Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C@H:14]([CH2:17][CH3:18])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:14]([CH2:17][CH3:18])[CH2:15][O:16][C:27]3=[O:29])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
(2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}butan-1-ol (2.80 g, 8.56 mmol), prepared in the previous step, and triethylamine (10.5 mL, 60 mmol) in dry dichloromethane (75 mL) was cooled to 0° C. under a nitrogen atmosphere. Triphosgene (5.90 g, 20 mmol) in dry dichloromethane (25 mL) was then added drop wise. After 16 h, the mixture was washed with water and dried (anhydrous MgSO4). The crude product was recrystallized from diethyl ether to afford (4R)-3-[4-(4-bromophenyl)-1,3-thiazol-2-yl]-4-ethyl-1,3-oxazolidin-2-one (1.46 g, 4.1 mmol). mp 134-135° C.; [α]D25=−46° (c=0.0107 g/mL, DMSO); MS (ES) m/z 353.0; HPLC purity 100% at 210-370 nm, 10.8 min; 100% at 270 nm, 10.8 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min. Anal. Calcd for C14H13BrN2O2S: C, 47.60; H, 3.71; N, 7.93. Found: C, 47.45; H, 3.43; N, 7.74.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18]CC)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[CH:25]([NH2:27])=[NH:26]>>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2=[N:27][CH:25]=[N:26][C:16](=[O:18])[CH:11]2[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C1N=CN=C2CCN(Cc3ccccc3)CC12

Procedure:
Various N-substituted-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine derivatives are prepared using a general procedure described below. Accordingly, ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride is reacted with formamidine acetate to yield 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(4aH)-one, which, in turn, is reacted with POCl3 to afford the 4-chloro derivative. The intermediate chloro derivative is then condensed with substituted aniline or amine to give the desired N-substituted-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine. Debenzylation using standard procedures known in the art followed by nucleophilic displacement of an appropriate 2-halo-pyridine yields the appropriate N-substituted-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine. As a representative example, synthesis of N-(4-tert-butylphenyl)-6-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine is depicted in Scheme 1.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].O.Cl>N1C=CC=CC=1>[C:1]([O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:12]2[CH2:13][CH2:14][CH:9]([CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]2)[CH:22]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCCC1CCC(c2ccccc2-c2cccc(O)c2)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC1CCC(c2ccccc2-c2cccc(OC(=O)CC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.9 %

Procedure:
Under a nitrogen atmosphere, 1.6 g of propanoyl chloride was added to 5.0 g of 3-((4-propylcyclohexyl)phenyl)phenol (1) dissolved in 10 mL (mili-litter) of pyridine under cooling with iced water, and after completing dropwise addition, the mixture was stirred at ambient temperature for 2 hours. The resulting solution was added to 20 mL of 3N hydrochloric acid. The aqueous layer was extracted with diethyl ether, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 6.42 g of 3-((4-propylcyclohexyl)phenyl)phenyl propanoate (2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[NH:13][C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:4]([O:33][CH2:34][CH3:35])[CH:3]=1.[C:36](Cl)([Cl:38])=[O:37]>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[N:16]([C:36]([Cl:38])=[O:37])[C:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[C:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[N:13]=2)=[C:4]([O:33][CH2:34][CH3:35])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(4-chloro-2-ethoxy-5-methanesulfonyl-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: P([O-])([O-])([O-])=O.[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]=[CH:11]2.ClC1C=CC=C(C(OO)=[O:24])C=1>C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]1[O:24][CH:11]12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cccc2c1CC=C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: Brc1cccc2c1C=C1OC12
Reaction time: 4 h
Yield: 38.4 %

Procedure:
250 ml of pH 8 phosphate buffer, 150 ml of methylene chloride, 200 mg of tetrabutylammonium hydrogenosulphate and 10 g of 4-bromo-3H-indene are mixed together. At 0° C. 10 g of metachloroperbenzoic acid is added in several lots, then the temperature of the mixture is allowed to rise to the ambient over 4 hours, 10 g of metachloroperbenzoic acid is added at 0° C. and the temperature is allowed to rise to 20° C. over 2 hours. 3 g of metachloroperbenzoic acid is added and the mixture is left for 16 hours at ambient temperature, then decanted and extracted with methylene chloride; the extracts are washed with water, with a thiosulphate solution and with water, dried and evaporated to dryness. The residue is chromatographed on silica, eluting with a mixture of hexane and isopropyl ether (9-1) with 3% of triethylamine, and 4.11 g of expected product is isolated.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].Cl.[C:6](Cl)(=[O:10])[C:7](Cl)=[O:8]>>[CH3:1][N:2]([O:3][CH3:4])[C:7]([C:6]([N:2]([CH3:1])[O:3][CH3:4])=[O:10])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.9 %

