Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[Cl:12])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]([NH2:30])=[S:29])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1.C(OCC)C>C(O)C>[Cl:12][C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[C:3]1[N:30]=[C:28]([NH:27][C:17]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:15]([O:14][CH3:13])[CH:16]=2)[S:29][CH:2]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C(CBr)c1cc(Cl)ccc1Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(Nc2nc(-c3cc(Cl)ccc3Cl)cs2)ccc1-n1cnc(C)c1
Yield: 100.5 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 89 mg (0.33 mmol) 2-bromo-1-(2,5-dichlorophenyl)ethanone and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was stirred with diethyl ether and little ethanol to yield 130 mg (100%) [4-(2,5-dichloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow solid. MS ISP (m/e): 431.2/433.0 (100/66) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.80 (s, 1H), 9.29 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.61 (d, 1H), 7.51 (d, 1H), 7.45 (d, 1H), 7.15 (d, 1H), 3.93 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:31]=[C:17]2[N:18]=[C:19]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1.CCN(CC)CC>CC#N>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:31]=[C:17]2[N:18]=[C:19]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][C:3]4[CH:7]=[C:6]([CH3:8])[O:5][N:4]=4)[CH2:26]3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1
Reactant: Nc1nc(NCC2CCCNC2)nc2nc(-c3ccco3)nn12
Reactant: Cc1cc(CCl)no1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(CN2CCCC(CNc3nc(N)n4nc(-c5ccco5)nc4n3)C2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 2-furan-2-yl-N5-piperidin-3-ylmethyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine (0.14 mmol) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.90 (br s, 2H), 7.80 (d, J=1.0 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.30 (s, 1H), 3.65 (m, 2H), 3.20-2.75 (m, 11 H), 2.35 (s, 3H) ppm. MS: m/z: 410 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3ccccc3)CC1)O2

Procedure:
Compound 130 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (bromomethyl)benzene and conditions outlined in procedure V. M.p.=170-172° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.9 (d, 1H), 7.8-7.7 (m, 2H), 7.55 (t, 1H), 7.35-7.2 (m, 5H), 3.55 (s, 2H), 3.05 (s, 2H), 2.7 (d, 2H), 2.35 (t, 2H), 1.95 (d, 2H), 1.8 (t, 2H); LCMS: 392 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[NH:19])=[CH:4][CH:3]=1.[Cl:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28]Cl)[N:27]=1.[Br-].[K+]>CC(=O)CC>[Cl:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=3)[C:11]2=[NH:19])[N:27]=1
Reactant: ClCc1csc(Cl)n1
Reactant: N=c1[nH]c2ccccc2n1CCCOc1ccc(F)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1csc(Cl)n1
Temperature: 95 °C
Reaction time: 22 h
Yield: 61 %

