Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:4][N:3]=1
Reactant: Oc1ccc(I)nc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(I)nc1
Reaction time: 100 h

Procedure:
To a solution of one gram of 2-iodo-5-hydroxypyridine (prepared as by Edgar, K. J. & Falling, S. N.; (1990) J. Org. Chem., 55: 5287) in dimethylformamide (14 ml) was added cesium carbonate (1.55 g) and bromooctane (1.56 ml). The reaction was allowed to stir for 100 hrs, at which time it was poured into water and extracted with 1:1 hexane:ethyl acetate. The combined organics were washed with brine and dried over sodium sulfate and potassium carbonate. The solvent was removed in vacuo to give a yellow oil. This oil was purified by flash chromatography using 10% ethyl acetate in hexanes as the eluent, giving a clear oil as a product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH3:7].[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1C(C2NC=CN=2)=[CH:20][N:19]=[C:18]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=2)[N:17]=1>>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[CH:20][N:19]=[C:18]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=2)[N:17]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: Cc1nccn1C
Product: Cn1ccnc1-c1cnc(NCCNc2ccc([N+](=O)[O-])cn2)nc1-c1ccc(Cl)cc1Cl

Procedure:
[4-(2,4-dichlorophenyl)-5-(1-methylimidazol-2-yl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 1,2-dimethylimidazole using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH3:1][C:2](=[O:4])[CH3:3].Cl[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[O-]CC.[Na+]>C(OCC)C>[CH3:1][C:2]1([CH3:3])[O:4][CH:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(C)=O
Reactant: CCOC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C1OC1(C)C
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a stirred solution of propan-2-one (11.52 ml, 157 mmol) and ethyl 2-chloroacetate (25.04 ml, 235 mmol) in dry diethyl ether (125 ml) at −10° C. under nitrogen was added sodium ethoxide (10.66 g, 157 mmol) portionwise, keeping the temperature below 5° C. After addition was complete, the mixture was stirred for two hours at −10° C., whereafter the reaction was continued at room temperature for three hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, the phases were separated, and the aqueous layer was extracted with diethyl ether (100 ml). The combined organic phases were dried over Na2SO4 and evaporated in vacuo). The resulting residue was purified by vacuum distillation. The major fraction (−25 mbar, 82° C.-85° C., 14.3 g) consisted of the desired product, containing 6.4 mol % ethyl chloroacetate. This was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34].[F:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)=[CH:18][CH:17]=2)[N:6]1[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(Br)cc2)N1c1cc(C(F)(F)F)ccc1OC
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(-c3ccc(F)cc3)cc2)N1c1cc(C(F)(F)F)ccc1OC

