Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (26.3 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (4.47 mL, 0.0276 mol) in tetrahydrofuran (33.61 mL). The reaction was warmed to room temperature and then cooled to 0° C. again. To the reaction mixture was added a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (5.0 g, 0.025 mol) in tetrahydrofuran (6.72 mL). The reaction was allowed to warm up to room temperature and stirred at room temperature overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 60% EtOAc in hexanes, to give the desired product (5.40 g, 97%). LCMS (M+Na) 244.9.
Reaction SMILES: C([S@@](N)=O)(C)(C)C.[C:8]1([C@@H:14]([O:28][S@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[C@@H:15]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH3:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C@H:14]([O:28][S@:29]([C:31]([CH3:32])([CH3:34])[CH3:33])=[O:30])[C@H:15]([NH:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH3:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)[C@H](O[S@](=O)C(C)(C)C)c2ccccc2)cc1
Agent: CC(C)(C)[S@@](N)=O
Product: Cc1ccc(S(=O)(=O)N[C@H](C)[C@@H](O[S@@](=O)C(C)(C)C)c2ccccc2)cc1
Yield: 86 %

Procedure:
Preparation of (S)-t-butyl sulfinamide from (S)-2-Methyl-2-propylsulfinic acid (1R, 2S)-1-phenyl-2-(4-toluenesulfonylamino)-propyl ester: The same procedure described above was followed, an furnished the title product in 86% yield and 96% ee. (HPLC, Chiralpak AS column, 90:10 hexane/ethanol; 1.2 mL/min, 222 nm; (R)-TBSA rt=6.6 min; (S)-TBSA, rt=9.4 min.). 1H NMR(CDCl3): δ 1.18 (s, 9H), 3.82 (br, s, 2H). 13C NMR (CDCl3): δ 22.1, 55.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.[H-].[Na+]>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:18][C:14]2[CH:13]=[C:12]([F:11])[CH:17]=[CH:16][CH:15]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Oc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2cccc(F)c2)cc1

Procedure:
p-chloro-nitrobenzene and m-fluoro-phenol in tetra-hydrofuran in the presence of sodium hydride were reacted to obtain 3-(4-nitrophenoxy)-fluorobenzene which was nitrated to form 4-nitro-3-(4-nitrophenoxy)-fluorobenzene which was reacted as in Example 1 to obtain 0-[4-nitro-3-(4-nitrophenoxy)-phenyl]-hydroxylamine melting at 132° C.
Reaction SMILES: CN(C)/C=C/[C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:8]([O:10][CH3:11])=[O:9].N1C=CC=C[CH:20]=1.[C:25](Cl)(=[O:27])[CH3:26].C(Cl)Cl>O.O1CCOCC1>[O:27]=[C:25]([CH3:20])[CH2:26][C:13]1[CH:12]=[C:7]([CH:6]=[CH:5][C:14]=1[N+:15]([O-:17])=[O:16])[C:8]([O:10][CH3:11])=[O:9]
Reactant: c1ccncc1
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(/C=C/N(C)C)c1
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])c(CC(C)=O)c1
Yield: 46.1 %

Procedure:
According to the method of Production Example 1, a mixed solution of methyl E-3-(2-dimethylaminovinyl)-4-nitrobenzoate (45.05 g), pyridine (23.51 g), acetyl chloride (21.20 g) and methylene chloride (200 ml) is stirred at room temperature for 61 hours, and then heated under reflux with 1,4-dioxane in water for 18 hours to obtain methyl 3-(2-oxopropyl)-4-nitrobenzoate (19.67 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:13]([CH3:15])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][NH:10][CH:13]([CH3:15])[CH2:12][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COc1ccc(-c2ccc(CC(C)=O)cc2)cc1
Product: COc1ccc(-c2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)cc1
Yield: 20.1 %

