Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=O)[CH2:6][C:7](=[O:17])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH3:2].C([O-])(=O)C.[NH4+:24]>CCO>[CH2:1]([O:3][C:4](=[O:19])/[C:5](/[NH2:24])=[CH:6]/[C:7](=[O:17])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)/C(N)=C/C(=O)/C=C/c1ccc(Cl)cc1
Yield: 59.2 %

Procedure:
Using the procedure of Example 4, (E)-6-(4-chlorophenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (4; 79.5 g, 0.284 mol) and ammonium acetate (43.78 g, 0.568 mol) were allowed to react in EtOH (795 mL) to provide (2Z,5E)-2-amino-6-(4-chlorophenyl)-4-oxo-hexa-2,5-dienoic acid ethyl ester (8; 47 g, 86%) as a yellow solid: mp 105-107° C.; 1H NMR (400 MHz, CDCl3) δ 9.40 (br s, 1H), 7.52 (d, J=15.9 Hz, 1H), 7.50-7.47 (m, 2H), 7.38-7.32 (m, 2H), 6.78 (d, J=15.9 Hz, 1H), 6.14 (s, 1H), 6.01 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C14H14ClNO3, 279.067. found, 279.066.
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[CH3:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH:16][CH2:23][C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: Cc1ccc(C=O)o1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Agent: [Cl-]
Product: Cc1ccc(CNCCOc2ccc3ccccc3c2F)o1
Yield: 63 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and 5-methylfuran-2-carbaldehyde in 63% yield as a yellow oil. 1H-NMR (CD3OD) δ: 8.00 (1H, d), 7.88-7.84 (1H, m), 7.70 (1H, d, J=8.88 Hz), 7.55 (1H, ddd, J=1.2 Hz, J=6.88 Hz, J=8.50 Hz), 7.46 (1H, ddd, J=1.88 Hz, J=6.88 Hz, J=8.2 Hz), 7.41 (1H, d, J=8.88 Hz), 6.50 (1H, d, J=3.31 Hz) 6.14 (1H, qd, J=0.9 Hz, J=3.31 Hz) 4.47 (2H, t, J=5.00 Hz), 4.41 (2H, s) 3.50 (2H, t, J=5.00 Hz), 2.31 (3H, d, J=0.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:4]2[CH:5]=[N:6][C:2]([NH2:1])=[N:3]2)=[CH:11][CH:10]=1
Reactant: Nc1nc[nH]n1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(Cn2cnc(N)n2)cc1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and 4-methoxy benzyl chloride. The title compound was obtained as a colorless solid, MS ISP (m/e): 205.2 (100) [(M+H)+].
Reaction SMILES: [OH:1][CH:2]([C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].CS([C:31]1[N:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[N:32]=1)(=O)=O>CN(C=O)C>[CH3:40][O:39][C:33]1[CH:34]=[C:35]([O:37][CH3:38])[N:36]=[C:31]([O:1][CH:2]([C:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[C:3]([O:5][CH3:6])=[O:4])[N:32]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(C)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
1.2 g (4.4 mmol) of methyl 2-hydroxy-3,3-diphenylbutyrate were dissolved in 10 ml of absolute DMF and, under nitrogen, 1.2 g (8.8 mmol) of K2CO3 and 0.97 g (4.4 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. The mixture was stirred at room temperature for 16 hours. It was then evaporated, and the residue was taken up in water and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated. 1.8 g of crude product were obtained and were reacted further without purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]([OH:18])(=[O:17])/[CH:14]=[CH:15]/[CH3:16].Cl>O1CCCC1>[C:7]1([CH:15]([CH3:16])[CH2:14][C:13]([OH:18])=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C/C=C/C(=O)O
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(CC(=O)O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
As presented in the following reaction formula, n-butyllithium (n-BuLi; 428 mL, 1.07 mol) was added dropwise at −78° C. to −65° C. to a mixture of bromobenzene (166 g, 1.07 mol) in tetrahydrofuran (THF; 500 mL), followed by stirring at −78° C. for 0.5 hours. Then, (E)-but-2-enoic acid (46 g, 0.53 mol) was added dropwise to the resulting mixture. After the completion of reaction, the mixture was treated with hydrochloric acid so that the pH thereof was adjusted to 1.0, and then extracted twice with 500 mL of dichloromethane (DCM). The combined organic phase was dried and concentrated with magnesium sulfate to give a crude product, which was purified by column chromatography (using 300 g of silica gel (product of Merck Co., Ltd.) to give 3-phenylbutanoic acid (52 g, yield: 60%) as a yellow liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:12]([NH:11][C:9]2[S:10][C:6]([CH2:4][OH:3])=[CH:7][N:8]=2)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: O=C(Nc1ncc(CO)s1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 53 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester (prepared as in Example 1(B)(g), 110 mg, 0.25 mmol) in diethyl ether (2 mL) at 0° C. was slowly treated with lithium aluminum hydride (12 mg, 0.31 mmol). The resulting reaction mixture continued to stir at 0° C. and was allowed to gradually warm to 25° C. The reaction mixture was then stirred at 25° C. over a period of 14 h. The reaction mixture was slowly quenched by the dropwise addition of water (5 mL). The resulting reaction mixture was partitioned between water and ethyl acetate. A saturated aqueous sodium chloride solution was added to break up the emulsions. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide (52.9 mg, 53%) as a light yellow solid: mp 128–130° C.; EI-HRMS m/e calcd for C18H20Cl2N2O2S (M+) 398.0623, found 398.0623.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:9]2[S:13][C:12]([NH2:14])=[N:11][N:10]=2)[CH2:8][CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:9]2[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: Nc1nnc(C2CCC2)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cyclobutyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-cyclobutyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@H:11]3[C@:15]([CH3:17])([OH:16])[C@H:14]([OH:18])[C@@H:13]([CH2:19][OH:20])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@H:11]3[C@:15]([CH3:17])([OH:16])[C@H:14]([OH:18])[C@@H:13]([CH2:19][O:20][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])[O:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1nnc2c(N)ncnc21
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2nnc3c(N)ncnc32)[C@](C)(O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Mixed compound 27.3 (969 mg, 3.4 mmol) with pyridine and concentrated under reduced pressure. The resulting solid was suspended in pyridine 5 mL, treated with TBSCl (615 mg, 4.1 mmol) and the mixture was stirred at r.t. for overnight. The mixture was concentrated down under reduced pressure and water was added to give solid. The suspension was stirred for 30 min, filtered and the solid was dried under reduced pressure to give compound 27.4 (1.33 g, 98% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][NH:6][CH3:7])[CH3:2].[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([N:6]([CH2:5][CH2:4][N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])[CH3:7])[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CCN(CC)CCNC
Product: CCN(CC)CCN(C)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 2-(diethylamino)-ethyl-methyl-amine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][CH:16]=O.[H-].[Na+].[CH3:20][C:21]1[N:34]=[C:33]([NH:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:24]2[N:25]=C(S(C)(=O)=O)[N:27]=[CH:28][C:23]=2[CH:22]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:27]=[CH:28][C:23]2[CH:22]=[C:21]([CH3:20])[N:34]=[C:33]([NH:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:24]=2[N:25]=1
Reactant: Cc1cc2cnc(S(C)(=O)=O)nc2c(NCC(C)(C)C)n1
Reactant: COc1cc(-c2cnn(C)c2)ccc1NC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2cc(C)nc(NCC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.3 %