Procedure:
To a solution of 1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (2.89 g, 10.1 mmol) in 2-butanone (58 ml) at rt was added 2-chloro-4-chloromethyl-thiazole (2.55 g, 15.2 mmol) followed by potassium bromide (1.20 g, 10.1 mmol). The reaction mixture was heated to 95° C. where it was maintained for 32 h. After this time, the reaction was cooled to rt and additional potassium bromide (0.30 g, 2.52 mmol) was introduced. The reaction was stirred for a further 22 h at 90° C. and then it was cooled to rt and filtered. The collected solid was partitioned between dichloromethane and a saturated solution of NaHCO3 (50 ml) and the organic layer was separated. The aqueous phase was extracted with additional dichloromethane (×1) and the combined organic fractions were washed with H2O, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1-(2-chloro-thiazol-4-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine as a brown oil (2.57 g, 61%). HPLC-MS 417 [M+1]+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1F.Cl>CS(C)=O>[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[CH:5]([C:3]#[N:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)c1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 6.13 g) in dimethyl sulfoxide (100 mL) was added ethyl cyanoacetate (18.0 g) at 0° C., and the mixture was stirred at room temperature for 2 hours. 2-Methyl-4-nitrofluorobenzene (9.15 g) was added to the mixture, and the resulting solution was stirred at room temperature for 12 hours. After quenching the reaction by the addition of 6 N hydrochloric acid at 0° C., and the mixture was extracted with ether. The ethereal solution was washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo to give ethyl (2-methyl-4-nitrophenyl)cyanoacetate. A solution of crude ethyl (2-methyl-4-nitrophenyl)cyanoacetate thus obtained in dioxane (200 mL) and 6 N hydrochloric acid (200 mL) was heated at 100° C. for 12 hours. After dilution of the mixture with water and sodium chloride, the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=2:1) of the residue gave (2-methyl-4-nitrophenyl)acetonitrile (5.32 g).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=C)=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CC[O+:35]([O-])CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[O:35])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Reactant: CN1CC[O+]([O-])CC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a stirred solution of 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydronaphtho[2,1-d]oxazole (Preparation 48B, 26.2 mg, 0.064 mmol) in 0.5 mL of THF were added 0.113 mL of 10% N-methyl-morpholine-1-oxide in water and 0.04 mL of 4% OsO4 in water, and 0.2 mL of water. The heterogeneous mixture was stirred at room temperature for 18 hrs. To the homogenous reaction mixture was added 0.14 mL of 10% sodium periodate in water, and the mixture was stirred for 3 hrs. The reaction mixture was extracted with EtOAc, washed with water, brine dried over Na2SO4 and evaporated to give a solid residue which was purified by Combiflash (24 g silica gel) eluting with 1:9 followed by 3:7 EtOAc-hexane to give 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazole-7-carbaldehyde (20.2 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.69 (1H, s), 7.51-7.61 (2H, m), 7.44 (1H, d, J=7.70 Hz), 7.36 (2H, d, J=7.70 Hz), 7.22-7.30 (3H, m), 2.99-3.05 (2H, m), 2.83 (2H, t, J=8.03 Hz).
Reaction SMILES: [N:1]([C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:5]=1[F:30])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:13]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:5]=1[F:30]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(SCc2ccccc2)c(N)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of methyl 4-azido-5-(benzylthio)-3-fluoro-2-((2-fluoro phenyl)amino)benzoate (19.43 g, 45.56 mmol) in MeOH (500 mL) was added and 10% palladium on carbon (3.40 g) under nitrogen atmosphere. Then the nitrogen atmosphere was completely changed to hydrogen atmosphere. The mixture was stirred for 3 h at ambient temperature. After the insoluble matter was filtered off, the solvent was evaporated in vacuo to give the desired product (18.06 g, 99.0%). 1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 7.78 (s, 1H), 7.11 (m, 9H), 4.65 (s, 2H), 3.88 (s, 2H), 3.84 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:29])=[CH:26][CH:25]=1
Reactant: OC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccc(Cl)cc2)CC1)c1ccc(Cl)cc1
Yield: 76.9 %

Procedure:
0.226 g (0.001 mol) of 1-(4-chloro-benzyl)-piperidin-4-ol and 0.350 ml (0.0025 mol) of triethylamine were dissolved in 10 ml of toluene, treated with 0.16 ml (0.00125 mol) of 4-chloro-benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.28 g (77%) of 1-(4-chloro-benzyl)-piperidin-4-yl 4-chloro-benzoate was obtained as colorless crystals; m.p. 67°-69°.
Reaction SMILES: Br[CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[SH:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[S:9][CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8]
Reactant: Sc1nc2ccccc2o1
Reactant: O=C1NC(=O)C(Br)S1
Product: O=C1NC(=O)C(Sc2nc3ccccc3o2)S1

Procedure:
This compound was prepared from 5-bromo-thiazolidine-2,4-dione and 2-mercaptobenzoxazole according to the procedure described in Example 5: mp 241-243 (dec).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)[C:5]([NH:16][CH:17]=O)=[C:4]([Cl:19])[N:3]=1.C(OC(OCC)OCC)C.Cl>CO.[OH-].[Na+]>[ClH:19].[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([N:16]=[CH:17][N:8]2[C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH:11]=[CH:10]2)=[C:4]([Cl:19])[N:3]=1
Reactant: Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(OCC)OCC
Solvent: CO
Product: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reaction time: 4 h
Yield: 184.4 %

Procedure:
A mixture of (1S,4R)-4-[(2-amino-6-chloro-5-formamido-4-pyrimidinyl)amino]-2-cyclopentene-1-methanol (Example 7, 1.00 g, 3.50 mmol) and triethylorthoformate (Aldrich, Sure Seal, 18 mL) was stirred while concentrated hydrochloric acid (37%, 1.25 mL) was added in one portion. The resulting clear, colorless solution was stirred under nitrogen. A white precipitate began to form after 15 minutes. After 4 hours, TLC of a drop of the reaction mixture dissolved in methanol and neutralized with sodium hydroxide (silica gel plates developed in 10% methanol-chloroform, visualized in UV light) showed almost complete conversion of VIa to a higher-Rf material. The precipitate was filtered, washed with t-butyl methyl ether (15 mL) and dried at 0.2 mm Hg/25° C. for 18 hours to give the title compound as a white powder (975 mg, 92%), m.p.>300° C. dec.; mass spectrum (CI/CH4): 266(M+1); 1H-NMR (DMSO-d6)δ: 8.18 (s, 1, purine CH), 7.2-6.7 (br s, NH2, OH overlapped by water), 6.20 and 5.90 (both m, 1 each, CH=CH), 5.48 (m, 1, NCH), 3.47 (d, J=5.7 Hz, 2, CH2O), 2.90 (m, 1, CH), 2.75-2.55 and 1.75-1.60 (both m, 1 each, CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[CH3:22][O:23][C:24](=[O:27])[CH2:25][NH2:26].CN1CCCC1=O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:26][CH2:25][C:24]([O:23][CH3:22])=[O:27])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Reactant: COC(=O)CN
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Temperature: 80 °C

