Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)=[C:2]=[S:3].[H-].[Na+].[NH2:18][C:19]1[C:24](=[O:25])[N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[CH2:22][CH2:21][C:20]=1[C:37](OCC)=[O:38].Cl>CN(C)C=O>[CH3:36][O:35][C:28]1[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=1[CH2:26][N:23]1[CH2:22][CH2:21][C:20]2[C:37](=[O:38])[N:1]([C:4]3[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=3)[C:2](=[S:3])[NH:18][C:19]=2[C:24]1=[O:25]
Reactant: FC(F)(F)COc1ccc(N=C=S)cc1
Reactant: CCOC(=O)C1=C(N)C(=O)N(Cc2ccc(OC)cc2OC)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCc3c([nH]c(=S)n(-c4ccc(OCC(F)(F)F)cc4)c3=O)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of 1-isothiocyanato-4-(2,2,2-trifluoroethoxy)benzene (115 mg) in N,N-dimethylformamide (2 ml) was added sodium hydride (60% in oil, 45 mg), and a solution of ethyl 5-amino-1-(2,4-dimethoxybenzyl)-6-oxo-1,2,3,6-tetrahydropyridine-4-carboxylate (150 mg) in N,N-dimethylformamide (2 ml) was added dropwise thereto over 5 min under ice-cooling. The mixture was stirred for 10 min, allowed to be warmed to room temperature, and stirred for 30 min. The reaction mixture was poured into 0.5M hydrochloric acid (4 ml) under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow solid was washed with diethyl ether to give the title compound (70 mg) as beige fine needle crystals.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][N:29]2[CH2:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:34]=2[O:43][CH3:44])=[CH:25][CH:24]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([CH2:6][C:7]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[CH:28][N:29]3[CH2:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:34]=3[O:43][CH3:44])=[CH:25][CH:24]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: COC(=O)c1ccc(Cn2ccc3ccc(N)cc32)c(OC)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2ccc3ccc(NC(=O)CC4CCCC4)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of cyclopentylacetic acid (0.24 ml) and 1,1'-carbonyldiimidazole (0.34 g) in methylene chloride (3 ml) was heated under reflux for 30 minutes and then treated with a solution of ester (B) (0.5 g) in methylene chloride (3 ml). The mixture was heated under reflux for 30 minutes, stirred at room temperature for 24 hours, and then diluted with ethyl acetate. This organic solution was washed sequentially with 10% v/v hydrochloric acid, water, and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on a 6×18 cm silica gel column using 99:1 v/v ethyl acetate:toluene as the eluent followed by recrystallization from hexane/ethyl acetate to give methyl 4-[6-(2-cyclopentylacetamido)indol-1-ylmethyl]-3-methoxybenzoate (P) as a solid; partial NMR: 2.0-2.5(br m, 3H, CH2CH), 3.9(s, 3H, OCH3), 4.0(s, 3H, OCH3), 5.3(s, 2H, NCH2).
Reaction SMILES: [C:1]1([C:7](=[O:17])[CH2:8][CH:9](O)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18]>>[C:1]1([C:7](=[O:17])[CH2:8][CH:9]([Cl:18])[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl
Reactant: O=C(CC(O)C1CCCCC1)c1ccccc1
Product: O=C(CC(Cl)C1CCCCC1)c1ccccc1
Yield: 96 %

Procedure:
The reaction and post treatment were carried out in the same manner as in Example 10 except that 1-phenyl-3-hydroxy-3-cyclohexylpropan-1-one obtained by the same production process as in Preparation Example 1, was used as the starting material, and hydrochloric acid (180 g) was changed to hydrogen chloride gas (20° C., 12,300 ml, 511 mmol), and the reaction was carried out at −20° C., whereby the desired 1-phenyl-3-chloro-3-cyclohexylpropan-1-one (97.1 g, 407 mmol) was obtained in a yield of 96%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([OH:14])[C:10]([F:13])([F:12])[F:11].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C@@H:9]([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: O[C@H](c1ccc(Cl)cc1Br)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O[C@H](c1ccc(Cl)cc1-c1ccccc1)C(F)(F)F
Temperature: 90 °C

Procedure:
To a solution of (R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethanol (300 mg, 1.1 mmol) in dioxane (12 mL) was added phenyl boronic acid (185 mg, 1.5 mmol), Pd2(dppf)Cl2 (35 mg, 0.07 mmol) and Na2CO3 (3 mL, 2.0 M, aq). The reaction was heated to 90° C. for 2 h, then cooled to RT, and concentrated in vacuo. The residue was taken up in CH2Cl2, washed with brine, and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4. Purification by normal phase silica gel column (EtOAc/hexanes) to provide a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([CH2:33][CH3:34])=[N:18][N:19]3[C:24]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:23][C:22](Cl)=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([CH2:33][CH3:34])=[N:18][N:19]3[C:24]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:23][C:22]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:21][C:20]=23)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1COCCN1
Reactant: CCc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nn2c(N3CCN(C)CC3)cc(N3CCOCC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
0.26 ml (3 mmol) of morpholine in 5 ml of DMF was added to a solution of 0.50 g (1.2 mmol) of 3-benzenesulphonyl-5-chloro-2-ethyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine in 15 ml of DMF and stirred at 100° for hr. After cooling to RT the reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 15:1) and crystallization from EtOH yielded 0.45 g (80%) of 3-benzenesulphonyl-2-ethyl-7-(4-methyl-piperazin-1-yl)-5-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidine as colorless crystals, m.p.>250°.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.C([NH:24][C@H:25]([C:30]([O-:32])=O)[C:26]([CH3:29])([CH3:28])[CH3:27])(OCC1C=CC=CC=1)=O.CCN(C(C)C)C(C)C.ClC(OCC(C)C)=O.[CH2:50]([CH2:52][NH2:53])[OH:51]>C(Cl)Cl>[NH2:24][C@@H:25]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:30]([NH:53][CH2:52][CH2:50][OH:51])=[O:32]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Reactant: NCCO
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)NCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Cbz-tert-leucine dicyclohexylammonium salt (1.34 g, 3.0 mmol) and DIEA (0.7 ml) in DCM (25 mL) cooled in an ice-water bath was added isobutyl chloroformate (0.47 mL, 3.6 mmol). After stirring at 0° C. for 1 h, ethanolamine was added (0.52 mL, 9.0 mmol) and stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate. The organic phase was separated and dried over sodium sulfate. After evaporation under reduced pressure, the residue was dissolved in MeOH and passed through a SCX (Phenomenex®, Torrance, Calif.) cationic ion-exchange column to remove dicyclohexylamine and DIEA. The filtrate was evaporated and hydrogenated with Pd/C (0.5 g) under 45 psi hydrogen in MeOH for 4 h. Palladium catalyst was removed by filtration through celite. The filtrate was concentrated and dried under vacuum overnight to give intermediate 23 (0.35 g), which was used without further purification. LCMS (+ESI) m/z=175 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1)(=O)=O>C(N(CC)CC)C.ClCCl>[C:1]([O:9][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CS(=O)(=O)On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(On1nnc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
Benzoic acid (2.44 g) is dissolved in a solution of triethylamine (2.80 ml) in dichloromethane (20 ml) under ice-cooling. To the solution is added 1-methanesulfonyloxy-1,2,3-benzotriazole (4.26 g) and the mixture is stirred at room temperature for 3 hours. The reaction mixture is washed with water, a saturated aqueous sodium hydrogen carbonate and water in order and dried to give crystals of 1-benzoyloxy-1,2,3-benzotriazole (5.0 g). The product is dissolved in dichloromethane (20 ml) and thereto are added triethylamine (2.80 ml) and methanol (4.8 ml) and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried and then the solvent is distilled off to give methyl benzoate (2.39 g). Infrared spectrum: 1728 cm-1.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].C(OC(=O)[C:10]([C:24]#[N:25])=[C:11]1[CH2:23][CH2:22][C:14]2([O:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][O:15]2)[CH2:13][CH2:12]1)C.[NH4+].[Cl-]>O1CCCC1.[Cu]I>[CH2:16]([O:15][C:14](=[O:19])[CH2:13][CH:10]([C:11]1([CH2:1][CH:2]=[CH2:3])[CH2:12][CH2:13][C:14]2([O:19][CH2:18][C:17]([CH3:20])([CH3:21])[CH2:16][O:15]2)[CH2:22][CH2:23]1)[C:24]#[N:25])[CH3:17]
Reactant: CCOC(=O)C(C#N)=C1CCC2(CC1)OCC(C)(C)CO2
