Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.I[C:9]1[CH:20]=[CH:19][C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:6]#[C:7][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(=O)CCc1ccc(I)cc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(C#CCCCCO)cc1
Reaction time: 2.5 h

Procedure:
To 40 ml of triethylamine were added 3.68 g of methyl p-iododihydrocinnamate, 1.49 g of 5-hexyl-1-ol, 40 ml of cuprous iodide and 77 mg of bis(triphenylphosphine)-palladium chloride, and the mixture was stirred under nitrogen flow for 2.5 hours. After adding 50 ml of ethyl acetate, the mixture was filtered to remove the resulting precipitate, washed three-times with 30 ml of water, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain 4.0 g of methyl p-(6-hydroxy-1-hexynyl)dihydrocinnamate as an oil. 4.0 g of this oil was stirred with 1.2 g of 5% palladium on carbon in 50 ml of methanol under a hydrogen atmosphere to obtain 2.41 g of methyl p-(6-hydroxyhexyl)dihydrocinnamate. To this compound was added 1.0 g of phosphorus tribromide with ice-cooling, and the mixture was heated at 80° C. for 2 hours, poured into 50 ml of ice-water. The mixture was extracted twice with 50 ml of ethyl acetate, dried over magnesium sulfate and evaporated under a reduced pressure to obtain a residue, which was then applied to a silica gel column and eluted with chloroform/hexane (1:1) to obtain 2.1 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:10]=2)=[CH:6][C:7]=1[NH2:8].[Cl:24][CH2:25][C:26](OCC)(OCC)OCC>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[Cl:24][CH2:25][C:26]1[NH:8][C:7]2[CH:6]=[C:5]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[C:11]([C:18]([F:21])([F:19])[F:20])[CH:10]=3)[N:4]=[C:3]([C:22]#[N:23])[C:2]=2[N:1]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: CCOc1ccc(-c2cc(N)c(N)c(C#N)n2)cc1C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CCOc1ccc(-c2cc3[nH]c(CCl)nc3c(C#N)n2)cc1C(F)(F)F
Yield: 41.9 %

Procedure:
3,4-Diamino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (1 g, 3.1 mmol) was dissolved in acetonitrile (20 ml) and ytterbium triflate (38 mg, 0.062 mmol) and 2-chloro-1,1,1-triethoxyethane (1.83 g, 9.3 mmol) were added. The mixture was heated to reflux overnight. Mixture was evaporated under reduced pressure, partitioned between ethyl acetate (100 ml) and water (100 ml), and organics were dried then evaporated under reduced pressure to afford a dark brown oil. Triturated with DCM (50 ml) to afford 495 mg of 2-chloromethyl-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a light brown solid. 1H NMR (DMSO) δ 8.47-8.33 (m, 3H), 7.41 (d, 1H), 5.05 (s, 2H), 4.26 (q, 2H), 1.38 (t, 3H). MS m/z 381.1 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Cu][C:11]#[N:12].O>CN(C=O)C>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:11]#[N:12])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cnc1C#N
Temperature: 115 °C

Procedure:
A mixture of 2,5-dibromo-3-methylpyridine (20.17 g, 80.4 mmol) and copper(I) cyanide (7.24 g, 80.8 mmol) in 200 mL DMF was heated to 115° C. overnight. The reaction mixture was cooled to 25° C. and poured into 600 mL of H2O. The solid was filtered, washed with copious amounts of H2O. The filtrate was extracted with EtOAc (4×) and the combined organic layers were washed with H2O and dried over Na2SO4. The solution was filtered, evaporated onto silica gel and purified by flash chromatography eluting with EtOAc:hexane (0:1→1:9) to give the title compound as a white solid. MS m/z: 197.0 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC1N=C(OC)N=C(OC)[N:32]=1.CN1CCOCC1.[NH4+].[OH-]>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:32])=[O:25])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(=O)O)cc1
Reactant: COc1nc(Cl)nc(OC)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}benzoic acid (12.0 g, 28.58 mmol) was suspended in tetrahydrofuran (100 mL). 2-Chloro-4,6-dimethoxy-1,3,5-triazine (6.02 g, 34.3 mmol) was added followed by 4-methylmorpholine (9.43 mL, 85.74 mmol). The resulting mixture was stirred at room temperature for 1.5 hours at which time NH4OH (50.0 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then partially concentrated. The precipitate was collected by filtration washing with H2O and diethyl ether to provide an off-white solid (12.11 g, >100%). 1H NMR (400 MHz, DMSO-d6) δ 7.91 (br s, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.63 (app q, J=7.9 Hz, 1H), 7.31 (dt, J=2.6, 10.5 Hz, 1H), 7.17-7.12 (m, 1H), 7.13 (app d, J=8.3 Hz, 2H), 6.59 (s, 1H), 5.32 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 419.0968 (M+H calcd for C21H18ClF2N2O3 requires 419.0969).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:10])=[O:9].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21].C(N(CC)CC)C>CN(C=O)C>[CH3:19][O:18][C:15]1[N:14]=[CH:13][C:12]([N:11]2[C:20](=[O:21])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]2(=[O:9])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2N)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)Nc3ccccc3S2(=O)=O)cn1
Yield: 62.7 %

