Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH:20]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([OH:44])[CH2:42][CH3:43])=[CH:36][CH:35]=3)[C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[CH:26]=3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[NH2:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:21](=[O:22])[CH:20]([NH:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([N:8]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:10][CH:11]=[CH:12]2)[C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH:41]([OH:44])[CH2:42][CH3:43])=[CH:38][CH:39]=1
Reactant: CCC(O)Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc([N+](=O)[O-])c2)cc1
Agent: [Pd]
Product: CCC(O)Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc(N)c2)cc1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 70F (110 mg in 10 mL MeOH, 0.16 mmol) was added 10% Pd/C (20 mg). The mixture was hydrogenated at 40 psi for 3 h, then filtered and concentrated to give 70G (107 mg, 100%). MS (ESI) m/z 670.7 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[OH:9])=[CH:4][CH:3]=1
Reactant: COc1ccccc1C(=O)c1ccc(N)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C(O)c1ccc(N)nc1

Procedure:
To a solution of (6-amino-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (14 g, 61.4 mol) in CH3OH (150 mL) was added NaBH4 (3.48 g, 92.1 mmol) portion-wise at 0° C.
Reaction SMILES: [CH2:1]([C:3]1[C:15]2[NH:14][C:13]3[CH:12]=[CH:11][C:10]([O:16]C)=[CH:9][C:8]=3[C:7]=2[C:6]2[C:18](=[O:22])[NH:19][C:20](=[O:21])[C:5]=2[C:4]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].B(Br)(Br)Br>>[CH2:1]([C:3]1[C:15]2[NH:14][C:13]3[CH:12]=[CH:11][C:10]([OH:16])=[CH:9][C:8]=3[C:7]=2[C:6]2[C:18](=[O:22])[NH:19][C:20](=[O:21])[C:5]=2[C:4]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2]
Reactant: CCc1c(-c2ccccc2)c2c(c3c1[nH]c1ccc(OC)cc13)C(=O)NC2=O
Agent: BrB(Br)Br
Product: CCc1c(-c2ccccc2)c2c(c3c1[nH]c1ccc(O)cc13)C(=O)NC2=O
Yield: 97 %

Procedure:
Demethylation of (825) prepared as described in example 423 with BBr3 using the procedure described in example 80 gave (826) (97%), mp 190–196° C. 1H NMR δ [(CD3)2SO] 11.63 (s, 1H), 10.81 (s, 1H), 9.21 (s, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.48–7.40 (m, 4H), 7.31–7.29 (m, 2H), 7.06 (dd, J=8.7, 2.4 Hz, 1H), 2.74 (q, J=7.4 Hz, 2H), 1.06 (t, J=7.4 Hz, 3H). Found: C, 72.43; H, 4.54; N, 7.54. C22H16N2O3.1/2H2O requires: C, 72.32; H, 4.69; N, 7.67.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH2:16][CH:17]2[NH2:23]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:23][CH:17]1[C:18]2[C:13](=[C:12]([CH3:11])[CH:21]=[C:20]([CH3:22])[CH:19]=2)[CH2:14][CH2:15][CH2:16]1
Reactant: Cc1cc(C)c2c(c1)C(N)CCC2
Reactant: Clc1nc2ccccc2[nH]1
Product: Cc1cc(C)c2c(c1)C(Nc1nc3ccccc3[nH]1)CCC2

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 5 ,7-dimethyl-1,2,3,4-tetrahydro-1-naphthylamine (prepared by Procedure B from 5,7-dimethyl-1-tetralone) by Procedure A (60 min at 170° C. followed by 20 min at 200° C.). The product was purified by recrystallisation to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 250-252° C.). MS(ES+) m/z 292 ([M+1]+, 100).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=12)=[O:5].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][C:4]([C:6]1[N:7]=[C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=12)=[O:5].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]
Reactant: CC(C)(C)CC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC(=O)c1nc(-c2ccccc2)n2c1CNCC2
Reaction time: 2 h

