Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][N:7]=1)=[O:5])C.[OH-].[Na+]>CO>[NH:8]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1n[nH]c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1n[nH]c2c1CCCC2
Yield: 81.8 %

Procedure:
A solution of 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester [0.606 g, Reference Example 18(a)] in methanol (50 ml) was treated with sodium hydroxide (0.500 g). The mixture was refluxed for 16 hours, then cooled and then evaporated. The residual white solid was treated with hydrochloric acid (30 ml, 2N) and the resulting solution was extracted three times with ethyl acetate (50 ml). The combined organic extracts were dried over sodium sulfate and then evaporated to yield 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.424 g) as a white solid. LC-MS (METHOD B): RT=2.44 minutes; 167 (M+H)+. (b) 5-Isopropyl-1H-pyrazole-3-carboxylic acid
Reaction SMILES: [OH:1][C@H:2]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH2:31][OH:32])[CH:25]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([N:19]3[CH2:23]CC[CH2:20]3)=[O:18])=[CH:10][CH:11]=2)[CH2:6]1.S(=O)(=O)(O)O.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>>[OH:1][C@H:2]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH2:31][OH:32])[CH:25]=1)[CH2:3][NH:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([N:19]([CH3:23])[CH3:20])=[O:18])=[CH:10][CH:11]=2)[CH2:6]1
Reactant: O=C(COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(O)c(CO)c1)CC2)N1CCCC1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=S(=O)(O)O
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(O)c(CO)c1)CC2

Procedure:
Using (-)-1-[2-[(2S)-2-[[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]acetyl]pyrrolidine (Compound 7) and sulfuric acid, L-tartaric acid or D-tartaric acid, the following salts were obtained in the same manner as that described in Example 7.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[S:7][CH:8]1[CH2:11][NH:10][CH2:9]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:43]=[C:44]1[NH:53][C:52]2[N:51]=[CH:50][C:49](/[CH:54]=[CH:55]/[C:56](O)=[O:57])=[CH:48][C:47]=2[CH2:46][CH2:45]1>CN(C)C=O.O.C(OCC)(=O)C>[O:57]=[C:56]([N:10]1[CH2:11][CH:8]([S:7][C:3]2[S:2][CH:6]=[CH:5][CH:4]=2)[CH2:9]1)/[CH:55]=[CH:54]/[C:49]1[CH:48]=[C:47]2[C:52](=[N:51][CH:50]=1)[NH:53][C:44](=[O:43])[CH2:45][CH2:46]2
Reactant: c1csc(SC2CNC2)c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(Sc4cccs4)C3)cnc2N1
Reaction time: 8 h

