Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1)=[O:4].O.C(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])=[N:7][CH:8]=1
Reactant: ClCCl
Reactant: Cc1ccnc(NC(=O)C(C)(C)C)c1
Solvent: O
Product: Cc1cc(NC(=O)C(C)(C)C)ncc1Cl
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
2,2-Dimethyl-N-(4-methyl-pyridin-2-yl)-propionamide (42 g, 0.22 mol) from Step 1 was placed in a 3-neck 3 L flask fitted with an overhead stirrer. To this was added water (650 mL), then Na2HPO4 (78 g, 0.55 mol), followed by DCM (220 mL). The mixture was stirred and cooled in an ice-bath to 0° C., then chlorine gas was bubbled slowly through a sparge-frit. The reaction was monitored by TLC (EtOAc/hexanes 1/1), and found to be complete after 80 min. The reaction mixture was poured into a separatory funnel and extracted. The aqueous layer was re-extracted with DCM (2×100 mL). The combined layers were dried over Na2SO4 and concentrated to a crude solid product which was recrystallized from hexanes to yield the purified N-(5-chloro-4-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (41 g, 0.18 mol). 1H NMR (CDCl3) δ 8.18 (s, 1 H), 8.12 (s, 1 H), 7.94 (br s, 1 H), 2.35 (s, 3H), 1.29 (s, 9H).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][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][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O.ON1C2C=CC=CC=2N=N1.[OH:50][CH2:51][C@@H:52]([C@@H:54]([C@@H:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[OH:57])[OH:55])[NH2:53]>O1CCCC1>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][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][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([NH:53][C@H:52]([C@@H:54]([C@@H:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[OH:57])[OH:55])[CH2:51][OH:50])=[O:39]
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Reactant: O=C(O)CCCCCCCCCCCCCCCCCCCCCCCCCCO
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@H](CO)NC(=O)CCCCCCCCCCCCCCCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropylcarbodiimide (1 ml, 6.4 mmoles) was added to a stirred suspension of 27-hydroxy-heptacosanoic acid (2.13 g, 5 mmoles), dry tetrahydrofuran (50 ml), dried 1-hydroxy-benzotriazole (1.6 g, 13.5 mmoles) and phytosphingosine (1.5 g, 4.7 mmoles) at 40° C. under nitrogen. After stirring overnight the mixture was cooled to room temperature and the precipitate was filtered off and washed with 20 ml of tetrahydrofuran.
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][CH2:7][CH2:8][OH:9])[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]12.[CH:16](O)=[O:17]>>[CH:16]([O:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]2[C:1]1=[O:15])=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Reactant: O=CO
Product: O=COCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 3-(phthalimido)-propanol (20.5 g) and formic acid (33 ml) was refluxed overnight and evaporated in vacuo to leave a yellow oil which crystallized from absolute ethanol to give colourless crystals with m.p. 68°-70° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[NH2:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][C:19]=4[NH:28][S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1)c1ccccc1

Procedure:
The title compound was prepared from 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine, (Example 163) and phenylsulfonyl chloride (Aldrich) analogous to the conditions described in Example 172. Mp: 168–170° C. MS (ESI, pos. ion) m/z: 523.1 (M+1).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl[Si](C)(C)C.CN(P(N(C)C)(N(C)C)=O)C.[CH:23]([Mg]Br)([CH3:25])[CH3:24]>C1COCC1>[CH:23]([CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)([CH3:25])[CH3:24]
Reactant: CC(C)[Mg]Br
Reactant: O=C1C=CCC1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)C1CCC(=O)C1
Temperature: -70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclopent-2-enone (1.5 mL, 18.27 mmol), CuBr—SMe2 (188 mg, 0.91 mmol), chlorotrimethylsilane (4.59 mL, 36.54 mmol) and HMPA (6.55 g, 36.54 mmol) in THF (30 mL) was added isopropylmagnesium bromide (36.54 mL, 1 M in THF) at −70° C. After stirring for 1 h at −70° C., the reaction mixture was quenched with HCl (10%). The mixture was extracted with Et2O. The organic layer was washed with aqueous NaHCO3 and brine. After dried over Na2SO4, the organic layer was concentrated to give 3-isopropylcyclopentanone (4 g, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C>ClCCl>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
1.0 eq 4-piperidinemethanol (10.00 g, 86.8 mmol) was dissolved in dichloromethane (350 mL), cooled in an ice-H2O bath and treated dropwise with a solution of 1.05 eq ethyl chloroformate (9.89 g, 91.1 mmol) in dichloromethane (50 mL), followed by the dropwise addition of a solution of 1.0 eq triethylamine (8.78 g) in dichloromethane (50 mL). The reaction was stirred at ≈0° C. for 15 minutes, then at room temperature for 10 minutes. The reaction was diluted with dichloromethane (250 mL) and washed successively with (150 mL each) H2O, 0.1 NHCl (aq) (×2), saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 15.60 g ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate as a viscous, pale bluish-green oil. 1H-NMR (400 MHz, CDCl3) δ 4.15 (br m, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.46 (d, J=6.4 Hz, 2H), 2.72 (br t, J=12.4 Hz, 2H), 2.07 (s, 1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 1.12 (m, 2H); tR=1.56 min [10-99% CH3CN gradient over 5 mins with 0.1% TFA (aq)]; Theoretical (M+H)+ m/z for C9H17NO3=188.1; Found 188.0.
