Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH:4]1[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]3[CH2:10][NH:9][C:8](=[O:17])[C:7]=3[C:6]=2[CH2:5]1)([O-])=O.C1COCC1.O.NN>CCO.[Ni]>[NH2:1][CH:4]1[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]3[CH2:10][NH:9][C:8](=[O:17])[C:7]=3[C:6]=2[CH2:5]1
Reactant: O=C1NCc2ccc3c(c21)CC([N+](=O)[O-])CO3
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: NC1COc2ccc3c(c2C1)C(=O)NC3
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of 8-nitro-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one ((69), 700 mg, 2.99 mmol) in EtOH (35 ml)/THF (5 ml) was added hydrazine monohydrate (1.65 ml, 34 mmol), followed by addition of Raney-Nickel (50 mg). The reaction mixture was stirred for 4 hr. The catalyst residue was filtered under vacuum and organic solution was concentrated in vacuo to give the title compound as a solid (420 mg, 69%). MS (ES) m/z 205.1
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCNC4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.[CH:59]1([C:63](Cl)=[O:64])[CH2:62][CH2:61][CH2:60]1>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:63]([CH:59]5[CH2:62][CH2:61][CH2:60]5)=[O:64])[CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCC1)N1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.11 mmol) in CH2Cl2 (1.40 mL) and DMF (300μ was added N,N-diisopropyl-N-ethylamine (0.30 mL, 1.70 mmol) followed by cyclobutanecarbonyl chloride (0.01 g. 0.12 mmol). The reaction mixture was allowed to stir at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 395.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[N:18][CH:19]=1.C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][C:30]1=[O:36]>C(O)C>[CH3:28][N:29]1[C:30](=[O:36])[CH2:31][C:32]2[N:8]([CH2:12][CH2:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:5]3[CH:4]=[CH:3][C:2]([CH3:10])=[CH:7][C:6]=3[C:33]=2[CH2:34]1
Reactant: CN1CCC(=O)CC1=O
Reactant: Cc1ccc(CCBr)cn1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CC(=O)N(C)C1
Yield: 1.5 %

Procedure:
Preparation of the title compound was carried out according to General Method 8. p-Tolylhydrazine hydrochloride (1.27 g, 8 mmol), 5-(2-bromoethyl)-2-methylpyridine (1.6 g, 8 mmol), triethyl amine (3.5 ml, 24 mmol) and 1-methylpiperidine-2,4-dione (4.2 g, 8 mmol) were taken in ethanol (25 ml) to obtain 40 mg of 1,2-dihydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-4H-pyrido[4,3-b]indol-3(5H)-one after purification on silica gel (230-400 mesh) chromatography eluting with methanol-dichloromethane gradient. To this intermediate (25 mg, 0.07 mmol) was added N-bromo succinamide (26 mg, 0.1), and azobisisobutyronitrile (1 mg) in carbon tetrachloride (10 ml) and the reaction mixture was heated at 80° C. for 12 h to obtain 5 mg of 4-bromo-1,2-dihydro-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-4H-pyrido[4,3-b]indole-3(5H)-one as a trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [Cl:1][CH:2]1[C:10](Cl)([OH:11])[CH:9]=[CH:8][C:4]([C:5]([OH:7])=O)=[C:3]1[OH:13].[ClH:14].[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:14])[C:10]([OH:11])=[C:2]([Cl:1])[C:3]=1[OH:13]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cl
Reactant: O=C(O)C1=C(O)C(Cl)C(O)(Cl)C=C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc(Cl)c(O)c(Cl)c1O
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 3,4-dichloro-2,4-dihydroxybenzoic acid (17 g), L-phenylalanine methyl ester hydrochloride (19.8 g), WSC.HCl (17.6 g) and HOBT (12.4 g) in DMF (70 ml) was added dropwise triethylamine (12.8 ml) at room temperature, and the mixture was stirred for 16 hours. Then, the mixture was post-treated in the same manner as in the above Example 1, (Step 5) to give the title compound (18.32 g, yield 57%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH2:12][C:13](=[O:18])[CH2:14]2)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH2:12][CH:13]([OH:18])[CH2:14]2)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81.1 %

Procedure:
NaBH4 (8.8 g, 0.23 mol) was added to a 0° C. solution of 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35 g, 0.16 mol) in ethanol (200 ml). The reaction mixture was stirred for 45 min at 0° C., whereupon it was allowed to reach 20° C. After stirring overnight the suspension was evaporated to dryness. EtOAc (350 ml) was added, and the precipitate was filtered off. Water (200 ml) was added to the filtrate, and the layers were separated. The aqueous layer was extracted with EtOAc (100 ml), and the combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford 29.5 g of an oil, which crystallised on standing. The two isomers were separated by flash chromatography (EtOAc/heptane 1:5 1:1), affording 5 g of the title compound. LC-MS (m/z): 250 (M+23 (Na)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[CH:11])=[CH:5][CH:4]=1.Br[C:13]1[C:14]([NH:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.O.[Cu]I.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>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][N:21]1[C:14]2[N:15]=[C:16]([C:19]#[N:20])[N:17]=[CH:18][C:13]=2[CH:11]=[C:10]1[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Reactant: C#CCc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 80 °C

