Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C[O:7][C:8]([C:10]1[C:14]([NH:15][C:16]([C:18]2[C:23]([NH:24][C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:21]=[C:20]([CH:31]3[CH2:33][CH2:32]3)[N:19]=2)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=1)=O>>[CH:1]1([NH:5][C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[C:23]([NH:24][C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)=[CH:22][CH:21]=[C:20]([CH:31]4[CH2:33][CH2:32]4)[N:19]=3)=[O:17])=[CH:13][N:12]([CH3:34])[N:11]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NC2CCC2)n1
Yield: 24 %

Procedure:
According to the general method described in step 5 of example 27, reaction of cyclobutylamine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (24%) as yellow powder.
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=O)[O:18][C:17]=2[CH3:24])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.C(O)C.O.[NH2:29][NH2:30].C(O)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:18])[N:29]([NH2:30])[C:17]=2[CH3:24])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: Cc1cc(=O)oc(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(=O)n(N)c(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 33 %

Procedure:
To a solution of 2,4-dimethyl-6-oxo-6H-pyran-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (419 mg, 1.27 mmol) in ethanol (4.0 mL, 70 mmol) were added hydrazine hydrate (370 uL, 7.6 mmol) and acetic acid (4.0 mL, 70 mmol). The mixture was heated at 80° C. for 24 hrs. More hydrazine hydrate (371 uL, 7.63 mmol) was added and stirring continued for 7 hrs. The reaction mixture was adjusted to neutral pH by addition of aq. Sat. Na2CO3. The crude mixture was extracted with dichloromethane (4×40 mL), combined organic phases were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash chromatography to give the title compound, yield 33%. LC-MS (m/z) 344.4 (MH+); tR=1.32 (method C). 1H NMR (600 MHz, CDCl3): 7.84 (d, J=8.6 Hz, 1H), 7.34 (td, J=7.9, 6.0 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 7.17-7.11 (m, 1H), 6.99 (td, J=8.3, 2.0 Hz, 1H), 6.02 (s, 1H), 5.22 (s, 2H), 5.11-5.02 (m, 1H), 2.87-2.75 (m, 1H), 2.29 (s, 3H), 2.24 (m, 1H), 2.05 (s, 3H), 2.00-1.75 (m, 5H). 13C NMR (151 MHz, CDCl3) 166.34, 162.14, 159.96, 146.98, 143.64, 142.71, 130.10 (d, J=8.2 Hz, 1C), 122.78, 118.63, 114.34 (d, J=21.0 Hz, 1C), 114.14, 113.79 (d, J=21.6 Hz, 1C), 58.74, 40.05, 26.17, 25.59, 19.48, 17.49, 16.63.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CCOCC.O.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: Nc1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1
Yield: 66.3 %

Procedure:
To a suspension of 1-(4-fluorophenyl)-4-[ (4-nitrophenyl)methyl ]piperazine (1.5 g, 0.005 M) in 15 ml of anhydrous ether is added dropwise a solution of 15 ml of titanium trichloride in water (20% solution in water), under nitrogen at room temperature. After complete addition, the mixture is quenched with 10% ammonium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is washed with water, dried (anhydrous sodium sulfate), and concentrated to a yellow solid. This, after recrystallization from ethyl acetate/Skellysolve® B, gives 900 mg (64%) of white crystalline 1-[ (4-aminophenyl)methyl ]-4-(4-fluorophenyl)piperazine of melting point 130° - 132° C.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]([CH3:10])[C:7](O)=[O:8])(=[O:4])=[O:3].[CH3:11][N:12]1[CH2:16][C@@H:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:14][C:13]1=[O:24]>>[CH3:11][N:12]1[CH2:16][C@@H:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[N:14]([C:7](=[O:8])[C@H:6]([O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:10])[C:13]1=[O:24]
Reactant: C[C@@H](OS(C)(=O)=O)C(=O)O
