Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=4)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=4)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])=[CH:14][CH:15]=3)[O:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc(N)cc4)coc3c2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)c1cccc(COc2ccc3c(=O)c(-c4ccc(NS(C)(=O)=O)cc4)coc3c2)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a mixture of prop-2-enyl 3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzoate, prepared as described in Example 7A, (169.5 mg, 0.397 mmol) and anhydrous pyridine (34.5 mg, 0.44 mmol) in dry methylene chloride (3 ml) at 0° C. was added methanesulfonyl chloride (68.1 mg, 0.60 mmol). The mixture was then stirred at room temperature for 21 hours, then mixed with silics gel and the solvent removed under reduced pressure. Flash chromatography of the silica gel mixture, eluting with methylene chloride/methanol (99.5/0.5) gave prop-2-enyl 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoate as a white solid (160.9 mg). (ESI) m/z 506 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:13])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cncc(Br)c1
Product: O=C(Cl)c1cncc(Br)c1

Procedure:
To 5.00 g of 5-bromonicotinic acid, 74 ml of thionyl chloride was added and the mixture was heated at reflux for 6 hours. After the solvent was distilled off under reduced pressure, the crystal was washed with diisopropyl ether and collected by filtration to obtain 4.09 g of the objective compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[OH:8])=[CH:5][N:4]=[CH:3]1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C(O)c1ccccn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cn1cncc1C(=O)c1ccccn1
Temperature: 25 °C

Procedure:
A heterogenous mixture of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol (1.41 g, 7.45 mmol, Intermediate 25: step a) and manganese dioxide (3.24 g, 37.27 mmol) in 1,4-dioxane (52 mL) was stirred at 100° C. for 2 hours. The reaction mixture was then cooled to room temperature, filtered through Celite®, washed with DCM, and concentrated to provide the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:9]=2[C:10](O)=O)[N:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:10]1[C:9]2[C:8](=[CH:16][CH:15]=[C:14]([C:17]([F:19])([F:18])[F:20])[CH:13]=2)[N:7]=[C:5]2[N:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:3]=[C:2]([CH3:1])[C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Nc2ccc(C(F)(F)F)cc2C(=O)O)n(-c2ccccn2)n1
Product: Cc1nn(-c2ccccn2)c2nc3ccc(C(F)(F)F)cc3c(Cl)c12
Temperature: 25 °C
Yield: 50.5 %

Procedure:
A solution of 2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-5-(trifluoromethyl)benzoic acid (14.0 g, 38.6 mmol) in phosphorous oxychloride (27.4 mL, 294 mmol) was heated under reflux for 1 hour. The solution was allowed to cool to room temperature, and the reaction solvent was evaporated under reduced pressure, and the residue was poured into iced water. The solution was neutralized by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:chloroform=1:1 to chloroform) to give the title compound (7.07 g, 50% yield).
Reaction SMILES: C([Li])CCC.[O:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]#N.Cl.[O:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CCCCCC.O>[O:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[C:10](=[O:6])[CH2:9][CH2:8][CH2:7][CH3:11]
Reactant: N#C[C@H]1CCCO1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CCCCC(=O)[C@H]1CCCO1
Reaction time: 1 h

Procedure:
A 1 L reactor at a temperature of 0° C. was added with 0.4 L of 1.6 M n-butyllithium in n-hexane, to which 13.5 g of (R)-2-tetrahydrofuran nitrile as previously obtained, in 0.07 L of tetrahydrofuran was slowly added dropwise. As such, the reaction was carried out for 1 hour with stirring, while the temperature within the reactor was controlled below 15° C. Next, the resulting solution was added dropwise to 65 g of concentrated hydrochloric acid in 0.4 L of water, while the temperature of the reaction was controlled below 25° C. Thereafter, the extraction was conducted by use of ethylacetate, followed by removing the solvent therein under reduced pressure, and the remainder was vacuum distilled off to produce 19.6 g of (R)-1-(2-tetrahydrofuranyl)-1-pentanone having an optical purity of 98.5% ee.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:28]([O:29][CH:30]3[CH2:34][CH2:33][O:32][CH2:31]3)=[CH:27][CH:26]=[CH:25][C:24]=2[F:35])[C:19]([Cl:36])=[CH:18][N:17]=1>>[Cl:36][C:19]1[C:20]([NH:22][C:23]2[C:28]([O:29][CH:30]3[CH2:34][CH2:33][O:32][CH2:31]3)=[CH:27][CH:26]=[CH:25][C:24]=2[F:35])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Reactant: Fc1cccc(OC2CCOC2)c1Nc1nc(Cl)ncc1Cl
Product: CN1C(=O)OCCc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4OC4CCOC4)n3)ccc21

