Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][CH:22]=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:10][CH:9]=1)[CH3:7].[CH:27](N1CCOCC1)=[O:28]>C1COCC1.ClCCl.Cl>[CH2:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[Se:21][C:22]([CH:27]=[O:28])=[CH:23][CH:24]=3)=[C:16]([F:25])[C:15]=2[F:26])=[CH:12][CH:13]=1)[CH3:7]
Reactant: O=CN1CCOCC1
Reactant: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2F)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(-c3ccc(C=O)[se]3)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.0 ml (35.3 mmol) of TMP are initially introduced at −20° C. in 30 ml of THF, and 21.5 ml (34.2 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 30 min at this temperature, a solution of 11.8 g (34.0 mmol) of 2-(4′-ethyl-2,3-difluorobiphenyl-4-yl)selenophene in 70 ml of THF is added. When the addition is complete, the batch is warmed to RT and left at this temperature for 90 min. The solution is cooled to −60° C., and 3.6 ml (36.0 mmol) of N-formylmorpholine are added. The reaction mixture is warmed to RT and stirred for 2 h. The solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is washed with water, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is recrystallised from toluene. 5-(4′-Ethyl-2,3-difluorobiphenyl-4-yl)selenophene-2-carbaldehyde is obtained as a brown solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH2:17][CH2:18]2)=[CH:13][CH:14]=1)=[O:8]
Reactant: CC1CC1CNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: CC1CC1CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-methylcyclopropylmethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (26% yield). 1H NMR (500 MHz, CDCl3) δ 8.06, 7.96, 7.75, 7.65, 7.58, 7.38, 7.01, 4.04-4.10, 3.86-3.93, 3.69-3.83, 3.25-3.42, 1.12, 1.05, 0.71-0.80, 0.64-0.72, 0.39-0.45, 0.25-0.30. MS (ES+) m/z 448 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[NH3:15]>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(F)c(S(N)(=O)=O)c1
Reactant: N
Solvent: CCO
Product: CC(=O)c1ccc(N)c(S(N)(=O)=O)c1

Procedure:
A solution of 5-acetyl-2-fluorobenzenesulphonamide (0.5 g) in ethanol (40 ml) saturated with ammonia was heated at 100° in a bomb overnight. Concentration of the resultant solution yielded a yellow crystalline solid, 0.4 g, m.p. 263°-264° (from ethanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][N:6]([C:15]([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]1)=[C:16]([C:19]#[N:20])[C:17]#[N:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[CH3:2].[H-].[Na+].O>O1CCCC1>[NH2:18][C:17]1[C:16]([C:19]#[N:20])=[C:15]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]2)[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:35]
Reactant: CCOC(=O)CN(Cc1ccccc1Cl)C(=C(C#N)C#N)N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(N)c(C#N)c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1Cc1ccccc1Cl
Temperature: 25 °C
Yield: 93.8 %

Procedure:
A solution of N-(1-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-2,2-dicyanovinyl)-N-(2-chlorobenzyl)glycine ethyl ester (320 mg) in tetrahydrofuran (5 ml) was cooled to 0° C., followed by adding thereto sodium hydride (33 mg), and the resulting mixture was stirred for 1 hour while being warmed to 25° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound (300 mg).
Reaction SMILES: [CH2:1]([OH:11])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1>CCOCC>[CH:18]1([C:21]([O:11][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:22])[CH2:20][CH2:19]1
Reactant: CCCCCCCC#CCO
Reactant: O=C(Cl)C1CC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCC#CCOC(=O)C1CC1
Reaction time: 8 h

Procedure:
To a solution of 3.85 g. of 2-decyn-1-ol and 3.95 g. of pyridine in 100 ml. ether is added 3.0 g. of cyclopropanecarboxylic acid chloride. The mixture is stirred overnight under nitrogen. The reaction mixture is poured into distilled water, washed with dilute hydrochloric acid and then with sodium bicarbonate and solvent removed to yield 2-decynyl cyclopropanecarboxylate, b.p. 96°-97° (bath) at 0.1 mm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH2:35]([O:37][CH:38]1[CH2:41][NH:40][CH2:39]1)[CH3:36].C(Cl)(Cl)Cl>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:40]4[CH2:41][CH:38]([O:37][CH2:35][CH3:36])[CH2:39]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCOC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC1CN(c2cc(C(=O)Nc3nc4c(OC)ccc(C5COCCO5)c4s3)ccn2)C1

