Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:6][C:7]1[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:9]([SH:12])=[N:10][N:11]=1.CCN(CC)CC.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH2:35]Br>C(Cl)Cl>[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:34]=1[CH2:35][S:12][C:9]1[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:11][N:10]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: COc1ccc(Cc2nnc(S)n2-c2ccc(F)cc2)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cc2nnc(SCc3c(F)cccc3F)n2-c2ccc(F)cc2)cc1OC
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 5-(3,4-dimethoxybenzyl)-4-(4-fluorophenyl)-4H-1,2,4-triazole-3-thiol (119 mg, 0.345 mmol) and Et3N (53 μL, 0.379 mmol) in CH2Cl2 (1.8 mL) was added 2,6-difluorobenzyl bromide (88 mg, 0.414 mmol). After stirring 2 h, the reaction mixture was concentrated and purified by flash chromatography (30% EtOAc/hexanes) to yield the title product (107 mg, 66%) as a white foam. 1H NMR (400 MHz, (CD3)2CO) δ 7.25 (m, 1H), 7.10 (m, 2H), 6.98 (m, 2H), 6.84 (m, 2H), 6.63 (d, J=8.2 Hz, 1H), 6.4 (d, J=2.0 Hz, 1H), 6.31 (m, 1H), 4.45 (s, 2H), 3.82 (s, 2H), 3.61 (s, 3H), 3.54 (s, 3H); MS (EI) m/z 472.3 (MH+).
Reaction SMILES: Cl.Cl.[OH:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH:17]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[F:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH2:19][CH2:18]1>CS(C)=O>[CH:17]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27]([N:7]4[CH2:8][CH2:9][N:4]([OH:3])[CH2:5][CH2:6]4)[C:28]=3[F:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH2:18][CH2:19]1
Reactant: ON1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCN(O)CC3)c(F)cc2c1=O
Temperature: 130 °C
Yield: 71.3 %

Procedure:
1-Hydroxypiperazine dihydrochloride (4.64 g), triethylamine (8.9 g) and dimethylsulfoxide (25 ml) are added to 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (5.0 g), which is prepared according to the procidures described in Japanese Patent First Publication No. 212474/1984, and the mixture is stirred with heating at 130° C. for 45 minutes. After cooling of the mixture to room temperature, the resulting crystals are filtered. To the crystals is added water (20 ml) and the mixture is stirred at 50° C. for 1 hour. The insoluble substance is filtered and recrystallized from a mixture of dimethylformamide and water to afford 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (4.6 g) as pale yellow prisms, m.p. 223°-227° C. (decomposed with foaming).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.O>[N:23]([C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[N+:24]=[N-:25]
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (659 mg) in dimethyl sulfoxide (10 ml) was added sodium azide (487 mg), and the mixture was stirred at 90° C. for 8 hours. The mixture was diluted with water (20 ml), and the precipitate was filtered and washed with water to give 4-azido-8-(2,6-dichlorobenzoylamino)quinoline (560 mg) as white solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1([C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2cc(C(=O)N3CCOCC3)cnc2c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 50.4 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with morpholine (11 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane and allowed to react overnight. The reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 28 mg of the title compound as a colorless solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:14]([O:47][CH3:48])=[CH:15][C:16]2[CH2:22][CH2:21][CH2:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=4)[CH2:27][CH:26]3[CH2:44]O)=[O:24])=[CH:18][C:17]=2[CH:46]=1.[CH2:49]([N:51](CC)[CH2:52][CH3:53])[CH3:50]>C(Cl)Cl>[CH2:49]([N:51]([CH2:44][CH:26]1[CH2:27][N:28]([CH2:31][C:32]2[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=2)[CH2:29][CH2:30][N:25]1[C:23]([C:19]1[CH2:20][CH2:21][CH2:22][C:16]2[CH:15]=[C:14]([O:47][CH3:48])[C:13]([O:12][CH3:11])=[CH:46][C:17]=2[CH:18]=1)=[O:24])[CH2:52][CH3:53])[CH3:50]
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCN(CC)CC1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
