Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[Cl:23]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:23])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 87 %

Procedure:
6-(4-Bromo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 28a (6.38 g, 17.51 mmol) is dissolved in N,N-dimethylformamide (275 mL). N-chlorosuccinimide (2.36 g, 17.70 mmol) is added as a solid and the reaction mixture is stirred at room temperature under N2 until the reaction is complete (5-6 days). The reaction mixture is quenched by the addition of aqueous saturated sodium bisulfite solution to give a suspension. The resulting solids are collected by filtration, washed with water and diethyl ether and dried under reduced pressure to yield 6.07 g (87%) of the pure desired product as a beige solid. MS ESI (+) m/z 398, 400 (M+Br pattern) detected.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[Cl:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:11]=1[C:12](OC)=[O:13]>C1COCC1>[Cl:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:11]=1[C:12](=[O:13])[CH2:7][C:6]#[N:8]
Reactant: CC#N
Reactant: COC(=O)c1c(Cl)cccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1c(Cl)cccc1Cl
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 103.4 %

Procedure:
n-Butyl lithium (20.1 mL, 32.2 mmol, 1.6M in hexanes) was added to THF (30 mL) and the solution was cooled to −78° C. Acetonitrile (1.7 mL, 32 mmol) was added dropwise and the reaction stirred at the temperature for 45 minutes. Methyl 2,6-dichlorobenzoate (1.00 g, 4.88 mmol) was dissolved in 2 mL THF and added to the reaction mixture. The reaction stirred at −78° C. for 0.5 hr. The solution was quenched with methanol and warmed to room temperature. The material was diluted with water and 1N HCl. The solution was then extracted with Ethyl acetate, dried, and concentrated to give 1.08 g of desired product at 85% purity. Material used as is in the next step.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([OH:21])=O.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C1COCC1>[CH2:34]([O:41][NH:42][C:19](=[O:21])[C:18]1[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:17]=1[NH:16][C:15]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:14]=1[F:13])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
Carbonyldiimidazole (3.1 g, 19.1 mmol) was added to a suspension of 2-(2,4-difluoroanilino)-4,5-difluorobenzoic acid (Example H-4, 4.54 g, 15.9 mmol) in 120 mL of THF, and the mixture was stirred for 24 hours at 25° C. O-Benzylhydroxylamine hydrochloride (2.54 g, 15.9 mmol) and triethylamine (2.66 mL, 19.1 mmol) were added, and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated and washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 5.66 g of the title compound as an oil.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.[CH3:5][NH2:6].[CH3:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH:9]=O>O.CO>[CH3:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH:9]([NH:6][CH3:5])[C:1]#[N:2]
Reactant: CN
Reactant: CC(C)(C=O)c1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CNC(C#N)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 95 %

Procedure:
To a solution of potassium cyanide (103 g, 1.56 mol) and methylamine hydrochloride (106 g, 1.56 mol) in water (1000 mL) is added a solution of 2-methyl-2-phenylpropanal (222 g, 1.50 mol) in methanol (1000 mL) over a period of 30 minutes. An ice-water bath is used occasionally to maintain the reaction temperature between 20–25° C. The mixture is stirred at room temperature for 25 hours. Water (2000 mL) is then added and the reaction mixture is extracted with CH2Cl2 (3×800 mL). The combined organic extracts are washed with brine (500 mL) and dried over Na2SO4. The organic extracts are filtered and concentrated to give 3-methyl-2-(methylamino)-3-phenylbutanenitrile as an oil (274 g, 95% yield, 76.6% by HPLC area, NMR (>95%)). Evidence of decomposition on the HPLC/GC column is noted.
Reaction SMILES: [ClH:1].Cl.N1C=C[C:6]([CH:9]2[CH2:14]N[CH2:12][CH2:11][N:10]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22]C)=[O:20])=CC=1.[CH3:24][N:25](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[CH:15]([N:10]([CH:9]([CH3:6])[CH3:14])[CH2:11][CH3:12])([CH3:16])[CH3:24].[ClH:1].[NH2:25][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)CCCCN1CCNCC1c1ccncc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(C)C)C(C)C
Product: COC(=O)CCN
Yield: 87 %

