Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH:16]=O)[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:18][NH2:19]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][NH:19][CH3:18])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(CC=O)C=CCCC2)c1
Reactant: CN
Solvent: CO
Product: CNCCC1(c2cccc(OC)c2)C=CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g of 1-(m-methoxyphenyl)-2-cyclohexene-1-acetaldehyde is dissolved in 10 ml of methanol, and after treatment with 10 ml of methylamine, the mixture is stirred at room temperature overnight with a magnetic stirrer in a bomb tube. After evaporation of the solvent, the residue is dissolved in ethanol. Then, the solution is treated with 0.5 g of sodium borohydride, stirred at room temperature for 2 hours. The solvent is removed by evaporation, and the residue is taken up with 3 N hydrochloric acid. The aqueous phase is extracted with ether and made alkaline by the addition of concentrated ammonia, whereupon the resulting rac. 1-(m-methoxyphenyl)-N-methyl-2-cyclohexene-1-ethylamine is taken up in methylene chloride. The hydrochloride of this compound melts at 177°-179° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:18][CH:19]=[CH2:20])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2].CO.[Br:23]Br.C[O-].[Na+]>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1([CH2:18][CH2:19][CH2:20][Br:23])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: C=CCC1(C(=O)OCC)CCCCC1c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C1(CCCBr)CCCCC1c1ccccc1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
The 2-phenyl-1-(2-propenyl)-cyclohexanecarboxylic acid ethyl ester (4.08 g, 15 mmol) was dissolved in THF (10 ml) and cooled to 0°, under nitrogen. Upon addition of 5.2 ml of 1M BH3 -THF, the solution was stirred at 0° for 30 min. then at RT for 30 min. The flask was cooled to 0° and 0.5 ml MeOH was added to destroy any excess hydride. Bromine (1 ml, 20 mmol) was added dropwise followed by the addition of 30 mmol of freshly prepared NaOMe (0.7 g Na metal/10 ml anhydrous MeOH). The color of the solution changes from bright yellow to clear. Stirring was continued for 30 min. Water (50 ml) was added and the solution was extracted with Et2O (2×50 ml). The combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration in vacuo of the organic material afforded 5.44 g crude. Distillation yielded 4.38 g (83%) of 1-(3-bromopropyl)-2-phenylcyclohexanecarboxylic acid ethyl ester as a yellow viscous oil.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8].[CH:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.O>CS(C)=O>[CH3:20][C:19]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:21]=[C:2]([N:31]2[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]2)[CH:3]=[CH:4][C:5]=1[N+:22]([O-:24])=[O:23]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(F)ccc2[N+](=O)[O-])c1
Reactant: CC(C)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCN(C(C)C)CC3)ccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.9 %