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)(O)[O-].[Na+].[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][NH:13]1)(=[O:11])[NH2:10]>CN(C)C=O>[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][N:13]1[CH2:1][CH3:2])(=[O:11])[NH2:10]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C[C@@H](SCc2ccc(OC)cc2)C[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
0.362 ml of ethyl iodide and 315 mg of sodium bicarbonate to a solution of 1000 mg of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine dissolved in 10 ml of dry dimethylformamide were added, whilst ice-cooling, and the mixture was stirred at room temperature for 5.5 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography through silica gel (Katayama Chemicals Co., Silica Gel 60K070) and 560 mg of the title compound were obtained as crystals, melting at 124°-125° C., from the fractions eluted with ethyl acetate.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][CH:8]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[Mg].B(OC)(OC)[O:16]C.OO>C(O)(=O)C.O1CCCC1>[CH3:5][CH2:4][C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CCC(C)(C)Oc1ccc(Cl)cc1
Reactant: COB(OC)OC
Agent: OO
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(C)(C)Oc1ccc(O)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A Grignard reagent was previously prepared using 99.3 g of 1-tert-amyloxy-4-chlorobenzene, 12.76 g of magnesium, and 200 mL of tetrahydrofuran. To the Grignard reagent, 57.1 g of trimethyl borate was added dropwise at an internal temperature below −50° C. At a reaction temperature of 5° C., stirring was continued for 3 hours. Thereafter, at an internal temperature below 30° C., 45.0 g of acetic acid and 145.7 g of 35% hydrogen peroxide solution were added. At room temperature, stirring was continued for 3 hours. Standard work-up and purification by silica gel chromatography gave 62.2 g of 4-tert-amyloxy-1-phenol (yield 69%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Mg].[CH:13]1[C:26]2[C:25](=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1>C(OCC)C>[C:2]1([C:18]2[C:19]3[C:24]([CH:25]=[C:26]4[C:17]=2[CH:16]=[CH:15][CH:14]=[CH:13]4)=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: O=C1c2ccccc2Cc2ccccc21
Agent: [Mg]
Solvent: CCOCC
Product: c1ccc2c(-c3c4ccccc4cc4ccccc34)cccc2c1

Procedure:
A Grignard reagent was prepared from 1-bromonaphthalene and magnesium in diethyl ether under an inert atmosphere. The reagent was reacted with 9-anthrone. The reaction was quenched with hydrochloric acid, and the mixture was purified as usual, to give the desired 9-α-naphthylanthracene.
Reaction SMILES: [OH:1][CH2:2][C:3]#[CH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:1][CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
To a stirred solution of 112 g (2.0 mol.) of 3-hydroxy-1-propyne and 260 g (3.0 mol.) of dihydropyran in 1.20 liters of methylene chloride cooled to 0° C. in an ice bath, is added a solution of 20 mg of para-toluenesulfonic acid in 100 ml of methylene chloride, dropwise. The reaction mixture is stirred at 0° C. for one-half hour, and at ambient temperature for one hour. It is then poured into 200 ml of a 5% solution of sodium bicarbonate, the organic phase is separated, the aqueous phase extracted with 100 ml of methylene chloride, the combined organic phases washed with 100 ml of a solution of brine, dried over sodium sulfate, and evaporated under vacuum (12 mm) at 45° C. to give 300 g of crude product, which is purified by fractional distillation, bp 71°-73° C. (14 mm) to yield 250 g (89%) of a liguid.
