Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:15])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a solution of N-Boc-6-aminohexanoic acid (4.78 g, 20.8 mmol) and pentafluorophenol (3.68 g, 20 mmol) in 50 mL of EtOAc was added DCC (4.12 g, 20 mmol). This was allowed to stir for 16 h, and was then filtered and the filtrate evaporated in vacuo to a syrup. On standing, this crystallized to give 7.46 g (94%) of the ester. Rerystallization from isopropanol/1% acetic acid gave 6.26 g of white needles, mp 81°-83° C. 1H NMR (CDCl3) δ 1.4-1.6 (m, 15H, Boc CH3 and internal CH2), 1.8 (m, 2H, CH2CH2CO2), 2.67 (5, J=7.3 Hz, 2H, CH2CO2), 3.1 (m, 2H, NHCH2), 4.5 (b, 1H, NH). 13C NMR (CDCl3) δ 24.38 (C4), 26.00 (C3), 28.39 (Boc CH3), 29.70 (C5), 33.20 (C2), 40.28 (C6), 79 (Boc C), 156 (Boc C=0), 169 (Cl).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.C(O)C.[CH3:18][NH:19][NH2:20]>O>[CH3:18][N:19]([C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1)[NH2:20]
Reactant: CNN
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Solvent: O
Solvent: CCO
Product: Cc1cc(C)n(-c2ccc(N(C)N)nn2)n1

Procedure:
A mixture of 4.17 g (0.02 moles) of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine, 42 ml of ethanol and 2.3 g (0.05 moles) of methyl hydrazine is heated to reflux for 9 hours, and after cooling the mixture is poured into 100 ml of water. The solution is extracted with 3×50 ml of chloroform and the combined organic phases are dried over magnesium sulphate. After evaporation the residue is recrystallized from a 3:1 mixture of isopropanol and petroleum ether. Yield: 1.9 g (44.5%); m.p.: 93°-94° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=CC=CC=1.[N:20]12CCC(C[CH2:25]1)[C@@H:22](O)[CH2:21]2>C(OCC)(=O)C>[C:13]1([CH2:12][C:11]([O:10][C@@H:8]2[CH:7]3[CH2:1][CH2:6][N:20]([CH2:21][CH2:22]3)[CH2:25]2)=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(Cc1ccccc1)OC(=O)Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)O[C@H]1CN2CCC1CC2
Yield: 93.3 %

Procedure:
Phenylacetic acid anhydride (prepared as described in J. Org. Chem., 1588, 30, 1965) (15 g) was added to a suspension of (R)-3-quinuclidinol (5 g) in ethyl acetate (250 ml) at room temperature. After 178 hour the solvent was evaporated and the residue dissolved in hydrochloric acid (2M). This was washed with ethyl acetate, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated to give the title compound as a yellow oil (9 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14]COC)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]1([C:32]2[CH:36]=[C:35]([NH:37][C:38](=[O:46])OC3C=CC=CC=3)[O:34][N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:38]([NH:37][C:35]2[O:34][N:33]=[C:32]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:36]=2)=[O:46])[CH:23]=[CH:24][CH:25]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(-c2ccccc2)no1)Oc1ccccc1
Solvent: CO
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(-c5ccccc5)no4)c3)c2cc1OC

Procedure:
The title compound was prepared according to the procedure described in Example 207 by using 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (102 mg, 0.3 mmol) and phenyl 3-phenylisoxazol-5-ylcarbamate from Example 114B (109 mg, 0.45 mmol) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-phenylisoxazol-5-yl)urea as a white solid upon trituration with methanol (26 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.13 (s, 1H), 9.13 (s, 1H), 7.83 (m, 2H), 7.59 (d, 2H), 7.50-7.41 (m, 5H), 7.33 (d, 2H), 7.00 (d, 1H), 6.56 (s, 1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.35 (s, 3H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[C:34]1([NH:40]N)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:40][C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc([N+](=O)[O-])c4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and phenylhydrazine: ESMS m/e: 525.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:29][OH:30]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[N:29][OH:30])[CH3:21])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NO)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Yield: 14 %

