Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:18]([OH:34])[C:19]([N:21]1[CH2:32][C@@H:31]([Cl:33])[CH2:30][C@H:22]1[C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])(C)(C)C.[CH3:42][O:43][C:44]1[C:52]2[O:51][C:50](C(O)=O)=[CH:49][C:48]=2[CH:47]=[CH:46][CH:45]=1>>[CH3:42][O:43][C:44]1[C:52]2[O:51][C:50]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:18]([OH:34])[C:19]([N:21]3[CH2:32][C@@H:31]([Cl:33])[CH2:30][C@H:22]3[C:23]([NH:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[O:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])=[CH:49][C:48]=2[CH:47]=[CH:46][CH:45]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Product: COc1cccc2cc(C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc3ccccc3)[C@H](O)C(=O)N3C[C@@H](Cl)C[C@H]3C(=O)NC(C)(C)C)oc12
Yield: 65.4 %

Procedure:
Following a procedure similar to that described in Example 16, but using 155 mg (0.26 mmol) of (4S)-1-[(2S,3S)-3-(N2 -t-butoxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide (prepared as described in Example 65) and 50 mg (0.26 mmol) of 7-methoxy-2-benzofurancarboxylic acid, 114 mg of the title compound were obtained as a colorless powder, melting at 125°-136° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:24][C:25]([F:28])([F:27])[F:26])=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:35][CH2:34]1)(=[O:32])=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:22])[NH:46][C:43]3[CH:44]=[CH:45][C:40]([CH2:39][N:36]4[CH2:35][CH2:34][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:38][CH2:37]4)=[CH:41][CH:42]=3)=[CH:17][CH:16]=2)[C:12]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)cc2)c1
Reaction time: 16 h

Procedure:
A mixture of 5′-tert-butoxycarbonylamino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid (50 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (35.2 mg), HBTU (49.6 mg) and N-Methylmorpholine (30 ul) in dry DMF (3 ml) was stirred for 16 hrs.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)C=CC=CC=1.[F:17][C:18]1([F:34])[O:22][C:21]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][C:20]=2[O:19]1>>[N:13]1[CH:12]=[CH:11][C:10]([NH:9][C:8]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:34])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:30]2)=[O:16])=[CH:15][CH:14]=1
Reactant: FC1(F)Oc2ccc(CN3CCNCC3)cc2O1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Product: O=C(Nc1ccncc1)N1CCN(Cc2ccc3c(c2)OC(F)(F)O3)CC1

