Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:38]([NH:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:48]2[CH:49]=[CH:50][C:45]([C:43]([NH:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])=[CH:46][CH:47]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)NC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 79.1 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (1.5 g, 2.78 mmol), [4-(tert-butylaminocarbonyl)phenyl]boronic acid (1.3 g, 5.56 mmol) and dichlorobis(triphenylphosphine)palladium (II) (195 mg, 0.28 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 3.5 mL, 7 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-N-tert-butyl-benzamide (1.2 g, 79.5%) as a light yellow solid: LC/MS m/e calcd for C31H32FN3O3S [M+H]+ 546.69, observed 546.1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][S:16][CH3:17])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][N:6]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:15][S:16]([CH3:17])=[O:26])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[O:7][N:6]=1
Reactant: CSC[C@H](N)COc1noc2ccc(Cl)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)C[C@H](N)COc1noc2ccc(Cl)cc12
Yield: 24.5 %

Procedure:
To a solution of 0.54 g of (R)-3-(2-amino-3-methylthiopropoxy)-5-chloro-1,2-benzoisoxazole in 5 ml of methylene chloride is added 0.43 g of m-chloroperbenzoic acid with ice-cooling, and they are subjected to reaction at the same temperature for 30 minutes, after which 0.21 g of m-chloroperbenzoic acid is added and they are subjected to reaction for a further 30 minutes at the same temperature. After completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution is added and shaken, after which the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluant:chloroform:methanol=20:1], to obtain 0.14 g of oily (R)-3-(2-amino-3-methanesulfinylpropoxy)-5-chloro-1,2-benzoisoxazole (Compound No. 139-1) and 0.38 g of oily (R)-3-(2-amino-3-methanesulfonylpropoxy)-5-chloro-1,2-benzoisoxazole (Compound No. 139-2).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17]C)=[O:16])[CH2:4]1.C(N(CC)CC)C.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[I-].[Na+]>CN(C=O)C>[CH2:26]([NH:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([OH:17])=[O:16])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1C[C@H](NCc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To a solution of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.300 g, 0.96 mmol) in anhydrous DMF (10 ml) was added triethylamine (0.403 ml, 2.89 mmol), benzyl bromide (0.230 ml, 1.92 mmol) and a catalytic quantity of sodium iodide. This mixture was stirred under an atmosphere of nitrogen at room temperature for 90 hours. The solvent was removed in vacuo and the residue obtained was partitioned between distilled water (100 ml) and ethyl acetate (200 ml). The organic layer was washed with saturated sodium hydrogen carbonate (2×100 ml), brine (2×100 ml) and distilled water (2×100 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatrography on silica gel (using from 10% ethyl acetate in hexane to 50% ethyl acetate in hexane as eluents) to give the title compound as colourless crystals, m.p. 112°-114° C. δ (360 MHz, DMSO), 1.41 (1H, ddd, J=13.4, 12.3 and 3.1 Hz, CHACHBHCCHD), 2.33 (1H, dm, J=13.4 Hz, CHACHBHCCHD), 3.73 (3H, s, CO2CH3), 3.84 (2H, 2 d, J=13.5 Hz, CH2C6H ), 4.13 (1H, m, CHACHBHCCHD), 4.27 (1H, dd, J=12.3 and 2.8 Hz, CHACHBHCCHD), 6.60 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.73 (1H, s, ArNH, 6.78 (1H, d, J=7.69 (1H, d, 2.1 Hz, 6-H or 8-H), 7.28 (3H, m, ArH), 7.37 (2H, m, ArH), 7.69 (1H, m, CHNHCH2); m/e (CI+) 365 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][CH2:12][Mg+].[Br-].B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>CCOCC.CCOC(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]1([NH2:5])[CH2:12][CH2:11]1
Reactant: N#Cc1cc(F)ccc1Br
Reactant: CC[Mg+]
Agent: Cl
Agent: FB(F)F
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NC1(c2cc(F)ccc2Br)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a stirred solution of 2-bromo-5-fluoro-benzonitrile (1 g, 5 mmol) and Ti(Oi-Pr)4 (1.81 mL, 5.5 mmol) in ether (20 mL) was added EtMgBr (3.67 mL, 11 mmol) at −78° C. After stirring at −78° C. for 10 min, the solution was warmed up to room temperature and stirred for 1 hour. BF3-Et2O (1.25 mL) was added before it was stirred for another 1 hour. After addition of 1 N aq. HCl (15 mL) and ether (30 mL), aq. NaOH (10%, 45 mL) solution was added to give two clear phases. The mixture was exacted with EtOAc (30 mL×5). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by column chromatography (PE:EA=5:1) to afford the title compound (800 mg, 70%) as oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:32])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C@H:20]([CH3:29])[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.CS(C)=O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C@H:20]([CH3:29])[NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[O:32]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N1CCC[C@H]1C(O)c1nc2ccccc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N1CCC[C@H]1C(=O)c1nc2ccccc2s1