To a solution of oxalyl chloride (360 mg) in methylene chloride (5 ml) is added dropwise at -78° C. a (340 mg) solution of dimethyl sulfoxide (340 mg) in methylene chloride (2 ml), and the mixture is stirred for 10 minutes. To the resulting reaction mixture is added dropwise a solution of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (750 mg) in methylene chloride (2 ml), then the mixture is stirred for 15 minutes. To the reaction mixture is added triethylamine (1 g), then the reaction temperature is raised up to room temperature. The reaction mixture is poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is dissolved in methanol (10 ml). To the solution is added diethylamine hydrochloride (1.4 g), and the mixture is stirred for 3 hours at 50° C. To the reaction mixture is added, after cooling, sodium cyanoborohydride (90 mg), followed by stirring for one hour at room temperature. The reaction mixture is poured into ice-water, followed by extraction with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:ethyl acetate-methanol=9:1) to give 2-diethylaminomethyl-1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine (230 mg). This product is converted to its hydrochloride, followed by recrystallization from ethanol to give colorless crystals, m.p. 157-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].O.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:17][CH3:18])=[O:14]
Reactant: O=C(O)Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 690.9 %

Procedure:
(2,5-dichloro-4-nitrophenyl)acetic acid (22) (Valerie K. Chamberlain and R. L. Wain. Ann. appl. Biol. (1971), 69, 65-72.) (500 mg, 2.0 mmol) was dissolved in ethanol (10 ml), and after adding p-toluenesulfonic acid monohydrate (50 mg, 0.26.mmol), the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and concentrated and exsiccated under reduced pressure. To the resulting residue was added a saturated solution of sodiumbicarbonate (30 ml), and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using silica gel, and from the eluate of chloroform was obtained the title compound (505 mg, 91%) as a pale yellow crystal powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][CH:28]=4)=[CH:20][CH:19]=3)=[CH:16][C:15]([C:29]([F:32])([F:31])[F:30])=[N:14]2)[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10].[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C=O)C>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:21]1[CH:20]=[CH:19][C:18]([C:17]2[N:13]([C:5]3[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([CH:4]=3)[CH2:2][N:37]3[C:33](=[O:43])[C:34]4[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:36]3=[O:38])[N:14]=[C:15]([C:29]([F:31])([F:32])[F:30])[CH:16]=2)=[CH:23][CH:22]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)cc2)cc1CCl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)cc2)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 70 %

Procedure:
A mixture of 1-[3-chloromethyl-4-(methylsulfonyl)phenyl]-5-[4-(2-furyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole from step1 of Example 160 (280 mg, 0.58 mmol) and potassium phthalimide (10 mg, 0.054 mmol) in DMF was heated at 90 ° C. for 1 hour. After cooled to room temperature, the mixture was poured into water (30 mL), and extracted with ether (30 mL×2), washed with water (30 mL) and brine (30 mL), dried over MgSO4, and concentarted in vacuo to give the title compound (240 mg, 70%).
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][N:19]2[CH2:23][C@H:22]3[C:24]4[CH:25]=[C:26]([C:32]#[N:33])[CH:27]=[CH:28][C:29]=4[O:30][CH2:31][C@@H:21]3[CH2:20]2)[CH2:13][CH2:12]1)C.[NH3:34].[ClH:35]>C(O)C.C(#N)C>[ClH:35].[NH2:34][C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][N:19]2[CH2:23][C@H:22]3[C:24]4[CH:25]=[C:26]([C:32]#[N:33])[CH:27]=[CH:28][C:29]=4[O:30][CH2:31][C@@H:21]3[CH2:20]2)[CH2:13][CH2:12]1
Reactant: N
Reactant: CCOc1c(N[C@H]2CC[C@H](CCN3C[C@H]4COc5ccc(C#N)cc5[C@@H]4C3)CC2)c(=O)c1=O
Agent: Cl
Solvent: CC#N
Solvent: CCO
Product: N#Cc1ccc2c(c1)[C@@H]1CN(CC[C@H]3CC[C@H](Nc4c(N)c(=O)c4=O)CC3)C[C@H]1CO2

Procedure:
