Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:8]3[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:11]4[S:12][CH2:13][CH2:14][CH2:15][N:10]4[N:9]=3)[CH:17]=2)=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2cccc(-c3nn4c(c3-c3ccncc3)SCCC4)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenylamine (prepared as described in Example 3) (50 mg, 0.162 mmol) in dichloromethane (5 mL), 4-methyl-benzenesulfonyl isocyanate (28 mg, 0.178 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The reaction mixture was purified by flash chromatography over silica gel using dichloromethane-methanol (97:3) as the eluant system. 1-(4-methyl-benzenesulfonyl)-3-[3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo-[5,1-b][1,3]thiazin-2-yl)-phenyl]-urea was obtained as a colorless solid (21 mg, 32%).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[Br:8][C:9]1[S:13][C:12](C=O)=[CH:11][CH:10]=1.N1CCCCC1>N1C=CC=CC=1>[Br:8][C:9]1[S:13][C:12](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(Br)s1
Temperature: 100 °C

Procedure:
Malonic acid (44.40 g, 426.7 mmol) was added to a mixture of 5-bromothiophene-2-carbaldehyde (50 g, 261.7 mmol), piperidine (2.84 mL) and pyridine (150 mL). The mixture was refluxed for 1 h at 80° C. and than at 100° C. over night. The volatiles were evaporated and the residue was dissolved in water and acidified with hydrochloric acid (pH 2). The crude product was crystallized in ethanol. Yield: 55.24 g (90.5%). 1H NMR (270 MHz, CH3OH-d4) δ ppm 6.14 (d, J=15.83 Hz, 1H) 7.11-7.16 (m, 2H) 7.68 (d, J=16.36 Hz, 1H); MS 233.1 (M−H)+; Purity (HPLC) 94%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][CH2:24][C:25]3=[O:29])[C@H:21]3[C:12]2=[C:13]2[C:18]([CH2:19][CH2:20]3)=[CH:17][C:16](=[O:30])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1.[Cl-].[S:32](=[CH2:35])(=[O:34])=[O:33]>C(Cl)Cl>[CH3:35][S:32]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[CH2:28][C@@:26]3([CH3:27])[C@@H:22]([CH2:23][CH2:24][C:25]3=[O:29])[C@H:21]3[C:12]2=[C:13]2[C:18]([CH2:19][CH2:20]3)=[CH:17][C:16](=[O:30])[CH2:15][CH2:14]2)=[CH:9][CH:10]=1)(=[O:34])=[O:33]
Reactant: C[C@]12C[C@H](c3ccc(CCCO)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Reactant: C=S(=O)=O
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@]12C[C@H](c3ccc(CCCOS(C)(=O)=O)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Temperature: 2.5 °C

Procedure:
To a solution of 3.41 g of 11β-[4-(3-hydroxypropyl)phenyl]estra-4.9-diene-3,17-dione prepared to preparation 1 in 30 ml of CH2Cl2, under inert atmosphere and at ambient temperature, 1.53 ml of TEA and 0.72 ml of sulfonyl methane chloride in solution in 2 ml of CH2Cl2 is added whilst maintaining the temperature at 0-5° C. and stirring at this temperature. After washing and drying it is evaporated under reduced pressure until 4.15 g of expected raw product is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:11]=1[CH3:10]
Reactant: Cc1c(N)cccc1Cl
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: Cc1c(Cl)cccc1N=Cc1ccccc1O
Reaction time: 0.25 h

Procedure:
o-Hydroxybenzaldehyde (0.20 mole) was treated with 2-methyl-3-chloroaniline (0.20 mole) with vigorous stirring in a 1 liter Erlenmeyer flask. After 15 mins. 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 45 mins. The reaction mixture was left standing at room temperature for 10 min., then it was placed in an ice-bath for 0.5 hour. The crystals which formed were collected, washed with 95% ethanol, and air dried. Recrystallization from 85% ethanol gave N-(o-hydroxybenzylidene)-2-methyl-3-chloroaniline. m.p. 95°-97° C.
Reaction SMILES: N=C=N.[CH3:4][N:5]([C:9]1[S:13][CH:12]=[N:11][CH:10]=1)[CH2:6][CH2:7][NH2:8].[Cl:14][C:15]1[CH:16]=[C:17]([C:21]#[C:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([C:21]#[C:22][C:23]([NH:8][CH2:7][CH2:6][N:5]([CH3:4])[C:9]2[S:13][CH:12]=[N:11][CH:10]=2)=[O:24])[CH:18]=[CH:19][CH:20]=1
Reactant: CN(CCN)c1cncs1
Reactant: O=C(O)C#Cc1cccc(Cl)c1
Agent: N=C=N
Solvent: ClCCl
Product: CN(CCNC(=O)C#Cc1cccc(Cl)c1)c1cncs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.5 %

