Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[CH:22][C:21](Br)=[CH:20][N:19]=1.C([Li])CCC.B(OC)(OC)[O:31]C.OO.FC1C(F)=C(CCCCC)C=CC=1C1N=CC(O)=CN=1>CCCCCC.C1COCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:18]1[N:23]=[CH:22][C:21]([OH:31])=[CH:20][N:19]=1
Reactant: COB(OC)OC
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: CCCCCc1ccc(-c2ncc(O)cn2)c(F)c1F
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(-c2ncc(O)cn2)c(F)c1F
Yield: 56.2 %

Procedure:
--Quantities: difluorophenylbromo-pyrimidine 4 (4.30 g, 10.8 mmol), 2.5M butyllithium (4.5 ml, 11.3 mmol), trimethyl borate (2.6 ml, 22.6 mmol), THF (100 ml), hexane (30 ml), 30% hydrogen peroxide (5.4 ml, 44 mmol) ether (200 ml). The experimental procedure was as described for compound 33. The crude product was purified by flash chromatography (10 to 30% ethyl acetate-light petroleum) to give the difluorophenyl-5-hydroxypyrimidine 35 (2.04 g, 56%) [from light petroleum (b.p. 60-80° C.)], m.p. 84-85° C.; νmax /cm-1 (KBr) 3 100br, 2920, 2850, 1620, 1560, 1510, 1475, 1430, 1300, 1285, 1200 and 1085; δ 0.91 (3H, t, Me), 1.19-1.52 (10H, m), 1.32 (2H, quint, OCH2CH2), 4.05(2H, t, OCH2), 6.79 (1H, ddd, J8, 7 and 2, 5'-H), 7.59 (1H, ddd, J8.5, 7 and 2, 6'-H) and 8.38 (2 H, s, 4- and 6-H); m/z 336 (M+), 335, 237, 223, 208, 195 and 155.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH2:4][CH3:5].Cl.[CH3:19][C:20](=[CH2:22])[CH3:21].OS(O)(=O)=O>O1CCOCC1>[CH3:5][CH2:4][CH:3]([C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[CH2:9][C@@H:10]([C:12]([O:14][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:13])[NH2:11])[CH2:2][CH3:1]
Reactant: C=C(C)C
Reactant: CCC(CC)c1cccc(C[C@H](N)C(=O)O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCC(CC)c1cccc(C[C@H](N)C(=O)OC(C)(C)C)c1
Yield: 74 %

Procedure:
According to example 54, 0.60 g of 3-(3-pentyl)-L-phenylalanine.HCl was treated with 30 mL of isobutylene in 35 mL of 1,4-dioxane in the presence of 0.5 mL of conc. H2SO4. Work-up in the usual manner followed by acidification with 2 mL of 1N ethereal HCl afforded 0.53 g (74%) of tert-butyl 3-(3-pentyl)-L-phenylalaninate.HCl as a light yellow glass.
Reaction SMILES: SCC.[Cl-].[Al+3].[Cl-].[Cl-].C(OC([NH:15][C:16]1[C:21]([CH3:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[O:24]C)=O)(C)(C)C>ClCCl>[NH2:15][C:16]1[C:21]([CH3:22])=[C:20]([F:23])[CH:19]=[CH:18][C:17]=1[OH:24]
Reactant: COc1ccc(F)c(C)c1NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: Cc1c(F)ccc(O)c1N
Temperature: 0 °C

Procedure:
To a mixture of mercaptoethane (56 ml) and dichloromethane (56 ml) was added aluminum chloride (22.4 g, 168 mmoles) under stirring at 0° C. To this was then added 2-(N-tert-butoxycarbonylamino)-4-fluoro-3-methylanisole (12.6 g, 56 mmoles) slowly at room temperature. Stirring continued for 11/2 hours. The reaction was quenched by adding ice and water and the solution acidified with 1N HCl. The organic substance was extracted with ethyl acetate (x3). The combined extracts were washed with NaHCO3 and with brine, dried over sodium sulfate and concentrated to give a solid. Recrystallization from chloroform gave 3.15 of pure title product; m.p. 118°-121° (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4](OS(C)(=O)=O)[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([N:21]=[N+:22]=[N-:23])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6]
Reactant: COC(=O)[C@H](OS(C)(=O)=O)[C@H](C)c1ccc(Cl)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](N=[N+]=[N-])[C@H](C)c1ccc(Cl)c(Cl)c1
Temperature: 55 °C
Yield: 71.1 %