Procedure:
40 (0.62 g, 0.134 mmol), oxalylchloride (0.207 ml, 2.41 mmol), DMSO (2.37 ml, 3.35 mmol), TEA (0.75 ml, 5.35 mmol)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([Cl:24])[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:16]=3[N:17]=2)[CH2:3][CH2:2]1>C(O)C>[Cl:24][C:13]1[N:14]=[C:15]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:16]2[N:17]=[C:8]([CH2:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(C=C3CCOCC3)ccc2n1
Solvent: CCO
Product: Clc1nc(N2CCOCC2)c2nc(CC3CCOCC3)ccc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.7 %

Procedure:
4-(6-((2H-Pyran-4(3H,5H,6H)-ylidene)methyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (0.22 g) was brought up in ethanol (30 mL) and ethyl acetate (30 mL) and the flask was purged with nitrogen before addition of 10% Palladium on Carbon (10 mol %). The reaction was placed under a hydrogen balloon and stirred at room temperature for 2.5 hours. The reaction was filtered thru celite and purified by flash column chromatography to obtain 0.11 g 4-(2-chloro-6-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[CH:13]3[C:26]([CH3:29])([CH2:27][CH:28]=2)[CH:25]2[C:16]([CH3:47])([C:17]4([CH3:46])[CH:22]([CH2:23][CH2:24]2)[CH:21]2[CH:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C:20]2([C:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4]>[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:48])([CH3:49])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C:22](=[CH:23][CH2:24]2)[C@H:21]2[C@:20]([C:36]([O:38][Si:39]([C:42]([CH3:44])([CH3:43])[CH3:45])([CH3:41])[CH3:40])=[O:37])([CH2:32][CH2:31][C:33]([CH3:34])([CH3:35])[CH2:30]2)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:9][CH:10]=1)=[O:4]
Reactant: C=C(C)C1CCC2(C(=O)O[Si](C)(C)C(C)(C)C)CCC3(C)C(CCC4C5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)C5CCC43C)C12
Agent: [Pd]
Product: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC=C5[C@@H]6CC(C)(C)CC[C@]6(C(=O)O[Si](C)(C)C(C)(C)C)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Yield: 54 %

