Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[Br:18])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1
Reactant: [Br-]
Reactant: CC1C(=O)NN=C2COc3ccc(N)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(Br)c(N)cc3N21
Reaction time: 1 h
Yield: 29.9 %

Procedure:
To a 30° C. solution of 6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #2, Step E, 3.0 g, 12.92 mmol) in MeOH (15 mL) and DCM (7.5 mL) was added tetrabutylammonium tribromide (3.31 g, 12.92 mmol) in portions and the resulting black solution was stirred for 1 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1-50% EtOAc in petroleum ether) to give 6-amino-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.2 g, 3.86 mmol, 30%). LC/MS (Table 1, Method 4) Rt=1.337 min.; MS m/z: 311/313 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+]>CS(C)=O>[CH3:10][S:11]([C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CS(=O)[O-]
Reactant: N#Cc1ccc(Br)cn1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C#N)nc1
Temperature: 100 °C

Procedure:
To 5-Bromo-2-cyanopyridine (17.5 kg, 1 mol eq, limiting reagent) and DMSO (103.6 L, 6 rel vol) was charged sodium methanesulfinate (13.7 kg, 1.4 mol eq) and the reaction heated to 100° C. for 24 hours. The reaction mixture was cooled to 50° C. and the product precipitated by addition of water (163 L, 9.3 rel vol). The mixture was then cooled to 25° C. and stirred for at least 9 hours. The solid was collected by filtration, washed twice with water (40 L, 2.3 rel vol) and dried to constant weight yielding the title compound (10.9 kg, 5.9 mol, 60%; 1H NMR (CDCl3): 9.24 (dd, 1H, J 0.8, 2.3 Hz); 8.41 (dd, 1H, J 2.3, 8.2 Hz); 7.93 (dd, 1H, J 0.8, 8.2 Hz); 3.17 (s, 3H) ppm.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)(=O)[CH3:10].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:1]1([NH:7][N:8]=[C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=NNc1ccccc1)c1cccnc1

Procedure:
A solution of 19.7 of phenylhydrazine (21.63 g) and 22 ml of 3-acetylpyridine (24.23 g) in glacial acetic acid (100 ml) is stirred and refluxed for 4.5 hours. The solution is cooled in an ice-water bath and neutralized with a saturated sodium bicarbonate solution (180 ml). The precipitate is collected, washed and dried to give 3-acetylpyridine phenylhydrazone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([F:16])[CH:3]=1.[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)(=[O:10])=[O:9])=[C:4]([F:16])[CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)cc1F
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NCC2CC2)c(F)c1
Reaction time: 16 h
Yield: 10.2 %

Procedure:
According to general procedure B, 4-bromo-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide (181 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide (20 mg, 10%) was provided after purification. MS (ESI) m/z 333. HPLC purity 100.0% at 210-370 nm, 11.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]=[C:26]([CH3:29])[CH2:25][C@H:24]1[C:30]([OH:32])=[O:31])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O)C.C(O)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:31][C:30]([C@@H:24]1[CH2:25][C:26]([CH3:29])=[CH:27][CH2:28][N:23]1[C:21]([O:20][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:22])=[O:32])[CH3:2]
Reactant: CC1=CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC(C)=CCN1C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
1,3-Dicyclohexylcarbodiimide (4.3 g, 20.8 mmol) was added to a stirred solution of the product from (f) above (3.35 g, 13.9 mmol), ethanol (4.1 ml, 69.4 mmol) and 4-dimethylaminopyridine (1.7 g, 13.9 mmol) in dichloromethane (40 ml). After 18 hours at room temperature, glacial acetic acid (0.4 ml) was added and the reaction mixture stirred for a further 0.5 hour before being filtered. The residue obtained by evaporation of the filtrate under reduced pressure was partitioned between ether and water, then the organic phase washed successively with 1M aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, dried (MgSO4) and evaporated under reduced pressure to give an oil (5.15 g), which was purified by chromatography on silica gel, using hexane:ether (4:1) as eluent, to furnish the required product (3.4 g) as a clear oil. Rf 0.30 (SS 4). m/e 270 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].ClCCl.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=O>ClCCCl>[Cl:27][CH2:28][C:29]1[N:4]([CH2:3][CH:2]([CH3:16])[CH3:1])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cn1c(CCl)nc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
N4-(2-Methylpropyl)quinoline-3,4-diamine (U.S. Pat. No. 5,389,640 Example 1, 41 g, 0.190 mol), dichloromethane (550 mL), triethylamine (40 mL, 0.286 mol), and chloroacetyl chloride (16.7 mL, 0.210 mol) were combined and then stirred at ambient temperature over the weekend. The reaction mixture was diluted with 1,2-dichloroethane (75 mL) and then washed with saturated aqueous sodium bicarbonate (3×400 mL). The organic layer was dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 52.81 g of 2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a brown solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[N:11]([CH2:12][CH2:13][CH2:14][N:15]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])[CH2:16]2)[N:10]=1)C1C=CC=CC=1>CCOC(C)=O.CN(C=O)C.[OH-].[OH-].[Pd+2]>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([N:15]2[CH2:14][CH2:13][CH2:12][N:11]3[C:17](=[CH:18][C:9]([OH:8])=[N:10]3)[CH2:16]2)=[O:20])=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(F)cc1)N1CCCn2nc(OCc3ccccc3)cc2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)N1CCCn2nc(O)cc2C1
Yield: 92.7 %