Reaction SMILES: [CH3:1][C:2]1([OH:7])[CH2:6][CH2:5][NH:4][CH2:3]1.FC(F)(F)S(O[C@H:14]([C:19]1[CH:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:15]([F:18])([F:17])[F:16])(=O)=O.C([O-])([O-])=O.[K+].[K+].C1COCC1>>[Cl:25][C:22]1[N:21]=[CH:20][C:19]([C@H:14]([N:4]2[CH2:5][CH2:6][C:2]([CH3:1])([OH:7])[CH2:3]2)[C:15]([F:18])([F:16])[F:17])=[CH:24][CH:23]=1
Reactant: O=S(=O)(O[C@H](c1ccc(Cl)nc1)C(F)(F)F)C(F)(F)F
Reactant: CC1(O)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(O)CCN([C@@H](c2ccc(Cl)nc2)C(F)(F)F)C1
Temperature: 50 °C
Yield: 54.6 %

Procedure:
A mixture of 3-methylpyrrolidin-3-ol (1.41 g, 13.9 mmol), (R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (4.30 g, 12.5 mmol) and K2CO3 (1.93 g, 13.9 mmol) in THF (69.7 mL, 13.9 mmol) was heated in a sealed tube to 50° C. overnight. The reaction was filtered, concentrated under reduced pressure and the residue was purified by preparative HPLC (C18, 300 g, 10% MeCN/water to 95% MeCN/water over column volumes) to give 1-((S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ol (2.01 g, 48.9% yield).
Reaction SMILES: CO[C:3](=O)[CH:4]([N+:13]([O-:15])=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=C.Cl>C(O)(C)(C)C.C(OCC)C>[CH3:22][O:21][C:17](=[O:20])[CH2:6][CH:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:4]([N+:13]([O-:15])=[O:14])[CH2:3][CH2:18][C:17]([O:21][CH3:22])=[O:20]
Reactant: C=CC(=O)OC
Reactant: COC(=O)C(C(C)c1ccccc1)[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccccc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 356 g of nitro-3-phenylbutanoic acid methyl ester, 138 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-phenylheptanedioic acid dimethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([NH2:19])[CH:13]=2)=[N:3]1.Cl.[N:21]([O-])=O.[Na+]>O>[CH3:1][N:2]1[C:6]([C:7]([F:9])([F:10])[F:8])=[CH:5][C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[N:18]=[N:21][NH:19][C:14]=3[CH:13]=2)=[N:3]1
Reactant: Cn1nc(Oc2ccc(N)c(N)c2)cc1C(F)(F)F
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1nc(Oc2ccc3nn[nH]c3c2)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
The o-phenylenediamine obtained in step B (1.0 g,3.7 mmol) in water (20 cm3) was treated with concentrated hydrochloric acid (1.7 cm3) at room temperature. After stirring for 15 minutes more water (10 cm3) was added and the mixture cooled in an ice/salt bath to ~0° C. A solution of sodium nitrite (0.544 g, 7.9 mmol) in water (5.5 cm3) was added dropwise, with stirring, maintaining the temperature at ≤0° C. When the addition was complete the reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for a further 2 hours. The mixture was extracted several times with ethyl acetate and the combined extracts washed with water, dried (MgSO4) and evaporated leaving 6-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)benzotriazole as a buff solid m.p. 129°-131° C.
Reaction SMILES: [C:1]1([N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][C@@H:9]2[O:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:32]12CC[CH:35]([CH2:36][CH2:37]1)[C@@H:34](O)[CH2:33]2>>[C:26]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C@@H:22]3[CH:35]4[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]4)[CH2:23]3)=[O:20])[CH2:10][C@@H:9]2[O:24][CH3:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCOC(=O)CCCCCN1CC[C@@H](N(c2ccccc2)c2ccccc2)[C@@H](OC)C1
Product: CO[C@H]1CN(CCCCCC(=O)O[C@H]2CN3CCC2CC3)CC[C@H]1N(c1ccccc1)c1ccccc1

Procedure:
esterifying the ethyl 6-((3S,4R)-4-(diphenylamino)-3-methoxypiperidin-1-yl)hexanoate with (R)-quinuclidine-3-ol to yield (R)-quinuclidine-3-yl 6-((3S,4R)-4-(diphenylamino)-3-methoxypiperidin-1-yl)hexanoate
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[N:3]=1.[BH4-].[Na+]>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:11][OH:12])[CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=Cc1cccc(-c2nccc(Cl)n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OCc1cccc(-c2nccc(Cl)n2)c1
Reaction time: 3 h

Procedure:
A 1.0 g portion of 3-(4-chloro-2-pyrimidinyl)benzaldehyde was dissolved in 230 ml of 2-propanol and 0.32 g of freshly ground sodium borohydride pellets was added. After stirring for 3 hours at 50°-60° C. in a water bath, the excess reducing agent was destroyed with 6N hydrochloric acid. The solution was neutralized with sodium bicarbonate and the mixture concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and then evaporated, giving 1.1 g of the desired intermediate as a colorless oil.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:30])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=3)=[C:12]([C:31]3[CH:36]=[CH:35][C:34]([O:37]S(C)(=O)=O)=[CH:33][CH:32]=3)[S:11][C:10]=2[CH:42]=1)(=O)=O.O1CCCC1.[OH-].