Procedure:
Yield: 20.1% of theory, Prepared from 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and 4'-acetonyl-4-methoxy-biphenyl.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[C:13]([CH3:16])[CH2:14]Br)=[CH:6][CH:5]=1>C(O)C(C)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[C:13]([CH3:16])[CH2:14][O:2][CH2:3][CH:4]([CH3:9])[CH3:5])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCC=C(C)CBr)cc1
Solvent: CC(C)CO
Product: COC(=O)c1ccc(OCC=C(C)COCC(C)C)cc1

Procedure:
A solution of 6.0 g (0.02 mol) of 4-(4-bromo-3-methyl-2-butenyloxy)-benzoic methyl ester and 2.9 g (0.03 mol) of sodium-isobutylate in 130 g of isobutanol is stirred at 70° for 6 hours. After this period the reaction mixture is filtered, the filtrate is evaporated at reduced pressure. The residue is dissolved in ether, the ether solution is washed with saturated salt solution, dried with sodium sulphate and evaporated. The residue (6.5 g) is dissolved in 50 cc of absolute methanol, 0.54 g (0.01) mol of sodium methylate is added and the mixture is boiled under reflux for 2 hours. After this period 40 cc of methanol are distilled off. The remaining residue is dissolved in 100 cc of ether, the ether solution is extracted twice with 100 cc amounts of saturated salt solution and dried with sodium sulphate. The ether is distilled off and the resulting 4-(4-isobutoxy-3-methyl-2-butenyloxy)-benzoic methyl ester is purified by chromatography on silica gel with hexane/ethyl acetate 20 : 1. nD20 = 1.5151.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][CH2:17][CH2:18]Br)[CH3:15]>>[C:1]1([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:15][CH2:14][O:16][CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CCOCCBr
Product: CCOCCC(c1ccccc1)c1ccccc1

Procedure:
According to a second process disclosed by Sperber (loc. cit.) diphenylmethane is reacted with 2-bromoethyl ethyl ether to yield 3,3-diphenyl-1-ethoxypropane. Alkylation of 3,3-diphenyl-1-ethoxypropane with 2-dimethylaminoethyl chloride yielded 5-ethoxy-3,3-diphenyl-N,N-dimethylamylamine; cleavage of the ethoxy group gave 5-hydroxy-3,3-diphenyl-N,N-dimethylamylamine hydrobromide, which was reacted with thionyl chloride to give 4,4-diphenyl-1,1-dimethylpiperidinium chloride, from which sublimation in vacuo yielded 1-methyl-4,4-diphenylpiperidine. This synthesis includes 5 reaction steps and provides an overall maximum yield of about 23 percent of theory. The availability of this synthesis for the preparation of homologues of 1-methyl-4,4-diphenylpiperidine, e.g. of 1-ethyl-4,4-diphenylpiperidine or 1-isopropyl-4,4-diphenylpiperidine has to be regarded as doubtful.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13]C)[CH:8]=2)[S:4][C:3]=1[C:15]([NH2:17])=[O:16].C[Si]([N:22]=[C:23]=[O:24])(C)C.CN(C)C=O>ClCCl>[NH2:22][C:23]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[S:4][C:3]=1[C:15]([NH2:17])=[O:16])=[O:24]
Reactant: C[Si](C)(C)N=C=O
Reactant: COc1cccc(-c2cc(N)c(C(N)=O)s2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)Nc1cc(-c2cccc(O)c2)sc1C(N)=O
Reaction time: 72 h

Procedure:
3-Amino-5-(3-methoxyphenyl)-2-thiophenecarboxamide (0.5 g), trimethylsilylisocyanate (2 mL), dimethylformamide (2 mL) and dichloromethane were heated at reflux for 3 days. After cooling the solid was filtered off, suspended in dichloromethane (100 mL) and treated with boron tribromide (5 mL of a 1M solution in dichloromethane). After 3 days. methanol (50 mL) was added. After 1 h, the solvent was evaporated and the residue was triturated with 2M hydrochloric acid. The title urea was filtered off (0.35 g).
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]=[C:16]=[S:17])=[CH:13][C:5]2[N:6]([CH2:10][CH:11]=[CH2:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N:18]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]1.C1(C)C=CC=CC=1.C(N(CC)CC)C>O>[F:1][C:2]1[C:14]([NH:15][C:16]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][N:18]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[S:17])=[CH:13][C:5]2[N:6]([CH2:10][CH:11]=[CH2:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1CCCCN1
Reactant: C=CCn1c(=O)sc2cc(F)c(N=C=S)cc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCn1c(=O)sc2cc(F)c(NC(=S)N3CCCCN3C(=O)OCC)cc21
Yield: 105.1 %