A solution of 1.17 g of the compound obtained in Step A of Example 20 (2.61 mmol) in 13 ml of ethanol is treated with 13 ml of a saturated solution of ammonia in acetonitrile for 16 hours. The solid obtained is filtered off and then washed with ethyl acetate to finally yield, after converting to a salt in ethanol in the warm state using 1N ethereal HCl, the title product.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>COCCOC>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: COCCOC
Product: Clc1nc(Cl)nc(N2CCOCC2)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
Cyanuric chloride (7.30 g, 39.6 mmol) was dissolved in ethylene glycol dimethyl ether (100 ml), cooled to -15° C. and gradually added dropwise with morpholine (7.00 ml, 80.3 mmol) dissolved in ethylene glycol dimethyl ether (50 ml). This reaction mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using n-hexane and ethyl acetate (6:4) as eluant, to obtain 6.32 g (yield: 68.0%) of 2,4-dichloro-6-morpholino-1,3,5-triazine as colorless crystals having melting point of 160.5° C.-161° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C([Sn](CCCC)(CCCC)/[CH:59]=[CH:60]\[O:61][CH2:62][CH3:63])CCC.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH2:62]([O:61]/[CH:60]=[CH:59]\[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[CH3:63]
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO/C=C\c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 84.5 %

Procedure:
A flask was charged with 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 50, Steps A-B; 100 mg, 0.21 mmol), tri-O-tolylphosphine (12.8 mg, 0.042 mmol) and tris(dibenzylideneacetone)dipalladium (19.3 mg, 0.021 mmol). To the flask was added DMF (3 mL), followed by (Z)-tributyl(2-ethoxyvinyl)stannane (114 mg, 0.316 mmol) and triethylamine (0.04 mL, 0.30 mmol). The reaction mixture was degassed under nitrogen, and stirred at 100° C. for 10 hours. The reaction mixture was cooled, diluted with water, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH/DCM as eluent to afford 82.8 mg of product as a yellow solid.
Reaction SMILES: [OH:1][C:2]1([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:7][S:6][CH:5]=[N:4][CH:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:9].CCN(CC)CC.[N:33]([CH2:36][C:37](Cl)=[O:38])=[N+:34]=[N-:35]>C(Cl)Cl>[N:33]([C@H:36]1[C:37](=[O:38])[N:4]2[CH:3]([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)=[O:9])[C:2]([OH:1])([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:7][S:6][C@H:5]12)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=NCC(=O)Cl
Reactant: CC(=O)OCC1(O)CSC=NC1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1(O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitrobenzyl 5-hydroxy-5-acetoxymethyl-5,6-dihydro-4H-1,3-thiazine-4-carboxylate (1.27 g., 3.45 mMol) and Et3N (0.58 ml., 4.16 mMol) in anhydrous CH2Cl2 (50 ml.) is stirred under a N2 atomsphere at room temperature while a solution of N3CH2COCl (0.36 ml., 4.13 mMol) in anhydrous CH2Cl2 (20 ml.) is added dropwise over 90 min. After stirring 30 more min., the solution is washed twice with H2O and brine, dried with MgSO4, filtered, and evaporated in vacuo. The residual oil us chromatographed on a column of Baker silica gel. Elution with 3:1 PhH-EtOAc yields p-nitrobenzyl 7α-azido-3-hydroxy-3-acetoxymethyl-cepham-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH2:5])=[O:3].C(O[CH:9](OCC)[CH2:10][CH2:11][CH2:12][NH2:13])C.Cl>C(OCC)C>[CH2:11]1[CH:12]2[N:13]([CH2:5][CH2:4][C:2](=[O:3])[CH2:1]2)[CH2:9][CH2:10]1
Reactant: CCOC(CCCN)OCC
Reactant: C=CC(C)=O
Agent: Cl
Solvent: CCOCC
Product: O=C1CCN2CCCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Methylvinyl ketone (18.0 g, 256 mmol) was added dropwise to a solution of the 4,4-diethoxybutylamine (24.8 g, 154 mmol) in diethyl ether at 0° C. and stirred for one hour. The reaction was allowed to warm to room temperature and stir for 2 hours. The reaction was poured into 350 ml of 2N hydrochloric acid and the layers were separated. The aqueous layer was heated on a steam bath for 1 hour and then allowed to stir at 40° C. for 18 hours. The reaction was made basic with a sodium hydroxide solution and then extracted with methylene chloride. The extracts were dried over sodium sulfate and concentrated to give 20 g of an orange oil. This oil was distilled in vacuo at 74-84° C./5 mmHg to give 6.68 g of racemic product. (31%). MS(FD) (m/e): 139. 1H-NMR.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=[O:8])=[O:5].[Cl:10][CH:11]=[CH:12][CH2:13][NH:14][CH2:15][CH:16]=[CH:17][Cl:18]>C(Cl)Cl>[Cl:10][CH:11]=[CH:12][CH2:13][N:14]([CH2:15][CH:16]=[CH:17][Cl:18])[C:4](=[O:5])/[C:3](/[Cl:9])=[C:2](/[Cl:1])\[C:7]([OH:6])=[O:8]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: ClC=CCNCC=CCl