Procedure:
Intermediate 26B (0.08 g, 0.20 mmol) was dissolved in DCM and TFA was added. The resulting mixture was stirred for 2 hours. The mixture was concentrated, diluted with water and acetonitrile and lyophilized to produce the desired product as a TFA salt. The residue was dissolved in methanol and filtered through a SPE SCX tube column, eluting with 2N ammonia in methanol to provide Compound 291 (0.055 g, 90%) as a free base. 1H-NMR (400 MHz, CD3OD) δ: 1.05 (s, 9H), 2.87 (s, 2H), 3.15 (t, 2H), 4.07 (t, 2H), 4.35 (s, 2H), 7.52 (m, 3H), 7.67 9m, 2H); LCMS (+ESI) m/z 298.1 [M+H]+.
Reaction SMILES: [CH:1](=[C:4]1[CH2:8][CH2:7][CH2:6][C:5]1=O)[CH2:2][CH3:3].[Na].C(OC)(=O)[CH2:12][C:13]([CH3:15])=[O:14]>CO>[CH2:2]([CH:1]1[CH:4]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:15][C:13](=[O:14])[CH2:12]1)[CH3:3]
Reactant: COC(=O)CC(C)=O
Reactant: CCC=C1CCCC1=O
Agent: [Na]
Solvent: CO
Product: CCC1CC(=O)C=C2CCCC21
Yield: 53.3 %

Procedure:
The procedure of Example 1 is repeated with 19.5 g (0.16 mol) of propylidene cyclopentanone, 0.46 g (0.02 g-atom) of sodium, 21 g (0.18 mol) of methyl acetoacetate and 100 ml of methanol. Fractional distillation yields 14 g (bp 95°-102° C. at 0.5 mm) of 5-ethylbicyclo [4.3.0] non-1-en-3-one having the structure: ##STR8##
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[C@@:32]([OH:36])([C:34]#[CH:35])[CH3:33]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:35]#[C:34][C@@:32]([C:27]4[N:26]=[CH:31][CH:30]=[CH:29][N:28]=4)([OH:36])[CH3:33])[CH:10]=3)[C:6]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2nc(C(=O)N3CCOCC3)c3ccc(I)cc32)n1
Reactant: C#C[C@](C)(O)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[C@](O)(C#Cc1ccc2c(C(=O)N3CCOCC3)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Reaction time: 18 h

Procedure:
To solution of 4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-amine (60 mg, 0.13 mmol) in triethylamine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (15.4 mg, 0.01 mmol), copper(I) iodide (2.5 mg, 0.01 mmol) and (2S)-2-(pyrimidin-2-yl)but-3-yn-2-ol (30 mg, 0.20 mmol). After 18 hr at RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished the title compound as an off-white solid: 1H NMR (500 MHz, DMSO-d6) delta 1.79-2.05 (3H, m), 3.59-3.68 (2H, m), 3.71-3.79 (4H, m), 3.89-4.01 (2H, m), 6.17-6.37 (1H, m), 6.98-7.10 (1H, m), 7.12-7.27 (2H, m), 7.32-7.42 (1H, m), 7.47-7.58 (1H, m), 7.92-8.05 (1H, m), 8.26-8.39 (1H, m), 8.80-9.04 (3H, m); LC-MS: m/z=+471.05 (M+H)+.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([C:22]2([Cl:25])[CH2:24][CH2:23]2)=O)=[CH:14][CH:13]=1.[OH-].[K+]>C(O)(C)(C)C>[Cl:25][C:22]1([C:20]2([CH2:19][CH2:18][C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=3)[CH2:10][O:9]2)[CH2:23][CH2:24]1
Reactant: COS(=O)(=O)OC
Reactant: O=C(CCc1ccc(Cl)cc1)C1(Cl)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CSC
Solvent: CC(C)(C)O
Product: Clc1ccc(CCC2(C3(Cl)CC3)CO2)cc1
Reaction time: 14 h
Yield: 74.4 %