Procedure:
6-Fluoro-3-(2-propenyl)-2(3H)-benzothiazolon-5-yl isothiocyanate (3.1 g) and ethyl hexahydropyridazine-1-carboxylate (1.17 g) were added to toluene (15 ml). A catalytic amount of triethylamine was added thereto, and the resultant mixture was stirred at 25° C. for 12 hours. Water was added thereto, and the resultant mixture was extracted with toluene. The extract was washed with water, dried and concentrated to give ethyl 2-[6-fluoro-3-(2-propenyl)-2(3H)-benzothiazolon-5-ylaminothiocarbonyl]-hexahydropyridazine-1-carboxylate (3.3 g). m.p., 40°-42° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH:15]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][C:6]=2[CH:15]=1
Reactant: COC(=O)C1=Cc2cc(Cl)ccc2OC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1COc2ccc(Cl)cc2C1
Reaction time: 8 h

Procedure:
700 mg of 5B was dissolved in 75 ml of ethyl acetate and the solution was treated with hydrogen (initial pressure of 30 psig), in the presence of a 10% palladium-on-carbon catalyst, for 8 hours. The reaction mixture then was filtered and stripped of solvent to give methyl 6-chloro-3,4-dihydro-2H-1-benzopyran-3-carboxylate (5C), as a yellow liquid, boiling point not determined.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH2:27][N:2]1[C:35]([C:31]2[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: Cn1ccnc1C=O
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first 6-chloroquinoline-4-carbaldehyde, followed by, followed by 1-methyl-1H-imidazole-2-carbaldehyde. 478 (M+H).
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].C(Cl)(=O)C([Cl:13])=O>ClCCl>[Cl:13][CH2:2][NH:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)C(=O)NCO
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask is charged with N-hydroxymethyl-2,2-dimethyl-propionamide (0.500 g, 3.81 mmol) and dichloromethane (4 mL). Oxalyl chloride (0.8 mL, 9.52 mmol) is added and the reaction mixture is stirred at room temperature for 2 h. Concentration in vacuo gives N-chloromethyl-2,2-dimethyl-propionamide as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 9H), 5.31 (s, 2H).
Reaction SMILES: [ClH:1].Cl.Cl.S1C(C2C=CN=C(NCCCN3CCN(C)CC3)N=2)=CC2C=CC=CC1=2.[CH:30]1([NH:33][C:34]([C:36]2[C:44]3[CH:43]=[C:42]([C:45]4[C:50]([Cl:51])=[CH:49][N:48]=[C:47](Cl)[N:46]=4)[S:41][C:40]=3[CH:39]=[CH:38][CH:37]=2)=[O:35])[CH2:32][CH2:31]1.C(OC([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][NH2:68])[CH2:62][CH2:61]1)=O)(C)(C)C>>[ClH:51].[ClH:1].[ClH:51].[CH:30]1([NH:33][C:34]([C:36]2[C:44]3[CH:43]=[C:42]([C:45]4[C:50]([Cl:51])=[CH:49][N:48]=[C:47]([NH:68][CH2:67][CH2:66][N:63]5[CH2:64][CH2:65][NH:60][CH2:61][CH2:62]5)[N:46]=4)[S:41][C:40]=3[CH:39]=[CH:38][CH:37]=2)=[O:35])[CH2:32][CH2:31]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Agent: Cl
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCN4CCNCC4)ncc3Cl)cc12

