Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:31][CH2:32][C:33](Cl)=[O:34]>ClCCl.C(Cl)(Cl)Cl>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])[CH2:32][Cl:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Dissolve 2-[(triphenylmethyl)thio]ethylamine (5.24 g, 16.4 mmol) and triethylamine (2.76 mL, 19.6 mmol) in 150 mL dichloromethane. Chloroacetyl chloride (1.56 mL, 19.6 mmol) is dissolved in 20 mL chloroform. Being cooled down with an ice bath, slowly drop chloroacetyl chloride into the solution. Then stir the solution at room temperature for 2 hours. Next wash organic phase with followings in turn: 2N hydrochloric acid solution (120 mL), and saturated sodium bicarbonate aqueous solution (100 mL). The organic phase is dehydrated by anhydrous sodium sulfate (Na2SO4) and then is concentrated in vacuo to yield yellow oily N-[2-((Triphenylmethyl)thio) ethyl]-chloroacetamide (5.62 g, 86.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:14]O)=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:18]>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([CH2:14][Br:18])=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1CO
Reactant: BrC(Br)(Br)Br
Solvent: ClCCl
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1CBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
(5-Hydroxymethyl-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.3 g) and 1 g of triphenylphosphine polystyrene (1.2 mmol/g) were taken in anhydrous dichloromethane (6 mL) and cooled to 0° C., and carbontetrabromide (0.4 g) added. The mixture stirred for 1 h. at 0° C. room temperature for 2 h. Resin was filtered and washed with 5 mL of dichloromethane, filtrate was concentrated and dried in vacuum give (5-Bromomethyl-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.3 g). This was used in the next reaction with no further purification. 1H NMR (400 MHz, Acetone-d6) 4.9 (s, 2H), 2.45 (s, 3H), 1.55 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26]C)=[O:25])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([OH:26])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c(-c2ccccc2C(=O)OC)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1c(=O)c(-c2ccccc2C(=O)O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C

Procedure:
A 1.40 g portion of methyl 2-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]benzoate was stirred in 20 ml of methanol and 10 ml of a 1M sodium hydroxide aqueous solution at 60° C. for 15 hours. The reaction mixture was cooled to room temperature and 10 ml of 1M hydrochloric acid was added thereto. The resulting precipitates were collected by filtration and recrystallized from ethyl acetate-diisopropyl ether to obtain 540 mg of 2-[4-(3-chlorophenyl)-l-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]benzoic acid 0.6 hydrate as a colorless crystalline solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[C:5]=12.[CH:22](=O)[CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[C:5]3[N:4]([CH:3]=[CH:2][N:1]=3)[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:23][CH3:24]
Reactant: CCC=O
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2ccnc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCC=C1SC(=O)N(CCCCOc2cccn3ccnc23)C1=O

Procedure:
To a solution of 1.53 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.36 ml (5.0 mmol) of 1-propanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The, residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1). After the solvent was distilled off, the residue was recrystallized from ether to yield 1.14 g (41.7%, white crystal) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][CH2:15][CH3:16])[CH2:11][O:10][C:9]1([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([CH2:15][CH3:16])[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]=2)[CH2:11][O:10][C:9]1([CH3:17])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: CCNC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccnc(C(F)(F)F)n1

Procedure:
A solution of (S)-4-ethylaminomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.310 g, 1.2 mmol), 4-chloro-2-(trifluoromethyl)pyrimidine (0.183 g; 1.0 mmol) and N,N-diisopropyl ethyl amine (0.34 ml, 2.0 mmol) in isopropanol (3 ml) was heated in a sealed vessel in a microwave oven for 30 min at 180° C. Ethyl acetate (20 ml) and silicagel (1 g) was added and the mixture was evaporated. The residue was purified by flash chromatography, column: Isolute® Flash-NH2 (Separtis); eluent: EtOAc/MeOH=95:5) to yield a light yellow oil, (0.362 g, 90%); MS (ISP): 405.5 ((M+H)+).
Reaction SMILES: [CH2:1]([N:3]([CH2:18]C)[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[C:11](Cl)[CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:17])=[N:8]1)C.[C:20]1(=O)N(C2C3C(=CC=CC=3)NN=2)C(=O)C2=CC=CC=C12.Br.CC(N(C)C)CCBr.C1(=O)N(C2C3C(=CC=CC=3Cl)NN=2)C(=O)C2=CC=CC=C12.Br.BrCCCN(CC)CC>>[CH3:18][N:3]([CH3:1])[CH:4]([CH3:20])[CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:17])=[N:8]1
Reactant: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Agent: Br
Agent: CC(CCBr)N(C)C
Agent: CCN(CC)CCCBr
Product: CC(CCn1nc(N)c2ccccc21)N(C)C

