Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:46])[CH2:16][C:17]3[NH:18][C:19]([CH2:39][CH2:40][C:41]4[S:42][CH:43]=[CH:44][N:45]=4)=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:34])[C:22]=3[C:23]([O:25][CH3:26])=[O:24])[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:47]1(=O)[CH2:51][CH2:50][CH2:49][CH2:48]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.CC(O)=O>[CH:47]1([NH:1][CH2:2][C:3]2([CH2:8][N:9]3[CH2:10][CH2:11][N:12]([C:15](=[O:46])[CH2:16][C:17]4[NH:18][C:19]([CH2:39][CH2:40][C:41]5[S:42][CH:43]=[CH:44][N:45]=5)=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:27]5[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=5[Cl:33])[C:22]=4[C:23]([O:25][CH3:26])=[O:24])[CH2:13][CH2:14]3)[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C1CCCC1
Reactant: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CN)CCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CNC4CCCC4)CCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Reaction time: 0.08 h

Procedure:
To a suspension of dimethyl 2-[2-[4-[[1-(aminomethyl)cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate (205 mg/0.298 mmol) and cyclopentanone (0.032 ml/0.36 mmol) in dichloromethane (2 ml) was added AcOH (1 drop) and the resulting mixture was stirred for 5 minutes. NaBH(OAc)3 (80 mg/0.36 mmol) was added to the mixture and the resulting mixture was stirred for 5 hours. The mixture was diluted with dichloromethane (50 ml) and the resulting solution was washed with water (10 ml) and brine (10 ml) successively. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (NH2 gel/dichloromethane:methanol=100:0-100:2) to give a yellow film (220 mg/98%).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCN3CCOCC3)cc12
Yield: 62 %

Procedure:
6-(2-Morpholin-4-yl-ethoxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime was prepared in 62% yield using the procedure described in example 85A, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 4-(2-chloroethyl)morpholine hydrochloride. The title compound was isolated as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]3[N:15]=[C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][N:17]4[C:18](=[O:21])[C:19]=3[CH3:20])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:31].[CH3:20][C:19]1[C:18](=[O:21])[N:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=[N:15][C:14]=1[O:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=2)=[CH:9][CH:10]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1c(OCc2ccc(C(=O)c3ccc(O)cc3)cc2)nc2ccccn2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(OCCN4CCOCC4)cc3)cc2)nc2ccccn2c1=O
Yield: 16.6 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzyloxy]-3-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (104 mg), 4-(2-chloroethyl)morpholine hydrochloride (90 mg) and potassium carbonate (179 mg) in DMF (7 ml) was stirred at 100° C. for 20 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. Then, hydrogen chloride-ethyl acetate was added and the precipitated hydrochloride was collected by filtration and dried to provide the title compound as colorless solid (24 mg).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C:11](=[CH:23][CH2:24]P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[CH3:44][C@@H:45]([C@H:57]1[CH2:66][CH2:65][CH2:64][C@@H:63]2[C@:58]1([CH3:68])[CH2:59][CH2:60][CH2:61][C:62]2=O)[CH2:46][C:47]#[C:48][C:49]([CH3:56])([O:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH3:50]>C1COCC1>[C:4]([Si:1]([CH3:2])([CH3:3])[O:8][C@H:9]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:17])[CH3:18])[CH2:12][C:11](=[CH:23]/[CH:24]=[C:62]2\[CH2:61][CH2:60][CH2:59][C@@:58]3([CH3:68])[C@H:63]\2[CH2:64][CH2:65][CH2:66][C@@H:57]3[C@H:45]([CH3:44])[CH2:46][C:47]#[C:48][C:49]([CH3:56])([O:51][Si:52]([CH3:53])([CH3:54])[CH3:55])[CH3:50])[CH2:10]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)[C@H]1CCC[C@H]2C(=O)CCC[C@]12C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=CCP(=O)(c2ccccc2)c2ccccc2)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)[C@H]1CCC[C@H]2/C(=C/C=C3C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C3)CCC[C@]12C
Reaction time: 0.5 h