Procedure:
Palladium catalyzed hydrosilylation of the benzyl esters intermediate B4 as described in the preparation of 1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-tert-butyldimethylsilyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate, (intermediate 5) afforded the title compound (54%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.25 (s, 3H), 0.26 (s, 3H), 0.87 (s, 3H), 0.92 (s, 3H), 0.93-0.97 (m, 18H), 1.07 (s, 3H), 1.12-1.17 (m, 2H), 1.18 (s, 4H), 1.21-1.30 (m, 3H), 1.30-1.53 (m, 5H), 1.62-1.80 (m, 5H), 1.82-1.95 (m, 1H), 1.95-2.03 (m, 2H), 2.07 (dd, J=17.07, 6.27 Hz, 1H), 2.88 (dd, J=13.93, 4.64 Hz, 1H), 3.92 (s, 3H), 5.31 (dd, J=6.27, 1.76 Hz, 1H), 5.35 (t, J=3.51 Hz, 1H), 7.22 (d, J=8.53 Hz, 2H), 7.94 (d, J=8.28 Hz, 2H).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]1(C)C=CC(S(O)(=O)=O)=CC=1.C=O>C1(C)C=CC=CC=1>[OH:1][N:2]1[C:3](=[O:17])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NO)c1ccccc1Nc1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2N(c2ccccc2)CN1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A mixture of N-hydroxy-2-(phenylamino)benzamide (1.4 g, 6.15 mmol), p-toluene sulfonic acid (400 ml), and paraformaldehyde (200 mg, 6.75 mmol) in toluene (50 ml) is stirred at room temperature for 30 minutes. The reaction mixture is heated for 10 minutes (in an oil bath preheated to 120°-130° C.) using a Dean-Stark trap to collect water. The reaction mixture is cooled and diluted with ethyl acetate (50 ml) and is extracted with saturated aqueous NaHCO3 (4×50 ml) and water (50 ml). The organic layer is dried (MgSO4) and evaporated. Recrystallization from EtOAc/hexane gives 0.6 g (40%) of 2,3-dihydro-3-hydroxy-1-phenyl-4(1H)-quinazolinone, mp 156°-160° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:37][CH:38]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][CH:29]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:37][CH:38]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(NCc2ccc(N3CCOCC3)nc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N3CCOCC3)nc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 78.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and (4-isopropylphenyl)[(6-morpholinopyridin-3-yl)methyl]amine (0.62 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(6-morpholinopyridin-3-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.90 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O>>[CH2:21]([O:1][C:2]1[C:7]2[O:8][C:9]([C:11]3[O:12][C:13]([CH3:16])=[CH:14][N:15]=3)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: Cc1cnc(-c2cc3cccc(O)c3o2)o1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Product: Cc1cnc(-c2cc3cccc(OC[C@@H]4CO4)c3o2)o1
Yield: 79.6 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(7-hydroxybenzo(b)furan-2-yl)-5-methyloxazole (2.0 g) obtained in Starting Material Synthesis Example 65 and (S)-glycidyl nosylate (1.8 g), (S)-7-glycidyloxy-2-(5-methyloxazol-2-yl)benzo(b)furan (1.5 g) was obtained. Then, by the reactions in the same manner as in Example 1 using 4-(naphthalen-2-yl)piperidine (0.7 g), the title compound (0.26 g) was obtained, melting point 147–149° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13]>>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([C:4]([NH2:5])=[N:12][NH:13]2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: N#Cc1ccc(F)cc1F
Solvent: O
Product: Nc1n[nH]c2cc(F)ccc12
Yield: 37.9 %

Procedure:
To 2,4-difluorobenzonitrile (1.21 g, 8.70 mmol) was added hydrazine monohydrate (8.46 mL, 174 mmol). The mixture was heated to reflux for 5 hours and then poured onto ice. The solution was extracted with ethyl acetate, dried with magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (25-100% ethyl acetate/hexane) to afford 6-fluoro-1H-indazol-3-amine (0.5 g, 3.3 mmol, 38% yield) as light yellow powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 11.42 (s, 1H), 7.70 (dd, J=8.55, 5.49 Hz, 1H), 6.97 (dd, J=10.07, 1.83 Hz, 1H), 6.72-6.79 (m, 1H), 5.40 (s, 2H). MS (LC/MS) R.T.=0.61; [M+H]+=152.11.
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:15])[N:6]=1)[NH2:4].C(N(CC)CC)C.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=O>C(O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24](=[N:4][NH:3][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=[C:7]([CH3:15])[N:6]=2)[CH3:23])=[CH:27][CH:28]=1
Reactant: Cc1nc(NN)c2ccccc2n1
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)=NNc2nc(C)nc3ccccc23)cc1
Yield: 40.8 %

