Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[Cl:3][C:4]1[C:5]([CH:10]([NH:24][C:25]([CH:27]2[CH2:29][CH2:28]2)=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][N:9]=1.CC#N.CN(C=O)C.O=P(Cl)(Cl)Cl>O>[Cl:3][C:4]1[C:5]2[N:6]([C:25]([CH:27]3[CH2:29][CH2:28]3)=[N:24][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: O=C(NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl)C1CC1
Agent: N#N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Clc1nccn2c(C3CC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In an oven-dried flask filled with N2 was added cyclopropanecarboxylic acid [(3-chloropyrazin-2-yl)-(4-phenoxyphenyl)-methyl]-amide (55 mg, 0.00014 mol), MeCN (4 mL, 0.07 mol) and DMF (0.7 mL, 0.009 mol). POCl3 was added dropwise at 0° C. The reaction mixture was warmed up to rt and stirred at that temperature overnight. The excess of POCl3 was removed under reduced pressure and the residue was quenched with solution of NH3 in i-PrOH (2 N) at 0° C. with vigorous stirring to adjust pH to 9. The crude reaction mixture was then charged with water and the aqueous layer was washed with DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound, which was used in next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([OH:21])[C:12]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:28]1([S:38](Cl)(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>ClCCl>[C:28]1([S:38]([O:21][C:13]2[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=2)(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(O)c2-c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(OS(=O)(=O)c3cccc4ccccc34)c2-c2ccccc2)cc1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-ol (0.1 g, 0.25 mmol, prepared according to the procedure described in PCT/IB03/01289) in dichloromethane (10 ml) was added naphthalene-1-sulfonyl chloride (0.086 g, 0.37 mmol) in dichloromethane (4 ml) at 0° C. and the mixture was stirred for 10 minutes. Subsequently pyridine (0.04 ml, 0.5 mmol) was added under stirring and the stirring was continued further for 6 hours at 37° C. Dichloromethane was removed under vacuo and the resultant mixture was diluted with water:ethyl acetate (1:1, 100 ml) and then extracted with ethyl acetate (25 ml×3). The organic layer was washed with brine (100 ml), dried over anhydrous sodium sulphate and evaporated to afford the title compound (0.096 g, yield 67%); m.p. 204-206° C.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:20])[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:24][CH2:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27].BrCCC(O)=O.C(N)CCC>O1CCCC1.C(Cl)Cl>[CH2:1]([NH:5][C:6](=[O:20])[CH2:7][CH2:8][N:9]([CH2:24][CH2:25][C:26](=[O:27])[NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)CCBr
Reactant: CCCCNC(=O)CCNS(=O)(=O)c1ccc(C)cc1
Agent: O=C(O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCCCNC(=O)CCN(CCC(=O)NCCCC)S(=O)(=O)c1ccc(C)cc1

Procedure:
Dissolve N-butyl-3-(toluene-4-sulfonylamino)-propionamide (10 mmol) prepared in Scheme VI, step B in tetrahydrofuran (50 mL) and treat with sodium hydride (10 mmol). Stir the reaction for 30 minutes and add 3-bromo-N-butyl-propionamide (10 mmol) [prepared from amidation between Br(CH2)2CO2H and butyl amine under conditions well known in the art as previously described generally]. Heat the reaction to reflux for 5 hours. After cooling dilute the reaction with methylene chloride (150 mL), rinse with water (100 mL), brine (100 mL), dry over sodium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide N-butyl-3-[(2-butylcarbamoyl-ethyl)-(toluene-4-sulfonyl)-amino]-propionamide.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CC(C)([O-])C.[K+].F[C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].Cl>C1COCC1.O>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH3:8]
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C#N)c1cc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 107.2 %