Procedure:
To a solution of 1-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-ethanone (i.e the product of Step 1, 250 mg) in methanol (10 mL) was added acetic acid (1 drop) and hydroxylamine hydrochloride (44 mg) and the mixture was stirred at room temperature over night. After concentration in vacuum, the residue was taken up in ethyl acetate and washed with water. The organic layer was separated, dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography on silica gel to yield the title compound (37 mg, 14%).
Reaction SMILES: C([O:4][C:5]([C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([NH:20][C:21]3[C:30]4[CH:31]=[CH:32][N:33]=[C:34]([O:35]CC)[C:29]=4[C:28]4[C:23](=[CH:24][CH:25]=[N:26][CH:27]=4)[N:22]=3)=[C:15]([Cl:38])[CH:14]=2)[N:9]=1)([CH3:7])[CH3:6])(=O)C.Cl>C1COCC1.C(OCC)(=O)C.C1COCC1>[Cl:38][C:15]1[CH:14]=[C:13]([C:10]2[N:9]=[C:8]([C:5]([OH:4])([CH3:7])[CH3:6])[O:12][N:11]=2)[CH:18]=[C:17]([Cl:19])[C:16]=1[NH:20][C:21]1[C:30]2[CH:31]=[CH:32][NH:33][C:34](=[O:35])[C:29]=2[C:28]2[C:23](=[CH:24][CH:25]=[N:26][CH:27]=2)[N:22]=1
Reactant: CCOc1nccc2c(Nc3c(Cl)cc(-c4noc(C(C)(C)OC(C)=O)n4)cc3Cl)nc3ccncc3c12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1nc(-c2cc(Cl)c(Nc3nc4ccncc4c4c(=O)[nH]ccc34)c(Cl)c2)no1
Temperature: 60 °C

Procedure:
To a solution of 1-(3-{3,5-dichloro-4-[(10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]phenyl}-1,2,4-oxadiazol-5-yl)-1-methylethyl acetate (63 mg, 0.11 mmol) in THF (3 mL) was added HCl (0.188 mL, 1.13 mmol, 6M in water) and the mixture was heated to 60° C. for 45 min in a sealed tube. After cooling to room temperature, the reaction was diluted with ethyl acetate/THF (3:1) and washed with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [N-]=C=O.[C:4]1([CH3:17])[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH2:16])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.N[C:20]1[S:21][C:22]([Br:25])=[CH:23][N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:25][C:22]1[S:21][C:20]([NH:16][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH3:17])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:15])=[N:24][CH:23]=1
Reactant: Nc1ncc(Br)s1
Reactant: Cc1ccc(S(=O)(=O)NC(N)=O)cc1
Agent: Cl
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ncc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of toluene-4-sulfonylurea isocyanate (2.6 g, 13 mmol) in CH2Cl2 (10 ml) was added slowly to a mixture containing 2-amino-5-bromothiazole hydrochloride (3.4 g, 13 mmol) and triethylamine (5.4 ml, 39 mmol) in CH2Cl2 (60 ml) under an argon atmosphere and stirred overnight at rt. The reaction mixture was concentrated under reduce pressure, diluted with ethyl acetate and washed with NaHCO3 (half sat. 3×), 5% KHSO4/10% K2SO4, water, NaCl sat., dried (MgSO4.2H2O), filtered and concentrated under reduced pressure. Recrystallization from MeOH/water yielded a beige solid: 2.8 g (58%), MS: m/e 376.1 (MH+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:11][C@H:10]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:9]1.C(Cl)(=O)C(Cl)=O.C[N:31](C=O)C.N>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:11][C@H:10]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21]([NH2:31])=[O:23])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:9]1
Reactant: CN(C)C=O
Reactant: C[C@H]1CCCCN1[C@H]1C[C@H](c2nc3ccc(C(=O)O)cc3s2)C1
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C[C@H]1CCCCN1[C@H]1C[C@H](c2nc3ccc(C(N)=O)cc3s2)C1
Reaction time: 1 h