Procedure:
16 ml (0.22 mol) of dimethyl sulphide and 24.2 g (0.19 mol) of dimethyl sulphate are added to 30 ml of tert.-butanol and allowed to stand at 20° C. for 14 hours. A solution of 17 g (0.07 mol) of 1-chlorocyclopropyl 4-chlorophenylethyl ketone in 70 ml of tert.-butanol is first added dropwise to the reaction mixture with stirring and 22 g of potassium hydroxide powder are then introduced, while the temperature of the reaction mixture is kept at 20° to 30° C. The mixture is stirred at 30° C. for 3 hours more, then the dimethyl sulphide is removed under reduced pressure and the reaction mixture is then poured into 50 ml of a 1% aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed with water and concentrated by removing the solvent under reduced pressure after drying over sodium sulphate. In this manner, 13.4 g (75 % of theory) of 2-(1-chlorocyclopropyl)-2-(4-chlorophenylethyl)-oxirane are obtained in the form of an oily product, which is reacted further without additional purification. ##STR64##
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[C:5]([CH2:18][CH3:19])[C:4]=1[O:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1.N.C([N:33](C(C)C)CC)(C)C>C(O)(C)C>[NH2:33][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[C:5]([CH2:18][CH3:19])[C:4]=1[O:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CBr)c1Oc1cc(Cl)cc(Cl)c1
Agent: N
Solvent: CC(C)O
Product: CCc1nn(CCNC(=O)OC(C)(C)C)c(CN)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 5 h
Yield: 92.9 %

Procedure:
The bromide of Example 137 (444 mg, 0.900 mmol) was added to a saturated solution of ammonia in isopropanol (25 ml) and diisopropylethylamine (173 μl, 1.00 mmol) at room temperature. The reaction was stirred for 5 hours and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to provide the title compound (359 mg) as a white solid, m.p. 112-114° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19]1>>[S:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccsc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccsc4)nc23)CC1
Yield: 64.2 %

Procedure:
Beginning with 1.5 gm (6.5 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 1.2 gm (7.8 mMol) 3-thiophenecarbonyl chloride, 1.42 gm (64%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1.N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[K+].[K+].N#N.[OH-].[NH4+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[CH3:13][C:14]1[N:15]([C:2]2[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)[NH2:5])[CH:16]=[CH:17][N:18]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1ncc[nH]1
Agent: [Cu]I
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
3-Bromo-5-(trifluoromethyl)aniline (1.2 mL, 8.60 mmol) and 2-methylimidazole (847 mg, 10.3 mmol) were dissolved in dimethyl sulfoxide (8.6 mL), and CuI (490 mg, 2.58 mmol), 8-quinolinol (370 mg, 2.58 mmol) and potassium carbonate (2.38 g, 17.2 mmol) were added thereto. The reaction mixture was treated with N2 gas for 10 minutes to remove gas and subjected to a reaction at 120° C. for 12 hours. The reaction mixture was cooled to room temperature, and 14% aqueous ammonium hydroxide solution was added thereto. The reaction mixture was stirred for 1 hours at room temperature, diluted with ethyl acetate (30 mL) and washed with an aqueous sodium hydrogen carbonate solution (30 mL). The organic layer was washed with water, dried with sodium sulfate, and the solvent was distilled under reduced pressure. The concentrated mixture was filtered with a silica column using ethyl acetate to remove copper impurities, and the filtrate was distilled under reduced pressure. The concentrated mixture was crystallized with ethyl acetate (3 mL) and n-hexane (30 mL) to obtain the title compound (1.31 g) as a bright green solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16]([OH:18])=[O:17])[C:6]2=[O:23].[Li+].[I-]>N1C(C)=CC(C)=CC=1C.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:16]([OH:18])=[O:17])[C:6]2=[O:23]
Reactant: COc1ccc2ncn(-c3cc(C(=O)O)ccc3C)c(=O)c2c1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(O)cc2c1=O
Temperature: 195 °C
Yield: 94.3 %