Procedure:
To an ice-cold solution of ethyl cyanoacetate (10.9 mL, 102.4 mmol) in anhydrous THF (170 mL) under N2 is added of potassium tert-butoxide (12.07 g, 107.5 mmol). The formed white suspension is stirred for 15 min then treated with 3-fluoro-4-nitroanisole [Halfpenny, P. R.; Horwell, D. C.; Hughes, J.; Hunter, J. C.; Rees, D. C. J. Med. Chem. (1990), 33, 286-91] (8.86 g, 51.2 mmol). The suspension is heated at reflux for 1.5 h. The solution is poured into H2O; and the aqueous mixture is acidified to pH 2 with concentrated HCl. The mixture is extracted three times with ether then the combined organic phases are dried (MgSO4) and concentrated to an oil that is pumped at 0.3 mm for 2 days. The oil is dissolved in dichloromethane and purified by flash silica gel chromatography eluting with dichloromethane. The product fractions are combined and concentrated to leave cyano-(5-methoxy-2-nitrophenyl)acetic acid ethyl ester (14.5 g) as a light yellow oil that is about 93-95% pure. 1H NMR (CDCl3): δ8.29 (1H, d, J=9.2 Hz), 7.22 (1H, d, J=2.7 Hz), 7.04 (1H, dd, J=9.2, 2.7 Hz), 5.69 (1H, s), 4.31 (2H, q, J=7.0 Hz), 1.34 (3H, t, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.O.CO.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[N:3]=1
Reactant: COC(=O)c1cc(N2CCOCC2)nc(Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(N2CCOCC2)nc(Cl)n1
Yield: 99.1 %

Procedure:
A suspension of methyl 2-chloro-6-morpholin-4-ylpyrimidine-4-carboxylate (0.30 g, 1.16 mmol) in a mixture of THF:H2O:MeOH (12 ml, 4:1:1) is stirred at room temperature for 24 hrs with lithium hydroxide (28 mg, 1.0 eq). The mixture is then evaporated to dryness to give 2-chloro-6-morpholin-4-ylpyrimidine-4-carboxylic acid as a solid (280 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35])[C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]([CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:10]2)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:43].C(=O)([O-])O.[Na+]>ClCCl>[CH:1]([O:4][C:5]1[N:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:35])([F:36])[F:37])[C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]([CH2:15][S:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:43])[NH:10]2)([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1=C(CSc2ccccc2)Nc2ccnc(OC(C)C)c2C1c1ccccc1C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=C(CS(=O)c2ccccc2)Nc2ccnc(OC(C)C)c2C1c1ccccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
A solution of 1.0 g (1.9 mMole) ethyl (±)-1,4-dihydro-5-isopropoxy-2-phenylthiomethyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate (Example 3.d) in 30 ml dichloromethane is cooled to 0° C. and 0.4 g (2.1 mMole) 3-chloroperoxy-benzoic acid (90%) is added portionwise thereto. After 10 minutes at 0° C., an aqueous solution of sodium hydrogen carbonate is added dropwise thereto and the organic phase is separated off, washed with water and dried over anhydrous sodium sulphate. After distilling off the solvent, the residue obtained is recrystallized from ethyl acetate. There is obtained ethyl (±)-1,4-dihydro-5-isopropoxy-2-phenylsulphinylmethyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylate in the form of colorless crystals; mp 206°-208° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])[CH2:13][C@H:12]2[CH3:29])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH3:30][S:31]([NH:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])[CH2:13][C@H:12]2[CH3:29])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:33])=[O:32]
Reactant: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(N)c2)[C@@H](C)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(NS(C)(=O)=O)c2)[C@@H](C)C1
Reaction time: 18 h

Procedure:
The title compound was prepared from the product of Example 57 and methane sulphonyl chloride by the method of Example 62. The solid obtained at the end of the reaction was suspended in ethanol (50 ml) to which a solution of K2CO3 (0.2 g) in water (10 ml) was added, and stirred for 18 hours, in order to hydrolyse any bis-sulphonamide. The ethanol was removed, water (50 ml) was added and the pH was adjusted to 5.0. The solid was filtered off, washed with water and ether and dried in vacuo to give the title compound as a white solid. Yield 0.13 g.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15]CC3C=CC=CC=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[Cl:31])[NH2:27].Cl>C(O)(C)C.C(OCC)C.C(#N)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:3]2[C:12]3[C:7](=[CH:8][C:9]([OH:15])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Temperature: 25 °C
Yield: 94.1 %