Solvent: ClCCl
Product: O=C(O)/C(Cl)=C(/Cl)C(=O)N(CC=CCl)CC=CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Dichloromaleic anhydride (1.7 g, 0.01 mol) and 30 ml methylene chloride were stirred under a mild reflux. Bis-(3-chloroallyl)amine (1.7 g, 0.01 mol) was then added. The exothermic reaction yielded a clear solution. The solution was stirred at room temperature for 3 hours. The mixture was stripped, resulting in 3.3 g of the above-named product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([N:14]1[C:18]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:17][C:16](=[O:27])[NH:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:12]([N:14]1[C:18]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:17][C:16]([O:27][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[N:15]1)[CH3:13]
Reactant: CCn1[nH]c(=O)cc1-c1cccc(C#N)c1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1cccc(C#N)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
1-fluoro-4-(trifluoromethyl)benzene (2.5 mL, 20 mmol, 6.0 equiv) was added to a mixture of 3-(2-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (688 mg, 3.23 mmol, 1 equiv) and potassium carbonate (1.11 g, 8.07 mmol, 2.50 equiv) in dimethyl sulfoxide (8 mL) in a high pressure reaction vessel. The vessel was sealed, and the reaction mixture was heated to 160° C. After stirring for 4 hours, the high pressure vessel was cooled to 22° C. and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 40% ethyl acetate-hexanes) to afford 3-{1-ethyl-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}benzonitrile (700 mg, 61%) as a white solid. Calcd (M+1)+: 358.1. Found: 358.0.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.[Br:12]P(Br)Br>CN(C)C=O>[Br:12][CH2:8][C:6]1[O:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:7]=1
Reactant: OCc1cc(C(F)(F)F)no1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CBr)on1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of (3-(trifluoromethyl)isoxazol-5-yl)methanol (2.5 g, 15 mmol) in dimethylformamide (25 mL) was added drop wise tribromophosphine (4.64 g 17.1 mmol, 1.15 eq) and the mixture was stirred at 0° C. for 15 min and at ambient temperature for 2 h. The reaction mixture was partitioned between 10% sodium bicarbonate and dichloromethane. The phases were separated and the organic phase was washed with water and passed over a plug of silica eluting with dichloromethane. The UV active product fractions were collected and evaporated to yield the title compound as colorless oil (2.04 g 59.3%), MS 229 and 231(M)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]([NH2:32])[CH3:31])=[CH:29][C:24]=2[O:23][CH2:22]1>C(#N)C.C(N(CC)C(C)C)(C)C>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]([NH:32][C:2]3[C:3]4[CH2:11][N:10]([C:12]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=5[C:14]#[N:15])[CH2:9][CH2:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH3:31])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: CC(N)c1ccc2c(c1)OCO2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc5c(c4)OCO5)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (100 mg, 0.35 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)ethanamine (150 mg, 0.91 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (400 μL) was subjected to microwave irradiation at 185° C. for 3 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid.
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[CH:15]=1
Reactant: Brc1cccnc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc(-c2cccnc2)cc1
Yield: 85.3 %

Procedure:
To a solution of 4-boronobenzoic acid (1.66 g, 10 mmol) and 3-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) were added. The mixture was degassed and purged withed nitrogen. The mixture was stirred under reflux for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.7 g of white solid of 4-(pyridin-3-yl)benzoic acid. Yield: 85%. LC-MS (ESI) m/z: 200 (M+1)+.