Procedure:
To a cooled (0° C.) suspension of N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 56, 8.5 mg, 0.037 mmol) in THF (1 mL) was added NaH (60% dispersion in oil, 2.4 mg, 0.059 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0° C. and 6-methyl-2-(methysulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 54, 12.5 mg, 0.040 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 5 hours, whilst slowly warming to room temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc (30 mL) and water (30 mL). The aqueous layer was re-extracted with EtOAc and DCM (25 mL). The combined organic layers were washed with water (25 mL) and brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in cyclohexane. The residue was purified by passage through a SCX-2 cartridge eluting with 100% MeOH-1M NH3 in MeOH to give the title compound (5.0 mg, 32%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:11]1[C:16](=O)[CH:15]=[C:14]([O:18]CC)[CH2:13][CH2:12]1)[CH2:8][CH:9]=[CH2:10]>CCOCC>[CH2:7]([CH:11]1[CH2:16][CH2:15][C:14](=[O:18])[CH:13]=[CH:12]1)[CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCC1CCC(OCC)=CC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCCC1C=CC(=O)CC1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a 0° C. slurry of 1.06 g. (26 mmoles) of lithium aluminum hydride in 75 ml. of ether was added a solution of 10 g. (51 mmoles) of 6-(3-butenyl)-3-ethoxy-2cyclohexen-1-one in 25 ml. of ether. After stirring for one hour, the reaction was quenched by addition of 100 ml. of 2 N hydrochloric acid. The quenched mixture was stirred for 30 minutes and then extracted with 300 ml. of ether. The ether extract was washed with 250 ml. saturated sodium bicarbonate, dried over magnesium sulfate and evaporated on a rotovapor. Distillation of the crude oil gave 5.98 g. (78%) of the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)[O:5][CH:6]1[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH:6]([O:5][C:4]2[CH:17]=[CH:18][C:19]([CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[C:2]([F:1])[CH:3]=2)[CH2:7]1
Reactant: CN1CCN(Cc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(OC3CNC3)cc2F)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
A solution of 29C (0.9 g, 2.4 mmol) in DCM (20 mL) was treated with TFA (10 g, 88 mmol) and stirred at 0° C. for 4 h. The reaction mixture was concentrated and the residue was dissolved in aqueous NaHCO3 (sat.). The mixture was extracted three times with DCM and the organic solutions were filtered through a phase separator. The solvent was removed by evaporation. There was obtained 0.21 g (32%) of 29D as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.28 (s, 3H), 2.28-2.68 (bm, 8H), 3.52 (s, 2H), 3.69-3.85 (m, 2H), 3.85-4.02 (m, 2H), 4.88-5.03 (m, 1H), 6.36-6.58 (m, 2H), 7.15-7.27 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13]([C:15]1[C:20]([CH3:21])=[C:19]([S:22][CH2:23][CH3:24])[CH:18]=[CH:17][N:16]=1)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[Cl:1][C:2]1[N:6]([CH2:12][C:13]([C:15]2[C:20]([CH3:21])=[C:19]([S:22][CH2:23][CH3:24])[CH:18]=[CH:17][N:16]=2)=[O:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CCSc1ccnc(C(=O)CBr)c1C
Reactant: Clc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCSc1ccnc(C(=O)Cn2c(Cl)nc3ccccc32)c1C

