Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][F:58])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.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>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:47]=[CH:48][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][F:58])=[O:54])=[CH:50][CH:51]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:33])([CH3:34])[CH3:35]
Reactant: CC1(C)OB(c2ccc(CC(=O)OCCF)cc2)OC1(C)C
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
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: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCF)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, 2-fluoroethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded 2-fluoroethyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH:2]=[CH2:3].[F-].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+](C1C=C(S(O[CH2:45][C@H:46]2[O:48][CH2:47]2)(=O)=O)C=CC=1)([O-])=O>C1COCC1.O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:45][C@@H:46]1[O:48][CH2:47]1)[CH:2]=[CH2:3]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: C=CCOc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOc1ccccc1OC[C@H]1CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
o-Allyloxyphenol (1.0 g) was dissolved in THF (10 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Potassium fluoride (1.55 g) and tetrabutyl ammonium fluoride (0.2 g) were added thereto and the mixture was stirred for 1 hour. Then (S)-glycidyl M-nitrobenzenesulfonate (1.73 g, 99.3% e.e.) was added thereto and the mixture was stirred for 40 hours at the same temperature. After the reaction water was added to the mixture, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/ethyl acetate; 3:2) to give 0.96 g of (R)-3-(o-allyloxyphenoxy)-1,2-epoxypropane (yield 70%, optical purity 95.9% e.e.) as a colorless oil.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[CH2:6][O:7][C:8](=[O:30])[NH:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C:16]2[N:17]=[C:18]([C:21](C)(C)[O:22][SiH2]C(C)(C)C)[O:19][CH:20]=2)[N:11]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[Cl:3][C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[CH2:6][O:7][C:8](=[O:30])[NH:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C:16]2[N:17]=[C:18]([CH2:21][OH:22])[O:19][CH:20]=2)[N:11]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2ncc(NC(=O)OCc3ccccc3Cl)n2)co1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(Nc1cnn(Cc2coc(CO)n2)n1)OCc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of {2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-ylmethyl]-2H-[1,2,3]triazol-4-yl}-carbamic acid 2-chloro-benzyl ester (144 mg, 0.30 mmol) in dry THF (3.0 mL) was treated at 0° C. with TBAF (0.46 mL of a 1M solution in THF, 0.46 mmol). The reaction mixture was stirred at 0° C. for 30 min. Sat. aq. NH4Cl (5 mL) was added, the layers separated and the aq. layer extracted with EA (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (EA) gave the title compound as a yellow oil. TLC: rf (EA)=0.25. LC-MS-conditions 01: tR=0.82 min; [M+H]+=363.90.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27](C1NC=CN=1)(C1NC=CN=1)=[O:28].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[C:27](=[O:28])[NH:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Temperature: 25 °C
Yield: 56.4 %

Procedure:
To a solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (about 1.15 mmol) in dry THF (10 mL) was added carbonyl diimidazole (373 mg, 2.3 mmol). The reaction mixture was stirred at room temperature until completion judged by LCMS. Aqueous sodium bicarbonate was added and the mixture extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, concentrated and the residue purified by flash column chromatography (10-100% ethyl acetate in hexanes) to give 279 as a colorless solid (308 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][C:11](=[CH:15]N(C)C)[C:10](=O)[C:9]=2[N:8]([CH3:20])[N:7]=1)=[O:5])[CH3:2].Cl.[NH2:22][C:23]([NH2:25])=[NH:24]>C(O)C.CC[O-].[Na+]>[NH2:24][C:23]1[N:25]=[CH:15][C:11]2[CH:12]=[CH:13][C:14]3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7][N:8]([CH3:20])[C:9]=3[C:10]=2[N:22]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1nn(C)c2c1CCC(=CN(C)C)C2=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nn(C)c2c1ccc1cnc(N)nc12
Yield: 85 %

