Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1)#[N:21].O>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[CH:35][CH:34]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CCl)cc1
Reactant: CCCCc1nc2c(C(=O)OC)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2c(C(=O)OC)cccc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.33 h
Yield: 84.1 %

Procedure:
To a solution of methyl 2-butylbenzimidazole-7-carboxylate (1.5 g) in DMF (15 ml) was added sodium hydride (60% oil, 0.13 g) under ice-cooling. The mixture was stirred for 20 minutes and there was added 4-(2-cyanophenyl)benzyl chloride (1.5 g). The resultant mixture was stirred for further 5 hours at room temperature and there was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel to give a pale yellow oil (2.3 g, 82%).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH:15]=O)[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1.[CH3:30][S:31][CH2:32][CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClCCCl>[CH3:29][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH2:15][NH:34][CH2:33][CH2:32][S:31][CH3:30])[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1
Reactant: CSCCN
Reactant: CC1(C)CC=C(c2cc(C(C)(C)C=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CSCCNCC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,1-dimethyl-2-oxo-ethyl)-phenyl]-amide (as prepared in the previous step, 60.0 mg, 0.154 mmol) and 2-methylsulfanyl-ethylamine (84 mg, 0.92 mmol) in 2 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (49.0 mg, 0.231 mmol). After stirring at RT for 3 h, the mixture was treated with EtOAc (40 mL) and washed with aqueous saturated NaHCO3 (10 mL), H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1-3% MeOH/DCM) to afford the title compound (45.0 mg, 63%) as a white solid. 1H-NMR (1:1 CD3OD/CDCl3; 400 MHz): δ 8.22 (d, 1H, J=8.6 Hz), 7.78 (s, 1H), 7.27 (dd, 1H, J=8.6, 2.0 Hz), 7.14 (d, 1H, J=2.0 Hz), 5.73 (m, 1H), 2.77 (s, 2H), 2.68 (t, 2H, J=6.3 Hz), 2.55 (t, 2H, J=6.3 Hz), 2.27 (m, 2H), 2.06 (m, 2H), 1.92 (s, 3H), 1.57 (t, 2H, J=6.3 Hz), 1.35 (s, 6H), 1.07 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H35N5OS, 466.3 (M+H). found 466.2.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][N:11]=1
Reactant: Cc1ccc(CO)cn1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(COc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
Thionyl chloride (1 mL) was added to (6-methyl-pyridin-3-yl)-methanol (300 mg, 2.44 mmol) at 0° C., and the solution was stirred at room temperature for 20 minutes. The reaction solution was partitioned in an aqueous solution of saturated sodium bicarbonate and ethyl acetate. This organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo. N,N-dimethylformamide (5 mL), phenol (230 mg, 2.44 mmol) and potassium carbonate (674 mg, 4.88 mmol) were added to this residue at room temperature. This reaction mixture was stirred at room temperature for 40 minutes, then, further stirred for at 60° C. 40 minutes. The reaction solution was partitioned in water and ethyl acetate. The organic layer was separated, washed with water and brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=2/1), and the title compound (323 mg, 66%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](I)=[C:8]([F:13])[C:7]=1[F:14])([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH:16]([Zn+])=[CH2:17].[Cl-].[NH4+]>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.C1COCC1>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:16]=[CH2:17])=[C:8]([F:13])[C:7]=1[F:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Zn+]
Reactant: CC(C)(C)Oc1ccc(I)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=Cc1ccc(OC(C)(C)C)c(F)c1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 1-liter reactor was charged with 31.2 g (0.10 mol) of 4-tert-butoxy-2,3-difluoro-1-iodobenzene and 100 ml of THF and heated at 60° C. To the reactor, 1.16 g (1 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, then 120 ml of a THF solution of 1 M vinyl zinc chloride was added dropwise. After the completion of dropwise addition, the reaction solution was ripened for 30 minutes and poured into a saturated ammonium chloride aqueous solution. From the solution, a crude product was extracted with ethyl acetate in a conventional way. It was purified by silica gel chromatography, obtaining 17.6 g (yield 83%) the end product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)C)(=O)[CH3:19].C([O-])(=O)C.[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:17][C:18]([CH3:19])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccccc1)c1cc(Br)ccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 97 %