Procedure:
To a solution of 4-hydrazino-2-methylquinazoline dihydrochloride (100 mg, 0.40 mmol) and triethylamine (0.14 mL, 0.81 mmol) in ethanol (3 mL) was added 61 mg (0.4 mmol) of 4-methoxyacetophenone. The resultant solution was refluxed overnight and the resultant reaction mixture was absorbed directly on Si gel. Purification by automated Si gel chromatography (gradient 100% hexanes to 100% ethyl acetate) on the Flashmaster II was performed yielding 50 mg (36%) of the titled compound as a bright yellow solid. HPLC Purity: 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](=O)[NH:7][C:6]=2[CH:16]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([Cl:18])=[N:7][C:6]=2[CH:16]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1Nc2cc(Cl)ccc2Oc2cscc21
Solvent: Cc1ccccc1
Product: ClC1=Nc2cc(Cl)ccc2Oc2cscc21

Procedure:
A 1.0 g. portion of 7-chloro-thieno[3,4-b][1,5]benzoxazepin-10(9H)-one (Example 4) and 1.0 g. of phosphorus pentachloride in 25 ml. of toluene are reacted as described in Example 1, giving 7,10-dichloro-thieno[3,4-b][1,5]benzoxazepine.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][NH:4][C:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:7])[CH3:6].[CH3:15]CN(CC)CC.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.O>ClCCl>[CH3:15][CH2:1][CH2:2][CH2:3][NH:4][C:5]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:7])[CH3:6]
Reactant: CCCNC(C)(C)CC1CCCCC1
Reactant: CCN(CC)CC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCCCNC(C)(C)Cc1ccccc1
Temperature: 25 °C
Yield: 134.6 %

Procedure:
To a solution of compound D-3-7 (100 g, 380 mmol) and Et3N (76.8 g, 760 mmol) in dichloromethane (1.5 L), cooled to 0° C., is added triflic anhydride (Tf2O) (107.0 g, 380 mmol) via an addition funnel. Upon complete addition of Tf2O the solution is then warmed to room temperature for 5 h. The reaction mixture is then treated with H2O and dichloromethane and the organic phase is separated. The organic phase is washed with brine and dried over anhydrous Na2SO4. The mixture is then filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (using 20:1 petroleum ether:EtOAc) to provide compound D-3-8 (105 g, 70% yield).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15].N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:12]3[CH2:18][CH2:17][CH2:16][C@H:13]3[CH2:14][OH:15])=[N:3][N:4]=2)[CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Fc1ccc2nnc(Cl)n2c1
Agent: N
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: OC[C@@H]1CCCN1c1nnc2ccc(F)cn12
Temperature: 160 °C
Yield: 51.1 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and L-prolinol (704 mg, 9.96 mmol) in NMP (4 mL) was heated in the microwave at 160° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (210 mg, 50%). LCMS (Method 4): Rt 1.50 min, m/z 237 [MH+].
Reaction SMILES: [O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+].[CH3:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[C:17]([CH3:19])[CH:18]=1.Cl[CH2:25]C(O)=O.[OH-].[Na+].Cl>O>[CH3:12][C:13]1[CH:14]=[C:15]([S:20]([CH3:25])(=[O:22])=[O:21])[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: O=C(O)CCl
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: Cc1cc(C)cc(S(C)(=O)=O)c1
Temperature: 135 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a stirring slurry of 3.2 g (25.4 mmol) of Na2SO3 and 6.2 g (73.8 mmol) of NaHCO3 in 20 mL of H2O at 75° C. was added 5.0 g (24.4 mmol) of 3,5-dimethylbenzene-1-sulfonyl chloride in several portions. After 2 h at 75° C., 3.5 g (37.0 mmol) of chloroacetic acid was added in portions followed by 1.5 g (37.5 mmol) of NaOH in 3 mL of H2O. The mixture was stirred at 135° C. for 13 h, and 3 N HCl was added to a pH=1. A colorless precipitate formed, and the mixture was filtered through a Buchner funnel to provide 3.8 g of 1,3-dimethyl-5-(methylsulfonyl)benzene in 84% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Clc1cc(-c2ccccc2)ncn1
Yield: 34 %