Procedure:
590 mg (1.03 mmol) of carefully dried (3R,5R)-[2-[3,5-bis-(t-butyldimethylsilanyloxy)-cyclohexylidene]-ethyl]-diphenyl-phosphine oxide (Tetrahedron Lett. 32, 7663 (1991)) was dissolved in 5 ml of abs. THF and treated at -78° with 0.644 ml of nBuLi (1.6M, hexane). 15 Minutes later, 187 mg (5.15 mmol) of (4aR,5R,8aR)-5-((R)-1,5-dimethyl-5-trimethylsilanyloxy-hex-3-ynyl)-4a-methyl-octahydro-naphthalen-1-one, dissolved in 0.5 ml of abs. THF, was added to the deep red solution and kept for 0.5 h at -78° and for 0.5 h at 0°. The reaction mixture was then poured onto crushed ice/KH2PO4, extracted twice with ether, washed with water and brine, dried over sodium sulfate, and the solvents carefully removed i.V. Flash chromatography (SiO2, hexane/AcOEt=95/5) afforded in the less polar fractions 129 mg of the title compound as colorless oil and in the more polar ones 67 mg of recovered ketone.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:18][CH2:17][C@@H:16]([O:19][CH3:20])[CH2:15]3)[CH:11]=[CH:10][C:9]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:4][CH2:3]1.[CH:28](=O)[CH2:29][CH2:30][CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:28]([N:24]1[CH2:23][CH2:22][N:21]([C:9]2[CH:10]=[CH:11][C:12]([N:14]3[CH2:18][CH2:17][C@@H:16]([O:19][CH3:20])[CH2:15]3)=[CH:13][C:8]=2[CH:5]2[CH2:4][CH2:3][C:2]([CH3:27])([CH3:1])[CH2:7][CH2:6]2)[CH2:26][CH2:25]1)[CH2:29][CH2:30][CH3:31]
Reactant: CO[C@@H]1CCN(c2ccc(N3CCNCC3)c(C3CCC(C)(C)CC3)c2)C1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCN1CCN(c2ccc(N3CC[C@@H](OC)C3)cc2C2CCC(C)(C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a mixture of the crude product of (R)-1-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine produced in Example (98b) (160 mg), butyraldehyde (0.052 mL, 0.584 mmol) and tetrahydrofuran (7 mL) were added sodium triacetoxyborohydride (164 mg, 0.774 mmol) and acetic acid (0.022 mL, 0.384 mmol) in that order, followed by stirring for 1 hour at room temperature. Ethyl acetate and saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 170 mg of (R)-1-butyl-4-[2-(4,4-dimethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine as a light brown oil.
Reaction SMILES: C([O:3][C:4](=[O:29])[C@H:5]([CH3:28])[CH2:6][C@H:7]([N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].C1C[O:35]CC1.C(O)C>O>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:21][C:25](=[O:26])[CH2:24][CH2:23][C:22]([OH:27])=[O:35])[CH2:6][C@@H:5]([CH3:28])[C:4]([OH:3])=[O:29])=[CH:10][CH:11]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N1C(=O)CCC1=O
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O)C(=O)O
Reaction time: 16 h