Procedure:
To a solution of (2R,3R)-3-(3,4-dichloro-phenyl)-2-methanesulfonyloxy-butyric acid methyl ester (0.70 g, 2.05 mmol) in DMF (10 mL) was added NaN3 (0.27 g, 4.10 mmol). The reaction was heated at 55° C. overnight. The mixture was quenched with water and extracted with EtOAc. The organic phase was washed with water (2×), dried (MgSO4), and concentrated. The product was purified by flash chromatography to give 0.42 g (71%) of product. 1H NMR (500 MHz, CDCl3): 7.39 (d, J=8.3, 1H), 7.35 (d, J=2.1, 1H), 7.10 (dd, J=8.3, 2.1, 1H), 3.96 (d, J=6.4, 1H), 3.71 (s, 3H), 3.29 (m, 1H), 1.33 (d, J=7.0, 3H).
Reaction SMILES: [CH2:1]([C:3]1O[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]=1)[CH3:2].[CH2:14]([CH2:16][NH2:17])[OH:15]>>[CH2:1]([C:3]1[N:17]([CH2:16][CH2:14][OH:15])[C:7](=[O:9])[C:6]2[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2c(=O)o1
Reactant: NCCO
Product: CCc1nc2ccccc2c(=O)n1CCO
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1 g of 2-ethyl-4H-3,1-benzoxazin-4-one was added to 10 mL of monoethanolamine and the mixture was heated to 100° C. for 40 minutes. The heating element was then removed and the reaction medium was kept under agitation for about eight hours (end of the reaction). 100 mL were added to the reaction medium and the mixture was extracted with three portions of 25 mL of ethyl acetate. The organic phase was separated, and dried with magnesium sulfate and spin dried, yielding the 2-ethyl-3-(2-hydroxyethyl)quinazoline-4 (3H)-one compound as a yellowish oil, which solidified when left to rest at room temperature, which was used in the next stage, with no purification.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([N:10](CC2C=CC(OC)=CC=2)[CH:11]([CH2:23][CH3:24])[CH2:12][NH:13]CC2C=CC(OC)=CC=2)=[N:5][CH:6]=[N:7][C:8]=1[CH3:9])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[CH2:1]([C:3]1[C:4]([NH:10][CH:11]([CH2:23][CH3:24])[CH2:12][NH2:13])=[N:5][CH:6]=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(C)ncnc1N(Cc1ccc(OC)cc1)C(CC)CNCc1ccc(OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1c(C)ncnc1NC(CC)CN
Yield: 287.9 %

Procedure:
N2-(5-Ethyl-6-methyl-pyrimidin-4-yl)-N1,N2-bis[(4-methoxyphenyl)methyl]butane-1,2-diamine (353 mg, 0.787 mmol) was dissolved in acetic acid (2 ml), the vial was flushed with argon, palladium (10% on activated carbon, 109 mg, 0.102 mmol) was added, and the mixture was stirred in an atmosphere of hydrogen at room temperature overnight. The mixture was filtered, the filter residue was washed with acetic acid, the combined filtrates were concentrated under reduced pressure to yield 472 mg of a brown oil. The residue was dissolved in DCM, washed with a saturated solution of sodium bicarbonate, the combined aqueous solutions were extracted three times with DCM. The organic phases were combined and concentrated under reduced pressure, the residue was purified by column chromatography (silica, gradient from DCM to a 9 to 1 mixture of DCM and 7N NH3 in methanol) to yield 94.6 mg of a yellow oil. The oil was dissolved in a mixture of diethylether and DCM, 1M HCl in diethylether was added until the product precipitated. The precipitate was isolated by decantation, washed with diethylether and dried in stream of nitrogen and under reduced pressure to give 127 mg of a white solid (0.498 mmol, 63%). MS (ESI) m/z=209.2 [M+1]+.
Reaction SMILES: C(O)(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[OH:13][C:14]1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.C1OC1>>[C:5]1([CH2:6][OH:8])([CH2:14][OH:13])[CH2:4][CH2:3][CH2:2][CH2:10][CH2:9]1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Solvent: C1CO1
Product: OCC1(CO)CCCCC1

