Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=1>>[CH3:13][C:12]1[C:7]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:33])([F:34])[F:23])[CH:27]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccc(OC(F)(F)F)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [3-(trifluoromethoxy)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.35 (s, 3H), 4.73 (d, J=5.6 Hz, 2H), 6.08 (bs, 1H), 6.48 (bs, 1H), 6.88 (d, J=7.3 Hz, 1H), 7.16 (t, J=7.3 Hz, 1H), 7.22-7.34 (m, 3H), 7.62 (t, J=9.4 Hz, 1H), 7.75 (s, 1H), 8.57 (d, J=3.2 Hz, 1H); MS (ESI) m/z 390.7 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.[C@@H:20]1([NH2:30])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>>[C@@H:20]1([NH:30][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:5]3[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=3)[CH:8]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=Cc1cccc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: FC(F)(F)c1cccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)c1

Procedure:
3-[3-(Trifluoromethyl)phenoxy]benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[H-].[Na+].Cl[S:22]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>CN(C=O)C.CCOC(C)=O>[C:14]([O:13][C:12]([N:11]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[CH3:1])[S:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1)(=[O:24])=[O:23])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(NC(=O)OC(C)(C)C)nc2ccccn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccccn3c2C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a solution of compound 1-E (0.174 g, 0.703 mmol) in DMF (5 mL), cooled to 0° C., was added 60% NaH (0.028 g, 0.703 mmol) and the reaction mixture was stirred at 0° C. for 20 min. Methyl 4-(chlorosulfonyl)benzoate (0.247 g, 1.06 mmol) was added in one-portion and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with EtOAc, washed with H2O (2×), brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a crude solid. The crude material was purified by flash column chromatography (SiO2) eluting with a heptanes-EtOAc gradient to afford compound 1-F as a white solid (0.188 g, 60%). 1H-NMR (CDCl3): δ 8.22-8.35 (dd, 2H), 7.90-7.92 (d, 1H), 7.61-7.64 (d, 1H), 7.22-7.24 (m, 1H), 6.90-6.93 (m, 1H), 3.98 (s, 3H), 2.55 (s, 3H), 1.32 (s, 9H); MS: m/z 446.1 (MH+).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:25]3[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:24]=3[N:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClCCl>CN(C)C=O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[C:25]3[CH:33]=[CH:34][C:35]([C:37]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:38])=[CH:36][C:24]=3[N:23]=2)=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Yield: 57.5 %

Procedure:
Methanesulfonamide (0.0188 g, 0.198 mmol), sodium hydride, and the acid chloride of 49 (0.0083 g, 0.019 mmol) were reacted in dimethylformamide and dichloromethane according to the procedure described for example 8. The crude material was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a white solid (0.0055 g, 52%). 1H NMR (CDCl3) δ 8.68 (s, 1H), 8.17 (d, 1H, J=8.8 Hz), 7.91 (d, 1H, J=8.8 Hz), 7.69 (d, 2H, J=8.5 Hz), 7.48-7.37 (m, 5H), 7.24 (d, 2H, J=8.7 Hz), 5.18 (s, 2H), 4.57 (m, 1H), 3.34 (s, 3H), 2.34 (br m, 2H), 2.06 (br m, 4H), 1.85 (br m, 1H), 1.39 (br m, 3H); ESI-MS m/e 504.3 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.Cl.[CH3:15]O>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:15])=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2cc(C(=O)O)ccc12
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2c(C)n[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-methyl-indazole-6-carboxylic acid (1.57 g, Reference Example 45) in methanol (75 ml) was treated with hydrogen chloride gas for 10 minutes. The reaction mixture was stirred for 12 hours at room temperature then evaporated. The residue was partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was washed with hexane to give the title compound (1.56 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].[CH3:20][O-:21].[Na+].Cl>CN(C=O)C>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([O:21][CH3:20])=[C:3]([OH:19])[CH:4]=[CH:5]3)=[CH:13][CH:14]=1
Reactant: Oc1ccc(-c2ccc3c(Br)c(O)ccc3c2)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(O)ccc2cc(-c3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 1-bromo-6-(4-hydroxyphenyl)-2-naphthol (0.41 g, 1.30 mmoles), CuBr (0.19 g, 0.13 mmoles), sodium methoxide (3 ml of 4.4 N in methanol), and DMF (6 ml) was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into HCl (50 ml of 1 N aqueous solution), and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate, filtered, stripped of solvent, and purified by silica column chromatgraphy (40% ethyl acetate—hexanes) to yield 0.31 g (89%) of the title compound as a white solid: mp 204-206° C.; 1H NMR (DMSO-d6): δ 6.88 (2H, d, J=8.47 Hz), 7.19 (1H, d, J=8.81 Hz), 7.57-7.60 (3H, m), 7.71 (1H, dd, J=1.41 Hz, J=8.78 Hz), 7.94-7.98 (2H, m), 9.54 (2H, s); MS m/z (M−H)— =265;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:16]([CH:13]([CH3:15])[CH3:14])[CH2:11]2
Reactant: CC(C)N
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Product: CC(C)N1Cc2cc(Br)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate (AstaTech Cat. No. 27012) and isopropylamine (Aldrich Cat No. 471291). LCMS (M+H)+=254.0/256.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: COc1cc2ncn(-c3nc(-c4ccc(F)c(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 18.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-chloro-4-fluorophenylboronic acid (26.2 mg, 0.15 mmol) gave 4-(3-Chloro-4-fluoro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (8.2 mg, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.79 (br.s., 1H); 8.84 (s, 1 H,); 8.22 (dd, 1 H); 8.01 (ddd, 1 H); 7.81 (s, 1 H); 7.57 (t, 1H); 7.39 (s, 1 H); 3.87 (s, 3 H); 3.85 (s, 3 H). MS m/z 434 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:15][C:16]1[N:21]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:19]=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 80 °C
Yield: 80.7 %

