Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[H][H].[Pt](=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1=CNCCN1C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CNCCN1C(=O)OC(C)(C)C
Yield: 90.3 %

Procedure:
A solution of ethyl 1-tert-butoxycarbonyl-1,4,5,6-tetrahydropyrazine-2-carboxylate (69.0 g) in acetic acid (AcOH, 500 ml) was subjected to catalytic reduction using platinum dioxide (4.0 g) at 40° C. in hydrogen at 3 atm for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was dissolved in H2O (800 ml) and the solution was washed with Et2O (500 ml×2). To the aqueous layer was added NaHCO3 to adjust the pH of the solution to 8 and the solution was extracted with AcOEt (800 ml×2). The combined organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo to give 62.8 g of ethyl 1-tert-butoxycarbonyl- piperazine-2-carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].Cl[C:22](OC1C=CC([N+]([O-])=O)=CC=1)=[O:23].CO[CH:36](OC)[CH2:37][NH:38][CH3:39].Cl>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:36]=[CH:37][N:38]([CH3:39])[C:22]1=[O:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNCC(OC)OC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N)C1
Agent: Cl
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2-n2ccn(C)c2=O)C1

Procedure:
(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (enantiomer B, preparation as described in WO2004085404), 4-nitrophenyl chloroformate and methylaminoacetaldehyde dimethyl acetal were reacted analogously to example 40, and the resulting intermediate (85 mg) was subsequently cyclized with a mixture of water (1 ml) and 10% hydrochloric acid (3.2 ml). Workup and purification were analogous to example 40. 65 mg of the title compound were isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].Cl.Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C.CCO>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:15]
Reactant: NCCCCO
Reactant: [O-][n+]1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)(C)O
Solvent: CCO
Product: [O-][n+]1ccccc1NCCCCO
Reaction time: 48 h

Procedure:
A mixture of 4-amino-1-butanol (1.76 g, 20 mmol), 2-chloropyridine N-oxide hydrochloride (3.98 g, 24 mmol), and NaHCO3 (8.40 g, 100 mmol) in tert-amyl alcohol (50 mL) is heated at reflux under argon. After 48 h, the reaction is cooled, diluted with EtOH, filtered, and concentrated. The residue is reconcentrated from toluene, and chromatographed (silica gel) to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.[C:26](OC(C)(C)C)(=[O:31])[CH2:27][C:28]([O-])=[O:29].C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>CO.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:22]([C:21]4[CH:24]=[CH:25][C:18]([N:15]5[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]5)=[CH:19][CH:20]=4)[C:28](=[O:29])[CH2:27][C:26]3=[O:31])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(C3C(=O)CC(=O)N3c3ccc4[nH]cnc4c3)cc2)CC1
Reaction time: 60 h

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.85 mg, 6.37 mmol), 4-(4-methylpiperazin-1-yl)benzaldehyde (1.3 g, 6.37 mmol), mono-tert-butyl malonate (1.53 g, 9.55 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (1.1 g, 7.01 mmol) in MeOH/CH2Cl2 1:1 (30 ml) with stirring for 2.5 days and sodium tert.-butoxide (0.235 g, 2.10 mmol) according to method 5.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:18]1[C:23]([I:24])=[C:22]([CH:25]([OH:27])[CH3:26])[N:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1>[OH:27][CH:25]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:23]=1[I:24])[CH3:26]
Reactant: NCCc1ccccc1
Reactant: CC(O)c1ncnc(Cl)c1I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(O)c1ncnc(NCCc2ccccc2)c1I
Temperature: 60 °C

Procedure:
In 20 ml of toluene were dissolved 2-phenylethylamine (0.6 g) and triethylamine (0.6 g), then, 4-chloro-6-(1-hydroxy-ethyl)-5-iodopyrimidine (1.4 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]([OH:9])=O)[CH2:2][CH2:3][CH3:4].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([N:17]=[C:18]=[S:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[CH2:6][C:7](=[O:9])[N:17]([C:15]2[CH:16]=[C:11]([Cl:10])[CH:12]=[CH:13][C:14]=2[CH3:20])[C:18]1=[S:19])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CCCCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 40.6 %

