Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:39][O:40][C:41]([CH2:43][CH:44]([CH3:48])[C:45](O)=[O:46])=[O:42].COC(CC(=C)C(O)=O)=O>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])[NH:11][C:45](=[O:46])[CH:44]([CH3:48])[CH2:43][C:41]([O:40][CH3:39])=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: COC(=O)CC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=C(CC(=O)OC)C(=O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: C1COCCO1
Product: COC(=O)CC(C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
L-alanine benzyl ester (44.7 g.) and hydroxybenzotriazole (34 g.) are dissolved in dioxane (750 ml.) and the solution is chilled with stirring in an ice-water bath. Dicyclohexylcarbodiimide (51.5 g.) and 3-methoxycarbonyl-2-methylpropanoic acid (36 g.), prepared by hydrogenation of 3-methoxycarbonyl-2-methylene propanoic acid, are added in that order and the mixture is stirred at room temperature for 18 hours. The precipitate is filtered off, and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The ethyl acetate is dried over magnesium sulfate and concentrated to dryness in vacuo to yield N-(3-methoxycarbonyl-2-methylpropanoyl)-L-alanine benzyl ester.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28](=[O:36])[NH:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31]1)([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28](=[O:36])[NH:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([NH:35][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Yield: 94.7 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (16.9 g, 49.9 mmol), racemic trans (3-amino-cyclopentyl)-carbamic acid tert-butyl ester (10.0 g, 49.9 mmol: Prepared according to J. Org. Chem. 2004, 69(13), 4538; Tetrahedron 1997, 53(9), 3347; WO94/17090 and Org. Lett. 2000, 2, 4169) and diisopropylethylamine (12.0 mL, 69.9 mmol) in propan-2-ol (175 mL) was heated at reflux for 4 hours. After cooling, the mixture was concentrated in vacuo and the residue triturated (water) to give 23.7 g (94%) of racemic trans [3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a yellow solid. LCMS (Method B, ESI): RT=4.25 min, m+H=502.3; 1H NMR (400 MHz, DMSO) δ: 8.89 (s, 1H), 8.87 (d, 1H), 8.12 (d, 2H), 7.83 (d, 1H), 7.76 (m, 1H), 7.65 (t, 2H), 7.17 (d, 1H), 7.06 (br d, 1H), 4.62 (m, 1H), 3.99 (m, 1H), 2.24 (m, 1H), 1.97 (m, 3H), 1.56 (m, 2H), 1.38 (s, 9H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[N:4]([CH3:13])[N:3]=1.IC1C2C(=CC(C#N)=CC=2)NN1C.C([Mg]Cl)(C)C.Cl[Sn:33]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37]>C1COCC1>[CH3:13][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[C:2]([Sn:33]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:34][CH2:35][CH2:36][CH3:37])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2ccc(C#N)cc21
Agent: CC(C)[Mg]Cl
Agent: CN1Nc2cc(C#N)ccc2C1I
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(C#N)ccc12
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
The crude mixture of 3-iodo-1-methyl-1H-indazole-6-carbonitrile and 3-iodo-2-methyl-1H-indazole-6-carbonitrile (97 mg, crude) was dissolved in THF (4 mL). The solution was cooled to −40° C. Isopropylmagnesium chloride (0.21 mL, 0.41 mmol, 2M in THF) was added drop-wise at −40° C. The reaction mixture was stirred at −40° C. for 20 min. Then chlorotributyltin (0.11 mL) was added slowly. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with EtOAc (3×5 mL), organics were washed with water (10 mL), brine (2×10 mL) and dried over Na2SO4 and concentrated. The residue was used to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH:28][C:29]1[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1)[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl>[CH3:12][O:11][C:10]1[C:9]([CH3:13])=[CH:8][C:4]([C:5]([N:38]2[CH2:39][CH2:40][N:35]([C:30]3[C:29]([NH:28][CH2:26][CH3:27])=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:36][CH2:37]2)=[O:7])=[CH:3][C:2]=1[CH3:1]
Reactant: CCNc1cccnc1N1CCNCC1
Reactant: COc1c(C)cc(C(=O)O)cc1C
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1cccnc1N1CCN(C(=O)c2cc(C)c(OC)c(C)c2)CC1
Reaction time: 1 h