Procedure:
Starting from 500 mg (0.91 mmol) of the bromide from Example 11A, reaction in analogy to general method [D] with 152.27 mg (1.09 mmol) of 4-fluorophenylboronic acid, 31.83 mg (0.05 mmol) of bis(triphenylphosphine)palladium(II) chloride and 115.34 mg (1.09 mmol) of sodium carbonate in 10 ml of 1,2-dimethoxyethane and 0.5 ml of water results in 370.7 mg (72% of theory) of the target compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([NH2:15])=[O:14])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[SH:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][OH:88]>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].O1CCOCC1>[OH:88][CH2:87][CH2:86][CH2:85][CH2:84][CH2:83][CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77][S:76][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([NH2:15])=[O:14])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(I)cc23)c1
Reactant: OCCCCCCCCCCCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(SCCCCCCCCCCCO)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Org. Lett. 2004, 6(24), 4587-4590. To a round bottom flask were added 6-iodo-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (1.0 g, 2.31 mmol), dry dioxane (23 mL) and i-Pr2NEt (0.81 mL, 4.62 mmol). Catalytic Pd2(dba)3 (63 mg, 0.07 mmol), Xantphos (80 mg, 0.14 mmol) and 11-mercapto-1-undecanol (494 mg, 2.42 mmol) were then added. The mixture was evacuated and backfilled with nitrogen (3 cycles). The mixture was heated to reflux for 2 h (HPLC confirmed the completion of the reaction). The reaction mixture was then allowed to reach ambient temperature followed by filtration and concentration. The crude product was used without further purification for the next step. ES/MS calcd. for C29H40N3O3S+ 510.3. Found m/z=510.4 (M+H)+.
Reaction SMILES: [CH2:1]1[C@@H:3]2[C:4](=[O:23])[C:5]([OH:22])=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.[CH:24]1C=CC=CC=1.IC>>[CH2:1]1[C@@H:3]2[C:4](=[O:23])[C:5]([O:22][CH3:24])=[C:6]3[C@:19]([CH3:20])([CH:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C(O)C(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Solvent: CI
Product: COC1=C2CC[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)C2C[C@@H]2C1=O
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a solution of 1,2β-methylene-4-hydroxyandrost-4-ene-3,17-dione (0.314 g, 1 mmol) in benzene (10 ml) potassium tert-butoxide (0.224 g, 2 mmol) is added and the mixture heated to reflux for 30 min. After cooling, iodomethane (0.710 g, 5 mmol) is added and the mixture boiled for further 2 hours. Then the organic solution is washed with water, dried and evaporated in vacuum. The flash column chromatography of the residue on silica gel using n-hexane/ethylacetate 60:40 affords 0.246 g (75% yield) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1>>[S:14]1[CH:15]=[CH:16][C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:13]1
Reactant: CC(=O)Nc1ccccc1
Reactant: Brc1ccsc1
Product: CC(=O)N(c1ccccc1)c1ccsc1
Yield: 25.2 %

Procedure:
Using acetanilide (6.0 g) and 3-bromothiophene (14.5 g), a reaction was made in the same manner as in 1) of Production Example 2. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:4) produced N-(3-thienyl)acetanilide (2.43 g; yield, 25%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[F:18][C:19]([F:24])([F:23])[C:20](O)=[O:21].C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]([NH:1][C:20](=[O:21])[C:19]([F:24])([F:23])[F:18])=[C:3]([CH:13]=1)[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(Cl)cc1C(O)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1C(O)c1ccccc1Cl)C(F)(F)F
Yield: 95.7 %

Procedure:
To a solution of 1.0 g of 2-amino-5-chloro-α-(2-chlorophenyl)benzyl alcohol in 12 ml of dichloromethane, a solution of 0.8 g of anhydrous trifluoroacetic acid in 2 ml of dichloromethane was added. After reaction, an aqueous solution of sodium hydrogen carbonate was added, and the organic layer was dried, after which the solvent was removed and the residue was recrystallized from hexane to yield 1.3 g of a crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([OH:40])=O)[CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:38]([C:34]2[CH:33]=[C:32]([C:31]([F:30])([F:42])[F:41])[CH:37]=[CH:36][N:35]=2)=[O:40])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cc(C(F)(F)F)ccn1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)c1cc(C(F)(F)F)ccn1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 4-trifluoromethyl-pyridine-2-carboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-(trifluoromethyl)pyridine-2-carboxylic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown foam. MS m/e: 611.2 [M]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[Cl:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:26][C:27](=O)[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[Cl:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:26]=[C:27]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(NC(N)=S)ncc2Br)c1
Reactant: O=C(CBr)CCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)c1
Temperature: 70 °C
Yield: 96.4 %

Procedure:
A flask was charged with ethyl 3-(5-bromo-2-thioureidopyridin-4-yloxy)-4-chlorobenzoate (0.200 g, 0.464 mmol), 1-bromo-4-phenylbutan-2-one (0.105 g, 0.464 mmol) and triethylamine (0.0470 g, 0.464 mmol). Ethanol (5 mL) was added and the reaction was heated at 70° C. for 6 hours, and then concentrated to provide ethyl the desired product (0.250 g, 95 yield) as white solid. LC/MS (apci) M+2H: 560 (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=O)=S)=[CH:4][CH:3]=1.[NH:26]([C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:27].C([O-])(=O)C.[Na+]>O1CCOCC1.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:26]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[N:27]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC(=S)c2ccc(F)cc2)CC1
Reactant: NNc1ncccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1
Temperature: 80 °C

