Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.O.[NH2:32][NH2:33].O>CN(C=O)C>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:33][N:32]=2)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc([N+](=O)[O-])cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 105 °C
Reaction time: 5 h
Yield: 86.1 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (304 mg, 0.76 mmol, prepared in Synthetic Example 18) in DMF (7.5 ml) was added hydrazine monohydrate (80%, 108 μl, 2.70 mmol, 3.6 eq.), and the mixture was then stirred at 100 to 110° C. for 5 hours. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-(4-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (260 mg, 86%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([C:14](=[O:16])[CH3:15])=[C:9]([CH3:17])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:18][CH2:15][C:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:8][C:9]=1[CH3:17])=[O:16]
Reactant: CC(=O)c1c(C)cc(OC2CCCC2)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(OC2CCCC2)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of 1-(4-(cyclopentyloxy)-2,6-dimethylphenyl)ethanone (4.60 g, 19.8 mmol) in acetonitrile (39.6 mL) was added tetrabutylammoniumtribromide (TBABr3, 10.5 g, 21.8 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(cyclopentyloxy)-2,6-dimethylphenyl)ethanone (6.2 g), which was used directly for the next step without further purification.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C1COCC1>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:38][CH:37]=2)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCOCC4)cc3)c2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 54, 100 mg, 0.231 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (45.34 mg, 0.254 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes (5 mL) were added to the reaction mixture. The crude mixture was concentrated in vacuo and then dissolved into hot EtOAc. Hexanes (˜5 mL) were added causing a precipitate to crash out. The precipitate was filtered and washed with ˜1 mL of i-prOH yielding 69% (95 mg, 0.160 mmol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1>CN(C)C=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)=[N:31][CH:32]=1
Reactant: Fc1ccc(CCl)nc1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cn4)cc3)no2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To 4-(5-(6-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (20.0 mg, 0.07 mmol) described in Manufacturing Example 177-1-1 were added tetrahydrofuran (3 mL) and a 5 N sodium hydroxide aqueous solution (14.9 μL, 0.07 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of the solid obtained above and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of the 2-chloromethyl-5-fluoro-pyridine (12.0 mg, 0.08 mmol) described in Manufacturing Example 41-1-2, which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (3.0 mg, 11%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[SH:12].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=O>CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]([CH:17]2[NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=3[S:12]2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: O=Cc1ccc(O)c(Br)c1
Solvent: CN(C)C=O
Product: Oc1ccc(C2Nc3cc(C(F)(F)F)ccc3S2)cc1Br
Temperature: 100 °C
Yield: 10.5 %

Procedure:
In a DMF (3 mL) solvent, a solution including 2-amino-4-trifluoromethylbenzenethiol (100 mg, 0.44 mmol) and 3-bromo-4-hydroxybenzaldehyde (88.4 mg, 0.44 mmol) was heated at a temperature of 100° C. for 2.5 hours. After DMF was evaporated, the residual was distributed between methylene chloride and water, and an organic layer was evaporated. The produced solid was filtered, and washed with ethyl acetate to obtain a solid Compound 119.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:21]3[C:20](=[O:28])[N:19]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:18](=[O:37])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])[C:21]3[C:20](=[O:28])[N:19]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:18](=[O:37])[N:17]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2CC=C(C)C
Temperature: 25 °C
Reaction time: 13 h

Procedure:
4-[1-(2,2-Dimethylpropionyloxymethyl)-7-(3-methylbut-2-enyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (43 mg) and potassium carbonate (13 mg) were suspended in N,N-dimethylformamide (1 ml), and ethyl bromoacetate (9.6 μl) was added to the suspension. After the reaction mixture was stirred at room temperature for 13 hours, the mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation from the organic layer to give 44 mg of the title compound. δ: 1.19 (s, 9H) 1.23–1.51 (m, 3H) 1.48 (s, 9H) 1.74 (s, 6H) 3.14–3.20 (m, 4H) 3.52–3.58 (m, 4H) 4.17–4.27 (m, 2H) 4.68–4.72 (m, 2H) 4.75 (s, 2H) 5.37–5.42 (m, 1H) 6.03 (s, 2H)
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].C([CH2:19][CH2:20][NH:21][C:22]1C=CC(C=O)=C[CH:23]=1)C1C=CC=CC=1>>[CH2:22]([N:21]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:10]=[C:20]1[CH3:19])[CH3:23]
Reactant: O=Cc1ccc(NCCCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: CCn1c(C)cc2ccccc21
Yield: 86.1 %