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Product: C[C@@H](OS(C)(=O)=O)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Yield: 75.8 %

Procedure:
D-lactic acid O-mesylate, namely (2R)-2-(methanesulfonyloxy)propionic acid (2.5 g) and t-butyl (4S)-1-methyl-2-oxoimidazolidine-4-carboxylate (3.42 g) were treated similarly as in Example 1 - (1), and the crude product was purified by silica gel chromatography (chloroform:ethyl acetate=1:2) and crystallized from n-hexane to give t-butyl (4S)-1-methyl-3-[(2R)-2-(methanesulfonyloxy)-propionyl]-2-oxoimidazolidine-4carboxylate (3.95 g). Yield: 75.8%., m.p.: 97°-100° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:18])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.I[CH2:31][CH3:32]>C(OCC)(=O)C>[C:12]1([S:9]([N:5]2[CH:6]=[C:7]([F:8])[C:2](=[NH:1])[N:3]([CH2:31][CH3:32])[C:4]2=[O:18])(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCI
Reactant: Nc1nc(=O)n(S(=O)(=O)c2ccccc2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(=N)c(F)cn(S(=O)(=O)c2ccccc2)c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a 25 mL sealed tube were added 4-amino-1-benzenesulfonyl-5-fluoro-1H-pyrimidine-2-one (1.0 g, 3.71 mmol), anhydrous potassium carbonate (K2CO3; 2.05 g, 14.9 mmol), and N,N-dimethylformamide (DMF; 10 mL), followed by iodoethane (EtI; 3.45 g, 22.3 mmol). The reaction vessel was sealed, and the reaction mixture was warmed to 60° C. and stirred for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (EtOAc; 250 mL), and washed with water (H2O; 3×100 mL). The organic phase was dried over magnesium sulfate (MgSO4), filtered, and the solvent evaporated under reduced pressure. Purification by flash chromatography (SiO2, EtOAc/Hexanes gradient) afforded benzenesulfonyl-5-fluoro-4-imino-3-ethyl-3,4-dihydro-1H-pyrimidin-2-one as a pale yellow solid (200 mg; 18%): mp 163-166° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (m, 1H), 8.29 (d, J=6.8 Hz, 1H), 8.02 (dd, J=8.4, 1.1 Hz, 2H), 7.79 (ddd, J=6.9, 2.3, 1.1 Hz, 1H), 7.66 (dd, J=10.7, 4.9 Hz, 2H), 3.31 (q, J=7.2 Hz, 2H), 1.09 (t, J=7.2 Hz, 3H); ESIMS m/z 298 ([M+H]+).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH:17]([CH2:18]O)[CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([NH:9][C:10]1[S:11][CH2:18][C@@H:17]2[CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][C@:13]2([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[N:12]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2cccs2)C1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccs2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of racemic tert-butyl 3-(benzoylcarbamothioylamino)-4-(hydroxymethyl)-3-(2-thienyl)pyrrolidine-1-carboxylate (3.8 g, 8.23 mmol) in dichloromethane (206 mL) cooled to 0° C. is added drop wise 1-chloro-N,N,2-trimethylpropenylamine (2.18 mL, 16.46 mmol). The reaction is warmed to room temperature and is stirred for 2 hours. To the reaction mixture is added a saturated solution of sodium bicarbonate and dichloromethane. The mixture is extracted with dichloromethane. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated to give a residue. The residue is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give the title compound (3.30 g, 90%). ES/MS (m/e): 444 (M+H). The racemic ten-butyl-3-(benzoylcarbamothioylamino)-4-(hydroxymethyl)-3-phenyl-pyrrolidine-1-carboxylate (3.2 g, 7.4 mmol) is dissolved in methanol/chloroform (36 ml/25 ml) and is separated into its constituent enantiomers by chiral SFC (Chiralpak OJ-H 50×250 mm; eluent: 25% methanol in 75% CO2; flow 300 g/min at UV 240 nm; column temperature −40° C.; 0.64 g/injection). Analysis of isolated enantiomer (Chiralpak OJ-H 4.6×150 mm; eluent: 25% methanol in 75% CO2; flow 5 mL/min at UV 240 nm, column temperature −35° C.) gave the title compound with Rt=1.5 min, isomer 1, (1.27 g, 39%, >99% ee).