Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=O)=[CH:15][C:14]=3[CH:25]=2)=[CH:6][C:5]=1[F:26])[CH3:2].S(Cl)(Cl)=O.[CH3:31][N:32]([CH:34]=O)[CH3:33]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([NH:19][C:13]4[CH:14]=[CH:25][C:10]([CH2:34][N:32]([CH3:31])[CH:33]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:11][CH:12]=4)=[O:24])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][C:5]=1[F:26])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
In DMF (5.5 ml) was dissolved 7-(4-ethoxy-3-fluorophenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (398 mg). To the solution was added thionyl chloride (0.20 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and to the residue was added THF (10.0 ml). On the other hand, to 4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]aniline dihydrochloride (394 mg) was added THF (10.0 ml), and then was added triethylamine (1.17 ml). To the obtained mixture was added dropwise at 0° C. the previously prepared acid chloride suspension, and the mixture was stirred at room temperature for 4 hours. To the mixture was added ethyl acetate, and the mixture was washed with water, 1N sodium hydroxide solution, water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 7-(4-ethoxy-3-fluorophenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (453 mg, 73%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1cncc(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cncc(OCc2ccccc2)c1
Yield: 34.7 %

Procedure:
To a suspension of 5-bromo-pyridin-3-ol (1.9 g, 10.9 mmol) in acetonitrile (152 mL) is added bromomethyl-benzene (2.1 g, 12.0 mmol) and potassium carbonate (4.5 g, 32.8 mmol). The resultant mixture is stirred at room temperature for 16 h. The crude product is purified by silica gel column to afford 3-benzyloxy-5-bromo-pyridine (1.0 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](/[C:21](=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[F:35])/[C:22](=[O:26])[NH:23]2)=[CH:19][C:18]=1[F:36].C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[CH:25][C:17]([Cl:16])=[C:18]([F:36])[CH:19]=3)[NH:23][C:22]2=[O:26])[CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Nc2cc(Cl)c(F)cc2/C1=C/c1cccc(Cl)c1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (2.85 g, 13.3 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one (2.9 g, 8.9 mmol) prepared in Example 45 in dichloromethane (100 mL) were added triethylamine (3.7 mL, 27 mmol) and AgF (1.1 g, 8.9 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (30 mL), and DBU (4.0 g, 27 mmol) was added. The reaction mixture was heated at 80° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3, 1:2) to give as rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a white solid (1.8 g, 38%)
Reaction SMILES: [C:1]1([C:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C)C=O>[CH2:22]([N:9]1[CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12](=[O:13])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)[CH3:23]
Reactant: CCI
Reactant: O=c1c(-c2ccccc2)c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccccc2)c(=O)c(-c2ccccc2)n1
Reaction time: 0.5 h

Procedure:
A 1 g. portion of the product of Example 2 was suspended in 40 ml. of dimethylformamide, the suspension was cooled under nitrogen to 0°-5° C., and an 0.3 g. portion of 50% NaH in oil was added. The reaction mixture was stirred for 30 minutes, and 3 ml. of ethyl iodide was added. The mixture was stirred at 0°-5° C. for 24 hours, and the mixture was then filtered to separate the precipitated product. The dried product was 1.0 g. of 1-ethyl-3,5-diphenyl-4(1H)-pyridazinone, m.p. 124°-25° C., which was identified by nuclear magnetic resonance analysis, infrared analysis, and mass spectrometry.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH3:16])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CCCCNC
Solvent: O=S(Cl)Cl
Product: CCCCN(C)C(=O)c1ccc(Br)c(C)c1

Procedure:
From 4-bromo-3-methylbenzoic acid (400 mg), thionyl chloride (0.4 ml) and N-methyl-1-butanamine (0.8 ml).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][CH3:16])=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=[C:10]([Cl:23])[N:9]=1)=O)C>CCO>[Cl:23][C:10]1[N:9]=[C:8]([CH2:6][OH:5])[C:13]([O:14][CH2:15][CH3:16])=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=1
Reactant: CCOC(=O)c1nc(Cl)nc(N2CCOCC2)c1OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1c(CO)nc(Cl)nc1N1CCOCC1
Yield: 97.3 %

Procedure:
NaBH4 (0.64 g, 4 eq.) was added to a stirred solution of 2-chloro-5-ethoxy-6-morpholine-4-yl-pyrimidine-4-carboxylic acid ethyl ester (1.34 g, 1 eq.) in EtOH (20 ml) and the mixture reacted to reflux for 2 h. The mixture was quenched with H2O, the solvent was removed in vacuo, and the residue was extracted with EA, washed with brine, and concentrated to give a product (1.13 g, 97.3%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2Cl)[CH2:11][O:12][CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:33]>>[Si:1]([O:8][CH2:9][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH2:33])[CH2:11][O:12][CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(Cl)ncnc21)OCC
Reactant: N
Product: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(N)ncnc21)OCC
Temperature: 120 °C

Procedure:
A solution of 9-(1-t-butyldimethylsilyloxy-3-diethoxyphosphorylmethoxyprop-2-oxy)-6-chloropurine (270mg, 0.53 mmol) in ethanolic ammonia (10 ml) was heated in a sealed: metal bomb at 120° C. for 2.5 hours before cooling for 16 hours. The solvent was evaporated, and the residue chromatographed on silica eluting with ethyl acetate-methanol (10:1-5:1)affording 9-(1-t-butyldimethylsilyloxy-3-diethoxyphosphorylmethoxyprop-2-oxy)adenine (182mg, 70%) as a clear gum; νmax (film) 3320, 1600, 1470, 1250, 1110, 1030, and 970 cm-1 ; δH (CDCl3) 0.07(6H, s, (CH3)2Si), 0.86(9H, s, (CH3)3C), 1.28(6H, t, J7.2 Hz, 2×CH2CH3), 3.83(2H, d, J8.2 Hz, CH2P), 3.90(4H, m, CH2OSi+CH2OCH2P), 4.11(4H, m, 2×CH2CH3), 4.51(1H, m, CHON); 5.59(2H, br.s, D2O exchangeable, NH2), 7.99(1H, s, H-2/H-8); 8.29(1H, s, H-2/H-8), m/z (NH3C.I.), 490 (MH+, 70%);
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][NH:26][C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:10])=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NNc1ccc(OCc2ccccc2)cc1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
To a solution of 2-chloropyridine-3-carboxylic acid (3.30 g) in DMF (50 ml) were added [4-(benzyloxy)phenyl]hydrazine (5.0 g), HOBt (3.7 g), EDCI (4.6 g) and diisopropylethylamine (9.0 g), and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([Li])CCC.CN(C)[CH:27]=[O:28]>C1COCC1.[Cl-].[NH4+]>[CH:14]1([CH2:13][O:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:27]=[O:28])[CH:3]=3)[N:8]=[CH:7][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2nccc(OCC3CCCCC3)c2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2nccc(OCC3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a solution of 6-bromo-4-cyclohexylmethoxy-quinoline (0.510 g, 1.59 mmol) in THF (10 mL) was added dropwise a 2.5M solution of n-butyllithium in hexanes (0.765 mL, 1.92 mmol, 1.2 equiv.) at −70° C. During the addition, the color of the solution was turned into red and this solution was stirred for 1 h at this temperature. Then, a solution of dimethylformamide (0.246 mL, 3.19 mmol) in THF (1 mL) was added dropwise. After addition, the mixture was allowed to warm to room temperature and stirred for 2 h. Then, the mixture was diluted with saturated ammonium chloride solution and the two layers were separated. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude residue which was purified by using a Biotage silica gel column chromatography to afford 0.205 g (48% yield) of 4-cyclohexylmethoxy-quinoline-6-carbaldehyde as a white solid: EI-HRMS m/e calcd for C17H19NO2 (M+) 269.3513, found 269.3511.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:36]>C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:32])([CH3:33])[C:30]([NH2:31])=[O:36])[CH2:25][CH2:24]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(C)(C)C#N)CC4)cc2OCC3)n(C(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(C)(C)C(N)=O)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 9 %