Procedure:
The same procedures for preparing 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole as described in Example 89 were repeated except that 8 g of 3-phthalimidoindazole and 8.6 g of (1-methyl-3-bromopropyl)dimethylamine hydrobromide were employed instead of the 3-phthalimido-4-chloroindazole and the 3-bromopropyldiethylamine hydrobromide, respectively. As a result, 9.2 g of 1-(3-dimethylaminobutyl)-3-aminoindazole was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[C:16](O)(=O)[CH3:17]>>[CH3:10][O:9][C:6]1[C:7]2[N:8]=[C:16]([CH3:17])[NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CCN(C)C)c(N)c1N
Product: COc1ccc(CCN(C)C)c2[nH]c(C)nc12

Procedure:
0.6 g of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dimethylamine is heated under reflux with 10 ml of acetic acid for 3 hours. The reaction mixture is concentrated, taken up in ethyl acetate, and extracted by shaking with sodium bicarbonate solution. The organic phase is separated, dried with sodium sulfate, and concentrated, thus obtaining 286 mg of 7-methoxy-4-[2-(N,N-dimethylamino)ethyl]-2-methylbenzimidazole as an oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:38])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[CH2:34][CH2:33][CH2:32]3)[CH:28]=1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:38])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:19][C:18]=2[N:27]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[CH2:34][CH2:33][CH2:32]3)[CH:28]=1)=[O:14])[CH3:11]
Reactant: NCCCN1CCCC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCN3CCCC3)ncc2c1=O

Procedure:
Using the procedure described in Example 1 Step F, the title compound was prepared from 3-pyrrolidin-1-yl-propylamine and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E), 10 mg, 0.022 mmol). 7 mg of 8-Indan-5-yl-5-oxo-2-(3-pyrrolidin-1-yl-propylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.24 (s, 1H), 8.76 (s, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.21 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 5.72 (br, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.27 (m, 2H), 2.98 (m, 4H), 2.50 (m, 6H), 2.17 (m, 2H), 1.80 (m, 4H), 1.68 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: CC1C=CC(N[N:9]=[C:10]2[C:15]3=[N:16][C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[C:23](=[O:24])[N:14]3[CH:13]([CH3:25])[CH2:12][CH2:11]2)=CC=1>O>[CH3:25][CH:13]1[N:14]2[C:15](=[N:16][C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=3[C:23]2=[O:24])[C:10]2[NH:9][C:19]3[C:20]([C:11]=2[CH2:12]1)=[CH:21][C:22]([CH3:23])=[CH:17][CH:18]=3
Reactant: Cc1ccc(NN=C2CCC(C)n3c2nc2c(c3=O)CCCC2)cc1
Solvent: O
Product: Cc1ccc2[nH]c3c(c2c1)CC(C)n1c-3nc2c(c1=O)CCCC2

