Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](Cl)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:35][CH:32]3[CH2:34][CH2:33]3)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NC2CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride (150 mg, 0.37 mmol) was dissolved in methylene chloride (3 ml) at 0° C., and triethyl amine (0.05 ml, 1.11 mmol) and cyclopropyl amine (0.03 ml, 0.56 mmol) were slowly added thereto. The resulting solution was stirred at room temperature for 3 hours, quenched with saturated ammonium chloride solution, extracted with ethyl acetate and filtrated with magnesium sulfate. The crude solution was evaporated and dried under a reduced pressure, to obtain 5-(4-chlorophenyl)-N-cyclopropyl-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, which are not further purified. The resulting product was dissolved in benzene (3 ml), and phosphorus pentachloride (85 mg, 0.41 mmol) was added thereto at room temperature. The solution was stirred for 20 minutes, hydroazoic acid (1.0 ml, 2.0 M solution in benzene) was added thereto and maintained room temperature for overnight. For completion of the reaction, reaction solution was refluxed for 10 minutes and purified by reverse phase preparative HPLC, to obtain the title compound (83 mg, 50%) as white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C=O)C.C(OCC)(=O)C>[Br:46][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)Cc1cc(-c2ccc(CO)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc(-c2ccc(CBr)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
3-(4Hydroxymethylphenyl)-5 -so-butyl-N-tert-butylthiophene-2-sulfonamide (280 mg, 0.734 mmol, see step (a) above) was dissolved in DMF (10 mL). PPh3 (459.2 mg, 1.75 mmol) and CBr4 (580.3, 1.75 mmol) were added to the resultant solution. The mixture was stirred for 24 h at room temperature and then diluted with ethyl acetate. The organic phase was washed with water (50 mL) and brine (50 mL) and then dried over MgSO4. After removing the solvents, the residue was purified by column chromatography using hexane:acetone (5:1) as eluent to give the sub-title compound (314.9 mg, 0.709 mmol, 76% yield).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([C@@H:31]([NH:33]C(=O)OC(C)(C)C)[CH3:32])=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41]>ClCCl.O1CCOCC1>[ClH:41].[C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([C@@H:31]([NH2:33])[CH3:32])=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution (S)-tert-butyl (1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)ethyl)carbamate (0.251 g) in dichloromethane (20 mL) was added 4.0 M HCl in dioxane (2 mL). The reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and then diluted with ether (20 mL). The product was removed by filtration under reduced pressure and dried to give (S)-1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)ethanamine hydrochloride as a yellow solid (0.215 g, 98% based on tris HCl salt). 1H NMR (DMSO-d6) 400 MHz δ 8.83 (br. s, 1 H), 8.69 (br. s, 3H), 8.16 (dd, JA=4.7 Hz, JB=1.6 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.52-7.44 (m, 3H), 7.40-7.30 (m, 3H), 7.28 (d, J=8.2 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.95-6.91 (m, 1H), 6.82-6.77 (m, 1H), 4.43 (quint., J=6.1 Hz, 1H), 1.52 (d, J=6.7 Hz, 3H); LCMS: 430 [M+H]; Calc. for C28H23N5.3.5HCl.0.05 dioxane.0.35 diethylether: C, 60.52; H, 5.22; N, 11.92. Found C, 60.57; H, 5.67; N, 12.02.
