Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[CH2:9][CH2:10][NH:11][CH2:12][C:13](OCC)=[O:14])=O)(C)(C)C.Cl.C(N(CC)CC)C>O1CCOCC1>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:13]2=[O:14])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: CCOC(=O)CNCCN(CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1CNCCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Ethyl [(2-{(tert-butoxycarbonyl) [2-(4-nitrophenyl)ethyl]amino}ethyl)amino]acetate (0.50 g, 1.3 mmol) in dioxane (4 mL) was added 4N HCl in dioxane (3.2 mL, 13 mmol). The solution was stirred at 25° C. for 2 hours. LC showed complete removal of the Boc group. The volatiles were removed under vacuum, and the residue was redissolved in toluene and ethanol. To that solution was added triethylamine (0.73 mL, 5.2 mmol). The mixture was heated to reflux for 48 hours. LC at that point showed mostly product. The product was purified by silica gel chromatography (DCM: MeOH) to afford 1-[2-(4-nitrophenyl)ethyl]piperazin-2-one. LC-MS (IE, m/z): 250 [M+1]+.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](F)=[O:11])=[CH:8][CH:7]=1)([F:4])[F:3].[OH-].[Na+].[Cl:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([NH2:27])[C:23]=1[C:24](O)=[O:25]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCCl>[Cl:17][C:18]1[C:23]2[C:24](=[O:25])[O:11][C:10]([C:9]3[CH:13]=[CH:14][C:6]([S:5][C:2]([F:4])([F:3])[F:1])=[CH:7][CH:8]=3)=[N:27][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(F)c1ccc(SC(F)(F)F)cc1
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1oc(-c2ccc(SC(F)(F)F)cc2)nc2cccc(Cl)c12
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 91.1 %