Procedure:
A mixture of N-butyl glycine (12.0 g), 5-chloro-2-methylphenyl-isothiocyanate (9.15 g), triethyl amine (12.0 g) and chloroform (200 mL) was heated at reflux for 5 hours. The solvent was evaporated. The residue was treated with diethyl ether (400 mL). The mixture was filtered. The solid was washed with diethyl ether then discarded. The filtrate was evaporated to dryness. Crystallization from ethanol afforded the title compound (6.0 g) as a tan solid, m.p. 102°-103° C. Anal. Calcd. for. C14H17Cl N2 O S: C, 56.65; H, 5.77; N, 9.44. Found: C, 56.41; H, 5.97; N, 9.36. Mass spectrum (EI, M.+) m/z 296/298.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[C:33]([NH:37][CH2:38][CH3:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:38][CH3:39])[C:12]=2[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CCCCC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCNC(C)(C)C
Product: CCCCC(=O)c1c(CN(CC)C(C)(C)C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 1, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-valerylquinoline was reacted with N-tert-butyl-N-ethylamine to give 4-(3,4-dimethoxyphenyl)-2-(N-tert-butyl-N-ethylaminomethyl)-6,7-dimethoxy-3-valerylquinoline. This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 137°-139° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(Cl)[Cl:9].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17].Cl>O.O1CCOCC1.CCOC(C)=O>[ClH:9].[CH3:1][C@H:2]1[CH2:7][N:6]([S:16]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)(=[O:18])=[O:17])[CH2:5][CH2:4][NH:3]1
Reactant: ClCCl
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: C[C@H]1CNCCN1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 500 mL round-bottomed flask was charged with (S)-2-methylpiperazine (10.23 g, 102 mmol, Sigma-Aldrich, St. Louis, Mo.) and 100 mL of CH2Cl2. After cooling to 0° C., 2-thiophenesulfonyl chloride (18.65 g, 102 mmol, Sigma-Aldrich, St. Louis, Mo.) was added. This mixture was stirred at 0° C. for 15 min then diluted with water (100 mL). The layers were separated and the organics were dried (MgSO4) and concentrated to give an oil. To this oil was added 300 mL of EtOAc and 28 mL of 4 M HCl in dioxane. The resulting white precipitate was collected by filtration to give (S)-2-methyl-4-(2-thiophenylsulfonyl)piperazine hydrochloride (26 g).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([OH:3])=[O:2].[CH2:18](O)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:18][CH3:19])=[O:2]
Reactant: CCO
Reactant: O=C(O)CCCCCCCCC1=CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCCCC1=CCCC1=O

Procedure:
The acid ketone from Example 22 is Fisher esterfied with 100 ml. of absolute ethanol, 100 ml. of benzene, and 20 mg. of p-toluenesulfonic acid for 6 hours, cooled, and the solvent is evaporated. The resulting oil is dissolved in 3:1 benzene-ether and the solution is passed through a column of 100 g. of Florisil. The filtrate is evaporated and the residue is distilled to yield 2.97 g. of a colorless oil, b.p. 137°-139° C. (0.05 Torr).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:6][CH2:7]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH2:13]1)[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH3:1][C:2]([CH3:33])([CH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH2:13]1)[C:3]([OH:5])=[O:4]
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CCC(C)(C)C(=O)OC(C)(C)C)C3)c(C)o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CCC(C)(C)C(=O)O)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
300 mg of tert-butyl 2,2-dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyrate are dissolved in 20 ml of dichloromethane, and 10 ml of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 1 hour. 200 ml of toluene are added and the solvents are then concentrated under reduced pressure. The residue is purified by RP-HPLC. This gives 180 mg of 2,2-dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyric acid as an oil. C24H33NO4 (399.53), MS(ESI): 400 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH2:16])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:5][CH:4]=1)#[N:2].[C:29](O)(=[O:34])[CH2:30][C:31]([NH2:33])=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH:16][C:29](=[O:34])[CH2:30][C:31](=[O:32])[NH2:33])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:27][CH:28]=1)#[N:2]
Reactant: N#Cc1ccc(C[C@@]23C[C@H](N)CN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reactant: NC(=O)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C[C@@]23C[C@H](NC(=O)CC(N)=O)CN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of (5S,7S)-5-(4-cyanobenzyl)-3-(3,5-dichlorophenyl)-7-amino-1,3-diazabicyclo[3.3.0]octane-2,4-dione (200 mg), malonamic acid (59.5 mg), EDC (112 mg), HOBT (97.5 mg) and DIEA (168 μL) in THF (5 mL) was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was dissolved in EtOAc and the resulting solution was washed with water, saturated aqueous NaHCO3 solution, brine, dried (Na2SO4) and concentrated to give 212 mg of the titled compound. MS (m/z) 500 (MH+).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C(Cl)(Cl)Cl.Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][OH:14]
Reactant: C1=COCCC1
Reactant: OCCCCCCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: OCCCCCCOC1CCCCO1
Yield: 57 %