Procedure:
Title compound was prepared from 2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a pale yellow solid (28 mg, 32%) HPLC purity=99%, LCMS=502.27 (M+H), HNMR (DMSO) 9.37 (s, 1H), 8.55 (bs, 1H), 8.11 (s, 1H), 7.37-7.34 (m, 2H), 7.23 (d, J=7.8 Hz, 1H), 7.00-6.95 (m, 3H), 5.00 (bt, 1H), 4.26-4.23 (m, 2H), 3.81-3.77 (m, 1H), 3.62-3.59 (m, 2H), 3.57-3.53 (m, 1H), 3.19 (s, 3H), 2.62-2.59 (m, 2H), 2.06-2.01 (m, 1H), 1.81-1.78 (m, 1H).
Reaction SMILES: [CH2:1]([N:17]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=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][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O:43]1CCO[CH2:45][CH2:44]1.[ClH:49]>C(O)C.C1C=CC=CC=1>[ClH:49].[ClH:49].[CH2:44]([O:43][C:41](=[NH:42])[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([CH2:34][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:36]=1)[CH3:45]
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C#N)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)OCC)c1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of α-[N,N-di(n-hexadecyl)amino]-m-toluonitrile (29.0 g., 0.05 mole), ethanol (40 ml., 0.67 mole) and dioxane (100 ml.) was saturated with dry hydrogen chloride gas for 40 minutes at 15°-25° C. It was then stoppered and held overnight at room temperature. Thin layer chromatography analysis (4:1, benzene:ethanol on silica gel) indicated complete reaction of the nitrile. The mixture was evaporated in vacuo yielding the named product quantitatively as a foam [35.0 g., ~ 100% yield, Rf .87 (4:1, benzene: ethanol on silica gel)].
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.N>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([NH2:22])=[O:19])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Agent: N
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3cccnc3n2CC(N)=O)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.6 %

Procedure:
A mixture of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. The reaction mixture was cooled in a dry ice/acetone bath, and liquid ammonia (50 ml) was added. The mixture was allowed to warm to room temperature and was stirred for 2 days under nitrogen atmosphere. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was recrystallized from hot methanol and dried under high vacuum at 40° C. to give 2.82 g (56%) of title compound, mp>250° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].[Cl:14]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[C:3]([O:9][C:10]([F:12])([F:11])[F:13])=[CH:4][C:5]([NH2:8])=[C:6]([Cl:14])[CH:7]=1
Reactant: Nc1ccc(Br)c(OC(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1cc(OC(F)(F)F)c(Br)cc1Cl
Temperature: 60 °C
Yield: 61.8 %

Procedure:
To a mixture of 4-bromo-3-trifluoromethoxy-phenylamine (2.0 g, 7.8 mmol) in ACN (60 mL) was slowly added a solution of N-chlorosuccinimide (1.0 g, 7.8 mmol) in ACN (40 mL). The reaction mixture was heated at 60° C. overnight and extracted with ethyl actetate/water. The organic layer was dried over sodium sulfate and purified by flash chromatography (40 g column, 100% hexanes to 10% EtOAc: hexanes) to produce the desired product as an orange-ish-colored oil (1.4 g, 64% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH2:27][C:28]1[S:29][CH:30]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CC(N(C)C)=O.C(OCC)(=O)C>[C:33]([C:31]1[N:32]=[C:28]([NH:27][C:17]([C:16]2[CH:20]=[CH:21][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:14][CH:15]=2)=[O:18])[S:29][CH:30]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nc(C(C)(C)C)cs4)cc3)c(Cl)cc21
Temperature: 50 °C
Yield: 64.7 %