Procedure:
3-(Thiophen-2-ylthio)-azetidine hydrochloride (170 mg, 0.82 mmol), EDCI (157 mg, 0.82 mmol), HOBt (110 mg, 0.82 mmol) and diisopropylethylamine (240 μL, 1.36 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (139 mg, 0.55 mmol) in dimethylformamide (14 mL) at room temperature. The reaction mixture was stirred overnight and then diluted by addition of ethyl acetate (40 mL) and water (40 mL). The aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (1:0 to 95:5) as eluent. After trituration in acetone, the title product was obtained as a white solid (114 mg, 37%).
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[C:59]([CH2:64][CH2:65][C:66](Cl)=[O:67])([O:61][CH2:62]C)=[O:60]>ClCCCl.CN(C1C=CN=CC=1)C>[CH3:49][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[C:66](=[O:67])[CH2:65][CH2:64][C:59]([O:61][CH3:62])=[O:60]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (48 mg, 0.072 mmol) in DCE (2 ml) was added Hunig's base (0.037 ml, 0.215 mmol), 3-carboethoxypropionyl chloride (21.54 mg, 0.143 mmol), and DMAP (1 mg, 8.19 mmol). The mixture was stirred at rt for 5 h then was loaded directly onto a silica gel column and was purified using a 0-5% MeOH in dichloromethane gradient to afford tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((N-(2-(dimethylamino)ethyl)-4-methoxy-4-oxobutanamido)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate as a white foam (53.8 mg, 0.051 mmol, 71.8% yield). LCMS: m/e 785.6 (M+H)+, 3.21 min (method 6).
Reaction SMILES: [Br:1][C:2]1[C:6](=[CH2:7])[S:5][CH:4]([C:8]([O:10][CH3:11])=[S:9])[CH:3]=1.BrC1C=C(C(O)=S)SC=1C.S(Cl)(Cl)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7]
Reactant: C=C1SC(C(=S)OC)C=C1Br
Agent: Cc1sc(C(O)=S)cc1Br
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=S)c1cc(Br)c(C)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
Methyl 4-bromo-5-methlylthiothiophene-2-carboxylate: To a stirred solution of 4-bromo-5-methylthiothiophene-2-carboxylic acid (87 mmol), prepared according to the procedure of Kleemann, et al., EP 0676395A2, in dry methanol (750 mL) was added thionyl chloride (7 mL, 96 mmol) dropwise. After stirring for 10 min at room temperature, the solution was heated to reflux and stirred 7.5 h. The solution was cooled and the solvents were removed in vacuo. The resulting solid was dissolved in dichloromethane (1500 mL) and washed with saturated sodium bicarbonate (2×300 mL), water (300 mL), saturated brine (300 mL), and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. The resulting solid was recrystallized twice from hexane/ethyl acetate to give methyl 4-bromo-5-methylthiothiophene-2-carboxylate (4.4 g, 19%). 1H-NMR (CDCl3, 400 MHz) δ 7.66 (s, 1H), 3.90 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Br:30][C:31]1[N:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.[Cl-].[NH4+]>O1CCCC1>[Br:30][C:31]1[N:36]=[CH:35][C:34]([CH2:37][CH:2]=[O:3])=[CH:33][CH:32]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=CCc1ccc(Br)nc1
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (4.65 g) in tetrahydrofuran (20 ml) was added dropwise potassium tert-butoxide (1.0 M solution in tetrahydrofuran) (14.6 ml) on an ice bath under a nitrogen atmosphere, the solution was stirred for 20 minutes, then a solution of 6-bromopyridine-3-carbaldehyde (2.1 g) in tetrahydrofuran (16 ml) was added dropwise thereto followed by stirring overnight at room temperature. A saturated aqueous solution of ammonium chloride was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. Obtained by purifying the residue by NH silica gel column chromatography (hexane-ethyl acetate system), 2-bromo-5-(2-methoxyvinyl)pyridine (2.2 g) was stirred in acetone (20 ml), water (10 m) and concentrated sulfuric acid (1 ml) were sequentially added thereto, the solution was stirred for 1.5 hours at 80° C., and then neutralized with a saturated aqueous solution of sodium bicarbonate. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo to provide the title compound (1.5 g).
Reaction SMILES: CSC.[S:4]1[C:8]([CH2:9][C:10]2[CH:11]=[C:12]([C@H:20]3[C@@H:25]([O:26]CC4C=CC=CC=4)[C@@H:24]([O:34]CC4C=CC=CC=4)[C@@H:23]([O:42]CC4C=CC=CC=4)[C@@H:22]([CH2:50][O:51]CC4C=CC=CC=4)[O:21]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:6]2[CH:59]=[CH:60][CH:61]=[CH:62][C:5]1=2.O>C(Cl)Cl>[S:4]1[C:8]([CH2:9][C:10]2[CH:11]=[C:12]([C@H:20]3[C@H:25]([OH:26])[C@@H:24]([OH:34])[C@H:23]([OH:42])[C@@H:22]([CH2:50][OH:51])[O:21]3)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:6]2[CH:59]=[CH:60][CH:61]=[CH:62][C:5]1=2
Reactant: c1ccc(COC[C@H]2O[C@@H](c3cc(Cc4cc5ccccc5s4)cc4ccccc34)[C@@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CSC
Product: OC[C@H]1O[C@@H](c2cc(Cc3cc4ccccc4s3)cc3ccccc23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.1 %

Procedure:
In a nitrogen stream, dimethylsulfide (3.5 ml) and boron trifluoride-diethyl ether complex (1.75 ml, 13.8 mmol) were added dropwise to an solution of (2S,3R,4R,5S,6R)-2-[3-(benzo[b]thiophen-2-ylmethyl)naphthalen-1-yl]-3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydropyran (1.1 g, 1.38 mmol) in anhydrous methylene chloride (30 ml) at 0° C. and the reaction mixture was stirred at room temperature for three days. Water (10 ml) was added thereto and the resulting mixture was then extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography [methylene chloride:methanol (30:1)] to obtain the title compound (0.35 g, 58.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]O)[CH:5]=[CH:6][C:7]=1[F:8].[BrH:12]>C(O)(=O)C.S(=O)(=O)(O)O>[Br:12][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: OCCc1ccc(F)c(F)c1
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Fc1ccc(CCBr)cc1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 25.4 %