Procedure:
A solution of (2-benzyloxy-7,8-dihydro-4H,6H-1,5,8a-triaza-azulen-5-yl)-(4-fluoro-phenyl)-methanone (0.902 g, 2.47 mmol) in a mixture of AcOEt/DMF (25/25 mL) was hydrogenated in a H-Cube reactor (1.5 ml/min, 70 mm, Pd(OH)2/C cartridge, full H2 mode, 80° C., 1 cycle). The solvents were evaporated in vacuo to yield (4-Fluoro-phenyl)-(2-hydroxy-7,8-dihydro-4H,6H-1,5,8a-triaza-azulen-5-yl)-methanone (0.63 g, 93% yield) as a colorless oil, that was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:13])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:14])[C:3]=1[N:15]1[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]1=[O:27].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:38](Cl)=[O:39]>O1CCOCC1>[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:38]([NH:1][C:2]1[C:7]2[N:8]([CH3:13])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:14])[C:3]=1[N:15]1[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]1=[O:27])=[O:39]
Reactant: CN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(N)c21
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1COCCO1
Product: CN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(NC(=O)c3ccc4ccccc4c3)c21
Yield: 43.8 %

Procedure:
3-[5-Amino-7-fluoro-4-methyl-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-6-trifluoromethyl-2,4-(1H, 3H)-pyrimidinedione (0.49 g) and 2-naphthoyl chloride (0.26 g) were mixed in dioxane (35 ml), the resulting mixture was refluxed for 7 hr. After evaporation, the residue was purified by silica gel column (hexane to 30% and 50% ethyl acetate) to yield the title compound (0.3 g).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]3[CH2:21][CH2:20][CH2:19][O:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:25])=[O:24])=[CH:5][NH:6]2.CO>C(=O)=O>[F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:16]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:25])=[O:24])=[CH:5][NH:6]2
Reactant: O=C(O)c1c[nH]c2cc(F)c(-c3ccc([C@@H]4CCCO4)cc3)c(F)c12
Agent: O=C=O
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(C4CCCO4)cc3)c(F)c12