Procedure:
1-Methoxy-4-prop-2-ynyl-benzene (3.01 mmol) is dissolved in DMF (7 ml) at room temperature under nitrogen atmosphere. To the solution, 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (2.01 mmol), triethylamine (6 mmol), copper(I) iodide (0.2 mmol), and dichlorobis(triphenylphosphine)palladium (II) (0.1 mmol) are added successively. The mixture is heated at 80° C. under nitrogen atmosphere for 3 h. After cooling at room temperature, the mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=7:1) to give 7-(2,2-dimethyl-propyl)-6-(4-methoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 57%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[C:9](C1NC=CN=1)(C1NC=CN=1)=[O:10].[CH:21]1([NH:28][C@H:29]2[CH2:34][CH2:33][C@H:32](C)[CH2:31][CH2:30]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]C1>CN(C1C=CN=CC=1)C.C1COCC1>[CH:29]1([N:28]([CH:21]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:9]([NH:1][C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)=[O:10])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ncc(C=O)s1
Reactant: C[C@H]1CC[C@H](NC2CCCCCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.3 %

Procedure:
2-Amino-5-formylthiazole (2.56 g, 20.0 mmol), carbonyl-diimidazole (3.25 g, 20.0 mmol) and a catalytic amount of DMAP were heated together in 60 mL THF at 50° C. for 3 h. To this solution was added cycloheptyl-(trans-4-methylcyclohexyl)amine (4.18 g, 20.0 mmol) and the reaction mixture was stirred for an additional 6 h at room temperature. The reaction mixture was concentrated and the crude product was purified by flash chromatography (silica, CH2Cl2-EtOAc, 4:1) to obtain 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (2.3 g, 31% yield).
Reaction SMILES: [CH:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li][CH2:13]CCC.IC>C1COCC1>[CH3:13][C:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: CCCCOS(=O)(=O)C1CC1
Solvent: C1CCOC1
Solvent: CI
Product: CCCCOS(=O)(=O)C1(C)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a solution of butyl cyclopropanesulfonate (1.5 g, 8.4 mmol) in THF (8 mL) at about −78° C., n-BuLi (1.6 M in hexanes, 5.26 mL, 8.42 mmol) and iodomethane (0.684 mL, 10.9 mmol) were added simultaneously and the resulting mixture was stirred at about −78° C. for about 2 h and then at ambient temperature for about 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl (7 mL) and the layers were separated. The aqueous layer was back extracted with EtOAc (15 mL) and the combined organic extracts were dried over anhydrous MgSO4 and concd under reduced pressure. The residue was subjected to silica gel column chromatography (5 to 25% EtOAc in heptane over 30 min) to yield butyl 1-methylcyclopropane-1-sulfonate (0.8 g, 49%) as a colorless oil. 1H NMR (DMSO-d6) δ 4.17 (t, 2H), 1.62 (m, 2H), 1.43 (s, 3H), 1.35 (m, 2H), 1.22 (m, 2H), 0.94 (m, 2H), 0.88 (t, 3H).
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][C:4]([N:7]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.I[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][C:61](I)=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82]>C1(C)C=CC=CC=1.[Cu].C(OCC)(=O)C>[C:30]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:31]=[CH:32][C:27]([N:7]([C:4]2[CH:3]=[CH:2][C:1]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:6][CH:5]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:46]4[CH:51]=[CH:50][C:49]([C:52]5[CH:57]=[CH:56][C:55]([C:58]6[CH:63]=[CH:62][C:61]([N:20]([C:80]7[CH:81]=[CH:82][C:77]([C:76]8[CH:71]=[CH:72][C:73]([N:7]([C:8]9[CH:9]=[CH:10][C:11]([C:14]%10[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=%10)=[CH:12][CH:13]=9)[C:4]9[CH:5]=[CH:6][C:1]([C:39]%10[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=%10)=[CH:2][CH:3]=9)=[CH:74][CH:75]=8)=[CH:78][CH:79]=7)[C:21]7[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=7)=[CH:60][CH:59]=6)=[CH:54][CH:53]=5)=[CH:48][CH:47]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)=[CH:28][CH:29]=1
Reactant: c1ccc(Nc2ccc(-c3ccc(N(c4ccc(-c5ccccc5)cc4)c4ccc(-c5ccccc5)cc4)cc3)cc2)cc1
Reactant: CCCCCCCCCCCC
Reactant: Ic1ccc(-c2ccc(-c3ccc(I)cc3)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccc(N(c5ccccc5)c5ccc(-c6ccc(-c7ccc(N(c8ccccc8)c8ccc(-c9ccc(N(c%10ccc(-c%11ccccc%11)cc%10)c%10ccc(-c%11ccccc%11)cc%10)cc9)cc8)cc7)cc6)cc5)cc4)cc3)cc2)cc1
Temperature: 45 °C
Yield: 65.9 %