Procedure:
(2R,4S)-5-Biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (590 mg) is added to a mixture of 1 M NaOH (2.75 ml), THF (9 ml) and ethanol (9 ml). The mixture is stirred for 16 h. The mixture is diluted with water (20 ml) and extracted with isopropyl acetate. The water phase is acidified with 1 M HCl (5 ml) and extracted with isopropyl acetate. The combined organic phases are dried (MgSO4) and concentrated in vacuo to give (2R,4S)-5-Biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methyl-pentanoic acid (3-a, R1=4-oxo-pentanoic acid, R2=H, R3=H). 1H NMR (DMSO): 1.05 (2H), 1.35 (1H), 1.79 (1H), 2.29 (2H), 2.39 (3H), 2.70 (2H), 3.97 (1H), 7.25 (2H), 7.34 (1H), 7.44 (2H), 7.56 (2H), 7.63 (2H), 7.74 (1H), 12.01 (2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl.Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:11]([CH3:10])(=[O:13])=[O:12])[CH:6]=[C:7]([I:9])[CH:8]=1
Reactant: Nc1cc(F)cc(I)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(F)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Dissolve 3-fluoro-5-iodoaniline (600 mg, 2.53 mmol) (prepared as described in published PCT International Application WO96/23783 A1, published Aug. 8, 1996), methanesulfonyl chloride (896 mg, 7.83 mmol), triethylamine (1.91 g, 18.9 mmol), and N,N-dimethylamino-4-pyridine (31 mg, 0.253 mmol) in CH2Cl2 (10 mL) and stir at room temperature overnight. Dilute with 1.00N aqueous HCl (20 mL) and extract into ethyl acetate. Dry (MgSO4) and concentrate organics to a yellow solid. Dissolve solid in THF (50 mL) and add 1.0M tetrabutylammonium fluoride (2.8 mL). Heat to reflux for 3.5 h. Cool to room temperature, dilute with H2O, and extract into ethyl acetate. Dry (MgSO4) and concentrate organics. Chromatograph on silica gel (40 g), eluting with 20% to 35% ethyl acetate/hexanes affords 618 mg (78%) of the title compound as a white solid. MS (ES) 314 (M−H); HPLC shows 100% purity.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([CH:16]2[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].[ClH:30].O1CCOCC1>C(Cl)Cl>[ClH:30].[ClH:30].[NH2:22][CH:19]1[CH2:20][CH2:21][CH:16]([N:15]2[C:7]3=[C:8]4[S:14][CH:13]=[CH:12][C:9]4=[N:10][CH:11]=[C:6]3[N:5]=[C:4]2[C@H:2]([OH:1])[CH3:3])[CH2:17][CH2:18]1.[ClH:30]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1C1CCC(N)CC1

Procedure:
tert-Butyl (4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)carbamate (0.22 g, 0.53 mmol) was treated with 4.0 M hydrogen chloride in dioxane (0.66 mL, 2.6 mmol) in methylene chloride (3 mL) at room temperature overnight. The mixture was concentrated to give the desired product as HCl salt (0.22 g, 94%). LCMS calculated for C16H21N4OS (M+H)+: m/z=317.1. Found: 317.0.
Reaction SMILES: CS(OC(C1C=NC(NC(C2(C3C=CC4OCOC=4C=3)CC2)=O)=CC=1)C1C=CC=CC=1OC)(=O)=O.CN.[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([C:47]3([C:50]([NH:52][C:53]4[CH:58]=[CH:57][C:56]([CH:59]([N:68](C)[CH3:69])[C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=5[O:66][CH3:67])=[CH:55][N:54]=4)=[O:51])[CH2:49][CH2:48]3)=[CH:46][C:41]=2[O:40][CH2:39]1>>[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([C:47]3([C:50]([NH:52][C:53]4[CH:58]=[CH:57][C:56]([CH:59]([C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=5[O:66][CH3:67])[NH:68][CH3:69])=[CH:55][N:54]=4)=[O:51])[CH2:49][CH2:48]3)=[CH:46][C:41]=2[O:40][CH2:39]1
Reactant: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Agent: CN
Agent: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: CNC(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)c1ccccc1OC

Procedure:
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-methoxyphenyl)(methylamino)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and methyl amine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:7][C:8]=1[CH3:9])[OH:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:14][CH:13]=1.[H-].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na+]>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:3]2[C:2]([CH3:1])=[C:8]([CH3:9])[CH:7]=[C:5]([OH:6])[C:4]=2[OH:10])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:17]=1
Reactant: Cc1cc(O)c(O)cc1C
Reactant: O=C(O)CCCCCC(O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(O)c(O)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1C
Reaction time: 20 h
Yield: 30.7 %