Procedure:
Following a procedure similar to that described in Example 4A but employing 6.5 g. of 81.9% sodium p-toluenesulfinate, 6.3 g. of 95% 4-(benzylethylamino)benzaldehyde and 3.8 g. of 86.1% 1-ethyl-2-methyl-1H-indole, there was obtained 15.3 g. of 3-{[4-benzylethylamino)phenyl](4-methylphenylsulfonyl)methyl}-1-ethyl-2-methyl-1H-indole as a gray tar-like product.
Reaction SMILES: O1CCCC1.[C:6]([O:11][Si](C)(C)C)(=[O:10])[C:7]([CH3:9])=[CH2:8].[C:16]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])[C:17]([CH3:19])=[CH2:18]>CC1C=CC(C)=CC=1>[C:16]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:20])[C:17]([CH3:19])=[CH2:18].[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: C=C(C)C(=O)O[Si](C)(C)C
Agent: C=C(C)C(=O)OCCCC
Solvent: C1CCOC1
Solvent: Cc1ccc(C)cc1
Product: C=C(C)C(=O)O
Reaction time: 0 h

Procedure:
A block copolymer of n-butyl methacrylate and methacrylic acid was prepared by adding 3750 grams of tetrahydrofuran and 7.4 grams of p-xylene to a 12-liter flask equipped with a mechanical stirrer, thermometer, nitrogen inlet, drying tube outlet and addition funnels. Feed I, which consisted of 3.0 ml of a 1.0 M solution of tetrabutyl ammonium m-chlorobenzoate catalyst in acetonitrile, was started at 0 minutes and added over 150 minutes and 291.1 gm (1.25 mole) of an initiator, 1,1-bis(trimethylsiloxy-2-methyl propene), was injected. Feed II, which consisted of 1976 gm (12.5 M) trimethylsilyl methacrylate, was started at 0 minutes and added over 35 minutes. One hundred eighty minutes after Feed II was completed (over 99% of the monomers had reacted), Feed III, which consisted of 1772 gm (12.5 M) butyl methacrylate, was started and added over 30 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[O:18][C:17]1=[O:33].[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(C)C>ClCCl>[CH3:29][C:26]1([CH3:30])[O:25][C:24]2[CH:31]=[CH:32][C:21]([C@H:19]3[O:18][C:17](=[O:33])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:3]=[C:2]([NH:1][C:44]([NH:43][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[O:45])[CH:36]=[CH:35][CH:34]=4)[CH2:20]3)=[CH:22][C:23]=2[CH2:28][O:27]1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5ccccc5)c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.057 g) in dichloromethane (2 ml) was treated with phenyl isocyanate (0.020 g) and the mixture stirred under nitrogen at 20° C. for 2 h. Isopropanol (5 ml) was added to quench excess isocyanate, and the mixture stirred for 30 min before leaving to stand for 15 h. The solvents were removed in vacuo to give a residue which was purified by SPE. Elution with a stepped gradient of eluants from cyclohexane to cyclohexane-EtOAc (9:1) and onwards to EtOAc followed by solvent evaporation in vacuo gave the title compound (0.062 g). LCMS RT=3.70 min, ES+ve 618 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[O:31]1[CH2:35][CH2:34][CH2:33][CH:32]1[C:36](O)=[O:37].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:30][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([N:15]([CH2:17][C:18]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][N:21]([C:36]([CH:32]3[CH2:33][CH2:34][CH2:35][O:31]3)=[O:37])[CH2:22][CH2:23]2)[CH3:16])[N:7]=1
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Reactant: O=C(O)C1CCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (210 mg), tetrahydro-2-furoic acid (70 mg) and triethylamine (180 μL) in dichloromethane was added BOP reagent (benzotriazol -1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate) (250 mg). The mixture was stirred at room temperature for 20 hours, evaporated to dryness, and distributed between ethyl acetate and water. The organic phase was washed with sodium bicarbonate, brine, and dried over sodium sulfate. The crude product was purified by flash chromatography to provide 1-(4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidin-1-yl)-1-(tetrahydro-furan-2-yl)-methanone 14, MS: 506 ([M+H]+), which was converted into the HCl salt: 180 mg as white crystals.
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([O:52]C)=O)=[N:48][CH:47]=[N:46]2)=[CH:31][CH:30]=1.CN>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[N:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([C:50]([NH:2][CH3:1])=[O:52])=[N:48][CH:47]=[N:46]2)=[CH:33][CH:34]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1ncnn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12
Agent: CN
Product: CNC(=O)c1ncnn1Cc1c(-c2ccc(Cl)cc2)nc2cccnn12