Procedure:
1 g. of 6-(4-Methyl-phenylhydrazono)-9-methyl-1,2,3,4,6,7,8,9-octahydro-pyrido[2,1-b]quinazoline-11-one is added to 10 g. of polyphosphoric acid heated to 180° C. and the reaction mixture is heated for 40 minutes at this temperature. After cooling the mixture is diluted with 60 ml. of water. A yellowish-white crystalline precipitate is obtained which is filtered and washed with water. After drying the obtained solid is dissolved in chloroform and the undissolved part is filtered off. The solution is treated with active charcoal and evaporated. The obtained yellowish white oil is crystallized from ethyl acetate. 0.4 g. of 7,10-dimethyl-5-oxo-1,2,3,4,7,8-hexahydro-5H,13H-indolo[2',3';3,4]pyrido [2,1-b]quinazoline are obtained melting at 220° C.
Reaction SMILES: CN(C)CCN.[CH:7]([O:10][N:11]1[C:15](=O)[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2C1=O)([CH3:9])[CH3:8].C(O)(=O)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[C:29](C(C2CCCCC2)=O)[CH:28]=1>CCO>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]([F:40])([F:38])[F:39])(=[O:36])=[O:35])=[C:31]([C:15]([CH:14]2[CH2:13][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:11][O:10][CH:7]([CH3:8])[CH3:9])[CH:32]=1
Reactant: O=C(c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F)C1CCCCC1
Reactant: CC(C)ON1C(=O)c2ccccc2C1=O
Agent: CN(C)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)ON=C(c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F)C1CCCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-isopropoxyphthalimide (308 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(4-chloro-2-cyclohexanecarbonylphenyl)-trifluoromethanesulfonamide 29E (370 mg, 1.0 mmol), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-[4-chloro-2-(cyclohexylisopropoxyiminomethyl)phenyl]trifluoromethanesulfonamide 210 (390 mg, 91%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (1:1 mixture of E- and Z-isomers) δ 10.59, br s, 1H; 8.11, br s, 1H, 7.61, d, J=8.8 Hz, 1H, 7.49, d, J=8.8 Hz, 1H, 7.46, d, J=2.4 Hz, 1H, 7.42, dd, J=2.4 and 8.8 Hz, 1H, 7.30, dd, J=2.4 and 8.8 Hz, 1H, 7.24, d, J=2.4 Hz, 1H, 4.49, m, 1H, 4.39, m, 1H, 2.97, m, 1H, 2.45, m, 1H, 1.97-1.71, m, 14H, 1.34-1.24, m, 18H. HRMS (M+) 426.0983.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:17][N:18]1CCCC1=O.Cl>O>[O:16]=[C:13]1[C:14]2[CH:15]=[C:2]([C:17]#[N:18])[CH:3]=[CH:4][C:5]=2[O:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1=2
Reactant: O=c1c2c(oc3ccc(Br)cc13)CCCC2
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: O
Product: N#Cc1ccc2oc3c(c(=O)c2c1)CCCC3
Temperature: 190 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of 252.6 g of 7-bromo-1,2,3,4-tetrahydro-9-xanthone obtained in Example 1, 89.1 g of cuprous cyanide and 900 ml of N-methyl-2-pyrrolidone was heated with stirring for 2 hours at 190° C. and then allowed to cool to 80° C. To the reaction mixture was added a mixture of 300 g of ferric chloride, 450 ml of water and 80 ml of concentrated hydrochloric acid, and the resulting solution was agitated for 30 minutes. After allowing the reaction mixture to stand overnight, the deposited crystals were collected by filtration and washed thoroughly with water. Subsequently, the crystals were dried and recrystallized from acetonitrile to obtain 169.6 g (yield: 83.6%) of 5,6,7,8-tetrahydro-9-oxo-xanthene-2-carbonitrile as brownish prism-like crystals having a melting point of 198° to 200° C.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[Br:7][C:8]1[CH:9]=[C:10]([NH2:15])[CH:11]=[N:12][C:13]=1[Cl:14].[N:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([C:19]3=O)[CH2:17]1)[CH2:23]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>C(O)(=O)C.C(OCC)(=O)C.CCO>[CH3:42][C:43]1[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:47][CH:48]=1.[Br:7][C:8]1[CH:9]=[C:10]([NH:15][C@@H:19]2[CH:20]3[CH2:25][N:16]4[CH2:23][CH:22]([CH2:24][CH:18]2[CH2:17]4)[CH2:21]3)[CH:11]=[N:12][C:13]=1[Cl:14]
Reactant: Nc1cnc(Cl)c(Br)c1
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Clc1ncc(NC2C3CC4CC2CN(C4)C3)cc1Br