Procedure:
Into a recovery flask equipped with a reflux pipe, 3.35 g of 4,6-dichloropyrimidine, 3.02 g of phenylboronic acid, 1.7 mL of tricyclohexylphosphine (abbreviation: PCy3), 14.7 g of cesium carbonate, 0.31 g of tris(dibenzylideneacetone)dipalladium(0) (abbreviation: Pd2(dba)3), and 30 mL of dioxane were put, and the air in the flask was replaced by argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 120 W) for 60 minutes. The solvent of this reaction solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using a mixed solvent of dichloromethane and hexane as a developing solvent in a volume ratio of 1:1, to give 4-chloro-6-phenylpyrimidine (light yellow powder, 34% in yield). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). The synthesis scheme of Step 1 is shown by (a-1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH2:22][CH2:23][Cl:24])[CH2:19][CH2:20][Cl:21])=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:24][CH2:23][CH2:22][N:18]([CH2:19][CH2:20][Cl:21])[C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:27](=[O:28])[CH2:26][Cl:25])[CH:7]=[CH:6][CH:5]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Solvent: C1CCOC1
Product: O=C(CCl)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 46a (3.0 g, 8.0 mmol) in THF (100 mL), chloroacetyl chloride (2.2 g, 20 mmol) in THF (50 mL) was added dropwise at RT and the resulting mixture was stirred at RT for additional 45 minutes. The reaction mixture was evaporated under reduced pressure and the solid residue was triturated with saturated aqueous solution of NaHCO3 and then filtered. The solid was washed successfully with water and hexane, and dried to yield N-(3-(3-(4-(bis(2-chloroethyl)amino)-phenyl)ureido)phenyl)-2-chloroacetamide, 2.8 g (82%); mp 232-233° C. 1H NMR (DMSO-d6) δ: 2.80-2.83 (2H, t, J=5.9 Hz, CH2), 3.68-3.71 (8H, m, CH2), 3.86-3.89 (2H, t, J=5.9 Hz, CH2), 6.70-6.72 (2H, d, J=8.5 Hz, Ar—H), 7.14-7.30 (5H, m, Ar—H), 7.76 (1H, s, Ar—H), 8.46 (1H, brs, NH), 8.73 (1H, brs, NH), 10.04 (1H, brs, NH).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][P:7](=[O:14])([O:11]CC)[O:8][CH2:9][CH3:10].O.Cl>C(O)C.[OH-].[K+]>[CH2:9]([O:8][P:7]([CH2:6][C:5]1[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:19])([F:1])[F:18])[CH:4]=1)(=[O:11])[OH:14])[CH3:10]
Reactant: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(O)Cc1cccc(C(F)(F)F)c1
Yield: 94.8 %

Procedure:
The diethyl 3-trifluoromethylbenzylphosphonate (10.0 g, 34.0 mmol) was dissolved in a mixture of 300 mL of 75% aqueous ethanol and 18.9 g of KOH and the resultant mixture was heated at reflux for 3 hours. The reaction mixture was poured into H2O, acidified with hydrochloric acid, and extracted with CHCl3 (3×500 mL). The chloroform extract was dried with anhydrous Na2SO4 and evaporated to yield 8.64 g (94.7%) of white solid product, mp=48°-51° C.; D.C.I.M.S.[MH+, 269].