Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][S:10][C:3]2[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=2[OH:1])=[CH:14][CH:13]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Cc1cc(O)c(S)c(=O)o1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2ccc(F)cc2)c(=O)o1
Reaction time: 4 h

Procedure:
To a stirred solution of 10.5 g. (0.0664 mole) of 4-hydroxy-6-methyl-3-mercapto-2-pyrone in 50 ml. of pyridine was added 9.60 g. (0.0664 mole) of p-fluorobenzyl chloride in one portion. The reaction was slightly exothermic, the temperature rising from 25° to 34°C. The reaction mixture was then allowed to stand at room temperature for four hours and at the end of this period was poured into a mixture of ice and 100 ml. of concentrated hydrochloric acid. The gummy precipitate was extracted with methylene chloride and the extract dried over anhydrous magnesium sulfate. The solvent was removed by evaporation in vacuo, leaving a light yellow oil, which crystallized upon cooling, weight 12.5 g. (71 percent). This was recrystallized from a solvent system of methylcyclohexane, benzene and ethanol to give light yellow crystals, m.p. 114.5°-118.5°C.; weight 7.20 g. Recrystallization from benzene gave the pure 3-(p-fluorobenzylthio)-4-hydroxy-6-methyl-2-pyrone as a pale yellow, crystalline solid, m.p. 118°-122°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:20]2[C@@H:16]([O:17][C:18](=[O:21])[CH2:19]2)[CH2:15][C@H:14]1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[O:21]=[C:18]1[O:17][C@H:16]2[CH2:15][C@@H:14]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:13]([CH:12]=[O:11])[C@H:20]2[CH2:19]1
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OCc3ccccc3)C[C@@H]2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of oxalyl chloride (3.3 mL, 38.1 mmoL) in dichloromethane (35 mL) at −78° C., was added DMSO (5.4 mL, 76.3 mmoL) and the mixture was stirred for 15 min. A solution of (3aR,4S,5R,6aS)-hexahydro-4-(hydroxymethyl)-5-(phenylmethoxy)-2H-cycloenta[b]furan-2-one (5, R1 is phenyl, and R2 and R3 are H, 5 g, 19 mmoL) in dichloromethane (35 mL) was then slowly added at −78° C. and the reaction mixture stirred for 0.5 h. Triethylamine (24 mL, 170 mmoL) was added at −78° C. and the reaction mixture stirred for 0.5 h. After completion of the reaction, the reaction mixture was washed with water (20 mL), and the organic layer was concentrated to dryness under vacuum to yield (3aR,4R,5R,6aS)-hexahydro-2-oxo-5-(phenylmethoxy)-2H-cyclopenta[b]furan-4-carboxaldehyde (6, R1 is phenyl, and R2 and R3 are H) in 80% yield.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CCO>C(N(CC)CC)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([N:22]3[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]3)=[N:3][C:4]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc2[nH]c(Cl)nc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc3cc(Cl)ccc3[nH]2)CC1
Temperature: 170 °C
Yield: 40 %

Procedure:
To 2,5-dichloro-1H-benzimidazole (100 mg, Synth. Commun, 1998, 28, 9, 1703-12) and Boc-piperazine (150 mg) was added dry EtOH (5 mL) and then triethylamine (0.112 mL) and the reaction was heated in a microwave at 150° C. for 1 h. The reaction was then heated further for 2.5 h at 170° C. The solvent was then evaporated in vacuo and the residue purified by column chromatography 30-100% EtOAC:hexanes to afford the title compound (72 mg) as a colourless oil.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([NH2:26])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:27].CO>>[ClH:27].[NH2:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[O:15][C@H:12]2[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]2)[CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cccc3cncc(N)c23)CC1
Agent: Cl
Solvent: CO
Product: Nc1cncc2cccc(O[C@H]3CC[C@H](N)CC3)c12

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 8 hours) by using Intermediate 125 (36.1 mg) and 10% hydrogen chloride/methanol solution (2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (13.3 mg).
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]2[O:36][CH2:35][CH2:34][CH:33](Br)[C:32](=[O:38])[C:31]=2[CH:39]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]2[O:36][CH2:35][CH2:34][CH:33]([O:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[C:32](=[O:38])[C:31]=2[CH:39]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCCC1Br
Reactant: COC(=O)c1cccc(O)c1
Solvent: Oc1ccccc1
Product: COC(=O)c1cccc(OC2CCOc3ccc(OCc4ccccc4)cc3C2=O)c1