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-b]pyridazin-3-yl)methyl)-1H-1,2,4-triazole-5-carboxylate and methylamine. 1H-NMR (CDCl3, 400 MHz, δ) 8.42 (dd, J=1.5, 4.4 Hz, 1H), 8.31 (s, 1H), 8.04 (dd, J=1.5, 9.2 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.20 (dd, J=4.5, 9.2 Hz, 1H), 7.06 (broad, 1H), 5.91 (s, 2H), 3.00 (d, J=5.1 Hz, 3H)ppm; m/e 368 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([N:14]=[N+]=[N-])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[H][H]>CO.[Re]>[CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:14]
Reactant: COC(=O)C(CSCc1ccccc1)N=[N+]=[N-]
Reactant: [H][H]
Agent: [Re]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CSCc1ccccc1
Yield: 73.6 %

Procedure:
0.91 gram (3.62 mmoles) of the 2-azido-3-benzylmercapto-propionic acid methyl ester obtained in Example 4 was dissolved in 8 ml of methanol, treated with 0.27 gram (7.41 mmoles) of HCl gas and there was added 1 mole % of rhenium VII sulfide, based on the amount of azido compound employed. Hydrogen was led into this vigorously stirred reaction mixture for 45 hours. The working up according to Example 19 gave 0.60 gram (63% of theory) of S-benzyl-cysteine methyl ester.HCl having a melting point of 84° to 87° C.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=O.C(OC)(=O)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20]>CCOCC>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:11]
Reactant: COC(=O)c1cccc(Cl)c1
Reactant: COC(=O)CCC(=O)OC
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)CCC(=O)c1cccc(Cl)c1

Procedure:
Sodium (11 g, spheres) was added to 200 ml ethanol with stirring. When the gas evolution ceased, methyl 3-chlorobenzoate (10 g, 0.057 mole) and dimethyl succinate (9.0 g, 0.615 mole) were added rapidly and the mixture was stirred for 5 minutes at room temperature. The mixture was slowly concentrated on a rotary evaporator to yield a greenish paste which was slurried in 100 ml ether and an additional 2 ml of dimethyl succinate was added. The reaction was evaporated to a paste, quenched with water and extracted with ether. The ether extracts were washed with water and brine, dried and evaporated in vacuo.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([N:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCCl>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:7]1[N:6]([N:5]2[C:4](=[O:11])[C:3]3=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]3[C:1]2=[O:16])[CH:10]=[CH:9][CH:8]=1)=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCCl
Product: O=C(c1ccccc1Cl)c1cccn1N1C(=O)c2ccccc2C1=O
Yield: 123.7 %

Procedure:
To a vigorously stirred mixture of 1-phthalimidopyrrole (45 g, 0.212 mol) and o-chlorobenzoyl chloride (37 g, 0.212 mol) in 500 ml of 1,2-dichloroethane was added freshly pulverized, fused zinc chloride (43.3 g, 0.318 mol) in one portion. The reaction mixture was heated at gentle reflux for 4.5 hours and then quenched with 700 ml of crushed ice and 500 ml of dichloromethane. The organic layer was separated and washed with water (2x 500 ml), dried over anhydrous MgSO4, filtered, and evaporated to give 92 g of an oil. This oil was purified by column chromatography (silica gel/dichloromethane) to give 33.8 g (45%) of needles, m.p. 158°-160° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:3][CH:2]=1.O(C)[Na]>CO>[NH:9]1[CH:10]=[CH:11][N:12]=[C:8]1[CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1
Reactant: c1cc(Cc2ncc[nH]2)ccn1
Agent: CO[Na]
Solvent: CO
Product: c1c[nH]c(CC2CCNCC2)n1
Reaction time: 0.17 h