Procedure:
33.6 g of 4-trifluoromethylmercaptobenzoyl fluoride and 12 g of 50% strength sodium hydroxide solution are added simultaneously via 2 feed apparatuses in the course of 30 minutes at from 20° to 39° C. to a stirred mixture of 25.7 g of 6-chloroanthranilic acid, 0.27 g of benzyltrimethylammonium chloride and 450 g of 1,2-dichloroethane. Stirring is continued for 90 minutes at 27° C., after which the water is separated off and 21.5 g of phosphoryl chloride are added at 70° C. Stirring is continued for 3 hours at 82° C., after which the mixture is cooled to 30° C. and extracted 3 times with water. Evaporating down the solution, in the final stage at 140° C. and under 2 mbar, gives 48.8 g (91%) of 5-chloro-2-(p-trifluoromethylmercaptophenyl)-4H-3,1-benzoxazin-4-one of melting point 135°-140° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:42]=[CH:43][CH:44]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[CH:9]=[N:8]1)#[N:2].[OH-].[Li+]>C1COCC1.O.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:42]=[CH:43][CH:44]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[N:8]1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C#N)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(C#N)c5)c4)c3c2)c1
Yield: 15.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(3-(3-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl) methane sulfonamide (90 mg, 0.14 mmol) was hydrolyzed with lithium hydroxide (18 mg, 0.43 mmol) in THF/water/methanol (1/0.5/1 ml) mixture to afford 10 mg (15% yield) of the pure product after purification by preparative TLC (Silicagel-1000 micron) using 10% ethyl acetate in hexane as eluent. 1H NMR (DMSO-d6, 400 MHz): δ11.88 (s, 1H), 9.85 (b, 1H), 8.478-8.475 (d, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.986 (s, 1H), 7.80-7.75 (m, 3H), 7.60-7.45 (m, 5H), 7.26-7.24 (d, 1H) 5.46 (s, 2H), 3.05 (s, 3H) MS: m/z=469.4 (M+1), HPLC 93.92%, (method A).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:66][S:67]([C:70]1[CH:77]=[CH:76][C:73]([CH2:74][NH2:75])=[CH:72][CH:71]=1)(=[O:69])=[O:68].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1C(=O)CCC1.O>[CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([NH:75][CH2:74][C:73]2[CH:72]=[CH:71][C:70]([S:67]([CH3:66])(=[O:69])=[O:68])=[CH:77][CH:76]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (7.43 g, 25 mmol), HATU (10.5 g, 27.5 mmol), HOAT (3.75 g, 27.5 mmol) and DIEA (14.2 ml, 82.5 mmol) in NMP (65 ml) was reacted for 1 h, then 4-methylsulphonylbenzyl amine hydrochloride (5.8 g, 26 mmol) was added. After 1 h, the reaction mixture was slowly poured into stirred ice water (1 L). A powder was formed, and the water mixture was acidified to pH 3 with citric acid (0.5 M), and stirring was continued for 1 h. The precipitate was filtered off, washed with water and dried in vacuum overnight. Recrystallisation from EtOAc gave 8.1 g (70%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:42])=[C:11]([CH:39]=[CH:40][CH:41]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:37][CH3:38])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:42])=[C:11]([CH:39]=[CH:40][CH:41]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:37][CH3:38])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 4-(3-chloro-2-fluoroanilino)-6-(1-tert-butoxycarbonylpiperidin-3-yloxy)-7-methoxyquinazoline (0.67 g) in methylene chloride (15 ml) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated under vacuum and the residue dissolved in methylene chloride. The methylene chloride solution was washed with a saturated solution of sodium bicarbonate, water, brine, dried over MgSO4 and evaporated to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline (0.28 g); Mass Spectrum: (M+H)+ 403.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH2:28]([Si:30]([CH2:44][CH3:45])([CH2:42][CH3:43])[O:31][CH2:32][CH2:33][NH:34][C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[CH:37][N:36]=1)[CH3:29].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:41][C:38]2[CH:37]=[N:36][C:35]([NH:34][CH2:33][CH2:32][O:31][Si:30]([CH2:42][CH3:43])([CH2:28][CH3:29])[CH2:44][CH3:45])=[CH:40][N:39]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: CC[Si](CC)(CC)OCCNc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC[Si](CC)(CC)OCCNc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 500 mg, 1.51 mmol) in methylene chloride (20 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (869 μL, 1.74 mmol) and N,N-dimethylformamide (1 drop). The reaction mixture was stirred at 0° C. for 30 min, concentrated in vacuo, and azeotroped with methylene chloride (2 mL) two times. The resulting oil was then dissolved in tetrahydrofuran (10 mL) at 25° C. and then treated dropwise with a solution of N-(2-triethylsilanyloxy-ethyl)-pyrazine-2,5-diamine (446 mg, 1.66 mmol) and 2,6-lutidine (211 μL, 1.81 mmol) in tetrahydrofuran (15 mL) via an addition funnel. The resulting cloudy solution was then stirred overnight for 16 h at 25° C. After this time, the reaction was diluted with water (10 mL) and then extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 85/15 to 50/50 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-triethylsilanyloxy-ethylamino)-pyrazin-2-yl]-propionamide (606 mg, 69%) as a light yellow foam: (ES)+-HRMS m/e calcd for C27H41ClN4O4SSi (M+H)+ 581.2379, found 581.2386.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[CH2:5][S:4]1(=[O:12])=[O:11])[CH3:2].[NH3:13]>CO>[CH2:1]([NH:3][S:4]([CH2:5][C:6](=[O:10])[CH:7]=[C:8]([NH2:13])[CH3:9])(=[O:12])=[O:11])[CH3:2]
Reactant: N
Reactant: CCN1C(C)=CC(=O)CS1(=O)=O
Solvent: CO
Product: CCNS(=O)(=O)CC(=O)C=C(C)N

Procedure:
A suspension of 13 g of 2-ethyl-3-methyl-1,2-thiazin-5(6H)-one 1,1-dioxide in 130 ml of methanol was reacted with ammonia in accordance with the procedure described in Example 1. The dark yellow solution obtained was concentrated to dryness under reduced pressure and the crystalline residue was recrystallized from ethanol. There were obtained 12.2 g of N-ethyl-4-amino-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 112°-114°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]1[C:17]2[C:16]3[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=3[N:14](COCC[Si](C)(C)C)[C:13]=2[N:12]=[CH:11][CH:10]=1.Br.[OH-].[Na+].Cl>O1CCOCC1>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]1[C:17]2[C:16]3[CH:18]=[C:19]([C:22]#[N:23])[N:20]=[CH:21][C:15]=3[NH:14][C:13]=2[N:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(OC[C@H]3CCCCN3)ccnc21
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc2c(cn1)[nH]c1nccc(OC[C@H]3CCCCN3)c12
Temperature: 75 °C
Yield: 36.1 %