Procedure:
As a thermoplastic resin there was used a 5:4:1 (by mole) of terephthalic acid, bisphenol A-ethylene oxide adduct and linear polyester obtained from cyclohexane dimethanol (Tg: 62° C.; Mn: 4,500; Mw: 10,000). This thermoplastic resin was ground using a jet mill, and then classified using an air classifier to prepare a particulate material having d50 of 6 μm.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:12]2[N:19]=[CH:20][C:21]([CH:22]=[C:23]3[NH:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:12]2[N:19]=[CH:20][C:21](/[CH:22]=[C:23]3/[C:24](=[O:29])[NH:25][C:26](=[O:28])[NH:27]/3)=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(SCc4ccccc4)nc23)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(SCc4ccccc4)nc23)N1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
5-((5-(Benzylthio)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (60 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). After 1 h, the solution was concentrated under a stream of air. The residue was triturated with Et2O (3 mL) and the precipitate was collected to provide (Z)-5-((5-(benzylthio)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (59 mg, 98%). LCMS (ES): >95% pure, m/z 407 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.[CH:19]([OH:21])=[O:20].[NH2:22][CH2:23][CH2:24][N:25]([CH3:36])[C:26]1[N:31]=[C:30]([NH2:32])[C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=1>>[CH:19]([OH:21])=[O:20].[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:4]1[N:3]=[C:2]([NH:22][CH2:23][CH2:24][N:25]([CH3:36])[C:26]2[N:31]=[C:30]([NH2:32])[C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=2)[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=1
Reactant: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Reactant: CN(CCN)c1ccc([N+](=O)[O-])c(N)n1
Solvent: O=CO
Product: CN(CCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12)c1ccc([N+](=O)[O-])c(N)n1

Procedure:
In analogy to the procedure for preparing Example 5, the product is obtained by reacting 5-chloro-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidine (Example 6A) with N6-(2-aminoethyl)-N6-methyl-3-nitropyridine-2,6-diamine formate (preparation analogous to Example 14A).
Reaction SMILES: Cl.[H][H].[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C@@H:15]2[C@H:20]([NH:21][C@@H](C3C=CC=CC=3)C)[CH2:19][CH2:18][O:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH3:5]>[Pd].CO>[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C@@H:15]2[C@H:20]([NH2:21])[CH2:19][CH2:18][O:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH3:5]
Reactant: CCOc1cc([C@H]2COCC[C@H]2N[C@H](C)c2ccccc2)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOc1cc([C@H]2COCC[C@H]2N)ccc1OC
Temperature: 25 °C

Procedure:
A suspension of 50 mmol of 3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-one, 75 mmol of (R)-phenylethyl amine, 5 mmol of p-toluenesulfonic acid mono-hydrate and 1 g of platin-on-carbon catalyst (3% Pt) in 400 ml of absolute methanol is hydrogenated at 60° C. and 100 mbar hydrogen pressure until no further ketone can be detected by TLC. After cooling to RT the suspension is filtered over a tonsil layer and the filtrate is concentrated under vacuum. The viscous residue is partitioned between dichloromethane and 20% citric acid solution. The pH of the aqueous phase is neutralized to about 6.0 with diluted sodium hydroxide solution and the aqueous phase is extracted 4 times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated under vacuum yielding [(3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-yl]-((R)-1-phenyl-ethyl)-amine as main compound. The viscous residue is not further purified and used for the next step as raw product as it is. The viscous residue is dissolved in 1.2 equivalent of 37% hydrochloric acid and methanol and palladium-on-carbon catalyst is added. The slurry is hydrogenated at 60° C. and 100 mbar hydrogen pressure until no further [(3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-yl]-((R)-1-phenyl-ethyl)-amine can be detected by TLC. After cooling to RT the suspension is filtered over a tonsil layer and the filtrate is concentrated under vacuum. The viscous residue is purified by silica gel or aluminium oxide chromatography. The main product fraction is concentrated in vacuo and affords the title compound as solid foaming residue.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:39]([CH3:40])=[CH:38][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[N:33]([CH3:37])[N:32]=[CH:31]5)[CH:23]=3)[S:21][C:17]=2[C:16]=1Br)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C([O-])(O)=O.[Na+].CCOC(C)=O>O1CCOCC1.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>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:39]([CH3:40])=[CH:38][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[N:33]([CH3:37])[N:32]=[CH:31]5)[CH:23]=3)[S:21][C:17]=2[C:16]=1[C:46]1[CH:47]=[CH:48][C:43]([Cl:42])=[CH:44][CH:45]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 120 °C

