Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[C:15]([Cl:28])=[CH:16][C:17]([F:27])=[C:18]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>N1C=CC=CC=1>[Cl:28][C:15]1[CH:16]=[C:17]([F:27])[C:18]([NH:20][C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])=[CH:19][C:14]=1[O:13][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:32]([CH:29]3[CH2:31][CH2:30]3)=[O:33])[S:3][C:4]=2[C:10]=1[C:11]#[N:12]
Reactant: O=C(Cl)C1CC1
Reactant: N#Cc1c(Oc2cc(NC(=O)C(F)(F)F)c(F)cc2Cl)ccc2nc(N)sc12
Solvent: c1ccncc1
Product: N#Cc1c(Oc2cc(NC(=O)C(F)(F)F)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a solution of N-{5-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]-4-chloro-2-fluorophenyl}-2,2,2-trifluoroacetamide (0.7 g, 1.63 mmol) in pyridine (3 mL) was added cyclopropanecarbonyl chloride (191 μL, 2.11 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80→80/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (348 mg, 43%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[CH2:11][CH3:12]
Reactant: CCCBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Combine 3-hydroxybenzonitrile (11.052 gm; 92.8 mmol), n-propyl bromide (24.4 gm; 198 mmol), and potassium carbonate (38.65 gm; 280 mmol) in 2-butanone (175 mL) and heat and reflux. After 17 h., cool the mixture to room temperature, and decant the solution and concentrate by rotary evaporation. Partition the residue between diethyl ether (150 mL) and water (150 mL), separate the layers and extract the aqueous layer with diethyl ether (2×100 mL). Combine the organic layers and wash with water, 1 N NaOH, and water, dry over MgSO4, and concentrate. Distill the residue to give the title compound.
Reaction SMILES: [N:1]([CH:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH3:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:21])[CH3:20]
Reactant: CCOC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: CCOC1=C2C=c3c(cnn3CC(C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.4 %

Procedure:
2.05 g (7.2 mmol) of (RS)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 50 ml of anhydrous ethanol were hydrogenated over 200 mg of platinum oxide for 1.5 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 100 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 836 mg (7.2 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 2.35 g (87%) of (RS)-2-(7-ethoxy-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 191° were obtained.
Reaction SMILES: C([O:3][C:4](=O)/[N:5]=[C:6](\OCC)/[CH3:7])C.Cl.[CH:13]([NH:16][NH2:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:13]([N:16]1[C:4](=[O:3])[NH:5][C:6]([CH3:7])=[N:17]1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)/N=C(/C)OCC
Reactant: CC(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nn(C(C)C)c(=O)[nH]1
Reaction time: 17 h