Procedure:
To a suspension of 3-(6-methoxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoic acid (8 g) in 2,4,6-collidine (80 ml) was added LiI (6.2 g) and heated to 195° C. for 54 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water. The aqueous phase was acidified to pH˜1 with 1N HCl and the resultant solid collected by filtration. The solid was dried in vacuo at 60° C. to yield 3-(6-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoic acid (7.2 g); NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 7.33 (m, 1H), 7.48 (d, 1H), 7.56 (d, 1H), 7.62 (d, 1H), 7.91 (s, 1H), 7.97 (d, 1H), 8.12 (s, 1H); Mass Spectrum: M+H+ 297.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[SH:17][C:18]1[N:19]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33]#[N:34])=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1>ClCCl>[C:33]([C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[S:17][C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:24][CH:25]=1)#[N:34]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: N#Cc1ccc(-n2ccnc2S)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)Sc1nccn1-c1ccc(C#N)c2ccccc12
Reaction time: 3 h

Procedure:
Triethylamine (1.1 eq), followed by ethyl 2-bromo-2,2-difluoroacetate (1.05 eq) were added to a stirring slurry of 4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile (prepared as described herein, 1 eq) in dichloromethane and stirring continued for 3 h. The mixture was washed with aqueous HCl solution (0.2M), 50% saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. Hexanes were added and the mixture concentrated to provide ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH:20]([C:22]1[C:23]([CH3:38])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH3:21]>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH:20]([C:22]2[C:23]([CH3:38])=[N:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH3:21])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Reactant: CCOC(=O)COc1ccc(O)c2ccccc12
Product: CCOC(=O)COc1ccc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc12

Procedure:
In analogy to the procedures described in example 5C] and 5D], (4-hydroxy-naphthalen-1-yloxy)-acetic acid ethyl ester was reacted with [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1L]) to give [rac]-(4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-naphthalen-1-yloxy)-acetic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:13]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[N:7]1([C:13]2([CH2:17][NH2:18])[CH2:14][CH2:15][CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N#CC1(N2CCCCC2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NCC1(N2CCCCC2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, to a mixture of 693 mg of lithium aluminum hydride and 30 mL of tetrahydrofuran was added dropwise a solution of 1.0 g of 1-(piperidin-1-yl)cyclobutanecarbonitrile in 18 mL of tetrahydrofuran under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours. Under ice-cooling, 1.5 mL of water and 1.5 mL of a 15% aqueous sodium hydroxide solution were added dropwise thereto. The mixture was diluted with ethyl acetate and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 932 mg of 1-[1-(piperidin-1-yl)cyclobutyl]methanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])=[CH:6][C:3]=1[CH2:4]Br.[CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[CH:18]([N:21]([CH2:4][C:3]1[CH:6]=[C:7]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[C:8]([F:10])=[CH:9][C:2]=1[Cl:1])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]
Reactant: CC(C)NC(C)C
Reactant: CC(=O)N(C(C)=O)c1cc(CBr)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)N(C(C)=O)c1cc(CN(C(C)C)C(C)C)c(Cl)cc1F
Yield: 95.7 %

Procedure:
A mixture of 0.82 g (0.0025 mole) of 2-chloro-4-fluoro-5-diacetylaminobenzyl bromide, 0.28 g (0.0028 mole) of diisopropylamine, 0.39 g (0.0028 mole) of potassium carbonate, and 25 ml of acetonitrile was heated at reflux overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water. After being dried, the solvent was evaporated under reduced pressure, yielding 0.82 g of N,N-diisopropyl-2-chloro-4-fluoro-5-diacetylaminobenzylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[CH3:18][C:19]1[N:20]=[N:21][C:22]([CH:25]=[CH2:26])=[CH:23][CH:24]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[N:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: C=Cc1ccc(C)nn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nn2)C2CCN(CC2)C1