Procedure:
By the method of Example 27, substituting the phenol with a molar equivalent of methyl 3-hydroxybenzoate, 7-benzyloxy-4-bromo-3,4-dihydro-1-benzoxepin-5(2H)-one (17.3 g) was converted to present title product, 10.9 g, m.p. 134-136° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].Cl[CH2:32][CH2:33][CH2:34][CH:35]1[O:39][CH2:38][CH2:37][O:36]1.[OH-].[Na+]>CN(C=O)C.C(O)C>[O:36]1[CH2:37][CH2:38][O:39][CH:35]1[CH2:34][CH2:33][CH2:32][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:28])=[O:2])[CH2:14][CH2:15]2)=[CH:20]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: ClCCCC1OCCO1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCCC3OCCO3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.75 g (7 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester (prepared as in Example 1, part D) in 10 mL of anhydrous DMF was added to a suspension of 0.36 g (9.1 mmol) of a NaH (60% dispersion in mineral oil) in 5 mL of anhydrous DMF under an inert atmosphere. After stirring for 30 minutes at room temperature, a solution of 1.1 mL (8.4 mmol) of 2-(3-chloro-propyl)-[1,3]dioxolane in 3 mL of DMF was added. The crude mixture was stirred at room temperature for 16 hours and the solvent was removed under reduced pressure. The residue obtained was dissolved with 150 mL of ethanol and 6 mL of a 2N NaOH aqueous solution were added. After 12 h at room temperature, the solvent was removed under reduced pressure. The crude mixture was dissolved with 50 mL of water and neutralised with a 2N HCl aqueous solution. The crude mixture was purified by flash chromatography over silica gel affording 0.83 g (29% of yield) of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.C[C@@H](O)[C@H](N)C(O)=O>>[NH2:11][CH2:10][CH2:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:12]
Reactant: N#CCC(O)c1cccc(Br)c1
Agent: C[C@@H](O)[C@H](N)C(=O)O
Product: NCCC(O)c1cccc(Br)c1

Procedure:
Reduction of 3-(3-bromophenyl)-3-hydroxypropanenitrile following thre method used in Example 50 gave 3-amino-1-(3-bromophenyl)propan-1-ol as a light green oil. Yield (2.30 g, 84%.) This material was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (m, 1H), 7.37 (dt, J=7.2, 1.6 Hz, 1H), 7.23-7.31 (m, 2H), 4.66 (t, J=6.8 Hz, 1H), 2.61 (m, 2H), 1.61 (q, J=6.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([N:17]([CH3:19])[CH3:18])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:20]>>[ClH:20].[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][N:17]([CH3:19])[CH3:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C(=O)C1(c2ccc(F)c(F)c2)CCCCC1
Agent: Cl
Product: CN(C)CC1(c2ccc(F)c(F)c2)CCCCC1
Yield: 8 %

Procedure:
The title compound was synthesized from 1-(3,4-difluorophenyl)-N,N-dimethylcyclohexanecarboxamide (195 mg, 0.73 mmol) using General Procedure E (the amide was prepared from the corresponding carboxylic acid according to General Procedure G), followed by HCl salt formation. The crude HCl salt was recrystallized from 1:1 CH3CN:EtOAc (3.0 mL) to give pure (1-(3,4-difluorophenyl)cyclohexyl)-N,N-dimethylmethanamine hydrochloride as an off-white solid (16 mg, 8%). HPLC Rt=8.24 min; 1H NMR (400 mHz, MeOH-d4) 7.51-7.46 (m, 1H), 7.37-7.34 (m, 2H), 3.31-3.30 (m, 2H), 2.62 (s, 6H), 2.26-2.23 (m, 2H), 1.78-1.38 (m, 8H); LC-MS 7.69 min, (M+1)+ 254 @ 791 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:14])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH3:15][N:16]([CH:18](OC)OC)[CH3:17]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](/[CH:14]=[CH:15]/[N:16]([CH3:18])[CH3:17])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cnc(SC)nc1C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1/C=C/N(C)C
Yield: 61.9 %