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:15]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (879 mg) was dissolved in DMF (3 mL), tert-butyl bromoacetate (421 mg) was added, and potassium carbonate (299 mg) was further added. The reaction solution was stirred at room temperature overnight. After water was carefully added, ethyl acetate (200 mL) was added, followed by extraction. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further, recrystallization from methanol afforded 846 mg of white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].S(Cl)(Cl)=O.C[N:40](C=O)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH2:40])=[O:29])=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(=O)O)cc3)C2=S)cc1C(F)(F)F
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(N)=O)cc3)C2=S)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanoic acid, RD141 (Formula 51) (60 mg, 0.12 mmol) in DMF (3 mL) was added thionyl chloride (0.01 mL, 0.15 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Then ammonia was bubbled into the mixture. The mixture was partitioned with ethyl acetate (25 mL) and water (25 mL). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 70:30) to yield 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanamide, RD130 (Formula 52) (37 mg, 61%) as a white powder. 1H NMR δ 7.97 (d, 1H, J=1.8 Hz), 7.95 (d, 1H, J=8.3 Hz), 7.85 (dd, 1H, J=8.3 Hz), 7.39 (d, 2H, J=8.3 Hz), 7.22 (d, 2H, J=8.3 Hz), 5.59 (br s, 2H), 2.77 (t, 21-1, J=7.5 Hz), 2.62-2.68 (m, 2H), 2.51-2.59 (m, 2H), 2.31 (t, 2H, J=7.5 Hz), 2.16-2.25 (m, 1H), 2.05 (p, 2H, J=7.5 Hz), 1.57-1.70 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22](=[O:26])[CH2:23][CH2:24][NH2:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:26])[CH2:23][CH2:24][NH:25][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)NCCC(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-β-alanine and β-alanine benzyl ester were coupled analogously to the above examples to give N-[N-(t-butoxycarbonyl)-β-alanyl]-β-alanine benzyl ester, m.p. 84°-85° C.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[NH:3][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:12][N:13]=[C:14]=[S:15]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:11])[N:3]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[C:14]([NH:13][CH3:12])=[S:15]
Reactant: CN(C)NCc1cccnc1
Reactant: CN=C=S
Solvent: Cc1ccccc1
Product: CNC(=S)N(Cc1cccnc1)N(C)C
Yield: 70.6 %

Procedure:
In 30 ml of toluene was dissolved 2.5 g of 1,1-dimethyl-2-(3-pyridylmethyl)hydrazine followed by addition of 1.2 g of methyl isothiocyanate and the mixture was refluxed for 1 hour. The reaction mixture was concentrated and the resulting crystals are collected by filtration, washed with ethyl ether and dried. The procedure gave 2.6 g of 1,1-dimethyl-4-methyl-2-(3-pyridylmethyl)thiosemicarbazide as white prisms.
Reaction SMILES: [CH:1]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10](=[O:15])[CH2:11][C:12](=O)[CH3:13].[CH3:16][O:17][C:18](=[O:21])[C:19]#[CH:20]>CO>[CH3:16][O:17][C:18](=[O:21])[CH:19]=[CH:20][C:11](=[C:12]([NH:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:13])[C:10]([O:9][CH3:8])=[O:15]
Reactant: C#CC(=O)OC
Reactant: NCC1CCCC1
Reactant: COC(=O)CC(C)=O
Solvent: CO
Product: COC(=O)C=CC(C(=O)OC)=C(C)NCC1CCCC1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
A mixture of cyclopentanemethylamine (4.52 g, 45.7 mmol) and 3-oxo-butyric acid methyl ester (5.9 mL, 54.8 mmol) in MeOH (170 mL) was refluxed for 2 h. Propynoic acid methyl ester (6.1 mL, 68.5 mmol) was added, and the resulting mixture was refluxed for 2 days. After cooling to r.t., the solvent was evaporated, and the residue was recrystallized from MeOH to give 7.17 g of the title compound as a light tan solid. MS: (+) m/z 282.33 (M+1).
Reaction SMILES: C=O.[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([NH2:14])=[S:13].CN.[CH3:17][N:18]([CH3:21])[CH:19]=O>C(OCC)C>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N:11]1[CH2:19][N:18]([CH3:21])[CH2:17][NH:14][C:12]1=[S:13]
Reactant: Cc1ccc(NC(N)=S)c(C)c1
Reactant: CN(C)C=O
Agent: C=O
Agent: CN
Solvent: CCOCC
Product: Cc1ccc(N2CN(C)CNC2=S)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Formaldehyde (4.86 g, 37% solution, 30 mmole) was added to a solution of 2,4-dimethyl-phenyl thiourea (4.5 g, 24 mmole) in dimethylformamide (40 ml) and the solution was stirred for 15 minutes at room temperature. Methylamine (3.72 g, 30 mmole) was added dropwise with stirring and the mixture was heated under reflux at 100° C. for 4 hours. The solution was cooled and the solvent removed under vacuum to yield an oil. This was diluted with diethyl-ether and refrigerated to yield 1-(2,4-dimethylphenyl)-5-methyl-tetrahydro-s-triazin-2[1H]-thione as a white crystalline solid which was collected, washed with a little cold diethyl ether and dried (4.5 g, 77%), m.p. 140°-143° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[Br:14]N1C(=O)CCC1=O.Cl>CN(C)C=O.CO>[Br:14][C:5]1[S:1][C:2]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(-c2cccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: O=Cc1ccc(-c2ccc(Br)s2)cc1