Procedure:
To a solution of [1-ethoxy-eth-(Z)-ylidene]-carbamic acid ethyl ester (834 mg, 5.24 mmol) in toluene (15 mL) was added isopropyl hydrazine hydrochloride (637 mg, 5.76 mmol) follwed by triethylamine (803 μL, 5.76 mmol). The reaction vessel was sealed and stirred at 45° C. for 45 minutes before the addition of triethylamine (803 μL, 5.76 mmol). The resultant mixture was heated to 90° C. and stirred for 17 hours, then cooled and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0% to 8% 2M NH3/MeOH in DCM) to give 2-Isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one as an off white solid (329 mg, 44%). LCMS: RT=2.16 min, [M+Na]+=164
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]#[N:12])[CH:2]=1.B1([O-])O[O:14]1.O.O.O.O.[Na+]>C(O)(=O)C>[C:11]([C:3]1[CH:2]=[N+:1]([O-:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)#[N:12]
Reactant: N#Cc1cnc2c(c1)CCCC2
Reactant: [O-]B1OO1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc2c([n+]([O-])c1)CCCC2
Temperature: 40 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a solution of 5,6,7,8-tetrahydroquinoline-3-carbonitrile (633 mg, 4.00 mmol) in acetic acid (5 ml) at 40° C. was portionwise added sodium perborate tetrahydrate (677 mg, 4.4 mmol) and the mixture was stirred at 40° C. for 16 hours. The acetic acid was removed by evaporation under reduced pressure, the residue was basified with aqueous saturated NaHCO3 solution, the mixture extracted thrice with ethyl acetate, the combined extracts were dried over Na2SO4 and the solvent removed in vacuum to give the 3-cyano-5,6,7,8-tetrahydroquinoline 1-oxide (645 mg, 3.7 mmol, 92.5% yield) as a white solid. MS (ISP): m/z=175.1 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:51][C:52]1[N:60]=[CH:59][CH:58]=[C:57]([CH3:61])[C:53]=1[C:54](O)=[O:55].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:51][C:52]1[N:60]=[CH:59][CH:58]=[C:57]([CH3:61])[C:53]=1[C:54]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5])=[O:55]
Reactant: CCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1ccnc(Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
[1-((R)-3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-ethoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (58.0 mg, 0.15 mmol), EDCI (30.9 mg, 0.16 mmol) and HOBT (21.8 mg, 0.16 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-chloro-4-methyl-nicotinic acid (27.5 mg, 0.16 mmol) followed by DIPEA (30.6 μL, 0.18 mmol) and the resulting mixture was stirred at room temperature for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by preparative TLC (91:8:1, CH2Cl2/MeOH/NH4OH) afforded 2-chloro-N-((R)-3-{4-[(4-ethoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide as a white foam (49.2 mg, 61%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=5 Hz), 1.25 (s, 1H), 1.35 (t, 4H, J=5 Hz), 1.58 (m, 1H), 1.84 (m, 4H), 2.15 (m, 1H), 2.35 (s, 6H), 2.54 (m, 1H), 2.86 (m, 3H), 3.31 (m, 2H), 3.78 (m, 1H), 3.93 (m, 4H), 6.66 (dd, 4H, J=9 Hz, 24 Hz), 7.00 (dd, 2H, J=6 Hz, 18 Hz), 8.01 (d, 1H, J=6 Hz), 8.35 (m, 2H). ES-MS m/z 550 (M+H). Anal. Calcd. For C31H40ClN5O2: C, 67.68; H, 7.33; Cl, 6.44; N, 12.73.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([NH:14][C:15]([C@H:17]1[O:19][C@@H:18]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:16])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][C@@H:2]([C@@H:9]([NH:14][C:15]([C@H:17]1[O:19][C@@H:18]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:27])[CH3:26]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](OC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In pyridine (0.6 mL) was dissolved ethyl (2S,3S)-3-[[1-(S)-[α-(R)-hydroxybenzyl]-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (300 mg, 0.894 mmol.). To the resulting solution was added acetic anhydride (0.085 mL, 0.901 mol.) under chilling with ice. The mixture was stirred for 18 hours at room temperature, and extracted with ether (8 mL, 3 portions) after addition of water (10 mL). The organic portion was washed successively with water, 1N hydrochloric acid, and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1), to give the titled compound as a slightly brownish crystalline product (267 mg, yield: 79%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[CH:1]([N:4]1[C:5]2[C:6](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]1=[O:20])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)Nc1ccccc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2ccccc2n(C(C)C)c1=O
Temperature: 100 °C
Yield: 61.3 %

Procedure:
A solution of 7.5 g of 2-isopropylaminobenzaldehyde, 11.0 g of diethyl malonate and 11.6 g of sodium bicarbonate in 800 ml of acetic anhydride was stirred under heating at 100° C. for 15 hours. After evaporation of the solvent under reduced pressure, water was added, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting oily substance was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 7.3 g of ethyl 1-isopropyl-2(1H)-quinolone-3-carboxylate.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[N:17]=[CH:18][C:19]([C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)=[CH:20][CH:21]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: OB(O)c1ccncc1
Reactant: CN(c1ccc(I)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(c1ccc(-c2ccncc2)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C

Procedure:
Under N2, a mixture of (R)—N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-5-iodo-N-methylpyridin-2-amine (90.0 mg, 0.21 mmol), pyridin-4-yl boronic acid (28.4 mg, 0.23 mmol), PdCl2dppf.CH2Cl2 (17.2 mg, 0.02 mmol) and K2CO3 (0.058 g) in DMF (5.0 mL) was stirred at 110° C. for 16 h. It was then cooled to ambient temperature, diluted with water (5.0 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts was washed with brine (3×5.0 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. The residue was purified by flash chromatography to give the title product. MS (m/z): 372 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH:21]12[NH:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][O:23][CH2:22]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:28]3[CH:21]4[CH2:27][CH2:26][CH:25]3[CH2:24][O:23][CH2:22]4)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: C1CC2COCC1N2
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CCN2C3CCC2COC3)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (117 mg, 0.40 mmol) in DCE (10 mL) was added 3-oxa-8-azabicyclo[3.2.1]octane (54 mg, 0.48 mmol) and powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 2 h, sodium triacetoxyborohydride (168 mg, 0.79 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a pale yellow oil (80 mg, 51%). LCMS (Method H): RT=2.34 min, [M+H]+ 393.5
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:21])=[C:15]([OH:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]2[O:11][C:10]([CH3:22])([CH3:23])[CH:9]([C:6]3[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:24])=[CH:4][CH:5]=3)[C:13]=2[C:14]=1[CH3:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(N(C)C)cc1)C(C)(C)O2
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(c1ccc(N(C)C)cc1)C(C)(C)O2
Yield: 40 %