Procedure:
In a similar manner to Example 189 (i), the product of Example 196 (840 mg), HBTU (950 mg), HOBt.H2O (380 mg), DMF (10 ml), diisopropylethylamine (2.6 ml) and methyl 3-aminopropionate, hydrochloride (280 mg) gave, after purification by flash chromatography on neutral alumina, eluting solvent ethyl acetate/methanol, 50:1 to 4:1, the title compound (303 mg) as a white crystalline solid: m.p. 118°-122° C.; NMR (d6 -DMSO) δ 1.45 (4H, m), 2.05 (2H, t), 2.27 (2H, t), 2.42 (6H, m), 3.26 (6H, m), 3.58 (3H, s), 6.78 (2H, m), 7.83 (1H, br, t), 8.12 (2H, m); m/Z 349 (M+H)+ ; calculated for C18H28N4O3 : C, 62.0%; H, 8.1%; N, 16.1%; found: C, 62.2%; H, 8.4%; N, 16.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:40])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:31])[C:25]4[CH:30]=[N:29][CH:28]=[CH:27][N:26]=4)[CH3:22])=[C:17]([CH2:32][O:33]CC[Si](C)(C)C)[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:40])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:31])[C:25]4[CH:30]=[N:29][CH:28]=[CH:27][N:26]=4)[CH3:22])=[C:17]([CH2:32][OH:33])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1COCC[Si](C)(C)C)CC(O)c1cnccn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)CC(O)c1cnccn1
Yield: 94.2 %

Procedure:
A solution of 144 mg of N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrazin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 3 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is adjusted to pH 10-11 with added NaOH, then extracted with 6 portions of CHCl3. The combined organic phase is dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel (compound pre-loaded onto silica gel using CHCl3-MeOH) using 5-8% MeOH in CH2Cl2 provides 114 mg of the title compound as a white solid. Trituration with boiling acetonitrile affords white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(OC3CCOCC3)cc2)OC1(C)C
Temperature: 85 °C
Yield: 24.5 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1 g, 4.5 mmole), tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (1.4 g, 5.4 mmole) and K2CO3 (1.3 g, 9 mmole) in DMF (10 mL) was heated at 85° C. for 20 h. The mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by ISCO (silica gel, elute: 10% ethyl acetate in hexane) to give the title compound (335 mg, 24% yield) as a solid. MS (ESI) m/z: Calc. 304.2 (M+). Found: 305.3 (M++1).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([C:17]([C:19]3[C:20]([C:40]([F:43])([F:42])[F:41])=[CH:21][C:22]4[O:27][C:26]([CH3:29])([CH3:28])[C:25](=[O:30])[N:24]([CH2:31][CH2:32][NH:33][C:34](=[O:38])[CH:35]([F:37])[F:36])[C:23]=4[CH:39]=3)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH2:9][N:8]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:3][CH2:2]1.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][C:59](O)=[O:60])=[CH:54][CH:53]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][C:59]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6][C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([C:17]([C:19]3[C:20]([C:40]([F:41])([F:42])[F:43])=[CH:21][C:22]4[O:27][C:26]([CH3:28])([CH3:29])[C:25](=[O:30])[N:24]([CH2:31][CH2:32][NH:33][C:34](=[O:38])[CH:35]([F:37])[F:36])[C:23]=4[CH:39]=3)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH2:9][N:8]2[C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])=[O:60])=[CH:54][CH:53]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)C(F)F)[C@@H]1CC[C@H](CCNC2CC2)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCNC(=O)C(F)F)[C@@H]1CC[C@H](CCN(C(=O)Cc2ccc(Cl)cc2)C2CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of tert-butyl (2R,5R)-2-[2-(cyclopropylamino)ethyl]-5-[{[4-{2-[(difluoroacetyl)-amino]ethyl}-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}-(isopropyl)amino]piperidine-1-carboxylate (86 mg) in N,N-dimethylformamide (1 ml) were added 4-chlorophenylacetic acid (22 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34 mg), 1-hydroxybenzotriazole monohydrate (24 mg) and triethylamine (50 μl), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution. Then, the mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/acetone=2/1) to give the title compound (90 mg).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9][CH2:8]1.C(N(CC)CC)C>ClCCl>[O:9]1[C:10]2([CH2:15][CH2:14][N:13]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:12][CH2:11]2)[O:16][CH2:7][CH2:8]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC2(CC1)OCCO2
Reaction time: 8 h