Procedure:
Under nitrogen, 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (260 mg, 1.15 mmol, Example 2B), was coupled with 3-methyl-6-vinylpyridazine (280 mg, 1.86 mmol, Example 148B) according to the procedure described in Example 1B to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.65-1.76 (m, 2H) 1.85-1.95 (m, 2H) 2.43 (s, 3H) 2.67 (s, 3H) 2.96-3.09 (m, 3H) 3.17-3.25 (m, 2H) 3.30 (t, J=7.1 Hz, 2H) 4.23 (s, 2H) 4.55 (t, J=7.1 Hz, 2H) 6.82 (d, J=8.5 Hz, 1H) 6.96 (dd, J=8.3, 1.2 Hz, 1H) 7.11 (dd, J=17.1, 8.4 Hz, 2H) 7.16 (s, 1H); MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[Cl:11][CH2:12][C:13](Cl)=[O:14].[Li+].CC([N-]C(C)C)C.Cl>C(OCC)(=O)C.CCOCC>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][C:13](=[O:14])[CH2:12][Cl:11])[O:3]1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: O=C(Cl)CCl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1(C)OC(=O)C=C(CC(=O)CCl)O1
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
In an argon gas stream, 20.6 ml of n-butyl lithium (1.6M solution in hexane) were added to 60 ml of an ether solution containing 3.53 g (0.033 mol) of diisopropylamine at -20° C. to form LDA. After stirring for 30 minutes, a mixture of 4.26 g (0.03 mol) of 2,2-dimethyl-6-methyl-1,3-dioxin-4-one and 60 ml of ether as well as 60 ml of an ether solution containing 1.69 g (0.015 mol) of chloroacetyl chloride were added to LDA. After the temperature was gradually returned to room temperature, 10% hydrochloric acid was added thereto to neutralize the solution, and extraction was then carried out with ether. The resultant organic layer was dried over anhydrous magnesium sulfate. Next, the solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate =4:1), thereby obtaining 2.26 g (yield 69%) of 2,2-dimethyl-6-(3-chloro-2-oxopropyl)-1, 3-dioxin-4 -one.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH:9]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([CH3:11])[CH3:10].[K+].[Br-]>>[CH:9]([C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[NH:2])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1ccc(N)cc1
Reactant: N#Cc1ccncc1
Agent: [Br-]
Agent: [K+]
Product: CC(C)c1ccc(NC(=N)c2ccncc2)cc1
Yield: 90.4 %

Procedure:
The title compound was prepared from 4-cyanopyridine (7.7 g, 74 mmol) and 4-isopropylaniline (10 g, 74 mmol) by following the procedure described in preparation 10 (16 g, yield 90.4%, mp 131-134 C, purity 96.43% by HPLC). 1H-NMR (DMSO): δ 1.20-1.22 (d, 6H), 2.82-2.87 (m, 1H), 6.54 (bs, 2H, D2O exchangeable), 6.8-6.82 (d, 2H), 7.18-7.2 (d, 2H), 7.89-7.9 (d, 2H), 8.65-8.67 (d, 2H). IR (KBr) cm−1: 3452, 3299, 3163, 2955, 1647, 1597. MS m/z:240.2 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[C:16]([CH3:33])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[NH2:34][C@@H:35]1[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]1>CN1CCCC1=O>[CH2:8]([C:7]1[N:6]=[C:5]([C:10]([NH2:12])=[O:11])[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:24][CH2:25]3)=[C:16]([CH3:33])[CH:15]=2)=[N:3][C:2]=1[NH:34][C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)[CH3:9]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1N[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-chloro-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (200 mg), tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (360 μL), and N-methylpyrrolidone (0.8 mL) was reacted in a microwave reaction device at 190° C. for 30 minutes. The mixture was subjected to liquid separation by the addition of chloroform and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. To the obtained residue and 1,2-dichloroethane (2.6 mL) were added trifluoroacetic acid (2.6 mL) under ice-cooling, followed by stirring at room temperature for 3 hours. The mixture was diluted with chloroform and neutralized with a 5% aqueous potassium carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-[(3R)-pyrrolidin-3-ylamino]pyrazine-2-carboxamide (109 mg) as a pale yellow solid.