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].CCN(C(C)C)C(C)C.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.[CH3:54][O:55][NH:56][CH3:57]>CN(C=O)C>[CH3:54][O:55][N:56]([CH3:57])[C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (10 g, 42.0 mmol) was dissolved in DMF (200 mL) and Hunig's Base (20.54 mL, 118 mmol). Benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP, 27.9 g, 63.0 mmol) and N-methoxy-N-methylamine hydrochloride (4.51 g, 46.2 mmol) were added to the reaction flask, and the resulting reaction mixture was stirred at 25° C. overnight. Crude reaction mixture was concentrated and purified on a silica gel column (340 g cartridge 0-10% EtOAc/Hexanes gradient) to afford N-methoxy-N-methyl-3-(1,1,2,2-tetrafluoroethoxy)benzamide. 1H NMR (400 MHz, CDCl3) δ 3.38 (s, 3H), 3.57 (s, 3H), 5.95 (t, J=52.9, 2.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.58 (s, 1H), 7.63 (d, J=7.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13]C(=O)C)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: CC(=O)Oc1ccc(Br)c2c1CCC(=O)N2
Agent: Cl
Product: O=C1CCc2c(O)ccc(Br)c2N1
Yield: 78.2 %

Procedure:
The thus-obtained 21 g of 8-bromo-5-acetyloxy-3,4-dihydrocarbostyril are dispersed in 150 ml of 8N-hydrochloric acid. The dispersion is heated under reflux conditions for 3 hours and then cooled. The insoluble matter thus formed is separated by filtration, washed with water and dried, and recrystallized from methanol-water to obtain 14 g of 8-bromo-5-hydroxy-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 212°-213° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:45][C:44]2[CH:46]=[CH:47][CH:48]=[C:42]([O:41][C:32]3[C:31]4[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=4)[N:35]=[CH:34][N:33]=3)[CH:43]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (0.14 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113 (0.119 g, 0.4 mmol) and DMAP (0.025 g) in THF (6 mL) was stirred at room temperature overnight. The reaction was quenched by adding DCM and concentrated. To the residue was added Et2O to give 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea as solid (0.181 g, 82%). 1H NMR (300 MHz, DMSO-d6) 1.25 (s, 9H), 2.37 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 6.33 (s, 1H), 6.93 (d, 1H), 7.16 (d, 1H), 7.32-7.40 (m, 6H), 7.55 (d, 2H), 8.41 (s, 1H), 8.55 (s, 1H), 9.23 (s, 1H); LC-MS (ESI) m/z 553 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[BrH:14]>>[Br:14][CH2:2][C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Br
Reactant: O=c1[nH]c2ccccc2cc1CO
Product: O=c1[nH]c2ccccc2cc1CBr
Reaction time: 3 h

Procedure:
To 5 g of 3-hydroxymethylcarbostyril was added 50 ml of 47%-hydrobromic acid and the mixture was stirred at 70°-80° C. for 3 hours. After cooled the reaction mixture, the crystals precipitated were collected by filtration and were recrystallized from methanol to obtain 6 g of 3-bromomethylcarbostyril in the form of colorless needle-like crystals.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[C@H:23]([C:34](=[O:39])[N:35]([O:37][CH3:38])[CH3:36])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(Cl)[Cl:41].[ClH:44]>CCOCC>[ClH:41].[ClH:44].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][NH:24][C@H:23]([C:34]([N:35]([O:37][CH3:38])[CH3:36])=[O:39])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: ClC(Cl)Cl