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-ethoxy-azetidine hydrochloride in DMF. [α]D20=+44.3° (c=0.57, CHCl3), ES-MS m/e (%): 471 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9]Cl)[CH:3]=1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: ClCc1cc(Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc(Br)cc1COc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(chloromethyl)benzene (12.2 g, 50.85 mmol) and phenol (4.79 g, 50.85 mmol) in DMF (102 mL) under nitrogen atmosphere, K2CO3 was added (35.14 g, 254.25 mmol). The resulting mixture was stirred at r.t. for 18 h. After completion of the reaction as confirmed by TLC, the reaction mixture was passed through celite plug and the filterate was evaporated. The residue obtained was dissolved in ethyl acetate (100 mL) and washed with water (2×100 mL) and brine (2×100 mL) successively. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:9 Ethyl acetate:Pet. Ether) to afford the title compound (14.7 g, 97.3%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][N:8]=[C:7]([F:11])[CH:6]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2-fluoropyridin-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (194 mg, 0.54 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (101 mg, 0.54 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.80 mmol) and 1-hydroxybenzotriazole hydrate (82 mg, 0.54 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (189 mg, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=O.[OH-].[NH4+:19]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[C:8]([OH:9])=[CH:12][CH:11]=[CH:10][N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: [NH4+]
Reactant: COc1ccc(C(=O)c2ccco2)cc1OC
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2ncccc2O)cc1OC

