Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].[N:2]([N:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:5][CH2:6][OH:7])=O.O1CCCC1.CO>O>[C:8]([N:4]([CH2:5][CH2:6][OH:7])[NH2:2])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)N(CCO)N=O
Agent: [Li]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)N(N)CCO
Temperature: 60 °C

Procedure:
A total of 12.2 g of lithium alanate are added in portions to a mixture of 23 g of N-nitroso-tert.-butyl-(2-hydroxy-ethyl)amine and 200 ml of anhydrous tetrahydrofuran at 60° C. When the addition has ended, the mixture is heated at 60° C. for a further hour and cooled in an ice bath and the excess lithium alanate is hydrolysed by careful dropwise addition of methanol and then water. The solids are removed by filtration with suction and the filtrate is concentrated. A colourless oil (14 g) remains and is subsequently used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[C:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15].Cl.[CH3:18][O:19][NH2:20].N1C=CC=CC=1>CCO>[CH3:18][O:19][N:20]=[C:11]([C:3]1[CH:4]=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CON
Reactant: CCCCC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCC(=NOC)c1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
A mixture of 1,2-dihydro-6-methyl-2-oxo-5-(1-oxopentyl)-3-pyridinecarbonitrile (0.70 g, 0.0032 mol), methoxyamine hydrochloride (0.32 g, 0.003B mol) and pyridine (2.0 ml) were heated and stirred at reflux in EtOH (30 ml) overnight. The solution was cooled to room temperature and concentrated on the rotary evaporator. The residue was diluted with H2O and the resulting solid collected by filtration. Recrystallization (MeOH--H2O) gave 0.38 g (48%) m.pt. 159-161.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][C:30]2([CH3:34])[CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:48]=[CH:47][C:39]([C:40]([NH:42][CH:43]2[CH2:46][O:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:49][CH3:50].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:50][O:49][C:37]1[CH:38]=[C:39]([CH:47]=[CH:48][C:36]=1[NH:35][C:2]1[N:3]=[C:4]([O:29][C:30]2([CH3:34])[CH2:31][CH2:32][CH2:33]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:6]=2[N:7]=1)[C:40]([NH:42][CH:43]1[CH2:44][O:45][CH2:46]1)=[O:41]
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5(C)CCC5)c34)cc2o1
Reactant: COc1cc(C(=O)NC2COC2)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2COC2)ccc1Nc1nc(OC2(C)CCC2)c2c(-c3ccc4nc(C)oc4c3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a degassed mixture of 6-(2-chloro-4-(1-methylcyclobutoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-methoxy-N-(oxetan-3-yl)benzamide (1.1 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.22 M) was added palladium acetate (0.1 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-2% DCM in MeOH) to afford the title compound (99% yield) as a yellow solid which was used without further purification. MS (ESI) m/z 685.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[C:14](B(O)O)[CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[CH:15]=[C:14]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:12][C:11]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1ccc(-c2ccccc2)c(F)c1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(-c2ccccc2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a solution of 3-bromopyridin-2-amine (1.0 g) in 1,2-dimethoxyethane (50 mL) were added 2-fluorobiphenyl-4-ylboronic acid (1.623 g), sodium carbonate (1.225 g), tetrakis(triphenylphosphine)palladium(0) (0.334 g), and water (10 mL) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80° C. overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (THF/diisopropyl ether) to give the title compound (1.175 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[CH:17][N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(O)CC>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][N:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: OB(O)c1ccnc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-c2ccnc(F)c2)nc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a flask containing ethyl 2-(6-chloropyridin-3-yl)acetate 208-1 (300 mg, 1.5 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (318 mg, 2.25 mmol), Pd(OAc)2 (17 mg, 0.075 mmoL), 2-dicyclohexylphosphino-2′,6′-dimethoxyybiphenyl (62 mg, 0.15 mmol), K3PO4 (800 mg, 9 mmol) under argon was added 2-butanol (1.5 mL). The reaction mixture was stirred at 100° C. for 10 hours. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in dichloromethane to give ethyl 2-(2′-fluoro-2,4′-bipyridin-5-yl)acetate 208-2 as a yellow solid. MS m/z 261.1 (M+1).
Reaction SMILES: CO[C:3]([C:5]1([N:13]([O:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[C:14](=[O:25])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].C[O-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[OH:4][C:3]1[C:5]2([CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]2)[N:13]([O:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[C:14](=[O:25])[C:15]=1[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24]
Reactant: COC(=O)C1(N(OC2CCCO2)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CON1CCC2(CC1)C(O)=C(c1c(C)cc(C)cc1C)C(=O)N2OC1CCCO1
Reaction time: 0.5 h