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloro-pyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid (80% yield). ES+(m/z) 457 (35Cl) and 459 (37Cl) [M(free base)+H].
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:8][CH:7](C(OC)=O)[C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.S(=O)(=O)(O)O>O>[C:1]([C:3]1([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:8][CH2:7][C:6](=[O:13])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(c2ccc(Cl)cc2)CCC(=O)CC1
Yield: 82 %

Procedure:
A mixture of 29.8 g. (0.102 mole) of methyl 5-cyano-5-(4-chlorophenyl)-2-oxocyclohexanecarboxylate (prepared in Example 7) in 660 ml. of acetic acid and 330 ml. of 10% sulfuric acid is stirred mechanically on a steam bath for about 24 hours. The mixture is then allowed to cool and diluted with water. This mixture is extracted thoroughly with benzene. The organic layer is washed successively with water, sodium bicarbonate solution and brine and evaporated to dryness. The solid residue is recrystallized from ether to give 19.49 g. (82% yield) of 4-cyano-4-(4-chlorophenyl)cyclohexanone, having a melting point of 94.5° to 97°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][Si](OC(C)C)(C)C)[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:19][CH:18]=2)[C:13]1=[O:31])[CH3:11].C(=O)([O-])[OH:42].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][OH:42])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]([F:29])([F:30])[CH:26]([F:28])[F:27])=[CH:21][CH:22]=2)[C:13]1=[O:31])[CH3:11]
Reactant: O=C([O-])O
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccc(F)cc1F)[C@@H](C)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Yield: 88.3 %

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (1.8 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 20 ml), to which 3.21 ml of 30% aqueous hydrogen peroxide and 0.262 g of sodium hydrogencarbonate were added. The mixture was heated at 70° to 80° C. for 90 minutes, cooled and extracted with 100 ml of ethyl acetate. The extract was washed with 50 ml of water, an aqueous solution of Na2S2O3 (50 ml×2) and 50 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=2:3) and recrystallized from diisopropyl ether to give 1.32 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (yield: 88%) as colorless prisms.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[CH:31][O:32][CH3:33])[C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([C@@H:18]2[O:9][C@H:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](=[CH:31][O:32][CH3:33])[C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC=C(C(=O)OC)c1ccccc1C=Cc1ccccc1
Solvent: ClCCl
Product: COC=C(C(=O)OC)c1ccccc1[C@@H]1O[C@H]1c1ccccc1
Yield: 57.7 %