Procedure:
The title compound (143 mg, 0.47 mmol) was prepared from 2-amino-N-(6-methoxypyridin-3-yl)benzenesulfonamide (209 mg, 0.75 mmol), 1,1′-carbonyldiimidazole (486 mg, 3.0 mmol) and triethylamine (0.28 mL, 1.5 mmol) in DMF (3.75 mL) using the methods of (IntA14), step 3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][Br:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(Br)c1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
AIBN (79 mg) was added to a stirred suspension of methyl 3-bromo-4-methylbenzoate (11.0 g, 48.0 mmol) and NBS (10.3 g, 57.6 mmol) in CCl4 (400 mL), and the resultant mixture was heated to reflux for 2 h. After cooling to room temperature, the mixture was diluted with hexanes (200 mL) before it was filtered and concentrated to give 14.7 g (crude yield 100%) of methyl 3-bromo-4-(bromomethyl)benzoate.
Reaction SMILES: [CH2:1]([CH:3]([CH2:17][CH3:18])[CH2:4][NH:5][C:6]1[N:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([O:10][CH2:11]C)=[O:9])[CH3:2].[O:19]=C(Cl)OC(Cl)(Cl)Cl>ClCCCl.O1CCOCC1>[CH2:1]([CH:3]([CH2:17][CH3:18])[CH2:4][N:5]1[C:6]2[N:16]=[CH:15][CH:14]=[CH:13][C:7]=2[C:8](=[O:9])[O:10][C:11]1=[O:19])[CH3:2]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Solvent: ClCCCl
Solvent: C1COCCO1
Product: CCC(CC)Cn1c(=O)oc(=O)c2cccnc21
Yield: 35.7 %

Procedure:
The product of Example 3A (0.664 g, 2.65 mmol) and diphosgene (1.57 g, 7.96 mmol) in 13 mL of 1,2-dichloroethane and 1.3 mL of 1,4 dioxane were reacted at 80° C. for 16 hours. The reaction was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (9:1) to provide the title compound (0.235 g, 36%). 1H NMR (300 MHz, CDCl3) δ 0.95 (m, 6H), 1.40 (m, 4H), 1.52 (m, 2H), 4.21 (m, 1H), 7.25 (m, 1H), 8.41 (dd, J=7.72, 1.84 Hz, 1H), 8.70 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@@H:5]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:6][NH2:7].C(N(C(C)C)CC)(C)C.[C:37]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl>[CH3:2][O:3][C:4](=[O:27])[CH:5]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10])[CH2:6][NH:7][S:43]([C:40]1[CH:39]=[CH:38][C:37]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:42][CH:41]=1)(=[O:45])=[O:44]
Reactant: COC(=O)[C@H](CN)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(CNS(=O)(=O)c1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
To 3-amino-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester hydrochloride (0.100 g, 0.273 mmol) prepared as per the above listed example 656 was added dry dichloromethane (10 ml) followed by diisopropylethylamine (0.095 g, 0.738 mmol) and stirred for 10 min. To this mixture at 0° C. was added Biphenyl-4-sulfonyl chloride (0.062 g, 0273 mmol) and the reaction was stirred at ambient temperature. After 2 hrs the reaction mixture was diluted with dichloromethane and washed with water (20 ml) followed by brine (20 ml). The organic layers were collected and dried over sodium sulfate and concentrated under reduced pressure to yield the 3-(Biphenyl-4-sulfonylamino)-2-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per procedure C to yield the title compound (0.045 g, 50%). 1H-NMR(400 MHz, DMSOd6): 3.65 (m, 2H), 4.85 (m, 1H), 7.78 (m, 4H), 8.02 (d, 2H), 8.17 (m, 7H), 8.27 (m, 4H), 8.62 (S, 1H), 8.9 (bs, 1H). LC/MS (m/z): 569.1 (M+1).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:16]([C:28]1[O:32][CH:31]=[N:30][CH:29]=1)=[CH:15]2.[Cl:33]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:33][C:31]1[O:32][C:28]([C:16]2[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)=[CH:29][N:30]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2cnco2)cc2cc(F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2cc(F)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
LiHMDS (1.06 M in THF, 3.44 mL, 3.43 mmol) was added to a solution of tert-butyl 5-fluoro-2-(oxazol-5-yl)-1H-indole-1-carboxylate 49 (0.865 g, 2.86 mmol) in THF (20 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of hexachloroethane (1.01 g, 4.29 mmol) in THF (5 mL) was added at −78° C., and the mixture was stirred at −78° C. for 2 h and allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by adding EtOAC: H2O (50 mL:15 mL), and then extracted with Ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. The product was purified by column chromatography (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-chlorooxazol-5-yl)-5-fluoro-1H-indole-1-carboxylate 50 (0.74 g, 77% yield) as white solid. MS (ES) m/z 337 (M+H+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])[OH:12].S(=O)(=O)(O)O>>[CH:1](=[C:19]([C@@H:17]([C@H:15]([C@@H:13]([C@@H:11]([CH2:10][OH:9])[OH:12])[OH:14])[OH:16])[OH:18])[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccccc1