Procedure:
To tert-butyl 4-hydroxypiperidine-1-carboxylate (389 mg, 1.933 mmol) and 2,4-dichloropyrimidine (240 mg, 1.611 mmol) in N,N-dimethylformamide (6.4 mL) was added cesium carbonate (1050 mg, 3.22 mmol) and the mixture was heated at 80° C. for 1 hour and then to 70° C. overnight. The reaction was then cooled to ambient temperature, diluted with ethyl acetate, and washed with water (3×) and brine (1×). The organic layer was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% ethyl acetate/hexanes) to provide 410 mg (1.3 mmol, 81%) of tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate as white solid. MS APCI: [M+H]+ m/z 314.2.
Reaction SMILES: [S:1]1[C:5]([CH:6](O)[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=2)=[CH:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][O:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[O:15][CH3:16])[CH2:6][C:5]1[S:1][C:2]2[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=2[CH:4]=1
Reactant: COc1cc(C(O)c2cc3ccccc3s2)cc(OC)c1OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cc2cc3ccccc3s2)cc(OC)c1OC

Procedure:
2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene was prepared in the same manner as described in Example 47B. Reaction of a-(2-benzo[b]-thienyl)-3,4,5-trimethoxybenzyl alcohol (4.5 mmoles, 1.5 g), triethylsilane (5.0 mmoles, 0.80 mls), CH2Cl2 (50 ml) and TFA (9.1 mmoles, 0.70 mls) yielded, after flash chromatography using 20% ethyl acetate/hexanes, 0.77 g (54%) of a white solid.
Reaction SMILES: C(S)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21]C)[C:17](=[O:23])[CH2:16][CH2:15][CH2:14]2)([CH3:10])[CH3:9]>ClCCl>[OH:21][C:20]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][CH2:16][C:17]2=[O:23])=[CH:12][C:11]=1[CH:8]([CH3:10])[CH3:9]
Reactant: COc1cc2c(cc1C(C)C)CCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CC(C)c1cc2c(cc1O)C(=O)CCC2
Reaction time: 0.08 h
Yield: 59.4 %