Procedure:
4-Methyl-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester 3 (18.0 g, 84.8 mmol) was dissolved in DMF (50 mL), N,N-Dimethylformamidedimethylacetal (22.5 mL, 170 mmol) and stirred at reflux for 3 hours. Then mixture was concentrated, the residue was dissolved in TCM, washed with water, dried, filtered, and concentrated. The product was purified by crystallization from ether to yield in a colorless solid (14.0 g, 52.5 mmol, 62%).
Reaction SMILES: C([O:4][CH:5]([C:33]1[N:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:36]=[N:35][CH:34]=1)[CH:6]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([NH:21][C:22](=[O:24])[CH3:23])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=O)C.C(NC1(C2C=CC=CC=2)CCNCC1)(=O)C.C(OC(C1N(C2C=CC=CC=2)N=NC=1)C(C1C=CC(Cl)=C(Cl)C=1)CC=O)(=O)C>>[Cl:32][C:27]1[CH:26]=[C:25]([CH:6]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][C:12]([NH:21][C:22](=[O:24])[CH3:23])([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)[CH:5]([C:33]2[N:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:36]=[N:35][CH:34]=2)[OH:4])[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CC(=O)NC1(c2ccccc2)CCN(CCC(c2ccc(Cl)c(Cl)c2)C(OC(C)=O)c2cnnn2-c2ccccc2)CC1
Agent: CC(=O)NC1(c2ccccc2)CCNCC1
Agent: CC(=O)OC(c1cnnn1-c1ccccc1)C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CC(=O)NC1(c2ccccc2)CCN(CCC(c2ccc(Cl)c(Cl)c2)C(O)c2cnnn2-c2ccccc2)CC1

Procedure:
5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenyl-1,2,3-(1H)-triazole. Using a procedure similar to that described in Example 7, except using 4-acetamido-4-phenylpiperidine as the amine component, and 5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole as the aldehyde component, the coupling product was prepared as a white foam (61%); NMR: 7.75 (s,1), 7.50-7.01 (m,10), 6.79 (d,1), 6.53 (dd,1), 5.94 (d, 1), 5.41 (s,H), 3.03 (m,1), 2.65-2.45 (m,2), 2.33 (m,2), 2.16 (s,3), 2.10-1.98 (m,6), 1.97 (s,3), 1.65 (broad m,2).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][N:30]2[CH:34]=[C:33]([Si:35]([CH3:38])([CH3:37])[CH3:36])[N:32]=[N:31]2)[N:24]=1.ClC1C=CN=C(CN2C=C([Si](C)(C)C)N=N2)N=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:27]2[CH:28]=[CH:23][N:24]=[C:25]([CH2:29][N:30]3[CH:34]=[C:33]([Si:35]([CH3:38])([CH3:37])[CH3:36])[N:32]=[N:31]3)[N:26]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: C[Si](C)(C)c1cn(Cc2nccc(Br)n2)nn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Agent: C[Si](C)(C)c1cn(Cc2nccc(Cl)n2)nn1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(Cn4cc([Si](C)(C)C)nn4)n3)s2)c(F)c1

Procedure:
The title compound was prepared by the procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (62.3 mg, 0.200 mmol) and a mixture of 4-bromo-2-{[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]methyl}pyrimidine (38 mg, 0.122 mmol) and 4-chloro-2-{[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]methyl}pyrimidine (21 mg, 0.078 mmol) as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[N:14][NH:13][C:12](=[O:16])[CH:11]=2)=[CH:4][CH:3]=1.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[O:30][CH3:31].N1C=CC=CC=1.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[N:14][N:13]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])=[C:22]([O:30][CH3:31])[CH:23]=3)[C:12](=[O:16])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(CSc2ccc(Cl)cc2)cn[nH]1
Reactant: COc1cc(B(O)O)ccc1OCC(C)(C)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-n2ncc(CSc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C