Procedure:
2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxylic acid (Example 143B, 20 mg, 0.062 mmol) was added to a solution of oxalyl chloride (17 mg, 0.13 mmol) in CH2Cl2 (1 mL) at 23° C., followed by 1 drop of catalytic amount of DMF. The reaction mixture was allowed to stir for 1 h. Solvent and excess of oxalyl chloride were removed under vacuum, the residue solid was re-dissolved in CH2Cl2 (0.5 mL). Excess of ammonia (2 mL, 1.2 mmol) in CH2Cl2 (2 mL) was then added to the reaction vial. The reaction mixture was then stirred overnight. Solvent was removed, and the crude product was purified via HPLC (C-18 column, 0.1% TFA in acetonitrile) to give 16 mg product as a TFA salt (65%). 1H NMR (500 MHz, CD3OD): δ=8.51 ppm (m, 1H), 8.01 (m, 2H), 4.00 (m, 1H), 3.80 (m, 1H), 3.83 (m, 2H), 2.80-3.15 (m, 5H), 2.74 (m, 1H), 1.94 (m, 3H), 1.75 (m, 3H), 1.41 (m, 3H). MS (ESI, M+H+): 330.0.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH:21]([N:25]1[CH2:28][C:27]3([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:26]1)[CH2:20][CH2:19]2.[CH:34]1([C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][CH:38]=2)[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:34]1([C:37]2[CH:38]=[CH:39][C:40]([CH2:43][C:44]([N:31]3[CH2:30][CH2:29][C:27]4([CH2:26][N:25]([CH:21]5[C:22]6[C:18](=[CH:17][C:16]([C:11]7[N:12]=[CH:13][CH:14]=[CH:15][N:10]=7)=[CH:24][CH:23]=6)[CH2:19][CH2:20]5)[CH2:28]4)[CH2:33][CH2:32]3)=[O:45])=[CH:41][CH:42]=2)[CH2:36][CH2:35]1
Reactant: c1cnc(-c2ccc3c(c2)CCC3N2CC3(CCNCC3)C2)nc1
Reactant: O=C(O)Cc1ccc(C2CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(C2CC2)cc1)N1CCC2(CC1)CN(C1CCc3cc(-c4ncccn4)ccc31)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.1 mL) was added to a solution of 2-(5-pyrimidin-2-yl-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane dihydrochloride (5-1b, 80 mg, 0.2 mmol), 4-cyclopropylphenylacetic acid (SM-1ag, 31 mg, 0.2 mmol), and HATU (93 mg, 0.24 mmol) in dichloromethane (5 mL) in a vial. The reaction was stirred at room temperature overnight and was quenched with aqueous sodium bicarbonate. The organic layer was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) using a 12 g silica column with dichloromethane-methanol as eluant. The final product was obtained as off-white solid (89 mg, 92%). MS (APCI) 478.6 (M+H)+. 1H NMR (CDCl3) δ 0.65-0.69 (m, 3H), 0.92-0.97 (m, 2H), 1.67-1.71 (m, 2H), 1.83-1.90 (m, 2H), 2.19-2.22 (m, 1H), 2.89 (s, 1H), 3.18-3.26 (m, 5H), 3.31-3.35 (m, 2H), 3.51-3.55 (m, 2H), 3.66-3.70 (m, 3H), 4.01-4.06 (m, 1H), 7.00-7.04 (m, 2H), 7.10-7.13 (m, 2H), 7.17-7.21 (m, 1H), 7.41 (s, 1H), 8.31 (s, 2H), 8.79-8.82 (m, 2H).
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[CH2:4]([N:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9]Cl)[CH3:5]>O1CCCC1>[CH2:4]([N:6]([CH2:11][CH3:12])[CH2:7][CH2:8][CH2:9][Zn:2][CH2:9][CH2:8][CH2:7][N:6]([CH2:11][CH3:12])[CH2:4][CH3:5])[CH3:5]
Reactant: CCN(CC)CCCCl
Reactant: [Zn+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCN(CC)CCC[Zn]CCCN(CC)CC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6.8 g (0.05 mol) of zinc chloride in 100 ml of tetrahydrofuran are added at room temperature to a Grignard reagent prepared from 4.9 g (0.2 mol) of Mg and 19.4 g (0.16 mol) of 3-diethylaminopropyl chloride in 100 ml of tetrahydrofuran. When the reaction has ended, the mixture is stirred at room temperature for 24 hours and filtered, the solvent is removed and the residue is distilled in vacuo. Bis(3-diethylaminopropyl)zinc is obtained as a colourless liquid having a boiling point of 103° C./0.1 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CSCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)N3CCSCC3)c2)=C(C)C1=O
Yield: 32.1 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (65 mg, 0.19 mmol) obtained in Example 31 and thiomorpholine (0.022 ml, 0.21 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (26 mg, 0.061 mmol, yield 32%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([NH:33][CH2:34][CH2:35][OH:36])=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[CH:29][C:30]([NH:33][CH2:34][CH2:35][OH:36])=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: OCCNc1ccc(Br)cn1
Product: OCCNc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 2-(5-bromo-pyridin-2-ylamino)-ethanol (example B.46) (195 mg, 0.9 mmol) according to general procedure II. Obtained as a red solid (50 mg, 10%). MS (ISP) 492.0 [(M+H)+]; mp 202-203° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=1.[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[N:6][CH:7]=2)=[CH:36][CH:35]=1
Reactant: Nc1ccc(F)cc1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)cn3)cc2)CCN1C(=O)OC(C)(C)C
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Nc4ccc(F)cc4)cn3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
The title compound was prepared 1,1-dimethylethyl (2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D72) and 4-fluoroaniline using a method similar to that described for D58 in Description 58 although the reaction time was 18 h. MS (ES): MH+ 534.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH:5]2O.O.[NH2:14]N>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([OH:11])=[N:6][N:14]=[CH:5]2
Reactant: O=C1NC(O)c2cc(Br)ccc21
Reactant: NN
Solvent: O
Product: Oc1nncc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.4 %

