Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
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: O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccccc2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (81 mg, 0.21 mmol), phenylboronic acid (34 mg, 0.28 mmol), tetrakis(triphenylphosphine)palladium(0)(25 mg, 0.02 mmol) and potassium carbonate (89 mg, 0.64 mmol) in dioxane (3 mL) and water (12 μL) was refluxed for 22 h before it was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (29 mg): 1H NMR (CDCl3, 200 MHz): δ=11.46 (s, 1H), 8.49 (m, 2H), 8.14 (m, 2H), 7.53 (m, 6H), 4.56 (q, J=7.0 Hz, 2H), 1.54 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:24]([O-])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH3:22])[CH2:8][CH2:7]2.C([O-])=O.[NH4+]>[Pd]>[Cl:1][C:2]1[C:3]([NH2:24])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH3:22])[CH2:8][CH2:7]2
Reactant: CCCc1ccccc1C(=O)NC1CCc2ccc([N+](=O)[O-])c(Cl)c2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCCc1ccccc1C(=O)NC1CCc2ccc(N)c(Cl)c2C1
Yield: 70.9 %

Procedure:
A mixture of 12 g (32 mmol) 8-chloro-7-nitro-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene, 25 g ammonium formate and 1.0 g Pd/C (added cautiously under inert atmosphere) was stirred over night. After filtering (Celite) and evaporation the material was brought to suspension in ethyl acetate. Filtering and evaporation yielded 7.8 g (22.7 mmol) of 8-chloro-7-amino-2-(n-propylbenzoyl)amino-1,2,3,4-tetrahydronaphthalene, which was recharged with 50 g ammonium formate, 2g Pd/C (added cautiously under inert atmosphere) and 200 ml ethanol. The mixture was stirred at room temperature for 4 days. The reaction ceased at about 1/1 ratio (GLC) of product and starting material. The mixture was worked-up as below and recharged with ammonium formate and Pd/C. After stirring for two days the reaction was almost completed. The mixture was filtered (Celite) and evaporated. Ethyl acetate and water where added, the mixture shaken and separated. The organic phase was washed (10% sodium carbonate),dried (magnesium sulfate), filtered and evaporated to yield 5.3 g (54%) crude product which was purified on silica column (dichloromethane/methanol, 19:1) giving 3.9 g product.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[NH2:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22]>>[C:21]([C:23]1[CH:28]=[C:27]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:22])[NH2:20]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Product: NC(=O)c1cccc(-c2ccc(OCc3nc(C(=O)O)cs3)cc2)c1

Procedure:
2-(3′-Carbamoyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure 2 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and (3-aminocarbonylphenyl)boronic acid (available from Apollo Scientific Ltd., Stockport, UK). Mass spectrum MH+=355.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:16][C:17]([C:19]2[NH:20][N:21]=[N:22][CH:23]=2)=[O:18])[CH2:9][C@@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.Cl.[CH3:31][O:32][CH2:33][CH2:34]O>O1CCOCC1>[CH3:31][O:32][CH2:33][CH2:34][O:12][C:11](=[O:13])[C@H:10]([CH2:14][OH:15])[CH2:9][C@H:8]([NH:16][C:17]([C:19]1[NH:20][N:21]=[N:22][CH:23]=1)=[O:18])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:2][CH:3]=1
Reactant: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O)c1cnn[nH]1
Reactant: COCCO
Agent: Cl
Solvent: C1COCCO1
Product: COCCOC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 60 °C

Procedure:
(2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (20 mg, 39 μmol, 1.0 eq.) was dissolved in 2-methoxyethanol (3 mL) followed by the addition of 4 M of HCl in dioxane (295.0 μL). The mixture was heated and maintained at 60° C. for 4 hours. The mixture was concentrated and purified by preparative HPLC to yield the title compound (10 mg; purity 95%). MS m/z [M+H]+ calc'd for C24H28N4O5, 453.21. found 453.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25]>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH2:21][CH2:16][CH2:17][F:25])=[C:17]([F:25])[CH:18]=1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: Nc1ccc(B(O)O)cc1F
Product: FCCCNc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1F

