Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[I:13]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([I:13])[C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: II
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Cc1cc([N+](=O)[O-])c(N)c(I)c1C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
Silver sulphate (103 g, 0.33 mol) was added over 5 minutes to a stirred suspension of 4,5-dimethyl-2-nitroaniline (50.0 g, 0.30 mol) in ethanol (1500 mL) at 20° C. Iodine (84.0 g, 0.33 mol) was added in portions, and the resulting mixture was stirred for 30 minutes at 20° C. The mixture was filtered, and the filter cake washed thoroughly with ethanol (1 L) and dichloromethane (1 L). The filtrate was concentrated under reduced pressure, and the residue was redissolved in dichloromethane (500 mL), and washed with 10% aqueous sodium metabisulphite (2×500 mL), and brine (250 mL). The solution was dried (MgSO4) and concentrated under reduced pressure to give 4,5-dimethyl-6-iodo-2-nitroaniline (82.1 g, 93%) as an orange solid.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:15]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:22]([O:24]C)=[O:23])[CH:12]=3)[N:7]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[OH-].[Na+].O>CO>[S:1]1[C:5]([C:6]2[C:15]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:22]([OH:24])=[O:23])[CH:12]=3)[N:7]=2)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of methyl 2-(benzo[b]thiophen-2-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylate (70 mg, 0.17 mmol) in MeOH (20 mL) was added sodium hydroxide (28 mg, 0.69 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 4 with HCl (1N). The solids were collected by filtration to afford 2-(benzo[b]thiophen-2-yl)-3-(piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (60 mg, 89%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:21][C@@H:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@@H:9]2[CH2:8]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:21][C@@H:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:13][C@@H:9]2[CH2:8]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(O)C[C@H]2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(OS(C)(=O)=O)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.18 mL, 2.33 mmol), was added dropwise to a solution of 1,1-dimethylethyl (3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.44 g, 1.94 mmol) and triethylamine (0.81 mL, 5.81 mmol) in 10 mL dichloromethane at 0° C. and the reaction mixture was stirred for 1 h at room temperature. The solvent was evaporated, the resulting crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), brine, 1M aqueous hydrochloric acid and brine again. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude 1,1-dimethylethyl (3aR,6aS)-5-{[(methylsulfonyl)oxy]}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate was used without further purification. MS (EI) for C13H23NO5S: 306 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:14]1([NH2:17])[CH2:16][CH2:15]1>ClCCl>[CH:14]1([NH:17][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(S(=O)(=O)NC2CC2)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To 4-chlorosulfonylbenzoic acid (10.0 g, 45.3 mmol) in dichloromethane (350 mL) at 0° C. was added cyclopropanamine (15.5 g, 19 mL, 271.9 mmol). The reaction mixture was allowed to warm to room temperature over 16 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in water (150 mL) and acidified using hydrochloric acid. The aqueous layer was extracted with EtOAc (2×200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 4-(cyclopropylsulfamoyl)benzoic acid (10.0 g, 92%) as a white solid. ESI-MS m/z calc. 241.0. found 242.5 (M+1)+; Retention time: 0.84 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.91 (d, J=2.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 2H), 2.03-1.90 (m, 1H), 0.38-0.28 (m, 2H), 0.23-0.15 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH3:25])[CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: COc1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: COc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1
Yield: 25.8 %

Procedure:
The title compound (0.095 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 3-methoxy-benzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C21H22ClN3O, 367.15. found, m/z 368.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.60 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.32 (d, J=7.9 Hz, 1H), 6.92 (dd, J=8.2, 2.1 Hz, 1H), 6.84 (s, 1H), 6.80 (d, J=8.2 Hz, 1H), 5.57 (s, 2H), 3.79 (s, 3H), 3.48-3.46 (br m, 2H), 3.44-3.42 (br m, 2H), 3.33-3.31 (br m, 2H), 3.16-3.14 (br m, 2H).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][N:30]=4)[N:25]=[CH:24][C:23]=3[N+:32]([O-])=O)[O:17][N:16]=2)=[CH:11][CH:10]=1>[Pt].C(O)(C)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][N:30]=4)[N:25]=[CH:24][C:23]=3[NH2:32])[O:17][N:16]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Nc1cnc2cccnc2c1NCc1cc(-c2ccc(F)cc2)no1

