Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[CH3:33][O-:34].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:10]1[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=[C:2]([O:34][CH3:33])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: C[O-]
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)nc12
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2c(C)cc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2,4-dichloro-8-methyl-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (1.1 g, 2.15 mmol, Intermediate 13: step d) and dry sodium methoxide (0.58 g, 10.75 mmol) in toluene (10 mL) was heated in a sealed tube at 110° C. for 12 hours. The mixture was cooled to room temperature, diluted with DCM, stirred for 30 minutes at room temperature and the resulting suspension filtered through Celite®, rinsing several times with DCM. The solvents were removed under reduced pressure and the residue chromatographed (DCM/10% MeOH in DCM, gradient) to provide the title compound as a white solid after recrystallization from MeOH and drying under reduced pressure overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:63]([N:66]1[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]1)(=[O:65])[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][N:66]([C:63](=[O:65])[CH3:64])[CH2:67][CH2:68]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)c2cc3ncnc(NC(C)c4nc5cc(Cl)ccc5[nH]4)c3cc2Cl)CC1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-acetyl-piperazine in DMSO at ambient temperature.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C@H:12]1[CH2:16][C@H:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C@H:14]([CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[C@H:13]1[CH2:36][OH:37].OS([O-])(=O)=O.[K+]>C(Cl)Cl.C(N(CC)CC)C>[F:11][C@H:12]1[CH2:16][C@H:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C@H:14]([CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[C@H:13]1[CH:36]=[O:37]
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CO)[C@@H](F)C[C@@H]1OC1CCCCO1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@@H](F)C[C@@H]1OC1CCCCO1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
Oxalyl chloride (25 mL, 50 mmol) was dissolved in DCM (400 mL) and cooled to −78° C. under a nitrogen atmosphere, to which a solution consisting of DMSO (4.5 mL) in DCM (150 mL) was added. The reaction mixture was stirred for 15 minutes at −78° C. and a solution consisting of (Z)-isopropyl 7-((1R,2S,3S,5S)-3-fluoro-2-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step F, 12.94 g, 33.36 mmol) in DCM was subsequently added slowly. The reaction mixture was stirred for 40 minutes and triethylamine (28 mL) was subsequently added. Stirring was continued as the reaction mixture was allowed to warm to room temperature for 2 hours, monitoring by TLC. The reaction was acidified with 5% KHSO4, extracted with DCM, and the organic layers were washed twice with brine. After drying over sodium sulfate, filtration, and solvent removal under reduced pressure, the crude product was purified on silica gel, eluted with hexanes-ethyl acetate (85:15) to afford the title intermediate (10.31 g, 80%).
Reaction SMILES: Br[C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3)[N:4]([CH3:17])[N:3]=1.[CH3:18][N:19]1CCCC1>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]1[N:4]([CH3:17])[N:3]=[C:2]([C:18]#[N:19])[C:14]1=[CH:13]2
Reactant: COc1ccc2nc3c(cc2c1)c(Br)nn3C
Reactant: CN1CCCC1
Product: COc1ccc2nc3c(cc2c1)c(C#N)nn3C
Temperature: 0 °C

Procedure:
A mixture of 32.0 g 3-bromo-6-methoxy-1-methyl-1H-pyrazolo[3,4-b]quinoline (Example 32) and 20.2 g cuprous bromide in 220 ml N-methylpyrrolidine was stirred and heated at reflux for 3 hours. The reaction mixture was poured into ice-water, and the solid product was collected by filtration. The latter product was treated with dilute aqueous sodium cyanide and purified by extraction with ethyl acetate and chromatography to give 4.5 g 6-methoxy-1-methyl-1H-pyrazolo[3,4-b]quinoline-3-carbonitrile, bright-yellow solid, m.p. 190°-191° C., when recrystallized from methanol.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>C(O)C.[Ni]>[NH2:8][C:7]1[C:2]([F:1])=[C:3]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[C:4]([F:11])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccncc2)c1F
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(F)c(-c2ccncc2)c1F
Yield: 68 %