Procedure:
A mixture of 48.0 g (0.49 mol) of N,O-dimethylhydroxylamine.HCl in 250 mL of 3:2 v/v CH2Cl2pyridine was cooled to −78° C. and was treated with 17.4 mL (0.2 mol) of oxalyl chloride maintaining the internal temperature at less than −70° C. The resulting mixture was allowed to warm to rt and stirred for 20 h. The reaction was quenched with 250 mL of sat'd NaCl and the quenched mixture was extracted with 3×400 mL of CH2Cl2. The extracts were combined, dried over MgSO4 and concentrated. Recrystallization from 250 mL of MTBE afforded 24.28 g (69%) of the title compound: 1H NMR (500 MHz) δ3.25 (s, 6H), 3.75 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:15]([O:17]C)=[O:16].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1nc2ccc(C(F)(F)F)cn2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)nc2ccc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 10-C (0.978 g, 3.79 mmol) in MeOH (6 mL) and H2O (3 mL) was added sodium hydroxide (0.227 g, 5.68 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was acidified with 2N HCl to pH 4-5 and concentrated in vacuo. The resulting residue was taken up in EtOAc, and the organic layer was washed with H2O and then dried over Na2SO4. The mixture was filtered and the filtrate concentrated in vacuo to give compound 10-D as a light yellow solid (0.866 g, 94%), which was used in the next reaction; MS m/z (M+H+) 245.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([CH3:22])=[O:21]>O.C(#N)C>[C:20]([C:16]1[O:15][C:19]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)(=[O:21])[CH3:22]
Reactant: CC(=O)c1ccco1
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(C#N)cc2)o1
Reaction time: 0.75 h
Yield: 18 %

Procedure:
A mixture of 50 g (0.42 mole) of p-aminobenzonitrile, 146 ml of concentrated hydrochloric acid, and 106 ml of H2O was heated at 80° for for 20 minutes and then cooled to 0°. A solution of 29 g (0.42 mole) of sodium nitrite in 105 ml of H2O was added dropwise while maintaining the temperature at 0°-5° by means of an ice bath. The reaction was kept at 0° for 45 minutes. A solution of 47 g (0.42 mole) of methyl 2-furyl ketone in 43 ml of acetonitrile was added followed by a solution of 10 g of CuCl2 .2H2O in 50 ml of water. The reaction became exothermic and was controlled below 40°. The reaction was allowed to stand overnight. The aqueous layer was decanted and the residual semisolid was extracted with 6000 ml of refluxing hexane. The hexane was cooled and the resulting precipitate was filtered and air dried to yield 16 g (18%) of p-(5-acetyl-2-furyl)benzonitrile. An analytical sample was prepared by recrystallizing a sample from hexane/charcoal, m.p. 115°-116°.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([O:15]CC)=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]c(C(=O)c2ccc(Cl)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(C(=O)c2ccc(Cl)cc2)c1
Yield: 87.4 %

Procedure:
Ethyl 5-(4-chlorobenzoyl)pyrrole-3-carboxylate (0.7 g.) was combined with 20 ml. of methanol and 15 ml. of 1 N sodium hydroxide and boiled in an open flask for 1 hour. Most of the methanol evaporated. The mixture was diluted to 40 ml. with water, treated with activated charcoal, and acidified to yield 5-(4-chlorobenzoyl)pyrrole-3-carboxylic acid [550 mg., m.p. 278°-280° C. (dec)]. Recrystallization from 1:1 methanol-acetone gave two crops of purified product [385 mg., m.p. 280°-282° C. (dec.)].
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]#[N:21].O>CN(C=O)C>[C:20]([CH2:19][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=2)[CH:6]=[C:7]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:21]
Reactant: CCOC(=O)c1cc2ccc(I)cc2[nH]1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(I)cc2n1CC#N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
A solution of ethyl 6-iodoindole-2-carboxylate (7.0 g, 22 mmol) in DMF (25 mL) was added dropwise over 15 min to a stirred suspension of sodium hydride (60%, 1.36 g, 34 mmol) in DMF (50 mL) at 0° C. under Ar. The reaction was stirred at 0° C. for 45 min then chloroacetonitrile (2.85 mL, 45 mmol) was added in one portion. The reaction was then heated to 75° C. and stirred for one h. After allowing to cool to room temperature the mixture was poured into water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (1×200 ml), dried (magnesium sulfate), filtered and the solvent removed under vacuum to give the product (1.8 g, 23%). IR νmax (Nujol)/cm−1 2924, 2854, 1895, 1703, 1601, 1527, 1464, 1446, 1426, 1398, 1377, 1366, 1334, 1308, 1261, 1204, 1148, 1135, 1119, 1103, 1048, 1024, 989, 949, 904, 894, 871, 842, 833, 800, 786, 762, 736, 654, 612, 584 and 471; NMR δH (400 MHz; CDCl3) 7.79 (1H, s), 7.51 (1H, d, J 8.6 Hz), 7.42 (1H, d, J 8.6 Hz), 7.32 (1H, s), 5.54 (2H, s), 4.37 (2H, q, J 7 Hz), 1.39 (3H, t, J 7 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCc3ccccc3)cc2)nc1
Reaction time: 18 h

