Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[C:24]([SiH2:28][O:29][C:30]([CH3:41])([CH3:40])[C@@H:31]1[O:35][C:34]([CH3:37])([CH3:36])[O:33][C@@H:32]1[CH2:38]O)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([SiH2:28][O:29][C:30]([CH3:40])([CH3:41])[C@H:31]1[O:35][C:34]([CH3:37])([CH3:36])[O:33][C@@H:32]1[CH2:38][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](CO)O1
Product: CC1(C)O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)[C@@H](C(C)(C)O[SiH2]C(C)(C)C)O1

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and [(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol.
Reaction SMILES: CO[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:11])=[O:10])[NH:4]1.Cl.[O:22]1CCOCC1>>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[S:9]([C:5]1[CH:6]=[CH:7][C:8](=[O:22])[NH:3][N:4]=1)(=[O:11])=[O:10]
Reactant: CON1C=CC=C(S(=O)(=O)c2cc3ccccc3[nH]2)N1
Reactant: C1COCCO1
Agent: Cl
Product: O=c1ccc(S(=O)(=O)c2cc3ccccc3[nH]2)n[nH]1
Temperature: 100 °C
Yield: 37 %

Procedure:
A mixture of 2-methoxy-6-(indole-2-sulfonyl)-pyridazine (1.03 mmol, 300 mg), conc. HCl (1 mL), and dioxane (6 mL) was heated at 100° C. for two hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue and the resulting solid was triturated with methanol (2 mL) to yield 6-(indole-2-sulfonyl)-2H-pyridazin-3-one (37%, 106 mg); mp 248° C.-249° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[N:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C(=O)C.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:5]5[N:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:9])[CH:43]=[CH:42][CH:41]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cn1cc(C(=O)O)nn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)nn1
Yield: 69.5 %

Procedure:
Using 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (99 mg, 0.78 mmol), tetrahydrofuran (4.0 mL), N,N-dimethylformamide (30 mL, 0.39 mmol), oxalyl chloride (135 μL, 1.55 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropylcarboxamide (200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL) as starting materials and in the same manner as in Example 119, the title compound (189 mg, 70%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]2[C:9]([C:10](=O)[NH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:18])=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:14]2[C:9]([C:10]([Cl:18])=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(=O)[nH]cnn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(Cl)ncnn12
Temperature: 160 °C

Procedure:
A mixture of 4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester (300 mg) and phosphorus oxychloride (1 mL) was heated at 160° C. for 15 minutes in a microwave reactor. The resulting mixture was cooled and poured into a mixture of ice-water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc, 90/10) to afford 120 mg of 4-chloro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester containing 4-chloro-pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[OH:13].Br[CH:15]([C:17](=[O:20])[CH2:18][CH3:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[O:13][CH:15]([CH3:16])[C:17](=[O:20])[CH2:18][CH3:19]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: CCC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)C(C)Oc1cc(C(=O)OC)ccc1OC
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxy benzoate (19.3 g), 2-bromo-3-pentanone (19.2 ml), potassium carbonate (29.3 g), and DMF (193 ml) was stirred at 90° C. for 2 hours. After being allowed to stand for cooling, water was added to the mixture followed by extraction with toluene. The organic layer was washed with a saturated saline and dried over sodium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=3:1) to give Compound IIk-a (25.8 g, 91.5%) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: O=C1Cc2cccc(F)c2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1
Temperature: -45 °C
Reaction time: 8 h

Procedure:
7-fluoro-1,3-dihydro-2H-indol-2-one (8.0 g, 52.9 mmol) was slurried in H2SO4 (conc., 86 ml) and the mixture cooled to −45° C. A solution of fuming nitric acid (>90%, 3.34 g, 52.9 mmol) in H2SO4 (20 ml) was added drop wise, while maintaining the temperature at −45° C. throughout the addition. The mixture was allowed to slowly warm to RT and stirred overnight. The mixture was poured into stirred ice-cold water (1500 ml). A white precipitate resulted, and the slurry was aged at 0° C. for 1 hour. The solid was collected by filtration, triturated with cold water (2×), and dissolved into EtOAc (1 L). This solution was washed with basic brine (containing sodium bicarbonate), dried over Na2SO4, filtered, and the volatiles removed in vacuum to give the titled compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:10]2[CH2:13][C:12]([C@H:15]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[S:16]([CH3:19])(=[O:18])=[O:17])(O)[CH2:11]2)=[CH:5][CH:4]=1.CS(Cl)(=O)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[N:10]2[CH2:13][C:12](=[C:15]([C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:11]2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)[C@@H](c1cc(F)cc(F)c1)C1(O)CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1

