Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](Cl)=[O:40]>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:39](=[O:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Reactant: O=C(Cl)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(NC(=O)c3ccccn3)cc1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a solution of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (100 mg, 0.32 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) in dichloromethane (5 mL) was added freshly prepared picolinoyl chloride (56 mg, 0.35 mmol) with ice cooling. Upon completion of addition, the resultant deep blue solution was allowed to warm back to room temperature and stir overnight. LC-MS showed the reaction was complete. Solvent was removed in vacuo and the residue was purified by preparative Thin layer chromatography to afford 70 mg of methyl 3,3-dimethyl-2-(4-(picolinamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid. Yield: 52%. MS (ESI+APCI) M+1=416.20.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:22]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:25])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)=[O:23])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>C1(C)C=CC=CC=1>[CH2:1]([SnH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH2:2][CH2:3][CH3:4]
Reactant: OCCCCCCO
Reactant: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCC[SnH](CCCC)OCCCCCCO
Reaction time: 6.5 h
Yield: 87 %

Procedure:
1 g (4.02 mmol) of dibutyltin oxide and 0.4747 g (4.02 mmol) of 1,6-hexanediol were introduced into a 100 ml reaction vessel equipped with a Dean-Stark device, and the atmosphere in the reaction vessel was replaced by argon. 70 ml of toluene was added, and the mixture was dehydrated by azeotropic distillation at 135° C. and stirred for 6.5 hours during which it became an uniform solution. After left overnight at room temperature, the precipitated white solids were filtered. The white solids were dried at 50° C. for 5 hours in vaccuo to give a 1,1-dibutylstanna-2,9-dioxanonane oligomer, 1.22 g (87.0% yield).
Reaction SMILES: [NH2:1][C:2](=[N:23]O)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1.[CH3:25][N:26]=[C:27]=[S:28]>CN(C)C=O.C(OCC)(=O)C>[CH3:25][NH:26][C:27]1[S:28][N:23]=[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]3)[CH:4]=2)[N:1]=1
Reactant: CN=C=S
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)ns1
Temperature: 100 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
2,2-Dimethylpropyl 4-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}piperazine-1-carboxylate (122 mg) obtained in Example 26-1) was dissolved in dimethylformamide (1 mL), and methyl isothiocyanate (41 mg) was added thereto and stirred at 100° C. for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 31.3 mg of the entitled compound as a colorless solid.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:19])=O>O1CCCC1>[ClH:19].[N:2]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([Cl:1])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Cl)c1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3-pyrrolidin-1-ylmethyl-benzoic acid hydrochloride (850 mg, 3.5 mmol) in dry tetrahydrofuran was treated with 2.55 mL of thionyl chloride (35 mmol, 10 eq) and stirred at room temperature for 2 hours. The solution thus obtained was then evaporated to dryness, the residue suspended in dry toluene, evaporated to dryness and dried under vacuum affording the title compound as pale brown solid (quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=[CH:6]2.[BH4-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:7][CH2:6]2
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C2CCc3cc(OC)ccc3N2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 6-methoxy-2-(3-methoxy-phenyl)-quinoline (96 mg, 0.36 mmol) in EtOH (3 mL) at 0° C. is added NiCl2.6H2O (86 mg, 0.36 mmol). The reaction mixture is stirred for 30 min before the addition of NaBH4 (55 mg, 1.45 mmol). The mixture is stirred for 16 h while warming to room temperature. An additional portion of NaBH4 (50 mg) is then added and stirring is continued for 3 h. The solvent is removed in vacuo and the resulting residue is partitioned between water and CH2Cl2. The organic phase is washed with water and brine, dried over MgSO4, filtered and concentrated. Flash chromotography (0-50% EtOAc/hexanes) yields 6-methoxy-2-(3-methoxy-phenyl)-1,2,3,4-tetrahydro-quinoline.