Procedure:
20 ml of ethanethiol was added to 100 ml of a suspension of 28 g of aluminium chloride in dichloromethane cooled with ice. The obtained mixture was stirred for 5 minutes, followed by the slowly, dropwise addition thereto of 50 ml of a solution of 15.3 g of 6-isopropyl-7-methoxy-1-tetralone in dichloromethane. After the completion of the dropwise addition, the obtained mixture was stirred for 3 hours at room temperature and poured onto ice-water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt successively, dried over anhydrous magnesium sulfate, and distilled to remove the solvent. The obtained solid residue was washed with n-hexane to give 8.5 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]=[O:12])=[CH:5][N:4]=1.Cl([O-])=[O:14].[Na+].O.P([O-])(O)(O)=O.[Na+].O>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([OH:14])=[O:12])=[CH:5][N:4]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ncc(C=O)c(OC)n1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ncc(C(=O)O)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-Bis(methyloxy)-5-pyrimidinecarbaldehyde (commercially available from Toronto, 1.400 g, 8.33 mmol) at 0° C. in t-Butanol (14.00 mL) an aqueous solution (7 mL) of Sodium chlorite (1.807 g, 19.98 mmol) was added over 25 min and sodium dihydrogen phosphate hydrate (3.64 g, 23.33 mmol). The yellow mixture obtained was warmed to 25° C. and after 6 h 14 mL of t-Butanol, 7 mL of water, and Sodium chlorite (2.26 g, 25 mmol) were added. The reaction mixture was stirred at room temperature overnight. After 24 h, the mixture was evaporated in vacuo, and the crude material purified by SPE 25 g cartridge eluting with DCM/MeOH 8:2 to recover 1 g of title compound.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:20])C(=O)C1.C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[Br:20][C:6]1[O:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:8][C:7]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1coc(C2CC2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(C2CC2)oc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
Into a 5000-mL 3-necked round-bottom flask were placed methyl 2-cyclopropyloxazole-4-carboxylate (140 g, 838.32 mmol, 1.00 equiv.), NBS (224 g, 1.26 mol, 1.50 equiv.), CCl4 (1400 mL) and BPO (20 g, 82.64 mmol, 0.10 equiv). The resulting solution was stirred overnight at room temperature, then it was diluted with 2000 mL of EtOAc. The solid was filtrated out. The filtrate was dried over anhydrous calcium chloride and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50˜1:20). This resulted in 120 g (58% yield) of methyl 5-bromo-2-cyclopropyloxazole-4-carboxylate as a white solid.
Reaction SMILES: C(O[C:4](=[O:18])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[C:6](=[O:8])[CH3:7])C.[NH2:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH2:9][CH:5]([C:6](=[O:8])[CH3:7])[C:4]([NH:19][C:20]1[CH:21]=[C:22]([OH:27])[CH:23]=[CH:24][C:25]=1[F:26])=[O:18]
Reactant: Nc1cc(O)ccc1F
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1Cl)C(C)=O
Product: CC(=O)C(Cc1ccc(Cl)cc1Cl)C(=O)Nc1cc(O)ccc1F
Temperature: 120 °C

Procedure:
A mixture of 2-(2,4-dichlorobenzyl)-3-oxobutyric acid ethyl ester (4.6 g) and 3-amino-4-fluorophenol (1.0 g) was heated by microwave irradiation at 120° C. for 20 minutes. The mixture was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1:19 to 1:1 by volume) to afford title compound, 0.67 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[C:19]([F:21])[F:20])[N:13]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH:19]([F:21])[F:20])[N:13]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(-c2cccc(C=C(F)F)n2)ccc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cccc(CC(F)F)n2)ccc1Cl

Procedure:
To a solution of methyl 2-chloro-5-(6-(2,2-difluorovinyl)pyridin-2-yl)benzoate (Preparation 33, 105 mg, 0.34 mmol) in EtOAc (1 mL) was added 10% palladium on alumina (36 mg, 0.03 mmol) and stirred at room temperature under 15 psi of hydrogen for 2 hours. The reaction was filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-20% EtOAc in heptanes to afford the title compound.
Reaction SMILES: [Cl-].[Cl-].[Ca+2].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[Cl:15][C:16]([Cl:21])([Cl:20])[CH:17](O)O.OS(O)(=O)=O>>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12]([CH:17]([C:16]([Cl:21])([Cl:20])[Cl:15])[O:10][C:9]2=[O:11])=[CH:13][CH:14]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [Cl-]
Product: COc1ccc2c(c1)C(=O)OC2C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.7 %