Procedure:
To 2-{4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile (140 mg, 0.31 mmol) was added concentrated sulfuric acid (1.75 mL). The mixture was stirred at RT for 3.5 hours before the reaction was diluted with ice and neutralised with sodium carbonate. The aqueous mixture was extracted with 10% MeOH in DCM (×5) before the organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM). The material was triturated with diethyl ether before being purified by reverse phase HPLC (C18, gradient 20-70% MeOH/0.1% formic acid in water/0.1% formic acid). The resultant residue was taken up into MeOH (1.2 mL) and treated with 0.2 M HCl in diethyl ether. The solution was concentrated in vacuo affording 289 (14 mg, 0.03 mmol, 9%). LCMS: RT=2.65 min, [M+H]+=478. 1H NMR δ (ppm) (DMSO-d6): 9.50 (1H, m), 8.33 (1H, d, J=8.29 Hz), 7.97 (1H, s), 7.93 (1H, s), 7.86 (1H, s), 7.02 (1H, dd, J=8.36, 1.75 Hz), 6.87 (1H, d, J=1.71 Hz), 5.78-5.71 (1H, m), 4.50-4.44 (4H, m), 3.19-3.04 (2H, m), 2.91-2.80 (1H, m), 2.25 (3H, s), 2.12 (2H, d, J=13.49 Hz), 1.98 (2H, d, J=13.54 Hz), 1.51 (6H, s), 1.43 (6H, d, J=6.59 Hz). 2H obscured by solvent.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]([OH:16])=[C:14]2[C:9]([C:10](=[O:19])[CH2:11][C:12]([CH3:18])([CH3:17])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].S(OC)(O[CH3:24])(=O)=O>[OH-].[Na+]>[CH2:1]([O:5][C:6]1[C:15]([O:16][CH3:24])=[C:14]2[C:9]([C:10](=[O:19])[CH2:11][C:12]([CH3:17])([CH3:18])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)COc1ccc2c(c1O)OC(C)(C)CC2=O
Agent: [Na+]
Agent: [OH-]
Product: COc1c(OCC(C)C)ccc2c1OC(C)(C)CC2=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
In 50 ml of a 10% sodium hydroxide solution under nitrogen 5.2 g (20 millimoles) of 7-isobutoxy-8-hydroxy-2,2,-dimethyl-4-chromanone are dissolved, whereupon 2.6 g (2 ml, 21 millimoles) of dimethyl sulfate are added and the reaction mixture is intensively stirred for 3 hours at 50° C. The mixture is diluted with 100 ml of ice cold water, extracted three times with 50 ml of chloroform each, the organic phase is washed twice with 40 ml of water dried over sodium sulfate and the solvent is evaporated. Thus 5.2 g of the desired compound are obtained in the form of yellow oil, yield 93%.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C[O:54][C:55](=O)[CH2:56][CH:57]([CH:67]1[CH2:71][CH2:70][CH2:69][CH2:68]1)[NH:58][CH2:59][C:60]1[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=1.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH:67]1([CH:57]2[N:58]([CH2:59][C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)[C:19](=[O:21])[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)=[C:55]([OH:54])[CH2:56]2)[CH2:71][CH2:70][CH2:69][CH2:68]1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)CC(NCc1ccc(F)cc1)C1CCCC1
Agent: CC[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(C1=C(O)CC(C3CCCC3)N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.089 g, 0.252 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.104 g, 0.274 mmol) and 4-methylmorpholine (0.055 mL, 0.500 mmol) were added sequentially to a solution of rac-3-cyclopentyl-3-(4-fluoro-benzylamino)-propionic acid methyl ester (0.070 g, 0.250 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (5 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.324 mL, 1.00 mmol) was added and the reaction mixture was heated to 60° C. for 6 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford (after trituration with diethyl ether) rac-N-{3-[6-cyclopentyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.018 g, 0.031 mmol, 12%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.07-1.17 (1H, m), 1.35-1.43 (1H, m), 1.45-1.68 (3H, m), 1.70-1.76 (1H, m), 2.20-2.26 (1H, m), 2.47 (1H, d, J=14.1 Hz), 2.95 (3H, s), 3.06-3.12 (1H, m), 3.43-3.47 (1H, m), 4.09 (1H, d, J=15.8 Hz), 4.23 (2H, d, J=6.3 Hz), 5.21 (1H, d, J=14.9 Hz), 7.11-7.15 (2H, m), 7.21 (1H, s), 7.34-7.38 (2H, m), 7.62 (1H, t, J=6.2 Hz). LC-MS (ESI) calculated for C24H27FN4O6S3 582.11. found 583.1 [M+H+].
