Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.S(Cl)(Cl)=O.[NH3:26]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([NH2:26])=[O:21])=[CH:5]2
Reactant: N
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reaction time: 2 h

Procedure:
To a suspension, stirred at 20° C., of 2 g (6.96 mmol) of 5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxylic acid, prepared in step 1.1, in 80 mL of dry toluene are added 5.08 mL (69.62 mmol) of thionyl chloride. The reaction mixture is stirred for 2 hours at reflux and is then concentrated under reduced pressure. The resulting product is taken up in 10 mL of dichloromethane, and this solution is poured dropwise into a solution of 9.12 mL (69.62 mmol) of 30% aqueous ammonia. The reaction mixture is stirred for 14 hours at 20° C. After this time, a solid is collected by filtration, and is triturated in 50 mL of diisopropyl ether. After filtering off and drying under reduced pressure, 0.58 g of the expected product is collected.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([CH2:13][S:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([CH:13]([CH3:29])[S:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCSC2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCSC2C
Reaction time: 1.5 h
Yield: 11.2 %

Procedure:
To a stirred solution of ethyl 3-(benzyloxy)-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]thiazepine-2-carboxylate (0.180 g, 0.5 mmol) and iodomethane (0.62 mL, 10 mmol) in THF (5 mL) at −78 C was added 1M solution of LiHMDS (1 mL, 1 mmol) over 2 minutes. After 1.5 h, the reaction mixture was quenched with saturated aq. NH4Cl, diluted with EtOAc (50 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by Prep-HPLC to afford the desired product as orange solid (0.021 g, 11%). 1H NMR (500 MHz, CDCl3) δ: 7.48-7.46 (2H, m), 7.37-7.29 (3H, m), 5.24 (2H, s), 5.15 (1H, dd, J=13.9, 4.4 Hz), 4.33 (2H, q, J=7.0 Hz), 4.18 (1H, q, J=7.0 Hz), 3.62 (1H, dd, J=13.6, 12.1 Hz), 3.14-3.09 (1H, m), 2.77 (1H, dt, J=14.4, 4.2 Hz), 2.34-2.27 (1H, m), 1.91-1.82 (1H, m), 1.62 (3H, d, J=7.0 Hz), 1.30 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C19H23N2O4S: 375.1379; found: 375.1375.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH:21]=[O:22]>O1CCCC1.CCCCCC>[S:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[CH:21]([C:20]1[CH:23]=[C:16]([Br:15])[CH:17]=[CH:18][C:19]=1[F:24])[OH:22]
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1cc2ccccc2s1)c1cc(Br)ccc1F
Temperature: -17.799999237060547 °C
Reaction time: 0.67 h
Yield: 84.8 %

Procedure:
Into a tetrahydrofuran (100 liters) solution of benzo[b]thiophene (17.4 kg) was dropwise added a n-hexane solution (56.2 kg) of n-butyl lithium (15.08%) in an argon atmosphere at −24.2 to −13.5° C., followed by stirring at −22.1 to −13.5° C. for 40 minutes. Into this solution was dropwise added a tetrahydrofuran (18 liters) solution of 5-bromo-2-fluorobenzaldehyde (25.5 kg) at −22.1 to −11.8° C., followed by stirring at −23.5 to −16.1° C. for 2 hours. To the reaction mixture were added water (100 liters), toluene (130 liters) and 38% hydrochloric acid (12.3 kg), and extraction was conducted. The organic layer was washed with water (130 liters) and then subjected to distillation at normal pressure to distill off the solvent until the residue became 100 liters. Toluene (130 liters) was added to the residue and the mixture was subjected to distillation at normal pressure to distil off the solvent until the residue became 100 liters. The operation of adding toluene to the residue and subjecting the mixture to distillation under reduced pressure to distill off the solvent, was repeated twice: Then, n-heptane (310 liters) was added to the residue, followed by heating to dissolve the residue. To the solution was added, as a seed crystal, about 26 g of the 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol produced in the same manner as that shown in the first step of Reference Example 1, followed by stirring at 1.2 to 5.0° C. for 13 hours. The separated-out crystals were collected by filtration, washed twice with a toluene-n-heptane (1:6) mixed solvent (26 liters), and subjected to vacuum drying to obtain, as white crystals, 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol [35.91 kg, yield: 84.8%, purity: 99% (HPLC)].
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: BrCc1cccc2ccccc12
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.5 g, 1.688 mmol), prepared as described in example 1, in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)naphthalene (0.448 g, 2.026 mmol) and potassium carbonate (0.700 g, 5.06 mmol). The resulting reaction mixture was stirred at 80° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (0.53 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57 (s, 3H) 2.97-3.13 (m, 4H) 3.61-3.89 (m, 4H) 5.76 (s, 2H) 6.53 (dd, J=7.07, 1.01 Hz, 1H) 6.56 (d, J=2.02 Hz, 1H) 7.17 (d, J=2.02 Hz, 1H) 7.32 (m, 1H) 7.58-7.73 (m, 2H) 7.83 (m, 1H) 7.98 (m, 1H) 8.08 (d, J=8.06 Hz, 1H); MS (ES+) m/e 436.1 [M+H]+.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[CH:16]1>>[NH2:26][C:19]1[C:18]2[N:17]=[CH:16][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: Cc1nc(N)c2ncn(CCCCN)c2c1C
Reactant: O=C(Cl)N1CCOCC1
Product: Cc1nc(N)c2ncn(CCCCNC(=O)N3CCOCC3)c2c1C