Procedure:
To a solution of 1-methoxy-4-{(tetrahydro-furan-2-yloxy)-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (70 g, 161.1 mmol) in dimethylformamide (350 ml) at 10° C. was added sodium methoxide (26.9 g, 483.3 mmol) in four portions and stirring continued at 10° C. for 30 minutes, then at room temperature for 2 hours. The reaction mixture was poured on cold saturated aqueous ammonium chloride and thoroughly extracted with ethyl acetate (6×100 ml). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated and dried in vacuo. The residue was triturated with hexane, filtered and the solid dried. Yield: 51.0 g of 4-hydroxy-8-methoxy-1-(tetrahydro-furan-2-yloxy)-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2ii.18) as a tan solid, mp 144-146° C.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH:8]1[C:15]2[N:11]([N:12]=[CH:13][CH:14]=2)[CH:10]=[CH:9]1>C(O)=O>[CH:5]([N:8]1[C:15]2[N:11]([N:12]=[CH:13][CH:14]=2)[CH:10]=[CH:9]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: c1cc2[nH]ccn2n1
Solvent: O=CO
Product: O=Cn1ccn2nccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of acetic anhydride (3.68 ml) and formic acid (3 ml) was stirred at room temperature for 1 hour. The solution was cooled in an ice-bath and 1H-imidazo-[1,2-b]pyrazole (2.1 g) was added thereto. The mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (1:1) as an eluent. Fractions containing the object compound were combined and the solvent was evaporated to give 1-formyl-1H-imidazo[1,2-b]pyrazole (1.83 g). NMR (DMSO-d6, δ) : 6.20 and 6.28 (total 1H, each d, J=2Hz), 7.65-7.72 (1H, m), 7.71 (1H, d, J=2Hz), 7.87-7.92 (1H, m), 9.02 (1H, br s)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)N(C1C=CC=CN=1)N=[CH:5]2.[Cl:17][C:18]1[N:19]=[N:20][C:21]([NH:24][NH2:25])=[CH:22][CH:23]=1>>[Cl:17][C:18]1[N:19]=[N:20][C:21]([N:24]2[C:8]3[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[CH:5]=[N:25]2)=[CH:22][CH:23]=1
Reactant: Ic1ccc2c(cnn2-c2ccccn2)c1
Reactant: NNc1ccc(Cl)nn1
Product: Clc1ccc(-n2ncc3cc(I)ccc32)nn1

Procedure:
Prepared as described for 118b using 3-chloro-6-hydrazinopyridazine. Yield 687 mg (45%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.[Br:19][C:20]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:21]=1N>[Cu](F)F.N1C=CC=CC=1>[Br:19][C:20]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:21]=1[O:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10]
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: Nc1ccc(Br)cc1Br
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccc(Br)cc1Br
Yield: 68.3 %

