction was stirred at rt ON (˜75% conversion by LCMS), concentrated to an oil, quenched with 1N HCl (˜1 mL) (prec. formed) and extracted with EtOAc (2×1 mL) and DCM (2×1 mL). The combined organics were concentrated to dryness, dissolved into MeOH (1.5 mL) and purified by preparative HPLC (CH3CN/H2O with 10 mM NH4OAc) to yield 13-cyclohexyl-N-((1-ethylcyclopropyl)sulfonyl)-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (30.9 mg, 0.046 mmol, 45% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.97-2.35 (m, 29H), 2.56-2.73 (m, 1H), 2.80-2.94 (m, 1H), 3.38-3.58 (m, 1H), 3.94 (s, 3H), 4.29-4.64 (m, 2H), 5.14-5.31 (m, 1H), 7.05 (s, 1H), 7.09-7.20 (m, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.65 (dd, J=8.4, 1.5 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 8.16 (br s, 1H). LC-MS retention time: 2.91 min; m/z 669 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.