Reaction SMILES: COP(=O)OC.[C:7](=O)([O-])[O-].[K+].[K+].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N:21]1[C:25]([CH3:26])=[C:24]([CH:27]=O)[N:23]=[C:22]1[CH3:29]>CO>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N:21]1[C:25]([CH3:26])=[C:24]([C:27]#[CH:7])[N:23]=[C:22]1[CH3:29]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(C=O)c(C)n1-c1ccc(F)cc1F
Agent: CO[PH](=O)OC
Agent: [K+]
Solvent: CO
Product: C#Cc1nc(C)n(-c2ccc(F)cc2F)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (0.37 g, 2 mmol) was dissolved in 20 mL methanol. Potassium carbonate (0.38 g, 3 mmol) was added. A solution of 1-(2,4-Difluoro-phenyl)-2,5-dimethyl-1H-imidazole-4-carbaldehyde (0.32 g, 1 mmol) in 5 ml methanol was added drop wise at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 15 ml water and extracted three times with ethyl acetate (15 ml each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10→50:50 gradient) and the desired compound was obtained as a light yellow solid (0.165 g, 52%), MS: m/e=233.1 (M+).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](C)(C)N[Si](C)(C)C.[Cl-].[NH4+].[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.CO.C(N(CC)CC)C>[C:19]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@H](CO)C(=O)O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To dichloromethane (400 ml), D-serine (50 g) was added at ambient temperature under nitrogen atmosphere to form a suspension and then hexamethyldisilazane (134.15 ml) was added to the suspension in 10-15 minutes at ambient temperature. Catalytic amount of ammonium chloride (1 gm) was added. The reaction mixture was refluxed at 35° C. to 40° C. for 3 hours and then it was cooled to 0° C. To this mixture, a solution of anhydrous methanol (22.83 g) in dichloromethane (50 ml) was added at 0° C. and the mixture was allowed to reach at room temperature. Triethylamine (48.14 g) was slowly added to it at 25° C. to 30° C. and then trityl chloride (132.63 g) was added in 3 lots to the mixture at an interval of 10 minutes. The reaction mixture was then stirred for overnight under nitrogen at ambient temperature. After completion of the reaction, methanol (76.12 g) was added at ambient temperature in 10-15 minutes and the solvent was recovered under vacuum at 40° C. to 45° C. Toluene (400 ml) and 5% citric acid solution (750 ml) was added to the recovered solid and filtered. The solid product obtained was washed with water (750 ml) and hexanes (200 ml) and then filtered. The filtered solid was washed with toluene (200 ml) and dried to obtain the titled product. Yield=100 gm; Mass: (−EI): 346 (M−1); 242.9 (−Tr).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[N:15]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH2:3][C:4]#[CH:5].C(N(C(C)C)CC)(C)C.[O:34]=[C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[N:36]1[CH2:45][CH2:46][CH:47]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.ClC(Cl)C>[Cl:24][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:23])[N:15]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]([C@H:2]([NH:1][CH2:47][CH2:46][CH2:45][N:36]3[C:37](=[O:44])[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:35]3=[O:34])[CH2:3][C:4]#[CH:5])=[N:7]2)=[CH:12][CH:11]=1
Reactant: C#CC[C@@H](N)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: C#CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a mixture of (R)-(1-amino-but-3-ynyl)-7-chloro-3-phenylamino-3H-quinazolin-4-one (4.60 g, 12.2 mmol) and diisopropylethylamine (DIPEA) (5.5 ml) in dichloromethane (60 ml) was added a solution of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (2.45 g, 12.1 mmol) in dichloroethane (10 ml), followed by a solution of sodium triacetoxy borohydride (NaBH(OAc)3) (0.25M in dichloroethane, 100 ml). The reaction mixture was stirred at room temperature and the reaction progress was monitored by HPLC/MS. Upon completion, a saturated sodium carbonate solution (100 ml) was added. The resulted organic layer was collected and washed with brine solution. The solvent was removed and residue was purified by flash column to afford 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (6.1 g, 95%) as off-white solid. M.p. 78-80° C. LCMS: m/e 526 [M+H]. 1H NMR (DMSO-d6): δ 9.09 (s, br, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.83-7.76 (m, 5H), 7.58 (dd, J=8.8 and 2.0 Hz, 1H), 7.17 (t, J=7.6 Hz, 2H), 6.83 (brm, 1H), 6.65 (m, 2H), 4.1 and 4.0 (s, s, br, 1H, rotomers), 3.6 (t, J=6.8 Hz, 2H), 2.75 (s, br, 1H), 2.67-2.52 (brm, 2H), 2.35 (brm, 2H), 1.67 (brm, 2H).