Reaction time: 2 h

Procedure:
In a two necked flask under argon, 0.75 g (3.98 mmol) of 4-(2-thienyl)benzaldehyde in 20 mL of dimethylformamide (DMF) are cooled to 0° C. 1.1 eq. (0.78 g, 4.38 mmol) of N-bromosuccinimide (NBS) are solubilised in a mixture of 10 mL of DMF and 10 mL of methanol. This solution of NBS (protected from light) is then added drop by drop (30 min) to the reaction medium. The temperature of the medium is then left to return to ambient temperature over 2 h. The medium is hydrolysed with a solution of 1 mol·L−1 HCl and extracted with ethyl ether. The combined organic phases are washed with a saturated NaCl solution then dried on anhydrous Na2SO4. After filtration and evaporation to dryness, the reaction mixture is recrystallised with acetone.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.Cl.Cl.[NH2:34][CH2:35][C@@H:36]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:37]([O:39][CH3:40])=[O:38]>ClCCl.CN(C)C=O>[CH3:9][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:34][CH2:35][C@@H:36]([N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:37]([O:39][CH3:40])=[O:38])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: COC(=O)[C@@H](CN)N1CCCCC1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
7.2 ml (51.5 mmol) of triethylamine and then 5.9 g (15.5 mmol) of 4-(2-methylquinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride are added to a solution of 3.34 g (12.9 mmol) of methyl (R)-3-amino-2-piperidin-1-ylpropanoate dihydrochloride in 30 ml of dichloromethane and 30 ml of dimethylformamide cooled beforehand using an ice bath. The reaction medium is stirred at ambient temperature for 3 h 30, hydrolyzed, and then diluted with dichloromethane. The product is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 50/50 heptane/ethyl acetate mixture. 4 g (62%) of methyl (R)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:36][C:33]([F:34])([F:35])[C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:26]([NH:25][CH2:24][C:22]([NH:21][C@@H:18]1[CH2:19][CH2:20][N:16]([CH:2]2[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]2)[CH2:17]1)=[O:23])=[O:37]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(N2CC[C@@H](NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a solution of the ketone of step A (0.4 g, 1.9 mmol) and the pyrrolidine intermediate obtained in step C, Example 114 (0.4 g, 1.3 mmol) in THF (15 mL) was added sodium triacetoxyborohydride (0.4 g, 1.9 mmol). The reaction was stirred at room temperature overnight and quenched by addition of aqueous NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic phase was washed with with NaHCO3 and brine, dried over MgSO4 and concentrated. Flash chromatography eluting with a gradient of 0-20% MeOH/CH2Cl2 provided 300 mg of the title compound. MS calculated (M+H)+ 513, found 513.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[NH:6][C:5]2=[O:22].[OH2:23].[C:24]1([CH3:34])C=CC(S(O)(=O)=O)=CC=1.O>C(O)CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([O:21][CH2:34][CH2:24][OH:23])([CH3:20])[CH3:19])=[CH:16][CH:17]=1)[NH:6][C:5]2=[O:22]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(O)c1ccc(-c2nc3ccc(F)cc3c(=O)[nH]2)cc1
Solvent: OCCO
Product: CC(C)(OCCO)c1ccc(-c2nc3ccc(F)cc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-fluoro-2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-3H-quinazolin-4-one (149 mg, 0.50 mmol) in ethane-1,2-diol (2 ml) is added toluene-4-sulfonic acid monohydrate (114 mg, 0.60 mmol). The reaction mixture is stirred for 3 hours at ambient temperature. The suspension is then heated to 80° C. and the resulting clear solution is stirred at this temperature for 5 hours. The reaction mixture is cooled to room temperature and water is added. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 6-fluoro-2-{4-[1-(2-hydroxy-ethoxy)-1-methyl-ethyl]-phenyl}-3H-quinazolin-4-one as white crystals; HPLC/MS 2.28 min (B), [M+H] 343;
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[CH3:31])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=3)=[N:14][C:12]=2[N:13]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]2[CH3:31])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:32](=[O:34])[CH3:33])[CH:19]=3)=[N:14][C:12]=2[N:13]=1
Reactant: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3ccnc(N)c3)nc2n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)ccn1
Temperature: 70 °C

Procedure:
To a 0.1 M solution of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-pyridin-2-ylamine (example 1cz) (1 equiv) in pyridine was added acetic anhydride (3 equiv). A reflux condenser was attached to the reaction vessel which was then heated to 70° C. for 2 days. Upon completion, the reaction was purified, in its crude for by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](/[C:12](/[F:29])=[C:13](\[F:28])/[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:31][CH2:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)/[C:12](/[F:29])=[C:13](\[F:28])/[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1
Reactant: OCCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: F/C(Cc1cccc(Oc2ccccc2)c1)=C(/F)C(CCBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a stirred solution of (4E)-3-(4-chlorophenyl)-4,5-difluoro-6-(3-phenoxyphenyl)-4-hexen-1-ol (0.10 g, 0.24 mmol) in ether (5 ml) under nitrogen was added carbon tetrabromide (0.085 g, 0.256 mmol), followed by triphenylphosphine (0.067 g, 0.255 mmol), and the resulting mixture was stirred overnight at room temperature. Additional quantities of carbon tetrabromide (0.17 g, 0.51 mmol) and triphenylphosphine (0.134 g, 0.51 mmol) were added, and the reaction mixture was stirred for five hours. The reaction mixture was concentrated in vacuo and the residue chromatographed on preparative thin layer silica gel plates, developing with methylene chloride to afford the title compound as a colorless oil (0.08 g) which was characterized by 1MMR, 19FNMR and mass spectral analysis.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[S:6]([NH:9]C(=O)OC(C)(C)C)(=[O:8])=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][CH2:3][N:2]1[S:6]([NH2:9])(=[O:8])=[O:7]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N1CCCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)N1CCCO1
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a cold (0° C.) solution of chlorosulfonyl isocyanate (0.437 mL, 5.02 mmol) in CH2Cl2 (10 mL) was added tert-BuOH (0.480 mL, 5.02 mmol) and the mixture was stirred for 1 h at 0° C. Then HCl salt of isoxazolidine (0.5 g, 4.56 mmol) and TEA (1.399 mL, 10.04 mmol) were added consecutively and the mixture was stirred overnight. Rxn was diluted with EtOAc and washed with ice cold 1N HCl, brine and then dried (MgSO4). Isolated crude product was purified by Biotage 25M column to afford tert-butyl isoxazolidin-2-ylsulfonylcarbamate as a beige solid (0.82 g, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (9 H, s), 2.38 (2 H, quin, J=7.37 Hz), 3.81 (2 H, m), 4.19 (2 H, t, J=7.30 Hz). To a cold (0-5° C.) solution of tert-butyl isoxazolidin-2-ylsulfonylcarbamate (0.82 g, 3.25 mmol) in DCM (2 mL) was added TFA (2 mL, 35.1 mmol) and the reaction mixture was stirred for 2 h at r.t and removed the solvent to afford isoxazolidine-2-sulfonamide (0.229 g, 46%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.40 (2 H, quin, J=7.32 Hz), 3.65 (2 H, m), 4.20 (2 H, t, J=7.32 Hz), 4.83 (2 H, brs).
Reaction SMILES: O.[K].[N+:3]([C:6]1[CH:7]=[C:8]([OH:14])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)([O-:5])=[O:4].C(Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23]N(C)C=O>C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=1[O:14][CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K]
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1OCc1ccccc1
Reaction time: 3 h
Yield: 100 %

Procedure:
4-Nitroguaiacol potassium salt monohydrate (25 g, 111 mmol) and cesium carbonate (3.25 g, 10 mmol) were transferred into a 500 ml one-neck flask and dry dimethylformamide (200 ml) was added, benzyl bromide (21.4 g, 125 mmol) was added dropwise at room temperature under N2 atmosphere and the reaction mixture was stirred vigorously for about 3 hours. The solvent and the excess of benzylbromide were then removed under reduced pressure. Water (200 ml) and ethanol (100 ml) was added to the crude product and refluxed for 10–15 minutes. The yellowish crystalls were filtered from the cold mixture, washed with water and dried to give 29 g (100% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)[C:6]([C:19](OC)=[O:20])=[CH:5]2.[NH:23]1[C:27]2=[N:28][CH:29]=[C:30]([NH2:32])[CH:31]=[C:26]2[CH:25]=[CH:24]1.C[Al](C)C>>[NH:23]1[C:27]2=[N:28][CH:29]=[C:30]([NH:32][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=4)[C:8]4[C:9]([CH:5]=3)=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)=[O:20])[CH:31]=[C:26]2[CH:25]=[CH:24]1
Reactant: COC(=O)c1cc2cc(F)ccc2n1Cc1cccc(C)c1
Reactant: Nc1cnc2[nH]ccc2c1
Agent: C[Al](C)C
Product: Cc1cccc(Cn2c(C(=O)Nc3cnc4[nH]ccc4c3)cc3cc(F)ccc32)c1
Yield: 39.9 %

Procedure:
Compound 5 was prepared according to a process similar to that described in step 5.2 by reacting 200 mg (0.673 mmol) of methyl 5-fluoro-1-[(3-methylphenyl)methyl]-1H-indole-2-carboxylate prepared according to the protocol described in step 6.1 with 107 mg (0.807 mmol) of pyrrolo[2,3-b]pyrid-5-ylamine in the presence of 0.5 mL (1.01 mmol) of a solution of trimethylaluminium (2M/toluene). The product is collected by filtration, to give 107 mg of the expected product.