Procedure:
3,5-Dimethyl-4-methoxybenzoic acid (I, PREPARATION 3, 0.36 g) is added to a solution of 1,1'-carbonyldiimidazole (0.33 g) in tetrahydrofuran (4 ml) at 20°-25°. After one hour of stirring, 4-[3-(ethylamino)-2-pyridinyl]piperazine (II, International Publication No WO 87/01706 based on International Patent application No PCT/US86/01797, PREPARATION A-47, 0.42 g) in tetrahydrofuran (6 ml) is added and the solution is stirred for 18 hours. The mixture is diluted with dichloromethane and a saturated aqueous sodium bicarbonate solution. The phases are separated, the organic phase is washed with water, then with saline and the phases are separated. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to give an oil. The oil is flash chromatographed on silica gel (230-400 mesh), the product eluted with chloroform, the appropriate fractions are pooled and concentrated to give the title compound.
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:13]1([CH:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:20]2[CH2:23][C:22](=O)[CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO>C(O)(=O)C>[N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH:22]3[CH2:23][N:20]([CH:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(C1CCNCC1)N1CCC1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)N1CCC1
Temperature: 120 °C
Yield: 67.4 %

Procedure:
To a mixture of 4-(azetidin-1-ylcarbonyl)piperidine (0.34 g, 2.0 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.37 g, 1.6 mmol), methanol (5 mL) and acetic acid (0.1 mL) was added (polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.61 g). The reaction mixture was heated for 10 min at 120° C. using microwave single node heating and then filtered through a phase separator. The solvent was removed by evaporation and the product was purified by chromatography on silica gel (methanol-methylene chloride, 5:95). There was obtained 0.42 g (70%) of 4-(azetidin-1-ylcarbonyl)-1-[1-(diphenylmethyl)azetidin-3-yl]piperidine as a colorless foam. 1H NMR (500 MHz, CDCl3): 1.6-1.7 (m, 2H), 1.7-1.8 (m, 4H), 2.0-2.1 (m, 1H), 2.2 (qn, 2H), 2.7-2.8 (m, 2H), 2.8-3.0 (m, 3H), 3.4 (t, 2H), 4.0 (t, 2H), 4.1 (t, 2H), 4.4 (s, 1H), 7.1-7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 390 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[C:3]([CH:8]=[N:11][OH:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=Cc1ncccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ncccc1F
Temperature: 0 °C
Yield: 77 %

Procedure:
Combine 3-fluoropyridine-2-carboxaldehyde (3.00 g, 0.024 mol) with hydroxylamine hydrochloride (1.70 g, 0.026 mol) and ice (50 g) in an ethanol/water (30 mL/30 mL) mixture. Add aqueous sodium hydroxide (2.46 g, 0.06 mol, in 25 mL of water) dropwise and stir for 4 h near ambient temperature. Adjust the mixture to approx. pH 7.0 with aqueous hydrochloric acid and extract with diethyl ether. Dry over sodium sulfate and concentrate in vacuo. Elute the resulting residue over silica gel using methanol/dichloromethane to give 2.59 g (77%) of the desired oxime as an off white solid. MS(ES): (M+1)+ 140.9, 142.0 m/z.
Reaction SMILES: [CH:1]1([CH:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH:18]([O:21][CH3:22])[O:19][CH3:20])[NH:10][C:9]([CH:23]([O:26][CH3:27])[O:24][CH3:25])=[C:8]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CC(C)=O.O>[CH:1]1([C:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH:18]([O:19][CH3:20])[O:21][CH3:22])[N:10]=[C:9]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[C:8]=2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1=C(C(OC)OC)NC(C(OC)OC)=C(C(=O)OCC)C1C1CCCCC1
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C(OC)OC)nc(C(OC)OC)c(C(=O)OCC)c1C1CCCCC1
Reaction time: 0.17 h
Yield: 95.4 %

