Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][Si:8]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][NH2:12])[CH3:6].N1C=CC=CC=1>C(OCC)C>[CH2:14]([O:13][Si:8]([O:16][CH2:17][CH3:18])([O:7][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][N:12]=[C:1]=[O:2])[CH3:15]
Reactant: O=C(Cl)Cl
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 70.1 %

Procedure:
In 150 ml of ethyl ether was dissolved 9.9 g of carbonyl chloride, and a solution of 22.1 g of γ-triethoxysilylpropylamine and 18.2 g of pyridine in 50 ml of ethyl ether was dropped into the above solution at -5° C. to -10° C. over a period of 3 hours to effect reaction. After the reaction, the crystal of pyridine hydrochloride was removed by filtration and the filtrate was distilled to recover ethyl ether, whereby 17.3 g of γ-triethoxysilylpropyl isocyanate was obtained as a fraction having a boiling point of 95° C. to 100° C. under 8 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]=O.Cl>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[O:9][CH3:10])[CH2:15][O:13][C:12](=[O:14])[CH2:11]2
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: C=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)OC2
Temperature: 120 °C

Procedure:
Heat at 120° C. for 1 hour a mixture of 19.6 g (100 mmol) of 3,4-dimethoxyphenyl acetic acid (VII), 7.4 g (246 mmol) of paraformaldehyde and 20 ml of concentrated HCl in 100 ml of AcOH. Evaporate to dryness. Add 100 ml of H2O, and extract three times with 200 ml of CH2Cl2. Wash the organic phases with 50 ml of 0.5 N NaHCO3 and dry on Na2SO4. Evaporate to dryness. Allow to crystallize for 2 hours in 50 ml of Et2O.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([NH:30][CH3:31])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:18])=[O:17])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:25].N1C=CC=CC=1.[C:38](Cl)(=[O:42])[O:39][CH2:40][CH3:41]>ClCCl>[CH2:40]([O:39][C:38]([N:30]([C:28]1[CH:27]=[CH:26][C:3]([CH2:4][N:5]2[C:9]3=[N:10][C:11]([C:14](=[O:24])[NH:15][S:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:17])=[O:18])=[CH:12][CH:13]=[C:8]3[N:7]=[C:6]2[CH3:25])=[C:2]([Cl:1])[CH:29]=1)[CH3:31])=[O:42])[CH3:41]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(NC)cc3Cl)c2n1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)OCC)cc3Cl)c2n1
Reaction time: 24 h
Yield: 39.2 %

Procedure:
To a suspension of 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (278 mg) in dichloromethane (3 ml) were added pyridine (148 mg) and ethyl chlorocarbonate (129 mg) under ice-cooling, and the mixture was stirred for 24 hr. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give 3-(4-(N-(ethoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (126 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH:11]2[CH2:13][CH2:12]2)=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=1.O=P(Cl)(Cl)Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[C:10]([CH:11]2[CH2:12][CH2:13]2)=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[N:3]=1
Reactant: CC(C)OCCOc1nc(Cl)c(C2CC2)cc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)OCCOc1nc(Cl)c(C2CC2)cc1C#N
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 6-chloro-5-cyclopropyl-2-(2-isopropoxyethoxy)nicotinamide (180 mg, 0.6 mmol) in acetonitrile (20 mL) was added POCl3 (276 mg, 1.8 mmol) and pyridine (285 mg, 3.6 mmol). After stirred at r.t for 2 hrs, the mixture was poured into aq. NaHCO3, extracted with EtOAc. The separated organics was dried and concentrated in vacuo to afford crude 6-chloro-5-cyclopropyl-2-(2-isopropoxyethoxy)nicotinonitrile (150 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([N+:22]([O-])=O)[C:3]=1[CH3:25].O>C(O)(=O)C.[Fe]>[NH2:22][C:4]1[C:3]([CH3:25])=[C:2]([Cl:1])[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21]
Reactant: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-(4-Chloro-6-fluoro-3-methyl-2-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (2.0 g, 5.2 mmol) was dissolved in acetic acid (20 ml) and iron powder (1.2 g, 21.5 mmol) was added. Solution was stirred at ambient temperature for 14 hr. Water was added and product extracted with ethyl acetate followed by evaporation under reduced pressure. Title compound was separated by column chromatography on silica gel (eluent, hexane-ethyl acetate, 7:3; 1.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[CH3:23])=[O:13].[H-].[Na+].Br[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH3:28]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH3:28])[C:15]=1[CH3:23])=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)[nH]c3ccccc23)c(=O)[nH]1
Reactant: CC(Br)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3ccc(F)cc3)c3ccccc23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.5 %