Procedure:
tert-Butyl 4-{[(4-fluorophenyl)carbonothioyl]-carbamoyl}piperidine-1-carboxylate (0.37 g, 1.01 mmol) was mixed with 2-hydrazinylprimidine (0.13 g, 1.21 mmol) and sodium acetate (0.099 g, 1.21 mmol) in 3 ml of 1,4-dioxane and acetic acid (1:1). After heating at 80° C. for 45 min, the solvents were removed under vacuum. The resulting residue was re-dissolved in dichloromethane and washed with saturated sodium bicarbonate solution and water. The organic layers were concentrated, and the residue was purified by column chromatography using a gradient of 0˜50% ethyl acetate in hexanes. LC-MS (m/z): 369.10 [M−56+H]+, 447.14 [M+Na+H]+. 1HNMR (CDCl3, 500 MHz): δ 8.92 (d, J=4.8 Hz, 2H), 8.25-8.28 (m, 2H), 7.38 (t, J=4.8 Hz, 1H), 7.15 (t, J=8.7 Hz, 2H), 4.24-4.27 (br, 2H), 3.94-4.00 (m, 2H), 2.91-2.96 (br, 2H), 2.00-2.10 (br, 4H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1]OC1C(OC)=CC2C(=O)CCCCC=2C=1.C[O-].[Na+].[CH3:20][O:21][C:22]1[C:23]([O:37][CH3:38])=[CH:24][C:25]2[C:31](=[O:32])[CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:36]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:34][C:33]([CH:30]1[CH2:29][CH2:28][CH2:27][C:26]2[CH:36]=[C:22]([O:21][CH3:20])[C:23]([O:37][CH3:38])=[CH:24][C:25]=2[CH:31]1[OH:32])=[O:35]
Reactant: COc1cc2c(cc1OC)C(=O)C(C(=O)O)CCC2
Reactant: COc1cc2c(cc1OC)C(=O)CCCC2
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCCc2cc(OC)c(OC)cc2C1O

Procedure:
Using 2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (10 g), powdery sodium methoxide [prepared by subjecting a 28% methanol solution of sodium methoxide (40 g) to concentration to dryness under reduced pressure] and dimethyl carbonate (150 g), a condensation reaction is carried out in a manner as that described in Example 42. The resulting methyl ester of 2,3-dimethoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid is dissolved in a mixture of methanol (100 ml) and methylene chloride (100 ml). The solution is subjected to reduction in a manner as that described in Example 42, using sodium borohydride (2 g). The product is purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to afford 2,3-dimethoxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid methyl ester (8 g) as a pale yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[C:9]([F:15])[CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:5][O:4][C:2](=[O:3])[NH:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][C:9]=1[F:15]
Reactant: NCc1ccc(Br)cc1F
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl chloroformate (85.0 μL, 1.1 mmol) was added to a solution of 1-(4-bromo-2-fluorophenyl)methanamine (0.204 g, 1.0 mmol) and triethylamine (148.1 μL, 1.1 mmol) in methylene chloride (5 mL) at 0° C. After 10 min, the ice-water bath was removed. The mixture was stirred at RT for 1 h, washed with water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue (220 mg, 83.9%) was directly used in next step without further purification. LCMS: (M+H)=263.9/261.8.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:21])[CH3:20])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[OH:1][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:21])[CH3:20]
Reactant: CC(O)CCCCCCC#CCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)CCCCCCC#CCCO
Temperature: 23 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 19 (2.9 g, 9.4 mmol) in THF (15 mL) was added 19 mL of tetra-n-butylammonium fluoride (19 mmole, 1M solution in THF). The reaction was stirred for 1 hr at 23° C. then diluted with 75 mL of water. The aqueous mixture was extracted with ether (3×50 mL) and the ether extract washed with brine (2×50 mL). Product isolation yielded 1.86 g (100%) of the diol (20). No further purification was carried out on 20.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=2)[C:11]([N:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[O:28][CH3:29])[CH3:14])=[O:12])(=[O:7])=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48].[NH4+].[Cl-]>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N:13]([CH3:14])[C:11](=[O:12])[C:10]2[CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=[C:8]([S:5]([CH:3]3[CH2:4][N:1]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:2]3)(=[O:7])=[O:6])[CH:9]=2)=[C:22]([O:28][CH3:29])[CH:23]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CNC2)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CN(S(C)(=O)=O)C2)c1
Temperature: 0 °C
Reaction time: 1.75 h