Procedure:
There were mixed 12.68 g (0.022 mole) of N,N-bis(biphenyl-4-yl)-N′-phenyl-4,4′-diaminobiphenyl, 5.00 g (0.01 mole) of 4,4″-diiodo-p-terphenyl, 4.14 g (0.030 mole) of anhydrous potassium carbonate, 0.32 g (0.005 mole) of copper powder and 10 ml of n-dodecane, followed by reaction at 195 to 210° C. for 30 hours. The reaction product was extracted with 800 ml of toluene, and the insoluble matter was removed by filtration. Then, the filtrate was concentrated. After the concentration, 100 ml of methanol was added to perform crystallization, and suction filtration was performed to obtain crude crystals. The crude crystals were dissolved in 300 ml of toluene under reflux, and allowed to cool down to 45° C. Then, 300 ml of ethyl acetate was added dropwise to perform crystallization, thereby obtaining crystals. N,N′-bis[4-{bis(biphenyl-4-yl)amino}biphenyl-4′-yl]-N,N′-diphenyl-4,4″-diamino-p-terphenyl was obtained in an amount of 9.43 g. The yield was 65.9%, and the HPLC purity was 94.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]3[O:33][CH2:32][C@H:31]([CH2:34]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:30][C:26]3=2)[N:21]=1.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][N:16]([CH2:34][C@@H:31]3[O:30][C:26]4=[C:27]5[C:22](=[CH:23][CH:24]=[C:25]4[O:33][CH2:32]3)[N:21]=[C:20]([CH3:19])[CH:29]=[CH:28]5)[CH2:15][CH2:14]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2nc(N3CCN(C[C@H]4COc5ccc6nc(C)ccc6c5O4)CC3)ccc2c1
Temperature: 90 °C
Yield: 48.1 %

Procedure:
A mixture of 6-methoxy-2-piperazin-1-yl-quinoline of Step D (1.05 g, 4.31 mmol) in dimethylsulfoxide (15 mL) and [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromobenzene sulfonate (1.62 g) is heated at 80° C. under nitrogen for 3 hours and at 90° C. for 1 additional hour. The solution is poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica gel Merck-60 using a gradient of methanol (0.5–3%) in dichloromethane-hexane (1:1) containing 0.1% ammonium hydroxide to provide the title compound (0.790 g). The pure material is charcoalized (in ethyl acetate), filtered, evaporated and induced to crystallize from hexane by sonication. The off-white solid melts at 158–160° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])(C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:29])([CH3:28])[CH2:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:29])([CH3:28])[CH2:21][C:22]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)([OH:27])[C:23]([F:25])([F:26])[F:24])=[CH:16][CH:15]=1
Reactant: Cc1ccccn1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(CC(O)(Cc1ccccn1)C(F)(F)F)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-picoline in 1 mL of THF was cooled down to −78° C. tert-Butyl lithium (1.7 M in pentanes, 0.2 mL (0.34 mmol)) was added dropwise over 5 minutes. The mixture stirred at −78° C. for 15 minutes, and then a solution of 40 mg of 4-(4-chlorophenyl)-1,1,1-trifluoro-4-methylpentan-2-one in 0.5 mL of THF was added. Stirring continued at −78° C. for 20 minutes. The reaction was quenched with 0.5 N HCl and extracted three times with EtOAc. The organic layers were combined and washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to yield 9.6 mg of the title compound as a light yellowish oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:29])([CH3:28])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[F:15])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[F:15][C:14]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[C:8]([CH3:29])([CH3:28])[CH2:7][C:6]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(F)ccc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2c(ccc(F)c2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (400 mg, 1.0 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (345 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25FN2O3 (M+H)+: 385.45, observed: 385.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]#N)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:3]1.[OH-:20].[Na+].[OH2:22].Cl>C(O)C>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([OH:22])=[O:20])=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:3]1
Reactant: [OH-]
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CC#N
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CC(=O)O
Temperature: 85 °C
Reaction time: 14 h