Procedure:
A oven-dried 25 mL three neck round-bottomed flask containing a stirring bar was fitted with a drying tube (CaCl2) and was charged with m-methoxybenzoic acid (5.04 g, 17.91 mmol) followed by chloral hydrate (2.96 g, 17.91 mmol). Concentrated H2SO4 (12.0 mL) was added and the reaction mixture was left stirring at room temperature for 24 h. It was then poured onto ice, a thick precipitate formed and the mixture was left stirring vigorously until the ice was dissolved. The precipitate was filtered, washed with water and dried. The solid was recrystallised from ethanol, the crystals were then filtered and dried to yield 6-methoxy-3-(trichloromethyl)isobenzofuran-1(3H)-one as off-white needles (3.16 g, 63%). Spectral data for this compound were consistent with those in the literature. M.p. 134-136° C. (lit. m.p. 136-137° C.); 1H NMR (400 MHz, DMSO-d6): δ=7.88 (d, J=8.3 Hz, 1H), 7.49-7.39 (m, 2H), 6.54 (s, 1H), 3.90 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH:5]1C#N)(=O)[CH3:2].F[B-](F)(F)F.[H+].[C:21]([C:27]([O:29][CH3:30])=[O:28])#[C:22][C:23]([O:25][CH3:26])=[O:24]>ClCCl.CN(C=O)C>[CH3:2][C:1]1[N:4]2[C:5]([S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=32)=[C:22]([C:23]([O:25][CH3:26])=[O:24])[C:21]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: CC(=O)N1c2ccccc2SC1C#N
Reactant: COC(=O)C#CC(=O)OC
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)OC)c2sc3ccccc3n2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-acetyl-2,3-dihydrobenzo[d]thiazole-2-carbonitrile (5 g, 24.5 mmol) in dichloromethane (50 mL) was added dropwise 7 mL of tetrafluoroboric acid (HBF4). The solution was stirred for 3 h at room temperature. The brown precipitates appeared were collected by filtration and the filter cake was washed with ether. The solid salt was added to a solution of dimethyl acetylenedicarboxylate (10.4 g, 73.0 mmol) in DMF (30 mL) and then warmed at 35° C. for 13 h. The reaction mixture was concentrated in vacuo and the residue was recrystallized from methanol to give dimethyl 1-methylbenzo[d]pyrrolo[2,1-b]thiazole-2,3-dicarboxylate, 1.7 g (23%); mp 143-144° C. 1H NMR (DMSO-d6) δ 2.85 (3H, s, Me), 3.83 (3H, s, COOMe), 3.85 (3H, s, COOMe), 7.50 (1H, t, J=7.6 Hz, ArH), 7.58 (1H, t, J=7.6 Hz, ArH), 8.07 (1H, d, J=8.0 Hz, ArH), 8.12 (1H, d, J=8.0 Hz, ArH). Anal. Calcd. for (C15H13NO4S): C, 59.39; H, 4.32; N, 4.62; S, 10.57. Found: C, 59.02; H, 4.23; N, 4.87; S, 10.42.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:52]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and benzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]=[C:18]=S)=[C:6]([CH:16]=1)[CH2:7][O:8][Si](C(C)(C)C)(C)C.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH:26]([NH2:30])[CH2:25][CH2:24]2>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]=[C:18]([NH:30][CH:26]3[C:27]4[C:23](=[CH:22][C:21]([F:20])=[CH:29][CH:28]=4)[CH2:24][CH2:25]3)[O:8][CH2:7][C:6]=2[CH:16]=1
Reactant: NC1CCc2cc(F)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1N=C=S
Product: Fc1ccc2c(c1)CCC2NC1=Nc2ccc(Br)cc2CO1
Yield: 68.5 %

Procedure:
Prepared from (5-bromo-2-isothiocyanato-benzyloxy)-tert-butyl-dimethyl-silane (Example 32, step B) (4.0 g, 11.2 mmol) and rac-5-fluoro-indan-1-ylamine (CAS 148960-33-2) (1.69 mg, 11.2 mmol) according to the procedure described for Example 1. Obtained the title compound as a light brown oil (2.77 g, 69%), MS (ISP) m/e=361.1 [(M+H)+].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH3:15][OH:16]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([O:16][CH3:15])=[O:12])=[CH:2]1
Reactant: CO
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Product: COC(=O)C(=O)c1c[nH]c2ccccc12

Procedure:
reacting the 3-indoleglyoxalyl chloride with methanol to give methyl 3-indoleglyoxylate, and
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[C:31]([C:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>[Cu]I.CN(C=O)C>[NH2:39][C:33]1([C:31]#[C:32][C:2]2[N:3]([CH3:23])[C:4]([C:13]3[S:14][C:15]4[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=4[N:21]=3)=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Reactant: C#CC1(N)CCCCC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C#CC2(N)CCCCC2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 90 °C
Yield: 41 %

Procedure:
A mixture of 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (0.02 g), PdCl2dppf (3.5 mg), triethylamine (0.1 mL), DMF (5 mL), copper(I) iodide (1 mg) and 1-ethynylcyclohexylamine (0.034 mL) was heated at 90° C., under an inert atmosphere, for 1.5 hours. The solvent was evaporated in vacuo then purification by flash chromatography on silica eluting with DCM:MeOH (9:1) gave the title compound as a beige solid (9 mg, 41%).