Procedure:
A mixture of ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (0.224 g, 0.761 mmol), glycine methyl ester hydrochloride (0.115 g, 0.914 mmol, 99% Aldrich), 1-methyl-2-pyrrolidinone (1.5 mL), and TEA (0.32 mL, 2.28 mmol) was heated at 80° C. for 4 hours. The resulting mixture was cooled to room temperature and treated with water (10 mL) causing a white solid to precipitate. The product was collected by vacuum filtration and rinsed with water. MS m/e=338.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:3]=1[O:4][CH2:5][C:6]1(O)[CH2:15][CH2:14][CH2:13][C:12]2[N:11]=[CH:10][N:9]=[CH:8][C:7]1=2.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[C:7]2[CH:8]=[N:9][CH:10]=[N:11][C:12]=2[CH2:13][CH2:14][CH:15]=1
Reactant: COc1ccc(Br)c(OCC2(O)CCCc3ncncc32)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Br)c(OCC2=CCCc3ncncc32)c1

Procedure:
A solution of 10 mmol of 5-(2-bromo-5-methoxyphenoxymethyl)-5,6,7,8-tetrahydroquinazolin-5-ol and 20 mmol of phosphorus oxychloride in 20 ml of pyridine is heated at reflux for 0.5-1 hour. The mixture is poured onto ice and extracted with tert-butyl methyl ether. The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60F) on the bias of the Rf value.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][C:14](N)=[O:15]>O>[Br:12][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([O:10][CH3:11])[CH:8]=1)[N:1]=[C:14]([OH:15])[N:13]=[CH:4]2
Reactant: COc1cc(Br)cc(C=O)c1N
Reactant: NC(N)=O
Solvent: O
Product: COc1cc(Br)cc2cnc(O)nc12
Temperature: 180 °C
Yield: 111 %

Procedure:
The mixture of 2-amino-5-bromo-3-methoxybenzaldehyde (43.96 mmol, crude material from step 3) and urea (35 g, 583 mmol) from the previous step was heated to 180° C. under argon for 1 hour. Water (300 mL) was added after cooling to room temperature. The solid was collected by filtration and air dried to give 12.45 g of powder. ES/MS m/z 254/256 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Li][CH2:13][CH2:14]CC.C(I)C>>[CH2:13]([C:9]1[S:8][C:7]2[CH:11]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=2[CH:10]=1)[CH3:14]
Reactant: COc1ccc2ccsc2c1
Reactant: [Li]CCCC
Solvent: CCI
Product: CCc1cc2ccc(O)cc2s1
Yield: 90 %

Procedure:
This material was prepared from 6-methoxybenzo[b]thiophene 1a (2.63 g, 16 mmole) by treatment with n-BuLi and ethyl iodide (7.80 g, 50 mmole) in a manner as previously described for example 1b to give a white solid (2.78 g, 90%). 1H NMR (DMSO-d6) δ 7.58 (1H, d, J=8.7 Hz), 7.44 (1H, d, J=2.3 Hz), 7.02 (1H, s), 6.92 (1H, dd, J=2.3, 8.7 Hz), 2.84 (2H, q, J=7.5 Hz), 1.27 (3H, t, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:21])[S:12][CH2:13][C:14](=O)[CH2:15][O:16]C(=O)C.Cl.S(=O)(=O)(O)O>C(O)C>[OH:16][CH2:15][C:14]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])[C:11](=[S:21])[S:12][CH:13]=1
Reactant: CC(=O)OCC(=O)CSC(=S)Nc1ccc(F)c(F)c1F
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: OCc1csc(=S)n1-c1ccc(F)c(F)c1F