Procedure:
A mixture of [2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-acetonitrile (267 mg, 1 mmol), sodium hydroxide (403 mg, 10 mmol), water (4 ml) and ethanol (4 ml) was stirred vigorously at 85° C. for 14 h. The reaction mixture was poured onto crushed ice and aqueous HCl and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 286 mg (1 mmol, quant.) of the title compound as off-white crystals.
Reaction SMILES: C(OC(NC(NCCO[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[CH:43]=[CH:42][CH:41]=[C:40]4[C:35]=3[CH2:36][CH2:37][CH2:38][N:39]4[C:44](=[O:57])[CH2:45][CH2:46][CH2:47][O:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=3[CH3:56])[CH:31]=[N:30]2)[CH:23]=1)=NC(=O)OC(C)(C)C)=O)(C)(C)C.C(OC(NC(NC(OC(C)(C)C)=O)=N)=O)(C)(C)C.[Br:76][CH2:77][CH2:78][CH2:79][OH:80]>>[Br:76][CH2:77][CH2:78][CH2:79][O:80][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[CH2:28][N:29]1[CH:33]=[C:32]([C:34]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:35]=2[CH2:36][CH2:37][CH2:38][N:39]3[C:44](=[O:57])[CH2:45][CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[C:50]=2[CH3:56])[CH:31]=[N:30]1
Reactant: OCCCBr
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c5)c4)cccc32)c1C
Agent: CC(C)(C)OC(=O)NC(=N)NC(=O)OC(C)(C)C
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCCBr)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to tert-butyl (tert-butoxycarbonylamino)(2-(3-((4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)methyl)phenoxy)ethylamino)-methylenecarbamate except that 1,3-bis(tert-butoxycarbonyl)-guanidine was replaced with 3-bromopropan-1-ol. LCMS, [M+H]+=616.3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:16]=[C:15]([C:26]([OH:28])=O)[CH:14]=1)#[N:2].Cl.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C@H:37]([NH2:39])[CH3:38])[CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=1[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:16]=[C:15]([C:26]([NH:39][C@H:37]([CH3:38])[CH2:36][N:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)=[O:28])[CH:14]=1)#[N:2]
Reactant: C[C@@H](N)CN1CCOCC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cc(C(F)(F)F)ccc3C#N)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3cc(C(F)(F)F)ccc3C#N)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 2′-cyano-5-(5-methylpyridin-2-yl)-5′-(trifluoromethyl)biphenyl-3-carboxylic acid (30 mg, 0.078 mmol), (R)-1-morpholinopropan-2-amine hydrochloride (33 mg, 0.18 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (145 mg, 0.38 mmol), N,N-diisopropylethylamine (106 μL, 0.61 mmol), N,N-dimethylformamide (0.5 mL) and the reaction was stirred overnight at room temperature. The mixture was purified by HPLC to afford the title compound as a light orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:15].P(Br)(Br)(Br)(Br)Br.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: BrP(Br)(Br)(Br)Br
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]

Procedure:
The conversion of 2-methyl-3-nitrobenzoic acid (II) to a 2-methyl-3-nitrobenzoyl halide (III) may be effected by reacting II with a suitable halogenating agent, such as phosphorus pentachloride, phosphorus pentabromide, thionyl chloride, and the like, preferably thionyl chloride, in a suitable inert solvent, such as dry benzene, at a temperature from room temperature to reflux until the reaction is complete and removing the solvent under reduced pressure. Preferably, II is converted to 2-methyl-3-nitrobenzoyl chloride by simply refluxing it in pure thionyl chloride for about 2-6 hours and removing the excess thionyl chloride under reduced pressure. The preferred 2-methyl-3-nitrobenzoyl chloride is obtained in yields of 95-100% of theoretical.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][CH:19](O)[CH2:20][CH2:21][CH2:22]Cl.ClCCC1[O:30]C1>>[Cl:18][CH2:19][CH:20]([OH:30])[CH2:21][CH2:22][O:17][C:15]1[CH:14]=[CH:13][C:10]2[CH2:11][CH2:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[CH:16]=1
Reactant: OC(Cl)CCCCl
Reactant: ClCCC1CO1
Reactant: Oc1ccc2c(c1)OC(c1ccccc1)CC2
Product: OC(CCl)CCOc1ccc2c(c1)OC(c1ccccc1)CC2

Procedure:
The starting 1-chloro-4-(2-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-2-butanol was prepared from 2-phenyl-7-hydroxy-3,4-dihydro-2H-1-benzopyrane (J.Chem. Soc., 3137; 1954) and 1,4-dichlorobutanol according to example 1 (b), or from 1-phenyl-7-hydroxy-3,4-dihydro-2H-1-benzopyrane and 1-chloro-3,4-epoxybutane according to example 1 (c).