Procedure:
A Parr vessel was charged with 5% platinum on carbon (0.12 g), purged with nitrogen, and then charged sequentially with toluene (2 mL), N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-3-nitro[1,5]naphthyridin-4-amine (6.00 g, 16.4 mmol), toluene (73 mL), and isopropanol (5 mL). The vessel was purged with hydrogen three times and then placed under hydrogen pressure (50 psi, 3.4×105 Pa) for 16 hours. An analysis by high-performance liquid chromatography (HPLC) indicated the presence of starting material. The catalyst was removed by filtration and washed with hot dichloromethane and methanol. The filtrate was concentrated under reduced pressure, and the residue was dissolved in hot methanol (100 mL) and added to a Parr vessel. Catalytic 5% platinum on carbon (0.12 g) was added, and the reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) for four hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to provide N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}[1,5]naphthyridine-3,4-diamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]([O:29]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(c3ccc(Cl)cc3)OC2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.8 g, 13 mmol) in CH2Cl2 (50 mL) was added 3-chloroperbenzoic acid (3.8 g, 17.0 mmol) and triethylamine (3.6 mL, 20 mmol). The solution was stirred at room temperature for about 4 hours. A white precipitate was observed. The reaction was quenched with aqueous sodium bicarbonate, extracted with CH2Cl2, and the organic layers were evaporated in vacuo. The residue was purified by flash chromatography on silica gel (35 g SiO2, gradient elution from 100% hexane to 100% ethyl acetate) to yield the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[N:31]=[CH:32][S:33][CH:34]=1)CCC>C1(C)C=CC=CC=1.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>[F:23][C:15]1[CH:14]=[C:13]([C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[N:31]=[CH:32][S:33][CH:34]=4)=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: Cc1onc(-c2ccc(Br)cc2)c1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccc(-c3cscn3)cc2)c1-c1ccc(S(C)(=O)=O)c(F)c1
Yield: 90.1 %

Procedure:
A mixture of 3-(4-bromophenyl)-4-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methylisoxazole (219 mg, 0.53 mmol), tributyl(1,3-thiazol-4-yl)tin (200 mg, 0.53 mmol) and tetrakis(triphenylphosphine)palladium (62 mg, 0.053 mmol) in toluene (5 ml) was refluxed for 26 h. The mixture was evaporated and the obtained residue was chromatographed on a column of silica gel (40 g) as eluting with ethyl acetate/hexane (1/2) to give 198 mg of a white solid, which was recrystallized from ethyl acetate/hexane to afford 128 mg (58%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[NH:11][C:4]=2[CH:3]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22].[OH-].[Na+].C(C(C)=O)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]([CH2:19][CH2:20][CH2:21][Cl:22])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1OCO2
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCC(C)=O
Product: ClCCCN1c2ccccc2OCOc2ccc(Cl)cc21
Temperature: 20 °C
Reaction time: 10 h

Procedure:
A mixture of 14.9 g. (0.06 moles) of 2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine, 37.8 g. (0.24 moles) of 1-bromo-3-chloropropane, 19.6 g. (0.48 moles) of sodium hydroxide and 180 ml. of methyl ethyl ketone is stirred under reflux for 10 hours. Thereafter further 19.6 g. (0.48 moles) of sodium hydroxide are added and the stirring under reflux continued for 10 hours. The reaction mixture is cooled to 20° C. and poured to 300 g. of broken ice under stirring. 100 ml. of benzene are added, the organic phase is separated and the solvent is removed in vacuo. The residue is subjected to vacuum destillation. There are obtained 14.3 g. of a yellow viscous liquid, b.p./0.3 mmHg: 165° to 171° C. This liquid solidifies upon trituration with petrol ether. Recrystallization from isopropanol affords 12.5 g. (64.0%) of a white product, melting at 105° to 108° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH3:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][C:7]=12)#[CH:2].[OH:23][CH2:24][CH2:25][NH:26][S:27]([C:30]1[S:31][C:32](Br)=[CH:33][CH:34]=1)(=[O:29])=[O:28]>>[OH:23][CH2:24][CH2:25][NH:26][S:27]([C:30]1[S:31][C:32]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([CH3:12])=[CH:10][C:9]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=4)=[N:8][C:7]=23)=[CH:33][CH:34]=1)(=[O:29])=[O:28]
Reactant: C#Cc1cnn2c(C)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCCO)c1ccc(Br)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C#Cc3ccc(S(=O)(=O)NCCO)s3)cnn12