Procedure:
2-(4-pyridylmethyl)imidazole (4 g, 0.025 M) and platinum oxide (0.4 g) in ethanol (40 ml) and 2 NHCl (50 ml) was hydrogenated at 45 psig for 4 hrs. The catalyst was removed by filtration and the filtrate was stripped to dryness. Crystallization from ethanol gave 4-(1H-imidazol-2-yl-methyl)piperidine as the dihydrochloride salt m.p. 251°-252° C. (5.2 g, 87% yield). The mixture of 2-(4-pyridylmethyl)-imidazole (2.38 g, 10 mM) and NaOCH3 (10 mM) in methanol (20 ml) was stirred for 10 min. and filtered. The filtrate was stripped to dryness and distilled from about 180° to about 200° C./0.3 mmHg to give the free base of 4-(1H-imidazol-2-yl-methyl)piperidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[C:5]=1[F:19].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]([F:19])=[C:6]2[C:7]([CH:47]([OH:51])[C:48]([CH3:50])([CH3:49])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[NH:10]2)=[CH:8][CH:9]=1)=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cccc(N=Cc2cccc(Br)c2)c1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(c1F)NC(c1cccc(Br)c1)C(C)(C)C2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
To a stirred mixture solution of 3-[(3-bromo-benzylidene)-amino]-2-fluoro-benzoic acid methyl ester (51.7 g, 153.8 mmol) and ytterbium(III) triflate hydrate (14.3 g, 23.1 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (14 mL, 153.8 mmol) and water (2.8 mL, 153.8 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (63.0 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrFNO3 (M+H)+: 409.27, observed: 390.0 & 392.0.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:16][S:17](O)(=[O:19])=[O:18].ClCCl>CO>[Cl:16][S:17]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:2]([CH3:15])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=1)(=[O:19])=[O:18]
Reactant: COC(=O)C(C)(C)COc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(C)(C)COc1ccc(S(=O)(=O)Cl)cc1
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
Methyl 2,2-dimethyl-3-phenoxypropionate (Intermediate A36, 36 g, 0.17 mol) was added dropwise over 60 min to rapidly stirred chlorosulfonic acid that was maintained at −5° C. The mixture was warmed to room temperature, stirred for an additional 90 min, and poured into a cooled, rapidly stirring mixture of dichloromethane (250 mL) and methanol (30 mL). The mixture was stirred for 30 min while being cooled and then for 60 min at room temperature. It was then washed with several portions of ice-water. The combined aqueous layers were extracted with a small portion of dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was stirred with hexanes and collected by filtration to yield 19 g (36%) of the title compound, sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:19]([F:22])([F:21])[F:20])[N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[C:16]([O:18][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:19]([F:22])([F:20])[F:21])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)=Nc2cccc(C(F)(F)F)c21
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(COc1cc(-c2ccc(Cl)cc2)nc2cccc(C(F)(F)F)c12)N1CCOCC1
Yield: 79.2 %

Procedure:
The procedure is as in Example 1, but starting with 2-(4-chlorophenyl)-5-trifluoromethyl-4-quinolone (2.9 g), 4-(2-chloroacetyl)morpholine (1.62 g) and anhydrous potassium carbonate (2.5 g) in 2-butanone (60 cc). After recrystallization in acetonitrile, 4-{[2-(4-chlorophenyl)-5-trifluoromethyl-4-quinolyl]oxyacetyl}morphline (3.2 g), m.p. 179° C., is isolated.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+].CN(C)C=O>O>[CH2:18]([N:9]1[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[C:3]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:2]=2[OH:1])[CH2:11][CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C(=O)C2CCNCC2)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)C2CCN(Cc3ccccc3)CC2)c(O)c1
Reaction time: 15 h
Yield: 57.4 %

Procedure:
A mixture of 14.50 g of 4-(2-hydroxy-4-methoxybenzoyl)piperidine, 6.40 ml of benzyl bromide, 10.20 g of sodium bicarbonate and 74.0 ml of dimethylformamide was stirred at 60° for 15 hrs. The reaction mixture was poured into 250 ml of water and a precipitate formed. The precipitate was collected, washed with water and recrystallized from ethanol to yield 10.0 g (57.4%) of product, mp, 123°-125°.