Procedure:
The title compound was prepared from pyridin-4-yl-carbamic acid phenyl ester and 1-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.36-8.34 (d, J=6.8 Hz, 2H), 7.41-7.39 (d, J=5.8 Hz, 2H), 7.10 (s, 1H), 6.99 (s, 2H), 3.55-3.53 (m, 4H), 3.49 (s, 2H), 2.47-2.44 (m, 4H).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[C:13]2[N:12]=[C:11]3[N:14]([C:18]4[C:19]([CH3:26])=[N:20][C:21](Cl)=[N:22][C:23]=4[CH3:24])[CH2:15][CH2:16][CH2:17][N:10]3[C:9]=2[C:8]([CH:27]([O:32][CH:33]([F:35])[F:34])[C:28]([F:31])([F:30])[F:29])=[CH:7][CH:6]=1>O1CCCC1.O.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:4][C:5]1[C:13]2[N:12]=[C:11]3[N:14]([C:18]4[C:23]([CH3:24])=[N:22][C:21]([CH3:1])=[N:20][C:19]=4[CH3:26])[CH2:15][CH2:16][CH2:17][N:10]3[C:9]=2[C:8]([CH:27]([O:32][CH:33]([F:34])[F:35])[C:28]([F:30])([F:31])[F:29])=[CH:7][CH:6]=1
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: C[Mg]Br
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Methylmagnesium bromide (1.0 M solution in tetrahydrofuran, 0.49 mL, 0.490 mmol) was added dropwise to a stirred suspension of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (163 mg, 0.328 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (17.8 mg, 0.0328 mmol) in tetrahydrofuran (1.3 mL) at 0° C., and the mixture was stirred at room temperature for 7 hr. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (49.8 mg, 0.105 mmol, 32%).
Reaction SMILES: N1C=CC(C(Cl)=O)=CC=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.[N:32]1[CH:37]=[CH:36][C:35]([C:38]([N:40]=[C:41]=[S:42])=[O:39])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(O)C>[N:32]1[CH:37]=[CH:36][C:35]([C:38]([N:40]=[C:41]=[S:42])=[O:39])=[CH:34][CH:33]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:41]([NH:40][C:38]([C:35]2[CH:34]=[CH:33][N:32]=[CH:37][CH:36]=2)=[O:39])=[S:42])=[CH:27][CH:26]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccncc1
Agent: O=C(N=C=S)c1ccncc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccncc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
4-Pyridinecarbonyl isothiocyanate was prepared using commercially available 4-pyridinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-pyridinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 94%).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([NH2:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:33]1[N:38]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:30][N:32]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: CC(C)(C)C(N)=NO
Product: CC(C)(C)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
85 mg (0.20 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]-piperidine-3-carboxylic acid (Example 108A) and 35 mg (0.3 mmol) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 2. Yield: 61 mg (60% of theory).
Reaction SMILES: [C:1]1([C:11]2[NH:12][C:13]3[C:18]([N:19]=2)=[C:17]([O:20][C@H:21]2[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22]2)[N:16]=[CH:15][N:14]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[S:29]([NH2:32])(=[O:31])=[O:30]>CC(N(C)C)=O.CC#N>[S:29](=[O:31])(=[O:30])([O:27][CH2:26][C@H:23]1[CH2:24][CH2:25][C@H:21]([O:20][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[C:18]=2[N:19]=[C:11]([C:1]2[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=2)[NH:12]3)[CH2:22]1)[NH2:32]
Reactant: NS(=O)(=O)Cl
Reactant: OC[C@H]1CC[C@H](Oc2ncnc3[nH]c(-c4cccc5ccccc45)nc23)C1
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: NS(=O)(=O)OC[C@H]1CC[C@H](Oc2ncnc3[nH]c(-c4cccc5ccccc45)nc23)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a solution of ((1S,3S)-3-{[8-(1-naphthyl)-9H-purin-6-yl]oxy}cyclopentyl)-methanol (66.1 mg, 0.000183 mol) in DMA (8.12 mL) at 0° C. was added chlorosulfonamide (106 mg, 0.000917 mol) in CH3CN (2.0 mL). The reaction was stirred at 0° C. for 10 mins, then 23° C. for 3 hours. The reaction was quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (2×), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (0 to 6% MeOH/CH2Cl2) to obtain 56.3 mg (70%) of the title compound as a white solid. 1H NMR (CD3OD, 400 MHz) δ: 8.52-8.48 (m, 2H), 8.10-8.07 (m, 1H), 8.01-7.98 (m, 1H), 7.90-7.87 (m, 1H), 7.65-7.57 (m, 3H), 5.89-5.85 (m, 1H), 4.12-4.07 (m, 2H), 2.75-2.66 (m, 1H), 2.30-2.21 (m, 2H), 2.16-2.01 (m, 2H), 1.93-1.85 (m, 1H), 1.62-1.53 (m, 1H) ppm. LC/MS: Rt=1.38 min, ES+ 442 (FA standard).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[N+:19]([C:22]1[CH:23]=[C:24]2[C:29](=O)[O:28][C:26](=[O:27])[C:25]2=[CH:31][CH:32]=1)([O-:21])=[O:20]>C(#N)C>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([N:1]3[C:29](=[O:28])[C:24]4[C:25](=[CH:31][CH:32]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=4)[C:26]3=[O:27])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: CC#N
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 21 %

Procedure:
4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (1.22 g, 5 mmol) was dissolved in refluxing acetonitrile (20 cm3) and a solution of 4-nitrophthalic anhydride (0.96 g, 5 mmol) in acetonitrile (10 cm3) was added dropwise with stirring to precipitate a yellow gum. The mixture was refluxed for a further 2-3 minutes then cooled in ice. The precipitated material was collected and heated in acetic anhydride on a steam bath for 1/2 hour. The solvent was evaporated. Methanol was added to the residue and evaporated to destroy excess acetic anhydride. The residue was then dissolved in very dilute aqueous acetic acid and insoluble material filtered off. The filtrate was basified by addition of conc. ammonia to precipitate a gum, which was triturated with methanol under reflux to give the title compound as a bright orange solid (0.44 g, 21%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]2[C:15]=1[C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[NH:12][C:11](=O)[CH2:10]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C(=O)(O)[O-].[Na+].O>COCCOCCOC>[Cl:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]2[C:15]=1[C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[NH:12][C:11](=[S:22])[CH2:10]2
Reactant: O=C1Cn2c(c(Cl)c3ccccc32)-c2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: S=C1Cn2c(c(Cl)c3ccccc32)-c2ccccc2N1
Temperature: 110 °C
Yield: 15.7 %