Procedure:
The title compound was prepared from 3-ethynyl-7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.12) (75 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-hydroxy-ethyl)-amide (example B.59) according to general procedure II. Obtained as a yellow solid (87 mg, 68%). MS (ISP) 503.3 [(M+H)+]; mp 162–164° C.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1>>[CH3:13][C:12]1[C:7]([NH:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(N[C@H]2CC[C@H](O)CC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using trans-4-aminocyclohexanol instead of cyclopentanamine. The crude material was purified by crystallization from ethanol to afford the titled compound as a hydrochloride salt as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.18-1.26 (m, 2H), 1.32-1.44 (m, 2H), 1.67 (d, J=11.28 Hz, 2H), 1.80-1.99 (m, 5H), 2.33 (s, 3H), 3.45-3.55 (m, 1H), 3.75-3.83 (m, 1H), 4.72 (s, 2H), 7.33 (bs, 1H), 7.44 (d, J=7.79 Hz, 1H), 7.83 (t, J=7.12 Hz, 1H), 8.53 (d, J=4.30 Hz, 1H); MS (ESI) m/z 328.3 (M+1)+.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([F:20])=[CH:18][C:10]3[NH:11][C:12](S(C)(=O)=O)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[Br:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1>N1C=CC=CC=1.CCOC(C)=O>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([F:20])=[CH:18][C:10]3[NH:11][C:12]([O:34][C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([Br:27])[CH:29]=4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Reactant: Oc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Fc1cc2[nH]c(Oc3cccc(Br)c3)nc2cc1-c1ccc(-c2ccccc2)cc1
Reaction time: 48 h

Procedure:
To a solution of compound 13-6 (1.53 g, 4.2 mmol) in 20 mL in pyridine was added 3-bromo-phenol (1.4 g, 8.4 mmol). The reaction mixture was heated to reflux and allowed to stir for 48 h. The reaction mixture was diluted with EtOAc (150 mL) and washed three times with 100 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried over MgSO4 filtered and concentrated in vacuo. The crude was purified on ISCO (EtOAc/Hexanes=1/1) to yield the title compound 13-7 along with recovered starting material 13-6.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.C(#N)C.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].P([O-])(O)(O)=O.[Na+]>[Cu](I)I.C(N(CC)CC)C>[CH3:18][Si:17]([C:15]#[C:16][C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ccc(Br)o1
Agent: I[Cu]I
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)o1

Procedure:
A solution of 5 g of the product of Stage A, 15 ml of acetonitrile, 15 ml of triethylamine, 4.5 ml of ethynyltrimethylsilane, 170 mg of (triphenylphosphine)palladium chloride and 30 mg of copper iodide was heated at 40° C. for 2 and a half hours and then allowed to return to room temperature and was poured into an aqueous sodium dihydrogenphosphate solution. The mixture was extracted with ethyl acetate and the extract was washed with water and dried. The solvent was evaporated to obtain after chromatography on silica (eluent: 95/5 hexane/ethyl acetate) 4.75 g of the expected product.
Reaction SMILES: Cl[CH:2]([N:12]=[C:13]=[O:14])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].[F:15][C:16]([F:31])([F:30])[C:17]1[CH:18]=[C:19]([NH:23][C:24]2[CH2:28][CH2:27][C:26](=[O:29])[CH:25]=2)[CH:20]=[CH:21][CH:22]=1>ClCCl>[O:14]=[C:13]1[N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:30])[F:31])[CH:18]=2)[C:24]2[CH2:28][CH2:27][C:26](=[O:29])[C:25]=2[CH:2]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[F:11])[NH:12]1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC1
Reactant: N#Cc1ccc(C(Cl)N=C=O)c(F)c1
Solvent: ClCCl
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)c(F)c1