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (309 mg, 1.0 mmol) was dissolved in 4 mL DMF, NaH (80 mg, 2.0 mmol) was added, the mixture was stirred at room temperature for 30 min, and then 1-(1-bromoethyl)-4-fluorobenzene (0.404 mg, 2.0 mmol) was added. The mixture was stirred at room temperature overnight and was directly purified by reverse phase HPLC (A:CH3CN, B:water+0.1% HCl. A:B=35:65 ASB C18 150*25 mm) to afford the title compound as a white solid (11 mg, yield 3%). LCMS 432 (M+H+) 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J=8 Hz, 1H), 7.33 (m, 1H), 7.14 (s, 1H), 6.96 (m, 2H), 6.92 (m, 1H), 6.85-6.92 (m, 4H), 5.85 (s, 1H), 5.72 (m, 1H), 4.56 (s, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 2.11 (s, 3H), 1.85 (d, J=7.2 Hz, 3H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17](Br)(Br)Br)[CH:11]=[CH:10]2.[OH2:21]>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]([OH:2])=[O:21])[CH:11]=[CH:10]2
Reactant: O=S(=O)(O)O
Reactant: Brc1ccc2nc(C(Br)(Br)Br)ccc2c1
Reactant: O
Product: O=C(O)c1ccc2cc(Br)ccc2n1
Temperature: 150 °C

Procedure:
Concentrated sulfuric acid (0.75 L) was added during 15 min to a stirred suspension of 6-bromo-2-(tribromomethyl)quinoline (350 g, 0.76 mol) in water (1.75 L). The resulting suspension was heated at 150° C. (bath temperature) for 5 hr. The mixture was cooled and the precipitate was collected by filtration, washed with water and dried to give 6-bromo-2-quinolinecarboxylic acid as a solid (127.6 g). The filtrate was diluted with water (3 L) and a second crop of the product was obtained (55.7 g, combined yield 183.3 g, 96%). 1H NMR (400 MHz, DMSO-d6): 8.50 (d, J=9 Hz, 1H), 8.38 (d, J=2 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 8.06 (d, J=9 Hz, 1H), 7.96 (m, 1H). ES-LCMS m/z 253 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH3:13])[CH3:12])=[O:4].ClNC(=O)CCC(N)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:48]=[C:49]1[CH2:54][CH2:53][CH:52]([C:55](O)=[O:56])[CH2:51][CH2:50]1>ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][C:9]=1[N:10]([CH:11]([CH3:13])[CH3:12])[C:55]([CH:52]1[CH2:53][CH2:54][C:49](=[O:48])[CH2:50][CH2:51]1)=[O:56])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Reactant: O=C1CCC(C(=O)O)CC1
Agent: NC(=O)CCC(=O)NCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(=O)CC1)C(C)C