Procedure:
A mixture of 12.5 g 13-chloroindolo[1,2-d][1,4]benzodiazepin-6(7H)-one, 22.6 g phosphorus pentasulfide and 8.6 g sodium bicarbonate in 240 ml diglyme was heated at 110° C. for two hours. The resulting mixture was cooled and poured into 2.5 L water to precipitate a solid. The solid was collected, washed with water and dried (P2O5) to give 11.9 g crude product. Recrystallization of 3.3 g from toluene (300 ml) gave 2.08 g fluffy solid, m.p. 280°-282° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C@H:13]([C:17]([NH2:19])=[O:18])[CH:14]([CH3:16])[CH3:15].C(NC(C)C)(C)C.COCC(O)C>>[CH3:15][CH:14]([CH3:16])[CH:13]([NH:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[C:17]([NH2:19])=[O:18]
Reactant: Clc1ccnc2ccccc12
Reactant: CC(C)[C@H](N)C(N)=O
Solvent: COCC(C)O
Solvent: CC(C)NC(C)C
Product: CC(C)C(Nc1ccnc2ccccc12)C(N)=O
Yield: 15.6 %

Procedure:
4-Chloroquinoline (0.82 g, 5 mmol), valinamide (0.64 g, 5.5 mmol) and diisopropylamine (1.9 ml, 11 mmol) were mixed with 1-methoxy-2-propanol (8 ml) and heated with stirring at reflux for 48 hours. The solvent was removed under reduced pressure, the residue was partitioned between water and ethyl acetate, the phases were separated, the aqueous phase was washed 3 times with ethyl acetate and basified with 50% NaOH. A precipitate formed that was filtered off and dried in air to give 0.2 g of a solid (0.78 mmol, 14%). MS (APCI) M/z=243.6 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:32]=[CH:31][C:8]([C:9]([NH:11][C:12]2[C:16]([NH:17]C(=O)OC(C)(C)C)=[CH:15][N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[B-](F)(F)(F)[F:34].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl.CN(C)C=O>[C:1]([NH:4][C:5]1[CH:32]=[CH:31][C:8]([C:9]([NH:11][C:12]2[C:16]([NH2:17])=[C:15]([F:34])[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CC(=O)Nc1ccc(C(=O)Nc2nn(-c3ccccc3)cc2NC(=O)OC(C)(C)C)cc1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=O)Nc2nn(-c3ccccc3)c(F)c2N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3-{[4-(acetylamino)benzoyl]amino}-1-phenyl-1H-pyrazol-4-yl)carbamate (15 mg, 0.034 mmol) in methylene chloride (1 mL) and dimethylformamide (1 mL) was added selectfluor (24 mg, 0.069 mmol) and the resulting solution was stirred overnight at rt. The reaction was evaporated to dryness and purified by reverse phase LC to give the desired product as white solid. ESIMS calcd 454.18 (M++H), found 454.2 (M++H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([O:24][C:25]([C:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH2:17]([O:24][C:25]([C:27]1([NH:32][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:5][CH:4]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCC1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1-c1ccc(CNC2(C(=O)OCc3ccccc3)CCCC2)cc1
Temperature: 0 °C

Procedure:
A mixture of 2.72 g (10 mmol) of 4-bromomethyl-2'-cyano-biphenyl, 2.63 g (12 mmol) of 1-aminocyclopentane-carboxylic acid benzyl ester, 3.4 ml (20 mmol) of Hunig base and 10 ml of N,N-dimethylformamide is heated to 130°-140° (bath temperature) for 2 hours while stirring. After cooling, the reaction mixture is poured onto 50 ml of ice/water. Extraction using ethyl acetate yields the crude N-(1-benzyloxycarbonylcyclopentyl)-N-(2'-cyanobiphenyl-4-ylmethyl)-amine, which forms a hydrochloride melting between 180° and 182° (ethanol/diethyl ether).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.N([Cl:13])=O>CCOCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=NO)cc1
Reactant: O=NCl
Solvent: CCOCC
Product: Cc1ccc(C(Cl)=NO)cc1
Yield: 29.7 %

Procedure:
By the method of Example I-B, 167.5 g of 4-methylbenzaldoxime in 1200 ml of ether was treated with 88.4 g of nitrosyl chloride. After removal of the ether, the product was recrystallized from hexane to give 62.5 g of 4-methylbenzohydroximoyl chloride, m.p. 70°-73°.
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15]([OH:17])=O)([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[C:1]1([C:7]23[CH2:14][CH2:13][C:10]([C:15]([Cl:21])=[O:17])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C12CCC(c3ccccc3)(CC1)CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C12CCC(c3ccccc3)(CC1)CC2
Temperature: 25 °C

