Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1.O=S(Cl)Cl>ClCCl>[CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(O)CCCCC1CCSS1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The synthesis of lipoic acid chloride (DL-thioctic acid) was carried out under argon at ambient temperature following a standard protocol: lipoic acid (5 g, 24 mmol) is solubilised in dichloromethane (40 ml) and SOCl2 (1.3 eq) is added dropwise. After 1 hour of stirring at ambient temperature, the lipoic acid chloride formed is poured onto a solution of resveratrol diacetate (1.2) (6 g, 19 mmol) in THF (100 ml), containing triethylamine (3 eq) and DMAP (0.45 eq). After 1 hour the reaction mixture is diluted with 100 ml CH2Cl2, then washed with two times 90 ml of HCl 5% v/v. The organic phase is dried over anhydrous MgSO4, filtered, then concentrated in a rotary evaporator. The crude product (11.4 g) is purified by chromatography on a column of silica with cyclohexane/ethyl acetate (4/1 v/v) as eluent. The fractions containing the pure product are evaporated to lead to 5.95 g of 3,5-resveratrol diacetate-4′-lipoate 1 (49% of yield) with a molar purity measured by NMR of the proton of 96%.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:12](=O)[CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH4+].[OH-]>C(O)C>[NH2:1][C:2]1[S:3][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH:13]([CH3:15])[CH3:14])[N:4]=1
Reactant: CCOC(=O)C(Br)C(=O)C(C)C
Reactant: NC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C(C)C
Temperature: 25 °C
Yield: 66.4 %

Procedure:
To a refluxing solution of thiourea (1.9 g, 25.6 mmol) in absolute ethanol (20 mL) was added ethyl 2-bromo-4-methyl-3-oxopentanoate (6.0 g, 25.3 mmol). The solution was stirred at reflux for another 1.5 hours. After cooling to room temperature, the solution was poured in ice/water (100 mL). The mixture was neutralized with concentrated NH4OH. The solid material was recovered by filtration, washed with water (2×20 mL) and hexanes (2×20 mL), and dried in vacuo, affording ethyl 2-amino-4-(propan-2-yl)-1,3-thiazole-5-carboxylate (3.6 g, 66% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](Cl)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:14]([N:21]1[CH2:25][C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C@H:23]([NH:33][CH3:34])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:14]([N:21]1[CH2:25][C@@H:24]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C@H:23]([N:33]([CH3:34])[C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([CH3:13])[CH3:12])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reactant: CC(C)(C(=O)Cl)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)C(C)(C)c1cccc(Cl)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 2-(3-chloro-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in DE2659404) (0.10 g, 0.46 mmol) in CH2Cl2 (4 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (the preparation of which is described herein above) (0.11 g, 0.38 mmol) and ethyl-diisopropyl-amine (0.10 ml, 0.58 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 2 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:3) yielded 0.14 g (80%) of the title product as light yellow oil. ES-MS m/e: 465.2 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8](=O)[CH:9]=[CH:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[C:1]1([N:7]=[C:8]([Cl:21])[CH:9]=[CH:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(C=CSc1ccccc1)Nc1ccccc1
Solvent: CN(C)C=O
Product: ClC(C=CSc1ccccc1)=Nc1ccccc1

Procedure:
Thus, for example, IN 2003-MU444 describes the reaction of N-cyclohexyl-5-hydroxypentanamide with phosphorus pentachloride to give 5-chloro-N-cyclohexylpentaneimidoyl chloride. WO 2007/063702 provides the reaction of N-phenyl-3-(phenylsulphanyl)acrylamide with thionyl chloride and catalytical amounts of N,N-dimethylformamide to give N-phenyl-3-(phenylsulphanyl)prop-2-enimidoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH2:13][CH3:14])[N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[O:15]=[C:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[N:17]1[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[C:3]([C:8]2[NH:12][N:11]=[C:10]([CH2:13][CH3:14])[N:9]=2)=[C:4]([NH:7][C:27](=[O:28])[CH2:26][N:17]2[C:18]3[C:23](=[N:22][CH:21]=[CH:20][CH:19]=3)[CH2:24][CH2:25][C:16]2=[O:15])[S:5][CH:6]=1
Reactant: O=C(O)CN1C(=O)CCc2ncccc21
Reactant: CCc1n[nH]c(-c2c(Cl)csc2N)n1
Product: CCc1n[nH]c(-c2c(Cl)csc2NC(=O)CN2C(=O)CCc3ncccc32)n1

Procedure:
The title compound was prepared from 4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine (18 mg, 78.7 umol) and 2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetic acid (20 mg, 97.0 umol) using protocol A. The residue was purified by HPLC to yield N-(4-chloro-3-(3-ethyl-1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)acetamide. Method [8] Retention time 4.47 min by HPLC (M+=417 and 419) and (M+Na=439 and 441). 1H NMR (300 MHz, CDCl3) δ 8.39 (dd, J=5.4 and 1.2 Hz, 1H), 7.67 (dd, J=8.1 and 1.2 Hz, 1H), 7.49 (dd, J=8.1 and 5.4 Hz, 1H), 6.85 (s, 1H), 4.93 (s, 2H), 3.49 (m, 2H), 3.01 (m, 2H), 2.84 (q, J=7.8 Hz, 2H), 1.39 (t, J=7.8 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][C:21]([F:24])=[C:22]([F:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:22]1[C:16]2[C:17](=[N:18][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:19]=[CH:20][C:21]=1[F:24]
Reactant: C#CCCn1nc2ccc(F)c(F)c2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2nc3ccc(F)c(F)c3n2)n1
Yield: 58.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.27 mmol) and 2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 45 mg (0.14 mmol, 59%) of 4,5-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N+:9]([O-:11])=[O:10])=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=[C:3]1SC.[C:20]1([CH2:26][C@H:27]([NH2:30])[CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[NH2:30][C@@H:27]([CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:28][NH:29][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]([N+:9]([O-:11])=[O:10])=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:4]=1
Reactant: CSc1nc(-c2ccncc2)c([N+](=O)[O-])c(=O)n1C
Reactant: NC[C@@H](N)Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-methyl-2-methylsulfanyl-5-nitro-6-pyridin-4-yl-3H-pyrimidin-4-one (0.31 mmol) in dimethylformamide (DMF) was added 3-phenyl-propane-1,2 (S)-diamine (0.92 mmol) and stirred overnight at room temperature. The DMF was removed under vacuum, and the product purified on silica as a mixture of isomers. M+1=381.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3([C:28]([NH2:30])=[O:29])[CH2:27][CH2:26]3)[C:14]([C:31]([F:34])([F:33])[F:32])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)[CH3:3].N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([NH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3([C:28]([NH2:30])=[O:29])[CH2:26][CH2:27]3)[C:14]([C:31]([F:33])([F:34])[F:32])=[CH:13][N:12]=2)=[CH:8][CH:9]=1)[CH3:3])(=[O:43])[CH3:42]
Reactant: CC(N)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC(C)c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 1-(2-(2-(2-(4-(1-aminoethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide 70A (0.015 g, 0.032 mmol) in DCM (1 mL) was added pyridine (0.0040 mL, 0.050 mmol) and acetic anhydride (0.0050 mL, 0.053 mmol) and the reaction mixture was stirred at ambient temperature overnight. The mixture was partitioned between water and EtOAc, the layers were separated and the water layer was extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to give the title compound 71 as a light brown solid (0.016 g, 98%). LCMS-C: rt 5.24 min; m/z 512 [M+H]+.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[H-].[Na+].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Cl>O>[F:6][C:7]1[CH:14]=[C:13]([O:15][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: ClCc1ccccn1
Reactant: O=Cc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To an N,N-dimethylformamide (10.0 mL) solution of 2-fluoro-4-hydroxy-benzaldehyde (1.60 g, 11.4 mmol) was added sodium hydride (547 mg, 13.7 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 30 minutes at room temperature. 2-Picolyl chloride (2.80 g, 17.1 mmol) was then added at room temperature and stirred for 1 hour at 70° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (1.07 g, 40.6%).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:51])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:50])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:49])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:48])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:47])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:46])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:45])[CH2:29][CH2:30][CH:31]=[C:32]([CH3:44])[CH2:33][CH2:34][CH:35]=[C:36]([CH3:43])[CH2:37][CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41].[NH2:52][CH2:53][C:54]12[CH2:61][CH2:60][CH2:59][N:58]1[CH2:57][CH2:56][CH2:55]2>C1C=CC=CC=1>[CH3:51][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:50])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:49])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:48])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:47])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:46])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:45])[CH2:29][CH2:30][CH:31]=[C:32]([CH3:44])[CH2:33][CH2:34][CH:35]=[C:36]([CH3:43])[CH2:37][CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])=[CH:3][CH2:2][NH:52][CH2:53][C:54]12[CH2:61][CH2:60][CH2:59][N:58]1[CH2:57][CH2:56][CH2:55]2