Procedure:
To a solution of 4,5-dimethylcatechol (663 mg) and 7-(4-fluorophenyl)-7-hydroxyheptanoic acid (1.15 g) in toluene (18 ml) was added sodium p-toluene sulfonate monohydride (455 ml) and the reaction was carried out at 100° C. for 20 hours. After cooling in air, the reaction mixture was extracted by addition of water and ethyl acetate. The organic layer was separated, washed in turn with water and saturated saline and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by subjecting it to silica gel column chromatography and eluting with ethyl acetate/hexane (1:7) to obtain 7-(4-fluorophenyl)-7-(2,3-dihydroxy-5,6-dimethylphenyl)heptanoic acid (530 mg) (Compound 57). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].[CH2:12](I)[CH2:13][CH3:14].Cl>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH2:12]([S:3][C:2]1[N:4]=[C:5]([OH:6])[CH:7]=[C:8]([OH:9])[N:1]=1)[CH2:13][CH3:14]
Reactant: CCCI
Reactant: O=C1CC(=O)NC(=S)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: CO
Product: CCCSc1nc(O)cc(O)n1
Temperature: 32.5 °C
Yield: 65.8 %

Procedure:
2-Thiobarbituric acid (100 g) was added to the water (250 ml) under stirring, followed by the addition of a solution of sodium hydroxide pellets or flakes (63.13 g) in water (147.35 ml) over a period of 15 to 20 minutes at 20-25° C. The resulting mass was stirred for 40 minutes at 20-25° C., followed by the addition of water (200 ml). The reaction temperature was raised to 30-35° C., followed by addition of methanol (200 ml), propyl iodide (123.36 g) and tetrabutyl ammonium bromide (1.0 g) under stirring at 30-35° C. The resulting reaction mixture was stirred for 24 hours at 30-35° C. The reaction was monitored by thin layer chromatography. After completion of reaction, the pH of the reaction mixture was adjusted to less than 2.0 by the addition of dilute hydrochloric acid (prepared by mixing of 60 ml of concentrated hydrochloric acid with 140 ml of water). The resulting slurry was stirred for 15 hours, and the product was isolated by filtration and washed successively with water (4×200 ml) and cyclohexane (200 ml). The wet product was dried under reduced pressure at 40-45° C. to produce 85 g of 2-propylthio-pyrimidine-4,6-diol as a white powder (Yield: 65.7%; Purity by HPLC: 90.96 area-%).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C=O)C>[CH2:1]([N:26]1[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[C:22]1=[O:32])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCN1C(=O)c2ccccc2C1=O

Procedure:
Phytanyl bromide (12.34 g), potassium phthalimide (6.95 g) and DMF (50 ml) were heated at 120-130° C. for 4 hours. Most of the DMF was removed under reduced pressure and the crude product was dissolved in dichloromethane (100 ml), washed with water (2×50 ml), dried (MgSO4). The light yellow crude product was chromatographed on flash silica (dichloromethane/hexane as eluant) to yield pure N-phytanyl phthalimide in 11.89 g (80.9%) 1H-n.m.r. (CDCl3) δ0.82-1.8 (m, 39H), 3.73 (t, 2H, CH2N), 7.73 (m, 2H, ArH), 7.88 (m, 2H, ArH); m/z 431 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:20]#[N:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(=O)(=O)(O)[OH:25]>O.C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]([NH2:21])=[O:25])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: NC(=O)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Yield: 83.9 %