Reactant: CON(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CON(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To the product from Step A (0.032 g, 0.0601 mmol) was added CHCl3 (0.600 mL) and HCl (0.451 mL, 1.80 mmol, 4.0M in dioxane). The mixture was stirred at ambient temperature for 9 hours, then diluted with Et2O (5 mL) and filtered. The solid was washed with Et2O and dried in vacuo. This provided 0.026 g (82%) of the desired product as a pale yellow solid. MS ESI (+) m/z 433.1 (M+1) detected.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[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:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.029 g, 27%). MP: 114-121° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 10.15 (s, 1H), 8.52 (d, 1H, J=8.3 Hz), 8.06-8.04 (m, 2H), 7.85 (s, 1H), 7.82-7.80 (m, 1H), 7.46 (s, 1H), 7.40-7.32 (m, 2H), 7.19 (t, 1H, J=7.7 Hz), 6.63 (s, 1H), 6.52-6.50 (m, 1H), 3.86 (s, 3H), 2.90-2.73 (m, 10H), 1.69 (t, 3H). MS: 540.43 (H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([N:5]1[CH2:11][CH:10]2[CH:12]([NH:13][CH3:14])[CH:7]([CH2:8][CH2:9]2)[CH2:6]1)=[O:4].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([N:13]([CH3:14])[CH:12]1[CH:10]2[CH2:9][CH2:8][CH:7]1[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:16])([F:1])[F:15])[CH2:11]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CNC1C2CCC1CN(C(=O)C(F)(F)F)C2
Solvent: CC#N
Product: CN(Cc1ccccc1)C1C2CCC1CN(C(=O)C(F)(F)F)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
A mixture of 2,2,2-trifluoro-1-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]-1-ethanone (see step (v) above; 4.5 g, 16 mmol), benzylchloride (3.0 g, 16 mmol) and TEA (6.6 mL) in MeCN (50 mL) was stirred at 60° C. overnight. The mixture was evaporated and then DCM and water were added. The organic phase was washed with NaHCO3 solution, dried (Na2SO4) and then evaporated. The resulting crude product was purified by chromatography on silica gel (DCM eluant) to give 2.2 g (42%) of the sub-title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH3:2])=[C:4]1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1, 0.110 g, 0.445 mmol) is suspended in THF (3 mL) and cooled to 0° C. KHMDS (0.5M in toluene, 2 mL, 1 mmol) is added dropwise, the cooling bath is lowered and the mixture is stirred at room temperature for 15 min, whereupon it is lowered in the ice-water bath. Benzyl bromide (0.093 g, 0.534 mmol) is added dropwise. After 3 h, additional benzyl bromide (0.046 g, 0.267 mmol) is added, and upon reaction completion, the mixture is quenched with 1M aqueous HCl and diluted with ethyl acetate. The aqueous phase is extracted and the combined organic phase is dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (dichloromethane-methanol, 99:1) affords 1-benzyl-3-methyl-2-pyridin-3-yl-1H-indole as a pale yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 2.18 (s, 3H), 5.19 (s, 2H), 6.69-6.71 (m, 2H), 7.01-7.11 (m, 5H), 7.21 (d, J=8.1 Hz, 1H), 7.37-7.41 (m, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.67-7.70 (m, 1H), 8.36 (s, 1H), 8.43-8.45 (m, 1H). MS (ESI) m/z 299 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:22]=[CH:21][C:17](C(O)=O)=[CH:16][CH:15]=1)=[O:13].C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>O.ClCCl>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:21]=[CH:22][C:14]([CH:12]=[O:13])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
1 g (4.45 mmol) of 1-bromo-4-(trifluoromethyl)benzene and 0.73 g (4.9 mmol) of 4-formylbenzoic acid are added to 30 ml of dimethoxyethane and mixed with 15 ml of 1M sodium carbonate solution. 110 mg of tetrakis(triphenylphosphine)palladium(II) are added, and the mixture is then heated at reflux temperature for 18 hours. The reaction solution is cooled, dichloromethane and water are added, the mixture is filtered through Extrelut and the solvent is distilled off under reduced pressure.