Procedure:
A solution of 10.4 g. of cyclopropanecarbonyl chloride in 150 ml. of dichloromethane is rapidly added to a solution of 12.5 g. of 4-piperidone ethylene acetal (1,4-dioxa-8-azaspiro[4.5]decane) and 20 g. of triethylamine in 200 ml. of dichloromethane, causing the solution to reflux. Heating to reflux with stirring is continued overnight; the mixture is cooled and the precipitated triethylammonium chloride filtered off. The mother liquor is concentrated to about half volume, washed with water, dried over anhydrous potassium carbonate, and stripped to dryness. The residual oil quickly solidifies, and on crystallization from 300 ml. hexane yields cyclopropyl 1,4-dioxa-8-azaspiro[4.5]dec-8-yl ketone, m.p. 72°-74°, as white needles. Reduction of 14.0 g. of this compound in 60 ml. freshly chromatographed, peroxide-free ether by dropwise addition to a suspension of 2.5 g. of lithium aluminum hydride in similarly treated ether, followed by three hours of refluxing, yields 8-(cyclopropylmethyl)-1,4-dioxa-8azaspiro[4.5]decane as a colorless oil. Hydrolysis of this ethylene acetal by refluxing in 2N hydrochloric acid, followed by basification with 50% sodium hydroxide, extraction into ether, drying of the extrct, and stripping off the solvent, yields a crude product which distills at 111°-122°/16 mm. to give 1-(cyclopropylmethyl)-4-piperidone, shown by gas-liquid chromatography to be 95-99% pure.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([C:20]3[O:21][C:22]4[C:28]([C:29]([O:31]C)=O)=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH4+:33]>CO>[C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([C:20]3[O:21][C:22]4[C:28]([C:29]([NH2:33])=[O:31])=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cccc2nc(-c3cccc(C(=O)N4CCN(C(=O)C(C)C)CC4)c3)oc12
Reactant: [NH4+]
Solvent: CO
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(-c3nc4cccc(C(N)=O)c4o3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14 %

Procedure:
Methyl 2-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)benzo[d]oxazole-7-carboxylate (150 mg, 0.34 mmol) was added to ammonium in methanol (10 mL) in a sealing tube and stirred at 25° C. for 3 days. The solvent was removed under reduced pressure. The crude product was purified by pre-HPLC to obtain 2-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (20 mg, yield 14%). 1H-NMR (400 MHz, CD3OD) δ: 1.12-1.13 (d, J=6 Hz, 6H), 2.97 (brs, 1H), 3.55-3.85 (m, 8H), 7.50-7.54 (t, J=8.0 Hz, 1H), 7.71-7.75 (m, 2H), 7.91-7.95 (m, 2H), 8.41-8.45 (m, 2H); LC-MS (ESI) m/z: 421 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[O:8].[C:19](N1C=CN=C1)(N1C=CN=C1)=[S:20].[N:31](=[C:33]([C:35]1[C:39]([OH:40])=[C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[N:37]([CH3:51])[N:36]=1)[CH3:34])[NH2:32].[OH-].[Na+]>C(O)C.O.CN(C)C=O>[Cl:18][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19]([NH:32][N:31]=[C:33]([C:35]2[C:39]([OH:40])=[C:38]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:45][CH:46]=3)[N:37]([CH3:51])[N:36]=2)[CH3:34])=[S:20])=[CH:17][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:8]
Reactant: CCOC(=O)CCNC(=O)c1cc(N)ccc1Cl
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(=NN)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(Cl)c(C(=O)NCCC(=O)O)c1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 20 %

Procedure:
Ethyl 3-(5-amino-2-chlorobenzoylamino)propionate (122.8 mg, 0.45 mmol) was stirred with a dimethylformamide solution of thiocarbonyldiimidazole (0.1 M, 4.5 mL) at room temperature for 1 hour and with a dimethylformamide solution of 3-(1-hydrazonoethyl)-1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-ol prepared in Reference Synthetic Example 14 (0.1 M, 3.0 mL) at room temperature for 6 hours. Water (3.0 mL) was added, and the precipitated solid was removed by filtration. The filtrate was separated by thin layer chromatography to give 57.0 mg of a crude product. An ethanol solution (1.0 mL) of the crude product (26.0 mg, 0.0435 mmol) was stirred with 1 M aqueous sodium hydroxide (131 μL, 0.131 mmol), and the precipitated solid was collected by filtration, washed with water and dried to give 14.6 mg of the desired product (yield 20%).
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.N/[C:10](/[CH3:14])=[CH:11]\[C:12]#[N:13]>C(O)C>[CH:2]1([N:7]2[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NNC1CCCC1
Reactant: C/C(N)=C/C#N
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)n(C2CCCC2)n1