Procedure:
To a solution of diethyl 4-cyclohexyl-2,6-bis(dimethoxymethyl)-1,4-dihydropyridine-3,5-dicarboxylate (30.7 g, 67.54 mmol) in acetone (450 mL) was added a solution of ceric ammonium nitrate (75.05 g, 135.08 mmol) in water (125 mL) fairly rapidly at room temperature. After stirring for 10 minutes, the resulting solution was concentrated to remove the acetone. Water (300 mL) was added and the mixture was extracted with CH2Cl2 (3×500 mL). The organic phase was washed with brine (600 mL), dried (MgSO4), and evaporated to afford 29.23 g of diethyl 4-cyclohexyl-2,6-bis(dimethoxymethyl)pyridine-3,5-dicarboxylate as an oil. The oil was chromatographed on silica gel using hexane/ethyl acetate mixtures to give single spot material: 1H NMR (CDCl3) δ 5.37 (s, 2H) 4.32 (q, J=7.2 Hz, 4H) 3.33 (s, 12H) 2.4-2.6 (m, 1H) 1.0-1.8 (m, 16H); 13C NMR (CDCl3) δ 167.79, 153.25, 151.44, 128.68, 104.01, 61.51, 54.41, 52.18, 44.41, 31.10, 27.19, 25.85, 14.04; MS (HR-ESI) m/z 460.2534 [M+Li]+ (460.2523 calcd for C23H35NO8Li).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1CCC(OCCO)CC1
Product: CC(=O)OCCOC1CCC(C)CC1

Procedure:
5.65 Grams (0.04 moles) of 2-(4-methylcyclohexoxy)ethanol (prepared above), 0.8 gm of Amberlyst 15 and 100 ml. of acetic anhydride are charged to a 250 ml flask fitted with a magnetic stirrer and Friedrick condenser. The mixture is heated at reflux for 11/2hours, filtered, and acetic anhydride removed by evaporation. The mixture is distilled and 7.92 gms of 2-(4-methylcyclohexoxy)ethylacetate obtained. The structure of the 2-(4-methylcyclohexoxy)ethylacetate is confirmed by NMR. The 2-(4-methylcyclohexoxy)ethylacetate has an extremely pleasant natural, fruity, wine-like odor.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: Br
Solvent: c1ccncc1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
1 g (0.0033 mol) of L-alanyl-L-proline ethylamide hydrobromide was dissolved in 20 ml of dry pyridine and 0.45 ml of pivaloyl chloride was added. The mixture was stirred for 1 hour at room temperature and then the pyridine was removed by evaporation. The oil was triturated with toluene, re-evaporated and then partitioned between chloroform and saturated brine. The chloroform layer was separated and dried over magnesium sulphate, filtered off and evaporated to a clear oil which crystallised on the addition of petrol. The solid was filtered off, washed with petrol and dried to yield 0.4 g (40%) of N-pivaloyl-L-alanyl-L-proline ethylamide of melting point 94°-96° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:14].[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CN(C=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:13]([C:3]2[C:4](=[O:12])[NH:5][C:6]3[C:11]([C:2]=2[NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:14])=[CH:18][CH:19]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2c(Cl)c3ccccc3[nH]c2=O)cc1
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Product: COc1ccc(CNc2c(C(=O)N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)c(=O)[nH]c3ccccc23)cc1
Temperature: 100 °C
Yield: 70.5 %