Procedure:
The title compound was prepared first using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (4-amino-3-fluorophenyl)boronic acid and then using General Experimental Procedure S for alkylation. 4-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluoro-N-(3-fluoropropyl)aniline was obtained as a orange solid. 1H NMR (400 MHz, methanol-d4): δ 9.12 (d, J=7.6, 1H), 8.06 (d, J=8.0 Hz, 1H), 8.04-7.98 (m, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 6.86 (t, J=8.4 Hz, 1H), 4.62 (t, J=5.6 Hz, 1H), 4.50 (t, J=5.6 Hz, 1H), 3.41 (t, J=6.8 Hz, 1H), 2.03 (m, 2H); MS (ESI) m/z [M+H]+339.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:15]#[C:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.C1COCC1.[Pd]>[CH2:8]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:28][CH:29]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2cnccc2C=Cc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(CCc2cnccc2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
tert-Butyl 4-[2-(4-(2-phenylethenyl)-3-pyridyl)ethynyl]benzoate (0.360 g, 0.95 mmol) was dissolved in ethanol/THF 1:1 (10 ml) and treated with palladium on carbon (10%, 0.13 g). The reaction was placed under a hydrogen atmosphere and stirred at ambient temperature for 6 hours. The reaction was then filtered and evaporated to give tert-butyl 4-[2-(4-phenethyl-3-pyridyl)ethyl]benzoate (0.36 g).
Reaction SMILES: [NH2:1][CH:2]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]12[CH2:10][CH2:9][CH2:8][N:7]1[CH2:6][CH2:5][CH2:4]2.[O:15]=[C:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:21][C:22](OCC)=[O:23]>>[O:15]=[C:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH2:21][C:22]([NH:1][CH:2]([C:3]12[CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH2:10]2)[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:23]
Reactant: C[Si](C)(C)C(N)C12CCCN1CCC2
Reactant: CCOC(=O)CN1CCCC1=O
Product: C[Si](C)(C)C(NC(=O)CN1CCCC1=O)C12CCCN1CCC2
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 150 mg (0.706 mmol) of 7a-[(amino)(trimethylsilyl)methyl]pyrrolizidine and 133 mg (0.777 mmol) of ethyl 2-oxo-1-pyrrolidineacetate was stirred at 80° C. for 5 hours. After cooled, the reaction mixture was chromatographed on alumina column to afford 95.3 mg
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1/[CH:4]=[N:16]/[OH:17]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O/N=C/c1cc(OC(F)(F)F)ccc1F
Yield: 87.8 %

Procedure:
A solution of 2-fluoro-5-trifluoromethoxy-benzaldehyde (9.78 g, 47 mmol) in ethanol (50 mL) was treated with hydroxylamine HCl (3.59 g, 52 mmol) and sodium acetate (4.27 g, 52 mmol). The resulting mixture was heated under reflux for 2 h. The solvent was then evaporated and the residue stirred with water (50 mL). The precipitate was filtered off, dried and chromatographed (SiO2, heptanes:ethyl acetate=100:0 to 80:2) to afford the title compound (9.21 g, 88%) as a white solid. MS: m/e=223.0 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21]C1C=C(OC)C=CC=1C=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:21][CH3:20])[CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Reactant: COc1ccc(C=O)c(OC)c1
Product: COc1ccc(-c2nc3ccccc3c(=O)[nH]2)c(OC)c1
Yield: 84.3 %