Procedure:
A mixture of 3 kg of commercial 1-benzyl-4-cyano-4-phenylpiperidine, 6 l of water, 8.98 l of toluene and 1.35 kg of an aqueous 35% sodium hydroxide solution is heated under nitrogen at 60° C. and the aqueous phase is separated out by settling at this temperature. The toluene phase is dried by azeotropic distillation and the solution thus obtained containing the 1-benzyl-4-cyano-4-phenylpiperidine base is added to a mixture of 2.83 kg of 95% sulfuric acid, 1.73 kg of glacial acetic acid and 3 l of toluene. The mixture thus obtained is heated for 6 hours, the heating is then stopped, the mixture is cooled to 60° C. and 3 l of water are added at this temperature. The mixture is allowed to cool to room temperature (about 20° C.) and is then poured into 8.65 l of 30% sodium hydroxide and 6.75 l of water. The temperature rises gradually to 75° C. The phases are separated by settling while hot and the organic phase is washed with water and dried azeotropically. The toluene solution is concentrated to half its volume and then cooled gradually to 60° C. and the crystallization is initiated. The crystallization is completed by cooling to 0° C. over 2 hours. The precipitate thus obtained is filtered off, washed and dried under vacuum at 60° C. 2.68 kg of 1-benzyl-4-phenyl-4-piperidinecarboxamide are thus obtained;
Reaction SMILES: Cl.O1CCOCC1.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]2[N:15]([CH:30]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[N:16]=[C:17]([C:18]#[C:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]=12>>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([C:19]#[C:18][C:17]2[C:10]3[C:11](=[N:12][CH:13]=[N:14][C:9]=3[NH2:8])[N:15]([CH:30]3[CH2:34][CH2:33][NH:32][CH2:31]3)[N:16]=2)[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=1
Reactant: COc1cc(C#Cc2nn(C3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C#Cc2nn(C3CCNC3)c3ncnc(N)c23)cc(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 127.5 %

Procedure:
4N-Hydrochloric acid/1,4-dioxane (4 ml) was added to the tert-butyl 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (32 mg) obtained in Step 3, and the mixture was stirred at room temperature for 1.5 hours. After distilling the solvent of the resulting reaction mixture off under reduced pressure, toluene azeotropic distillation was subsequently performed to obtain a crude product of 3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (32 mg). Chloroform (2.0 ml) and triethylamine (20 μl) were added to a portion of the resulting crude product (12 mg). After cooling to 0° C., acrylic chloride (2.3 μl) dissolved in chloroform (100 μl) was added thereto, and the mixture was stirred at room temperature for 10 minutes. After halting the reaction using a saturated aqueous sodium bicarbonate solution, the resulting product was extracted with ethyl acetate. After drying the result over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound as a white solid (6.5 mg). Table 1 shows the physical properties thereof.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:7]
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 17.9 gm (86 mmol) of 3-trifluoromethylbenzoyl chloride in 70 mL of dichloromethane was added 10.0 gm (66 mmol) of methyl 3-aminobenzoate. Triethylamine (9.38 gm, 13 mL, 93 mmol) was then added slowly to the mixture. After the addition was complete, the solution was warmed to 45° C. and stirred overnight. Ice was added to the solution to quench excess benzoyl chloride. After one hour, the layers were separated. The organic fraction was washed with 5% aqueous hydrochloride acid, saturated sodium bicarbonate, and finally with saturated sodium chloride solution. The dichloromethane solution was dried over magnesium sulfate. The drying agent was filtered off, and the solvent was removed by rotoevaporation to give the desired methyl 3-(3-trifluoromethylbenzamido)benzoate. 1H NMR (CDCl3): δ3.92 (s. 3H), 7.52 (t, 1H), 7.74 (t, 1H), 7.80 (m, 1H), 7.92 (m, 1H), 7.96 (m, 1H), 8.21 (d, 1H), 8.26 (s, 1H), 8.43 (s, 1H), and 9.07 (br s, 1H). MS m/z: 324.0 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.O[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:4]1[CH2:5][CH2:6][C@@H:2]([O:1][C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: O[C@H]1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(O[C@@H]2CCOC2)cc1
Reaction time: 2 h
Yield: 54 %

Procedure:
In 30 ml of tetrahydrofuran were dissolved 3.0 g of (S)-(+)-3-hydroxytetrahydrofuran, 6.6 g of methyl 2-(4-hydroxyphenyl)-2-oxoacetate and 8.90 g of triphenylphosphine. The thus prepared solution was mixed with 6.0 g of diethyl azodicarboxylate, and the mixture was stirred for 2 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using chloroform as an eluant, thereby obtaining 4.60 g of methyl 2-[4-[((3R)-tetrahydro-3-furanyl)oxy]phenyl]-2-oxoacetate in an oily form.