Procedure:
A reactor was charged with 106 g (1 mole) of benzaldehyde, 270 g (1 mole) of a 70% aqueous solution of D-sorbitol and 20 g of 50% sulfuric acid, and they were reacted at 15° C. with stirring. Thirty minutes after the formation of fine crystals in the mixture within the reactor, the torque of the stirrer became about 3 times as high as that at the start of the reaction. At this time, the amount of monobenzylidene sorbitol formed was 42% of theory.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26].[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(O)C.C(Cl)Cl.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]([N:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:29][CH2:28]4)=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(CBr)N1CCc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1CCc2ccccc21

Procedure:
A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (10 g, 45.4 mmol), K2CO3 (7.2 g, 52.5 mmol) and N-(2-bromoacetyl)indoline (12 g, 50 mmol) in acetronitrile (300 ml) was heated at reflux for 4 hours. The mixture was cooled and filtered. The solution was concentrated down until solid appeared. The crystals were collected: weight 12.68 g. The mother liquor was concentrated to dryness. The residues were purified further by flash chromatography to yield an additional 1.35 g. Total yield was 14.03 g. A 2 g sample was dissolved in ethanol/methylene chloride and was treated with a solution of fumaric acid (612 mg) in ethanol to yield 2.58 g, m.p. 226°-227° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10][C:11]([CH:17]=O)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([O:34][C:35]([NH:37][CH:38](P(OC)(OC)=O)[C:39]([O:41][CH3:42])=[O:40])=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C(=N)N(C)C>C1COCC1.C(OCC)(=O)C>[CH2:27]([O:34][C:35]([NH:37]/[C:38](=[CH:17]\[C:11]1[N:10]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1)/[C:39]([O:41][CH3:42])=[O:40])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C(=C/c1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 5-phenyl-4-(pyridin-2-ylmethylamino)quinazoline-2-carbaldehyde (0.9 g, 3 mmol) in THF (10 mL) was added methyl 2-benzyloxycarbonylamino-2(dimethoxyphosphinyl)acetate (0.96 g, 2.9 mmol) followed by tetramethyguanidine (0.66 mL. 5.3 mmol). The resulting solution was stirred at RT for 3 h. After this time, the reaction mixture was diluted with ethyl acetate, washed successively with water and brine, dried over Na2SO4, filtered then and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (30% ethyl acetate in hexane) to yield (Z)-methyl 2-(benzyloxycarbonylamino)-3-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)acrylate (0.7 g (48% yield). LCMS Method V: retention time 1.94 min; [M+1]=546.0.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8]C(=O)O[C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([C:14]#[N:15])[CH:3]=1.Cl.[C:17]1([NH2:23])([CH:20]2[CH2:22][CH2:21]2)[CH2:19][CH2:18]1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:14]#[N:15])=[CH:5][C:6]=1[C:11]([NH:23][C:17]1([CH:20]2[CH2:22][CH2:21]2)[CH2:19][CH2:18]1)=[O:12]
Reactant: NC1(C2CC2)CC1
Reactant: Cc1cc(C#N)cc2c(=O)oc(=O)[nH]c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(=O)NC2(C3CC3)CC2)c1N

