Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:40]([O:41][CH3:42])=[O:43])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:28])([CH3:29])[NH:14]2
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.0 mg, 0.058 mmol) was dissolved in tetrahydrofuran (0.5 mL), triethylamine (23 μL, 0.17 mmol) and methyl chlorocarbonate (6.8 μL, 0.088 mmol) were added thereto, and then the mixture was stirred at room temperature for 20 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.0 mg) as a colorless amorphous product. (Yield 99%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:24]1([S:34](Cl)(=[O:36])=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[S:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)(=[O:36])=[O:35])[CH2:4][CH2:3]1
Reactant: CC1CCN(CC[C@H]2CCCN2)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CCN(CC[C@H]2CCCN2S(=O)(=O)c2cccc3ccccc23)CC1
Reaction time: 12 h

Procedure:
To a solution of (R)-2-[2-(4-Methyl-piperidin-1-yl)ethyl]pyrrolidine (D6) 1 mmol and -diisopropylethylamine (1 mmol) in dichloromethane (10 mL) at 0° C. was added 1-naphthalene sulfonyl chloride. Stirring was continued at room temp. for 12 hours. The solution was washed with 10% aqueous NaOH and brine, dried and concentrated. The residue was purified by chromatography on silica gel to afford the title compound (MH30 387).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:21][S:18]([C:15]1[N:16]=[CH:17][C:12]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccc(Br)cn1
Reactant: OB(O)c1ccc(O)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: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cn1
Yield: 78.8 %

Procedure:
4-[6-(Methylsulfonyl)-3-pyridinyl]phenol was prepared as a brown solid from (4-hydroxyphenyl)boronic acid (0.34 g, 2.40 mmol), 5-bromo-2-(methylsulfonyl)pyridine (0.54 g, 2.29 mmol), 2M Na2CO3 (15 mL) and Pd(PPh3)4 (25 mg, 0.02 mmol) in DME (5 mL) in a manner similar to Example 1, Step 1. The crude product was triturated with 1:1 CH2Cl2/hexane to give 0.45 g (79%) of 4-[6-(methylsulfonyl)-3-pyridinyl]phenol as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 9.88 (s, 1H), 9.01 (d, 1H, J=2.2 Hz), 8.30 (dd, 1H, Ja=8.3 Hz, Jb=2.2 Hz), 8.02 (d, 1H, J=8.3 Hz), 7.66 (d, 2H, J=8.8 Hz), 6.90 (d, 2H, J=8.5 Hz), 3.27 (s, 3H); LRMS (APCI), m/z 250 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:25][N:26]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)[S:27]([CH2:30][C:31](O)=[O:32])(=[O:29])=[O:28].C(N(C(C)C)C(C)C)C.Cl.NO>CN(C)C=O>[OH:17][NH:8][C:31](=[O:32])[CH2:30][S:27]([N:26]([CH3:25])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:42]=[CH:43][C:44]([C:47]#[N:48])=[CH:45][CH:46]=2)=[CH:37][CH:36]=1)(=[O:28])=[O:29]
Reactant: CN(Cc1ccc(-c2ccc(C#N)cc2)cc1)S(=O)(=O)CC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(-c2ccc(C#N)cc2)cc1)S(=O)(=O)CC(=O)NO
Reaction time: 16 h
Yield: 8.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU 263 mg, 0.72 mmol) was added to a solution of 2-({methyl[(4'-cyanobiphenyl-4-yl)methyl]amino}sulfonyl)acetic acid (185 mg, 0.48 mmol) and N-ethyl-N,N-diisopropylamine (0.08 ml, 0.48 mmol) in anhydrous dimethylformamide (3 ml) at ambient temperature under an atmosphere of nitrogen. After stirring for 20 minutes a solution of hydroxylamine hydrochloride (131 mg, 1.92 mmol) and N-ethyl-NN-diisopropylamine (0.33 ml, 1.92 mmol) in anhydrous dimethylformamide (1 ml) was added and the solution was stirred for a further 16 hours. The mixture was partitioned between aqueous phosphate buffer (at pH 7) and ethyl acetate. The organic layer was washed with water, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonia 90:10:1 as eluent) to give the title compound as a colourless solid (14 mg).
Reaction SMILES: [CH:1]1([N:7]([CH3:24])[C:8]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:15]([NH2:17])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>N1C=CC=CC=1>[CH:1]1([N:7]([CH3:24])[C:8]([C:10]2[CH:23]=[CH:22][C:13]3[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:30]([C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)=[O:31])[C:15]([NH:17][C:30]([C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)=[O:31])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)c1cccs1
Reactant: CN(C(=O)c1ccc2c(c1)nc(N)n2CCCO)C1CCCCC1
Solvent: c1ccncc1
Product: CN(C(=O)c1ccc2c(c1)nc(NC(=O)c1cccs1)n2CCCOC(=O)c1cccs1)C1CCCCC1
Reaction time: 6 h
Yield: 43.2 %