Procedure:
Using 3-[(4-(dimethylamino)phenyl]-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and benzyl bromide, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH:1]([CH3:3])[CH3:2])[C:14]#[N:15])=[CH:9][CH:8]=1
Reactant: CC(C)Br
Reactant: COc1ccc(CC#N)cc1
Solvent: O
Product: COc1ccc(C(C#N)C(C)C)cc1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a stirred suspension of sodium hydroxide pels (320.0 g; 8.0 mol) in isopropyl bromide (492.0 g; 4.0 mol) is added 4-methoxyphenylacetonitrile (294.3 g; 2.0 mol) over a 30-minute period at a temperature of 50°-55° C. Following this addition the reaction mixture is stirred at reflux (68°-74° C.) for 4 hours. It is then cooled to 50° C. and water (498 ml) is added. The mixture is subsequently stirred for 15 minutes with cooling. The aqueous and organic phases are then separated and the excess isopropyl bromide is removed from the organic phase by distillation. The resulting product (367.88 g of 2-(4-methoxyphenyl)-3-methylbutyronitrile) is 96.9% pure and corresponds to a real yield of 99.1%. The results of this experiment are included in Table Ia under No. 7.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1.C([N:32](CC)CC)C.N.O>CN(C)C=O.O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH2:32])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(=O)(=O)Cl)c3)nc(OC)n2)cc1
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(S(N)(=O)=O)c3)nc(OC)n2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonylchloride [0.2 g, Intermediate (10)] and triethylamine (0.3 mL) in dimethylformamide (5 mL) is cooled to 0° C. and treated with a solution of ammonia in 1,4-dioxane (5 mL, 0.5M). The solution is allowed to reach room temperature overnight and poured into water (100 mL). The mixture is extracted twice with EtOAc (100 mL). The combined extracts are washed with water, dried over sodium sulfate, filtered, and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonamide [140 mg, Example 3]. MS: 415 (M+H), 1H NMR [(CD3)2SO]: δ 8.4 (1H, s); 8.2 (1H, m); 7.9 (1H, d, J=3 Hz); 7.7 (1H, m); 7.4 (2H, m); 7.1 (2H, d, J=7 Hz); 6.8 (2H, d, J=7 Hz); 6.6 (1H, s); 3.9 (3H, s); 3.7 (3H, s); 3.5-3.6 (2H, m); 2.8 (2H, t). IC50=2.9 nM
Reaction SMILES: C1([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([CH3:19])[C:11](=[O:20])[CH:10]([NH:21][C:22]([O:24]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:9]=2)CCCCCC1.C(N([CH2:39][CH3:40])CC)C.[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:43]=1>CN(C)C=O>[CH2:40]1[CH2:39][CH2:17][CH:18]([C:10]2([NH:21][C:22]([NH:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([N:48]4[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]4)[CH:43]=3)=[O:24])[N:9]=[CH:8][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([CH3:19])[C:11]2=[O:20])[CH2:13][CH2:14][CH2:8]1
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCCC2)c2ccccc21
Reactant: CCN(CC)CC
Reactant: CN1CCN(c2cccc(N)c2)CC1
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(NC(=O)NC3(C4CCCCCC4)N=Cc4ccccc4N(C)C3=O)c2)CC1
Temperature: 50 °C

Procedure:
To a stirred solution of 5-cycloheptyl-1,3-dihydro-1-methyl-3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (200 mg) in anhydrous dimethylformamide (5 ml), under an atmosphere of nitrogen, was added triethylamine (61 μl). After 2 min a solution of 1-amino-3-(N-methyl-N'-piperazinyl)benzene (85 mg) in anhydrous dimethylformamide (5 ml) was added and the solution heated at 50° C. for 1.5 h. After this time the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (20 ml) and water (20 ml). An undissolved solid was filtered off and triturated with anhydrous diethyl ether to give the desired urea (128 mg) as a white solid. 1H NMR (360 MHz, D6 -DMSO) δ 1.13-1.94 (12H, m), 2.19 (3H, s), 2.40-2.43 (4H, m), 3.03-3.12 (5H, m), 3.30 (3H, s), 5.04 (1H, d, J=8.4 Hz), 6.49 (1H, dd, 8.1 and 1 Hz), 6.62 (1H, d, J=9.0 Hz), 7.03 (1H, t, J=8.1 Hz), 7.12 (1H, m), 7.22 (1H, d, J=8.4 Hz), 7.38 (1H, dd, J=7.6 and 7.6 Hz), 7.54 (1H, d, J=7.7 Hz), 7.63 (1H, dd, J=8.3 and 8.3 Hz), 7.76 (1H, d, J=7.6 Hz), 8.86 (1H, s). MS (CI, NH3) 502 (M+).
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[Cl:5][SiH:6]([Cl:8])[Cl:7]>CCCCCC>[Cl:4][CH2:1][CH2:2][CH2:3][Si:6]([Cl:8])([Cl:7])[Cl:5].[CH2:1]([Si:6]([Cl:8])([Cl:7])[Cl:5])[CH2:2][CH3:3]
Reactant: C=CCCl
Reactant: Cl[SiH](Cl)Cl
Solvent: CCCCCC
Product: CCC[Si](Cl)(Cl)Cl
Product: ClCCC[Si](Cl)(Cl)Cl
Temperature: 23 °C
Yield: 8 %
Yield: 92 %