Procedure:
That is, first the compound (VI) is obtained from the compound (V) in the same manner as in the process (a). The compound (VI) is then reacted with 1-acetoxy-3-halogenoacetone in an organic solvent such as chloroform, methylene chloride or a lower alcohol to give 3-acetoxy-2-oxopropyl N-(2,3,4-trifluorophenyl)dithiocarbamate (XVI). The compound (XVI) is then heated with an inorganic acid such as hydrochloric acid or sulfuric acid in a lower alcohol such as ethanol to give 4-hydroxymethyl-3-(2,3,4-trifluorophenyl)-2(3H)-1,3-thiazolethione (XVII). The compound (XVII) is then reacted with an inorganic base such as sodium hydride, potassium carbonate or sodium carbonate in an aprotic organic solvent such as N,N-dimethylformamide, acetonitrile or dioxane to give 6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazine-1-thione (XVIII). The compound (XVIII) is then reacted with a lower alkyl halide such as methyl iodide or ethyl iodide in a polar organic solvent such as N,N-dimethylformamide, acetonitrile or ethanol to give 6,7-difluoro-1-alkylthio-4H-[1,4]benzoxazino[4,3-c]thiazolium halide (XIX). The compound (XIX) is then reacted with di(lower alkyl) malonate sodium salt, which is prepared from di(lower alkyl) malonate and sodium hydride, in an organic solvent such as tetrahydrofuran or dioxane to give di(lower alkyl)(6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate (XI), which is treated in the same manner as in the process (a) to give the compound (II).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20]CC2C=CC(OC)=CC=2)=[CH:8][N:7]=1)(=[O:3])[CH3:2].C([SiH](CC)CC)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]([OH:20])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COc2cnc(COC(C)=O)cc2OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OCc1cc(OCc2ccccc2)c(O)cn1

Procedure:
A solution of {5-({[4-(methyloxy)phenyl]methyl}oxy)-4-[(phenylmethyl)oxy]-2-pyridinyl}methyl acetate (26.3 g, 67 mmol) in dichloromethane (700 ml) was treated with triethylsilane (10 ml, 62.6 mmol)and trifluoroacetic acid (35 ml). After 16 hours the mixture was evaporated and triturated with toluene/ethyl acetate (250 ml/5 ml) affording a white solid that was isolated by filtration and dried in vacuo (22.5 g).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=[CH:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:32]([N:26]1[CH2:27][CH:9]2[CH:8]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=[CH:11][C:10]2=[O:13])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)C=C1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12

Procedure:
Trifluoroacetic acid (2 drops) is added to a solution of 4,4-diphenyl-cyclohexa-2,5-dien-1-one (7.7 g) and N-butoxymethyl-N-trimethylsilylmethylbenzylamine (11 cc) in dry dichloromethane (80 cc) and the reaction mixture is refluxed for 1 hour and a half. Additional N-butoxymethyl-N-trimethylsilylmethylbenzylamine (5 cc) and trifluoroacetic acid (2 drops) are added and the reaction mixture is heated for 1 hour and a half. The reaction mixture is treated with potassium carbonate (3 g) and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropyl ether (15 cc). The crystals obtained are drained, washed with isopropyl ether (2×5 cc) and dried; (3aRS,7aRS)-2-benzyl-7,7-diphenyl-2,3,3a,4,7,7a-hexahydro-4-1H-isoindolone (4.4 g) melting at 132° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH2:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH2:30][CH3:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCO[C@@H]1CN(c2ncc(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 84.4 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (126b) (0.27 g, 0.59 mmol), 2 N lithium hydroxide (5 mL, 10 mmol), methanol (5 mL) and THF (5 mL), to obtain 0.22 g of the title compound as a colorless solid (87%).
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[N:16]1([CH2:22][CH2:23]Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCOCC.O>[C:3]1([CH:13]([CH2:23][CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1cccc2ccccc12
Reactant: ClCCN1CCCCC1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#CC(CCN1CCCCC1)c1cccc2ccccc12
Reaction time: 5 h

Procedure:
8.2 g of sodium amide are added in small quantities on a solution of 33.4 g of 1-naphthyl acetonitrile in 450 ml of anhydrous ether. The mixture is heated for 2 hours to reflux, then 29.5 g of 2-piperidino-1-chloroethane are added, a heating to reflux is repeated for 5 hours. The mixture is then cooled, poured in water, and the organic phase is extracted 3 times with 600 ml of hydrochloric acid at 10%. The aqueous phase is washed with ether and neutralized with soda at 30%. The decanting oil is extracted, washed with sodium chloride-saturated water and dried over magnesium sulphate. After evaporation of the solvent, the resulting oil is distilled under reduced pressure (vane pump).