Procedure:
1.5 g (≅1.8 mmol) PS carbodiimide was added to a solution of 146 mg (0.93 mmol) N1-methyl-N1-(thiazol-5-yl)ethane-1,2-diamine and 252 mg (1.39 mmol) 3-(3-chlorophenyl)propiolic acid in DCM (10 ml) and the reaction solution was shaken for 16 h at RT. The resin was subsequently filtered off, washed with DCM and ethanol and the filtrate concentrated in a vacuum. CC (DCE/EtOH 10:1) was performed with the residue, whereby 63 mg (0.20 mmol, 21%) 3-(3-chlorophenyl)-N-(2-(methyl(thiazol-5-yl)amino)ethyl)propiolamide was obtained.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:11]=[N:10]1)[CH2:6][C:7]#[N:8].[OH:23]O.C(#N)C>>[CH3:1][S:2]([CH2:3][CH2:4][CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:11]=[N:10]1)[CH2:6][C:7]#[N:8])=[O:23]
Reactant: CSCCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Reactant: OO
Solvent: CC#N
Product: CS(=O)CCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Yield: 30.5 %

Procedure:
A solution of 5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-nitrile (0.065 g, 0.00021 mol) and hydrogen peroxide (0.022 mL, 0.00023 mol) in ACN (1 mL, 0.02 mol) was stirred overnight. The reaction was concentrated and purified by HPLC to give 21 mg of a solid. The solid was triturated with MTBE (1 mL)/DCM (10 drops). The solid was filtered and washed to give 13 mg of a white solid (20% yield) which was dried rt to 50° C. for 2 h.
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:23]1([CH2:28][CH2:29][O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35]([CH:40]=O)=[CH:34]3)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[C:16]3=[CH:40][C:35]2[NH:36][C:37]3[C:33]([CH:34]=2)=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:39][CH:38]=3)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1Cc2cc(S(=O)(=O)N3CCc4ccccc43)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCc4ccccc43)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
5-(2,3-Dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@H]2C[NH:22][C:21](=[O:24])[CH2:20]2)C=CC=CC=1>CO>[C:21]([CH2:20][N:10]1[CH2:11][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]1=[O:12])(=[O:24])[NH2:22]
Reactant: O=C1C[C@@H](c2ccccc2)CN1
Reactant: O=C1C[C@H](c2ccccc2)CN1
Solvent: CO
Product: NC(=O)CN1C[C@H](c2ccccc2)CC1=O

Procedure:
Substituting pyrrolidinone 1 in Example 1 by 4(S)-phenyl-2-pyrrolidinone (1a) S-enantiomeric N-carbamoylmethyl-4(S)-phenyl-2-pyrrolidinone (4a) was obtained. [α]D20=−8.3° (c=3, MeOH). 1H NMR (CDCl3), δ: 2.61 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H, quintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (1H and 1H, br.s and br.s, NH2); 7.20-7.40 (5H, m, C6H5).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1>C(O)C.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)NCCC(=O)O)cc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
Ethyl 3-({[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}amino)propanoate (1000 mg) which is a synthetic intermediate in Example 148 was dissolved in ethanol-hexane (1:1, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (1:1, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 11.5 min were collected, and concentrated. The obtained amorphous compound (487 mg) was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL), 1N lithium hydroxide (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (454 mg, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C1C[O:23]CC1>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH:4]=[O:23]
Reactant: Cc1cccc(C)c1C#N
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: Cc1cccc(C)c1C=O
Reaction time: 3 h

Procedure:
To a stirred solution of 2,6-dimethylbenzonitrile (1 g, 7.6 mmol) in THF (15 mL) under argon at 0° C. a solution of DIBAL (1 M in THF, 8 mL, 8 mmol) was added dropwise over 5 minutes. After 3 hr at 0° C., the reaction mixture was brought to room temperature and stirred overnight. The reaction was quenched with 5% sulfuric acid at 0° C., extracted with ether, washed with brine and dried (MgSO4). Concentration provided 2,6-dimethylbenzaldehyde (0.9 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([CH3:8])=O.Cl.[NH2:14][OH:15]>[OH-].[Na+].C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](=[N:14][OH:15])[CH3:8]
Reactant: NO
Reactant: CC(=O)COc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(COc1ccccc1Cl)=NO
Yield: 3.9 %