Procedure:
4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (53 mg, 0.141 mmol) and 2-amino-4-tert-butylthiazole (44.0 mg, 0.281 mmol) in DMA were treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.9 mg, 0.281 mmol) followed by 1-hydroxy-7-azabenzotriazole (19.1 mg, 0.141 mmol) at ambient temperature. The reaction was heated to 50° C. for 14 hours. The reaction was diluted with ethyl acetate, washed with 1 N HCl, saturated aqueous bicarbonate, and brine. The ethyl acetate layer was dried with sodium sulfate and the product purified on SP1 (20 to 65% Ethyl acetate/hexane) to provide the desired compound (47 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)=[CH:5][C:4]=1[F:20].CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32].Cl>ClCCl>[Cl:2][C:3]1[C:4]([F:20])=[CH:5][C:6]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:31][CH3:32])=[O:33])=[CH:7][C:8]=1[F:9]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2cc(F)c(Cl)c(F)c2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
Methyl 2-(4-chloro-3,5-difluorophenyl)piperidine-4-carboxylate hydrochloride (1.82 g, 5.58 mmol) was dissolved in dichloromethane (50 mL). DIPEA (2.430 mL, 13.95 mmol) and methyl carbonochloridate (0.527 mL, 6.70 mmol) were added and the mixture was stirred at room temperature for 3 h. 0.1 M HCl was added and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated to yield dimethyl 2-(4-chloro-3,5-difluorophenyl)piperidine-1,4-dicarboxylate (1.83 g, 94%). MS m/z 348 (M+H)+
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][C:3]1=[O:18].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(O)C>[CH2:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][N:2]([N:1]=[C:29]2[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]2)[C:3](=[O:18])[CH2:4]1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1

Procedure:
A solution of 1-amino-4-benzyloxycarbonyl-2-piperazinone (2.49 g) and 1-(tert-butoxycarbonyl)-4-piperidone (1.99 g) in ethanol (40 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 15 hours. The reaction mixture was concentrated to obtain a crude 4-benzyloxycarbonyl-1-[1-(tert-butoxycarbonyl)-4-piperidinylideneamino]-2-piperazinone as an oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:23]1([N:29]2[CH2:34][CH2:33][N:32]([CH2:21][CH2:20][CH2:19][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1

Procedure:
116 mg (89%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-phenylpiperazine (0.041 mL, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[CH3:12][CH:13]([CH3:16])[CH2:14][SH:15].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[S:15][CH2:14][CH:13]([CH3:16])[CH3:12]
Reactant: CC(C)CS
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)CSc1nc(C(=O)O)ccc1Br
Temperature: 150 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
5-Bromo-6-chloropicolinic acid (2 g, 8.46 mmol; CAN 959958-25-9), 2-methylpropane-1-thiol (915 mg, 1.1 mL, 10.2 mmol) and cesium carbonate (6.89 g, 21.1 mmol) were suspended in DMSO (100 mL). The reaction mixture was heated to 150° C. and stirred for 1 d and was poured onto icewater/1N HCl (100 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined extracts were washed with icewater/brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (2.49 g, 51%) as an orange solid which was used in the next step without further purification. MS (EI): m/e=288.4 [M−H]−.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: OB(O)c1cncnc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cncnc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (25 mg, 33%), MS (ISN) m/z=302.4 [(M−H)+], mp 325° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available pyrimidin-5-ylboronic acid (40.3 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:23][CH2:24]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ncccc1NCC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccc(Cl)cn1)c1ncccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 16 h
Yield: 16.3 %