Procedure:
To a stirred solution of the above amino benzimidazole (0.7 g, 2.1 mmol) in pyridine (10 mL) was added 2-thiophenecarbonyl chloride (0.68 mL, 6.4 mmol). The reaction was complete in 6 h. The pyridine was evaporated and the resulting orange solid was purified by flash chromatography with 1% MeOH/dichloromethane to give thiophene-2-carboxylic acid 3-{5-(cyclohexyl-methyl-carbamoyl)-2-[(thiophene-2-carbonyl)-amino]-benzoimidazol-1-yl}-propyl ester (0.50 g, 43%), m.p. 92-94° C.
Reaction SMILES: Br[C:2]([F:19])([F:18])[S:3]([C:6]1[N:10]=[CH:9][N:8]([C:11](=[O:17])[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=1)(=[O:5])=[O:4].[CH2:20](SC1SCCN=1)[CH:21]=[CH2:22].P([O-])([O-])(O)=O.[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[CH2:13]([N:12]([CH2:15][CH3:16])[C:11]([N:8]1[CH:9]=[N:10][C:6]([S:3]([C:2]([F:19])([F:18])[CH2:22][CH:21]=[CH2:20])(=[O:5])=[O:4])=[N:7]1)=[O:17])[CH3:14]
Reactant: CCN(CC)C(=O)n1cnc(S(=O)(=O)C(F)(F)Br)n1
Reactant: C=CCSC1=NCCS1
Agent: O=P([O-])([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(F)(F)S(=O)(=O)c1ncn(C(=O)N(CC)CC)n1
Reaction time: 2 h
Yield: 28.7 %

Procedure:
To a stirred solution of 10 g (0.028 mol) 3-(bromodifluoromethylsulfonyl)-1-(N,N-diethylcarbamoyl)-1,2,4-triazole, prepared as in Example 1, and 8.81 g (0.055 mol) 2-(2-propenylthio)-2-thiazoline in a mixture of 30 ml dimethylformamide and 20 ml water at 0° C., was added 5.9 g (0.042 mol) sodium hydrogen phosphate and 7.23 g (0.042 mol) sodium dithionite. After 2 h, the reaction mixture was diluted with 100 ml water and extracted with ethyl acetate (3×100 ml). The combined resulting organic layers were washed with saturated sodium chloride solution, dried over MgSO4 and evaporated. Preparative LC purification of the residue with 40% ethyl acetate-hexane gave 2.59 g (29% yield) of the desired product as a colorless oil having n D 25 = 1.4896 .
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][S:10](Cl)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][S:10]([O:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(Cl)C=Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(C=Cc1ccc(F)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
163 g of 2-(4-fluorophenyl)ethenesulfonyl chloride were dissolved in 1.5 l of toluene and, at RT, 69.64 g of phenol were added. Subsequently, at RT, 103 ml of triethylamine were added dropwise, during which the temperature rose to 44° C. The mixture was then stirred at RT for 90 minutes, left to stand for 16 hours and stirred at RT for a further 2 hours. The solvent was then removed in vacuo, and the crude product was taken up in 2.5 l of EA. Washing 3 times with 750 ml of a saturated aqueous NaHCO3 solution was followed by washing 3 times with 750 ml of 2 N aqueous HCl solution each time. After drying over Na2SO4, the solvent was removed in vacuo. The product was then stirred in 350 ml of HEP for 1 hour and, on cooling, the product crystallized and was washed with HEP and dried under medium vacuum. 145.0 g of white crystals were obtained, mp 108° C.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:7][N:8]=1.[CH2:17]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:17]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:7][N:8]=2)=[O:33])=[CH:35][CH:36]=1)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20]
Reactant: Nc1nnc(SCc2ccccn2)s1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2nnc(SCc3ccccn3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
Sodium hydride (0.3 g) and 2-amino-5-(2-pyridylmethyl) thio-1,3,4-thiadiazole (1.3 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.5 g) and carbonyldiimidazole (1.0 ) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.9 g of the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:5]2=[O:20].CC(O)=O.[I:26][C:27]1[C:32]([CH:33]=O)=[C:31]([O:35][CH3:36])[N:30]=[CH:29][CH:28]=1>CO>[I:26][C:27]1[CH:28]=[CH:29][N:30]=[C:31]([O:35][CH3:36])[C:32]=1[C:33]1[NH:11][C:10]2[C:2]([N:1]=1)=[C:3]([CH3:21])[C:4]1[C:5](=[O:20])[N:6]([CH:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[C:7](=[O:12])[C:8]=1[CH:9]=2
Reactant: COc1nccc(I)c1C=O
Reactant: Cc1c(N)c(N)cc2c1C(=O)N(C1CCN(C)CC1)C2=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1nccc(I)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Temperature: 60 °C
Yield: 47.2 %