Procedure:
To a mixture of 5-((4-chlorophenylthio)methyl)pyridazin-3(2H)-one Part D (60 mg, 0.24 mmol), copper(II) acetate (95 mg, 0.48 mmol), and 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (114 mg, 0.48 mmol) in CH2Cl2 (20 mL) stirring at RT open to air was added pyridine (1.92 mL, 23.74 mmol) in portions over 4 hours. The mixture was poured into 3.0 N aqueous HCl (100 mL) and extracted with CH2Cl2. The CH2Cl2 layer was dried over Na2SO4 and concentrated. The crude product was subjected to flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, using LC-MS to identify fractions containing the desired product). This material was further purified by preparative HPLC (C18 column/Water:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient). The clean fractions were lyophilized using MeCN/H2O (1:1, 10 mL) to obtain the title compound 5-((4-chlorophenylthio)methyl)-2-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridazin-3(2H)-one E-1 (57 mg, 53% yield) as white solid. LC/MS 447 (M+H)+, tR 0.95 min (method 5); 1H NMR (400 MHz, Chloroform-D) δ ppm 7.85 (1H, d, J=2.26 Hz), 7.30 (4H, s), 7.09-7.14 (2H, m), 6.96 (1H, d, J=9.29 Hz), 6.68-6.72 (1H, m), 3.87 (7H, t, J=5.40 Hz), 1.35 (6H, s).
Reaction SMILES: N1C=CC(=O)N=1.[Br-].[CH3:8][C:9]1[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N+:11]2CCC[O:13][C:12]=2[CH:17]=1.CC1(CC(OCC)=O)OCCO1.C1(NN)C=CC=CC=1.C[O-].[Na+].CC1(CC(NNC2C=CC=CC=2)=O)OCCO1.Cl>C1C=CC=CC=1>[OH:13][C:12]1[CH:17]=[C:9]([CH3:8])[N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:11]=1
Reactant: Cc1cc2[n+](n1-c1ccccc1)CCCO2
Agent: CC1(CC(=O)NNc2ccccc2)OCCO1
Agent: CCOC(=O)CC1(C)OCCO1
Agent: C[O-]
Solvent: NNc1ccccc1
Solvent: c1ccccc1
Product: Cc1cc(O)nn1-c1ccccc1
Temperature: 90 °C