Procedure:
1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form B isomer, may be prepared by carrying out the operation as described in Example 87, starting with 7.3 g of the mixture of the 2 diastereoisomers (B forms) 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidin-3-ol and 1-{(R*) -[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol, 8.2 g of 4-dimethylaminopyridine, 150 cm3 of dichloromethane and 3.2 cm3 of methanesulfonyl chloride. The crude product is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at an argon pressure of 0.2 bar, eluting with dichloromethane and collecting 100 cm3 fractions. Fractions 15 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 2.50 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-{(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form B isomer, are obtained in the form of a white foam.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH2:32]([NH:34][C:35]1[C:36]([NH2:48])=[CH:37][C:38]([S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])=[CH:39][CH:40]=1)[CH3:33]>C(#N)C>[CH2:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([C:44]([F:45])([F:46])[F:47])(=[O:42])=[O:43])=[CH:37][C:36]=1[NH:48][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)[CH3:33]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CCNc1ccc(S(=O)(=O)C(F)(F)F)cc1N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNc1ccc(S(=O)(=O)C(F)(F)F)cc1NC(=O)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methylsulfonylphenylacetic acid (100 mg, 0.467 mmol) in acetonitrile was added 1-hydroxybenzotriazole (76 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carboiimide hydrochloride (108 mg, 0.56 mmol), triethylamine (0.143 mL, 1.03 mmol) and N1-ethyl-4-[(trifluoromethyl)sulfonyl]benzene-1,2-diamine (125 mg, 0.467 mmol). The mixture was stirred at room temperature for overnight. The reaction was extracted with ethyl acetate, washed with water and brine, dried, concentrated and recrystallized from ethyl acetate to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ9.54 (br s, 1H, NH), 7.88 (d, J=8.3 Hz, 2H), 7.75 (d, J=2.1 Hz, 1H), 7.64 (dd, 1H), 7.61 (d, J=8.3 Hz, 2H), 6.90 (d, J=9.0 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H, NH), 3.86 (s, 2H, CH2), 3.31 (s, 3H, CH3), 3.29 (m, 2H, NCH2CH3), 1.20 (t, J=7.1 Hz, 3H, NCH2CH3). MS 465 [M++1].
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[CH3:7][C:8]([CH3:13])([CH3:12])[C:9](Cl)=O.C(N(CC)CC)C>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:7]([C:8]([CH3:13])([CH3:12])[CH3:9])[O:6][N:5]=1
Reactant: N=C(CCl)NO
Reactant: CC(C)(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(CCl)no1
Temperature: 130 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
5.0 g of 2-chloro-N-hydroxyacetoamidine and 6.11 g of trimethylacetyl chloride were dissolved in 100 ml of N,N-dimethylformamide, and 5.6 g of triethylamine was then added dropwise under ice-cooling. After completion of the addition, the reaction mixture was stirred at 130° C. for 6 hours and then cooled to room temperature. After aqueous saturated sodium chloride, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.0 g of 3-(chloromethyl)-5-t-butyl-1,2,4-oxadiazole.
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)=O.[BH4-].[Na+]>CO>[CH:1]1([NH:7][C:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[CH3:16])[CH2:14][CH2:15]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(c1cccc([N+](=O)[O-])c1)N1CCC(C(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.6 %

Procedure:
Piperidine-4-carboxylic acid cyclohexylamide (1.5 g 7.132 mmol) and 3-nitroacetophenone (1.77 g, 10.7 mmol) are dissolved in MeOH (40 mL). Tetraisopropyl-orthotitanate (3.167 mL, 10.7 mmol) is added and the mixture is stirred at RT for 18 h. NaBH4 (539.6 mg, 14.3 mmol) is added carefully. The mixture is evaporated under reduced pressure. DCM (25 mL) and water (25 mL) are added, following by 1 M NaOH solution (50 mL). The organic phase is separated and the aqueous phase is extracted with DCM (25 mL). The combined organic phases are dried over MgSO4, filtered and concentrated. The crude residue is purified by flash chromatography on silica gel using a gradient of heptane/EtOAc 4:1 to EtOAc 100%. After concentration of the product-containing fractions, the title compound (0.375 g, 15%) is obtained as a colorless solid LC-MS A: tR=0.64 min; [M+H]+=360.26.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([F:31])[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].CO>C(COC)OC.C1COCC1.O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:27]4[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4cc(F)cc(F)c4)c3c2CC1
Yield: 100 %