Reactant: NCC12CCCN1CCC2
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCBr
Solvent: c1ccccc1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCNCC12CCCN1CCC2
Temperature: 50 °C
Reaction time: 5 h
Yield: 51.1 %

Procedure:
Under an atmosphere of argon, a solution of 1-bromo-3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaene [8.00 g, 10.5 mmol, prepared as described in Example 4-a)] in 48.0 ml of benzene was added in dropwise to a solution of 5-aminomethyl-1-azabicyclo-[3.3.0]octane (1.76 g, 12.6 mmol) in 48.0 ml of benzene at 15° C. and the resulting solution was stirred at 50° C. for 5 hours. The solvent in the reaction mixture was evaporated in vacuo to dryness and the remaining residue was partitioned between chloroform and 10% sodium hydroxide aqueous solution. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness to give a brown residue. The residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (10.0:0-10:1.5) to afford 4.4 g (51.1%) of the desired compound, as colorless crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.N1C=CC=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][C:27](=O)[CH2:28][CH2:29][CH2:30][OH:31])=[CH:21][CH:20]=1>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=[C:27]([CH2:28][CH2:29][CH2:30][OH:31])[CH:26]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
4-Methoxyphenylhydrazine hydrochloride [35.0 grams (g), 0.20 moles] was added to CH3OH [50 milliters (ml)] containing pyridine (20 ml). An additional amount of CH3OH (25 ml) was added to the thick resulting slurry. 1-(4-Chlorophenyl)-6-hydroxyhexan-1,3-dione (48.2 g, 0.20 moles), was added neat, followed by more CH3OH (25 ml). The slurry was stirred at room-temperature for 1.5 hours, after which time the mixture was concentrated and taken up in CHCl3 (300 ml). The CHCl3 solution was washed with 1N HCl (300 ml), dried (Na2SO4), fitered, and concentrated. The oil was decolorized (Norit) in hot diethyl ether (Et2O) (300 ml). The Et2O solution was cooled, and crystallization from Et2O (300 ml) afforded 2 (49.4 g). From the filtrate was obtained additional 2 (9.28 g), total yield 91%, mp 87.5°-88°. NMR (CDCl3) 1.7-2.3 (m, 2H, CH2CH2CH2), 2.55 (brs, 1H, OH), 2.80 (t, 2H, J=7 Hz, CH2), 3.75 (t, 2H, J=6 Hz, CH2O), 3.77 (s, 3H, OCH3), 6.28 (s, 1H, C4 --H), 6.93 (ABq, 4H, J=12, 9, 4--OMe--C6H4), 6.9-7.3 (m, 4H, 4--Cl--C6H4); IR (KBr) 3320, 2920, 1495; MS, m/e 342 (M+), 312, 298 (100%);
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]=[C:11](Cl)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>ClCCl>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]=[C:11]([NH:26][NH2:27])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)nc2ccc(C(F)(F)F)cc2n1OCc1ccccc1
Reactant: NN
Solvent: ClCCl
Solvent: O
Product: NNc1nc2ccc(C(F)(F)F)cc2n(OCc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A mixture of 1-benzyloxy-3-chloro-7-trifluoromethylquinoxalin-2(1H)-one (27 g, 76 mmol) and hydrazine hydrate (14.7 ml, 0.30 mol) in 250 ml of dichloromethane was stirred at 0° C. for 2 h. The precipitate was isolated by filtration, washed with dichloromethane and water and dried to give 22.8 g (76%) of the title compound. M.p. 174°-176° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[CH:7][CH:6]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[C:43]([CH2:45][C:46](O)=[O:47])#[N:44]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:46](=[O:47])[CH2:45][C:43]#[N:44])[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3F)cc1)nn2C[C@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[4-(2-fluorophenoxy)phenyl]-1-((2R)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (10 mL), 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (80 mg, 0.49 mmol, 1.25 equiv), and 2-cyanoacetic acid (50 mg, 0.59 mmol, 3.80 equiv). The resulting solution was stirred for 1 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane/methanol (100:1; 50:1) to give 0.05 g (43%) of 3-[(2R)-2-([4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as alight yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[H-].[Na+].[CH3:17]I>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([C@H:7]1[CH2:8][CH2:9][C@@H:10]([O:13][CH3:17])[CH2:11][CH2:12]1)([CH3:6])[CH3:5]
Reactant: CI
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)[C@H]1CC[C@@H](OC)CC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
