Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:28]=[C:27]5[C:22]([C:23]([CH3:33])([CH3:32])[CH2:24][N:25](C(=O)C)[CH2:26]5)=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:28]=[C:27]5[C:22]([C:23]([CH3:33])([CH3:32])[CH2:24][NH:25][CH2:26]5)=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N1Cc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc2C(C)(C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)CNCc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Temperature: 90 °C
Yield: 55 %

Procedure:
A mixture of 1-(7-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,4-dihydro-4,4-dimethylisoquinolin-2(1H)-yl)ethanone (10 mg), acetonitrile (2 mL), and 5 N HCl (0.5 mL) was heated overnight at 90° C. The cooled solution was treated with aq. Na2CO3, extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried, and evaporated. The residue was purified by TLC to give a light yellow solid (5 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:6]=[C:7]([OH:22])[C:8]2[N:12]=[C:11]([CH3:13])[N:10](C(OC(C)(C)C)=O)[C:9]=2[CH:21]=1)=[O:4].[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:36])=[C:29]2[C:34]=1[O:33][CH2:32][CH2:31][CH:30]2O>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:36])=[C:29]2[C:34]=1[O:33][CH2:32][CH2:31][CH:30]2[O:22][C:7]1[C:8]2[N:12]=[C:11]([CH3:13])[NH:10][C:9]=2[CH:21]=[C:5]([C:3]([N:2]([CH3:1])[CH3:23])=[O:4])[CH:6]=1
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C(=O)OC(C)(C)C
Reactant: Cc1ccc(F)c2c1C(O)CCO2
Product: Cc1nc2c(OC3CCOc4c(F)ccc(C)c43)cc(C(=O)N(C)C)cc2[nH]1
Yield: 32 %

Procedure:
The title compound was prepared as a white solid in 32% yield (38 mg) from 1,1-dimethylethyl 6-[(dimethylamino)carbonyl]-4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylate (100 mg, 0.31 mmol, STEP 2 in Example 9) and 8-fluoro-5-methylchroman-4-ol (0.23 g, 1.2 mmol, STEP 1-3) by the same manner in STEP 3-2 of Example 9.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[C:11]([NH:16][NH2:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: NN
Reactant: COc1ccc2nc(Cl)c(Cl)nc2c1
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(Cl)c(NN)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2,3-Dichloro-6-methoxyquinoxaline (4.2 g., 0.018 mole), the product of Preparation E(b), and 2.7 ml. of hydrazine hydrate in 100 ml. of ethanol were heated under reflux for 4 hours and stirred at room temperature overnight. The precipitate was removed by filtration and washed with ethanol to afford 3.9 g. (97% yield) of 2-chloro-3-hydrazino-6-methoxyquinoxaline, m.p. <250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:26]([N:27]1[CH2:32][CH2:31][N:30]([CH2:18][CH2:17][CH2:16][CH:14]2[O:13][N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:15]2)[CH2:29][CH2:28]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)cc1OC
Yield: 71.9 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (20.0 mg, 0.079 mmol), 1-(diphenylmethyl)piperazine (19.94 mg, 0.079 mmol), molecular sieve(5 beads) and NaBH(OAc)3 (50.2 mg, 0.237 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 28.4 mg (72.0%) of the target compound was obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.[I:40]N1C(=O)CCC1=O>CC#N.ClCCl>[CH3:37][Si:34]([CH3:36])([CH3:35])[CH2:33][CH2:32][O:31][CH2:30][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:38])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:40])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
To tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-9f, 18.8 g, 32.5 mmol) in CH3CN (130 mL) and dichloromethane (130 mL) was added N-iodosuccinimide (8 g, 35.8 mmol) portionwise and the resulting mixture was stirred at room temperature for 1.5 h, at which time LC/MS confirmed full conversion of starting material to product. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) gave the desired product, tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-9g) (21.7 g, 95%). LC/MS: m/z=704.2 (M+H4).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:28][C:29]1[CH:52]=[CH:51][C:32]([CH2:33][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[C:35]2[C:43]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:44])=[CH:31][CH:30]=1>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:27]=[CH:26][C:22]2[O:23][CH2:24][O:25][C:21]=2[CH:20]=1)[CH2:13][CH2:14][N:48]1[CH2:49][CH2:50][CH:45]([C:43]([C:35]2[N:34]([CH2:33][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:52][CH:51]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=2)=[O:44])[CH2:46][CH2:47]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccc2c(c1)OCO2)C(=O)c1ccccc1
Product: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccc2c(c1)OCO2)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(benzo[1,3]dioxol-5-yl)-4-methanesulfonylbutyl)benzamide and 4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1cccc2oc(-c3ccc(N)cc3)nc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a solution of 2-(4-aminophenyl)benzo[d]oxazole-4-carboxamide (150 mg, 0.59 mmol) in dichloromethane (5 mL) was added pyridine (51 mg, 0.65 mmol) and acetyl chloride (49 mg, 0.62 mmol) at 0° C., and the mixture was stirred at room temperature for 4 hr, then the solvent was evaporated under reduced pressure and the residue was re-crystallized in methanol to obtain 2-(4-acetamidophenyl)benzo[d]oxazole-4-carboxamide as a white solid (155 mg, yield 89%). 1H-NMR (400 MHz, DMSO-d6) δ 2.10 (s, 3H), 7.49-7.53 (t, J=8 Hz, 1H), 7.83-7.85 (d, J=8 Hz, 2H), 7.95-7.99 (m, 3H), 8.23-8.26 (d, J=8 Hz, 2H), 8.48 (s, 1H), 10.36 (s, 1H); LC-MS (ESI) m/z 296 [M+1]+.
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=3)[C:11](=[O:24])[N:10]([CH2:25][CH3:26])[C:8]=2[N:9]=1)=O.[ClH:27].[NH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C(#N)C.C(O)C>[ClH:27].[NH:28]=[C:29]1[CH:34]=[CH:33][N:32]([C:4]2[N:5]=[CH:6][C:7]3[CH:13]=[C:12]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=4)[C:11](=[O:24])[N:10]([CH2:25][CH3:26])[C:8]=3[N:9]=2)[CH:31]=[CH:30]1
Reactant: Nc1ccncc1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(S(C)=O)nc21
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(-n3ccc(=N)cc3)nc21
Temperature: 40 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of 220 g (0.59 mol) of the product of Example 2, 2-methylsulfinyl-6-(3,5-dimethoxy-phenyl)8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one, in 2 L of acetonitrile was added a solution of 100 g (0.765 mol, 1.3 eq) of 4-aminopyridine hydrochloride in 700 mL of ethanol. The mixture was heated to 40° C. and stirred for 6 hours. The mixture was then cooled to 24° C. and filtered to provide 256 g (99%) of 2-(4-imino-4H-pyridin-1-yl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]-pyrimidin-7-one hydrochloride; mp 295-300° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([CH:20]3[CH2:25][CH2:24][CH2:23][O:22][CH2:21]3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:26].[I-].N.CCO>>[NH2:26][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([CH:20]3[CH2:25][CH2:24][CH2:23][O:22][CH2:21]3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Yield: 107.9 %