Procedure:
To a solution of 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.5 g, 5.45 mmol) in 1,2-dichloroethane, N-chlorosuccinamide (0.940 g, 7.091 mmol), triphenylphosphine (1.9 g, 7.091 mmol) and 4-oxo-cyclohexanecarboxylic acid (800 mg, 5.455 mmol) were added. The reaction mixture was stirred at reflux for overnight under an atmosphere of N2. The reaction mixture was diluted with CH2Cl2 and extracted with saturated solution oh NaHCO3. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified using silica gel column chromatography using ethyl acetate:hexane (1:4) as eluent to obtain 3-[Isopropyl-(4-oxo-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. (1.2 g, 55%) as syrup. 1H NMR (CDCl3, 400 MHz): δ7.75-7.50 (m, 2H), 7.70-7.38 (m, 3H), 7.12 (s, 1H), 4.95 (m, 1H), 3.87 (s, 3H), 2.75-0.83 (m, 15H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@:4]([CH3:29])([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:5][C:6]([O:8][CH:9]1[CH:16]2[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:18][CH:10]1[CH2:11]3)[CH2:15]2)=[O:7].[Li+].[OH-]>O1CCOCC1>[CH:10]12[CH2:18][CH:14]3[CH2:13][CH:12]([CH2:17][CH:16]([CH2:15]3)[CH:9]1[O:8][C:6]([NH:5][C@@:4]([CH3:29])([C:3]([OH:30])=[O:2])[CH2:19][C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=1)=[O:7])[CH2:11]2
Reactant: COC(=O)[C@@](C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@](Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a stirred solution of N-[(2-adamantyloxy)-carbonyl]α-methyl-D-tryptophan methyl ester (1.36 g, 3.3 mmol) in aqueous 1,4-dioxan (1:2) (20 mL) was added an excess of LiOH (0.210 g, 5 mmol) and stirred at room temperature overnight. After removing the solvent in vacuo the residue was chromatographed using 5% MeOH: 95% CH2Cl2 then 10% MeOH:90% CH2Cl2 as eluants to yield the acid (0.953 mg, 90%) as a white solid, crystallized from n-hexane, mp 210°-215° C. (EtOAc/n-hexane); IR (film) 1689 cm-1 ; NMR (CDCl3 -D2O), δ 1.3--2.2 (14H, m), 1.70 (3H, s), 3.26 (1H, d, J 1.35 Hz), 3.63 (1H, d, 13.5 Hz); 4.77 (1H, br.s), 6.85-7.60 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C@H:9](CC([O-])=O)[C@H:8]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].C[O-:34].[Na+]>CO>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C@H:9]([OH:34])[C@@H:8]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: C[O-]
Reactant: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@H](OCc2ccc(Cl)cc2Cl)[C@H]1CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3R,4R,5R)-5-(2,4-dichloro-benzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-tetrahydrofuran-3-acetate I-1 (10 g, 19.1 mmol) in MeOH (150 ml) is added a solution of 30% NaOMe in MeOH (5.37 ml, 28.6 mmol, 1.5 equiv.) and the reaction is stirred at room temperature for 30 mins. The reaction mixture is concentrated and dissolved in ethyl acetate (180 ml), washed with 1 N HCl solution and saturated brine, dried (anhyd Na2SO4) and concentrated to give (3R,4S,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-tetrahydrofuran-3-ol I-2 as yellowish oil. The obtained crude compound is used for the next step without further purification.
Reaction SMILES: [CH:1]([CH:9]=[CH:10][C:11]([O-:13])=[O:12])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O>[C:11]([OH:13])(=[O:12])[CH:10]=[CH2:9].[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])C=CC=Cc1ccccc1
Agent: *CC*
Solvent: O
Product: C=CC(=O)O
Product: C=Cc1ccccc1