Procedure:
The procedure of Example 1 is repeated using 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 3.92 g (38 mmol) of tert-butyl nitrite, 12.5 mg (0.125 mmol) of copper(II) fluoride, 120 mL of pyridine and 6.30 g (25 mmol) of 2,4-dibromoaniline at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 3.34 g of the title compound as a light yellow oil in 68.5% yield. The structure is confirmed by 1Hnmr analysis.
Reaction SMILES: [Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O[K])(C)(C)C.[CH2:30]([CH2:33][O:34][CH3:35])OC.C1(C)C=CC=CC=1.[CH3:43][C:44]1[N:49]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=2)[C:48](=[O:60])[N:47]([C@H:61](C)[CH:62]=O)[C:46](=[O:65])[C:45]=1[C:66]1[N:70]([C:71]2[CH:78]=[CH:77][C:74]([C:75]#[N:76])=[CH:73][CH:72]=2)[N:69]=[CH:68][CH:67]=1>C(OCC)(=O)C.O>[CH3:35][O:34][CH:33]=[CH:30][C@H:61]([N:47]1[C:46](=[O:65])[C:45]([C:66]2[N:70]([C:71]3[CH:72]=[CH:73][C:74]([C:75]#[N:76])=[CH:77][CH:78]=3)[N:69]=[CH:68][CH:67]=2)=[C:44]([CH3:43])[N:49]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:57])[F:58])[CH:51]=2)[C:48]1=[O:60])[CH3:62]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n([C@H](C)C=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: COCCOC
Agent: CC(C)(C)O[K]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC=C[C@@H](C)n1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
To (methoxymethyl)triphenylphoshonium chloride (1.74 g) and tertiary-butoxy potassium (853 mg) was added at 0° C. glyme/toluene (10 ml/10 ml) and the resulting mixture was stirred for fifteen minutes. To the reaction mixture was added at 0° C. (R)-4-(5-(6-methyl-2,4-dioxo-3-(1-oxopropane-2-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 373) (500 mg) and the resulting mixture was stirred at room temperature for fifteen hours. To the reaction mixture was added water (20 ml) followed by an addition of ethyl acetate (30 ml×2) such that the intended products were extracted into an organic layer. The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-4-(5-(3-(4-methoxy-3-buten-2-yl)-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (350 mg). UPLC/MS 522 (M+H)/1.00 min. (measurement condition 9)
Reaction SMILES: C([O:8][C:9]1[C:10]([O:36][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:11][C:12]([CH2:15][O:16][C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH:37]1([O:36][C:10]2[C:9]([OH:8])=[CH:14][N:13]=[C:12]([CH2:15][O:16][C:17]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:11]=2)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: c1ccc(COc2cnc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2OC2CCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1cnc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
5% Palladium on charcoal catalyst (2 g) is added to a solution of 5-benzyloxy-4-cyclopentyloxy-2-trityloxymethylpyridine (24.2 g) in ethanol (500 mL) and the mixture stirred at room temperature under a hydrogen atmosphere for 3 hours. After filtering the filtrate is concentrated in vacuo to give a colourless oil which is purified by flash chromatography (n-pentane/ethyl acetate 7:3 v/v as eluent on silica) to give 4-cyclopentyloxy-5-hydroxy-2-trityloxymethylpyridine (18.8 g) as a colourless foam. [1Hnmr in deuterochloroform with Me4Si as standard: 1.70, 2H, m; 1.82, 2H, m; 1.90-2.08, 4H, m; 4.25, 2H, s; 493, 1H, m; 7.19, 1H, s; 7.24, 7.30, 7.49, 15H, Ar; 8.04, 1H, s.].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].C(=O)([O-])[O-].[NH4+].[NH4+].Cl>CC(C)P([O-])(=O)[O-].O.[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: CC(C)P(=O)([O-])[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: Clc1cc(Cl)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
1.84 g (0.0281 gram atom) of zinc dust is introduced into a solution, heated to 80° C., of 5.1 g (0.02 mol) of pentachloropyridine in 35 ml of dimethylmethanephosphonate. A solution of 2.44 g (0.0254 mol) of ammonium carbonate in 10 ml of water is subsequently added dropwise at a temperature of 90° to 95° C. in the course of 70 minutes with vigorous stirring. The reaction mixture is then stirred into 250 ml of ice water; there is added 5 ml of concentrated hydrochloric acid and the mixture is stirred for a further 10 minutes, and is subsequently extracted twice with 100 ml of ether each time. The combined extracts are washed with 70 ml of water, dried over sodium sulfate, filtered, and evaporated to dryness to yield as residue 4.05 g (92% of theory) of 2,3,5,6-tetrachloropyridine having a melting point of 86° to 88° C. According to gas-chromatographical analysis, the product contains 93.4% of 2,3,5,6-tetrachloropyridine, 2.1% of 2,3,5-trichloropyridine, 2.2% of 2,3,6-trichloropyridine and 0.8% of pentachloropyridine.
Reaction SMILES: [C:1](=[O:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:13]1(O)C=CC=C[CH:14]=1.C(=O)(OCCCC)N>[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4]>[C:1](=[O:12])([O:2][C:3]1[CH:14]=[CH:13][CH:6]=[CH:5][CH:4]=1)[O:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Oc1ccccc1
Reactant: CCCCOC(=O)OCCCC
Agent: [Ti+4]
Agent: CCCCOC(N)=O
Agent: CCCC[O-]
Product: CCCCOC(=O)Oc1ccccc1
Reaction time: 0.17 h
Yield: 12.3 %