Procedure:
A mixture of 2-(3,4-difluoro-phenyl)-ethanol (5 g, 0.032 mol, from step (iii) above), 51.84 ml (49%, 0.64 mol) of HBr in acetic acid and 5 ml of sulfuric acid was stirred at 100° C. for 4 h. The reaction mixture was poured into ice and extracted with diethylether. Organic layer was washed with NaHCO3, water and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification (three times) over silica gel using petroleum ether as eluent afforded (1.8 g) of the title compound as a liquid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.P([O-])(O)(O)=[O:13].[K+].N(S([O-])(=O)=O)(S([O-])(=O)=O)[O].[K+].[K+]>CO.O>[N:7]1[C:8]2[C:9](=[O:13])[CH:10]=[CH:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2ncccc12
Reactant: O=P([O-])(O)O
Agent: [K+]
Agent: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Solvent: CO
Solvent: O
Product: O=C1C=CC(=O)c2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of 23.2 g of 5-hydroxyquinoline in 1600 ml of methanol in an ice bath was added a total of 36 g of potassium dihydrogen phosphate and 96 g of potassium nitroso disulfonate in 8.8 liters of water in five portions over a 1 hour period. The mixture was then stirred overnight at room temperature, followed by extraction with four 1500 ml portions of chloroform. The extracts were combined, dried, filtered through alumina and evaporated to dryness, giving 12.0 g of crude product. An analytical sample was prepared by crystallization from petroleum ether, mp 110° C.
Reaction SMILES: [CH3:1][C:2]([C:19]1[N:23]([CH3:24])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[N:21][N:20]=1)([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13](C(O)=O)[N:12]=2)=[CH:7][CH:6]=1)[CH3:3].O>CS(C)=O>[CH3:3][C:2]([C:19]1[N:23]([CH3:24])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:33])([F:34])[F:32])=[N:21][N:20]=1)([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(-c2nc(C(=O)O)no2)cc1
Solvent: CS(C)=O
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C(C)(C)Oc1ccc(-c2ncno2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
5-[4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,2,4-oxadiazole-3-carboxylic acid (172 mg) was dissolved in DMSO (1 ml), followed by stirring at 60° C. for 2 hours. The reaction solution was cooled to room temperature and water was added thereto, followed by stirring for 15 minutes. The formed solid was collected by filtration and washed with water. The resulting solid was dissolved in ethyl acetate and washed with water and then saturated brine in this order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid was washed with ethyl acetate to obtain 5-[4-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,2,4-oxadiazole (103 mg), as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC=CC=1.O.[BH4-].[Na+]>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNc2ccccc2)c(OC)c1

Procedure:
Trifluoroaceticacid (10 drops) was added to a solution of 2,4-dimethoxybenzaldehyde (16.62 g, 100 mmol) and aniline (9.31 g, 100 mmol) in toluene (100 mL). The reaction mixture was stirred at reflux temperature and toluene/water was distilled off during 1.5 h. After cooling the reaction mixture was concentrated at reduced pressure and the residue was dissolved in MeOH (200 mL). NaBH4 (2.0 g, 54 mmol) was added in portions during 20 min and the reaction mixture was then stirred for 1 h. The product (22.16 g, 91%) crystallized from the reaction mixture and was isolated by filtration.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F:11][CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:11][CH2:12][O:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Reactant: Cc1cc(O)cnc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(OCF)cnc1C#N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-3-methyl-pyridine-2-carbonitrile (CAS registry 228867-86-5) (228 mg, 1.70 mmol) in DMF (10 ml) was added a solution of toluene-4-sulfonic acid fluoromethyl ester (CAS registry 114435-86-8) (521 mg, 2.55 mmol) and Cs2CO3 (1.386 g, 4.26 mmol) in DMF (4 ml). The reaction mixture was stirred for 1 h at 100° C., then for 1 h at 70° C., diluted with EtOAc and washed with saturated aqueous NH4Cl soln. and brine. The aqueous layers were reextracted with EtOAc, the combined organic layers dried over Na2SO4, filtrated and the filtrate was concentrated. The title compound was obtained as a white solid after flash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min 95:5, 3-30 min 95:5 to 65:35).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1F
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccc(Cl)cc1
Yield: 89.5 %

Procedure:
A mixture of 4-chlorophenol (2.00 g, 15.56 mmol), 2-fluorobenzonitrile (1.88 g, 15.56 mmol) and potassium carbonate (2.15 g, 15.56 mmol) in DMF (10 mL) was stirred under reflux for 4 h. After removal of DMF, the residue was dissolved in DCM and washed with NaOH (5%, 3×20 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 2-(4-chlorophenoxy)benzonitrile (3.2 g, 90%) as a white solid, mp 84-86° C., which was used in the next step without further purification. Rf: 0.62 (DCM) 1H NMR (270 MHz, CDCl3) δ 6.86 (1H, dd, J=8.4, 0.8 Hz), 7.02 (2H, AA′BB′), 7.15 (1H, td, J=7.7, 1.0 Hz), 7.35 (2H, AA′BB′), 7.48 (1H, m) and 7.65 (1H, dd, J=7.7, 1.5 Hz). LC/MS (APCI) tr=4.66 min, m/z 232.28 (31), 230.27 (M++H, 100).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]5[CH:26]=[N:27][N:28](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:29]=5)[CH:23]=4)[N:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[ClH:51]>>[ClH:51].[ClH:51].[NH:27]1[CH:26]=[C:25]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[C:15]3[N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:50])[F:49])[CH:4]=3)[CH2:14][CH2:13]2)[CH:29]=[N:28]1
Reactant: FC(F)(F)c1cccc(N2CCN(c3ccnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)c1
Agent: Cl
Product: FC(F)(F)c1cccc(N2CCN(c3ccnc4ccc(-c5cn[nH]c5)cc34)CC2)c1