Procedure:
16.00 g (0.06 mol) of ethyl-6-[(dimethylamino)methylene]-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate were dissolved in 600 mL of ethanol and 3.90 g of sodium ethylate, and 5.44 g of guanidine hydrochloride were added consecutively. The solution was stirred at reflux for 12 hours. The solvent was then evaporated, the residue redissolved with dichloromethane and washed with water. The organic layer was then dried over anhydrous Na2SO4 and concentrated. The residue was triturated with diethyl ether and the product collected by filtration (85% yield as a white solid).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)cc1
Yield: 34 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. Yield: 34% of theory, C37H46N6O5 (654.8) Rf value: 0.15 (silica gel; dichloromethane/ethanol=19:1) ##EQU102##
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1([CH2:15][CH:16]2CC2)[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:4](F)(F)[F:5]>>[NH2:2][CH:3]([C:8]1([CH2:15][CH3:16])[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[CH2:4][F:5]
Reactant: NC(C(F)(F)F)C1(CC2CC2)CCC(O)CC1
Agent: Cl
Product: CCC1(C(N)CF)CCC(O)CC1

Procedure:
99 mg of 55 were synthesized as mixture of stereoisomers as its hydrochloride from 236 mg (704 μmol) of 53 using the protocol described for the synthesis of compound 21. Rt=0.09, 0.14 min (Method P). Detected mass: 190.3 ([M+H+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:17]1[C:22]([O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:10][CH:11]=2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Oc1ccc(Nc2ncccc2F)cc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cccnc1Nc1ccc(Oc2nccnc2Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3-fluoropyridin-2-ylamino)phenol (1.0 g, 0.048 mol) and 2,3-dichloropyrazine (1.01 g, 0.006 mol) in DMF (10 mL) was added potassium carbonate (1.32 g, 0.0096 mol). The reaction mixture was heated to 100° C. for overnight. After cooling to RT, the reaction mixture was concentrated under high vacuum and diluted with water to get precipitate. After stirring for 1 h, the solid was collected by filtration, washed with water and ether, dried to give desired product as tan solid. MS (ESI, pos. ion) m/z: 317.05 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=[O:17])[C@H:4]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:19][C:20]([F:41])([F:40])[C:21]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:41][C:20]([F:19])([F:40])[C:21]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][CH:27](/[CH:30]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:18])[CH3:1])=[O:17])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:26][CH2:25]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(C)C(=O)[C@H](CS(C)(=O)=O)NC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@H](CS(C)(=O)=O)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a solution of N,N-dimethyl-3-(methylsulfonyl)-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-alaninamide (150 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (173 mg) in 2-propanol (5 mL) was added piperidinium acetate (74 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (55 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH2:48])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:49](N)([NH2:52])(=[O:51])=[O:50]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][S:49](=[O:51])(=[O:50])[NH2:52])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NS(N)(=O)=O
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN)CCC3)cc1
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCNS(N)(=O)=O)CCC3)cc1
Temperature: 0 °C
Yield: 63.2 %

Procedure:
A solution of 0.100 g (0.152 mmol) (3R,4R)-3-[1-(2-amino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 15(b)] and 0.029 g (0.303 mmol, 2.0 equiv.) of sulfamide in 3 ml of tetrahydrofuran was refluxed for 72 h. The reaction mixture was poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 25 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 100:10:1 v/v/v mixture of dichloromethane/methanol/28% ammonium hydroxide solution as eluent to yield 0.071 g (0.096 mmol, 63.2% of theory) of (3R,4R)-3-[1-(2-sulfamoylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4 -[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil; MS: 739 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.C1COCC1.[O:21]([CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[O:21]([CH2:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[S:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:10]2=[O:11])(=[O:14])=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Reactant: c1ccc(OC[C@@H]2CCCN2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 64 h
Yield: 88.3 %