Procedure:
To a solution of methyl 3-[(5-fluoro-2-nitrobenzoyl)amino]-4-methylbenzoate (8 g) in DMSO (24 ml) was added N-isopropylpiperazine (3.4 g) and N,N-diisopropylethylamine (4.7 ml) and the reaction stirred at room temperature for 6 hours. Water (200 ml) was added and the resultant solid collected by filtration, washed with water (×3) and dried in vacuo at 50° C. for 16 hours to yield methyl 4-methyl-3-{[5-(4-isopropylpiperazin-1-yl)-2-nitrobenzoyl]amino}benzoate as a yellow solid (10.7 g); NMR Spectrum: (DMSOd6) 0.99 (d, 6H), 2.34 (s, 3H), 2.55 (m, 4H), 2.71 (m, 1H), 3.50 (m, 4H), 3.85 (s, 3H), 7.07 (m, 2H), 7.39 (d, 1H), 7.71 (m, 1H), 8.06 (d, 1H), 8.20 (m, 1H), 9.96 (s, 1H); Mass Spectrum: M+H+ 441.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.[F-].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: OB(O)c1ccccc1F
Reactant: O=C(O)c1ccc(Br)c(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2ccccc2F)c(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
A mixture of 4-bromo-3-(trifluoromethyl)benzoic acid (15.0 g, 55.7 mmol), 2-fluorophenylboronic acid (9.4 g, 66.9 mmol), cesium fluoride (25.4 g, 167 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (5.7 g, 13.9 mmol) and palladium(II) acetate (1.25 g, 5.6 mmol) was prepared in dioxane (150 mL) and water (150 mL) under N2 atmosphere. The reaction mixture was purged with vacuum for 5 minutes, and then the reaction mixture was degassed with N2 at RT for 10 min. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to RT and was filtered through a pad of Celite. The filtrate was concentrated under vacuum affording a yellow solid. After purification by flash chromatography (silica, DCM containing 1% of AcOH), the title compound was obtained as a pale yellow powder. HPLC (Method A), Rt 4.3 min (purity: 99.9%). LC/MS (Method B): 283.0 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.60 (s, 1H), 8.31 (d, J=1.4 Hz, 1H), 8.25 (dd, J=8.0, 1.4 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.52 (m, 1H), 7.38-7.26 (m, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][CH:15]([OH:30])[CH2:16][CH2:17][CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl>C(OCC)(=O)C>[CH3:1][S:2]([O:30][CH:15]([CH2:16][CH2:17][CH2:18][O:19][Si:20]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[CH:27]([CH3:29])[CH3:28])[CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)[Si](OCCCC(O)COCc1ccccc1)(C(C)C)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCCCC(COCc1ccccc1)OS(C)(=O)=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.35 mL of methanesulfonyl chloride was added dropwise to a solution of 1.5 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-ol and 0.7 mL of triethylamine in 15 mL of ethyl acetate at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the reaction mixture was added to a mixture of 100 mL of ethyl acetate and 50 mL of 1 mol/L hydrochloric acid. The organic layer was fractionated. The obtained organic layer was successively washed with 50 mL of a saturated sodium hydrogen carbonate aqueous solution, 50 mL of water and 50 mL of a saturated sodium chloride aqueous solution, and it was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.8 g of 1-benzyloxy-5-((triisopropyl)silyloxy)pentan-2-yl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8]>C(O)C>[NH:2]([C:6](=[O:5])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[O:8])[NH2:3]
Reactant: NN
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrazine hydrate (229 mg, 4.57 mmol) was added in one portion to a stirred solution of trans-ethyl 2-[4-(4-{[methoxy(oxo)acetyl]amino}phenyl)cyclohexyl]propanoate (1.3 g, 3.6 mmol) in ethanol (25 mL) and the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered to leave a solid, which was washed with ethanol (10 mL) to give the title compound (Intermediate 99) (1.2 g, 92%) as a solid; 1H NMR δ 1.07 (3H, d), 1.1-1.3 (2H, m), 1.2 (3H, t), 1.36-1.5 (2H, m), 1.5-1.63 (1H, m), 1.65-1.72 (1H, m), 1.75-1.88 (3H, m), 2.2-2.32 (1H, m), 2.35-2.49 (1H, m), 4.0-4.17 (2H, m), 4.6 (2H, s), 7.19 (2H, d), 7.7 (2H, d), 10.44 (1H, s); MS m/e MH+ 362.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])=O)[C:17]([O:19]CC)=[O:18].CC(O)C.C(=O)(O)[O-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:2][C:3]1[C:11]([C:12]2[S:14][C:16]([C:17]([OH:19])=[O:18])=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[N:13]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1nn2ccccc2c1C(N)=S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1nn2ccccc2c1-c1nc(-c2ccccc2[N+](=O)[O-])c(C(=O)O)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
A mixture of 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (1.2 g, 5.2 mmol) obtained in Example 11-B(v), ethyl 2-chloro-3-(2-nitrophenyl)-3-oxopropanoate (1.7 g, 8.4 mmol) obtained above and 2-propanol (20 mL) was stirred at 80° C. for 4 h. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate, EtOAc and THF. Insoluble materials were removed by filtration and the filtrate was extracted with a 1:1 mixture of EtOAc and THF. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. To the residue were added MeOH (10 mL), THF (25 mL) and 8N aqueous sodium hydroxide solution (2.5 mL), and the mixture was stirred at 70° C. for 1 h. The reaction mixture was allowed to cool to 0° C., 6N hydrochloric acid was added to adjust the solution to about pH 3.0. The resulting precipitate was collected by filtration, washed with diisopropyl ether, and dried to give the title compound (620 mg, 31%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N)CCC>[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]#[C:26][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][CH:6]=[CH:5]4)[CH2:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCCN1CC=C(c2ccccc2)CC1
Reactant: Brc1ccc2[nH]ccc2c1
Solvent: CCCCN
Product: C(#Cc1ccc2[nH]ccc2c1)CCN1CC=C(c2ccccc2)CC1