Procedure:
1-(2-Chlorophenoxy)acetone (106.6 g, 0.58 mol) (J. Am. Chem. Soc., 75, 1953, 1134) was added to a solution of hydroxylamine hydrochloride (27.8 g, 4 mol) in 2N sodium hydroxide solution (420 ml) and sufficient ethanol to give a clear solution. The reaction mixture was refluxed for 30 minutes then concentrated in vacuo, the crude residue was extracted with diethyl ether (3×200 ml). The combined organic layers were dried over magnesium sulphate and concentrated in vacuo. The residue was distilled to give the title product (134-136° C./1.35 mmHg) (4.5 g, 3.9%); 1H NMR (CDCl3400 MHz) δ: 2.05 (s, 3H), 5.00 (s, 2H), 6.90-7.00 (m, 2H), 7.10 (t, 1H), 7.30 (d, 1H), 7.60 (s, 1H); Anal. Found C, 54.95; H, 5.05. C9H10NO2Cl requires C, 54.15; H, 5.05%.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(N)=[O:23].O>O1CCOCC1>[OH:23][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: NC=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(CO)c1c[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 110 °C
Reaction time: 6.5 h
Yield: 55 %

Procedure:
A solution of 19 in dioxane was added to formamide-water (10:1) and the mixture was stirred at 110° C. for 6.5 hrs., then was worked up as for 12 above. Purification by column chromatography gave 20 (55%) whose structure was established by spectral data. Calcd for C17H15NO3 : 281.1052 Found: 281.1052 (HREIMS).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=O.[CH:18]1([O:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>CO>[CH3:1][O:2][C:3](=[O:17])/[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=[N:24]/[O:23][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)C(=O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: NOC1CCCC1
Solvent: CO
Product: COC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
(3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (1.75 g, 6.32 mmol) was stirred in methanol (14 mL) and warmed in a 70° C. oil bath. O-Cyclopentyl-hydroxylamine (1.09 g, 7.92 mmol) was added. After 2 h, the reaction mixture was allowed to cool and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 □m; 20% ethyl acetate/hexanes) gave (E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid methyl ester (1.01 g, 44%) eluting second as a clear, colorless oil which solidified over time: H1-NMR (400 MHz, CDCl3) δ=1.62 (4H, m), 1.85 (4H, m), 3.31 (3H, s), 3.91 (3H, s), 4.96 (1H, m), 7.48 (1H, dd, J=8.2 Hz, J=1.3 Hz), 7.59 (1H, d, J=1.2 Hz), 8.17 (1H, d, J=8.2 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N:10]1([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH2:16][CH2:17][OH:18])[CH2:11][CH2:12]2)[CH:7]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(Cl)cc(N2CCN(CCO)CC2)n1
Reaction time: 4 h

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (3.00 g) in dichloromethane (35 mL) was added 2-(piperazin-1-yl)ethanol (4.51 mL) at room temperature, and the mixture was stirred for 4 hr. To the reaction mixture was added triethylamine (0.513 mL) at room temperature, and the reaction mixture was stirred overnight. The resulting solid was collected by filtration, washed with dichloromethane, and dried under reduced pressure to give the title compound (4.08 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:9]1[N:14]=[C:13]([CH2:15][C@@H:16]2[C@H:20]([O:21][CH2:22][CH:23]=O)[CH2:19][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:17]2)[CH:12]=[C:11]([CH3:32])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][NH2:48].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C:9]1[N:14]=[C:13]([CH2:15][C@@H:16]2[C@H:20]([O:21][CH2:22][CH2:23][NH:48][CH2:47][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[F:40])[CH2:19][N:18]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:17]2)[CH:12]=[C:11]([CH3:32])[CH:10]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NCc1ccccc1F
Reactant: Cc1cc(C[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2OCC=O)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2OCCNCc2ccccc2F)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Yield: 97 %