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinamide (0.097 g, 0.4 mmol) in 5 mL of methanol with benzylamine (0.4 mmol), and 1 g of 3 {acute over (Å)} molecular sieves. Stir for 18 h. Add sodium borohydride (0.076 g, 2 mmol), and stir for 18 h. Flush the reactions down through a 5 g SCX column, first wash with 1:1 chloroform/methanol, then collect washes with 1:1 chloroform/2 M ammonia in methanol. Adsorb the collected material on silica, then purify via a ISCO® Combiflash 16× system (use a 10 g silica cartridge, and elute with 98:2:0.2 chloroform/ethanol/ammonium hydroxide, gradient to 90:10:1 chloroform/ethanol/ammonium hydroxide). 1H NMR (DMSO-d6): 8.58 (d, 1H), 8.22 (m, 1H), 8.0 (s, 1H), 7.46 (s, 1H), 7.27-7.38 (m, 6H), 7.20 (m, 1H) 7.02-7.08 (m, 3H), 3.67-3.68 (d, 4H). TLC Rf (90:10:1 chloroform/ethanol/ammonium hydroxide): 0.31.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[O:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:29]1[O:30][C:31]2[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=2[C:33]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CC(N4CCOCC4)C3)cc2n1
Temperature: 140 °C
Yield: 80.8 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-(3-morpholin-4-ylazetidin-1-ylmethyl)thieno[3,2-d]pyrimidine (100 mg, 0.24 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzofuran (94 mg, 0.36 mmol), tetrakis(triphenylphosphine)palladium (28 mg, 0.02 mmol) and Cs2CO3 (160 mg, 0.48 mmol) in dioxane (6 mL) and H2O (3 mL) was purged with argon then heated at 140° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with DCM/MeOH then eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-5%) to afford 213 as a white foam (98 mg, 81%). LCMS (Method G): RT 9.09 min, [M+H]− 506.3. 1H NMR (CDCl3, 400 MHz): δ 8.42-8.39 (m, 1 H); 7.46-7.42 (m, 1 H); 7.32-7.24 (m, 3 H); 4.02 (t, J=4.7 Hz, 4H); 3.97 (s, 2 H); 3.89 (t, J=4.7 Hz, 4 H); 3.73 (m, 4 H); 3.63 (s, 2 H); 3.06 (m, 3 H); 2.93 (s, 3 H) and 2.33 (m, 4 H)
Reaction SMILES: [N:1]1[C:13]2[N:4]([C:5](=[O:14])[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[NH:3][C:2]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:22][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2=[N:1][C:2]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:3][N:4]2[C:5]1=[O:14]
Reactant: CCOC(=O)c1nc2c3ccccc3nc(=O)n2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2c3ccccc3n(C)c(=O)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.0 g (0.047 mole) of ethyl 1,2,4-triazolo[1,5-c]quinazolin-5-one-2-carboxylate in 100 ml of absolute dimethylformamide were added dropwise to a suspension of 0.053 mole of NaH in 100 ml of absolute dimethylformamide at room temperature. After 2 hours, 7.5 g (0.053 mole) of methyl iodide were added, and the mixture was stirred overnight at room temperature and then poured into 400 ml of ice water. The precipitate was filtered off under suction and dried. Yield: 6.6 g (52%), mp.: 258° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:20]([O:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26](F)[C:25]=1[N+:33]([O-:35])=[O:34])[CH:21]=[CH2:22]>C1COCC1>[CH2:20]([O:23][C:24]1[C:25]([N+:33]([O-:35])=[O:34])=[C:26]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[Cl:1])[C:27]([F:31])=[C:28]([F:30])[CH:29]=1)[CH:21]=[CH2:22]
Reactant: Nc1ccc(I)cc1Cl
Reactant: C=CCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(I)cc2Cl)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To solution of 2-chloro-4-iodo-phenylamine (1.09 g, 4.3 mmol) in THF (50 mL) was dropwise added LHMDS solution (5.6 mL, 5.6 mmol, 1 M in THF) at −78° C. After stirring for 1 h at −78° C., a solution of 1-allyloxy-3,4,5-trifluoro-2-nitro-benzene (1.1 g, 4.7 mmol) in THF (10 mL) was added dropwise into the reaction mixture, which was stirred at −78° C. for 1 h and at room temperature for 16 h. The progress of reaction was monitored by 1H NMR. After completion, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue obtained was re-crystallized in hexane to yield (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-chloro-4-iodo-phenyl)-amine as an orange solid (843 mg). 1H-NMR (400 MHz, CDCl3): δ 4.63 (2H, d, J=5.2), 5.37 (1H, d, J=10.4), 5.46 (1H, d, J=17.2) 5.96-6.00 (1H, m), 6.50-6.54 (1H, m), 6.60-6.65 (1H, m), 7.04 (1H, s), 7.43 (1H, d, J=8), 7.68 (1H, d, J=2).
Reaction SMILES: Br[CH:2]=[CH:3][CH3:4].[CH:5]1[CH:6]=[CH:7][C:8]([C:27]([OH:29])=[O:28])=[C:9]([C:11]2[C:21]3[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=3[O:19][C:18]3[C:12]=2[CH:13]=[CH:14][C:15]([CH:17]=3)=[O:16])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:4]([O:29][C:27](=[O:28])[C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[C:11]1[C:12]2[C:18]([O:19][C:20]3[C:21]=1[CH:22]=[CH:23][C:24](=[O:26])[CH:25]=3)=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=2)[CH:3]=[CH2:2]
Reactant: CC=CBr
Reactant: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 65 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
Bromo-1-propene (0.78 mL, 9.0 mmol) was added dropwise under argon to a stirred mixture of fluorescein 16 (3.0 g, 9.0 mmol) and K2CO3 (1.24 g, 9.0 mmol) in dry DMF (40 mL). The resulting mixture was stirred for 4 h at 65° C. The mixture was concentrated, diluted with ethyl acetate, washed with 10% NaHCO3, brine, dried with anhydrous Na2SO4, and evaporated. The residue was purified by column chromatography (ethyl acetate/hexane=2:1) to give 21 as a brown solid (0.70 g, 21%). 1H NMR (CDCl3, 500 MHz) δ 4.42 (d, J=6.0 Hz, 2H, CH2), 5.06 (m, 2H, 2CH), 5.53 (m, 1H, CH), 6.81 (m, 2H), 6.88 (m, 2H), 6.98 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H), 8.26 (d, J=7.5 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 66.26, 103.90, 115.01, 119.49, 122.30, 130.02, 130.51, 130.65, 131.00, 131.38, 132.77, 134.48, 155.89, 158.06, 165.08, 175.84. ESIMS calcd for C23H17O5 [M+H]+ 373.1. Found 373.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[C:12]([F:22])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[NH:16][C:15]=3[CH:21]=2)[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[H-].[Na+].[CH2:25](I)[CH3:26].O>CN(C)C=O>[Cl:1][C:2]1[N:3]([C:11]2[C:12]([F:22])=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH2:25][CH3:26])[C:15]=3[CH:21]=2)[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: O=C1COc2cc(F)c(-n3nc4c(c3Cl)CCCC4)cc2N1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)COc2cc(F)c(-n3nc4c(c3Cl)CCCC4)cc21
Reaction time: 3 h