Procedure:
2-Chlorobenzimidazole is reacted with 2-bromoacetyl-4-ethylthio-3-methylpyridine in the presence of K2CO3 to give 2-chloro-1-[2-[4-ethylthio-3-methylpyridyl)-2-oxoethyl]benzimidazole. This is reacted with thiourea and treated with NH4OH to give 2-mercapto-1-(2-(2-(4-ethylthio-3-methylpyridyl))-2-oxoethyl)benzimidazole
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:13][C:12]([O:15]CC1C=CC=CC=1)=[CH:11][CH:10]=3.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]2=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=3
Reactant: [H][H]
Reactant: Cc1ccccc1-c1nc2c3cc(OCc4ccccc4)ccc3ccn2c1N
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1-c1nc2c3cc(O)ccc3ccn2c1N
Yield: 83.9 %

Procedure:
To a solution of 5.0 g of 3-amino-9-benzyloxy-2-(2-methylphenyl)imidazo[2,1-a]isoquinoline (Compound 40) in 100 ml of ethanol was added 0.5 g of palladium on activated carbon (Pd 10%). After introduction of hydrogen, the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. Resultant residue was purified by column chromatography on silica gel and recrystallized from water/methanol to give 3.2 g of the title compound as pale yellow needles.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][CH2:21][C@H:20]4[C:11](=[CH:12][CH2:13][C:14]5[CH:15]=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.N.[Li].C(O)C>C1COCC1>[CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][CH2:21][C@H:20]4[C:11](=[CH:12][CH2:13][C:14]5[CH2:15][C:16]([O:23][CH3:24])=[CH:17][CH2:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1
Reactant: COc1ccc2c(c1)CC=C1[C@@H]2CC[C@]2(C)C3OCCOC3C[C@@H]12
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Product: COC1=CCC2=C(CC=C3[C@@H]2CC[C@]2(C)C4OCCOC4C[C@@H]32)C1
Temperature: -33 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of the arene 1 (1.63 g, 5 mmol) in THF (25 mL) was condensed liquid ammonia (100 mL). Small pieces of freshly cut lithium wire (0.6 g, 86 mmol) were added over a period of 5 min at −50° C. The deep blue solution was stirred at −33° C. for 30 min and ethanol (100%, 10 mL) was added over a period of 10 min. The ammonia was allowed to evaporate and water (20 mL) was added. The biphasic mixture was transferred to a separatory funnel and extracted with ether (3×30 mL). The ether extracts were combined, washed with brine, dried over potassium carbonate and concentrated to afford a shiny white solid which was washed with ether (4×20 mL) to give the enol ether 2 (1.2 g, 73%).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[C:23]([Cl:39])=[CH:22][N:21]=1>>[Cl:39][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.043 g, 44%). MP: 61-70° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.33 (s, 1H), 8.52 (d, 1H, J=8.3 Hz), 8.14 (s, 1H), 8.00 (s, 1H), 7.88 (d, 1H, J=7.8 Hz), 7.55 (t, 1H, J=7.5 Hz), 7.50 (s, 1H), 7.26-7.21 (m, 1H), 6.65 (s, 1H), 5.91 (tt, 1H, J=56.1 Hz and 4.2 Hz), 3.87 (s, 3H), 2.97-2.69 (m, 16H). MS: 567.46 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][C:37](O)=[O:38]>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([C:37](=[O:38])[CH2:36][CH2:35][N:34]([CH3:40])[CH3:33])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CCC(=O)O
Agent: Cl
Product: CN(C)CCC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Yield: 18.3 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.183 mmol) was coupled to N,N-dimethyl-beta-alanine hydrochloride (29 mg, 0.189 mmol) following the procedure described in step 1 of Example 120. The product was purified via HPLC using a Sunfire Prep C18 OBD 5 micron, 30×75 mm column. The compound was eluted using a gradient 10-70% acetonitrile/water with 0.1% TFA over 20 minutes to yield (17 mg, 18%) title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.92 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.36-7.32 (m, 4 H), 7.14 (d, 1 H), 6.68 (d, 1 H), 5.64 (s, 2 H), 4.00-3.30 (m, 9 H), 2.45-2.05 (m, 2H), 2.07 (s, 6 H); ES-MS m/z 509.2 [M+H]+, HPLC RT (min) 2.11.
Reaction SMILES: [CH3:1][C:2]1[C:3](I)=[C:4]([OH:23])[CH:5]=[C:6]([CH3:22])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=1>CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([CH:19]([CH3:21])[CH3:20])[CH:10]=2)=[C:6]([CH3:22])[CH:5]=[C:4]([OH:23])[C:3]=1[C:16]([O:15][CH3:12])=[O:17]
Reactant: COCOc1ccc(Cc2c(C)cc(O)c(I)c2C)cc1C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Product: COCOc1ccc(Cc2c(C)cc(O)c(C(=O)OC)c2C)cc1C(C)C
Temperature: 80 °C
Yield: 75.7 %