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Magnesium sulfate (1.80 g, 15 mmol) and 5-bromo-6-chloropyridin-3-amine (310 mg, 1.49 mmol) were added to a solution of 1-azatricyclo[3.3.1.13,7]decan-4-one (151 mg, 1.00 mmol) in acetic acid (5 mL). The resulting suspension was stirred for 10 minutes, then sodium triacetoxyborohydride (412 mg, 1.94 mmol) was added. The mixture was stirred at room temperature for 14 hours, then concentrated under vacuum to dryness. The white solid residue was slurried in ethyl acetate (3 mL), applied to the top of a silica column and eluted with chloroform-methanol-concentrated ammonium hydroxide (90:10:1) to provide a pink solid. This material was heated with ethyl acetate (3 mL) and a solution of 4-methylbenzenesulfonic acid monohydrate (40 mg, 1 eq.) in warm ethyl acetate (1 mL) was added. Additional ethyl acetate (3 mL) and EtOH (3 mL) were added with heating to bring the mixture to homogeneity. After cooling to room temperature and finally to −10° C., the mixture was filtered and the collected solid was washed with ethyl acetate (3 mL) and dried under vacuum to provide the titled compound: 1H NMR (300 MHz, methanol-D4) δ 1.91 (br d, J=13.1 Hz, 2H), 2.11-2.21 (m, 1H), 2.22-2.32 (m, 4H), 2.36 (s, 3H), 3.54 (s, 2H), 3.59-3.72 (m, 4H), 3.91 (s, 1H), 7.23 (d, J=7.9 Hz, 2H), 7.47 (d, J=2.8 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.85 ppm (d, J=2.8 Hz, 1H); MS DCI/NH3 m/z 342/344/346 (M+H)+; Anal. Calcd. for C14H17N3ClBr.C7H8O3S: C, 48.99; H, 4.89; N, 8.16. Found, C, 48.95; H, 4.66; N, 8.02.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH3:34]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29]([NH2:34])=[O:31])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: N
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(N)=O
Yield: 88 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.54 mmol) was reacted with ammonia to give the title compound as a white solid (212 mg, 88%); NMR Spectrum 1.67 (d, 3H), 5.14 (q, 1H), 6.04 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.56 (br s, 1H), 7.66 (d, 1H), 7.83-7.72 (m, 4H), 7.90 (br s, 1H), 8.19 (s, 1H), 8.53 (s, 2H), 10.82 (br s, 1H); Mass spectrum 446.
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Na+].[Br:34]N1C(=O)CCC1=O>O>[C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][C:16]([Br:34])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a cold solution of a compound of formula IV, preferably 2-benzoyl-[3,3-di(ethoxycarbonyl)propyl]pyrrole, in an aprotic polar solvent, such as tetrahydrofuran, is added a slight excess of a strong base, preferably sodium hydride. The reaction mixture is allowed to stir for about 30 minutes. To the reaction mixture is then added a halogenating agent, preferably N-bromosuccinimide. The reaction mixture is allowed to stir until complete The mixture is poured into water and extracted with an aprotic polar solvent, such as diethyl ether. The organic layers are combined, washed with water and brine, dried, and concentrated under reduced pressure. The residue may be purified by conventional means to produce a compound of formula VII, preferably 2-benzoyl-[3-bromo-3,3-di(ethoxycarbonyl)propyl]pyrrole.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH:18](F)[F:19])([CH2:14][CH:15]([CH3:17])[CH3:16])C(OCC)=O)=[O:7])(C)(C)[CH3:2]>FC(F)(F)C(O)=O>[CH2:14](/[C:8](=[CH:18]\[F:19])/[C:6]([O:5][CH2:1][CH3:2])=[O:7])[CH:15]([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(CC(C)C)(C(=O)OC(C)(C)C)C(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C(=C/F)CC(C)C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 2-(tert-butoxycarbonyl)-2-(difluoromethyl)-4-methylvalerate (35.68 g) in trifluoroacetic acid (243 ml) is stirred for 1 hour, then the excess trifluoroacetic acid is removed by evaporation. The residual oil (30.89 g) is dissolved in THF (400 ml) and treated slowly with M NaOH (121 ml) so that the pH does not rise above 7.02. After completion of the addition the solution is stirred for another 15 minutes and the product is extracted into ether. Careful distillation at atmospheric pressure, then at 24 mm allows the separation of essentially pure acrylate as a colorless oil (5.72 g), bp 70°-72° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:13])([CH3:12])[C:7](OCC)=[O:8].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][OH:8]
Reactant: CCOC(=O)C(C)(C)CCCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CO)CCCCBr
Yield: 99.7 %

