Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:11]1[C:2]([NH:1][S:38]([C:35]2[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=2)(=[O:40])=[O:39])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[O:21][CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C)cc2)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.04 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 0.953 g of 4-methyl-benzenesulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 4-(2-methoxy-phenoxy)-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-5-(toluene-4-sulphonylamino)-benzoate as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]3[C:18]4[C:23]([CH2:24][CH2:25][C:14]=23)=[CH:22][C:21]([CH:26]2[CH2:28][O:27]2)=[CH:20][CH:19]=4)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH2:32][C@H:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]1>CC(O)C.O1CCOCC1.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]3[C:18]4[C:23]([CH2:24][CH2:25][C:14]=23)=[CH:22][C:21]([CH:26]([OH:27])[CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]2)=[CH:20][CH:19]=4)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: CCOc1ccc(-c2onc3c2CCc2cc(C4CO4)ccc2-3)cc1OCC
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc3c(c2)CCc2c-3noc2-c2ccc(OCC)c(OCC)c2)C1
Temperature: 60 °C
Yield: 26.4 %

Procedure:
To 3-(3,4-diethoxyphenyl)-7-(oxiran-2-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 81A, 0.08 g, 0.212 mmol) in a mixture of 2-propanol (1 mL) and dioxane (1.000 mL) was added DMAP (5.18 mg, 0.042 mmol) followed by (S)-ethyl piperidine-3-carboxylate (0.033 mL, 0.212 mmol) at room temperature. The reaction mixture was heated at 60° C. (oil bath temp.) for 26 h, concentrated under reduced pressure, and purified by column chromatography using an ISCO setup (12 g, RediSep® silica gel column). The desired fractions were collected and concentrated to yield (0.03 g, 0.056 mmol, 26.5% yield) of the product as a diastereomeric mixture. The individual diastereomers were separated using a CHIRALCE1® OJ-H column under SFC conditions (25% MeOH with 0.1% diethylamine in CO2). Isomer 1 (7.7 mgs), retention time on chiral HPLC, 4.39 min; Isomer 2 (9 mgs), retention time on chiral HPLC, 6.15 min. The absolute stereochemistry at the carbon anchoring the secondary alcohol, of Isomer 1 and Isomer 2 was not determined.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5](=O)[CH:6]([CH3:8])[CH3:7])[CH3:2].[C:11](=[O:15])([O:13][CH3:14])[NH2:12].CC1C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:14][O:13][C:11]([NH:12][C:5](=[C:6]([CH3:8])[CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:10])=[O:15]
Reactant: COC(N)=O
Reactant: CCOC(=O)C(=O)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)C(NC(=O)OC)=C(C)C

Procedure:
A benzene solution (90 mL) of ethyl-3-methyl-2-oxobutanoate (4.03 g, 28.0 mmol), methyl carbamate (2.098 g, 28.0 mmol) and pyridine 4-methylbenzenesulfonate (0.70 g, 2.80 mmol) was heated to reflux in a round bottom flask equipped with a Dean-Stark trap and reflux condenser. After 44 hours of heating the mixture was cooled and then partitioned between ethyl acetate (50 mL) and brine (50 mL). The organic phase was washed with brine (2×50 mL) then dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (ethyl acetate-hexanes) to provide the title compound as an off white crystalline solid (1.487 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]([NH2:16])[C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.O=[C:23]([CH3:29])[C:24](OCC)=[O:25]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:9]2[CH:10]=[C:11]3[C:12](=[CH:13][CH:14]=2)[NH:15][C:24](=[O:25])[C:23]([CH3:29])=[N:16]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1N
Solvent: CO
Product: Cc1nc2cc(C(c3cccc(Cl)c3)n3ccnc3)ccc2[nH]c1=O
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
A mixture of 9.1 parts of 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine, 3.7 parts of ethyl 2-oxopropanoate and 160 parts of methanol was stirred for 30 minutes at reflux temperature. The reaction mixture was evaporated to dry. The residue was crystallized from a mixture of 36 parts of 2-propanone and 4 parts of methanol. After stirring for 30 minutes at room temperature, the precipitated product was filtered off (the filtrate was set aside) and recrystallized from a mixture of methanol and dichloromethane. The product was filtered off and dried, yielding 3 parts (28.1%) of 6-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-3-methyl-2(1H)-quinoxalinone; mp. 270.9° C. (comp. 73). The filtrate (see above) was evaporated and the residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in a mixture of 2-butanone and 2-propanone and the whole was allowed to stand for a few days. the precipitated product was filtered off and dried, yielding 1.4 parts (11.5%) of 7-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]-3-methyl-2(1H)-quinoxalinone hemihydrate; mp. 201.9° C. (comp. 81).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.I[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].CCCCCCCCCCCC>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([N:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([N:7]([C:8]5[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=5)[C:4]5[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=5)=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[CH:9][CH:10]=1
Reactant: Ic1ccc(-c2ccc(-c3ccc(I)cc3)cc2)cc1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(-c4ccc(N(c5ccc(C)cc5)c5ccc(C)cc5)cc4)cc3)cc2)cc1
Temperature: 205 °C
Reaction time: 30 h
Yield: 65.5 %