Procedure:
To an ice-water cooled solution of 4-phenylbicyclo[2.2.2]octane-1-carboxylic acid (479 mg, 2.07 mmol) in DCM (20 mL) was added DMF (2-3 drops) followed by oxalyl chloride (0.20 mL, 2.14 mmol). The reaction mixture was allowed to warm to ambient temperature overnight and then solvent was evaporated under reduced pressure to leave crude 4-phenylbicyclo[2.2.2]octane-1-carbonyl chloride which was used directly in the next stage.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH:11]=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)[O:4]1.CCN(C(C)C)C(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:18]1[CH2:19][CH2:20][CH:15]([N:13]2[CH:14]=[C:10]([B:5]3[O:6][C:7]([CH3:8])([CH3:9])[C:3]([CH3:21])([CH3:2])[O:4]3)[CH:11]=[N:12]2)[CH2:16][CH2:17]1)(=[O:34])=[O:33]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2cnn(C3CCN(S(C)(=O)=O)CC3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
A suspension of 4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine hydrochloride (200 mg, 0.64 mmol) in DCM (4 mL) was cooled to 0° C. and treated with DIPEA (280 μL, 1.6 mmol). Methanesulfonyl chloride (74 μL, 0.96 mmol) was added dropwise slowly and the mixture was stirred at RT for 18 hours. The mixture was concentrated in vacuo, taken up in MeOH and purified by MDP to afford 100 mg (40%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.34 (s, 12H) 2.05-2.22 (m, 2H) 2.22-2.34 (m, 2H) 2.81-2.90 (m, 4H) 2.90-3.04 (m, 3H) 3.86-4.03 (m, 2H) 4.26-4.43 (m, 1H) 7.77 (s, 1H) 7.81-7.90 (m, 1H).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[CH3:10][O:11][C:12]1[C:13]([CH3:21])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C(Cl)Cl.O>[CH3:10][O:11][C:12]1[C:13]([CH3:21])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:16]
Reactant: COc1cccc(C(=O)Cl)c1C
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C(=O)NNC(C)(C)C)c1C
Temperature: 25 °C
Yield: 96 %

Procedure:
To a stirred suspension of tert-butylhydrazine hydrochloride (397 g, 3.27 mol) in methylene chloride (2 L) at 0° C., was added sodium hydroxide (50% aqueous, 260 g) diluted with water (400 mL). Following this, 3-methoxy-2-methylbenzoyl chloride (140 g, 0.78 mol) in methylene chloride (1 L) and sodium hydroxide (50% aqueous, 80 g) diluted with water (400 mL) were added concurrently at -20° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and after additional 30 minutes, the organic layer was washed with water (4×500 mL), dried over magnesium sulfate and stripped to yield N-(3-methoxy-2-methylbenzoyl)-N'-tert-butylhydrazine (177 g, 96% yield). 1H-NMR (CDCl3)δppm 1.19 (s, 9H, t-Bu), 2.29 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 6.90 (d, 1H, C-4 or 6), 6.95 (d, 1H, C-4 or C6) 7.19 (dd, 1H, C-5).
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>>[F:23][C:3]1[C:2]([C:33]#[C:32][C:30]([OH:34])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH3:31])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)c1ccccn1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(O)c3ccccn3)cc1-2
Yield: 10 %

Procedure:
10-bromo-9-fluoro-N3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with 2-(pyridin-2-yl)but-3-yn-2-ol via General Procedure E to yield 8.4 mg (10%) of (±)-9-fluoro-10-[3-hydroxy-3-(2-pyridyl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[N:5][CH:4]=1)=[O:2].P([O-])(O)(O)=[O:21].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:8]([C:6]2[S:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][N:5]=2)[CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(C=O)s2)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(C(=O)O)s2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
tert-Butyl 3-(5-formylthiazol-2-yl)pyrrolidine-1-carboxylate (3.65 g, 12.93 mmol) was suspended in water (35 ml) and t-butanol (60 ml). Sodium dihydrogenphosphate (2.094 g, 17.45 mmol) was added, followed by 2-methylbut-2-ene (5.34 ml, 50.4 mmol). After 5 minutes, sodium chlorite (2.92 g, 32.3 mmol) was added in portions over about 5 minutes (mildly exothermic). The reaction was stirred for 1 hour at room temperature, then additional 2-methyl-2-butene (2 mL) was added. After stirring for 2 hours at room temperature, the reaction was concentrated and water (100 mL) was added. The mixture was adjusted to pH 2 by addition of 1N hydrochloric acid, then extracted dichloromethane. The organic extracts were dried over sodium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8]
Reactant: O=C(O)c1ccsc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccsc1
Yield: 91.7 %

Procedure:
3-Thiophene carboxylic acid (10.04 g, 78.3 mmol) was dissolved in dichloromethane (250 ml) and 4-dimethylaminopyridine (9.57 g, 78.3 mmol), N,O-dimethylhydroxylamine hydrochloride (7.64 g, 78.3 mmol), N-methylmorpholine (8.6 ml, 78.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.01 g, 78.3 mmol) added and the resultant solution stirred for 24 h at room temperature. The reaction was diluted with dichloromethane (100 ml) and washed with aqueous 2M hydrochloric acid (3×30 ml), aqueous saturated sodium bicarbonate solution (2×30 ml) and water (3×30 ml). The organic phase was dried (magnesium sulphate), filtered and evaporated to give the title compound as a colourless oil (12.3 g, 92%).