Procedure:
236 mg (1.16 mmol) 8-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile, 234 mg (1.75 mmol) bicyclopropyl-1-ylamine hydrochloride and 177 mg (1.75 mmol) triethylamine in 25 ml THF are heated 4 h at reflux. The mixture is cooled down and evaporated. The residue is dissolved in ethyl acetate and extracted with water. After purification on a short path of silicagel, 63 mg of the title compound are isolated as yellow crystals. F: 171-172° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.[OH-].[Na+].[CH3:16][Si:17]([CH3:22])([CH3:21])[CH2:18]CO>C(OC(C)C)(C)C>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5](=[CH:12][CH:13]=1)[C:6]([O:7][CH2:8][CH2:16][Si:17]([CH3:22])([CH3:21])[CH3:18])=[O:11]
Reactant: C[Si](C)(C)CCO
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Product: C[Si](C)(C)CCOC(=O)c1ccc(F)cc1N

Procedure:
7-Fluoro-1H-3,1-benzoxazine-2,4-dione (2.0 g), sodium hydroxide (0.05 g) and 2-(trimethylsilyl)ethanol (1.31 g) were heated together at 100° for 30 minutes until effervescence ceased. After cooling, the residue was suspended in diisopropyl ether, then filtered and evaporated. The residue was recrystallised from petroleum ether to give 2-(trimethylsilyl)ethyl 4-fluoroanthranilate, mp 43°-44°. (Compound 20).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:44]([F:54])[CH:43]=1>C(Cl)Cl>[CH3:49][O:48][C:46](=[O:47])[C:45]1[CH:50]=[C:51]([O:52][CH3:53])[C:42]([NH:41][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:43][C:44]=1[F:54]
Reactant: COC(=O)c1cc(OC)c(N)cc1F
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(OC)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 15 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (250 mg, 535 μmol, Eq: 1.00), was combined with CH2Cl2 (3 ml) to give a clear solution. DIPEA (242 mg, 327 μl, 1.87 mmol, Eq: 3.5) and diphenylphosphenic chloride (316 mg, 255 μl, 1.34 mmol, Eq: 2.5) were added and the reaction was stirred at RT for 5 minutes. Methyl 4-amino-2-fluoro-5-methoxybenzoate (107 mg, 535 μmol, Eq: 1.00) was added and the reaction mixture was stirred at RT overnight.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[C:6]([Cl:25])[CH:5]=1.Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[C:6]([Cl:25])[CH:5]=1
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)cc(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3c(Cl)cc(Cl)cc23)CC1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol) was added to a solution of tert-butyl 7,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.30 g, 0.84 mmol) in DMF (5 mL). After 30 min, β-bromophenetole was added (0.23 mL). The reaction was quenched with saturated aqueous NH4Cl after 18 h and extracted with EtOAc (1×50 mL, 2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (17:3) and crystallized from EtOAc/heptane to give 0.31 g (77%) of a white solid: mp 154.0-155.0° C.; 1H NMR (300 MHz, DMSO) δ 7.54 (d, J=1.9 Hz, 1H), 7.20 (m, 3H), 6.85 (m, 3H), 4.86 (m, 2H), 4.24 (m, 2H), 3.69 (m, 2H), 3.54 (m, 2H), 3.12 (m, 2H), 2.91 (m, 2H), 1.42 (s, 9H); IR (diffuse reflectance) 1683, 1463, 1410, 1366, 1345, 1293, 1242, 1232, 1227, 1174, 1167, 1113, 857, 756, 693 cm−1; MS (EI) m/z 474 (M+), 474, 420, 419, 418, 334, 332, 311, 238, 84, 57; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.19; H, 5.97; N, 5.86.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reaction time: 7 h

Procedure:
Dimethylformamide (0.6 ml) is added to a mixture of 2,3,4,5-tetrafluorobenzoic acid (100 g) and thionyl chloride (135 ml), and the mixture is heated under reflux with stirring for 7 hours. The reaction mixture is condensed under vacuum to yield crude 2,3,4,5-tetrafluorobenzoyl chloride as a pale yellow oily residue (110.5 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:22]([CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[CH2:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C1C=CC2N(O)N=NC=2C=1.N=C=N>CN(C=O)C>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:22]([CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:10]=2)=[O:35])=[CH:32][CH:31]=1)[CH2:23][C:24]1[NH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CCCN(CCC)Cc1cccc(N)c1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1cccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The compound (51.6 mg) obtained in Example 33-2, the compound (117 mg) obtained in Example 2-2, and HOBt (50.0 mg) were dissolved in anhydrous DMF (2.5 ml). Then, the solution was added with PS-carbodiimide (manufactured by Argonaut Technologies, Inc.) (373.1 mg), followed by stirring at room temperature for 17 hours. After completion of the reaction, the mixture was filtrated and the solvent was then distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution. The residue was dried with anhydrous magnesium sulfate and the solvent was distilled off, followed by treatment with hydrochloric acid. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (18.5 mg) of the subject compound as a white solid.