Procedure:
Racemic-4,6-difluoro-5-[4-(tetrahydrofuran-2-yl)phenyl]-1H-indole-3-carboxylic acid was subjected to separation by preprative SFC (Column: OJ (250MM*30MM,5UM); Mobile phase: 30% MeOH NH3H2O 60ML/MIN 3; Wavelength: 220 nm) Peak 1 was isolated and arbitrarily called 4,6-difluoro-5-{4-[(2S)-tetrahydrofuran-2-yl]phenyl}-1H-indole-3-carboxylic acid. Peak 1 was isolated as Isomer 1 (Example 152) Retention time=8.43 min; Column: Chiralcel OJ-H 250×4.6 mm I.D., 5 um Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40% Flow rate: 2.5 mL/min Wavelength: 220 nm. MS (ES+) 343.8 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H) 7.42 (m, 5H) 7.25 (d, 1H) 4.88 (t, 1H) 4.03 (q, 1H) 3.85 (q, 1H) 2.35 (m, 1H) 1.99 (m, 2H) 1.75 (m, 1H). Peak 2 was isolated as Isomer 2 (Example 153), Retention time=8.86 min; Column: Chiralcel OJ-H 250×4.6 mm I.D., 5 um Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40% Flow rate: 2.5 mL/min Wavelength: 220 nm. MS (ES+) 343.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H) 7.41 (m, 4H) 7.24 (d, 1H) 4.87 (t, 1H) 4.02 (q, 1H) 3.84 (q, 1H) 2.35 (dq, 1H) 1.97 (m, 2H) 1.73 (m, 1H).
Reaction SMILES: O=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH:2]1([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH2:25])[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CCCCCCCCCCCCN
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: NCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O

Procedure:
The preparation is analogous to Example 1, starting from 18 g of mannose and 19 g of dodecylamine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([OH:17])[C:8](Br)=[C:9]2[O:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]=12)=[O:4].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([OH:17])[CH:8]=[C:9]2[O:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]=12)=[O:4]
Reactant: COC(=O)c1cc(O)c(Br)c2c1CC(C)(C)O2
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: COC(=O)c1cc(O)cc2c1CC(C)(C)O2
Yield: 81 %