Procedure:
Intermediate 1 (8.9 g, 30.56 mmoles) was taken in a RB flask and to this acetic anhydride (59 ml) and sodium acetate (17.5 g, 213 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as white solid (9.4 g, 97% yield). MP: 119-121° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.35(d, J=2.4 Hz, 1H), 7.75(dd, J=11.3, 2.4 Hz, 1H), 7.46(t, 2H), 7.39(d, J=7.2 Hz, 1H), 7.36(d, J=8.8 Hz, 1H), 7.28(m,2H), 2.32(s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:24][C:12]1[CH:13]=[C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16][C:11]=1[C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])[N:8]([C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2[C@@H]1CCCNC1
Yield: 74.6 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (320 mg, 0.63 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of trifluoroacetic acid (10 mL) dropwise with stirring. The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was diluted with water and the pH value of the solution was adjusted to >7 with sodium carbonate. The resulting solution was extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 190 mg (74%) of 3-(2-fluoro-4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown solid.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[F:8][C:9]1[CH:14]=[CH:13]C(O)=C[C:10]=1[C:16]1[CH:17]=[N:18][C:19]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:32])[CH:29]=3)[C:24]([S:39]([CH3:41])=[O:40])=[CH:23]2)=[N:20][CH:21]=1>N1C=CC=CC=1.O>[C:5]([O:4][C:1]1[CH:13]=[CH:14][C:9]([F:8])=[C:10]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:32])[CH:29]=4)[C:24]([S:39]([CH3:41])=[O:40])=[CH:23]3)=[N:20][CH:21]=2)[CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)c1cn(-c2ncc(-c3cc(O)ccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc(F)c(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (0.18 mL, 1.9 mmol) was added at 0° C. to 264a) (0.45 g, 0.94 mmol) in pyridine (2.0 mL) and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was diluted with cold water and extracted with dichloromethane/methanol (9:1; 3×30 mL). The organic layers were washed with saturated sodium hydrogen carbonate solution (2×20 mL) and brine (20 mL), dried over sodium sulfate and evaporated. The remnant was purified by flash column chromatography [silica; dichloromethane with 1.5% methanol]. Yield: 0.09 g (38% of theory)
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH2:6]([C:8]1[N:13]=[C:12]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:11]2=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:9]=1[CH:28]=[C:29]1[S:33][C:32](=[O:34])[NH:31][C:30]1=[O:35])[CH3:7].C(OCC)C.O1CCCC1>C(OCC)C.[Cu]I>[CH2:6]([C:8]1[N:13]=[C:12]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:11]2=[C:10]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[C:9]=1[CH:28]([CH:29]1[S:33][C:32](=[O:34])[NH:31][C:30]1=[O:35])[CH2:1][CH2:2][CH3:3])[CH3:7]
Reactant: CCc1nc2sc3c(c2c(-c2ccc(C)cc2)c1C=C1SC(=O)NC1=O)CCCC3
Reactant: CCC[Mg]Cl
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(c1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3)C1SC(=O)NC1=O
Reaction time: 0.33 h
Yield: 9 %

Procedure:
To a cold (−15° C.) solution of copper(I)iodide (0.200 g; 1.05 mmol) in anhydrous diethyl ether (5 mL) was added a 2M solution of n-propylmagnesium chloride in diethyl ether (1.0 mL; 2.0 mmol). The mixture was stirred for 20 min and a solution of 5-[1-(2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methylene]thiazolidine-2,4-dione (0.083 g; 0.197 mmol) in a mixture diethyl ether-tetrahydrofurane (2/1, 3 mL) was added dropwise and stirring was carried on for 2 h at −15° C. and 18 h at room temperature. The reaction was quenched with a saturated solution of ammonium chloride (50 mL) and diluted with diethyl ether (20 mL). Both phases were separated, the aqueous layer was extracted with diethyl ether, the combined organic phases were washed with a saturated solution of ammonium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 1) furnished 0.008 g (9%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][NH:31][CH2:32]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][N:31]([C:7]1[C:2]([F:1])=[C:3]3[C:4]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:18]3[CH:13]=[CH:14][C:15]([F:21])=[CH:16][C:17]=3[F:19])=[CH:5][C:6]=1[F:8])[CH2:32]2
Reactant: COc1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c1F)C2
Yield: 30.9 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 90 mg of 4-methoxyisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 75 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:29]([N:25]1[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]2[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=2)[CH2:27][CH2:26]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Product: Cc1nc(OCC(=O)N(C)C2CCN(C(=O)c3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and benzoyl chloride in the same manner as in Example 32.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3CCN(C(OC(C)(C)C)=O)CC3)=C(C)C=2N=1.Cl.[CH3:33][C:34]1[C:38]2[N:39]=[C:40]([C:49]3[CH:50]=[CH:51][C:52]([C:55]#[N:56])=[N:53][CH:54]=3)[N:41]=[C:42]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[C:37]=2[S:36][C:35]=1[CH2:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1.[C:64](O)(=[O:68])[C@H:65]([CH3:67])[OH:66]>>[OH:66][C@@H:65]([CH3:67])[C:64]([N:61]1[CH2:60][CH2:59][N:58]([CH2:57][C:35]2[S:36][C:37]3[C:42]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:41][C:40]([C:49]4[CH:50]=[CH:51][C:52]([C:55]#[N:56])=[N:53][CH:54]=4)=[N:39][C:38]=3[C:34]=2[CH3:33])[CH2:63][CH2:62]1)=[O:68]
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3ccc(C#N)nc3)nc12
Reactant: C[C@H](O)C(=O)O
Agent: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3ccc(C#N)nc3)nc12