Procedure:
The mixture of (S)-2-(7-bromo-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (24 mg, 0.0379 mmol), 4-chlorophenylboronic acid (9 mg, 0.0568 mmol), 2N NaHCO3 (100 μL), Pd(PPh3)4 (4 mg, 0.0038 mmol) in dioxane (2 mL) was heated at 120° C. for 3 hrs. The reaction mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C39H40ClN3O3S: 666.2 (M+H+); Found: 666.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(OC(N1CCC(C(=O)NC2CCCCC2)CC1)=O)(C)(C)C>>[CH:18]1([NH:24][C:14]([C:11]2([F:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(=O)O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)NC2CCCCC2)CC1
Product: O=C(NC1CCCCC1)C1(F)CCNCC1

Procedure:
The title compound is prepared according to the reaction sequence 3.01a-2.01b described above using 1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid instead of 1-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid and cyclohexylamine as in 3.01a: LC-MS A: tR=0.49 min; [M+H]+=229.25.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:16][C:15]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[CH3:22])=[N:14][C:13]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)(=O)=[O:3].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(=O)([O-])[O-].[K+].[K+].[ClH:41].C(OCC)(=O)C>CO.O.CN(C)C=O>[OH2:3].[ClH:29].[ClH:41].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:13]2[N:14]=[C:15]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:16][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:24][CH:25]=1.[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:13]2[N:14]=[C:15]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:16][C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:24][CH:25]=1.[ClH:29].[ClH:29]
Reactant: c1c[nH]cn1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCCCCOS(C)(=O)=O)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCCCCn2ccnc2)o1
Temperature: 92.5 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A mixture of 6-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]hexyl methansulfonate(2.11 g), imidazole(660 mg), potassium carbonate(1.33 g) and N,N-dimethylformamide(40 ml) was stirred for 2 hours at 90-95° C. Water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The residue obtained by evaporating the solvent was subjected to silica gel column chromatography. From the fraction eluted with methanol-chloroform(3:97, v/v), obtained was 4-(4-chlorophenyl)-5-[6-(i-imidazolyl)hexyl]-2-(2-methyl-1-imidazolyl)oxazole(1.26 g, 64%). The oily substance (1.26 g) was dissolved in methanol(5 ml), and thereto a 4N-hydrochloric acid-ethyl acetate solution (1.7 ml) was added. The reaction mixture was concentrated. Ethyl acetate was added to the residue. The precipitated white powder was collected by filtration. This was recrystallized from methanol-acetone to give 4-(4-chlorophenyl)-5-[6-(l-imidazolyl)hexyl]-2-(2-methyl-1-imidazolyl)oxazole dihydrochloride hemihydrate(1.16 g, 49%). mp 171-173° C.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].C(O)CCCO.[CH3:11][CH:12]([CH2:15]O)[CH2:13][OH:14]>>[CH:3]([CH:1]1[O:14][CH2:13][CH:12]([CH3:15])[CH2:11][O:2]1)=[CH2:4]
Reactant: CC(CO)CO
Reactant: C=CC=O
Solvent: OCCCCO
Product: C=CC1OCC(C)CO1