Procedure:
A solution of 6-bromo-1′-methyl-2′-(methylthio)-2-(tetrahydro-2H-pyran-3-yl)spiro[c-hroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.047 mmol), NH4I (54.5 mg, 0.37 mmol) in a solution of NH3/EtOH (2 mL, 8 N) was heated at 120° C. in a tube in a microwave reactor for 3 h. After cooling, the mixture was concentrated in vacuo to give 2′-amino-6-bromo-1′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8]([CH3:13])[CH:7]([OH:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:10]2[S:9](=[O:11])(=[O:12])[N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(O)c2cccc(Br)c2S1(=O)=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CN1C(=O)c2cccc(Br)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.4 %

Procedure:
To a solution of 7-bromo-2-methyl-2,3-dihydro-1,2-benzisothiazol-3-ol 1,1-dioxide(0.34 g, 1.2 mmol) in methylene chloride (20 mL), prepared according to the method described in Example 3 was added PDC (1.4 g, 3.6 mmol). The reaction mixture is stirred at ambient temperature over 6 h, filtered through a pad of Celite and concentrated under the reduced pressure. The residue was purified by flash chromatography (ethyl acetate/hexane, 1:4) to afford the desired product 7-bromo-2-methyl-1,2-benzisothiazol-3-one 1,1-dioxide (0.24 g, 72%). 1H NMR (CDCl3): δ3.9 (s, 3H), 7.71 (t, 1H), 7.99 (d, 1H), 8.03 (d, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].Br[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[C:26]1([C:7]2[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]([C:17]([C@H:19]3[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH:11]3[CH2:12][CH2:13][N:14]([CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[CH2:15][CH2:16]3)[CH:8]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: BrCc1cccnc1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2CCN(Cc3cccnc3)CC2)CC1

Procedure:
Alkylation of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester with 3-bromomethylpyridine and subsequent hydrolysis of the derived ester afforded the title compound compound #121
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][CH2:11][C:12](=O)[CH2:13]Cl.C(=O)([O-])O.[Na+]>C(O)C>[Cl:10][CH2:11][C:12]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[S:9][CH:13]=1
Reactant: NC(=S)N1CCCCC1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: ClCc1csc(N2CCCCC2)n1
Yield: 66.6 %