Procedure:
6-(2-Tetrahydropyranyloxy)hexanol was prepared by a modification of the method described by Bohlmann, Jeute and Reinecke, Chem. Ber., 1969, 102, 3283. 3,4-Dihydro-2-H-pyran (33.6 g., 0.4 mole) was added dropwise at 30°C. with stirring to hexane-1,6-diol (47.2 g., 0.4 mole) in chloroform (500 ml.) and concentrated hydrochloric acid (30 drops). The temperature was allowed to rise to 40°C. and maintained at this level for 3 hours. The solution was then washed with aqueous sodium bicarbonate and then water and dried over potassium carbonate. The solvent was removed in vacuo, and the residue distilled under reduced pressure to give 6-(2-tetrahydropyranyloxy)hexanol (46.1 g., 57%), b.p. 102°-120°C./0.2 mm.Hg.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][S:16][C:17]3[N:26]([CH3:27])[C:25](=[O:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]=4[CH3:29])[N:18]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:1].[ClH:1].[CH3:27][N:26]1[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[CH3:29])[N:18]=[C:17]1[S:16][CH2:15][C:14]1[CH:30]=[CH:31][C:11]([C:9](=[O:10])[C:8]2[CH:32]=[CH:33][C:5]([O:4][CH2:3][CH2:2][N:35]([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[CH3:34])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CNCCc1ccccn1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCCl)cc4)cc3)n(C)c(=O)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCN(C)CCc5ccccn5)cc4)cc3)n(C)c(=O)c12
Product: Cl

Procedure:
A solution of 2-[4-[4-(2-chloroethoxy)benzoyl]-benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (381 mg), 2-(2-methylaminoethyl)pyridine (0.17 ml) and triethylamine (0.33 ml) in DMF (7 ml) was stirred at 100° C. for 21 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane: methanol: aqueous ammonia =9:1:0.1) and treated with hydrogen chloride/ethyl acetate to provide the title compound as colorless solid (256 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7](O)[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl.[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CCOCC>[Cl:19][C:20]1[C:24]([Cl:25])=[C:23]([CH3:26])[NH:22][C:21]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH:7]2[CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:8]2)[CH2:32][CH2:31]1)=[O:28]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCCl
Product: COC(=O)[C@@H]1CC(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-BOC-trans-4-Hydroxy-L-proline methylester (0.20 g, 0.81 mM) and 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide (free base of Intermediate 1), 0.16 g, 0.81 mM) were stirred in 1,2-dichloroethane (3.5 ml). Sodium triacetoxyborohydride (0.24 g, 1.1 mM) was added followed by acetic acid (0.05 ml). The reaction was stirred under nitrogen at room temperature overnight then diluted with ether and washed with 1 N sodium hydroxide. The organic phase was washed with brine, dried over MgSO4 and concentrated to give an orange oil. The oil was chromatographed using EtOAc to give the desired product as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1>[N+:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]([O-:15])=[CH:3][C:2]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([O-:14])=[O:13]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1c(Br)c[n+]([O-])c2ccccc12
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(N2CCCCC2)c[n+]([O-])c2ccccc12
Temperature: 25 °C

Procedure:
3-Bromo-4-nitroquinoline-N-oxide (10 g, 0.037 mol) was dissolved in tetrahydrofuran (100 ml). To the solution, piperidine (7.9 g, 0.093 mol) was added and the mixture was stirred at room temperature until gradual crystallization occurred. Tetrahydrofuran was distilled off from the whole reaction mixture under vacuum and the residue was dissolved in chloroform. The chloroform layer was washed with water and dried with anhydrous sodium sulfate. After distilling off the chloroform under vacuum, the residue was washed with a small amount of ethanol and recovered by filtration under vacuum to obtain 4-nitro-3-piperidinoquinoline-N-oxide in an amount of 6.0 g (yield, 59%).
Reaction SMILES: C(OC(N[C@H](C1C=CC=CC=1)[C@H](O)C(OC(C)C)=O)=O)C1C=CC=CC=1.[CH2:27]([O:34][C:35]([NH:37][C@@H:38]([C@H:45]([OH:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])=[O:36])[C:28]1C=CC=CC=1>>[CH2:27]([O:34][C:35]([NH:37][C@@H:38]([C@H:45]([OH:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])=[O:36])[CH3:28]
Reactant: CC(C)OC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](O)c1ccccc1
Agent: CC(C)OC(=O)[C@@H](O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Product: CCOC(=O)N[C@H](C(=O)OC(C)C)[C@H](O)c1ccccc1