Reaction SMILES: [Br-].[C:2]1([CH2:8][C:9]([NH:11][C@@H:12]2[C:47](=[O:48])[N:14]3[C:15]([C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40])=[C:16]([CH2:19][P+](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:49]=O.P([O-])([O-])(O)=O.[Na+].[Na+]>CN(C)C=O.O>[C:2]1([CH2:8][C:9]([NH:11][C@@H:12]2[C:47](=[O:48])[N:14]3[C:15]([C:39]([O:41][CH2:42][C:43]([Cl:44])([Cl:46])[Cl:45])=[O:40])=[C:16]([CH:19]=[CH2:49])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: C=O
Agent: O=P([O-])([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1

Procedure:
[7β-Phenylacetamido-4-(2,2,2-trichloroethoxycarbonyl) ceph-3-em-3-ylmethyl]-triphenylphosphonium bromide (403 mg, 0.5 mmole) was dissolved in N,N-dimethylformamide (10 ml.) and 40%-formaldehyde solution (3 ml.) was added. The solution was stirred vigorously while a solution of disodium hydrogen phosphate (400 mg.) in water (5 ml.) was added dropwise. A white crystalline solid, subsequently identified as the title ester, separated before the addition was complete. The reaction mixture was diluted with chloroform (5 ml.) and water (10 ml.), whereupon the solid dissolved. The aqueous phase was re-extracted with chloroform (25 ml.), and the combined organic phases were washed with 2N-hydrochloric acid (50 ml.) and water (4 × 25 ml.), dried (MgSO4), and evaporated to give the title ester as a pale-yellow solid (128 mg., 54%), λmax. (EtOH) 297 nm (ε13,700). Crystallisation by trituration with ethanol (2 ml.) gave a white solid (75 mg., 31.5%), m.p. 163 to 165°, [α]D23 - 54° (C 1.15; Me2SO), λmax. (EtOH) 297 nm (ε 13,550), νmax. (CHBr3) 3410 (NH), 1772 (azetidin- 2-one), 1730 (CO2R), 1674 and 1500 (CONH) and 912 cm-1 (=CH2), τ (CDCl3) 2.68 (5H, s; C6H5), 2.84 (1H, dd, J 11 and 18 Hz; CH=CH2), 3.61 (1H, d, J 8 Hz; NH), 4.13 (1H, dd, J 8 and 5 Hz; C7 -H), 4.48 (1H, d, J 18 Hz) and 4.60 (1H, d, J 11 Hz) (CH=CH2), 4.98 (1H, d, J 5 Hz; C6 -H), 4.99 and 5.25 (2H, AB-q, J 12 Hz; CH2CCl3), 6.30 and 6.53 (2H, AB-q J 18 Hz; C2 -H2), 6.37 (2H, s; C6H5CH2) (Found: C, 46.8, 47.1; H, 3.6, 3.6; Cl, 21.8; N, 5.5, 5.5; S, 6.5. C19H17Cl3N2O4S (475.8) requires C, 48.0; H, 3.6; Cl, 22.4; N, 5.9; S, 6.7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=1>CCO.CC(O)=O.O=[Pt]=O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH2:13]1
Reactant: COC(=O)CCc1ccccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)CCc1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
23 (310 mg, 0.90 mmol) was dissolved in EtOH/AcOH (4 mL/4 mL). The solution was degassed with Ar for 2 min. PtO2 (61 mg, 0.27 mmol) was added to the mixture and H2 was bubbled in for 2 min. The reaction was stirred under a H2 balloon overnight. The reaction mixture was filtered through Celite and was concentrated to yield tert-butyl 4-(2-(3-methoxy-3-oxopropyl)phenyl)piperidine-1-carboxylate. LC/MS RT (5 min method)=2.47 min. Mass observed: 248.21 (M-Boc+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])[OH:6])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])=[O:6])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c(C(O)C(=O)OCC)c(I)n2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1c(C)nc2cc(C(=O)OCC)nn2c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a mixture of ethyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (3.7 g, 6.41 mmol) in CH2Cl2 (80 mL) was added Dess-Martin Periodinane (2.72 g, 6.41 mmol) and the resulting mixture was stirred at rt for 1 hr. Then diluted with ethyl acetate (500 mL) and washed with sat. NaHCO3 solution (100 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford desired ethyl 6-(2-ethoxy-2-oxoacetyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (2.5 g, 5.80 mmol, 91% yield) as off-white solid. 1H NMR (400 MHz, CDCl3) δ: 7.36 (s, 1H), 4.50 (dq, J=14.5, 7.1 Hz, 4H), 2.56 (s, 3H), 1.46 (t, J=7.2 Hz, 3H), 1.48 (t, J=7.2 Hz, 3H). LCMS (M+H)=431.87.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.[Br:31]C(Cl)(Cl)C(Br)(Cl)Cl>C1COCC1>[Br:31][C:30]1[C:17]([F:16])=[C:18]([CH:27]=[CH:28][CH:29]=1)[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1
Reactant: CN1CCC(Oc2ccccc2F)CC1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(Oc2cccc(Br)c2F)CC1
Reaction time: 0.25 h

Procedure:
Add n-butyl lithium (1.6 M in hexane, 7.4 mL) to a solution of 2,2,6,6-tetramethyl-piperidine (1.67 g) in THF (30 mL) at −78° C. and stir. After 15 min., add dropwise a solution of 4-(2-fluoro-phenoxy)-1-methyl-piperidine preparation 17, 1.65 g) in THF (20 mL) and stir. After 1 hr., add dropwise 1,2-dibromo-1,1,2,2-tetrachloro-ethane (2.57 g) in THF (15 mL) and stir. After 30 min. at −78° C. and 1 hr. at room temperature, partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (110 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to give the title compound (1.25 g). Mass spectrum (electric spray) m/z=288 (M+1), 290 (M+2+1); 1H NMR (CDCl3): 7.12 (m, 1H), 6.92 (m, 2H), 4.30 (m, 1H), 2.69 (m, 2H), 2.30 (s, 3H), 2.28 (m, 2H), 1.97 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CO>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[CH2:14]3)=[O:12])[CH2:9][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C1=CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: Cc1ccccc1C1CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}-3-(2-methylphenyl)-2,5-dihydro-1H-pyrrole (5 mg, 0.00001 mol) in methanol (1 mL, 0.02 mol) was added Pd/BaSO4 (reduced) and the mixture was stirred under an atmosphere of hydrogen at rt for 1 h. The crude product was purified using prep-HPLC. LCMS: m/z 340.4 (M+H)'
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH:32]1([NH2:42])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1>>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:42][CH:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:35][CH2:34][CH2:33]4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:27][CH:26]=1
Reactant: NC1CCCc2ccccc21
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Product: O=C(NC1CCCc2ccccc21)c1ccc2n1Cc1ccccc1N(C(=O)CSc1ccc(Br)cc1)C2

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and 1,2,3,4-tetrahydronaphthalen-1-ylamine, m.p. 163-165° C. MS [(+)ESI, m/z]: 586 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16]2/[C:17](=[O:22])NC(=S)[S:20]/2)=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[Na+]>Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[SH:20])/[C:17]([OH:25])=[O:22])=[CH:11][C:10]=1[O:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C2\SC(=S)NC2=O)ccc1OCc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1cc(/C=C(\S)C(=O)O)ccc1OCc1ccccc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
5-[1-(4-Benzyloxy-3-methoxy-phenyl)-meth-(Z)-ylidene]-2-thioxo thiazolidin-4-one (38 g) and 2.5M NaOH were warmed at 80° C. for one hour. Next the solution was cooled to 10° C. and poured slowly into 6M HCl-solution (200 ml). The reaction mixture was stirred at room temperature for one hour. The solid was filtered, washed with water and dried under vacuum.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: CC(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(Cc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To 4 mols of 1,1-diphenylethane was added 0.001 to 0.005 mol of aluminum chloride. The mixture was heated to 60° C. and allowed to react upon 1 mol of benzyl chloride added thereto for 20 minutes. Then, the reaction mixture was washed with water to remove the used catalyst and subsequently distilled to expel the unreacted portions of the reactants. The isolated 1-(benzylphenyl-1-phenylethane (mixture of isomers) was supplied to an autoclave and, in the presence of a nickel catalyst, subjected to hydrogenation under the conditions of 100 kg/cm2G of initial hydrogen pressure, 140° to 170° C. of temperature for five hours, to afford hydrogenated 1-(benzylphenyl)-1-phenylethane (mixture of isomers). The general attributes of this reaction product were as shown in Table 2.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[C:10]([O:17][CH3:18])=[CH:9][C:8]=1[CH3:19])(=O)C.C(O)C>C(O)(=O)C>[CH3:19][C:8]1[CH:9]=[C:10]([O:17][CH3:18])[C:11]([NH:13][C:14](=[O:16])[CH3:15])=[CH:12][C:7]=1[OH:6]