Procedure:
A solution of 5-bromoindole (0.5 g, 0.0025 mol) and the acetylene prepared in Example 9, Step (a) in 15 mL of N-butylamine is degassed by bubbling in dry nitrogen for 15 minutes, and 0.06 g, (5.0×10-5 mol) of tetrakis (triphenylphosphine)palladium(0) is added. The flask is flushed with nitrogen and the mixture is headed at reflux for 18 hours. The solvent is removed under reduced pressure, and the residue is partitioned between 50 mL of dichloromethane and 50 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 25 mL of dichloromethane and the combined organic layers are washed with 25 mL of water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound containing 0.3 mol of water; mp 173°-174° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]>CO.[Pt](=O)=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: CO
Product: CCCOc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.5 %

Procedure:
A mixture of 9-(4-propoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (300 mg) and platinum(IV) oxide (32.1 mg) in MeOH (10 mL) was stirred at room temperature under H2 for 20 hr. The reaction mixture was filtered by Celite and the filtrate was concentrated in vacuo. The residue was recrystallized from EtOAc-MeOH to give the title compound (114 mg) as a white solid.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[N+:5]([CH2:24][C:25]2[CH:26]=[C:27](C)[CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[CH:16]=2)[C:11]1=[O:23].[BH4-].[Na+].[CH3:34]O>C1COCC1>[Br:2][C:3]1[CH2:4][N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:34])[CH:6]=[CH:7][C:8]=1[CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[CH:16]=2)[C:11]1=[O:23]
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+](Cc3cccc(C)c3)cc1Br)C2
Reactant: CO
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)C(CC1=C(Br)CN(Cc3ccccc3C)C=C1)C2
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of compound 146 (45 mg, 0.08 mmol) in a mixture of methanol and THF (5 mL, respectively 1:4) was added sodium borohydride (3 mg, 1 equiv) in one portion at 0° C. The reaction mixture was then stirred at this temperature for 1 h and quenched with 35% aqueous ammonia solution (3 mL). The mixture was extracted with dichloromethane (3×) and the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. The crude residue was purified by column chromatography on silica gel (petroleum ether/EtOAc: 2/3) to afford the title compound 168 as a yellow solid (Yield 21.9 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:22]([O:29][C:30](=[O:47])[N:31]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42](Br)[N:41]=1)[CH2:32][C:33]([NH:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:47])[N:31]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[N:41]=1)[CH2:32][C:33]([NH:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)NC(=O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)NC(=O)CN(Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared by using the procedure described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.92 g, 0.30 mmol) and benzyl[(6-bromopyridin-2-yl)methyl][2-(isopropylamino)-2-oxoethyl]carbamate (0.12 g, 0.30 mmol) as the starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:31]12([N:38]3[CH2:42][CH2:41][CH2:40][CH:39]3[CH2:43][NH2:44])[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32]2>O.CC(C)=O>[C:31]12([N:38]3[CH2:42][CH2:41][CH2:40][CH:39]3[CH2:43][NH:44][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=3[O:2][CH3:1])[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32]2
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: NCC1CCCN1C12CCC(CC1)C2
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(S(C)(=O)=O)cc1C(=O)NCC1CCCN1C12CCC(CC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
69 g of 2-methoxy-5-methylsulphonylbenzoic acid (0.30 mole), 360 ml of acetone, 120 ml of water and 30.3 g of triethylamine (0.30 mole) are placed in a 1 liter flask fitted with an agitator, thermometer, a condenser and a dropping funnel. The solution is chilled to 0° C., then 40.8 g of isobutyl chloroformate (0.30 mole) is added drop by drop. The mixture is agitated for 30 minutes at room temperature, then chilled to 0° C. again, and 58.2 g of 1-norbornyl-2-aminomethyl pyrrolidine (0.30 mole) is poured in drop by drop. The reaction mixture is agitated for 3 hours at room temperature then evaporated dry. The residue is dissolved in 500 ml of water and 80 ml of hydrochloric acid (density 1.18). The solution is filtered with acticarbone 3S and the filtrate is made alkaline with 120 ml of soda lye. A thick oil is decanted off, washed with 500 ml of water then dissolved hot, at about 60° C., in 90 ml of ethyl acetate. The product crystallises. The crystals are frozen, filtered and washed in water and dried in an oven at 60° C. 72 g of product is obtained (melting point 125° C.). This is re-crystallised in 150 ml of isopropanol to give 62 g (51%) of amide melting at 132° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:13][C:12]([C:26]#[N:27])=[CH:11][C:10]=1[NH:28][C:29]1[N:34]=[C:33]([N:35]([CH:45]2[CH2:47][CH2:46]2)CC2C=CC(OC)=CC=2)[C:32]2=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]2[N:30]=1.C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:14]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:13][C:12]([C:26]#[N:27])=[CH:11][C:10]=1[NH:28][C:29]1[N:34]=[C:33]([NH:35][CH:45]2[CH2:46][CH2:47]2)[C:32]2=[N:48][CH:49]=[C:50]([C:51]#[N:52])[N:31]2[N:30]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC4CCN(C5COC5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(OC2CCN(C3COC3)CC2)c1
Temperature: 45 °C
Yield: 66.7 %