[Na+]>CO>[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:30])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:19][CH:20]=3)=[C:12]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[S:11][C:10]=2[CH:42]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 3.6 g. portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene was dissolved in 100 ml. of tetrahydrofuran and 40 ml. of methanol, and 10 ml. of 5N sodium hydroxide was added. The mixture was stirred for 16 hours at ambient temperature, and was then worked up by the procedure of Example 1 above to obtain 3.5 g of a yellow solid. The impure product was purified by column chromatography on silica gel, eluting with a gradient solvent from 5% methanol in chloroform to 30% methanol in chloroform. The product-containing fractions were evaporated to obtain 1.85 g. of oily product, which was recrystallized from acetone to obtain 1.25 g of purified product, m.p. 141°-144° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27]OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:9]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH2:1]([N:8]1[CH2:25][C@H:26]([O:39][CH:40]([O:42][CH2:43][CH3:44])[CH3:41])[CH2:27][C@H:20]([C:21]([O:23][CH3:24])=[O:22])[C@H:9]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)O[C@H](COS(=O)(=O)c1ccc(C)cc1)CN(Cc1ccccc1)[C@@H](CC(=O)OC)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H]1C[C@H](C(=O)OC)[C@@H](C(=O)OCc2ccccc2)N(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 1-benzyl 4-methyl(2S)-2-[benzyl((2S)-2-(1-ethoxyethoxy)-3-[(4-methylphenyl)sulfonyl]oxypropyl)amino]succinate (35.7 g, 0.0569 mol) in a mixture of tetrahydrofuran (95.5 mL, 1.18 mol) and toluene (490 mL, 4.6 mol) at −78 Celsius was was added 1.00 M of Lithium hexamethyldisilazide in tetrahydrofuran (68.2 mL). The reaction was stirred at −78 Celsius overnight then allowed to warm up to −20 Celsius and stirred at −20 Celsius for 3 h. After quenched with aq ammonium chloride, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to dry. The residue was applied on silica gel column, eluting with 0 to 20% EtOAc in hexane, to afford the product (18.1 g, 69.9%). MS (ESI): (M+H)+=456.2. The corresponding diastereoisomer was also obtained (4.52 g, 17.5%).
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][C@H:23]([CH3:26])[CH2:24][OH:25]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][C@H:23]([CH3:26])[CH2:24][OH:25])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: C[C@@H](N)CO
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 2 step a), using the product of example 4 step b) and (R)-(−)-2-amino-1-propanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:13](=[O:14])[C:12](=[C:15]3[S:19][CH:18]=[CH:17][S:16]3)[C:11](=[O:20])[CH:10](C(OC)=O)[CH2:9]2)[CH:2]=1.[OH-].[Na+].O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:9][CH2:10][C:11](=[O:20])[C:12](=[C:15]3[S:16][CH:17]=[CH:18][S:19]3)[C:13]2=[O:14])[CH:2]=1
Reactant: COC(=O)C1CN(Cc2cccnc2)C(=O)C(=C2SC=CS2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CCN(Cc2cccnc2)C(=O)C1=C1SC=CS1
Yield: 55.6 %

Procedure:
Methyl 1-(3-pyridylmethyl)-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-3-carboxylate (244 mg) obtained in Example 27 is dissolved in methanol (15 ml), and thereto is added a 10% sodium hydroxide solution (2 ml). The mixture is refluxed for 2 hours. The mixture is poured into water, and extracted with chloroform. The extract is washed with water, dried and then distilled to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and and n-hexane to give 1-(3-pyridylmethyl)-3-(1,3-dithiol-2-ylidene)-2,4-dioxopiperidine (114 mg, 66.1%) as yellow plates, m.p. 131.5°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O>[Pd].C([O-])([O-])=O.[Ca+2].CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: O
Product: CN[C@@H]1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
The mixture of 4-(3,4-Dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine (10 gm), 5% Pd/CaCO3 (grade-21, 0.6 gm), water (2 ml) and methanol (150 ml) is taken in a hydrogenation flask and then subjected to hydrogenation under a hydrogen pressure of 0.5 Kg at 20-35° C. for 3 hours 30 minutes. The catalyst is removed by filtration and the solvent is evaporated completely under vacuum to obtain cis-(±)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine. (cis-(±):trans-(±): 99.8:0.2).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:14]>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Product: NC(=O)c1cc([N+](=O)[O-])ccc1N
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-amino-5-nitrobenzonitrile (25.4 g) and sulfuric acid (70 mL) was stirred at 130° C. for 40 min. The reaction mixture was added slowly to ice water, and the precipitate was collected by filtration, washed with water, ethanol and diethyl ether to give 2-amino-5-nitrobenzamide (24.6 g).