Procedure:
A solution of 4-(2,6-difluoro-3-nitrophenyl)pyridine (10.9 g) in ethanol (500 ml) was hydrogenated (50 p.s.i.) for 1 hour over 15 g of Raney Nickel. The reaction mixture was then filtered through diatomaceus earth and the filtrate was evaporated in vacuo to give the product as a white solid of m.p. 190°-192° C. (6.6 g, 68% yield). NMR (DMSO d6, 250 MHz): 8.7 (m, 2H), 7.5 (m, 2H), 6.95 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][N:6]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:5][N:6]=1
Reactant: CO
Reactant: Cc1ncc(CCC(=O)O)s1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnc(C)s1

Procedure:
A mixture of 31.7 g of 2-methyl-5-thiazolepropanoic acid, 3.2 ml of concentrated sulfuric acid and 300 ml of methanol was refluxed for 16 hours and was then concentrated to dryness. The residue was taken up in 100 ml of water and the pH was adjusted to 12-13 with addition of concentrated ammonium hydroxide. The mixture was extracted with methylene chloride and the extracts were dried over magnesium sulfate and was evaporated to dryness under reduced pressure to obtain 35 g of raw methyl 2-methyl-5-thiazolepropanoate. Its hydrochloride had a melting point of 115° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:27][CH:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:29].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1)=[N:27][CH:28]([CH3:29])[C:30]([CH3:33])([CH3:32])[CH3:31])#[N:24]
Reactant: CC(N)C(C)(C)C
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C
Yield: 46 %

Procedure:
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.8 mmol, 300 mg), 2-amino-3,3-dimethylbutane (0.88 mmol, 0.09 g) and triethylamine (0.88 mmol, 0.123 ml) in acetonitrile (2 ml) was stirred for 8 h at 75° C. After concentration the residue was purified by column chromatography (heptane:ethyl acetate 2:1) to give the title compound (140 mg, 46%) as white crystals. Mp 165.5-166.5° C.; EI SP/MS: 380 (M+); 1H-NMR (CDCl3): δ 0.92 (s, 9H),1.13 (d, 3H), 3.8 (m, 1H), 4.8 (br d, 1H), 7.74 (br s, 3H), 8.5 ppm (br, 1H); MA calc for C16H18F6N4 : C, 50.53%; H, 4.77%; N, 14.73%. Found: C, 50.48%; H, 4.74%; N, 14.45%.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:21]1([O:27][N:28]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH:31]([OH:36])[CH2:30][C:29]2([CH3:38])[CH3:37])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([O:27][N:28]2[C:29]([CH3:37])([CH3:38])[CH2:30][CH:31]([O:36][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:32][C:33]2([CH3:35])[CH3:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Yield: 69 %

Procedure:
The title compound is prepared in 69% yield from the reaction of octadecanoyl chloride with 1-cyclohexyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine following the procedure in Example 17. Purification (Waters Prep. 500A HPLC, 100:1 heptane:ethyl acetate) yields a white solid, m.p. 44°-47° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J14) (311 mg, 1.0 mmol) and 3-(3-imidazol-1-yl-phenyl)-3-oxo-propionic acid tert-butyl ester (Example K16) (286 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (160 mg, 31%).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:13]([CH2:17][CH3:18])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[CH2:17]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:9][NH:8][CH2:16]2)[CH3:18]
Reactant: CCc1cc2c(cc1C1CCOCC1)CN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(cc1C1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-ethyl-6-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 232.1 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)/[CH3:6].[C:18](#[N:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:4]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:25][N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[C:5]=1[CH3:6])=[O:17]
Reactant: COC(=O)/C=C(/C)Nc1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1c(-c2ccccc2)nn(-c2ccc([N+](=O)[O-])cc2)c1C
Yield: 75 %