Procedure:
In another embodiment of this invention, the present process represents an intermediate synthesis step in the conversion of acrolein to 1,4-butanediol. For example, a new and efficient method for producing 1,4-butanediol comprises (1) condensing 2-methyl-1,3-propanediol with acrolein to form 2-vinyl-5-methyl-1,3-dioxane, (2) converting the 2-vinyl-5-methyl-1,3-dioxane in accordance with the present invention hydroformylation method to a mixture of 2-(5'methyl-1',3'-dioxane)propionaldehyde and 3-(5'-methyl-1',3'-dioxane)-propionaldehyde, and (3) hydrogenating said mixture of propionaldehydes at a pH of about 7 to yield a mixture of 1,4-butanediol and 2-methyl-1,3-propanediol, and (4) separating the components of the diol mixture, and recycling the 2-methyl-1,3-propanediol to the first step of the process.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:26]=[C:25]([CH3:27])[C:19]([O:20][CH2:21][CH2:22][CH2:23]I)=[C:18]([CH3:28])[CH:17]=2)[N:12]=1>CN(C=O)C>[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:26]=[C:25]([CH3:27])[C:19]([O:20][CH2:21][CH2:22][CH2:23][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)=[C:18]([CH3:28])[CH:17]=2)[N:12]=1
Reactant: Cc1nc(-c2cc(C)c(OCCCI)c(C)c2)no1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(C)c(OCCCc3cccnc3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
To a suspension of sodium hydride (70 mg, 2.8 mmol) and 3-hydroxypyridine (0.24 g, 2.56 mmol) in DMF was added dropwise 1 g (1 g, 2.8 mmol) of 4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxypropyl iodide in DMF, and the mixture was stirred at room temperature for 2 days. The mixture was washed with water, extracted with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The dry organic layer was concentrated in vacuo, passed through a pad of silica gel eluting with hexane/ethyl acetate (1:1) to afford 0.48 g (55.1%) of 3-[3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]propyl]-pyridine, as an oil, which crystallized on standing in ether, m.p. 46°-49° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[C@@H:14]([O:18]C(C)(C)C(C)(C)C)[C@H:13]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([CH3:17])[C@@H:14]([OH:18])[C@H:13]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OC(C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Benzyl-(3R,4R,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1,1,2,2-tetramethylpropoxy)piperidine-1-carboxylate (1.88 g, 4.06 mmol) was dissolved in THF (20 mL) and a 1.0 M solution of tetra-n-butylammonium fluoride in THF (4.7 mL, 4.7 mmol) was added. The reaction mixture was stirred for 30 min. at room temperature and then diluted with EtOAc. The mixture was washed 2 times with brine, then dried and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with 25-75% EtOAc in hexanes to give the sub-title compound as a white solid (1.48 g, 82%). LCMS calc. for C19H28N2NaO5 (M+Na)+ m/z=387.2. found 387.0.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11](OC)=[O:12])=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][C:8]([CH2:11][OH:12])=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1=CCC2(CC1)OCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1=CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 92.8 %

Procedure:
Methyl 1,4-dioxaspiro[4,5]dec-7-ene-8-carboxylate [J. Org. Chem. 40, 538 (1975)] (1.00 g, 5.0 mmol) was stirred under Ar in dry THF (50 ml) at -78° C. as diisobutylaluminium hydride (1.5M in toluene, 8.4 ml, 12.6 mmol) was added dropwise. The mixture was stirred, warming to ambient temperature, for 2.5 h, and then quenched by successive addition of methanol (9 ml), ethanol (9 ml) and water (9 ml). The gelatinous mixture was diluted with ethyl acetate, and filtered through kieselguhr. The filtrate was washed with brine, dried (Na2SO4) and evaporated to give the title compound (0.79 g, 92%) as a colourless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[OH-:14].[Na+]>CCO.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]([NH2:10])=[O:14]
Reactant: N#Cc1cccc(C2OCCO2)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1cccc(C2OCCO2)c1
Yield: 69.6 %

Procedure:
To a solution of 3-(1,3-dioxolan-2-yl)-benzonitrile (5.86 g) in a mixture of EtOH (140 mL) and H2O (60 mL) was added sodium hydroxide (6.46 g) and the mixture was heated under reflux for 2 hours. The solvent was evaporated under reduced pressure and the aqueous layer was extracted with CH2Cl2. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated to give the title compound (4.5 g) as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[N:7]([CH3:25])[N:6]=1)=[O:4].C[O:27][C:28]([C:30]1[CH:34]=C(OCC2C(C3C=CC=CN=3)=NOC=2C)N(C)[N:31]=1)=O>>[OH:27][CH2:28][C@@H:30]([NH:31][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[N:7]([CH3:25])[N:6]=1)=[O:4])[CH3:34]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n(C)n1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n(C)n1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)N[C@@H](C)CO)nn1C
Yield: 59 %

Procedure:
As described for example 114d, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol), instead of 1-methyl-5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-1H-pyrazole-3-carboxylic acid methyl ester, was converted, to the title compound (66 mg, 59%) which was obtained as a colorless oil. MS: m/e=390.1 [M+H]+.