Procedure:
(R)-4-(piperidin-2-ylmethoxy)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (467 mg, 1.1 mmol) was dissolved in 1,4-dioxane (0.5 mL) and then treated with 48% HBr(aq) (0.5 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (122 mg, 37%). 1H NMR (400 MHz, d6-DMSO) δ 8.97 (d, J=0.7, 1H), 8.54 (m, 2H), 7.05 (d, J=5.8, 1H), 4.30-4.18 (m, 2H), 3.11 (m, 1H), 3.03 (m, 1H), 2.69-2.60 (m, 1H), 1.79 (m, 2H), 1.58 (m, 1H), 1.45-1.33 (m, 2H), 1.33-1.21 (m, 1H). LCMS (Method D): RT=7.41 min, M+H+=308.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([C:7](=[O:16])[NH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[NH:8][C:7](=[O:16])[C:6]2[C:11](=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc2c(=O)[nH]c(=O)[nH]c2c1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(=O)[nH]c(Cl)nc2c1OC

Procedure:
Equimolar amounts (0.10 mole) of 7,8-dimethoxy-2,4-(1H,3H)-quinazolinedione and phosphorous oxychloride are stirred at room temperature overnight and the volatiles evaporated in vacuo to afford a residue of 2-chloro-7,8-dimethoxy-4-(3H)-quinazolineone which is purified by washing with aqueous sodium bicarbonate, extraction with chloroform and evaporation of solvent. To the residue is added a solution of 0.10 mole of 3-methylpiperidine in 300 ml. of isoamyl alcohol and the mixture heated at reflux for three hours, the solvent is then evaporated in vacuo to afford 2-(3-methylpiperidin-1-yl)-7,8-dimethoxy-4(3H)-quinazolineone hydrochloride. To this is added 150 ml. of phosphorous oxychloride and the resulting mixture is heated at reflux for two hours. The liquids are evaporated to give a residue of 2-(3-methylpiperidin-1-yl)-4-chloro-7,8-dimethoxyquinazoline hydrochloride. The product is dissolved in dilute aqueous sodium bicarbonate, extracted with chloroform, dried (Na2SO4) and the solvent evaporated.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2>Cl.CC(C)=O>[N:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH2:4][CH:3]=[O:2])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(COc1ccc2ncccc2c1)OC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCOc1ccc2ncccc2c1

Procedure:
6-(2,2-dimethoxyethoxy)quinoline (9.0 g) was dissolved in aqueous 1N hydrochloric acid (60 mL) and acetone (30 mL). The reaction mixture was heated under reflux for 3 h. Acetone was removed under reduced pressure. To the residue was added ethyl acetate, and the solution was neutralized with aqueous 1N NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the desired product which was used in the next step without further purification. (4.8 g) LCMS: (M+H2O)=205.9, and (M+MeOH)=219.9.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH:27]=C)[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:29]=[O+][O-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl.C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][OH:29])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:17])([CH3:18])[N:13]1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 340 %

Procedure:
A solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (15 g) in dry CH2Cl2 (250 mL) was treated with a stream of O3 until the reaction mixture turned blue at −78° C. The system was then flushed with O2 to remove excess ozone. Me2S was added and the mixture was allowed to warm to rt. Solvents were removed in vacuo to give the crude product (12 g). The crude product was dissolved in 250 mL of dry THF. The resulting mixture was cooled to 0° C. before LiAlH4 was added. After being stirred for 30 min, the reaction was quenched with 40 mL of H2O followed by 120 mL of 1 N NaOH. The resulting white slurry was filtered through celite, and the clear, colorless filtrate was dried over anhydrous Na2SO4. Filtration followed by concentration in vacuo gave the crude product, which was purified by flash column to give the pure product (S)-tert-butyl 4-((S)-2-((tert-butyldimethylsilyloxy)methyl)-4-hydroxybutyl)-2,2-dimethyloxazolidine-3-carboxylate (5.2 g, 340%). 1H NMR (CDCl3, 400 MHz) δ 0.06 (s, 6H), 0.89 (s, 9H), 1.46 (s, 12H), 1.50 (m, 3H), 1.53 (m, 3H), 3.09 (m, 1H), 3.49 (m, 2H), 3.50 (m, 2H), 3.7 (m, 2H), 3.90 (m, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([N:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[CH:18][CH:19]=4)[C:14]3=[O:34])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.CO>Cl.O1CCOCC1>[NH2:26][CH2:25][CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][N:13]([C:11]3[CH:12]=[C:7]([CH:8]=[CH:9][C:10]=3[CH3:35])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:6])[C:14]2=[O:34])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCNC(=O)OC(C)(C)C)cc2c1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCN)cc2c1=O
Yield: 89 %

