Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[N:12]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][CH:21]=2)[CH2:14][CH2:13]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][CH:21]=3)[CH2:14][CH2:13]2)=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([N+](=O)[O-])c1N1CCCN(Cc2cnc(-c3ccccc3)s2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cccc(N)c1N1CCCN(Cc2cnc(-c3ccccc3)s2)CC1
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A mixture of 1-(2-methoxy-6-nitrophenyl)-4-(2-phenylthiazol-5-ylmethyl)-[1,4]diazepane (250 mg), 5% Pd/C (20 mg) in 50 mL of ethyl acetate was subjected to a Parr shaker at 65 psi of hydrogen for 16 hours. More 5% Pd/C (10 mg) was added and the reaction continued for another 16 hours. Filtration through celite followed by flash chromatography (0 to 10% MeOH in ethyl acetate) gave 3-methoxy-2-[4-(2-phenylthiazol-5-ylmethyl)-[1,4]diazepan-1-yl]-phenylamine (210 mg, 90%). MS (ES) m/z 395.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]3[NH:11][C:12]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[N:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(OCC)C>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([O:6][C:7]3[CH:20]=[CH:19][C:10]4[NH:11][C:12]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[N:13][C:9]=4[CH:8]=3)=[CH:4][CH:3]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)Nc1nc2cc(Oc3ccc(N)cc3)ccc2[nH]1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)Nc1nc2cc(Oc3ccc(NC(=O)Nc4cccc(Cl)c4)cc3)ccc2[nH]1
Temperature: 45 °C
Yield: 68 %

Procedure:
A mixture of methyl (5-(4aminophenoxy)-1H-benzimidazol-2-yl)carbamate (Intermediate 3) (80 mg, 0.27 mmol) and 3-chlorophenylisocyanate (49 mg, 0.32 mmol) in dry THF (2 ml) was heated to 45° C. overnight. After cooling, diethyl ether was added to form a precipitate. The solid was collected by filtration to provide the title compound (83 mg, 69%): 1H NMR (DMSO-d6) δ 11.60 (brs, 2H), 9.00 (s, 1H), 8.83 (s, 1H), 7.70 (m, 1H), 7.42 (d, 2H), 7.38 (d, 1H), 7.32–7.24 (m, 2H), 7.01 (m, 2H), 6.93 (d, 2H), 6.80 (dd, 1H) 3.75 (s, 3H); MS m/e 452 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[O:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[O:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncco2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncco2)=NC1c1ccc(F)cc1Br
Yield: 35.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(oxazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.29 g, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:23](Br)[CH:24]=[CH2:25]>>[CH2:25]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:24]=[CH2:23]
Reactant: COc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Li+]
Product: C=CCn1c(=Nc2ccc(OC)cc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 428 mg of 2-(4-methoxyanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.13 ml of allyl bromide were used. As a result, 213 mg of 3-allyl-2-[(4-methoxyphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 85 mg of 2-[N-allyl-N-(4-methoxyphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:6])[CH2:4][CH3:5].Cl[CH2:8][CH2:9][C:10](=[O:12])[CH3:11]>O1CCCC1>[CH2:3]([S:6][CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH2:4][CH3:5]
Reactant: CC(=O)CCCl
Reactant: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCSCCC(C)=O
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
Solid sodium hydride (60% dispersion in oil, 2.90 g, 72.3 mmol) was added in portions over 5 minutes to a stirred solution of 1-propanethiol (6.00 g, 78.8 mmol) in tetrahydrofuran (262 mL). After 15 minutes, a thick white suspension had formed. To the suspension was added 1-chloro-3-butanone (7.00 g, 65.7 mmol), which caused the reaction mixture to warm and a cloudy solution to form. After 30 minutes, the cloudy solution was partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a pale brown oil. The crude product was purified by flash chromatography (silica gel, elution with 20% ethyl acetate in hexanes) to provide 9.0 g of 4-(propylthio)butan-2-one as a clear liquid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[S:11])[CH:6]=[CH:7][CH:8]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:17]=1[NH2:18]>C1(C)C=CC=CC=1>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:18][C:17]2[CH:19]=[C:20]([C:23]([F:25])([F:26])[F:24])[CH:21]=[CH:22][C:16]=2[O:15][CH3:14])=[S:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Solvent: Cc1ccccc1
Product: COc1ccc(C(F)(F)F)cc1NC(=S)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
3-(trifluoromethyl)phenyl isothiocyanate in toluene (0.76 ml, 5.0 mmol) was added to a solution of 2-methoxy-5-(trifluoromethyl)aniline in toluene (10 ml). The resulting reaction mixture was stirred at RT overnight and the product was subsequently filtered off. 1.00 g (51%) of the title compound was isolated.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:15][C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccccc1