Procedure:
4-Chloro-6-(methyl-oxy)-7-[(phenylmethyl)oxy]quinazoline hydrochloride (22.91 g, 67.9 mmol) was suspended in isopropanol followed by addition of 3,4-dichloroaniline (13.2 g, 81.5 mmol) and concentrated aqueous hydrochloric acid (1 mL). The mixture was brought to reflux over 12 hours and diluted with ethyl ether (150 mL). The solid was collected by filtration, washed with additional ethyl ether and dried. The material was then taken into trifluoroacetic acid (150 mL) and brought to reflux over 1 hour. The solution was cooled to room temperature then concentrated in vacuo to give a crystalline residue. The residue was suspended in acetonitrile (100 mL) followed by addition of ethyl ether (100 mL). The solid was collected by filtration and washed with additional ethyl ether then dried in vacuo to give 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (21.49 g, 64% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO): 11.09 (br s, 1H), 8.87 (s, 1H), 8.07 (d, 1H), 8.00 (s, 1H), 7.23 (s, 1H), 3.98 (s, 3H); MS (EI) for C15H11N3O2Cl2: 337 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C@H:12]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:13][CH2:14][O:15][C:16](=[O:29])[C@H:17]([CH:26]([CH3:28])[CH3:27])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:4](Cl)[N:3]=1.C([O-])=O.[NH4+]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C@H:12]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:13][CH2:14][O:15][C:16](=[O:29])[C@H:17]([CH:26]([CH3:28])[CH3:27])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][N:3]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2c(Cl)nc(N)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)Cn1cnc2cnc(N)nc21
Reaction time: 1 h

Procedure:
To the solution of (R)-2-amino-9-(2-stearoyloxymethyl-4-(N-tert-butoxycarbonyl-L-valyloxy)butyl)-6-chloropurine (240 mg, 0.33 mmole) in methanol/ethyl acetate (6 ml, 3:1 V/V) were added ammonium formate (105 mg, 1.65 mmole) and 10% palladium on carbon (15 mg). The reaction was kept under reflux for 1 hour and recharged with ammonium formate (70 mg). After one hour more the TLC showed completion of the reaction and the mixture was filtered through Celite and washed extensively with ethanol. The filtrate was evaporated and purified by silica gel column. Yield: 193 mg.
Reaction SMILES: C([O:4][C@:5]1(O)[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([CH2:17][O:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH2:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:13]([O:12][C:10]([N:8]1[CH2:9][C@@H:5]([OH:4])[CH2:6][C@H:7]1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@](O)(OC(C)=O)CN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](O)CN2C(=O)OC(C)(C)C)cc1
Reaction time: 24 h
Yield: 86.7 %

Procedure:
To a stirred solution of methyl 4-[(2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinyl]methoxybenzoate (7.43 g, 18.9 mmol) in MeOH (150 ml) was added cat. K2CO3 at room temperature. After 1 day stirring, the mixture was concentrated in vacuo. The resulting residue was recrystallized by the addition of CHCl3-n-hexane, to give methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinyl]methoxybenzoate (5.76 g, 87%) as a colorless solid. 1H-NMR (CDCl3) δ1.46 (s, 9H), 2.11 (m, 1H), 2.35 (br, 1H), 3.27-3.65 (m, 2H), 3.89 (s, 3H), 4.07-4.54 (m, 4H), 6.96 (d, J=6.9 Hz, 2H), 7.99 (d, J=6.9 Hz, 2H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)/[CH:16]=[CH:17]/[C:18](OCC)=[O:19].O>C1COCC1>[F:11][C:12]([F:26])([F:27])[C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)/[CH:16]=[CH:17]/[CH2:18][OH:19]
Reactant: CCOC(=O)/C=C/c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OC/C=C/c1cccc(C(F)(F)F)c1
Yield: 50.7 %