Procedure:
A mixture of 5-bromo-3-hydroxyisoindolin-1-one (16, 17.0 g, 75 mmol), and hydrazine, monohydrate (60 mL, 1193 mmol) was stirred at room temperature for 15 h, after which a white solid precipitated out (M+1=225, 227). The mixture was diluted with 100 mL H2O, neutralized with conc. HCl to a PH of about 7. The precipitate was filtrated and washed with 100 mL H2O. The solid was collected, azeotropically dried with toluene (3×50 mL) and further dried in a vacuum oven at 45° C. for 15 h, to yield 6-bromophthalazin-1-ol 17 (16.1 g). Found MS (ES+): 225, 227 (M+H)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][CH:21]=[N:20][C:19]=2[CH3:23])=[CH:14][C:13]=1[F:24].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOCC>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([Cl:25])=[N:20][C:19]=2[CH3:23])=[CH:14][C:13]=1[F:24]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ncoc1-c1ccc(Br)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(Cl)oc1-c1ccc(Br)c(F)c1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
LiHMDS (1 M in THF, 4.4 mL, 4.4 mmol) was added dropwise via syringe to a solution of Example 29A (1.03 g, 4.02 mmol) in THF (20 mL) at −78° C. After 30 min solid hexachloroethane (1.90 g, 8.04 mmol) was added in one portion and the reaction mixture was allowed to gradually warm to ambient temperature over 16 hr. The reaction was diluted with Et2O and quenched with half-saturated aqueous NH4Cl solution. The separated aqueous phase was extracted with Et2O, and the combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (Analogix® Intelliflash 280™; 0% to 15% EtOAc/hexanes eluant; SF25-120 g column) afforded 1.07 g (92%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.84 (dd, J=8.4, 7.4 1H), 7.57 (dd, J=9.9, 2.0 1H), 7.39 (dd, J=8.5, 2.0 1H), 2.36 (s, 3H). MS (DCI+) m/z 290/292 (M+H).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22].CCN(C(C)C)C(C)C>>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH:32][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH3:31])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CC(N)c1ccc(S(C)(=O)=O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1)c1ccc(S(C)(=O)=O)cc1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(4-methanesulfonyl-phenyl)-ethylamine and DIEA to give 2-[1-(4-methanesulfonyl-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 438 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[Cl:12].[F:13][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.CC(=O)OCC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH2:10][F:13])=[CH2:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[Cl:12]
Reactant: C=C(C)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(CF)c1cc(Cl)c(Cl)c(Cl)c1
Temperature: 75 °C
Reaction time: 3 h
Yield: 36.2 %

Procedure:
To a mixture of 1,2,3-trichloro-5-(prop-1-en-2-yl)benzene (660 mg, 3 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium bis(tetrafluoroborate) (1.115 g, 3.15 mmol) in DMF (25 ml). The mixture was stirred at 75° C. for 3 h. The mixture was washed with H2O and extracted with EA (30 ml×2). The mixture was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (7:1 to 5:1) to give the desired product (260 mg, yield 36%).
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:17](=[O:23])[CH2:18][NH:19][CH2:20][CH2:21][OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:24]1[C:26]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:25]1.O>CCO>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:17](=[O:23])[CH2:18][N:19]([CH2:25][C:26]2([OH:24])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:20][CH2:21][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CNCCO)N1CCc2ccccc2C1C1CCCCC1
Reactant: C1CCC2(CC1)CO2
Solvent: O
Solvent: CCO
Product: O=C(CN(CCO)CC1(O)CCCCC1)N1CCc2ccccc2C1C1CCCCC1
Yield: 74.7 %

Procedure:
2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}ethanol (342 mg) was dissolved in EtOH (5 mL). 1-oxaspiro[2.5]octane (363 mg) and water (5 mL) were added thereto, followed by stirring under heating at reflux for 2 days. The solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-({[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl](2-hydroxyethyl)amino}methyl)cyclohexanol (346 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.C(N(CC)CC)C.[Br:14][CH:15]([CH3:19])[C:16](Br)=[O:17]>C(Cl)(Cl)Cl>[Br:14][CH:15]([CH3:19])[C:16]([NH:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1)=[O:17]
Reactant: CC(Br)C(=O)Br
Reactant: Nc1ccon1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)Nc1ccon1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−40° C.) stirring solution of 3-aminoisoxazole (0.88 ml, 11.9 mmol) and triethylamine (1.99 ml, 14.3 mmol) in chloroform (6 ml) is added slowly, 2-bromopropionyl bromide (1.37 ml, 13.1 mmol) in chloroform (6 ml). The reaction mixture is stirred at −40° C. for 30 minutes, and then allowed to warm to room temperature. The mixture is then partitioned between 1M aqueous hydrochloric acid and ethyl acetate. The organic extract is washed with saturated sodium hydrogen carbonate, dried over Na2SO4 and the solvent removed in vacuo to afford the titled compound as a yellow oil.