Procedure:
Using the method of Examples 16-26, 4-morpholinecarbonyl chloride was reacted with 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 347.2214.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23]C=1>>[CH:24]1([CH2:23][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([N:12]4[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]4)=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:25][CH2:26][CH2:21][CH2:27]1
Reactant: Cc1ccccc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(ccn3CC3CCCC3)c2)CC1
Temperature: 110 °C

Procedure:
A mixture of 21.7 mg (0.08 mmol) (1H-indol-5-yl)-(4-isopropyl-piperazin-1-yl)-methanone (intermediate 1), 16 mg (0.16 mmol) cyclopentylmethynol (commercially available), 38.6 mg (0.16 mmol) cyanomethylenetri-n-butylphospborane in toluene was heated to 110° C. for an extended period of time. After evaporation the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. The combined product fractions were evaporated to yield 5.4 mg of the title compound. MS (m/e): 354.4 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:25]1([CH3:31])[CH:30]=C[CH:28]=[CH:27][CH:26]=1.C1C[O:35]CC1>CN(C)C=O>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:28][CH:27]([OH:35])[CH2:26][CH:25]([CH3:31])[CH3:30])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Reactant: C1CCOC1
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2ccc(OCC(O)CC(C)C)cc2)cc1
Temperature: 60 °C

Procedure:
THF (20 ml) was added to sodium hydride (55%) (1.7 g) and the solution was cooled, followed by adding to the solution, a solution of 4'-hydroxy-4-octyloxy-biphenyl (8 g) in THF (100 ml), successively adding a solution of 2S-2-(2'-tetrahydropyranyloxy)-4-methyl-pentyl-p-toluenesulfonate (10 g) obtained above in the item 2 in N,N-dimethylformamide (hereinafter abbreviated to DMF) (200 ml), heating the mixture at 80°-90° C. for 8 hours, cooling the resulting material, adding toluene (300 ml), washing with water, then with an alkali and further with water, concentrating, purifying the concentrate according to column chromatography using a column having activated alumina filled therein and using toluene as an eluent, concentrating the resulting elute, adding ethanol (300 ml), further adding 12M+HCl (5 ml), heating the mixture at 60° C. for 2 hours, cooling, filtering off the resulting solids, and recrystallizing from a mixed solution of ethanol with ethyl acetate to obtain S -1-(4'-octyloxy-4-biphenylyloxy)-4-methylpentan-2-ol ([α]D24 +8.2 (C 0.54, CHCl3)) (8 g). This product exhibited phase transition points of C 95° C. (S5.58° C.), S4.103° C., S3.113.1° C., S2.113.6° C., S1.115.6° C., SA.119.5° C. and I wherein C represents crystalline phase; I , isotropic liquid phase; SA, smectic A phase; S1 -S5, smectic phases whose attributions are at present unknown; and (), monotropic phase.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=C=O)=[CH:35][CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[F:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:6]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10]2)=[O:7])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccnc3cc(Cl)ccc23)C1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)NC1CCN(c2ccnc3cc(Cl)ccc23)C1