Procedure:
104 mg 4-[4-(3-trifluoromethylphenyl)piperazin-1-yl]-6-(1-trityl-1H-4-pyrazolyl) quinoline obtained in Example 175 and 1.2 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 163, to give 74 mg of the title compound as yellowish orange crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[CH3:15])[NH2:11]>>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccc(N)cc1Br
Reactant: CC(C)C(=O)Cl
Product: Cc1ccc(NC(=O)C(C)C)cc1Br

Procedure:
Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 3-bromo-4-methylaniline: ESMS m/e: 255.9 (M+H)+.
Reaction SMILES: [NH2:1][OH:2].C([O-])([O-])=O.[K+].[K+].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>C(Cl)Cl>[C:10]([NH:1][OH:2])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(NO)OCc1ccccc1
Reaction time: 0.5 h
Yield: 135.7 %

Procedure:
A solution of crude amino alcohol 29 (223 g, 1.19 mol) in 1 L of CH2Cl2 was treated with a 1 L aqueous solution of K2CO3 (200 g, 1.45 mol) and cooled in a ice bath. The mixture is stirred vigorously while benzyl chloroformate (225 g, 1.3 mol) is added slowly. After the addition is complete the mixture is stirred an additional 30 min. The organic layer is separated and washed with water, brine and concentrated to give 390 g of crude solid. This is recrystallized from hexane to give 270 g of N-CBZ amino alcohol 30.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].C[N+]([O-])=O.Cl[CH:21](Cl)[O:22]C>C(Cl)CCl>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH:21]=[O:22])[CH:9]=1)=[O:4]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCCl
Product: O=Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-ethanone (5.0 g, 23.53 mmol) and AlCl3 (3.8 g, 28.50 mmol) in co-solvents of EDC (20 mL) and MeNO2 (20 mL) was cooled to −10° C. A solution of dichloro-methoxy-methane (3.25 g, 28.27 mmol) in EDC (5 mL) was added fairly rapidly and the mix was then stirred at −10° C. to room temperature for overnight. It was poured over crushed ice, the layer were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed, dried over MgSO4, and concentrated, yielding a slightly reddish solid (3.6 g, 64%). 1H NMR (500 MHz, CDCl3) δ10.10 (s, 1H), 10.06 (br, 1H), 7.96 (m, 2H) ppm. MS (ES−): m/e=238 (M−H); LC/Method A/3.15 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([CH3:10])[N:5]=2)[CH2:3][CH2:2]1.[F:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)[CH:15]=[CH:14][C:13]=1[NH:31][C:32](=O)[O:33]C(C)=C.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:32]([NH:31][C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)[CH:20]=4)=[CH:17][C:12]=3[F:11])=[O:33])[N:6]([CH3:10])[N:5]=2)[CH2:3][CH2:2]1
Reactant: C=C(C)OC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Reactant: Cn1nc(C2CC2)cc1N
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C5CC5)nn4C)c(F)c3)ccn2)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
To a solution of 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine (60 mg, 0.434 mmol) in dioxane (1 mL) was added prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate from Example 21 (0.16 g, 0.434 mmol), and DBU (6.61 mg, 0.043 mmol) and the mixture was stirred overnight at 70° C. The reaction was checked by LC-MS, solvent was removed and the residue was purified by silica gel column chromatography (EtOAc/hexane→CH2Cl2/MeOH). Pure fractions were combined and concentrated. The residue was dissolved in CH3CN:H2O (1:1, 2 mL) and lyophilized to obtain 1-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (26 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.39 (d, J=6.0 Hz, 1H), 8.28 (s, 1H), 8.18 (t, J=9.6 Hz, 1H), 7.99 (s, 1H), 7.26 (m, 2H), 7.02 (m, 1H), 6.70 (dd, J=2.4, and 6.0 Hz, 1H), 3.87 (s, 3H), 3.59 (s, 3H), 1.76 (m, 1H), 0.80 (m, 2H), 0.59 (m, 2H); MS (ESI) m/z; 448.1 (M+H+).