Reaction SMILES: Br[C:2]1[C:11]([NH:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[CH3:18][Sn](C)(C)C>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.CN(C)C=O>[CH3:18][C:2]1[C:11]([NH:12][C:13]2[NH:14][CH2:15][CH2:16][N:17]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2
Reactant: C[Sn](C)(C)C
Reactant: Brc1c(NC2=NCCN2)ccc2nccnc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(NC2=NCCN2)ccc2nccnc12
Temperature: 145 °C
Yield: 56.8 %

Procedure:
A sealable reaction tube was charged with 5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline (104 mg., 0.36 mmol) (prepared as noted above), tetramethyl tin (214 mg., 1.2 mmol) and (Ph3P)2PdCl2 (10 mg) and dry dimethylformamide (2 ml) in a reaction tube. The reaction mixture was purged with dry nitrogen gas. The tube was sealed and heated to 145° C. for 6 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The dark brown residue was chromatographed (SiO2 ; 5/1 CHCl3 /CH3OH saturated with NH3 (g)) to yield 46.5 mg (53%) of the title compound as a light yellow solid. An analytical sample was prepared by recrystallization from CHCl3 /CH3OH and had a melting point of 183°-186° C. The title compound was characterized by 1H and 13CNMR, IR and mass spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]([F:24])([F:23])[C:9]1[C:18]([C:19](Cl)=[O:20])=[C:17]([OH:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>N1C=CC=CC=1>[F:24][C:8]([F:7])([F:23])[C:9]1[C:18]([C:19]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:20])=[C:17]([OH:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2ccccc2c1O
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=C(Nc1nccs1)c1c(C(F)(F)F)nc2ccccc2c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.5 g of 2-amino-thiazole and 20 ml of pyridine were added to a solution of the product of Step F in 120 ml of anhydrous pyridine and the mixture was heated at 80°-85° C. for one hour. The mixture was stirred at room temperature for 16 hours and was then evaporated to dryness. The residue was triturated with 200 ml of water and was then vacuum filtered. The filter was washed and the combined wash water and filtrate were cooled in ice and acidified with concentrated hydrochloric acid. The mixture was vacuum filtered and the recovered product was washed with water and dried to obtain 13.7 g of 2-trifluoromethyl-4-hydroxy-N-(2-thiazolyl)-3-quinoline-carboxamide melting at >280° C.
Reaction SMILES: [C:1]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Cl[CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].O>C1COCC1>[C:1]([N:8]([CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NN(CCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of di-Boc-hydrazine (2.0 g, 8.6 mmol) in THF (30 mL) was slowly added sodium hydride (210 mg, 8.6 mmol). After stirring at 0° C. for 5 minutes and then at room temperature for 30 minutes, the mixture was added to a solution of 3-chloro-1-phenylpropan-1-one (1.50 g, 8.6 mmol) in THF (10 mL). After stirring at room temperature for 30 minutes, water was added, and the mixture was partitioned between brine and ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (15% ethyl acetate in hexanes) to provide the crude product.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:5]1[CH2:9][CH2:8][C@H:7]([NH:10][CH3:11])[CH2:6]1)[CH3:4].C(N1CC[C@@H](N(C)C(=O)OCC2C=CC=CC=2)C1)C>>[ClH:1].[ClH:1].[CH2:3]([N:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][CH3:11])[CH2:6]1)[CH3:4]
Reactant: CCN1CC[C@H](NC)C1
Agent: CCN1CC[C@@H](N(C)C(=O)OCc2ccccc2)C1
Agent: Cl
Product: CCN1CC[C@@H](NC)C1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 127, starting from benzyl N—((R)-1-ethylpyrrolidin-3-yl)-N-methylcarbamate (Intermediate 133) as a light coloured viscous oil, which was used without further characterization.