Procedure:
According to AVV A, (Z-3-(4-nitrophenylamino)-but-2-enoic acid methylester (236.2 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into benzonitrile (3.0 ml, 29.4 mmol, 29.4 equiv.) for 14 hours at 120° C. The brown solid obtained as raw product (533.2 mg) was purified by means of column chromatography (silica gel (50 g), CH2Cl2/EtOAc 100:0→90:10→0:100), whereby the pure product was obtained in the form of a slightly yellowish solid (253.5 mg, 0.75 mmol, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[BH3-]C#[N:31].[Na+]>CO>[NH2:31][CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH2:19][CH2:18][N:10]([C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:9])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C[C@@H](c1ccc(Br)cc1)N(CCCC(N)c1ccccc1)C(=O)OC(C)(C)C
Yield: 93 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-(4-bromophenyl)ethyl(4-oxo-4-phenylbutyl)carbamate (193 mg, 0.43 mmol) and NH4OAc (670 mg, 8.6 mmol) in MeOH (15 mL) was added NaCNBH3 (270 mg, 4.3 mmol). The mixture was heated at reflux for 22 h and concentrated under reduced pressure. The residue was partitioned between 1 M aq NaOH (25 mL) and CH2Cl2 (2×50 mL). The combined CH2Cl2 layers were washed with brine (15 mL), dried over Na2SO4 and concentrated to afford tert-butyl 4-amino-4-phenylbutyl((1S)-1-(4-bromophenyl)ethyl)carbamate (179 mg, 93%) as an oil which was used without further purification. LC-MS Method 1 tR=1.57 min, m/z=449, 447.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[H-].[Na+].[N+]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20])([O-])=O>CS(C)=O>[N+:25]([C:21]1[CH:22]=[CH:23][CH:24]=[C:17]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]=1[C:19]#[N:20])([O-:27])=[O:26]
Reactant: OCCOc1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Product: N#Cc1c(OCCOc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.7 %

Procedure:
2-Phenoxyethanol (4.15 ml, 0.033 mole) is added to dimethylsulfoxyl sodium prepared from 1.39 g of 57 percent sodium hydride and 40 ml dimethylsulfoxide, giving a mixture of the solid salt of the alcohol after about 20 minutes. This mixture is added to a solution of 5.8 g (0.030 mole) 2,6-dinitrobenzonitrile in 20 ml of dimethylsulfoxide at 30°-40° C., and the resulting purple solution is stirred over night at room temperature. The solvent is removed at 70° C. on a rotary evaporator, and the residue is triturated with water. A solid is filtered off and it is dissolved in ethylacetate. The ethylacetate solution is washed twice with H2O, brine, and dried with calcium sulfate. Evaporation of the ethylacetate, gives 8.5 g of 2-nitro-6(2-phenoxyethoxy)benzonitrile, which is crystallized from 200 ml ethyl alcohol, giving 6 g, m.p. 129°-137.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=2[Cl:17])=[C:4]([CH2:18][O:19]C)[N:3]=1.C[Si](I)(C)C>S1(CCCC1)(=O)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=2[Cl:17])=[C:4]([CH2:18][OH:19])[N:3]=1
Reactant: COCc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Agent: C[Si](C)(C)I
Solvent: O=S1(=O)CCCC1
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)c(CO)n1

Procedure:
This compound was made from the compound of Example 2 by reaction with trimethylsilyl iodide in sulpholane at 80° C., mp. 101°-105° C.
Reaction SMILES: [ClH:1].[O:2]=[C:3]([NH:33][C:34]1[NH:35][CH2:36][CH2:37][CH2:38][N:39]=1)[CH2:4][CH2:5][C:6]1[CH:32]=[CH:31][C:9]2=[C:10]([CH2:13][CH:14]([NH:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:11][CH:12]=[C:8]2[CH:7]=1.[CH2:40]1COCC1>>[CH:10]([O:11][CH:12]([CH3:8])[CH3:40])([CH3:9])[CH3:13].[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[CH2:13][C:10]1[O:11][CH:12]=[C:8]2[CH:7]=[C:6]([CH2:5][CH2:4][C:3](=[O:2])[NH:33][C:34]3[NH:35][CH2:36][CH2:37][CH2:38][N:39]=3)[CH:32]=[CH:31][C:9]=12)[CH3:19].[ClH:1]
Reactant: C1CCOC1
Agent: CCOC(=O)C(Cc1occ2cc(CCC(=O)NC3=NCCCN3)ccc12)NC(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)OC(C)C
Reaction time: 0.17 h