Procedure:
Tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (75 mg) was reacted with 6-cyanopyridin-3-yl-3-boronic ester via General Procedure A. This crude intermediate was subjected to General Procedure D in which the crude HCl salt of 5-(7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyridine-2-carbonitrile was reacted with L-Lactic acid via General Procedure B to give 8.6 mg of 405 after reverse phase HPLC purification. MS (Q1) 508.2 (M)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.C(Cl)(=O)C([Cl:31])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([Cl:31])=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A stirred solution of 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylic acid (2.55 g, 5.87 mmol) (i.e. the product of Example 2, Step C) in dichloromethane (100 mL) was cooled to −10° C., and 1 drop of N,N-dimethyl-formamide was added. A solution of oxalyl chloride (0.60 mL, 6.8 mmol) in dichloromethane (10 mL) was added dropwise to the stirred reaction mixture. The reaction mixture was stirred at −10° C. for 30 minutes more, and then allowed to warm to room temperature and stir an additional 16 h. The resulting homogeneous mixture was evaporated in vacuo, and the residue was placed under high vacuum for several hours to give 2.46 g of the title compound as a light yellow solid. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [Cl:1]Cl.[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH3:10])[CH:4]=1.O>C(Cl)(Cl)(Cl)Cl>[CH:7]1[C:8]([OH:9])=[CH:3][CH:4]=[C:5]([CH3:10])[CH:6]=1.[Cl:1][C:7]1[C:8]([OH:9])=[CH:3][CH:4]=[C:5]([CH3:10])[CH:6]=1
Reactant: ClCl
Agent: Cc1ccc(O)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(O)c(Cl)c1
Reaction time: 16 h
Yield: 3.3 %

Procedure:
Four grams of chlorine was bubbled through a stirred solution of 10.8 g of p-cresol (10 mmoles) in 100 ml of carbon tetrachloride for about 30 minutes. A five-gram sample, removed and analyzed showed 46.9% p-cresol and 53.1% 2-chloro-p-cresol. Then 0.1 ml of ethanol and 10.00 g powdered anhydrous calcium bromide were added to the chlorinated p-cresol mixture. The mixture was stirred in the absence of atmospheric moisture for about 16 hours. A washed-and-dried solid was obtained weighing 10.40 g. A sample of the solid was hydrolyzed by water and extracted five times with carbon tetrachloride. GC analysis of the combined extract gave 96.6% p-cresol and 3.3% 2-chloro-p-cresol, showing substantially complete separation of p-cresol from its chlorinated derivative by complexation with calcium bromide.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[SH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]>N1C=CC=CC=1.[OH-].[Na+]>[CH3:1][NH:2][C:3]([S:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[S:4]
Reactant: O=C(O)CCS
Reactant: CN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CNC(=S)SCCC(=O)O
Reaction time: 2 h