Procedure:
TFA (25% in DCE, 2 ml, 6.49 mmol) was added to a solution of 2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg, 0.080 mmol) and anisole (0.035 ml, 0.319 mmol) in DCE (1 mL) and the reaction mixture was heated at 45° C. for 3 hours. Solvent was evaporated in vacuo and the residue was dried under vacuum overnight. The residue was washed with hexane (2×2 ml), dissolved in acetonitrile (2 ml) and 2N ammonia in methanol was added to give a suspension. Solvent was evaporated until a very small amount and the precipitate was collected by filtration. 2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (27 mg) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[C:10](=[O:15])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: Cc1ccc(C2CCCCC2=O)cc1F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C2CCCC(Br)C2=O)cc1F
Temperature: 25 °C
Yield: 103.8 %

Procedure:
2 (3 fluoro-4-methyl-phenyl)-cyclohexanone (51 mg, 0.25 mmol) was dissolved in chloroform (1 mL). To this solution bromine (41.5 mg, 0.27 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the title compound (74 mg) which was used directly in the next step without further purification.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[Br:5][C:6]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([Br:15])[C:7]=1[NH2:8]>O1CCCC1.C(=O)([O-])O.[Na+]>[Br:5][C:6]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([Br:15])[C:7]=1[N:8]=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: COc1cc(Br)c(N)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Br)c(N=C=S)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
Thiophosgene (1.52 mL, 20.5 mmol) was added dropwise to a stirred mixture of 2,6-dibromo-4-methoxyaniline (2.86 g, 10.2 mmol) in tetrahydrofuran (25 mL) and saturated aqueous sodium hydrogen carbonate (25 mL) at 0° C. The mixture was stirred at room temperature for 1 h, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (3.22 g, 9.97 mmol, 98%).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[CH2:7]([S:19]([CH2:22][CH2:23][CH2:24][C:25](O)=O)(=[O:21])=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N+](C1C=C(B(O)O)C=CC=1)([O-])=O>C1(C)C=CC=CC=1>[NH2:6][N:5]1[C:3]([SH:4])=[N:2][N:1]=[C:25]1[CH2:24][CH2:23][CH2:22][S:19]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:20])=[O:21]
Reactant: CCCCCCCCCCCCS(=O)(=O)CCCC(=O)O
Reactant: NNC(=S)NN
Agent: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCS(=O)(=O)CCCc1nnc(S)n1N
Yield: 87.2 %

Procedure:
To a mixture of 4.9 g (47 mmol) of thiocarbohydrazide and 15 g (47 mmol) of 4-(dodecylsulfonyl)butanoic acid in 30 ml of toluene was added 0.8 g (4.7 mmol) of 3-nitrobenzeneboronic acid. The mixture was heated at reflux for 24 hr. Upon cooling, the thick precipitate was collected, rinsed with a small amount of acetonitrile (10 ml), dried in vacuo to yield 16 g (87.4%) of the desired product as a white solid. All of the analytical data confirmed the assigned structure.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[N:19]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:26])[CH2:20]2>O1CCCC1>[CH2:17]([O:16][C:13](=[O:15])[CH2:14][C:21]1([OH:26])[CH:22]2[CH2:25][N:19]([CH2:24][CH2:23]2)[CH2:20]1)[CH3:18]
Reactant: O=C1CN2CCC1C2
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1(O)CN2CCC1C2
Temperature: 25 °C

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (2.65 ml, 0.0203 moles) in tetrahydrofuran (150 ml) was added 2.5M n-BuLi in hexanes (8.1 ml, 0.0203 moles) dropwise over one minute. After ten minutes, ethyl acetate (1.97 ml, 0.0203 moles) was added dropwise over one minute. After a further ten minutes, 1-azabicyclo[2.2.1]heptan-3-one (1.5 g, 0.0135 moles, prepared by the method of J Chem Soc, Chem Commun, 1618, 1988) in tetrahydrofuran (25 ml) was added dropwise over five minutes. After twenty five minutes, the cold bath was removed and the mixture was allowed to warm to ambient temperature. To this mixture was added water (100 ml) followed by chloroform (250 ml). The organic layer was separated and the aqueous layer was extracted with chloroform (100 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give the subtitle compound (1.12 g).