Procedure:
tert-Butyl {2-[(2-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1-oxo-1,2-dihydroisoquinolin-7-yl)oxy]ethyl}carbamate (145 mg) was dissolved in 4N HCl in dioxane (1.2 ml) and methanol (0.9 ml) stirred at room temperature for 18 hours. The orange solution was concentrated and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 3-[7-(2-aminoethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide as a white solid (102 mg); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.69 (m, 2H), 2.10 (s, 3H), 2.22 (s, 2H), 2.86 (m, 1H), 2.94 (t, 2H), 4.05 (m, 2H), 6.73 (d, 1H), 7.22 (d, 1H), 7.43 (m, 1H), 7.50 (d, 1H), 7.66 (d, 1H), 7.72 (d, 1H), 7.76 (d, 1H), 7.87 (m, 1H), 8.46 (d, 1H); Mass Spectrum: M+H+ 378.
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30]([OH:32])=O)=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH2:42]([NH2:45])[CH:43]=[CH2:44]>C1COCC1>[CH2:42]([NH:45][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:10][C:11]=2[CH:29]=1)=[O:32])[CH:43]=[CH2:44]
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: C=CCN
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: C=CCNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of allylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 482.2 (M+H)+.
Reaction SMILES: C(OC1C=CC=CC=1CCC1C=CC(C(OC)=O)=C(O)C=1)C1C=CC=CC=1.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1/[CH:42]=[CH:43]/[C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[C:46]([O:54][CH3:55])[CH:45]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][CH2:43][C:44]1[CH:53]=[CH:52][C:47]([C:48]([O:50][CH3:51])=[O:49])=[C:46]([O:54][CH3:55])[CH:45]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2OCc2ccccc2)cc1OC
Agent: COC(=O)c1ccc(CCc2ccccc2OCc2ccccc2)cc1O
Product: COC(=O)c1ccc(CCc2ccccc2OCc2ccccc2)cc1OC

Procedure:
Methyl 4-[2-(2-benzyloxyphenyl)ethyl]-2-methoxybenzoate was prepared from methyl 4-[2-(2-benzyloxyphenyl)ethyl]-2-hydroxybenzoate (prepared as described in Example 14) using the method described in Example 14 for the preparation of methyl 4-[2-(2-benzyloxyphenyl)-(E)-ethenyl]-2-methoxybenzoate.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f26) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[C:16]=1[CH2:22][CH3:23]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[C:16]=1[CH2:22][CH3:23])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCc1c(Br)cccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cccc(Br)c1CC
Reaction time: 0.25 h
Yield: 45.3 %

Procedure:
To a solution of malonic acid diethyl ester (24.72 g, 154.36 mmol) in dioxane (400 mL) was added sodium hydride (6.17 g, 60%, 154.36 mmol). The mixture was stirred for 15 minutes. Then 1-bromo-2-ethyl-3-iodo-benzene (D126) (40 g, 128.63 mmol) and cuprous bromide (22.13 g, 154.36 mmol) was added. The reaction mixture was refluxed for 10 hr, and then filtered. The filtrate was concentrated in vacuo to give the crude product, which purified by column chromatography to afford 2-(3-bromo-2-ethyl-phenyl)-malonic acid diethyl ester (D127) (20 g). δH (CDCl3-d6, 400 MHz): 1.13 (3H, t), 1.26 (6H, q), 2.88 (2H, m), 4.17 (1H, m), 4.93 (1H, s), 6.68 (1H, t), 7.41 (1H, d), 7.51 (1H, d).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([S:18](=[O:25])(=[O:24])/[N:19]=C/N(C)C)=[C:7]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]>C(O)C.Cl>[CH2:1]([O:4][C:5]1[C:6]([S:18](=[O:25])(=[O:24])[NH2:19])=[C:7]([NH:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:16])[CH3:14])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(NC(=O)C(C)(C)C)c1S(=O)(=O)/N=C/N(C)C
Agent: Cl
Solvent: CCO
Product: C=CCOc1cccc(NC(=O)C(C)(C)C)c1S(N)(=O)=O

Procedure:
A solution of N-(3-allyloxy-2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-phenyl)-2,2-dimethyl-propionamide (387 mg, 1.05 mmol) in ethanol (12 ml) and 12 drops of conc HCl (aprox. 0.2 ml) is refluxed for 36 h. After evaporation of the solvent, the residue is partitioned between ammonia (pH 10 to 11) and EtOAc. The organic layer is dried (Na2SO4) and evaporated. Chromatography (silica gel, EtOAc/hexanes=2:1) afforded N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide containing some N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide. Treatment of this material with ethanol (20 ml) and conc. HCl (2 ml) for 30 h at reflux temperature and workup as above gives N-(3-allyloxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30]>>[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:30]
Reactant: O=C(O)c1ccccc1Br
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4Br)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-bromobenzoic acid as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.