Procedure:
To a solution of 5,6-Diamino-4-methyl-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione (1.7 g, 5.90 mmol) in MeOH (50 mL) were added AcOH (3 mL) and 4-iodo-2-methoxynicotinaldehyde (1.55 g, 5.90 mmol) and the resulting mixture was heated at 60° C. for overnight. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography (5-10% (6% NH3 in MeOH)/CHCl3) to afford 2-(4-Iodo-2-methoxy-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (1.48 g, 47%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[NH:10][C:9](=[O:18])[N:8]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:7]2=[O:24])([O-])=O>[Pd].CCO.CC(O)=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:16])([F:15])[F:17])[NH:10][C:9](=[O:18])[N:8]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:7]2=[O:24]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc2c1=O
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Yield: 60.9 %

Procedure:
A solution of N-(6-nitro-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (109 mg) in 1:1 EtOH:CH3CO2H (6 mL) was hydrogenated in the presence of 10% palladium on carbon (30 mg). After disappearance of the starting material (TLC control), the reaction mixture was diluted with EtOH and CH3CO2H and slightly warmed up. The catalyst was filtered off and the filtrate concentrated to dryness. Trituration of the residue with EtOAc gave N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (61 mg, 61%) as a yellow powder, m.p. 240° C. (decomp.). 1H-NMR (DMSO-d6, 400 MHz): 3.12 (s, 3H), 5.66 (s, 2H), 7.24 (s, 1H), 7.46 (s, 1H), 10.3 (br s, 1H), 11.4 (br s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[CH:7]=[CH:6][C:5]=1/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(O)cc1C(C)=O
Temperature: 15 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl (2E)-3-[2-acetyl-4-(benzyloxy)phenyl]prop-2-enoate (1.09 g, 3.36 mmol, 1.00 equiv), ethyl acetate (30 mL), Palladium on carbon (700 mg), hydrogen was introduced last. The resulting solution was stirred overnight at 15° C. in an oil bath. The reaction progress was monitored by LCMS. The solids were removed by filtration and washed with EA. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the resulting mixture was concentrated under reduced pressure to give 0.8 g (96%) of ethyl 3-(2-acetyl-4-hydroxyphenyl)propanoate as a light yellow solid. Mass spectrum (ESI, m/z): Calcd. for C13H16O4, 235.1 (M−H). found 235.1.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].[O:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1>>[O:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:3]([C:5]2[S:9][C:8]([CH2:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])=[N:7][CH:6]=2)=[O:4])[CH2:23]1
Reactant: CCCCc1noc(C)c1CCc1ncc(C(=O)OC)s1
Reactant: NC1CCOC1
Product: CCCCc1noc(C)c1CCc1ncc(C(=O)NC2CCOC2)s1
Yield: 71 %

Procedure:
As described for example 57b, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.29 mmol) was converted, using tetrahydrofuran-3-amine instead of isopropylamine, to the title compound (45 mg, 71%) which was obtained as a light yellow oil. MS: m/e=364.3 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:8])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:9]([CH2:13][CH2:14][C:15](Cl)=[O:16])([O:11][CH3:12])=[O:10].C(N(CC)CC)C>ClCCl>[C:1]([NH:4][C:5](=[O:8])[CH2:6][S:7][C:15](=[O:16])[CH2:14][CH2:13][C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(=O)NC(=O)CS
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)SCC(=O)NC(C)=O
Reaction time: 1 h

Procedure:
The concentrated product of Step A. above was added to 100 ml. of dichloromethane and cooled to -5° C. under nitrogen. There was then added 8.3 g. (0.055 mole) of 3-carbomethoxypropionyl chloride in 20 ml. of dichloromethane, over from 5 to 10 minutes. Next, there was added 5.57 g. (0.055 mole) of triethylamine in 20 ml. of dichloromethance and the reaction mixture was aged for 1 hour at -5° C., then permitted to come to room temperature over 2 hours. The reaction mixture was then concentrated under vacuum after having been made slightly acidic with acetic acid. Ice water was then added to the reaction mixture, and the water was extracted with dichloromethane dried over magnesium sulfate and concentrated to an oil of 15.4 g. The oil was changed to a silica gel column and eluted with 25% ethylacetate/hexane to obtain 2.3 g. of final product having an m.p. of 111°-113° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[C:9]([O:11]C)=[O:10])=O.C(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:9]([OH:11])=[O:10])[CH3:2]
Reactant: COC(=O)c1cc(NC(=O)C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methyl 3-amino-5-(trifluoromethyl)benzoate (cf. procedures (116a) and (80a); 177 mg, 0.81 mmol) was dissolved in MeOH (12 mL) and the resulting solution was charged successively with acetaldehyde (0.045 mL, 0.81 mmol) and sodium cyanoborohydride (64 mg, 1.01 mmol). The reaction was stirred at RT for 12 h, concentrated in vacuo, and diluted with EtOAc. The organic phase was washed with sat. NaHCO3, water (2×), and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. This product was dissolved in 3:1 THF/MeOH (12 mL) and the resultant solution was charged with lithium hydroxide (3 mL of a 1N solution). The reaction was stirred for 14 h, acidified with 1N HCl, and extracted with EtOAc (2×). The organic extracts were combined, washed with water, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide 3-ethylamino-5-(trifluoromethyl)benzoic acid.
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:15]1([C@@H:21]2CCC[C@H:22]2[NH2:26])[CH:20]=[CH:19][CH:18]=CC=1>>[ClH:1].[C:2]1([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:22]2[CH2:21][CH2:15][CH2:20][CH2:19][CH2:18][NH:26]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCC[C@H]1c1ccccc1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Product: c1ccc([C@@H]2CCC[C@H]2N=C2CCCCCN2)cc1