0.500 g of 2-(cis-4-hydroxy-cyclohexyl)-2-methyl-propionic acid methyl ester (Example 125b) are dissolved in 5 ml of dry tetrahydrofuran. 0.120 g of sodium hydride (60% dispersion) is added in portions and the mixture stirred at 40° C. for 1 hour. Methyl iodide (0.233 ml) is added and the mixture heated to 40° C. for 5 hours. The reaction mixture is then cooled to room temperature, quenched with 5 ml of water and extracted with tert-butyl methyl ether (2×50 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1>CO>[CH2:4]([N:16]1[CH2:17][CH:18]=[C:13](/[CH:12]=[CH:11]/[C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[CH:3]=[CH:4]3)[CH2:14][CH2:15]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cn1ccc2cc(/C=C/c3ccncc3)ccc21
Solvent: CO
Product: Cn1ccc2cc(/C=C/C3=CCN(Cc4ccccc4)CC3)ccc21

Procedure:
The title compound was prepared from (E)-4-(1-methylindol-5-yl)ethenylpyridine by an analogous procedure to Example 1, m.p. 137.5°-138.5° C. (MeOH); (Found: C, 84.17; H, 7.11; N, 8.48. C23H24N2 requires C, 84.11; H, 7.37; N, 8.53%); δH (CDCl3) 2.45 (2H, br s, tetrahydropyridinyl CH2), 2.68 (2H, m, tetrahydropyridinyl CH2), 3.13 (2H, br s, tetrahydropyridinyl CH2), 3.63 (2H, s, PhCH2N), 3.77 (3H, s, N-CH3), 5.77 (1H, br s, tetrahydropyridinyl CH), 6.43 (1H, m, 3'-H), 6.58 (1H, d, J 16.1 Hz, CH=CHAr), 6.77 (1H, d, J 16.1 Hz, CH=CHAr), 7.00 (1H, d, J 3.1 Hz, 2'-H), 7.23-7.39 (7H, m, ArH), and 7.61 (1H, s, ArH); m/z (ES+) 329 (+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)(C(OC(C)(C)C)=O)[C:9]([O:11][C:12](C)(C)C)=[O:10])=[CH:3][CH:2]=1.Cl.C(OCC)(=O)C>FC(F)(F)C(O)=O>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([CH2:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccncc1)(Cc1ccncc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccncc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
The crude crystals (17.1 g) of di-tert-butyl 2,2-bis[(4-pyridyl)methyl]malonate synthesized by the above process were dissolved in trifluoroacetic acid (90 ml), and the solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the resultant concentrated residue was heated for 20 minutes in a bath controlled at 200° C. and then dissolved in methanol (170 ml). A 4N hydrogen chloride in ethyl acetate (100 ml; 400 mmol) was added to the solution, and the mixture was stirred for 2 hours and then concentrated under reduced pressure. The resultant concentrated residue was made basic by addition of aqueous 2.5N sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 6.0 g (yield: 51%) of methyl 2,2-bis[(4-pyridyl)methyl]acetate as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([CH3:32])[CH:24]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([OH:21])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[C:8]([CH3:22])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:34][O:35][C:36](=[O:39])[CH2:37][NH2:38]>>[CH3:34][O:35][C:36](=[O:39])[CH2:37][NH:38][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([C:3]([CH2:4][CH3:5])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([OH:21])([CH:18]([CH3:19])[CH3:20])[CH:15]([CH3:16])[CH3:17])=[C:8]([CH3:22])[CH:7]=2)[CH2:1][CH3:2])=[CH:24][C:25]=1[CH3:32]
Reactant: CCC(CC)(c1ccc(OCC(O)(C(C)C)C(C)C)c(C)c1)c1ccc(C(=O)O)c(C)c1
Reactant: COC(=O)CN
Agent: Cl
Product: CCC(CC)(c1ccc(OCC(O)(C(C)C)C(C)C)c(C)c1)c1ccc(C(=O)NCC(=O)OC)c(C)c1
Yield: 86.8 %

Procedure:
Using a procedure analogous to Example 1J, 4-{1-ethyl-1-[4-(2-hydroxy-2-isopropyl-3-methyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.30 g, 0.68 mmol) and glycine methyl ester hydrochloride (0.094 g, 0.75 mmol) gives the titled compound (0.30 g, 0.59 mmol, 86%).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH2:24])[CH3:23])[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][N:16]=[CH:17]2.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:23])[C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][N:16]=[CH:17]2
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2ccncc2c1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (74 mg, 0.37 mmol), 1-[5-chloro-8-(3-fluorophenyl)isoquinolin-7-yl]ethanamine (0.075 g, 0.25 mmol), and N,N-diisopropylethylamine (0.087 mL, 0.50 mmol) in isopropyl alcohol (2 mL) was heated at 90° C., under nitrogen, overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H17ClFN6 (M+H)+: m/z=419.1; Found: 419.1. 1H NMR (DMSO-d6, 400 MHz) δ 8.58 (2H, m), 8.30 (2H, m), 8.06 (1H, s), 8.00 (1H, d, J=5.2 Hz), 7.92 (1H, d, J=6.0 Hz), 7.58 (2H, m), 7.37˜7.20 (2H, m), 5.19 (1H, m), 3.29 (1H, br s), 1.39 (3H, m) ppm. 19F NMR (DMSO-d6, 376 MHz) δ −113.5 ppm.