Procedure:
A yellow styrene acrylate high gloss toner was prepared at a 2 liter bench scale (about 165 grams dry theoretical toner). The core toner slurry included about 221.4 grains of 42% solids of a styrene-acrylate latex, produced by emulsion polymerization (glass transition temperature (Tg) 51° C.+/−2° C.), with about 511.8 grams of deionized water, about 59.4 grams of polyethylene wax (commercially available from IGI) (about 31.3% solids) and about 54 grams of yellow pigment (Y74 from Sun Chemical Inc., about 20% solids), that were mixed together in a 2 liter plastic beaker. The slurry was then homogenized for a total of about 10 minutes with mixing at from about 3000 to about 4000 revolutions per minute (rpm) while adding in a coagulant solution, which included about 2.97 grams polyaluminum chloride and about 26.73 grams of about 0.02M nitric acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH:12][CH2:13][CH3:14])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH2:15](Cl)[CH:16]=C.[H-].[Na+].[CH3:21]N(C)C=O>>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH:14]=[CH2:21])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CN(C)C=O
Reactant: C=CCCl
Reactant: CC#CCOc1cc(NCC)ncn1
Agent: [H-]
Agent: [Na+]
Product: C=CCN(CC)c1cc(OCC#CC)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 2 ml of N,N-dimethylformamide were dissolved 153 mg of 4-(2-butynyloxy)-6-(ethylamino)pyrimidine and 67 mg of allyl chloride, to which 40 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 3 hours. Then, ice water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed twice with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to preparative silica gel thin layer chromatography to give 157 mg of 4-(2-butynyloxy)-6-(N-ethyl-N-allylamino)pyrimidine (the present compound (110)).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]#[C:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][N:15]=[C:14]3OC2C=CC=CC=2)([OH:8])[CH2:4][CH2:3]1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:33]=[CH:32]2.Cl.[NH+]1C=CC=CC=1.C1(O)C=CC=CC=1>CCOC(C)=O>[CH2:38]([N:34]1[C:35]2[C:31](=[CH:30][C:29]([NH:28][C:14]3[C:13]4[C:18](=[CH:19][CH:20]=[C:11]([C:10]#[C:9][C:5]5([OH:8])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH:12]=4)[N:17]=[CH:16][N:15]=3)=[CH:37][CH:36]=2)[CH:32]=[CH:33]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CN1CCC(O)(C#Cc2ccc3ncnc(Oc4ccccc4)c3c2)CC1
Reactant: Nc1ccc2c(ccn2Cc2ccccc2)c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: CN1CCC(O)(C#Cc2ccc3ncnc(Nc4ccc5c(ccn5Cc5ccccc5)c4)c3c2)CC1
Temperature: 100 °C
Yield: 60.6 %

Procedure:
In a 1 mL Wheaton vial quinazoline 22 (80 mg, 0.22 mmol) was combined with 5-amino-1-benzylindole (54 mg, 0.24 mmol), pyridinium hydrochloride (5 mg, 0.04 mmol) and phenol (104 mg, 1.11 mmol). The vial was capped and heated at 100° C. for 16 hours. After cooling the contents of the Wheaton vial were solvated in a minimal amount of EtOAc and placed atop a silica gel (5 g) column. Elution of the column with 1:1:0.1 Hexanes:EtOAc/NEt3 removed high Rf impurities. The desired product 23 (Rf 0.05, 10:1 CH2Cl2:MeOH) was eluted off with 10:1 CH2Cl2:MeOH and gave a yellow solid (65 mg, 60%). 1H NMR (DMSO d6; 400 MHz): δ: 9.88 (s, 1H, NH), 8.67 (s, 1H), 8.45 (s, 1H), 7.92 (d, 1.7 Hz), 7.76 (d, 1H, J=8.5 Hz), 7.67 (d, 1H, J=8.5 Hz), 7.50 (d, 1H, J=3.1 Hz), 7.42 (d, 1H, J=8.9 Hz), 7.35 (dd, 1H, J=8.9 Hz, 1.9 Hz), 7.31-7.18 (m, 6H), 6.48 (dd, 1H, J+3.1 Hz, 0.8 Hz), 5.41 (s, 2H), 2.97 (br, 2H), 2.67 (br, 2H), 2.47 (s, 3H), 1.92 (br, 2H), 1.82 (br, 2H). LRMS: 488.2 (MH+), 126.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1)O.[CH2:26](N(CC)CC)[CH3:27].S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH2:26][CH3:27])[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(O)(c2ccc(Br)cc2)N1CC(F)(F)F
Reactant: CCN(CC)CC
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCC1(c2ccc(Br)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Reaction time: 0.08 h