Procedure:
4-chloro-N,N-bis(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carboxamide (Example 74b) (4.25 g, 9.18 mmol) was dissolved in DMF (20 mL), and 4-methoxybenzylamine (2.68 mL, 20.6 mmol) was added. The reaction was heated at 100° C. for 1.5 hours, then cooled to room temperature and poured into ice water (300 mL). The resultant precipitate was collected by filtration and further chromatographed on silica gel (0% to 20% MeOH in dichloromethane) to give crude N,N-bis(4-methoxybenzyl)-4-(4-methoxybenzylamino)-2-oxo-1,2-dihydroquinoline-3-carboxamide (3.65 g, 71%), which was used without further purification. MS 564 (MH+).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17]([C:20]([C:22]2[C:27]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=3)(=[O:31])=[O:30])=[CH:26][C:25]([Cl:43])=[CH:24][N:23]=2)=[O:21])[CH2:18][CH3:19])=[N:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:18]([N:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][N:9]=1)[C:20]([C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:39]([F:41])([F:42])[F:40])[CH:33]=2)(=[O:31])=[O:30])=[CH:26][C:25]([Cl:43])=[CH:24][N:23]=1)=[O:21])[CH3:19]
Reactant: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1nn(C(=O)OC(C)(C)C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-indazole-1-carboxylic acid tert-butyl ester was dissolved in a mixture of DCM and TFA (1:1) (5 mL). It was stirred at RT for 1 hour, concentrated, purified with HPLC to give 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid ethyl-(1H-indazol-3-yl)-amide. MS m/z: 557.9 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH:9]=[O:10])[CH2:3][CH2:2]1.[N:11]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[N:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1CN[C@@H](C(O)=O)C1.[BH4-].[Na+]>CC#N.C(O)C>[OH:10][CH2:9][C@@H:8]([N:11]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=CCCC1CCOCC1
Reactant: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C(O)[C@H]1CCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: O=C(NN(C(=O)OCc1ccccc1)[C@H](CO)CC1CCOCC1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 88.9 %

Procedure:
To a stirred solution of 3-(tetrahydro-pyran-4-yl)-propionaldehyde (8.59 g, 0.06 mol) and dibenzyl azodicarboxylate (12.8 g, 0.042 mol) in MeCN (250 mL) at 0° C. was added (R-proline) (0.48 g, 0.0042 mol). After stirring the mixture at 0° C. for 15 h, ethanol (100 mL) and NaBH4 (1.56 g, 0.042 mol) were added, and the mixture was stirred at 0° C. for 40 min. The reaction was quenched by slow addition of 10% aq citric acid (15 mL), and the whole solution was concentrated in vacuo. This residue was diluted with EtOAc (200 mL), washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give crude product which was purified by column chromatography to give (S)-dibenzyl 1-(1-hydroxy-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)hydrazine-1,2-dicarboxylate (16.52 g, 89%). 1H NMR (CD3OD) δ 1.0-1.5 (m, 8H), 2.9-3.3 (m, 2H), 3.4-3.6 (m, 2H), 3.7-3.9 (m, 2H), 4.4-4.7 (m, 2H), 5.1-5.4 (m, 4H), 7.2-7.4 (m, 10H).
Reaction SMILES: [C:1]1([CH3:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9]1(C)C=CC=CC=1>>[CH3:8][C:1]1[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=1[CH3:7]
Reactant: Cc1ccccc1C
Reactant: Cc1ccccc1
Product: Cc1ccc(C)c(C)c1