Procedure:
According to the preparation of 42, 2,4-dimethoxybenzaldehyde (37) (1.2 g, 7.3 mmol) was used to afford 46 (1.7 g, 84.3%) as pale yellow needles.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH2:39])=[S:38])=[C:32]([CH3:40])[CH:31]=1>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:2]([NH:1][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[N:16]=[CH:15][N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:3])=[S:38])=[C:32]([CH3:40])[CH:31]=1
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: COc1ccc(NC(N)=S)c(C)c1
Product: COc1ccc(NC(=S)NC(=O)NCCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c(C)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(4-methoxy-2-methylphenyl)thiourea isolated as a white solid (0.105 g, 34%): 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.07 (s, 1H), 9.42 (s, 1H), 8.13-8.05 (m, 2H), 8.04-7.96 (m, 2H), 7.66-7.57 (m, 2H), 7.53-7.45 (m, 1H), 7.42-7.32 (m, 2H), 7.01 (t, J=5.7 Hz, 1H), 6.85-6.81 (m, 1H), 6.76 (dd, J=8.7, 2.9 Hz, 1H), 3.74 (s, 3H), 3.45 (q, J=6.6 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.15 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 517 ([M+H]+), 569 [(M−H)+].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[C:28]([NH:36][C:37]([O:39][CH3:40])=[O:38])[C:27]=3[O:41][CH3:42])=[O:24])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].O.[Li+].[OH-].Cl>CO>[C:32]([C:30]1[CH:29]=[C:28]([NH:36][C:37]([O:39][CH3:40])=[O:38])[C:27]([O:41][CH3:42])=[C:26]([NH:25][C:23](=[O:24])[NH:22][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=3)=[CH:13][CH:14]=2)[CH:31]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccnc(C(=O)OC)c3)c3ccccc23)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)Nc1cc(C(C)(C)C)cc(NC(=O)Nc2ccc(Oc3ccnc(C(=O)O)c3)c3ccccc23)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a solution of 4-{4-[3-(5-tert-butyl-2-methoxy-3-methoxycarbonylamino-phenyl)-ureido]-naphthalen-1-yloxy}-pyridine-2-carboxylic acid methyl ester (1.114 g, 2 mmol) in MeOH (12 mL) was added water (2 mL) and LiOH (58 mg, 2.4 mmol). The resulting mixture was stirred at room temperature for 16 h then neutralized with 2N HCl. The resulting suspension was concentrated to dryness and the residual solid triturated with a mixture of methylene chloride and acetonitrile (300 mL, 2:1). The inorganic salt was filtered and the mother liquor concentrated to give the title compound as a dark tan solid (900 mg, 80%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[Br-].[CH3:11][C:12]1[CH:37]=[CH:36][CH:35]=[CH:34][C:13]=1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[CH:11]/[C:12]1[CH:37]=[CH:36][CH:35]=[CH:34][C:13]=1[CH3:14]
Reactant: Cc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(I)c1
Agent: [Br-]
Product: Cc1ccccc1/C=C/c1cccc(I)c1

Procedure:
Coupling of 3-iodobenzaldehyde with (2-methylbenzyl)triphenylphosphonium bromide followed by flash chromatography (silica gel, eluent: hexanes) gave (E)-1-(3-iodostyryl)-2-methylbenzene as a colorless oil. Yield (0.498 g, 36%): 1H NMR (500 MHz, CDCl3) δ 7.87-7.86 (m, 1H), 7.59-7.55 (m, 2H), 7.45 (d, J=7.8 Hz, 1H), 7.30 (d, J=16.2 Hz, 1H), 7.23-7.18 (m, 3H), 7.09 (t, J=7.9 Hz, 1H), 6.86 (d, J=16.2 Hz, 1H), 2.43 (s, 3H) and (Z)-1-(3-iodostyryl)-2-methylbenzene as a colorless oil. Yield (0.0.540 g, 39%): 1H NMR (500 MHz, CDCl3) δ 7.47-7.45 (m, 2H), 7.21-7.15 (m, 2H), 7.11-7.01 (m, 3H), 6.85 (t, J=7.8 Hz, 1H), 6.68 (d, J=12.2 Hz, 1H), 6.49 (d, J=12.1 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=3[CH:22]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:22]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccc(C)cc3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To methyl 2-(4-methylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (2.34 g, 7.26 mmol) dissolved in a mixed solvent of methanol (25 ml) and THF (25 ml) was added a 1N aqueous solution of sodium hydroxide (23 ml), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was mixed with 1 N hydrochloric acid (23 ml) at room temperature, was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed successively with water and hexane, and was dried under reduced pressure to obtain 2-(4-methylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (2.11 g, 6.84 mmol, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][NH2:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC1(c2cccc(Br)c2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2cccc(Br)c2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 34 %

Procedure:
This compound was synthesized from (4-(3-bromophenyl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (40 mgs, 34% yield). 1H NMR (300 MHz, CDCl3) δ 8.30-8.22 (m, 2H) 7.86 (d, J=3.7 Hz, 1H), 7.60 (t, J=3.7 Hz, 1H), 7.52-7.44 (m, 2H), 7.38-7.30 (m, 2H), 3.90 (m, 2H), 3.71 (d, J=3.3 Hz, 2H), 3.64 (m, 2H), 2.13 (m, 2H), 2.02 (m, 2H). MS (ESI) m/z: Calculated for C22H19BrF3N3O3: 509.06. found: 509.9 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][S:6][CH:5]1[C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=1[OH:19])(=[O:3])[CH3:2].S1CCN[CH2:21]1>>[CH3:21][O:10][C:9]([CH:8]1[CH2:7][S:6][CH:5]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=2[OH:19])[N:4]1[C:1](=[O:3])[CH3:2])=[O:11]
Reactant: C1CSCN1
Reactant: CC(=O)N1C(C(=O)O)CSC1c1cc(O)ccc1O
Product: COC(=O)C1CSC(c2cc(O)ccc2O)N1C(C)=O