Procedure:
2-(3,4-Dimethoxybenzoyl)furan (764.0 g, 3.28 moles, described in Example 2) is heated at 140° C in an autoclave in the presence of concentrated ammonium hydroxide (7 liters) and methanol (6 liters) for 17 hours. The mixture is cooled and concentrated to 4 liters. Methylene chloride (3 liters) is added and the mixture is extracted with 8N aqueous sodium hydroxide (500 ml). The aqueous extract is washed with methylene chloride. Ice is added to the aqueous phase followed by 6N hydrochloric acid to bring the pH between 7.5-7.0. The brown precipitate is collected, dried and milled to give the title compound, mp 150°-155° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH:29]=O>>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1cc2ccccc2s1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cc5ccccc5s4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-benzothiophene-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1-benzothiophen-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][CH3:25])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:26]>ClCCl.C(O)(=O)C>[C:8]([O:7][C@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][CH3:25])[O:22][C@@H:5]1[Br:26])(=[O:10])[CH3:9]
Reactant: Br
Reactant: COC[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC[C@H]1O[C@H](Br)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-6-O-methyl-β-D-mannopyranose (2.8 g) in dry dichloromethane (2 ml) at 0°-5° C. is treated with 30% hydrobromic acid in glacial acetic acid (25 ml) for 2 hours. The reaction mixture is worked-up in the normal manner to give 2,3,4-tri-O-acetyl-6-O-methyl-α-D-mannopyranosyl bromide (2.8 g), which is reacted with thiourea (0.76 g) in dry acetone (5 ml) at reflux temperature for 2 hours. The solution is evaporated in vacuo to a syrup, which is partitioned between ethyl ether (25 ml) and water (25 ml). The aqueous layer is extracted three times with ethyl ether. A solution of cinnamyl bromide (1.44 g) in acetone (30 ml) is added to the aqueous solution containing 2-S-(2,3,4-tri-O-acetyl-6-O-methyl-α-D-mannopyranosyl)-2-thiopseudourea hydrobromide. This is followed by the addition of potassium carbonate (1.26 g) and potassium metabisulfite (1.77 g) and the reaction mixture is stirred vigorously for 2 hours at room temperature. Acetone is evaporated in vacuo and the product is extracted with chloroform and washed twice with water. The solution is dried and evaporated to an oil, which is put on a column of silica gel and eluted with CHCl3 --EtOAc (98:2, v/v). The desired fractions are combined and evaporated in vacuo to give 19 as an oil (1.15 g, 33% overall yield): [α]D27 +147° (C 2.08, chloroform).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:15](OC)=[O:16])#N.[OH2:23].Cl>C(Cl)Cl>[OH:16][CH2:15][C:14]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:12]([CH:13]=1)[CH:10]=[O:23]
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Reactant: O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(CO)cc1C=O
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a stirring solution of 27 mL of DIBAL-H (1.5 M solution in toluene) in 10 mL of CH2Cl2 at −78° C. was added 1.32 g (7.54 mmol) of methyl 3-cyano-4-methylbenzoate in 35 mL of CH2Cl2 dropwise over a period of 30 min. After stirring for about 40 min. at −78° C., the solution was allowed to warm to r.t. After 75 min., the solution was cooled to −78° C. and 10 mL of H2O and 16 mL of 1N HCl were added. The cold bath was removed, and the mixture was allowed to warm to r.t. Concentrated HCl (5-6 mL) was added and stirring was continued for 1.5 h. Chloroform was added, the layers were separated, and the organic layer was washed with 20 mL of brine. The combined aqueous layers were extracted with chloroform (4×). The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (50% EtOAc/hexanes) provided the 800 mg of 5-(hydroxymethyl)-2-methylbenzaldehyde as a yellow oil with some impurity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](Cl)=[O:13].N1C=CC=CC=1.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH:40]3[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]3)[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([O:38][CH3:39])[CH:32]=3)[C:23]=12>ClCCl>[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([CH:40]3[CH2:45][CH2:44][C:43](=[O:46])[CH2:42][CH2:41]3)[N:29]=[C:30]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:12](=[O:13])[C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[F:1])=[C:33]([O:38][CH3:39])[CH:32]=3)[C:23]=12
Reactant: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of 2-fluoro-4-trifluoromethyl-1-benzenecarbonyl chloride (0.87 g, 3.83 mmol) in dichloromethane (5 mL) was added into a mixture of pyridine (15 mL) and 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (1.00 g, 2.56 mmol) in dichloromethane (5 mL) at 0° C. over 5 minutes. The mixture was stirred at 0° C. for 10 minutes and at ambient temperature overnight. The solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane. The dichloromethane layer was washed with saturated aqueous ammonium chloride twice and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography on silica using Isco system to provide N1-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo [3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.95 g, 1.76 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.90 (dd, 1H), 8.30(d, 1H), 8.28 (s, 1H), 7.99 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.34 (s, 1H), 7.30 (d, 1H), 6.90 (br, 2H), 5.27 (m, 1H), 3.94 (s, 3H), 2.70 (m, 2H), 2.47 (m, 4H), 2.17 (m, 2H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100A, 250×4.6 mm; 25%-100% acetonitrile—0.05M ammonium acetate over 10 min, 1 mL/min) Rt 9.23 min. MS: MH+ 543.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:10]#[C:11]Br>C(OCC)C>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:6][C:11]#[N:10])[CH:7]=[CH:8][CH:9]=1
Reactant: CSc1cccc(N)c1
Reactant: N#CBr
Solvent: CCOCC
Product: CSc1cccc(NC#N)c1
Temperature: 25 °C

Procedure:
To a cooled solution (0° C.) of 3-Methylthio-aniline (1.850 g, 13.30 mmol) in anhydrous diethylether (10 ml) was added a diethylether solution (10 ml) of cyanogen bromide (0.704 g, 6.65 mmol). CAUTION: Cyanogen bromide is highly toxic. The resulting solution was allowed to stir at room temperature over night. The resulting mixture was filtered to remove the precipitate and the diethylether filtrate was washed with 1M HCl (20 ml) and brine (20 ml) before the solvent was removed under vacuum to yield an oily yellow residue. Purification of the crude product by column chromatography on silica gel using 95:5 dichloromethane/ethyl acetate afforded (3-methylthio-phenyl)-cyanamide as a near colourless oil which crystallised on standing (0.570 g, 52%).
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+]>O1CCOCC1>[CH:5]([C:4]1([CH3:8])[C:1](=[O:3])[NH:2][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[N:9]1)([CH3:7])[CH3:6]
Reactant: Cc1ccc(C(=O)NC(C)(C(N)=O)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(C2=NC(C)(C(C)C)C(=O)N2)cc1