Procedure:
12.29 ml of 1M diisobutylaluminum hydride solution in THF diluted with 20 ml of THF are introduced under argon and a solution of 1.00 g (4.095 mmol) of ethyl E-3-trifluoromethylcinnamate in 20 ml of THF is added dropwise. The mixture is subsequently stirred for 30 min, hydrolyzed with water, then extracted with dichloromethane, and the combined extracts are dried and concentrated. Column chromatography on silica gel (mobile phase:cyclohexane:ethylacetate:=7:3) yields in the first fraction 420 mg (50.7% of theory) of E-3-trifluoromethylcinnamyl alcohol which is employed further for the oxidation.
Reaction SMILES: BrCC1C=CSC=1.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:16]=[C:17]1[CH:26]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:25][C:24]2[C:19](=[C:20]([N:35]3[CH2:39][CH2:38][CH2:37][C:36]3=[O:40])[CH:21]=[CH:22][CH:23]=2)[NH:18]1>>[CH2:8]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][C:20]=2[N:35]2[CH2:39][CH2:38][CH2:37][C:36]2=[O:40])[CH2:25][CH:26]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:17]1=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc(N3CCCC3=O)c2NC1=O
Agent: BrCc1ccsc1
Product: CC(C)(C)OC(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccccc2)C1=O

Procedure:
Instead of 3-bromomethylthiophene, benzylbromide (1.48 mL) was used with respect to tert-butyl 2-oxo-8-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (Compound B) (4.3 g), which had been produced through the same method as employed in Example 7(a), whereby the title compound (5.87 g) was yielded.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.F[C:20]1C(C)=CC=C(F)C=1B(O)O>>[F:1][C:2]1[C:7]([CH3:20])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: Cc1ccc(F)c(B(O)O)c1F
Product: Cc1ccc(F)c(-c2nc(C(=O)O)cs2)c1F

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2,6-difluoro-3-methylphenyl)boronic acid gave the title compound.
Reaction SMILES: Cl.[CH:2]([NH:5][C@@H:6]([CH3:9])[CH2:7][OH:8])([CH3:4])[CH3:3].[C:10]1([CH2:16][C:17]([Cl:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[ClH:19].[CH:2]([NH:5][C@@H:6]([CH3:9])[CH2:7][O:8][C:17](=[O:18])[CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])[CH3:3]
Reactant: CC(C)N[C@@H](C)CO
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)N[C@@H](C)COC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 10 g of (S)-2-isopropylamino-propan-1-ol hydrochloride in 300 ml of dichloromethane 10 ml of phenylacetic acid chloride are added. The reaction mixture is stirred at RT for about 15 h and then substantially concentrated under reduced pressure, and the highly viscous residue is partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. The resin-like residue is purified by silica gel chromatography, and the product fraction is separated off and concentrated. The residue is dissolved in 150 ml of 2-propanol and 25 ml 2 N HCl in water are added. The mixture is stirred for about 15 h and the resulting crystals are filtered off. This gives 10.9 g of the title compound. M. p. 114-118° C. (unsharp)
Reaction SMILES: Cl.CO.C([Si](C)(C)O[CH:10]1[C:19]2[C:14](=[C:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=[CH:17][CH:18]=2)[O:13][CH2:12][CH2:11]1)(C)(C)C.[N-:29]=[N+:30]=[N-:31].[Na+]>CCOCC.CCCCCC.O>[N:29]([CH:10]1[C:19]2[C:14](=[C:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=[CH:17][CH:18]=2)[O:13][CH2:12][CH2:11]1)=[N+:30]=[N-:31]
Reactant: CC(C)(C)[Si](C)(C)OC1CCOc2c(CN3CCCCC3)cccc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: [N-]=[N+]=NC1CCOc2c(CN3CCCCC3)cccc21
Reaction time: 1 h