Procedure:
A mixture of 3-benzoyl -10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.923 g, 2.5 mmol) and tetrakis(triphenylphosphine)paliadium (0.29 g, 0.25 mmol) in dimethoxyethane (10.0 mL) and a solution of 3,5-difluorophenylboronic acid (0.95 g of a 50% by weight solution in THF/H2O, 3.0 mmol) and sodium carbonate (2 M, 12.0 mL) were reacted in a manner similar to Preparation 1. Column chromatography (silica gel, 1-5% MeOH/CHC1-3) afforded 1.03 g (100%) of a white solid: mp 198-201° C.; 1H NMR (400 MHz, CDCl3) δ 8.32, 7.40-7.28, 7.14, 6.98-6.80, 6.80-6.70, 4.04-3.94, 3.83-3.73, 3.65-3.58, 3.60-3.50, 3.20-3.13, 2.94-2.84, 2.71-2.60, 2.45-2.36; IR (drift) 3235, 3211, 1607, 1466, 1431, 1336, 1291, 1117, 984, 864, 789, 751, 737, 704, 698 cm−1; MS (EI) m/z 402 (M+); Anal. Calcd for C25H20F2N2O: C, 74.61; H, 5.01; N, 6.96. Found: C, 74.57; H, 5.05; N, 6.99.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:21](C(OC4C=CC=CC=4)=O)[C:22](=[O:30])OC4C=CC=CC=4)[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].C(N(CC)CC)C.Cl.[NH2:48][C@H:49]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:50]([NH2:52])=[O:51]>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([NH:48][C@@H:49]([C:50](=[O:51])[NH2:52])[CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:30])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: NC(=O)[C@H](N)Cc1ccccc1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N[C@H](Cc4ccccc4)C(N)=O)c3)ccc21
Reaction time: 18 h
Yield: 76 %

Procedure:
Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (104 mg, 0.200 mmol) and triethylamine (1 ml) were dissolved in N,N-dimethylformamide (3 ml), and (2R)-2-amino-3-phenylpropionamide hydrochloride (201 mg, 1.00 mmol) was added, and the reaction mixture was stirred for 18 hours. The reaction mixture was partitioned between ethyl acetate and the saturated aqueous solution of ammonium chloride. The organic layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=50:1). The crystals were precipitated from a solvent mixture of ethyl acetate-hexane, filtered off, and dried under aeration to yield the title compound (77.2 mg, 0.152 mmol, 76%) as white crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].O.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]2[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17]2)[C:6]2[N:22]=[C:2]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=3[O:33][CH3:34])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: C[C@@H]1CCC(N2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CC[C@@H](C)C1)CC(F)(F)C(=O)N2C
Temperature: 85 °C
Reaction time: 48 h