Procedure:
A mixture of 24.8 g (0.10 mol) of N-(1-carbamoyl-1,2-dimethylpropyl)-p-toluamide in 263 mL of a 2N sodium hydroxide solution (0.50 mol NaOH) is heated with 100 mL p-dioxane and heated on a steam bath for 72 hours. The p-dioxane is removed in vacuo and the remaining aqueous solution is cooled to 5°-10° C. After carefully acidifying to pH 3-4 with concentrated sulfuric acid, the reaction mixture is extracted with a total of 750 mL methylene chloride. The organic phase is washed with 200 mL of a saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo to give a yellow solid residue, weighing 22.1 g. The nmr spectrum is consistent with the desired structure. This compound can be recrystallized from acetonitrile to give analytically pure 4-isopropyl-4-methyl-2-p-tolyl-2-imidazolin-5-one mp 151°-154° C.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH2:10][C:11]([O:13]CC)=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>O.C(O)C>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH2:10][C:11]([OH:13])=[O:12])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)N(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC(=O)N(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
22.6 g (0.08 mol) of ethyl N,N-diphenylcarbamoylacetate (m.p.=75°-76° C.) are added to a solution of 5.6 g(0.1 mol) of KOH in a mixture of 50 ml of water and 25 ml of ethanol. The mixture is heated to 40° C. with agitation until dissolution is complete (that is, for about 1 hour) and agitation is continued for two hours. Acidification is then carried out with 3 N HCl, followed by drying without heat, washing with water and drying.20.2 g (yield: 98%) of N,N-diphenylcarbamoylacetic acid (m.p.=126°-127° C.) are obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:17]([O:19][CH:20]3[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]3)=[N:16][CH:15]=[N:14][C:13]=2[S:12][CH:11]=1.C=O.[BH3-][C:31]#N.[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:17]([O:19][CH:20]3[CH2:21][CH2:22][CH:23]([N:26]([CH3:31])[CH3:27])[CH2:24][CH2:25]3)=[N:16][CH:15]=[N:14][C:13]=2[S:12][CH:11]=1
Reactant: CNC1CCC(Oc2ncnc3scc(-c4cc5ccccc5o4)c23)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)C1CCC(Oc2ncnc3scc(-c4cc5ccccc5o4)c23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
A solution of tert-butyl N-(4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]cyclohexyl)-N-methylcarbamate (60 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (5 mL) was added hydrochloric acid (1 mL, 12 M) at 0° C. and stirred for 1 h at room temperature. The pH value of the solution was adjusted to 9 with sodium carbonate (sat.) and extracted with 3×20 mL of dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 40 mg (84%) of 4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N-methylcyclohexan-1-amine as colorless oil which was used directly for next step. To a solution of 4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N-methylcyclohexan-1-amine (40 mg, 0.11 mmol, 1.00 equiv) in methanol (2 mL) was added HCHO (37%, 0.07 mL, 1.06 mmol) and stirred for 1 h at room temperature. Then NaBH3CN (20 mg, 0.32 mmol, 3.01 equiv) was added and stirred for addional 1 h at room temperature. The reaction was then quenched by the addition of 20 mL of NH4Cl (sat.) and extracted with 3×20 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product (60 mg) was re-crystallized from ethyl acetate to give 15 mg (36%) of pure 4-[[5-(1-benzofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy]-N,N-dimethylcyclohexan-1-amine as a white solid. MS (ES, m/z): 394 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.66 (s, 1H), 8.08 (s, 1H), 7.68-7.65 (d, 1H), 7.56-7.54 (d, 1H), 7.38-7.25 (m, 3H), 5.45-5.42 (m; 1H), 3.33 (s, 1H), 2.90 (s, 6H), 2.53-2.50 (d, 2H), 2.23-2.20 (d, 2H), 1.82-1.66 (m, 4H).