Procedure:
A suspension of 7-bromo-6-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (197d) (52 g, 0.17 mol) and 10% Pd on Carbon (5 g) in MeOH (1 L) was stirred under 50 Psi of H2 at 35-40° C. for 3 days. After HPLC indicated complete consumption of 197d, the reaction mixture was filtered through Celite and the filtrate was concentrated to give the title compound (30.6 g, 79.6%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.93 (s, 1H), 6.39 (s, 1H), 5.32 (s, 1H), 3.81 (s, 3H), 3.17 (s, 2 H), 1.40 (s, 6H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH:6]2[CH2:11]/[CH:12]=[CH:13]/[C:14](OC)=[O:15])[O:4][CH2:3][CH2:2]1.[Li+].[Cl-].[BH4-].[Na+].CCO>C1COCC1>[O:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)/C=C/CC1COCCC12OCCO2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCCCCC1COCCC12OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl (2E)-4-(1,4,8-trioxaspiro[4.5]dec-6-yl)but-2-enoate (0.747 g, 3.08 mmol) in THF (9 mL) was added anhydrous LiCl (0.261 g, 6.71 mmol) and Sodium borohydride (0.233 g, 6.17 mmol). EtOH (12 mL) was then added slowly and the mixture was stirred at rt overnight. It was cooled to 0° C. and quenched with 10% aqueous citric acid. The organic layer was then concentrated and the mixture was diluted with water and CH2Cl2. Extracted 3× with CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 3.91-4.05 (m, 4H), 3.77-3.90 (m, 2H), 3.60-3.70 (m, 3H), 3.44 (dd, 1H, J=8.8 Hz, 11.0 Hz), 1.14-1.82 (m, 9H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=C)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:27].[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]=[O:27])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:2])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-vinyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.300 g, 0.000894 mol) was dissolved in THF (20 mL) and H20 (10 mL). Osmium tetroxide (0.550 mL, 0.0716 mmol, 4% wt in water) was added followed by Sodium metaperiodate (0.383 g, 0.00179 mol). The reaction was stirred overnight at room temperature. The reaction was quenched using saturated sodium thiosulfate. 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carbaldehyde (0.302 g, 95.1% yield) was isolated using an aqueous workup and carried on without further purification
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].C(N(CC)CC)C.[C:13]1([C:23](Cl)=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:4]([CH2:3][NH:2][C:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)=[O:24])#[N:5]
Reactant: N#CCN
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CCNC(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 9.3 g (0.1 mole) aminoacetonitrile hydrochloride and 20.2 g (0.2 moles) triethylamine in 200 ml chloroform which had been stirred for about 15 minutes to give a clear solution, the naphthoyl chloride from step (a) in 25 ml methylene chloride was dropped in over about 30 minutes in a slightly exothermic addition. The reaction mixture was stirred 20 minutes, and then was mixed with 200 ml ice water. A precipitate formed immediately; however, the mixture was cooled in an ice bath for about 15 minutes before being filtered. The precipitate was filtered, washed with 100 ml water and vacuum dried at about 55° C. to a constant weight, to give 18.7 g of the above-identified product as a beige solid, melting point 160° C. to 163° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([C:26]1[S:30][CH:29]=[N:28][C:27]=1[CH:31]=O)(=[O:25])=[O:24]>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:27]2[N:28]=[CH:29][S:30][C:26]=2[S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)(=[O:25])=[O:24])=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ncsc1S(=O)(=O)c1ccccn1
Product: COC(=O)Cn1c(C)c(Cc2ncsc2S(=O)(=O)c2ccccn2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 5-(pyridine-2-sulfonyl)thiazole-4-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH2:15][OH:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:15]=[O:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: COCCc1cc(CO)c2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCCc1cc(C=O)c2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of {3-[2-(methyloxy)ethyl]-1-naphthalenyl}methanol (1 eq.) from the previous step and sodium bicarbonate (1.1 eq.) in dichloromethane (0.1 M) was added DMP (1.1 eq.) at 0° C. The resulting mixture was stirred at RT for 2 h before it was quenched with sat. aq. NaHSO3 and then extracted with Et2O. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 19:1 (v/v) Hex:EtOAc 1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(OCC)(=O)C>O1CCOCC1.[Cu]I>[Br:1][C:2]1[CH:17]=[C:6]([C:7]2[O:8][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Nc1ccccc1Br)c1cncc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Brc1cncc(-c2nc3ccccc3o2)c1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
A mixture of 5-bromo-N-(2-bromophenyl)nicotinamide 6 (3.44 g, 9.7 mmol), CuI (0.106 g, 0.56 mmol), Cs2CO3 (3.91 g, 12 mmol) and 1,10-phenanthroline (0.20 g, 1.12 mmol) in anhydrous 1,4-dioxane (50 ml) was heated at 100° C. overnight. After cooling to RT, the mixture was poured into ethyl acetate (200 ml), then washed with water. The aqueous phase was extracted with ethyl acetate (200 ml×2), and the organic phase was collected and dried over Na2SO4, purified by flash chromatography (silica gel, hexanes/ethyl acetate 3:1) to give a light yellow solid 7 (2.0 g, 75% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19]Br.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Fc1ccc(CBr)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NC1CCN(Cc2ccc(F)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (5 g, 25.0 mmol), 3,4-difluorobenzyl bromide (4.7 g, 22.7 mmol) and diisoproylethylamine (5.9 ml, 34.0 mmol) in dichloromethane (50 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (31 ml) was added and the reaction was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane and the separated organic layers were dried (Na2SO4), filtered, and the solvent evaporated in vacuo to yield D7 (5.2 g, 93%) as a solid. C12H16F2N2 requires 226. Found 227 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:12]=2)[N:7]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[N:15]([CH3:24])[C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:12]=2)[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(=O)[nH]c(Cc3cccc(Cl)c3)nc2c1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1ccc2c(=O)n(C)c(Cc3cccc(Cl)c3)nc2c1
Yield: 80.6 %

Procedure:
A mixture of 160 mg of methyl 2-(3-chlorobenzyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate which was synthesized in Production Example 1, 65 mg of potassium carbonate, 20 mL of acetonitrile and 67 mg of methyl iodide was heated for 2 hours under reflux. Further 20 mg of methyl iodide was added, followed by another hour's heating under reflux. The reaction mixture was allowed to cool off, and then concentrated under reduced pressure, 10 mL of water was added thereto, and extracted with 60 mL of ethyl acetate. The organic layer was washed with 10 mL of saturated saline solution, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified on silica gel chromatography (hexane:ethyl acetate=2:1) to provide 130 mg of the title compound.