Procedure:
To a solution of 3-chloro-2-[7-fluoro-2H-1,4- benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-indazole (1.0 g) in N,N-dimethylformamide (10 ml), sodium hydride (0.3 g) and ethyl iodide (0.5 g) were successively added, and the resultant mixture was heated at 50° to 60° C., followed by stirring for 3 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and purified by silica gel column chromatography using a mixture of ethyl acetate and hexane as an eluent to give Compound No. 1 (0.9 g). m.p., 101.5°-102.5° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:39](=[O:41])[CH3:40])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(=O)Cl
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 90.9 %

Procedure:
To a solution of 25 mg of amine prepared in Example 11 and 0.05 mL of DIPEA in 0.5 mL of methylene chloride was added 7 mg of acetyl chloride. After 1.5 h in a sealed vial, the volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with ethyl acetate to afford 25 mg of title compound. Mass spec (NH3 /CI): 460 (M+1).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:5]=[C:4]([S:30][CH3:31])[N:3]=1.[CH3:32][NH:33][CH3:34].C1COCC1>C1COCC1>[CH3:32][N:33]([CH3:34])[C:2]1[C:15]2[C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:5]=[C:4]([S:30][CH3:31])[N:3]=1
Reactant: CNC
Reactant: CSc1nc(Cl)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Solvent: C1CCOC1
Product: CSc1nc(N(C)C)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.6 %

Procedure:
(S)-5-[3-(7-Chloro-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-(2-methyl)-1,3,4-oxadiazol-2(3H)-one (30.0 mg, 0.0654 mmol) obtained in Step 8 of Example 156 was dissolved in THF (3 mL), and the mixture was stirred at room temperature for 2.5 hours after adding a 2.0 mol/L N,N-dimethylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (S)-5-[3-(7-dimethylamino-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (26.8 mg, 88%).