Procedure:
Following the procedure of Example 23, only substituting for cis-2-phenylcyclopentylamine hydrochloride the appropriate molar equivalent amount of trans-2-phenylcyclopentylamine hydrochloride, M.P. 147°-149° C, the desired product is obtained, M.P. 192°-195° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[OH:29][C:26]([CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:28])[CH3:27]
Reactant: CC(C)(O)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cccnc1
Product: CC(C)(O)C1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cccnc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 142.1) and pyridin-3-ylboronic acid to afford an off-white powder. HPLC (Condition 4) tR=4.61 min, UPLC-MS (Condition 7) m/z=473.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 6H) 3.24-3.34 (m, 1H) 3.59 (m, J=8.60 Hz, 4H) 4.36 (s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.49 (dd, J=7.82, 4.69 Hz, 1H) 7.84 (d, J=8.99 Hz, 3H) 8.00 (d, J=1.95 Hz, 1H) 8.53-8.62 (m, 1H) 8.65 (d, J=1.95 Hz, 1H) 8.74 (d, J=1.96 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]([C:15]1[C:20]([O:21][CH2:22][CH3:23])=[C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:18]=[C:17]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[N:16]=1)=[O:14])[CH3:11]>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13]([C:15]1[C:20]([O:21][CH2:22][CH3:23])=[C:19]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:18]=[C:17]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])=[CH:34][CH:35]=2)[N:16]=1)=[O:14])[CH3:11]
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc(N2CCOCC2)c1OCC
Yield: 83 %

Procedure:
Phenyl isocyanate (0.22 ml, 1.5 eq.) was added to a stirred solution of 2-(4-Amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (500 mg, 1 eq.) in toluene (25 ml) and the mixture was reacted for 4 h at 80° C. The reaction mixture was cooled, the solvent was removed in vacuo, and the residue was washed with EA and filtered to give a product (550 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18]C)=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[Cl:17].Cl.N1C=CC=CC=1.Cl>>[Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[Cl:17]
Reactant: COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
A mixture of 6.0 g of 6,7-dichloro-5-methoxy-2-phenylbenzo[b]thiophene and 42 g of pyridine hydrochloride is stirred at 190°-195° for 4 hours. The slightly cooled reaction mixture is poured into a mixture of 800 g of ice and 10 ml of conc.hydrochloric acid. Extraction with ether, followed by washing and drying, yields 5.23 g of 6,7-dichloro-5-hydroxy-2-phenylbenzo[b]thiophene as an off-white solid, mp 122°-124°. Recrystallization from ether-hexane yields prisms, mp 124°-126°.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1.[Br:9][C:10]1[CH:11]=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:19]2[CH2:18][CH2:17][N:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[CH:11]=3)[CH2:21][CH2:20]2)[N:4]=1
Reactant: Cc1nc(CCl)cs1
Reactant: Brc1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(CN2CCN(c3cccc(Br)c3)CC2)cs1

Procedure:
A mixture of 4-chloromethyl-2-methylthiazole (7.4g; 0.05 mole), 1-(3-bromophenyl)piperazine (12.05g; 0.05 mole) and anhydrous sodium carbonate (10g) was suspended in absolute ethanol (150 ml). The mixture was stirred and boiled under reflux for 8 hours. The solvent was then evaporated to dryness and water added (100 ml). The emulsion thus formed was extracted with dichloromethane, the organic extracts being dried over magnesium sulphate and evaporated to an oil. This was dissolved in hot benzene, treated with decolourising charcoal and filtered. The filtrate was evaporated to give the title compound as an oil which crystallised completely, m.p. 82° C. (ether).