Procedure:
Ueda et al. (Synthesis of pyrazolone derivatives. XLII. Synthesis and analgesic activity of 2-methyl-1-phenyl-6,7-dihydro-1H,5H-pyrazolo[5,1-b][1,3]oxazin-8-ium bromide. Yakugaku Zasshi (1982), 102(8), 743-7) proposes in Chart I of page 744 and in the last two paragraphs on page 745, the reaction of an ethyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate with phenylhydrazine in the presence of sodium methoxide as a base and benzene as a solvent, thereby obtaining 2-(2-methyl-1,3-dioxolan-2-yl)-N′-phenylacetohydrazide, which is further cyclised after treatment with hydrochloric acid 10% and heating on a water bath at 90° C., to obtain 3-hydroxy-5-methyl-1-phenylpyrazole. However, this method presents the disadvantage that both sodium methoxide and benzene are unsuitable for industrial upscaling, in particular, sodium methoxide is a dangerous and highly toxic reagent and benzene is carcinogenic and therefore unsuitable for use in large quantities. Moreover, the reaction devised by Ueda et al. presents a non-optimal yield for 2-(2-methyl-1,3-dioxolan-2-yl)-N′-phenylacetohydrazide (30%). Most importantly, when the inventors tried to reproduce said reaction with similar conditions and a naphthylhydrazine was used instead of the phenylhydrazine (see Example 26 below), they were unsuccessful in preparing the desired final intermediate in optimal isomeric purity. Adversely, an isomeric mixture (80:20) of 5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-ol (desired isomer) and 3-methyl-1-(naphthalen-2-yl)-1H-pyrazol-5-ol (non-desired isomer) was obtained. This process does not avoid the distal nitrogen of the hydrazine from reacting with the ketone carbonyl of the ketoacetate, thereby generating by-products that make this route not interesting for industrial production.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:17][C:18]1([CH3:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH3:17][C:18]1([CH3:24])[CH2:23][CH2:22][N:21]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC1(C)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (4.74 g, 0.03 mol) in toluene (50 mL), Na2CO3 (3.39 g, 32.0 mmol) and 4,4-dimethylpiperidine (J. Org. Chem., 47(20), 3890, (1982), 3.3 g, 0.033 mmol) were added. The resulting mixture was stirred at 50° C. for 1 h and concentrated in vacuo. Water (20 mL) and EtOAc (50 mL) were then added. The organic layer was separated, dried and concentrated to afford 4,4-dimethyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl which was directly subjected to catalytic hydrogenation as described in Example 47, step (a) to obtain 4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine (4.1 g, 67%). Mass spectrum (ESI, m/z): Calcd. for C12H19N3, 206.1 (M+H), found 206.2.
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH2:7][CH2:8][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:10]([C:12](OC)=[O:13])[CH3:11]>ClCCl>[CH3:11][C@@H:10]1[C:12](=[O:13])[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: COC(=O)[C@@H](C)N(CCCN)C(=O)OC(C)(C)C
Agent: C[Al](C)C
Solvent: ClCCl
Product: C[C@@H]1C(=O)NCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a 2M solution of trimethylaluminum in dichloromethane (30 mL) was added slowly a solution of methyl N-(3-aminopropyl)-N-(tert-butoxycarbonyl)-D-alaninate (11.5 g) in dichloromethane. The reaction mixture was stirred at room temperature for four days and then poured into a flask containing 30 g of Celite. The mixture was stirred and quenched by the slow addition of about 10 mL of saturated aqueous ammonium chloride solution. Sodium sulfate (20 g) and methanol (50 mL) were added. The mixture was stirred for 1 h, then filtered. The solids were washed with 5% methanol/dichloromethane. The filtrate was concentrated. The residue was purified by flash chromatography (silica gel, eluting sequentially with 4, 6, 7 and 12% of 10:1 methanovaqueous concentrated ammonium hydroxide in dichloromethane) to provide the title compound containing less than 3% of the (3S)-isomer. MS 228.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:26])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:26][C:18]1[CH:17]=[C:16]([CH2:15][O:13][C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:10][CH2:9][CH2:8]3)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(CBr)cc1F
Reactant: O=[N+]([O-])c1cc2c(cc1O)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2cc3c(cc2[N+](=O)[O-])CCC3)cc1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
7.17 g of 6-nitroindan-5-ol was dissolved in 80.0 mL of DMF, and 10.9 g of methyl 4-(bromomethyl)-2-fluorobenzoate and 6.63 g of potassium carbonate were added thereto, followed by stirring at 50° C. overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain 11.1 g of methyl 2-fluoro-4-{[(6-nitro-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate.
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[CH:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:9]=1
Reactant: C#CCCn1ncc(-c2ccccc2Cl)n1
Reactant: Brc1ccccn1
Product: Clc1ccccc1-c1cnn(CCC#Cc2ccccn2)n1
Yield: 45.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(2-chlorophenyl)-2H-1,2,3-triazole (200 mg, 0.86 mmol) and 2-bromopyridine (150 mg, 0.95 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 120 mg (0.39 mmol, 45%) of 2-(4-(4-(2-chlorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)[S:5][CH:6]=1
Reactant: Clc1nccc(Oc2ccccc2)n1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1csc(Nc2nccc(Oc3ccccc3)n2)n1
Yield: 10.3 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (7.66 mL, 3.07 mmol), 2-chloro-4-phenoxypyrimidine (0.697 g, 3.37 mmol), potassium phosphate (0.716 g, 3.37 mmol), Pd2(dba)3 (0.0702 g, 0.0766 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.0488 g, 0.0843 mmol) were reacted in toluene (8 mL) and water (3 mL) to afford 4-methyl-N-(4-phenoxypyrimidin-2-yl)thiazol-2-amine (0.09 g, 9.40% yield) as a light yellow solid. 1H NMR (CDCl3) δ 8.36 (d, 1H), 7.45 (m, 2H), 7.30 (m, 1H), 7.18 (m, 1H), 7.16 (m, 1H), 6.42 (d, 1H), 6.27 (bs, 1H), 2.30 (d, 3H); Mass spectrum (esi) m/z=385 (100) (M+H1).