Procedure:
A solution of 4-(chloro(isocyanato)methyl)-3-fluorobenzonitrile (Step 1, 3.05 g, 14.5 mmol) in dichloromethane (10 mL) is added to a solution of 3-(3-(trifluoromethyl)-phenylamino)cyclopent-2-enone (3.50 g, 14.5 mmol) in dichloromethane (10 mL), and the mixture is heated at reflux over night. All volatiles are removed under reduced pressure, and the residue is purified by reversed phase HPLC (Agilent ZORBAX™ SB-C18, gradient of acetonitrile in water, 0.1% formic acid). Yield: 474 mg; ESI mass spectrum [M+H]+=416; Retention time HPLC: 0.94 min (Z017_504). LB5FAI00917
Reaction SMILES: [Br:1]Br.[CH2:3]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1C=CC=CC=1)[CH2:4]C=C>C(Cl)Cl.O>[Br:1][CH2:11][CH:10]1[O:9][C:8](=[O:17])[NH:7][CH2:3][CH2:4]1
Reactant: BrBr
Reactant: C=CCCNC(=O)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C1NCCC(CBr)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (11 g, 68 mmol) was added to a mixture of benzyl but-3-en-1-ylcarbamate (7 g, 34 mmol) in DCM at room temperature under N2. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc) to afford 6-(bromomethyl)-1,3-oxazinan-2-one. 1H NMR (400 MHz, CDCl3) δ 6.14 (s, 1H), 4.49-4.45 (m, 1H), 3.59-3.56 (m, 1H), 3.46-3.39 (m, 3H), 2.24-2.20 (m, 1H), 1.95-1.89 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(Cl)Cl>[C:16]([O:20][C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][N:26]([S:12]([C:10]2[C:11]3[C:2]([Br:1])=[CH:3][N:4]=[CH:5][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:14])=[O:13])[CH2:25]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A solution of 4-bromo-5-isoquinolinesulfonyl chloride (0.50 g) prepared according to a known method (described in Japanese Patent No. 2763791), and (S)-3-(tert-butoxycarbonylamino)pyrrolidine (0.33 g, Tokyo Kasei Kogyo) in methylene chloride (5 ml) was added with triethylamine (0.68 ml, Wako Pure Chemical Industries) at 0° C., and the mixture was stirred at the same temperature for 30 minutes, and then further stirred at room temperature for 5 hours. The reaction mixture was washed with saturated brine (10 ml), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (0.62 g).
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10][CH3:11])[N:5]=[CH:4][CH:3]=1.CC(=CC)C.O.Cl([O-])=[O:19].[Na+]>CC(O)(C)C>[I:1][C:2]1[C:7]([C:8]([OH:19])=[O:9])=[C:6]([O:10][CH3:11])[N:5]=[CH:4][CH:3]=1
Reactant: COc1nccc(I)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1nccc(I)c1C(=O)O
Reaction time: 0.08 h

Procedure:
To a solution of 4-iodo-2-methoxynicotinaldehyde (1 g, 3.58 mmol) in t-BuOH (6 mL), cooled at 25° C., is added 2-methyl-2-butene (6 mL, 2 M solution), Na2HPO4 (1.2 g) and water (3 mL). The reaction mixture is stirred for 5 minutes and sodium chlorite (800 mg, 8.9 mmol) is added slowly. Stirring of the mixture is continued until the aldehyde is completely consumed (3 hours, monitored by LCMS). The reaction is quenched with aq. formic acid. The mixture is partitioned between ethyl acetate (100 mL) and the organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The white powder was used for the next reaction without any further purification. 1H NMR 400 MHz (DMSO-d6) δ 10.06 (s, 1H), 7.89 (d, 1H, J=5.6 Hz), 7.48 (d, 1H, J=5.6 Hz), 3.87 (s, 1H); MS m/z 294.1 (M+1). MS m/z 280.01 (M+1).
Reaction SMILES: [NH2:1][C:2]([CH3:14])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>C1(C)C(C)=CC=CC=1>[CH2:7]([O:6][CH2:5][C:2]1([CH3:14])[CH2:3][O:4][C:22]([C:21]2[CH:25]=[CH:26][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)=[N:1]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(N)(CO)COCc1ccccc1
Solvent: Cc1ccccc1C
Product: CC1(COCc2ccccc2)COC(c2ccc([N+](=O)[O-])cc2)=N1
Reaction time: 15 h

Procedure:
2-Amino-3-benzyloxy-2-methylpropanol (13.5 grams) and 4-nitrobenzoic acid (11.7 grams) in dry xylene (100 milliliters) were heated together under reflux for 24 hours using a Dean-Stark trap for collection of the water formed during the reaction. The cooled solution was evaporated to dryness under reduced pressure and the residue was treated with ether and allowed to stand for 15 hours at 0°C. The yellow solid formed was recrystallized from ethanol to yield the desired product, melting point 65°-66°C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1>>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CCCCCCO)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCN(C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 210 g (1.01 mol) of N-(6-hydroxyhexyl)-N-methylaniline, 112 g (1.10 mol) of acetic anhydride, and 86 g (1.1 mol) of pyridine was heated at reflux with stirring for 2 hours. After cooling, the solution was poured onto 500 g of ice and extracted with ethyl acetate (4×300 mL). The combined extracts were dried (MgSO4) and the solvent was removed at reduced pressure. The residue was distilled in vacuo, collecting the fraction boiling at 130° C. (0.01 mm). Yield: 231 g (93%) of a colorless oil.