Procedure:
2-Chloro-7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (500 mg, 1.51 mmol) and 4-amino-3-methoxybenzoic acid (316.0 mg, 1.89 mmol) were weighed into a flask. 4-Methylbenzenesulfonic acid monohydrate (230.0 mg, 1.21 mmol) was weighed into a separate flask and dissolved in dioxane (15 ml). The toxic acid solution was then added to the flask containing the two starting materials. The reaction was stirred at 85° C. for 48 hours followed by 100° C. for an additional 48 hours. The dark brown mixture was cooled to room temperature and filtered through paper. The solids were washed with ethyl acetate (15 ml). m/z 462.4 (M+H)+.
Reaction SMILES: [C:1](OCC)(=[O:17])/[CH:2]=[CH:3]/[CH2:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12](OCC)=[O:13].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[CH2:12]([OH:13])/[CH:11]=[CH:10]/[CH2:9][CH2:8]/[CH:7]=[CH:6]/[CH2:5][CH2:4]/[CH:3]=[CH:2]/[CH2:1][OH:17]
Reactant: CCOC(=O)/C=C/CC/C=C/CC/C=C/C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OC/C=C/CC/C=C/CC/C=C/CO
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
The solution of the ester 4c (4.01 g, 14.3 mmol) in methylene chloride (100 mL) was cooled to -78° C. and diisobutylaluminium hydride (16.0 g, 11.2 mmol) was added dropwise to the solution. The reaction mixture was stirred at -78° C. for 1.5 h and it was quenched with methanol (30 mL) followed by addition of saturated aqueous ammonium chloride solution (50 mL). The mixture was then warmed slowly to room temperature. The solid was filtered and washed with methylene chloride (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by MPLC to give the alcohol 5 (2.71 g, 97%) as a white solid (mp=37.0°-38.0° C.).
Reaction SMILES: [Br:1][C:2]1[C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:19].[CH3:20][N:21](C)C=O>[C-]#N.[C-]#N.[Zn+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Br:1][C:2]1[C:10]([C:20]#[N:21])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:19]
Reactant: O=C1CCc2c1ccc(OS(=O)(=O)C(F)(F)F)c2Br
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1Br)CCC2=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Zn(CN)2 (0.60 g) and 1,1′-bis(diphenylphosphino)-ferrocene (0.92 g) are added to a solution of trifluoro-methanesulfonic acid 4-bromo-1-oxo-indan-5-yl ester (5.90 g) in N,N-dimethylformamide (30 mL) at room temperature. The mixture is purged with Ar for 5 min prior to addition of tris(dibenzylideneacetone)dipalladium(0) (760 mg). The mixture is heated to 70° C. and stirred at this temperature for 1 h. After cooling to room temperature, ethyl acetate is added and the resulting mixture is washed with water and brine. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound. LC (method 2): tR=0.88 min; Mass spectrum (ESI−): m/z=234/236 (Br) [M−H]−.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH2:11]([N:15]([CH3:29])[C:16]([C:18]1[CH:19]=[C:20]([CH:25]=[C:26](I)[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH2:12][CH2:13][CH3:14]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:11]([N:15]([CH3:29])[C:16]([C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (167 mg, 2.4 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.7 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 7.3 mL, 7.3 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-{[butyl(methyl)amino]carbonyl}-5-iodobenzoate (864 mg, 2.3 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0)tetrakis(triphenylphosphine) (112 mg, 0.10 mmol). The reaction mixture is heated at reflux for 1.5 h. The reaction mixture is cooled, diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides the title compound. ESI MS m/z 317.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH2:21])[CH3:17]>O1CCOCC1>[CH2:16]([N:18]([CH2:19][CH2:20][NH:21][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[CH2:22][CH3:23])[CH3:17]
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCN(CC)CCN
Solvent: C1COCCO1
Product: CCN(CC)CCNC(=O)c1cc(S(C)(=O)=O)ccc1OC

Procedure:
2.3 g (0.01 mol) of 2-methoxy 5-methylsulfonylbenzoic acid, 2.9 g (0.025 mol) of N,N-diethyl ethylenediamine and 40 ml of dioxan are placed in a 100 ml balloon flask provided with a stirrer and a condenser.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:22])[CH2:17][O:18][CH2:19][CH:20]=[CH2:21])[CH3:14].[CH:23]([CH:25]=[CH2:26])=[O:24]>C1COCC1>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([O:18][CH2:19][CH:20]=[CH2:21])[CH:23]([OH:24])[CH:25]=[CH2:26])[CH3:14]
Reactant: C=CCOCC(=O)OCC
Reactant: C=CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCOC(C(=O)OCC)C(O)C=C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under an atmosphere of argon, n-BuLi (3 mmol, 1.2 ml, 2.5 M in hexane) was added dropwise to a solution of diisopropylamine (281 mg, 2.78 mmol) in dry THF (20 ml) at −78° C. After stirring for 20-30 min, a solution of allyloxy-acetic acid ethyl ester (200 mg, 1.38 mmol) in THF (4 ml) was added and the mixture was stirred at −78° C. for 10 min. Acrolein (79 mg, 1.38 mmol) was added into the reaction mixture and stirring was maintained until all starting materials were consumed. The reaction was quenched by addition of EtOH (2 ml) and warmed to room temperature. The solution was diluted with EtOAc (60 ml), washed with H2O (20 ml×2), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.