Procedure:
To a −18° C. solution of 6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (1 g, 2.3 mmol) in anhydrous THF (10 mL) was added triethylamine (1.6 mL, 11 mmol). The reaction was stirred for 5 min and then thionyl chloride (0.18 mL, 2.5 mmol) was added dropwise. After 10 min, 1M ethylmagnesium bromide in THF (9 mL, 9 mmol) was added. The reaction mixture was warmed from −18° C. to 0° C. and allowed to stir for 30 min and then quenched with 15 mL 1N aqueous HCl and extracted with 50 mL ethyl acetate. The organic layer was washed with brine (60 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (90 g silica gel cartridge, linear gradient 10-70% EtOAc/hexanes) gave 6-chloro-4-ethyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as an off-white solid. 1H NMR (CDCl3, 500 MHz) δ 8.41 (s, NH); 7.53 (br d, 2H, J=8.79 Hz); 7.28 (br d, 2H, J=8.54 Hz); 7.11 (dd, 1H, J=8.54 and 2.19 Hz); 6.69 (d, 1H, J=8.55 Hz); 6.46 (d, 1H, J=2.20 Hz); 3.87 (dq, 1H, J=9.28 and 16 Hz); 3.52 (dq, 1H, J=8.30 and 17 Hz); 2.39 (dq, 1H, J=7.08 and 14 Hz); 2.22 (dq, 1H, J=7.08 and 14 Hz); 0.90 (t, J=7.08 Hz, 3H); MS (Electrospray): m/z 447.1 (M+H, Br=79).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[ClH:1].[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[N:24]([C:2]2[N:11]=[C:10]([NH:20][CH:17]3[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH2:16]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:23]=1
Reactant: CC1CCC(N)CC1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: Cc1cc(C)n(-c2nc(NC3CCC(C)CC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, 4-methylcyclohexylamine and 3,5-dimethylpyrazole. Mp. 80.4-81.6° C.
Reaction SMILES: [I:1]Cl.[CH2:3]([O:10][CH2:11][C@H:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[NH:16][C:15]=1[Si](CC)(CC)CC)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.CO.C1COCC1.F[B-](F)(F)F.[Ag+]>[CH2:3]([O:10][CH2:11][C@H:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[NH:16][C:15]=1[I:1])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClI
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(C(C)(C)C(=O)OC)cc2c1[C@H](C)COCc1ccccc1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1cnc2[nH]c(I)c([C@H](C)COCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of iodine monochloride (2.83 g, 17.4 mmol) in MeOH (25 mL) was added over approximately 0.5 h via pressure equalizing addition funnel to a vigorously stirred mixture of methyl (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-triethylsilyl-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate (6.00 g, 13.4 mmol) and silver tetrafluoroborate (3.39 g, 17.4 mmol) in MeOH/THF (1:2; 75 mL) at 0° C. After an additional 0.5 h, the reaction was quenched with 1M Na2S2O3, warmed to room temperature and filtered through celite® washing copiously with ethyl acetate. The filtrate was concentrated under reduced pressure, poured into 1M Na2S2O3 and extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes as eluent) to give the title compound as a colourless solid (5.54 g, 84%).
Reaction SMILES: C(OC([N:11]1[CH2:25][CH2:24][C:14]2([O:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH3:22])[C:15]2=[CH2:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.NN>O.CO.[Pd]>[CH2:23]=[C:15]1[C:14]2([CH2:24][CH2:25][NH:11][CH2:12][CH2:13]2)[O:18][C:17](=[O:19])[N:16]1[CH2:20][CH2:21][CH3:22]
Reactant: C=C1N(CCC)C(=O)OC12CCN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: C=C1N(CCC)C(=O)OC12CCNCC2
Temperature: 25 °C
Yield: 95 %

Procedure:
A suspension containing 0.5 g of 10% by weight palladium-on-carcoal catalyst in 5 ml of water is added to the solution of 5.0 g of 8-benzyloxycarbonyl-4-methylene-2-oxo-3-n-propyl-1-oxa-3,8-diazaspiro[4,5]decane in 45 ml of methanol at 0° C. under argon while stirring. To this mixture 1 ml of 45.8% aqueous hydrazine solution is introduced and the reaction mixture is refluxed for 10 to 15 minutes. After cooling down to room temperature and filtering off the catalyst the solvent is evaporated under reduced pressure and the crude evaporation residue is recrystallized from benzene to give the title compound in 95% yield, m.p.: 96°-97° C.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[Cl:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53](O)=[O:54]>>[Cl:47][C:48]1[CH:49]=[CH:50][C:51]([N:57]2[CH:61]=[CH:60][CH:59]=[N:58]2)=[C:52]([CH:56]=1)[C:53]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:54]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(Cl)ccc1-n1cccn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1cccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 5-chloro-2-(1H-pyrazol-1-yl)benzoic acid (CAS number 1214622-57-7; 120 mg, 0.54 mmol) except this was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.