Procedure:
The procedure described above for preparation of 3-acetyl-2-(2,5-dihydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid (3) was followed to prepare 8, except that the methyl ester of the thiazolidine starting material was employed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][NH:12][C:11](=O)[C:10]=2[C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[N:12]=[N:13][C:14]([CH3:15])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]=1[C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2c(C)n[nH]c(=O)c2-c2c(F)cc(F)cc2F)cc1
Product: COc1ccc(-c2c(C)nnc(Cl)c2-c2c(F)cc(F)cc2F)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
2.06 g of 5-(4-methoxyphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.14 g of 3-chloro-5-(4-methoxyphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xix) of the present invention).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]2=[O:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:29]>ClCCl.O1CCOCC1>[ClH:29].[ClH:29].[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:28])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CCCN(Cc3ccccc3)C2)C(=O)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1CNCCN1CC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-[(1-benzylpiperidin-3-yl)methyl]-3-oxopiperazine-1-carboxylate (95 mg) in dichloromethane (1 mL) was added 4M hydrochloric acid in dioxane (1 mL). The mixture was stirred at room temperature for 15 minutes and then evaporated to give the title compound as a sticky white solid (89 mg, 100%).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8]([C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1)#[N:9]>CCO.[Pd]>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH2:9][CH2:8][C:10]1[CH:11]=[C:12]([S:16]([NH2:19])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1cccc(S(N)(=O)=O)c1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: NCc1cccc(S(N)(=O)=O)c1
Reaction time: 20 h

Procedure:
TFA (5 mL) can be added to a solution of 3-cyano-benzenesulfonamide (0.90 g, 4.94 mmol) in EtOH (50 mL) followed by Pd/C (100 mg) and the mixture hydrogenated at 40 psi and r.t. for 20 h. The reaction mixture can be filtered through celite and the solvent concentrated to give 3-Aminomethyl-benzenesulfonamide TFA salt as a white solid in quantitative yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[N:25][N:26]([CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH:27]=1.C(O)(=O)C>C(O)CCC>[NH2:19][C:17](=[O:18])[CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:6]1[C:5]([Cl:21])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]3)[CH:27]=2)[N:7]=1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(N)cn2)CC1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Solvent: CCCCO
Solvent: CC(=O)O
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1Cl

Procedure:
A stirred solution of 2-(2-(2-(2,5-Dichloropyrimidin-4-yl)ethyl)phenyl)propanamide (A30) (0.120 g, 0.370 mmol), tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.177 g, 0.666 mmol) in n-butanol (3 mL) and glacial acetic acid (0.004 mL, 0.074 mmol) was stirred at 150° C. in the microwave for 30 minutes. After cooling, the solvent was removed to afford a crude purple oil which was purified by silica gel column chromatography (Combiflash Rf, 0-30% MeOH in DCM) to give the title compound A32 as a red oil (0.090 g, 44% yield). LCMS-C: rt 5.44 min; m/z 554 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][CH:9]=[N:8][C:7]=2[CH:11]=1.I>O>[S:10]1[C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:11][C:7]=2[N:8]=[CH:9]1
Reactant: COc1ccc2scnc2c1
Agent: I
Solvent: O
Product: Oc1ccc2scnc2c1
Yield: 82.6 %

Procedure:
A mixture of intermediate 24 (272 mg, 1.65 mmol) and hydroiodic acid (45%, 2 mL) was heated to reflux for 5 h. The mixture was diluted with water and filtered. The filtrate was neutralized and the solids were filtered, washed with water, and combined to give benzo[d]thiazol-5-ol (intermediate 25) (206 mg, 83%). HPLC: 99%, RT 2.038 min. MS (ESI) m/z 152.1 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Clc1ccc(Br)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 4-bromochlorobenzene (2.87 g, 15 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 2.02 g (89%) of the product 4-(4-chloro-phenyl)-1H-indole as a white solid.