Procedure:
To an ice-cold solution of 3-(azetidin-3-ylsulfonyl)-N-(4-(4-fluoro-2-methoxyphenyl)-pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.05 g, 95.5 μmol, example 280) and DIPEA (24.7 mg, 33.4 μL, 191 μmol) in CH2Cl2 (1 mL) was added methanesulfonyl chloride (16.4 mg, 11.2 μL, 143 μmol) and stirring was continued in an ice-bath for 1.75 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 5 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.044 g; 76%). MS (ESI): m/z=602.10 [M+H]+.
Reaction SMILES: [I-].[K+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>O1CCCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:30][CH:27]4[CH2:29][CH2:28]4)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1
Reactant: NC1CC1
Reactant: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNC3CC3)n1-2

Procedure:
In the manner given in Example 1, potassium iodide and 8-fluoro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-fluoro-1-[(cyclopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: [CH3:1][CH:2]([CH2:15][CH3:16])[CH2:3][O:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)=[O:6].[CH2:17]([O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:17]([O:31][C:32]1[CH:38]=[CH:37][C:35]([N:36]=[CH:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:15][CH3:16])=[O:6])=[CH:8][CH:9]=2)=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCC(C)COC(=O)c1ccc(C=O)cc1
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(N=Cc2ccc(C(=O)OCC(C)CC)cc2)cc1

Procedure:
44.3 g of said p-(2-methylbutoxycarbonyl)benzaldehyde, 32 g of p-n-tetradecyloxyaniline, and 0.1 g of p-toluenesulfonic acid were dissolved in toluene. The solution was heated under reflux, and water generated in the dehydrating condensation was removed with a Dean-Stark condenser. After the reaction solution was cooled, the organic layer was washed with water, and the solvent (toluene) was distilled off in vacuum. The solid residue was recrystallized from ethanol to obtain yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:9](SC)[S:8][CH2:7][C:6]=2[CH:13]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1>C(O)CCC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:9]2[S:8][CH2:7][C:6]3[CH:13]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[N:10]=2)=[CH:16][CH:17]=1)(=[O:23])[CH3:22]
Reactant: CSC1=Nc2ccc(Cl)cc2CS1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CCCCO
Product: CC(=O)c1ccc(NC2=Nc3ccc(Cl)cc3CS2)cc1
Yield: 39.1 %

Procedure:
A mixture of 6-chloro-2-methylthio-4H-3,1-benzothiazine (57.5 g, 0.25 mole) and p-aminoacetophenone (33.8 g, 0.25 mole) in n-butanol (200 ml) was refluxed overnight. After cooling in a refrigerator for three days, the solid was collected by filtration and recrystallized from ethanol-water mixture to yield 31 g (39%) of product. Recrystallization from ethanol-water mixture gave an analytical sample, m.p. 174°-175°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11]O)([O-:3])=[O:2].P(Br)(Br)[Br:14].O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][Br:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1CCBr

Procedure:
2.5 ml of 2-(2-nitrophenyl)ethanol and 5.4 ml of PBr3 were stirred and mixed at 0° C. for 30 minutes to carry out reaction, and the resultant reaction mixture was diluted with 30 ml of benzene and the diluted mixture was then poured into 30 ml of water. The separated organic layer was separated, dried over anhydrous sodium sulfate, and then treated under reduced pressure to distill off the solvent, thereby obtaining 3 g of the crude product of 2-(2-nitrophenyl)ethyl bromide.