Procedure:
1795 g of the top section liquid obtained above containing 862 g of dibutyl carbonate, 932 g of phenol and 1 g of butyl carbamate and 16.8 g of titanium tetrabutoxide were charged into a round bottom flask of capacity 5 L in which a distillation column made from glass provided with a vacuum jacket (filled Sulzer Labopacking, inner diameter 50mmφ, height of filling portion 1100 mm) was connected to an upper portion thereof. The contents in the flask were heated with a mantle heater while stirring at 300 rpm with a mechanical stirrer. When the bottom section temperature became 191° C., reflux was started. All reflux was performed for 10 minutes after starting of reflux and then distillation-out was started in a reflux ratio of 30. The starting time of distillation-out was regarded as starting of the reaction. The yield (mol %) of butyl phenyl carbonate based on charged dibutyl carbonate was analyzed by gas chromatography. The yield was 12.3% in the reaction for 30 min., 18.6% in the reaction for 60 min., 22.5% in the reaction for 90 min., 27.4% in the reaction for 120 min., and 30.0% in the reaction for 150 min. The amount of distilled-out liquid was 131 g and the distilled-out liquid contained 128 g of butanol and 3 g of phenol. The bottom section temperature was 192° C. at the starting time of distillation-out and 197° C. after 150 minutes of starting of the reaction.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].C(OCC)(=O)C>ClCCl.C1COCC1>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3][CH:4]=1)#[N:9]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1cnc(N)cn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cnc(NC(=O)Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A solution of Example 1B (6.0 g, 50 mmol) in a mixture of dichloromethane (100 mL) and THF (200 mL) in a room temperature water bath was treated with pyridine (4.45 mL, 55 mmol), treated dropwise with phenyl chloroformate (10.0 mL, 80 mmol), and stirred at room temperature overnight. The mixture was treated with ethyl acetate (500 mL) and filtered. The filter cake was washed with ethyl acetate and the combined filtrates were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated with 30% ethyl acetate/hexanes to provide 8.50 g (70.8%) of the desired product. MS (APCI(+)) m/z 241 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 9.20 (s, 1H), 8.98 (s, 1H), 7.20–7.50 (m, 5H).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)C.N1C=CN=C1.C(OC(OCC)CCCl)C.[H-].[Na+].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>Cl>[N:7]1([CH2:6][CH2:5][CH:4]=[O:3])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: CCOC(CCn1ccnc1)OCC
Agent: CCOC(CCCl)OCC
Agent: Cl
Agent: O=C([O-])O
Product: O=CCCn1ccnc1
Reaction time: 8 h

Procedure:
A solution of 3-(imidazol-1-yl)propionaldehyde diethyl acetal, (2.5 g, prepared as described in DE 2,842,759, by reacting imidazole with 3-chloropropionaldehyde diethyl acetal in the presence of sodium hydride) in 5M hydrochloric acid (10 ml) was left to stand at ambient temperature overnight. The solution was basified with solid sodium bicarbonate, sodium chloride was added and the mixture extracted with chloroform. The combined chloroform extracts were concentrated under reduced pressure at ambient temperature to give a solution of 3-(imidazol-1-yl)propionaldehyde in a small volume of chloroform. This aldehyde was dissolved in acetonitrile (20 ml). 1-Methyl-1-[4-(3,4-xylylsulphonylmethyl)phenyl]ethylamine (2.0 g) and molecular sieves type 4A, (1.0 g) were added to this solution and the mixture was stirred at ambient temperature overnight. The mixture was filtered. The filtrate was evaporated under reduced pressure to give a residue which was dissolved in absolute ethanol (20 ml). Sodium borohydride (1.4 g) was added to the solution and the mixture was boiled under reflux for 3 hours. The mixture was evaporated to dryness. Dilute sodium hydroxide solution was added to the residue and the mixture extracted with ethyl acetate to give an oil which was purified by flash chromatography on silica, using ethyl acetate/triethylamine (98:2) as the mobile phase to elute unreacted starting material and then ethyl acetates/methanol (9:1) to elute the product as an oil which was dissolved in ether and acidified with ethereal hydrogen chloride. The precipitate was collected by filtration and recrystallised from propan-2-ol containing a small amount of water to give 3-(imidazol-1-yl)-N-{1-methyl-1-[4-(3,4-xylylsulphonylmethyl)phenyl]ethyl}propylamine dihydrochloride hydrate, m.p. 150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.I[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(=O)(=O)(O)O>O1CCCC1.CCCCCC.CCOCC.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ICCCc1ccccc1
Reactant: COc1cccc(OC)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(OC)c1CCCc1ccccc1
Temperature: -20 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
A solution of 8.70 g (63 mmol) of 1,3-dimethoxybenzene in 164 mL of anhydrous tetrahydrofuran was stirred at -20° C. while 1.6M n-butyllithium in hexane (42.1 mL; 67.2 mmol) was added dropwise, over 20 min. The solution was stirred at -20° C. for 3 hr and then allowed to warm to -5° C. whereupon 15.66 g (63.6 mmol) of 1-iodo-3-phenylpropane was added over 15 min. The reaction mixture was stirred at -5° C. for 1 hr and then at room temperature for 3 d. After being recooled to -5° C., the reaction mixture was decomposed by the addition of 1.5N aqueous sulfuric acid. Water was added and the mixture was worked-up with ether in the usual manner. The residue was treated with 100 mL of hexane and the mixture was filtered. Removal of the solvent in vacuo gave 15.28 g (94.7%) of the title compound as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:18][S:19]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCC(=O)N1CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN1C(=O)CCC1=O

Procedure:
The N-(2-hydroxyethyl)succinimide (Aldrich, 0.19 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.