Procedure:
In this example, transalkylation was carried out for obtaining xylene from toluene and 1,2,4-trimethylbenzene using the zeolite C-1 of this invention (silica/alumina mole ratio=39.2) and the zeolite A as a comparison (silica/alumina mole ratio=32.8).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CCOCC.I[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2>C1COCC1.[Cl-].[Cl-].[Zn+2]>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: c1cocn1
Reactant: Ic1ccc2[nH]ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1coc(-c2ccc3[nH]ccc3c2)n1
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a stirred solution oxazole (0.1 g, 1.45 mmol) in anhydrous THF (3 mL), n-BuLi (1.6 mL, 1.6 mmol) was added at −78° C. and stirred for 30 minutes. The reaction mixture was brought to 0° C., ZnCl2.Et2O (4.35 mL, 4.35 mmol) was added and stirred for 1 h. 5-iodo-1H-indole (0.352 g, 1.45 mmol) and (Ph3P)PdCl2 (0.050 g, 0.072 mmol) were added and stirred at 80° C. for 1 h. The reaction mixture was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography to give 2-(1H-indol-5-yl)oxazole (0.060 g, 22%); MS: 185.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:14]([OH:17])[C:15]#[CH:16].[H-].[Na+].O>O1CCCC1>[C:8]1([C:6]2[CH:7]=[C:2]([O:17][CH2:14][C:15]#[CH:16])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cc(-c2ccccc2)ncn1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCOc1cc(-c2ccccc2)ncn1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
In 5 ml of tetrahydrofuran were dissolved 194 mg of 4-chloro-6-phenylpyrimidine and 68 mg of 2-propyn-1-ol, to which 50 mg of sodium hydride (60% in oil) was added with stirring at room temperature, followed by further stirring for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 190 mg of 4-phenyl-6-(2-propynyloxy)pyrimidine (the present compound (37)), m.p.: 65.1° C.
Reaction SMILES: [C:1]([C:4]([CH3:33])([CH3:32])[CH:5]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:23][CH2:22]3)[N:19]=2)[N:14](COCC[Si](C)(C)C)[CH:13]=1)=[O:11])[CH:6]1[CH2:8][CH2:7]1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:4]([CH3:33])([CH3:32])[CH:5]([NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([CH:21]3[CH2:22][CH2:23]3)[N:19]=2)[NH:14][CH:13]=1)=[O:11])[CH:6]1[CH2:7][CH2:8]1)(=[O:3])[NH2:2]
Reactant: CC(C)(C(N)=O)C(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C(N)=O)C(NC(=O)c1c[nH]c2ncc(C3CC3)nc12)C1CC1
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-carbamoyl-1-cyclopropyl-2-methyl-propyl)-amide (108 mg, 0.23 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL). The yellow reaction mixture was stirred for 3 h then concentrated The residue was redissolved in CH2Cl2 (4 ml) and ethylenediamine (0.5 mL) was added. The reaction mixture was stirred for 1 h then concentrated. The residue was purified by SiO2 chromatography (50% to 100% EtOAc/hexanes to 5% MeOH/EtOAc) followed by trituration with Et2O to afford 44 mg (56%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-carbamoyl-1-cyclopropyl-2-methyl-propyl)-amide as a white solid. MS: (M+H)+=342; mp=222.0-224.0.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[Cl:27][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc(SC)nc1O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc(SC)nc1Cl
Temperature: 100 °C
Yield: 82.8 %

Procedure:
Ethyl 4-hydroxy-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (0.2 g, 0.876 mmol), tetraethylammonium chloride (0.145 g, 0.876 mmol), and N,N-dimethylaniline (0.112 mL, 0.876 mmol) were dispersed in acetonitrile (10 mL). The reaction mixture was stirred briefly followed by the addition of phosphorous oxychloride (0.204 mL, 2.190 mmol). The reaction was heated at 100° C. for 4 h. The solvent was subsequently removed in vacuo. The residue was poured onto ice to give an off-white oil, which was extracted with DCM (2×15 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo to give the title compound as a yellowish-green oil (0.179 g, 83%). [M+H] calc'd for C9H11ClN2O2S, 247; found, 247.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1C=C(C2(O)CCCCC2CCN2CCN(C)CC2)C=CC=1OCC1C=CC=CC=1C(F)(F)F.Cl.Cl.[Cl:40][C:41]1[CH:42]=[C:43]([CH:59]([C:67]2([OH:73])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[CH2:60][N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[C:55]([F:58])([F:57])[F:56]>>[ClH:3].[ClH:40].[Cl:40][C:41]1[CH:42]=[C:43]([CH:59]([C:67]2([OH:73])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[CH2:60][N:61]2[CH2:62][CH2:63][N:64]([CH3:4])[CH2:65][CH2:66]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[C:55]([F:57])([F:58])[F:56]
Reactant: OC1(C(CN2CCNCC2)c2ccc(OCc3ccccc3C(F)(F)F)c(Cl)c2)CCCCC1
Reactant: CN1CCN(CCC2CCCCC2(O)c2ccc(OCc3ccccc3C(F)(F)F)c(Cl)c2)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(OCc3ccccc3C(F)(F)F)c(Cl)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-[1-(3-chloro-4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)-2-(4-methylpiperazin-1-yl)ethylcyclohexanol dihydrochloride was prepared from 1-[1-(3-chloro-4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride (See Example 421). MS (ESI) m/z 511; HRMS: calcd for C27H34ClF3N2O2+H+, 511.23336; found (ESI, [M+H]+), 511.2314.