Procedure:
To a cold solution of 2,3-dioxo-2,3-dihydro-1-H-indole-5-sulfonylchloride (3.80 g, 15.5 mmol ) in a 1:1 mixture of THF:CHCl3 (194 mL) was added drop-wise via syringe pump a solution of (2S)-2-(phenoxymethyl)pyrrolidine (2.85 g, 16.1 mmol, 1.03 eq) (J. Med. Chem, 44, 2014, 2001) and N,N-diisopropylethylamine (5.61 mL, 32.2 mmol, 2 eq) in CHCl3 (30 mL) over a period of 50 minutes under a dry N2 atmosphere with cooling in an ice bath. After stirring at room temperature for 64 hr the reaction mixture was concentrated and the crude product was flash chromatographed twice using Biotage KP silica gel, and gradient of 98/2 CH2Cl2/CH3OH as eluent on the first column and 90/10 CH2Cl2/CH3OH as eluent on the second column to give the title compound as a dark green solid (5.29 g, 88% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (ES−) m/z 385 [M−H]. MS: (ES+) m/z 387 [M+H].
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH2:44][N:45]1[CH2:50][CH2:49][CH2:48][N:47]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[C:46]1=[O:58]>C(Cl)Cl.O>[F:57][C:54]1[CH:53]=[CH:52][C:51]([N:47]2[CH2:48][CH2:49][CH2:50][N:45]([NH:44][C:26](=[O:28])/[CH:25]=[CH:24]/[C:14]3[CH:15]=[CH:16][C:17]([N:18]4[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]4)=[C:12]([O:11][CH3:10])[CH:13]=3)[C:46]2=[O:58])=[CH:56][CH:55]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NN1CCCN(c2ccc(F)cc2)C1=O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C(=O)NN2CCCN(c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 100 %

Procedure:
IPEA (0.51 mL), (E)-3-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]acrylic acid (150 mg) and BOPCl (0.18 g) were added to a solution of 1-amino-3-(4-fluorophenyl)tetrahydropyrimidin-2-one (132 mg) in methylene chloride (5 mL) at room temperature, and the reaction solution was stirred at room temperature for 13 hours. Water was added to the reaction solution, followed by extraction with chloroform. The resulting extract was washed with a saturated sodium bicarbonate solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 261 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1.Cl>C1COCC1.CCCCCC.CCOCC.C(O)C>[Cl:16][C:17]1[C:22]([C:26]2([OH:30])[CH2:27][CH2:28][CH2:29][N:24]([CH3:23])[CH2:25]2)=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: CN1CCCC(=O)C1
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1CCCC(O)(c2nccnc2Cl)C1
Temperature: -77 °C
Reaction time: 0.33 h
Yield: 53.4 %

Procedure:
A solution of 7.2 ml 2,2,6,6-tetramethylpiperidine (0.034 mol) in 300 ml of dry THF was cooled to -8° C. as 25 ml of 1.6 M butyllithium (0.04 mol) in hexane was added dropwise. The reaction was stirred 20 min then cooled to -77° C. A solution of 2.9 ml of 2-chloropyrazine (0.031 mol) in 5 ml of THF was added dropwise to the reaction. After another 15 min, 3.5 g of 1-methylpiperidin-3-one (0.035 mol) in 10 ml of THF was added dropwise. After the addition, the reaction was stirred 1.5 h followed by addition of a mixture of 8 ml of concentrated HCl and 4 ml of ethanol. The cooling was removed and when the temperature had reached -15° C., 20 ml of 5 N NaOH was added. The volatile organics were evaporated and the aqueous residue was extracted 4 × with 30 ml of CH2Cl2. The extracts were washed with brine, dried and the solvent evaporated to give a brown solid that was dissolved in 300 ml of ether and filtered. The ether was evaporated and the residue recrystallized from hexane to give 3.77 g of (1), 53% yield, mp 111°-112° C. NMR ppm (CDCl3) 1.7-2.2 (5H,m), 2.4 (3H, s), 2.7 (1H, d), 2.85-3.05 (2H, m), 4.4 (1H, bs), 8.35 (1H, d), 8.5 (1H, d). Anal. C10H14ClN3O, requires C: 52.75; H: 6.20; N: 18.46%. Found C: 52.64; H: 6.21; N: 18.21%.
Reaction SMILES: C([N:4]1[CH2:16][C:14]2=[C:15]3[C:10](=[CH:11][CH:12]=[CH:13]2)[C@H:9]2[CH2:17][CH2:18][CH2:19][C@H:8]2[N:7]3[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>CO>[CH2:6]1[N:7]2[C:15]3[C:10]([CH:9]4[CH2:17][CH2:18][CH2:19][CH:8]42)=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:16][NH:4][CH2:5]1
Reactant: CC(=O)N1CCN2c3c(cccc3[C@H]3CCC[C@H]32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1cc2c3c(c1)C1CCCC1N3CCNC2