Procedure:
A mixture of piperidine-1-carbothioamide (1.0 g), 1,3-dichloro-2-propanone (0.91 g) and ethanol (30 mL) was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4-chloromethyl-1,3-thiazol-2-yl)piperidine as a colorless oil (1.00 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: Cl[C:2]1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:7](=[O:8])[CH2:6][CH2:5][CH2:4]C1=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[C:20]([CH2:19][CH2:18][CH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH:4]=1)([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CCCc1ccccc1CC1(Cl)C(=O)CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COC(=O)CCCc1ccccc1CC1=CCCC1=O
Yield: 141.2 %

Procedure:
A mixture of 10 g (0.026 mol) of 2-chloro-2-[2-(3-carbomethoxypropyl)benzyl]-1,3-cyclohexanedione, VIIIb and 18.5 g (0.175 mol) of anhydrous Na2CO3 was refluxed in 200 ml xylene for 2 hours. Filtration and evaporation gave a brown oil (10 g). Evaporative distillation at 175° C/0.2 mm gave 6 g of a pale yellow oil. This was chromatographed on silica gel and eluted with 7:3 v:v CCl4 :acetone. Like fractions were combined to give 4.1 g of the keto ester IXb as a pale yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C:12]#[CH:13].C([Mg]Br)C.Br[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O1CCCC1.CCOCC.[Cl-].[NH4+]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C:12]#[C:13][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCC#CCBr
Reactant: C#CCC#CCOC1CCCCO1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCC#CCC#CCC#CCOC1CCCCO1
Reaction time: 2 h

Procedure:
To a stirred solution of 10.8 g (60 mmole) of hexa-2,5-diyn-1-ol tetrahydropyranyl ether [D. Van der Steen et al, Recueil 82, 1015 (1963)] in 100 ml of dry tetrahydrofuran there were added dropwise, under argon atmosphere, at 0°-5° C. 16.9 ml (0.60 mmol) of a 3.5N ethylmagnesium bromide solution in ether, maintaining the temperature at 0°-5° C. The mixture was stirred for 2 hours at 10°-15° C. and then 0.1 g of cuprous chloride were added. After 15 minutes a solution of 5.35 g (26 mmole) of 1-bromo-2-nonyne in 60 ml of dry tetrahydrofuran was added dropwise and the mixture stirred at room temperature for 3 hours. The reaction mixture was diluted with 70 ml of saturated ammonium chloride solution and extracted with methylene chloride. The organic extracts were dried and evaporated, and the residue purified by column chromatography on 450 g of silica gel, using hexane-ethyl acetate (99:1) as eluant, to provide pentadeca-2,5,8-triyn-1-ol tetrahydropyranyl ether.
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[Li]>CCOCC>[CH2:7]([O:6][CH2:5][C:3]1[CH2:4][CH:2]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCOCC1(Br)CC1(Br)Br
Agent: [Li]C
Solvent: CCOCC
Product: CCCCCCOCC1=CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.5 %

Procedure:
A solution of 1.15 g of 1,1,2-tribromo-2-(hexyloxymethyl)cyclopropane (2.9 mmol) in 6 ml of ether was treated at −78° C. with 1.4 ml of methyllithium (1.4 M, 8.8 mmol). After 5 minutes, the reaction mixture was warmed to 0° C. and held at this temperature. The reaction was quenched with saturated ammonium chloride. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and stripped to give 320 mg of 1-hexyloxymethyl-cyclopropene, as a dark yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:3]=1>[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2cccc(Cl)c2)cc1
Agent: [Pt]
Product: Nc1ccc(CCc2cccc(Cl)c2)cc1