Procedure:
According to the procedure described for the synthesis of 206e (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818), 205c (500.0 g, 2.0 mol) was reacted with LiBH4 (65.0 g, 3.0 mol) and methanol (95.0 g, 3.0 mol) in CH2Cl2 (6.0 L) to afford 206c (417.0 g, 99%) as an oil. 1H NMR (CDCl3): δ 3.38 (t, 2H, J=7.4), 3.50-3.40 (br. s, 1H, OH), 3.22 (d, 2H, J=5.6), 1.85 (qv, 2H, J=7.4), 1.50-1.35 (m, 2H), 1.30-1.20 (m, 2H), 0.85 (s, 6H). 13C NMR (CDCl3) δ 71.4, 37.5, 34.9, 33.9, 33.4, 23.7, 22.4.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cnc(Br)s1
Product: COC(=O)c1cnc(-c2cccc(C(F)(F)F)c2)s1

Procedure:
Synthesized as described in Example 310D using methyl 2-bromo-1,3-thiazole-5-carboxylate and [3-(trifluoromethyl)phenyl]boronic acid: 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.28 (s, 1H), 8.16 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH2:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.O.[CH3:20]I>[Na].C(O)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:20])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CC(=O)Cc1ccc2c(c1)Cc1cccnc1O2
Reactant: CI
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)C(C)c1ccc2c(c1)Cc1cccnc1O2
Yield: 74.8 %

Procedure:
24 g of 5H-[1]benzopyrano[ 2,3-b]pyridin-7-yl-acetone is dissolved in a solution of 2.5 g of metallic sodium in 120 ml of isopropyl alcohol at 50°-60°C with stirring. The solution is cooled to 40°C with water, 17.2 g of methyl iodide is added, and the mixture is stirred under reflux for 1 hour. The isopropyl alcohol is distilled off under reduced pressure, and the residue is dissolved in chloroform. After water cooling, the solution is dried over anhydrous magnesium sulfate and concentrated, and the residue is recrystallized from isopropyl alcohol to give 19 g of 3-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-2-butanone melting at 136°-136°C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:57]1([N:60]2[CH:65]3[CH2:66][CH2:67][CH2:68][CH:61]2[CH2:62][CH:63]([NH2:69])[CH2:64]3)[CH2:59][CH2:58]1>CN(C=O)C.O>[CH:57]1([N:60]2[CH:65]3[CH2:66][CH2:67][CH2:68][CH:61]2[CH2:62][CH:63]([NH:69][C:16]([C:12]2[N:8]4[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]5[C:2]([F:1])=[CH:22][CH:21]=[CH:20][C:19]=5[F:23])[C:7]4=[N:14][C:13]=2[CH3:15])=[O:18])[CH2:64]3)[CH2:59][CH2:58]1
Reactant: NC1CC2CCCC(C1)N2C1CC1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CC2CCCC(C1)N2C1CC1
Reaction time: 0.25 h

Procedure:
70 mg of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0.22 mmol), 209 mg of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 0.55 mmol) and 85 mg of N,N-diisopropylethylamine (0.66 mmol) were initially charged in 1.5 ml of DMF and stirred for 15 min. 59 mg of 9-cyclopropyl-9-azabicyclo[3.3.1]nonane-3-amine (0.33 mmol) were added, and the mixture was stirred at RT overnight. The mixture was then stirred overnight once more, at 60° C. 12 ml of water were added to the reaction solution, and the precipitate formed was filtered off, washed with water and dried. The residue formed was purified by silica gel chromatography (mobile phase: dichloromethane/methanol 40:1). This gave 60 mg of the title compound (53% of theory, purity 94%).