Procedure:
3 ml of 2N hydrochloric acid is added to 339 mg of the ethyl ester of Example 3 in 20 ml of THF, the reaction medium is agitated for 10 minutes and evaporated under reduced pressure while adding toluene. After treatment with ether and isopropyl ether, 312 mg of the expected hydrochloric acid salt is obtained.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[H-].[Na+].Cl[C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1.O>O1CCCC1>[CH2:1]([O:6][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: C=CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-penten-1-ol (640 mg, 7.5 mmol) and sodium hydride (260 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH2:14])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16].[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][NH:14][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:8][CH2:9]2)=[CH:5][C:4]=1[O:15][CH3:16]
Reactant: CCCC(=O)Cl
Reactant: COc1cc2c(cc1F)CC=C2CCN
Agent: Cl
Product: CCCC(=O)NCCC1=CCc2cc(F)c(OC)cc21

Procedure:
Starting with 2-(6-fluoro-5-methoxy-1H-inden-3-yl)ethylamine hydrochloride and butyryl chloride, the title compound was synthesized in otherwise the same manner as Example 8 (yield 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[N:4]=[C:5]([S:45][CH3:46])[C:6](=[N:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:29]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([O:15][Si](C(C)C)(C(C)C)C(C)C)[C:8]=1[F:26].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[CH3:1][O:2][C:3](=[O:47])[N:4]=[C:5]([S:45][CH3:46])[C:6](=[N:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([CH2:36][NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH:29]=1)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]([OH:15])[C:8]=1[F:26]
Reactant: CCc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(=Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cc(O)c(F)c(C(=Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)C(=NC(=O)OC)SC)c1
Reaction time: 1.5 h
Yield: 85.7 %

Procedure:
To a mixture of {2-[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylimino]-2-(5-ethyl-2-fluoro-3-triisopropylsilanyloxyphenyl)-1-methylsulfanylethylidene}carbamic acid methyl ester (523 mg) and THF (10 mL) there was added a 1M THF solution of tetrabutylammonium fluoride (1.56 mL) under a nitrogen atmosphere. The mixture was stirred for 90 minutes, and then ethyl acetate (300 mL) and water (100 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated off, washed twice with water (100 mL) and once with saturated aqueous sodium chloride (100 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane mixture) to obtain the target compound (346 mg) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:19](O)=[O:20])=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.Cl.[O:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:19]([NH:30][CH:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)=[O:20])=[C:14]([C:16]([NH2:17])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: NC(=O)c1nc2n(c1C(=O)O)C1CC(C1)c1ccc(Br)cc1-2
Reactant: NC1CCOCC1
Agent: Cl
Product: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)C1CC(C1)c1ccc(Br)cc1-2

Procedure:
10-bromo-2-carbamoyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-3-carboxylic acid (0.1 g) was reacted with tetrahydro-2H-pyran-4-amine hydrochloride similarly to the conditions described in Example 2 to produce 10-bromo-N3-(tetrahydro-2H-pyran-4-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide. This intermediate was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 5.7 mg (10%) of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3-tetrahydropyran-4-yl-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2,3-dicarboxamide. M+1=516.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH:8][C:9]([CH3:18])([CH3:17])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:9]([CH3:17])([CH3:18])[CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:28](=[O:30])[NH:19][C:4]=2[CH:3]=1
Reactant: CC(C)(CN1CCOCC1)Nc1ccc(Br)cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CN1CCOCC1)n1c(=O)[nH]c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 139.1 %

Procedure:
Mix 4-bromo-N1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-benzene-1,2-diamine (3.76 g, 11.5 mmol), triethylamine (4.6 mL, 34.4 mmol) in THF (150 mL). Cool to 0° C. and carefully add solid triphosgene (2.0 g, 6.9 mmol). Allow the reaction to warm to room temperature and stir for 18 h. Cautiously quench the reaction with aqueous K2CO3 and extract into EtOAc. Dry (MgSO4) and concentrate to give 3.4 g yellow solid. Purify by column chromatography using 3% 3N NH3 in MeOH/methylene chloride to give 2.25 g (55%) title compound as a white solid, MS (es) 354, 356 (M+1), 352, 354 (M−1). HPLC(ISO80-10M) t=1.55.