Procedure:
To a mixture of phenol (0.01 mol) and ethyl 2-bromo-2-methylpropanoate (0.01 mol) in acetonitrile was added Cs2CO3 (0.015 mol), and the reaction mixture was refluxed overnight. After removal of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with 1 N aqueous NaOH solution, water, and brine, and then dried sodium sulfate. Concentration gave the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.21˜7.25 (m, 2H), 6.98 (t, J=7.2 Hz 1H), 6.83˜6.86 (m, 2H), 4.23 (q, J=7.2 Hz 4H), 1.60 (s, 6H), 1.24 (t, J=7.2 Hz 3H); LCMS (ESI+) m/z 209 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4c(F)cccc4OC)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12g and 4-bromoanisole
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:17])=[CH:4][CH:3]=1.Cl[C:19]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:29][Si:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][O:25][CH2:24][N:23]1[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=[C:19]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(O)cc1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Oc2ccc(-n3c(=O)[nH]c4cccnc43)cc2)nc2ccccc21
Temperature: 25 °C
Yield: 72.6 %

Procedure:
3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (370 mg), 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (507 mg) and cesium carbonate (1.17 g) in DMF (10 mL) was heated at 100° C. for 4 h. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=1/1 to 0/1) to give 3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (560 mg) as white crystals.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:21]3[CH:26]=[CH:25][C:24](CCC(OCC)=O)=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-:36].[Na+]>C1COCC1.CO>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([CH:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([CH:13]([CH3:12])[C:15]([OH:20])=[O:36])=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CCCCC(Oc1ccc(CCC(=O)OCC)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(C(C)C(=O)O)cc1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
To a stirred solution of ethyl 3-{4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}propanoate (92 mg, 0.19 mmol) in THF (3 mL) and methanol (3 mL) was added, drop-wise, aqueous NaOH (2M, 3 mL). After 17 hours the mixture was concentrated under vacuum and the solid residue acidified with aqueous HCl (2M, 3.5 mL), diluted with water (10 mL) and extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated under vacuum. The acid was loaded onto a PE-AX isolute SPE cartridge (pre-conditioned with 1 column volume of methanol) in 9 mL of methanol and a few drops of Et3N. The cartridge was washed with 3 column volumes of methanol followed by 10% aqueous HCl (2M) in methanol (2×5 mL) and 20% aqueous HCl (2M) in methanol (2×5 mL), yielding the title compound (38 mg).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[NH4+].[Cl-]>C(Cl)(Cl)Cl>[C:32]1([C:31]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)=[O:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (90 mg, 0.276 mmol) (Example 11b) in chloroform (2 mL) was added triethylamine (0.115 mL, 0.827 mmol) followed by benzoyl chloride (0.053 mL, 0.414 mmol). The reaction mixture was stirred at room temperature for 1 hr. A saturated solution of NH4Cl was added, and layers were separated. The organic layer was evaporated and the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixture was stirred for 1 hour at the room temperature and then it was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. Phenyl(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methanone (45 mg, 0.128 mmol, 46.3% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.44-7.50 (m, 3H), 7.36-7.43 (m, 2H), 7.20-7.28 (m, 2H), 7.10-7.17 (m, 1H), 7.03-7.09 (m, 2H), 4.66 (d, J=12.88 Hz, 1H), 3.74 (d, J=12.63 Hz, 1H), 3.03-3.22 (m, 1H), 2.87 (t, J=12.51 Hz, 1H), 2.66 (dd, J=3.03, 6.32 Hz, 2H), 2.22-2.37 (m, 1H), 1.80-2.05 (m, 3H), 1.74 (d, J=13.14 Hz, 1H), 1.12-1.40 (m, 2H), 1.09 (dt, J=4.86, 9.47 Hz, 1H), 0.98-1.05 (m, 1H); LC-MS Rt=0.81 min; MS (ESI): 335.3 [M++H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.[CH3:19][N:20]([CH3:26])[C@@H:21]1[CH2:25][CH2:24][NH:23][CH2:22]1.CCN(CC)CC>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:23]3[CH2:24][CH2:25][C@@H:21]([N:20]([CH3:26])[CH3:19])[CH2:22]3)=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CN(C)[C@@H]1CCNC1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 43.3 %