Procedure:
In an analogous manner to that described in Example 36 b), the hydrogenation of (E)-1-chloro-3-[2-(4-nitrophenyl)ethenyl]-benzene using platinum on carbon (5%) as the catalyst but with a reaction time of 18 hours and simultaneous reduction of the double bond yields the 4-[2-(3-chloro-phenyl)-ethyl]-phenylamine as a dark brown oil; MS: m/e=232 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1I.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:24]#[C:23][C:25]1[CH:31]=[CH:30][CH:29]=[C:27]([NH2:28])[CH:26]=1
Reactant: C#Cc1cccc(N)c1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To the reaction vessel containing methyl 5-{N-[(6-amino-5-iodopyridin-3-yl)carbonyl]-S-methylsulfonimidoyl}pentanoate (2.0 g, 4.56 mmol, 1 eq), 3-ethynylaniline (0.715 mL, 1.5 eq), and bis(triphenylphosphine)palladium(II) dichloride (320 mg, 0.1 eq) in anhydrous DMF (10 mL) under anhydrous nitrogen atmosphere was added triethylamine (2.54 mL, 4 eq) and copper(I) iodide (173 mg, 0.2 eq). The reaction mixture was stirred at RT for 15 minutes and then partitioned between saturated aq NaHCO3 and EtOAc. The organic layer was separated, washed with aq NH4Cl (1×) and brine (1×), followed by drying with anhydrous Na2SO4. The upper clear liquid was decanted, concentrated, and the brown oily residue was subject twice to a gradient column chromatography (EtOAc-Hex from 1:3 to MeOH-EtOAc-Hex 1:30:6). Concentration of the product eluting fractions provided the title compound as a white foam (1.32 g, 68%).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]=[C:9]=[O:10])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:30][C:31]([NH2:35])=[N:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[NH2:35][C:31]1[CH:30]=[C:29]([N:36]2[CH2:37][CH2:38][N:39]([C:9]([NH:8][C:7]3[C:2]([F:1])=[C:3]([F:14])[C:4]([F:13])=[C:5]([F:12])[C:6]=3[F:11])=[O:10])[CH2:40][CH2:41]2)[C:28]2[C:33](=[CH:34][C:25]([Cl:24])=[CH:26][CH:27]=2)[N:32]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: O=C=Nc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1cc(N2CCN(C(=O)Nc3c(F)c(F)c(F)c(F)c3F)CC2)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of pentafluorophenyl isocyanate (0.03 mL, 0.23 mmol) and iPr2NEt (0.05 mL, 0.29 mmol) in DMF (1 mL), a hot solution of 7-chloro-4-(1-piperazinyl)-2-quinolinamine (50 mg, 0.19 mmol) in DMF (2 mL) was added. After stirring at rt overnight, the mixture was poured into ice-water. The solid was collected by filtration and re-dissolved in CH2Cl2-MeOH, then purified by preparative TLC (CH2Cl2-MeOH, 9:1) affording the product as a light yellow solid. LC-MS: 472 (M++1). 1HNMR (DMSO-d6) δ 3.02 (br.s, 4H), 3.70 (br.s, 4H), 6.28 (s, 1H), 6.50 (s, 2H), 7.10 (d, 1H), 7.39 (s, 1H), 7.78 (d, 1H), 8.80 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CCOCC.Br[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[O:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:24][N:23]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[O:29]1[CH2:30][CH2:31][CH2:32][O:33][CH:28]1[C:25]1[CH:26]=[CH:27][C:22]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[N:23][CH:24]=1
Reactant: Clc1ccnc2ccsc12
Reactant: Brc1ccc(C2OCCCO2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of 7-chlorothieno[3,2-h]pyridine (1) (13.33 g, 79 mmol) in THF (204 mL) at −5° C./−10° C. was added n-BuLi (2.5 M in hexanes, 31.6 mL, 79 mmol) over 50 min. After 30 min, a solution of zinc chloride in ether (1M, 79 mL, 79 mmol) was added at −5° C./0° C. over 50 min and the reaction mixture was allowed to warm-up to r.t. After 45 min, 2-bromo-5-(1,3-dioxan-2-yl)pyridine (316) (15.98 g, 65.5 mmol) and palladium tetrakistriphenylphosphine (2.27 g, 1.964 mmol) in THF (28 mL) were added and the mixture was heated to reflux for 2 h, cooled down to r.t., and concentrated. The residue was diluted with DCM (600 mL), H2O (500 mL) and NH4OH (100 mL), stirred at r.t. for 1 h and the phases were separated. The aqueous phase was extracted with DCM (2×100 mL); the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with MTBE (150 mL), to afford intermediate 317 (12.796 g, 59% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.66-8.65 (m, 2H), 8.43 (d, J=0.8 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.59 (dd, J=5.0, 0.6 Hz, 1H), 5.68 (s, 1H), 4.19 (dd, J=11.6, 4.8 Hz, 2H), 3.99 (t, J=11.4 Hz, 2H), 2.07-2.01 (m, 1H), 1.49 (d, J=13.2 Hz, 1H). MS (m/z): 333.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([CH3:24])[NH:8][C:7]=1[CH2:25][N:26]1C(=O)C2=CC=CC=C2C1=O)=[O:5])[CH3:2].O.NN>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([CH3:24])[NH:8][C:7]=1[CH2:25][NH2:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(CN2C(=O)c3ccccc3C2=O)=C(C(=O)OCC)C1c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CN)=C(C(=O)OCC)C1c1ccccc1Cl

Procedure:
14 g of 2-phthalimidomethyl-6-methyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are heated to the boil in 150 ccs of ethanol, with the addition of 5 ccs of hydrazine hydrate, for 2-3 hours, the mixture is filtered hot and the filtrate is filtered again after cooling and concentrated in vacuo.