Procedure:
(±)-(2S,3R)-Isopropyl 3-(Benzyloxycarbonylamino)-2-hydroxy-3-phenylpropanoate (12a) and (±)-(2S,3R)-isopropyl 2-(benzyloxycarbonylamino)-3-hydroxy-3-phenylpropanoate (12b).
Reaction SMILES: [CH2:1]([N:3]([CH3:5])[CH3:4])[CH3:2].[CH3:6][O:7][CH2:8][Cl:9]>CC(C)=O>[Cl-:9].[CH2:1]([N+:3]([CH2:6][O:7][CH3:8])([CH3:5])[CH3:4])[CH3:2]
Reactant: COCCl
Reactant: CCN(C)C
Solvent: CC(C)=O
Product: CC[N+](C)(C)COC
Product: [Cl-]
Temperature: 15 °C
Reaction time: 5 h

Procedure:
A 47.50 g quantity of ethyldimethylamine (reagent, product of Tokyo Kasei Co., Ltd.) was dissolved in 300 g of dehydrated acetone (reagent, Wako Pure Chemical Ind. Ltd.), followed by replacement with nitrogen. To the solution was added dropwise 52.30 g of chloromethyl methyl ether (reagent, product of Tokyo Kasei Co., Ltd. as purified by distillation) at 5° C. over a period of 1 hour. The mixture was thereafter stirred at a temperature of not higher than 15° C. for 5 hours to terminate the reaction. The reaction mixture was cooled to 5° C., and the resulting solids were filtered off in nitrogen. The filter cake was washed with 150 g of acetone, and thereafter dried in a vacuum, giving 85.90 g of N-ethyl-N-methoxymethyl-N,N-dimethylammonium chloride (white solid).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN1CCOCC1.[C:20](Cl)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)Cl>[CH2:23]([O:22][C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(O)CCCCN
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)C(O)CCCCNC(=O)OCc1ccccc1

Procedure:
To a well stirred mixture of 0.05 moles of ethyl 6-amino-2-hydroxyhexanoate and 100 ml of methylene chloride which has been cooled to 0° to 5° C is added 0.1 moles of N-methylmorpholine followed by 0.055 moles of carbobenzoxy chloride. The reaction mixture is stirred for 1 hour then washed with saturated sodium bicarbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo. Chromatography of the residue on silica gel and elution with methanol/chloroform gives ethyl 6-(benzyloxycarbonylamino)-2-hydroxyhexanoate.
Reaction SMILES: [C:1]([N:9]([C:18]([C:20]1[C:29]2[C:24](=[C:25]([C:32]([F:35])([F:34])[F:33])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.O>[C:1]([N:9]([C:18]([C:20]1[C:29]2[C:24](=[C:25]([C:32]([F:33])([F:35])[F:34])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:19])[CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(C(=O)N(CC(=O)OC(C)(C)C)C(=O)c3ccccc3)cccc2c1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(C(=O)N(CC(=O)O)C(=O)c3ccccc3)cccc2c1C(F)(F)F
Yield: 34.2 %

Procedure:
A solution of N-benzoyl-N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine, 1,1-dimethylethyl ester (6.03 g, 12.4 mmole) in trifluoroacetic acid (40 mL) was stirred at room temperature for 10 minutes, then diluted with water (600 mL) and extracted with ether (2×300 mL). The extracts were combined, washed with saturated aqueous sodium chloride (1×100 mL), dried with magnesium sulfate, and the ether was removed. The resultant oil was suspended in water (300 mL) and the aqueous phase was slowly neutralized to pH 5 with 10% aqueous sodium hydroxide solution. The precipitate was collected by suction filtration, washed with water (2×25 mL), dried and flash chromatographed (9:1 chloroform:acetonitrile, 5% phosphoric acid in methanol treated silica). The solid was then recrystallized in 2:1 benzen:hexane to provide the product as white crystals (1.83 g, 33%), m.p. 143°-145° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.[CH3:11]OS(OC)(=O)=O.S(C)C.[OH-].[Na+]>CS(C)=O>[CH3:1][C:2]1[C:3]2([C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1)[O:10][CH2:11]2
Reactant: CC1=CCCC(C)(C)C1=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: CS(C)=O
Product: CC1=CCCC(C)(C)C12CO2
Yield: 73 %

Procedure:
Prepared under the conditions described in a., starting from 25.0 g (181 mmol) of 2,6,6-trimethyl-2-cyclohexen-1-one, 31.9 g (253 mmol) of (CH3)2SO4, 17.0 g (274 mmol) of (CH3)2S and 43.0 g (1086 mmol) of NaOH in 60 ml of DMSO. 22.09 G of the desired product, 91% pure, were obtained.