Procedure:
A pressure tube (Aldrich) was charged with N-(5-chloropyridin-2-yl)-3-[(piperidin-4-ylmethyl)amino]pyridine-2-carboxamide (500 mg, 1.45 mmol), 4-chloropyridine hydrochloride (435 mg, 2.90 mmol), triethylamine (293 mg, 2.90 mmol) and EtOH (5 mL), sealed, and placed in a 110° C. bath. After 16 h, the mixture was cooled, concentrated, and the residue purified by column chromatography (SiO2: 5 to 7.5% methanol:methylene chloride) yielding 100 mg (16%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].O>CN(C)C=O>[CH:15]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:1][C@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:17])[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCOC(=O)C[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H](C)O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
0.077 mol (10.0 g) of ethyl(R)-3-hydroxybutyrate is dissolved in 90 ml of dimethylformamide and 0.151 mol (10.3 g) of imidazole is added. The mixture is cooled to 0° C. under protective gas in an ice bath and 0.083 mol (16.05 g) of triisopropylsilyl chloride is added dropwise over 5 min. The mixture is stirred at room temperature for a further 5 hours, hydrolyzed with water, the product is extracted with tert-butyl methyl ether, and the organic phase is dried using Na2SO4 and concentrated under reduced pressure on a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][CH3:21])[N:13]=2)[CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][C:28]2[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:9])=[C:6]([O:11][C:12]2[N:13]=[C:14]([O:20][CH3:21])[N:15]=[C:16]([O:18][CH3:19])[N:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)O)n1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step G, using equimolar amounts of 6-chloro-2-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoic acid, 4-nitrophenol, and dicyclohexylcarbodiimide in methylene chloride to yield 4-nitrophenyl 6-chloro-2-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CC(C)=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[O:5][CH2:6][C:2]([CH3:14])([CH3:1])[N:3]=2)=[CH:8][CH:9]=1
Reactant: CC1(C)COC(c2ccc(O)cc2)=N1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)COC(c2ccc(OCCCCl)cc2)=N1
Yield: 97 %

Procedure:
A mixture of 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenol ax7 (5 g, 26 mmol, 1 eq), potassium carbonate (7.19 g, 52 mmol, 2 eq), and 1-bromo-3-chloropropane (2.8 ml, 29 mmol, 1.1 eq) in acetone (120 ml) is stirred at reflux for 36 h. The mixture is then concentrated; the residue is dissolved in dichloromethane, and washed with a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate and concentrated under vacuum to obtain 2-[4-(3-chloropropoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax10 as a white solid (6.75 g).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>ClCCl.C(N(CC)CC)C>[C:10]([C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=1[NH:7][C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])(=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccccc1NC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dichloroacetylchloride (88 ml) in dichloromethane (200 ml) was added dropwise to a stirred solution of 2-aminobenzophenone (157.6g) in dichloromethane (400 ml) and triethylamine (116 ml) while keeping the temperature between 20°-30°C by cooling in ice. On completion of the addition the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was washed with successive portions of distilled water-dilute hydrochloric acid and finally distilled water. After drying over anhydrous magnesium sulphate the solvent was removed under reduced pressure to leave a solid which on recrystallisation from absolute, ethanol gave 222 g of 2'-benzoyl-2,2-dichloroacetanilide, m.p. 112°-114°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>CN1C(=O)CCC1.Cl.O1CCOCC1>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]=3[CH3:11])=[CH:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: Cc1cc2cc(F)ccc2[nH]1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(F)cc2c1-c1ccnc2cc(Cl)ccc12
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of 5-fluoro-2-methylindole (149 mg) and 4,7-dichloroquinoline (198 mg) in NMP (2 ml) and 4M hydrogen chloride in dioxan (0.2 ml) was stirred at 140° C. overnight and then at 150° C. for 1 h. and evaporated. The residue was taken up in ethyl acetate, washed with brine (3×), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica chromatography using acetone/isohexane (2:8) as eluent to give the sub-title compound (250 mg).