Procedure:
The title compound was prepared in the same manner as described for intermediate 19 using cyclopentylhydrazine hydrochloride (2 g, 14.64 mmol), (2Z)-3-amino-2-butenenitrile (1.202 g, 14.64 mmol) and ethanol (20 mL). The final product was collected as 0.57 g (24%). LCMS E-S (M+H)=166.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60-1.69 (m, 2 H), 1.86-1.95 (m, 2 H), 1.99-2.09 (m, 4 H), 2.19 (s, 3 H), 3.46 (br. s., 2 H), 4.38 (quin, J=7.89 Hz, 1 H), 5.36 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH:24]=2)[NH2:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43])=[CH:38][CH:37]=1.[Si](I)(C)(C)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([NH:22][C:42](=[O:43])[C:41]([O:40][C:39]2[CH:47]=[CH:48][C:36]([Cl:35])=[CH:37][CH:38]=2)([CH3:46])[CH3:45])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH:24]=2)=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:12]1[CH:11]=[C:10]([CH2:20][CH:21]([NH:22][C:42](=[O:43])[C:41]([O:40][C:39]2[CH:47]=[CH:48][C:36]([Cl:35])=[CH:37][CH:38]=2)([CH3:46])[CH3:45])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[S:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH:24]=2)[C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: Cc1ccc(-c2cccc(C(N)Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)c2)s1
Agent: C[Si](C)(C)I
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc(C(Cc3cc(Cl)c4cccnc4c3O)NC(=O)C(C)(C)Oc3ccc(Cl)cc3)c2)s1
Product: Cc1ccc(-c2cccc(C(Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)NC(=O)C(C)(C)Oc3ccc(Cl)cc3)c2)s1
Yield: 132 %

Procedure:
N-{2-(8-Benzyloxy-5-chloro-quinolin-7-yl)-1-[3-(5-methyl-thiophen-2-yl)-phenyl]-ethyl}-2-(4-chloro-phenoxy)-2-methyl-propionamide was prepared from 2-[8-(benzyloxy)-5-chloroquinolin-7-yl]-1-[3-(5-methyl-2-thienyl)phenyl]ethanamine (0.409 mmol) and 2-(4-chlorophenoxy)-2-methylpropanoyl chloride (0.450 mmol, 1.1 eq.) according to the general procedure described above (Alternate General Procedure for N-Acylations). Ethyl acetate was used in place of dichloromethane in the workup procedure. Crude product obtained was a tan solid that was subjected to the conditions described above for TMSI-mediated O-benzyl deprotection. Crude product from the deprotection was a brown solid that was purified by column chromatography using 5% methanol/dichloromethane to give the title compound as a white solid (0.270 mmol, 66% for 2 steps). MS (ESI) m/z 591.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH:9]([CH3:11])[CH3:10].Br[C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21].COC1C=C(C=CC2C=CC(C(O)=O)=CC=2)C=C(OC)C=1C(C)C>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH:14]=[CH:15][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=2)[C:20]([OH:22])=[O:21])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH:9]([CH3:11])[CH3:10]
Reactant: C=Cc1cc(OC)c(C(C)C)c(OC)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: COc1cc(C=Cc2ccc(C(=O)O)cc2)cc(OC)c1C(C)C
Product: COc1cc(C=Cc2cccc(C(=O)O)c2)cc(OC)c1C(C)C
Yield: 77 %

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-i-propylphenyl)ethene and 3-bromobenzoic acid in 77% yield in the same way as described in preparation of 1B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.63 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.76 (s, 6H), 7.08 (d, J=17 Hz, 1H), 7.25 (d, J=17 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 8.04 (d, J=7.7 Hz, 1H), 8.31 (s, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:28][CH2:29]1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 34 %

Procedure:
As described for example 69, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (39 mg, 34%) which was obtained as a white foam. MS: m/e=396.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:12])[N:7]=1)=[O:5])[CH3:2].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:14][CH:15]2[CH2:17][CH2:16]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(S)n1
Reactant: BrCC1CC1
Product: CCOC(=O)c1cccc(SCC2CC2)n1
Yield: 81 %

Procedure:
6-Mercapto-pyridine-2-carboxylic acid ethyl ester (0.54 g, 2.94 mmol) obtained in Step A and bromomethyl cyclopropane were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (0.568 g, 81%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].FC(F)(F)C(O)=O.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46]([NH:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[C:52]([O:57][C:58]3[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=3)[C:51]=1[F:67])=[O:47])=[CH:40]2.[CH3:68][C:69]([O:72][C:73]([N:75]1[CH2:80][CH2:79][CH2:78][CH2:77][C@H:76]1[C:81](O)=[O:82])=[O:74])([CH3:71])[CH3:70].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([NH:36][C:81]([C@@H:76]2[CH2:77][CH2:78][CH2:79][CH2:80][N:75]2[C:73]([O:72][C:69]([CH3:71])([CH3:70])[CH3:68])=[O:74])=[O:82])=[CH:45][CH:44]=3)=[O:47])=[C:51]([F:67])[C:52]=1[O:57][C:58]1[CH:63]=[C:62]([C:64]#[N:65])[CH:61]=[C:60]([Cl:66])[CH:59]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
BOP chloride (0.079 g, 0.309 mmol) was added to a solution of 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), (2S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-piperidinecarboxylic acid (0.0236 g, 0.103 mmol) and diisopropylethylamine (0.090 mL, 0.514 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography with hexane:ethyl acetate to give the partially pure (˜85%) compound (0.028 g) as a clear resin.