Procedure:
HCl (1.2 mL, 37%) was added to a MeOH (60 mL) solution of 1-[4-(tert-butyl-dimethyl-silanyloxy)-chroman-8-ylmethyl]-piperidine (Step C) (3.00 g, 8.30 mmol). After stirring for 1 h, the mixture was evaporated to dryness from benzene. The resulting crude alcohol was dissolved in SOCl2 (5 mL) and stirred for 3 days at RT. Following the removal of the excess SOCl2 in vacuo from hexane, the crude chloride was dissolved in DMF (20 mL) and NaN3 (1.618 g, 24.9 mmol) was added. The mixture was stirred at 80° C. for 1 h and, upon cooling, it was diluted with Et2O (100 mL), hexane (100 mL) and H2O (100 mL). After separation, the organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound. MS (APCI+, m/z): 273 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]2[N:50]3[C:45]([CH:46]=[N:47][C:48](O)=[N:49]3)=[CH:44][CH:43]=2)[CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:48]2[N:47]=[CH:46][C:45]3=[CH:44][CH:43]=[C:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([S:33](=[O:35])(=[O:34])[NH:32][C:28]([CH3:29])([CH3:31])[CH3:30])[CH:37]=4)[N:50]3[N:49]=2)=[CH:23][CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(N)cc2)C1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CN(C(=O)OC(C)(C)C)CCN5C(=O)OC(C)(C)C)cc4)nn23)c1

Procedure:
Analogous to Example 1510b, 2-(4-Amino-phenyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.180 g, 0.477 mmol) and N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (149 mg, 0.429 mmol) were reacted to afford 2-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazine-1,4-dicarboxylic acid di-tert-butyl ester, which was treated with 10% TFA in dichloromethane overnight. Conc. and purification by HPLC afforded N-tert-Butyl-3-[2-(4-piperazin-2-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as the TFA salt (162 mg, 61%). LCMS (HPLC): 0.8 min, m/z=506 (M+H); 1H-NMR (DMSO-d6): 9.81 (s, 1H), 9.44 (br s, 3H), 9.09 (s, 1H), 8.57 (s, 1H), 8.34 (d, 1H, J=8.0 Hz), 7.87 (m, 3H), 7.74 (m, 1H), 7.62 (s, 1H), 7.48 (d, 2H, J=8.5 Hz), 7.24 (d, 1H, J=4.8 Hz), 7.05 (d, 1H, J=4.8 Hz), 4.46 (m, 1H), 3.59 (m, 3H), 3.27 (m, 3H), 1.11 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)(=[O:3])[CH3:2].[H-].[Na+].[C:15](OCC)(=[O:17])[CH3:16]>>[NH:8]1[C:9]2[C:5](=[C:4]([C:1](=[O:3])[CH2:2][C:15](=[O:17])[CH3:16])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: CC(=O)c1cccc2[nH]ccc12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Product: CC(=O)CC(=O)c1cccc2[nH]ccc12

Procedure:
4-Acetylindole (0.101 g) was refluxed in 5 mL of ethyl acetate. Sodium hydride (0.20 g, 60% oil dispersion) was added in portions to the refluxing solution until thin layer chromatography analysis showed complete consumption of the starting material. The reaction mixture was quenched with water and acidified to pH 3. The ethyl acetate layer was dried (magnesium sulfate) and concentrated to give a crude product. The crude material was chromatographed on silica gel, eluting with hexane/ethyl acetate to give 1-(1H-indol-4-yl)-1,3-butanedione (0.104 g), a compound of formula (11), m.p. 104-105° C.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:16][N:17]=[C:10]1[N:9]([CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:8]2=[O:32])(=O)C>Cl>[NH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:16][N:17]=[C:10]1[N:9]([CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:8]2=[O:32]
Reactant: CC(=O)Nc1ccc2c(c1)c(=O)n(C/C=C/c1ccccc1)c1nnc(N3CCCC3)n21
Agent: Cl
Product: Nc1ccc2c(c1)c(=O)n(C/C=C/c1ccccc1)c1nnc(N3CCCC3)n21
Reaction time: 0.25 h
Yield: 45 %

Procedure:
In a 20 ml balloon flask, we resuspend 0.2 g (0.46 mmol) of 7-acetamido-4-[(E)-3-phenylallyl]-1-(pyrrolidin-1-yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (describe example 222) in 5 ml of 6N hydrochloric acid solution and heat by reflux, under shaking, for 15 minutes. After cooling down, the obtained solution is alkalinized by soda solution, extracted 3 times by methylene chloride. The joined organic phases are washed with a NaCl-saturated solution, dried on Na2SO4 then evaporated under vacuum. The crude product (0.12 g) is recrystallized in ethanol to give 0.08 g of the pure compound from example 223.