Procedure:
A mixture of 3,5-dimethyl-2-iodo-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)phenol (compound 47, step a; 1.0 g, 2.27 mmol) and PdCl2(PPh3)2 (0.10 g, 0.14 mmol) in TEA (1.6 mL) and methanol (8.0 mL) was heated under a CO atmosphere (60 psi) at 80° C. for 72 h. The reaction mixture was cooled to room temperature and filtered through a Celite plug. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluting with 10% ethyl acetate in hexanes to afford methyl 2,4-dimethyl-6-hydroxy-3-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzoate (0.32 g, 38%): 1H NMR (300 MHz, CD3OD): δ 6.93 (m, 2 H), 6.67 (s, 2 H), 5.18 (s, 1 H), 3.98 (s, 2 H), 3.92 (s, 3 H), 3.48 (s, 3 H), 3.30 (m, 1 H), 2.22 (m, 6 H), 1.18 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:5); Rf=0.60.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([OH:15])[CH2:10][CH2:11][C:12]([O-:14])=[O:13].[Na+].[H-].[Na+].F[C:20]1[CH:27]=[C:26]([O:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>O1CCCC1>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][C:20]=1[O:15][CH:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])#[N:23]
Reactant: N#Cc1ccc(OCc2cccnc2)cc1F
Reactant: Cc1cccc(C(O)CCC(=O)[O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C(CCC(=O)O)Oc2cc(OCc3cccnc3)ccc2C#N)c1C
Temperature: 57.5 °C
Yield: 47 %

Procedure:
A solution of sodium (RS)-4-(2,3-dimethylphenyl)-4-hydroxybutanoate (1 g) is added to a stirred suspension of sodium hydride (0.5 g, 60% dispersion in mineral oil) in tetrahydrofuran (50 mL) under nitrogen. The mixture is stirred at room temperature for 3 hours when 2-fluoro-4-(3-pyridylmethoxy)benzonitrile (1 g) is added in one portion. The reaction mixture is heated at 55-60° C. for 18 hours and evaporated. The residue is dissolved in water (100 mL), the solution acidified to pH 1 with 1 N hydrochloric acid. The precipitated solid Is filtered, washed with water, ethyl acetate and ether, dried, and recrystallised from ethyl acetate to give (RS)-4-[2-cyano-5-(3-pyridylmethoxy)-phenoxy]-4-(2,3-dimethylphenyl)butanoic acid (0.85 g) as a white solid, m.p. 187-189° C. [Elemental analysis:- C,71.76; H,6.59; N,5.67%. Calculated:- C,72.10; H,6.73; N,5.81%]
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>CN(C=O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][C:7]([C:5]2[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH:16]=1
Reactant: Nc1cccnc1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2cccnc2)c(C(F)(F)F)n1
Reaction time: 72 h
Yield: 38.2 %

Procedure:
2.5 g (12.9 mmol) of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid in 25 mL of N,N-dimethylformanid (DMF) and 2.1 g (12.9 mmol) of N,N′-carbonyl diimidazole (CDI) were stirred at ambient temperature for 1 hour prior to addition of 1.2 g (12.9 mmol) of 3-aminopyridine. After three days of stirring the solvent was evaporated, the residue dissolved in dichloromethane, washed twice with a saturated solution of NaHCO3 and water. The combined organic phases were evaporated and the crude product was purified by flash column chromatography (silica using dichloromethane/methanol=95/5) to give 1.33 g (48%) of the title compound.