Procedure:
A solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin1-yl]-7-chloroquinoline (214 mg, 0.62 mmol) in CH2Cl2 (5 mL) is treated with trifluoroacetic acid (1 mL). After 1 h the reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (10 mL), and 4-fluorophenyl isocyanate (70 μL, 0.62 mmol) and triethylamine (1 mL) are added. The reaction mixture is concentrated, and the residue is purified by column chromatography and an aqueous work-up step yielding the title product.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH2:18])=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH:24](Br)[C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1.O>CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([N:18]4[CH2:31][C:26]5[C:25](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:24]4)=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1C(Br)Br
Reactant: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1Cc2ccccc2C1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under N2. The mixture was heated to 65° C. for 3 hours. α,α-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 70° C. for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1%CH3OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184°-185° C.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.BrBr.C1C(=O)N([Br:30])C(=O)C1>C(#N)C>[Br:30][C:13]1[C:8]([O:7][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=1
Reactant: CCOC(=O)CCc1ccc(OCC2CCCC2)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Solvent: CC#N
Product: CCOC(=O)CCc1cnc(OCC2CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A solution of Intermediate 31 (5.20 g) in acetonitrile (50 ml) was warmed to 35° C., added dropwise with bromine (1.1 ml, WAKO), then added with NBS (3.72 g), and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, then added with ethyl acetate (200 ml), and washed successively with saturated aqueous ammonium chloride, 5% aqueous sodium sulfite, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Compound No. E-1, 6.51 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CCCCO>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2cc(Cl)ncn2)cc1
Yield: 91.5 %

Procedure:
A mixture of 4,6-dichloropyrimidine (Aldrich, 3.6 g, 24.2 mmol), 4-methoxybenzylamine (2.7 g, 19.7 mmol), DIPEA (5 ml, 28.8 mmol), and n-BuOH was heated at reflux for 3 h. The mixture was concentrated and the residue treated with H2O (150 mL) and EtOAc (175 mL). The EtOAc phase was separated, washed with saturated aq. NaHCO3 solution and brine, dried (MgSO4), and concentrated to give the title compound (4.5 g) which was used without further purification. 1H NMR (DMSO-d6) δ 8.29 (s, 1H), 8.13 (br s, 1H), 7.25 (d, 2H, J=8.2 Hz), 6.90 (d, 2H, J=8.2 Hz), 6.56 (s, 1H), 4.48 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=2[Cl:23])=[CH:10][CH:9]=1>>[Cl:19][C:18]1[CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=[C:14]([Cl:23])[C:13]=1[O:12][C:11]1[CH:24]=[CH:25][C:8]([O:7][CH3:6])=[C:9]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:10]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To cooled chlorosulfonic acid (2.0 mL) at 0° C. was added 4-(4-methoxy-phenoxy)-3,5-dichloro-nitrobenzene (700 mg, 2.2 mmol) in several portions. The resulting mixture was stirred at 0° C. for 5 min, then at RT for 2.5 h. The solution was added dropwise to ice water (40 mL) and the product was extracted with EtOAc (3×50 mL). The combined organic extracts were dried and concentrated to yield the title compound of Step A (920 mg) as a crude product which was used in the next step without purification. MS (APCl−) Calc.: 410.9, Found: 392.1 (M−1-Cl+OH, sulfonic acid).
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH2:7])(=[O:6])=[O:5])[CH3:3].CN(C)C=O.[H-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([N:23]=[C:24]=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24]([NH:7][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC(C)S(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
2-propanesulfonamide (4.40 g) was combined with THF (150 ml) and then dimethylformamide (40 ml) and sodium hydride (2.1 g) were added and the mixture stirred two hours at room temperature. To the mixture was added 3,4-dichlorophenyl isocyanate (7.52 g) in THF (50 ml) and the mixture stirred overnight. The solvent was removed under vacuum, water was added and the mixture filtered. The filtrate was evaporated and then more water introduced when crystals did not form. The solution was made acidic and stirred overnight. The precipitated solid was recovered by filtration. Recrystallization from toluene provided 4.9 g of product with a melting point 151-4° C.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:31][CH2:30][CH2:29][C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCc1ccncc1
Product: CCCc1c(OCCCCCC(=O)NCCc2ccncc2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid was allowed to react with 4-pyridine ethanamine according to procedure A and the product was purified by chromatography on silica gel to give 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[2-(4-pyridinyl)ethyl]hexanamide, the title compound, mp 80°-83° (from methylene chloride-ether) in 58% yield.
Reaction SMILES: N.[CH3:2][O:3][C:4]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:9]([C@H:10]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:13]3([CH2:17][CH:16]([OH:18])[CH2:15][O:14]3)[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=1.O1CCCC1.[Li]>CO.CC(C)(O)C>[CH3:2][O:3][C:4]1[CH2:5][C:6]2[CH2:7][CH2:8][C@@H:9]3[C@@H:23]([C:24]=2[CH2:25][CH:26]=1)[CH2:22][CH2:21][C@@:19]1([CH3:20])[C@H:10]3[CH2:11][CH2:12][C:13]21[CH2:17][CH:16]([OH:18])[CH2:15][O:14]2
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21CC(O)CO1
Agent: N
Agent: [Li]
Solvent: CO
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC23CC(O)CO3)C1
Reaction time: 0.75 h