Reactant: C=CC[Mg]Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC1(C(C#N)CC(=O)OCC)CCC2(CC1)OCC(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Allylmagnesium chloride (2 mol/L in tetrahydrofuran, 56 ml) is added to a solution of cyano-(3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-ylidene)-acetic acid ethyl ester (13.7 g) and CuI (2.7 g) in tetrahydrofuran (100 mL) under argon atmosphere and chilled in an ice bath. The mixture is warmed in the cooling bath to room temperature and stirred overnight. Aqueous NH4Cl solution is then added and the resulting mixture is extracted with tert-butyl methyl ether. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:02:3) to give the title compound. Yield: 5.0 g (31% of theory); Mass spectrum (ESI+): m/z=336 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[O:20][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1)#[N:24]
Reactant: N#Cc1ccccc1O
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2C#N)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-hydroxy-benzonitrile via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:24]=[CH:23][C:22]([NH2:25])=[N:21]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C:22]2[CH:23]=[CH:24][N:20]([CH3:19])[N:21]=2)[CH:7]=1)=[O:18]
Reactant: Cn1ccc(N)n1
Reactant: O=C(Nc1ccnc(Br)c1)c1c(Cl)cccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1ccc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)n1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a microwave tube were added N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (0.12 g, 0.36 mmol), 1-methyl-1H-pyrazol-3-amine (0.045 g, 0.46 mmol), Pd2(dba)3 (0.031 g, 0.033 mmol), XantPhos (0.031 g, 0.052 mmol), Cs2CO3 (0.31 g, 0.94 mmol) and dioxane (3 mL). The mixture was degassed with N2 for 10 min. The resulting mixture was irradiated in a microwave reactor at 140° C. for 1 hour and then cooled to room temperature. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was in DMF and purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product (30 mg, yield: 24%). 1H NMR (500 MHz, DMSO-d6): δ 10.92 (s, 1H). 9.16 (s, 1H), 8.01 (m, 1H), 7.60-7.50 (m, 5H), 7.04 (d, J=4.0 Hz, 1H), 6.27 (d, J=1.5 Hz, 1H), 3.72 (s, 3H). LCMS (ESI) m/z: 362.0 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=2)[N:3]=1.C(Cl)(=O)C([Cl:21])=O>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([Cl:21])=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a 100 mL flask, 3-bromo-1-(3,5-dichloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (0.4 g, 1.2 mmol), dichloromethane (10 mL) and oxalyl dichloride (0.31 g, 2.4 mmol) were added. After five drops of N,N-dimethyl formamide was added, a large number of gas was released. After being stirred for 8 hours at room temperature, the reaction mixture was evaporated to dryness at reduced pressure. Then toluene (100 mL) was added, and the reaction mixture was concentrated again under vacuum to give the product (0.42 g) as green solid in 100% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11][CH2:12][C:13](Cl)=C.[CH3:16]COC(C)=O.O>CC(O)=O.[Fe]>[NH2:8][C:5]1[C:4]2[CH:16]=[C:12]([CH3:13])[S:11][C:3]=2[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: C=C(Cl)CSc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(N)ccc(Cl)c2s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A solution of 1.09 g (4.67 mmol) of compound 260A in 20 mL AcOH with 10 mL EtOAc and 2 mL H2O was heated to 80° C. and treated with iron powder (1.3 g, 23.4 mmol). The mixture was heated at 80° C. for 40 min and then allowed to cool to rt. The mixture was filtered through Celite eluting with EtOAc. The filtrate was washed with sat. aq. NaHCO3, dried over MgSO4, and concentrated in vacuo. N,N-diethylaniline (10 mL) was added, and the reaction was heated at 215° C. for 6 h. After cooling to rt, 1 N aqueous HCl (20 mL) was added, and the reaction was stirred at room temperature for 2 h. The mixture was extracted with EtOAc (3×30 mL). The organic phase was washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting with 25% EtOAc in hexanes to give compound 260B (320 mg, 35%) as a beige solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC)[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2].[C:20]1([Li])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([C:3]1[C:4](/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Reactant: [Li]c1ccccc1
Product: CCc1cccc(-c2ccccc2)c1/C=N/C(C(C)C)C(C)C

Procedure:
(E)-[1-(3-Ethyl-biphenyl-2-yl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine was prepared from (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine (Example 3 a) and phenyl lithium in analogy to procedure Example 5 a): colourless liquid: MS (ISP): 308.1 ((M+H)+.), 192.9 (((M-((iPr2)2CHNH2))+.), 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]=12.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:8]1=[C:7]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: Oc1ccc2c(c1)c(-c1ccccn1)c1n2CCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccccn1)c1n2CCCCC1

Procedure:
The above compound was prepared from 7,8,9,10-tetrahydro-11-(2-pyridyl)-6H-azepino[1,2-a]indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:9](=[O:20])[N:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:11][C:5]2=[CH:4][N:3]=1>NC1C=CC=CC=1>[CH:22]1([CH2:21][N:8]2[C:6]3=[N:7][C:2]([NH:10][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:3][CH:4]=[C:5]3[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9]2=[O:20])[CH2:24][CH2:23]1
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N(CC3CC3)C2=O)cc1
Solvent: Nc1ccccc1
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(CC3CC3)C2=O)cc1
Temperature: 120 °C

Procedure:
The mixture of 7-chloro-1-cyclopropylmethyl-3-(4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-one (129 mg, 0.37 mmol) in aniline (1.0 mL) (Aldrich) was heated to 120° C. for 5.5 hours. After cooling, the reaction mixture was washed with hexanes (4×100 mL) and the crude product was purified by preparative thin layer chromatography to give 1-cyclopropylmethyl-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidine-2-one as an off-white solid. (Yield 20.6 mg, 13.7%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4ncoc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.24 mmol) in DCM (5 mL) was added triethylamine (74 mg, 0.73 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (66 mg, 0.36 mmol) and DMAP (15 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (120 mg, 89.0% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.70-7.68 (d, 2H), 7.27 (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).
Reaction SMILES: [C:1](/[CH:3]=[CH:4]/[C:5]1[N:10]=[C:9]([CH2:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14](C(OC(C)(C)C)=O)[C:13]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:8]=[CH:7][CH:6]=1)#[N:2].FC(F)(F)C(O)=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C.ClCCl>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12]([CH2:11][C:9]3[N:10]=[C:5](/[CH:4]=[CH:3]/[C:1]#[N:2])[CH:6]=[CH:7][CH:8]=3)=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(Cc3cccc(/C=C/C#N)n3)c(-c3ccccc3)n(C(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc2c(Cc3cccc(/C=C/C#N)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of tert-butyl 3-[6-((E)-2-cyanovinyl)pyridin-2-ylmethyl]-6-methoxy-2-phenyl-1H-indole-1-carboxylate (100 mg) in acetonitrile/dichloromethane (1 mL/1 mL) was added trifluoroacetic acid (1 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture were added ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (68.7 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.40 (2H, s), 6.60 (1H, d, J=16.1 Hz), 6.76 (1H, dd, J=2.1, 8.7 Hz), 6.91 (1H, d, J=2.1 Hz), 7.07-7.16 (2H, m), 7.32-7.49 (5H, m), 7.50-7.63 (3H, m), 8.05 (1H, br s).
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)[OH:26].[F:34][C:35]([F:47])([F:46])[O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:25]([OH:26])[C:3]2[C:4]3[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[C:7](=[O:21])[N:6]([CH3:22])[C:5]=3[N:23]=[CH:24][C:2]=2[C:39]2[CH:40]=[CH:41][CH:42]=[C:37]([O:36][C:35]([F:34])([F:46])[F:47])[CH:38]=2)=[N:28][CH:29]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cn3)c(Br)cnc21
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cn3)c(-c3cccc(OC(F)(F)F)c3)cnc21
Temperature: 100 °C
Yield: 35 %

Procedure:
To a solution of 6-bromo-5-((5-chloropyridin-2-yl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (75 mg, 0.138 mmol) in toluene (4 mL) and EtOH 1.3 mL) was added 3-(trifluoromethoxy)phenylboronic acid (43 mg, 0.208 mmol), Pd(dppf)Cl2 (10.7 mg) and aq. Na2CO3 (1M, 0.57 mL). The reaction was heated at 100° C. for 18 h, cooled to RT and filtered. The filtrate was concentrated and dried to a residue which was purified by Prep TLC eluted with PE/EA (4:1) to give 5-((5-chloropyridin-2-yl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethoxy)phenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (30 mg, 35.2% yield) as a solid. LCMS: MH+ 621 and TR=2.047 min.