Procedure:
Methylisothiocyanate (4 g) is added to a solution of 3-mercaptopropanoic acid (5.3 g) in a mixture of pyridine (250 ml) and 0.5 N sodium hydroxide (100 ml). The solution is kept at 40° for two hours and concentrated to dryness in vacuo. The residue is dissolved in water (100 ml.), acidified with concentrated hydrochloric acid and extracted with ether. The organic phase is concentrated to dryness to yield 3-[[(methylamino)thiocarbonyl]thio]propanoic acid, m.p. 86°-87°.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:18])([CH2:8][CH2:9][C:10]([O:13][C:14](=[O:17])[CH2:15]Cl)([CH3:12])[CH3:11])[CH3:7])=[O:4].[CH2:19]([CH2:21][NH2:22])[OH:20]>C(Cl)Cl>[OH:20][CH2:19][CH2:21][NH:22][CH2:2][C:3]([O:5][C:6]([CH3:18])([CH2:8][CH2:9][C:10]([O:13][C:14](=[O:17])[CH2:15][NH:22][CH2:21][CH2:19][OH:20])([CH3:12])[CH3:11])[CH3:7])=[O:4]
Reactant: NCCO
Reactant: CC(C)(CCC(C)(C)OC(=O)CCl)OC(=O)CCl
Solvent: ClCCl
Product: CC(C)(CCC(C)(C)OC(=O)CNCCO)OC(=O)CNCCO
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of compound (61) (0.898 g, 3 mmol) in 5 ml, of methylene chloride at 0° C., ethanolamine (40) (2.504 g, 41 mmol) was added drop wise over the course of one hour. The solution was then allowed to warm to 20° C. and stirred for 18 hours. On completion, the reaction was diluted with CH2Cl2 (15 mL) and washed with brine (1×20 mL) and dried. The solvent was evaporated to get clear yellow oil. (0.380 g) 1H NMR (400 MHz, CDCl3): δ 1.35 (s, 12H), 1.79 (s, 4H), 2.68-2.71 (t, J=5.1, 4H), 3.08 (b, 4H), 3.26 (s, 4H), 3.58-3.60 (t, J=5.1, 4H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:17]1[C:18]2[CH:25]=[C:24]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[S:23][C:19]=2[N:20]=[CH:21][N:22]=1>C1COCC1>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([O:13][C:17]3[C:18]4[CH:25]=[C:24]([CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[S:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH2:11][CH2:12]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: OC1CCC(N2CCOCC2)CC1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(Cl)ncnc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1cc2c(OC3CCC(N4CCOCC4)CC3)ncnc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.2 %

Procedure:
To a solution of 4-(morpholin-4-yl)cyclohexan-1-ol (143 mg, 0.77 mmol, 1.10 equiv) in THF (20 mL) was added sodium hydride (140 mg, 3.50 mmol, 5.00 equiv, 60% dispersion in mineral oil) at 0° C. The solution was stirred for 30 min at room temperature under nitrogen. Then tert-butyl N-(2-[4-chlorothieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (220 mg, 0.70 mmol, 1.00 equiv) in 5 mL of THF was added via syringe and the resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of brine and extracted with EtOAc. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was purified by a silica gel column with DCM/MeOH (30:1-10:1) to provide 127 mg (39%) of tert-butyl N-[2-(4-[[4-(morpholin-4-yl)cyclohexyl]oxy]thieno[2,3-d]pyrimidin-6-yl)ethyl]carbamate as a white solid. MS (ES): m/z 463 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH:15]=[C:16]([CH:19]=[O:20])[NH:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:22]1COCC1.[H-].[Na+].IC>O>[CH3:22][N:17]1[CH:18]=[C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:21])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)[CH:15]=[C:16]1[CH:19]=[O:20]
Reactant: CC1(C)CCC(C)(C)c2cc(-c3c[nH]c(C=O)c3)ccc21
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1cc(-c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1C=O

Procedure:
1.3 g (4.6 mmol) of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-pyrrolecarboxaldehyde and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 300 mg (10 mmol) of sodium hydride (80% in oil) are added portionwise and the mixture is stirred until the evolution of gas has ceased. 640 μl (10 mmol) of iodomethane are then added and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of dichloromethane and heptane (70/30). After evaporation of the solvents, 600 mg (44%) of the expected product are collected.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.[F-:23].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[F:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1
Reactant: BrCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: FCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-[4-(7-Bromoheptyloxy)phenyl]bromobenzene (0.25 g) in a solution of tetra n-butylammonium fluoride (tetrahydrofuran solution, 1M, 2.9 ml) was heated to 50° C. for 2 hours. After cooling to ambient temperature, the solution was taken up into a mixture of ethyl acetate (20 ml) and water (20 ml). The separated organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation gave a residue which was chromatographed on silica gel (30 ml) eluting with a mixture of n-hexane and ethyl acetate (100:0-97:3, V/V). The fractions which contained the objective compound were collected and evaporated a residue which was triturated with n-hexane to give 4-[4-(7-Fluoroheptyloxy)phenyl]bromobenzene (104 mg).