Procedure:
To 122 parts of liquid ammonia under reflux is added, with vigorous agitation, a solution of 3 parts of 4',5'-dihydro-3-methoxyspiro[estra-1,3,5(10)-triene 17,2'(3'H)-furan]-4'-ol in a mixture of 81 parts of tetrahydrofuran and 72 parts of 1,1-dimethylethanol, followed -- portionwise -- by 2 parts of lithium wire cut into small pieces. Approximately 2 hours later, 5 parts of methanol is slowly introduced. After an additional 45 minutes, the blue color originally characteristic of the reaction mixture has disappeared, at which point the ammonia is allowed to evaporate and 500 parts of water is added to the residue. The precipitate which forms is filtered off, washed with water, dried in air, and recrystallized from ethyl acetate to give 4',5'-dihydro-3-methoxyspiro[estra-2,5(10)-diene-17,2'(3'H)-furan]-4'-ol melting at 152°-155°.
Reaction SMILES: [Cl-].[NH4+].[NH2:3][C:4]1[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]>[Fe].C(O)C.O>[NH2:3][C:4]1[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: Nc1c(C(=O)OCc2ccccc2)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(C(=O)OCc2ccccc2)c1N
Yield: 97.6 %

Procedure:
Iron powder (0.78 g) and ammonium chloride (0.15 g) were added in that order to an ethanol/water (4/1) solution (40 mL) of benzyl 2-amino-3-nitrobenzoate (0.38 g), and this was heated under reflux for 20 minutes with vigorous stirring. The insoluble matter was separated by filtration while hot, and the filtrate was evaporated under reduced pressure to about ⅕, and then aqueous sodium hydrogencarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried, and evaporated under reduced pressure to obtain benzyl 2,3-diaminobenzoate (0.33 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:24])=O>CN(C)C=O>[Cl:24][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[N:20]=1
Reactant: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2nc(Cl)c3ccccc3n2)cc1

Procedure:
A mixture of 8.9 g of 2-(4-tert-butylphenyl)quinazolin-4(3H)-one and 60 ml of thionyl chloride was treated with 2.34 g of dimethylformamide as described in Example VI. The initial solid was triturated with cyclohexane, filtered, and the filtrate concentrated to give an oil which solidified on standing to give a solid, m.p. 74°-77°. This solid was recrystallized twice from petroleum ether (30°-60° fraction) using a low-temperature recrystallization apparatus to give 6.3 g of 4-chloro-2-(4-tert-butylphenyl)quinazoline, m.p. 75°-76.5°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22](OC)=[O:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH3:28]>CO>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]([NH2:28])=[O:23])=[CH:21][C:13]2=3)(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Reactant: N
Solvent: CO
Product: NC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Reaction time: 72 h
Yield: 100 %

Procedure:
A solution of methyl 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (500 mg, 1.243 mmol) in 7 M NH3 in MeOH (10 mL) was heated to 60° C. and stirred at that temperature for 72 h. The solvent was removed under reduced pressure to provide 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide (481 mg, 1.243 mmol, 100% yield) as a white solid. LCMS (+ESI) m/z=388.1 [M+H]+.