Procedure:
To a solution of aldehyde 6 (100 mg, 0.18 mmol) in DCM (4 mL) was added (2-fluorophenyl)methanamine (45 mg, 0.36 mmol), triethylamine (11 μL, 0.36 mmol), followed by NaHB(OAc)3 (100 mg, 0.45 mmol). The reaction mixture was stirred for an additional 3 hand then concentrated. The crude product was purified by flash column chromatography (EtOAc/hexanes, 1:1, Rf=0.15) to yield 7a (115 mg, 91%) as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 1.43-1.44 (s, 27H), 2.29-2.30 (m, 3H), 2.60-2.75 (m, 1H), 2.76-2.85 (m, 2H), 2.92-3.00 (m, 1H), 3.05-3.14 (m, 1H), 3.20-3.50 (m, 5H), 3.52-3.70 (m, 2H), 3.72-3.80 (m, 1H), 3.91 (s, 2H), 6.84-6.85 (d, J=8.0 Hz, 1H), 6.89-6.91 (d, J=10.0 Hz, 1H), 7.02-7.06 (dd, J=9.0, 9.5 Hz, 1H), 7.10-7.13 (dd, J=7.0, 7.5 Hz, 1H), 7.20-7.30 (m, 1H), 7.35-7.40 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 20.9, 24.7, 27.9, 28.47, 28.50, 29.7, 34.6, 34.7, 36.6, 42.6, 43.3, 46.8, 48.2, 48.8, 49.1, 50.3, 50.8, 68.0, 68.2, 78.7, 79.2, 79.3, 79.4, 82.8, 115.2, 115.3, 115.4, 115.5, 119.5, 119.6, 122.8, 124.17, 124.19, 128.89, 128.92, 128.95, 128.99, 130.46, 130.51, 130.55, 149.6, 151.4, 151.5, 151.8, 154.5, 154.8, 159.08, 159.14, 160.3, 162.2; LC-TOF (M+H+) calcd for C35H52FN4O7 659.3820. found 659.3818.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:6](=[O:20])[N:5]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]([CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[C:9]2[C:8](=[O:11])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:6](=[O:20])[N:5]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]=2[N:3]=1
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2[nH]c(Cl)nc2n(COC(=O)C(C)(C)C)c1=O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(Cl)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2,2-Dimethylpropionic acid [8-chloro-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (600 mg) and potassium carbonate (630 mg) were suspended in N,N-dimethylformamide (10 ml), and 4-bromo-2-methyl-2-butene (183 μl) was added to the suspension at room temperature. After the reaction mixture was stirred at room temperature for 24 hours, the mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After the solvent was removed by distillation from the organic layer, the residue was purified by silica gel column chromatography to give 470 mg of the title compound from the elution fraction of hexane-ethyl acetate (3:1).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([C:18](=[O:35])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[N:21][CH:20]=3)[CH2:16][CH2:15][CH2:14][C:13](=O)[C:12]=2[CH:37]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([C:18](=[O:35])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:34])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[N:21][CH:20]=3)[CH2:16][CH2:15][CH2:14][C:13](=[CH2:1])[C:12]=2[CH:37]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)cn1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Temperature: -5 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (0.86 g) in tetrahydrofuran (20 ml) is added with stirring potassium t-butoxide (0.23 g) at -5° C., and the mixture is stirred at -5° C. for one hour. To the mixture is added 7-chloro-5-oxo-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.58 g) at the same temperature, and the mixture is stirred at room temperature for one hour. The reaction mixture is poured into ice-water, and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-methylidene-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.28 g) as yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.764 mmol) in N,N-dimethyl acetamide (5 mL) were added 2-pyridine carboxaldehyde (0.082 g, 0.764 mmol), sodium hydrogen sulphite (58.5%, 0.15 g, 0.84 mmol), and p-toluenesulfonic acid (15 mg, 0.0764 mmol). The reaction mixture was stirred at 150° C. overnight. The mixture was cooled to room temperature. Water (40 mL) was added and the reaction mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water and dried over anhydrous Na2SO4. The solvent was removed and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 1% methanol in CH2Cl2 as eluent) to give 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one (0.077 g, 36%) as a white solid. 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one was converted to the corresponding hydrochloride. Selected data: MS (m/z): 284.0; MP 215-217° C. (hydrochloride).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:24])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH2:27]([O:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[N:41]3[CH:42]=[C:43]([O:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[C@@H:50]([NH2:57])[CH2:49][CH2:48]4)[CH:44]=[CH:45][C:40]3=[N:39][N:38]=2)[CH2:33][CH2:32]1)[CH:28]=[CH2:29].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:27]([O:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[N:41]3[CH:42]=[C:43]([O:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[C@@H:50]([NH:57][C:5]([NH:6][C:7]5[N:8]([C:16]6[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][CH:17]=6)[N:9]=[C:10]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:11]=5)=[O:24])[CH2:49][CH2:48]4)[CH:44]=[CH:45][C:40]3=[N:39][N:38]=2)[CH2:33][CH2:32]1)[CH:28]=[CH2:29]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(CO)cc2)n1
Reactant: C=CCOC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5-c5ccc(CO)cc5)c5ccccc54)cn23)CC1
Yield: 64.9 %

Procedure:
A yellow-brown solution of Intermediate 33a (99.6 mg, 0.237 mmol), Intermediate 57b (90.3 mg, 0.215 mmol) and DIPEA (0.047 mL, 0.269 mmol) in dioxane (3 mL) was stirred at 60° C. for 18 h. The solution was concentrated in vacuo, then the residue suspended in water (5 mL) and extracted with DCM (2×5 mL). The combined organics were passed through a hydrophobic fit and concentrated in vacuo. The residue was purified by FCC, using 2-8% [2M NH3 in MeOH] in DCM, to give the title compound as a pale yellow solid (96.4 mg, 65%). LCMS (Method 3): Rt 3.54 min, m/z 691 [MH+].