Procedure:
This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.214 g, 1.0 mmole) by treatment with thionyl chloride followed by reaction of the resultant acyl chloride with (3R)-N,N-dimethylpyrrolidin-3-amine (0.114 g, 1.0 mmole) and Et3N (0.139 ml, 1.0 mmole), in a manner as previously described for example 9d to give a brown solid (0.134 g, 43%). 1H NMR (300 MHz, CD3OD) δ7.24 (1H, d, J=5.1 Hz), 6.57 (1H, d, J=8.48 Hz), 6.15 (1H, d, J=5.1 Hz), 2.70 (1H, m), 2.51 (2H, m), 2.24 (1H, m), 2.04 (1H, m), 1.49 (1H, m), 0.93 (3H, s), 0.90 (3H, s), 0.52 (1H, m); ESIMS (MH+): 310.10.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6]O.N1C=CC=CC=1.P(Br)(Br)[Br:17]>C(OCC)C>[Br:17][CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: BrP(Br)Br
Reactant: C[Si](C)(C)C#CCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: C[Si](C)(C)C#CCCBr
Yield: 117 %

Procedure:
4-Trimethylsilyl-3-butyne-1-ol (14.2 g, 0.1 mol) and 0.2 ml of pyridine were dissolved in 50 ml of diethyl ether under a nitrogen atmosphere. Phosphorus tribromide (3.8 ml, 0.04 mol) was slowly added and the mixture was heated under reflux for 2 hours. Isolation of the product by conventional means yielded 9.6 g of 4-bromo-1-trimethylsilyl-1-butyne as a clear liquid, bp 35°-38° C. at 1 mm Hg.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]([C:17]2[CH:18]=[N:19][C:20]([NH:23]C(=O)OC(C)(C)C)=[N:21][CH:22]=2)[N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([N:36]1[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]1)[N:12]2[CH2:31][C:32]([F:35])([F:34])[F:33].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]([C:17]2[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)[N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([N:36]1[CH2:37][CH2:38][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:40][CH2:41]1)[N:12]2[CH2:31][C:32]([F:34])([F:33])[F:35]
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(NC(=O)OC(C)(C)C)nc2)nc2c1nc(N1CCN(S(C)(=O)=O)CC1)n2CC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)nc2c1nc(N1CCN(S(C)(=O)=O)CC1)n2CC(F)(F)F
Yield: 83.8 %