Procedure:
7.2 g of m-chloroperbenzoic acid (about 50% pure) are added to a solution of 10.2 g of methyl 2-[2-(2-phenylethenyl)phenyl]-3-methoxyacrylate in 80 ml of methylene chloride. The reaction mixture is refluxed for two days and then the precipitate is filtered off with suction and the filtrate is washed twice with saturated sodium bicarbonate solution and water. The isolated organic phase is dried over sodium sulfate and concentrated, and the residue is recrystallized from methyl tert-butyl ether. 6.2 g (58%) of methyl trans-2-[2-(3-phenyl-2-oxiranyl)phenyl]-3-methoxyacrylate are obtained of melting point 110°-113° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=3)[CH:14]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:33]=1[CH:34]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH2:34][C:33]4[C:36]([CH3:41])=[CH:37][C:38]([CH3:40])=[CH:39][C:32]=4[CH3:31])[CH:23]=3)[CH:14]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN1Cc2cc(Oc3cccc(CN)c3)ccc2N=C1NC(=O)OC(C)(C)C
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN1Cc2cc(Oc3cccc(CNCc4c(C)cc(C)cc4C)c3)ccc2N=C1NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Under N2, a mixture of [6-(3-aminomethyl-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acid tert-butyl ester (0.0007 mol) and 2,4,6-trimethyl-benzaldehyde (0.0007 mol) in DCE (10 mL) was stirred at room temperature, then NaBH(OAc)3 (0.2 g) was added, and the reaction mixture was stirred overnight at room temperature. A saturated NaHCO3 solution was added, and the layers were separated. The organic layer was dried, filtered off and the solvent was evaporated. The residue was purified by Biotage column chromatography (gradient eluent: CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:14][O-].[Na+]>CO.CCOCC>[C:3]([CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][NH:1]1)([O:5][CH3:14])=[O:4]
Reactant: C[O-]
Reactant: O=C(O)C1CCCCN1
Agent: [Na+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C1CCCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A slurry of 26 g (0.20 mole) of pipecolinic acid in 100 ml of methanol is cooled to -10° and 16.7 ml (0.22 mole) of thionyl chloride added over 5 minutes. The slurry is allowed to warm to ambient temperature and stirred overnight whereupon a thick slurry forms. Addition of 300 ml of methanol gives a solution which is evaporated in vacuo. The residue is suspended in 100 ml of methanol, treated with a solution of 10.8 g (0.2 mole) of sodium methoxide in 100 ml of methanol, and diluted with 400 ml of ether. The solid which forms is filtered and the filtrate evaporated and redissolved in ether. Filtration, evaporation and solution are repeated three times and the final residue distilled in vacuo to give 24.6 g (85%) of the above titled ester, bp. 70°-70.5° at 4.0 mm.
Reaction SMILES: CO[CH:3](OC)[CH:4]([NH2:6])[CH3:5].[C:9](N1C=CN=C1)(N1C=CN=C1)=[S:10].C(N(CC)CC)C.[N:28]1([CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3([CH2:49][NH2:50])[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1.Cl>CN(C=O)C>[CH3:3][C:4]1[N:6]=[C:9]([SH:10])[N:50]([CH2:49][C:43]2([C:40]3[CH:41]=[CH:42][C:37]([O:36][CH2:35][CH2:34][CH2:33][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:38][CH:39]=3)[CH2:44][CH2:45][O:46][CH2:47][CH2:48]2)[CH:5]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: COC(OC)C(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cn(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)c(S)n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.9 %

Procedure:
2-Aminopropionaldehyde dimethyl acetal (0.2 g, 1.7 mmol), thiocarbonyldiimidazole (0.36 g, 2.0 mmol) and triethylamine (0.23 ml, 1.7 mmol) were stirred in DMF (2.0 ml) at ambient temperature for 30 minutes before heating to 50° C. for 18 hours. {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (540 mg, 1.7 mmol) was added and stirred at ambient temperature for 4 hours. 2M HCl (6 ml) was added, stirred at 70° C. for 18 hours, then c.HCl (1.0 ml) was added and the mixture stirred at 110° C. for 18 hours. The reaction mixture was cooled and partitioned between ethyl acetate (100 ml) and dilute aqueous sodium carbonate (50 ml). The organics were dried over Na2SO4 and concentrated in vacuo to give the title compound as a grey solid (600 mg, 84%). LRMS ESI+ m/z 416 [M+H]+.
Reaction SMILES: [Br:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:12](=O)[CH3:13].N1CCCCC1>C(Cl)Cl>[CH:12](=[C:4]([C:3](=[O:10])[CH:2]([Br:1])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CC=O
Reactant: CCOC(=O)CC(=O)C(C)Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC=C(C(=O)OCC)C(=O)C(C)Br

Procedure:
A solution of 100 g (0.45 mol) of ethyl 4-bromo-3-oxovalerate in 100 ml of absolute methylene chloride is cooled to -20° C. under nitrogen, and 50 g (1.12 mol) of acetaldehyde are added. 1 g of piperidine, dissolved in 10 ml of methylene chloride, is then added dropwise at -20° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][CH2:41][C:42]([NH2:44])=[O:43])[CH:39]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CO.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>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][N:38]([CH2:40][CH2:41][C:42]([NH2:44])=[O:43])[CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CCC(N)=O)c2)OC1(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: C1COCCO1
Solvent: O
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(CCC(N)=O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanamide (7.6 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in 1,4-dioxane (0.2 mL) and water (0.1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with methanol, and purified with RP-HPLC (pH=10) to afford the desired product (3.2 mg). LCMS (M+H)+: m/z=476.2.