Procedure:
(7bR,10aR)-3-Acetyl-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1-hi]indole was treated with solid NaOH in MeOH under reflux to give 7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1-hi]indole mp: 57-59° C.
Reaction SMILES: BrC1C=CC2C(=O)CCCCC=2C=1.BrC1C=CC2C(=O)CCC(OC)CC=2C=1.C1C(Br)C(=O)C2C(=CC=CC=2)C1.[N:41]1[CH:46]=[CH:45][C:44]([C:47]2[NH:51][N:50]=[C:49]3[C:52]4[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=4C[CH2:55][CH2:56][C:48]=23)=[CH:43][CH:42]=1.COC1C=CC2CCCC3C(=NNC=3C3C=CN=CC=3)C=2C=1>>[N:41]1[CH:46]=[CH:45][C:44]([C:47]2[NH:51][N:50]=[C:49]3[C:52]4[C:53]([CH2:55][CH2:56][C:48]=23)=[CH:57][CH:58]=[CH:59][CH:60]=4)=[CH:43][CH:42]=1
Reactant: c1ccc2c(c1)CCCc1c-2n[nH]c1-c1ccncc1
Agent: COC1CCC(=O)c2ccc(Br)cc2C1
Agent: COc1ccc2c(c1)-c1n[nH]c(-c3ccncc3)c1CCC2
Agent: O=C1CCCCc2cc(Br)ccc21
Product: c1ccc2c(c1)CCc1c-2n[nH]c1-c1ccncc1

Procedure:
When an equivalent amount of 2-bromo-benzo[b]cycloheptanone or 2-bromo-8-methoxy-benzo[b]cycloheptanone is substituted for the 2-bromo-α-tetralone in step A of example 1 above, there is obtained following the processes of steps A of example 1 and B above, 3-(4-pyridyl)-2,4,5,6-tetra-hydrobenzo[6,7]-cyclohepta[1,2-c]pyrazole(m.p. 217°-219°C) or 9-methoxy-3-(4-pyridyl)-2,4,5,6-tetrahydrobenzo[6,7]cyclohepta [1,2-c]pyrazole (m.p. 200°-201°C) respectively.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:18][CH2:17][CH2:16][C:11]21OCC[O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CC(C)=O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:18][CH2:17][CH2:16][C:11]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CCCC23OCCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCCC1COCc1ccccc1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 136.8 %

Procedure:
A mixture of 4 (7.95 g, 32.0 mmol) and p-toluenesulfonic acid monohydrate (0.30 g, 1.58 mmol) in acetone (160 mL) was stirred at ambient temperature for 100 min. The mixture was neutralized with NaHCO3 solution and acetone was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with NaCl solution and dried over Na2SO4. Filtration and concentration gave 8.94 g of an oily material, which was purified by column chromatography (SiO2 gel 50 g EtOAc in n-hexane 5-10%), to give 5.83 g (89.2%) of 5, as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([CH:17]=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.B(O[O-])=[O:20].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:17]([OH:20])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Reactant: O=BO[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
4′-Chloro-3-(1,1-dichloromethyl)-4-nitrobiphenyl (0.4 g, 1.26 mmol) was dissolved in methanolic sodium methoxide (15 mL; 0.5 M). The mixture was refluxed for 12 hours under argon. The solvent was evaporated and the residue diluted in 1,4-dioxane (15 ml) and water (1 ml), then a few drops of concentrated HCl were added. The reaction mixture was stirred at 100° C. for 4 hours. The solvent was then evaporated and the crude mixture purified by flash chromatography on silica gel (eluting with dichloromethane in petroleum ether) to yield the 4′-chloro-4-nitrobiphenyl-3-carbaldehyde (0.32 g, 1.26 mmol); m/z (APCI−) 260 (40%, [M−H]−), 231 (100%). This aldehyde (0.32 g, 1.26 mmol) was dissolved in acetic acid (5 mL) and sodium perborate (0.23 g, 1.5 mmol) was added. The resulting mixture was stirred at 50° C. for 16 h. The mixture was cooled, the solvent was evaporated, ethyl acetate was added and the organic layer washed with water, dried over MgSO4 and evaporated to yield the 4′-chloro-4-nitrobiphenyl-3-carboxylic acid (0.14 g, 41%); m/z [APCI−] 276 (100%, [M−H−], 247 (60%).