Procedure:
A methylene chloride (5 ml) solution of tert-butyl (5-{6-[(3S)-3-methylmorpholin-4-yl]-8-[4-(methylsulfonyl)piperazin-1-yl]-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-yl)carbamate (199 mg, 0.30 mmol) and trifluoroacetic acid (1 ml) was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the residue and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=96:4) to give a solid. The resulting solid was washed with ether-hexane and dried to give the title compound (140 mg, 83%) as a powder.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[H-].[Na+].[CH2:42]([O:49][C:50](Cl)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CC(O)=O>CN(C=O)C>[F:39][C:2]([F:1])([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]([CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]=3[C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C:50]([O:49][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:51])(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1c(CNS(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1c(CN(C(=O)OCc2ccccc2)S(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A solution of Example 9E (1.255 g, 2.25 mmol) in DMF (20 mL) under N2 at 0° C. was treated with NaH (60% dispersion in mineral oil, 180 mg, 4.50 mmol) and allowed to stirr for 30 minutes. Benzylchloroformate (0.68 mL, 4.50 mmol) was added, the mixture was allowed to stir for 2 hours, and HOAc was added. The solvent was removed and the residue was dissolved in ethyl acetate (100 mL), washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. Purification over silica gel with 30% hexanes/CH2Cl2 provided 1.19 g (77%) of the desired compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[S:17][CH:18]=[CH:19][C:20]=2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:6]1[CH3:31].O1CCCC1.[OH-].[Na+].Cl>CO>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]([CH3:31])=[C:7]2[CH2:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[S:21]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)(=[O:23])=[O:22]
Reactant: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2sccc2S(=O)(=O)c2ccc(F)cc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 40 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of {5-fluoro-3-[3-(4-fluorobenzenesulfonyl)thiophen-2-ylmethyl]-2-methylindol-1-yl}acetic acid methyl ester (0.17 g), tetrahydrofuran (2.0 mL) and methanol (1.0 mL) was treated with 5.0 M aqueous sodium hydroxide solution (1.5 mL), and the resulting mixture was stirred at 40° C. overnight. The mixture was acidified by the addition of 5.0 M aqueous hydrochloric acid solution and concentrated to low bulk under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to afford the title compound as a cream solid (0.11 g).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:36][CH:35]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Yield: 42 %

Procedure:
To a solution of 6-(((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 5) (1.67 g, 3.86 mmol), ethyl 2-(4-bromophenyl)acetate (1.127 g, 4.64 mmol) and potassium carbonate (1.602 g, 11.59 mmol) in toluene (10 mL) and ethanol (10.0 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.446 g, 0.386 mmol) under nitrogen. The reaction mixture heated at 100° C. for 1 h, then partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (25 g), eluting with an EtOAc/cyclohexane gradient (10 to 80%). The appropriate fractions were combined and concentrated in vacuo to give ethyl 2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)acetate (752 mg, 42%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=1.10 min, MH+=469.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:19][C:20]([NH2:22])=[S:21]>C(O)C>[NH2:22][C:20]1[S:21][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[N:19]=1
Reactant: CCOC(=O)C(Br)C(=O)c1cc(Cl)ccc1OC
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1cc(Cl)ccc1OC
Temperature: 25 °C
Yield: 31.5 %

Procedure:
A mixture of ethyl 2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (assumed to be 13.2 mmol) and thiourea (1.01 g, 13.3 mmol) in ethanol (25 mL) were heated to reflux for 3 hours, then cooled to room temperature for 18 hours. The resultant solid was removed by filtration and the filtrate evaporated under vacuum. DCM was added to the residue, the organics washed with sodium hydrogen carbonate (sat. aq.), water and brine, and evaporated to dryness. The residue was triturated (DCM) to give 1.30 g (31%) of ethyl 2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate as a yellow solid. LCMS (ESI) m+H=313.2. 1H NMR (400 MHz, DMSO-d6): δ 7.77 (s, br, 2H); 7.39 (dd, 1H); 7.22 (d, 1H); 7.05 (d, 1H); 4.00 (q, 2H); 3.70 (s, 3H); 1.04 (t, 3H).