Procedure:
A mixture of 15.306 grams of allyl chloride, 27.09 gram of trichlorosilane and 0.04 grams of [SG]--S--Pt sufficient to provide 1×10-5 mm Pt/SiH was stirred at 23° C. under a nitrogen atmosphere. The mixture was heated to 60° C. for 16 hours. The mixture was allowed to cool to ambient temperatures and was diluted with 50 ml of hexane and filtered. The filtrate was concentrated on a rotary evaporator to give 33 grams of a clear, colorless oil. Based on method of preparation, NMR and VPC analysis there was obtained about a 92% yield of γ-chloropropyltrichlorosilane and about an 8% yield of n-propyltrichlorosilane.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([CH2:22][C:23](=[O:49])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([CH:33]1[CH2:38][CH2:37][N:36](C(OCC2C=CC=CC=2)=O)[CH2:35][CH2:34]1)=[O:32])[C:10](=[O:21])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([CH2:8][N:9]([CH2:22][C:23](=[O:49])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])[C:10](=[O:21])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)Nc1ccccc1C(=O)C1CCN(C(=O)OCc2ccccc2)CC1)C(=O)Nc1cccc(C(=O)O)c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)CN(CC(=O)Nc1ccccc1C(=O)C1CCNCC1)C(=O)Nc1cccc(C(=O)O)c1
Reaction time: 0.5 h
Yield: 1495.3 %

Procedure:
To a solution of 3-(3-(tert-butoxycarbonylmethyl(2-(N-(benzyloxycarbonyl)piperidine-4-carbonyl)phenylcarbamoylmethyl)ureido)benzoic acid (compound 53) (19 mg, 1.49 μmol) in ethanol (1.0 ml) are added cyclohexene (144 μl) and 10% palladium-carbon (15 mg), and the mixture is refluxed with stirring for 30 minutes. The reaction solution is filtered and the filtrate is concentrated under reduced pressure to obtain the titled compound 54 (12 mg). Yield 79%.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:27])[CH2:25]Br)[CH:18]=3)=[N:10][C:11]([S:15][CH3:16])=[N:12]2)=[C:7]([NH2:28])[C:6]=1[C:29]([NH2:31])=[O:30])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O.Cl>C(#N)C.C(Cl)Cl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:27])[CH2:25][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:18]=3)=[N:10][C:11]([S:15][CH3:16])=[N:12]2)=[C:7]([NH2:28])[C:6]=1[C:29]([NH2:31])=[O:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nc(-c2cccc(NC(=O)CBr)c2)c2c(N)c(C(N)=O)c(C(C)(C)C)cc2n1
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CSc1nc(-c2cccc(NC(=O)CN3CCOCC3)c2)c2c(N)c(C(N)=O)c(C(C)(C)C)cc2n1
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 5-amino-2-methylthio-4-(3-(2-bromoacetamido)-phenyl)-quinazoline-6-carboxamide (example 28a, 88 mg) in acetonitrile was added morpholine (148 l) and the mixture was stirred for 18 h. After this time CH2Cl2 (15 ml) was added and the mixture was washed with sat. aqueous NaHCO3. The organic layer was dried (MgSO4) and concentrated in vacuo. The title compound was purified by chromatography on silica gel using CH2Cl2MeOH=1/0 to 9/1 (v/v) as eluent. The title compound was lyophilized from a mixture of acetonitrile and water containing 1.5 equiv. of HCl.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9]([OH:10])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]1=[O:8])[CH3:23]
Reactant: Br[Mg]c1ccccc1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2)c2c1cc(I)cc2C(F)(F)F
Yield: 53 %

Procedure:
The title compound (53%) was prepared from 1-(2-diethylaminoethyl)-6-iodo-4-trifluoromethylisatin and phenylmagnesium bromide by the procedure similar to that described in Example 1. The compound obtained was further purified by reverse phase HPLC with water-acetonitrile-trifluoroacetic acid.