Reactant: COc1cc(C)c(OC(C)=O)cc1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C)c(O)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To 35 ml of a 0.4N aqueous solution of sodium hydroxide were added 1.70 g (7.17 mmol) of 2-methyl-4-methoxy-5-acetylaminophenyl acetate and 10 ml of ethanol. The mixture was stirred at room temperature for 10 minutes. When crystals were completely dissolved, the stirring was ceased. Then 0.3 ml of acetic acid was added and thus crystals were precipitated. The crystals were collected by filtration, purified by column chromatography (Silica Gel 60, trade name, manufactured by Merck Co., 230-400 mesh, 200 g, eluent: ethyl acetate) and recrystallized from the solvent mixture of ethyl acetate/hexane (2:1). Thus 1.05 g (5.38 mmol) of 2-methyl-4-methoxy-5-acetylaminophenol was obtained. The yield was 75%.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:4]([C:9]([NH:11][C@H:12]([C:17]([O:19]C)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7]>O.CC(C)=O>[NH:3]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:4]([C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
A solution of NaOH (1.34 g, 33.5 mmol) in water (15.0 g) was added dropwise over 10 min to the solution of Boc-Leu-Leu-OMe (10.0 g, 27.9 mmol) in acetone (20.0 g) and water (50.0 g) at 18-22° C. The reaction mixture was stirred at this temperature for 1 h and then analyzed by HPLC. When the methyl ester is under 5%, the reaction stirred for an additional 0.5 h. A white turbidity formed by the end of the reaction which was removed by filtration and rinsed with water (5.0 g). The clear filtrate was treated with formic acid (ca 0.8 g) to form a cloudy solution followed by immediate crystallization of product. Additional formic acid (1.5 g) was added (to pH 4.0-4.5) and the resulting product was collected by filtration then was washed by a mixture of acetone (10.0 g) and water (40.0 g). The solid product was suspended in a mixture of acetone (14.0 g) and water (56.0 g) for 15 min. The solid was collected by filtration and washed with a mixture of acetone (7.5 g) and water (30.0 g) and dried in vacuo at 45° C. Yield: 8.6-8.8 g (89.6-91.7%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH2:2][CH2:3][O:4][C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(Cl)cc2)cc1
Yield: 76.2 %

Procedure:
Methyl 4-(2-aminoethoxy)benzoate (19.5 g) and 13.8 g of anhydrous potassium carbonate were added to 200 ml of chloroform and the mixture was stirred with cooling. p-Chlorobenzoyl chloride (17.5 g) was dropped thereinto at 10°-20° C. The mixture was stirred for 3 hours. The reaction solution was washed with water, the chloroform layer was dried with anhydrous magnesium sulphate, concentrated in vacuo, the residue was crystallised with n-hexane, and the crystals were recrystallised with ethyl acetate/n-hexane to give 25.4 g of crystals of m.p. 125°-127° C., yield 76%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][N:26]=2)[CH2:20][CH:21]2[CH2:24][O:23][CH2:22]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+]>CS(C)=O>[CH:31]([C:28]1[CH:29]=[CH:30][C:25]([N:19]([CH2:20][CH:21]2[CH2:22][O:23][CH2:24]2)[S:16]([C:13]2[CH:14]=[CH:15][C:10]([O:8][CH2:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[N:26][CH:27]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1ccc(N(CC2COC2)S(=O)(=O)c2ccc(F)cc2)nc1
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1ccc(N(CC2COC2)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2)nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (20.08 mg, 0.173 mmol) and 4-fluoro-N-(5-isopropylpyridin-2-yl)-N-(oxetan-3-ylmethyl)benzenesulfonamide (63 mg, 0.173 mmol) in dimethyl sulfoxide (DMSO) (1 mL) stirred in air at room temperature was added sodium hydride (6.91 mg, 0.173 mmol, 60% wt in mineral oil). The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was carefully quenched with methanol (2 mL) and water (2 mL), then solvents evaporated in vacuo. The crude product was purified by flash silica (Si) (25% ethyl acetate-cyclohexane gradient) to give the title product (63.2 mg). LCMS (2 min, High pH) Rt 1.23 min, m/z (ES+) 461 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([F:20])=[CH:9][C:8]=2[Cl:21])(=[O:3])[CH3:2].[CH2:23]([NH2:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>>[C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1[NH:28][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:11][C:10]([F:20])=[CH:9][C:8]=2[Cl:21])(=[O:3])[CH3:2]
Reactant: CC(C)CCN
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(F)cc(Cl)c2[nH]c1=O
Product: CC(=O)c1c(NCCC(C)C)c2cc(F)cc(Cl)c2[nH]c1=O
Yield: 85.9 %

Procedure:
3-Acetyl-8-chloro-6-fluoro-4-methylsulfoxy-2-quinolinone (3.02g, 0.01 mol) and isoamylamine (0.87g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.79g, yield: 86% ).