Procedure:
Di-p-tolylamine (12.8 g (0.065 mol)), 14.0 g (0.029 mol) of 4,4″-diiodo-p-terphenyl, 4.7 g (0.034 mol) of anhydrous potassium carbonate, 0.51 g (0.008 mol) of copper powder and 30 ml of n-dodecane were mixed, and heated up to 200 to 210° C. while introducing nitrogen gas, followed by stirring for 30 hours. After the termination of the reaction, the reaction product was extracted with 500 ml of toluene, and insoluble matter was removed by filtration. Then, the filtrate was concentrated to dryness. The resulting solid matter was purified by column chromatography (carrier: silica gel, eluent: toluene:hexane=1:2) to obtain 11.8 g of N,N,N′,N′-tetra-p-tolyl-4,4″-diamino-p-terphenyl (comparative compound No. 1) (yield: 65.7%, melting point: 232.5 to 233.5° C.).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:37]([O:39][CH3:40])=[O:38])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Oc1cccc(-c2nc(SC)nc3sc(C(=O)NC(C)(C)C)c(N)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) was dissolved in dry CH2Cl2 (5 ml). DIPEA (500 μl ) and methyl chloroformate (199 μl ) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H2O. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:8]2)[CH2:4][C@H:3]1[NH:14][C:15]1[C:16]2[N:17]([CH:24]=[C:25]([C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH:26]=2)[N:18]=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22].IC.[C:34](=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:1][C@@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:8]2)[CH2:4][C@H:3]1[NH:14][C:15]1[C:16]2[N:17]([CH:24]=[C:25]([C:27]3[N:28]=[N:29][N:30]([CH3:34])[N:31]=3)[CH:26]=2)[N:18]=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3nnn[nH]3)cc12
Agent: [K+]
Solvent: CI
Solvent: CN1CCCC1=O
Product: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3nnn(C)n3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the crude 4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)-6-(1H-tetrazol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 2, iodomethane (6.8 μl, 0.109 mmol) and potassium carbonate (23.2 mg, 0.168 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was stirred at room temperature for 2 h. Attempted purification by RP-HPLC gave impure product. The mixture was further purified by silica gel chromatography, eluting with 0 to 10% methanol in dichloromethane to give the title compound (4 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (d, J=7.3 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J=1.5 Hz, 1H), 7.40 (d, J=1.5 Hz, 1H), 5.91-5.90 (m, 1H), 4.40 (s, 3H), 4.28-4.05 (m, 1H), 3.35-3.13 (m, 4H), 2.93 (s, 3H), 2.90-2.75 (m, 1H), 2.62-2.55 (m, 1H), 2.46-2.30 (m, 1H), 1.66-1.54 (m, 1H), 1.39-1.29 (m, 1H), 1.08 (d, J=6.6 Hz, 3H); MS (ES+) m/z: 460.3 (M+H); LC retention time: 6.988 min (analytical HPLC Method E).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCO
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOC(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-trifluoromethylphenylacetic acid (150.0 g), n-octanol (130.0 g), p-toluenesulphonic acid (9.5 g) and benzene (800 ml) is refluxed for 7 hours with a Dean-Stark separator. The solution is washed with a 10% aqueous solution of sodium carbonate (3×500 ml) and with water (3×500 ml). After drying over magnesium sulphate, the solvent is evaporated in vacuo. The residue is distilled (95°-97°/2.10-2Torr) to yield n-octyl 3-trifluoromethylphenylacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8]2.[OH-:16].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[CH2:8][C@@H:7]([CH3:15])[C@H:6]([OH:16])[CH2:5]2
Reactant: [OH-]
Reactant: COc1ccc(OC)c2c1CC=C(C)C2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c2c1C[C@@H](C)[C@H](O)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4 (5.00 g, 24.5 mmol) in tetrahydrofuran (100 ml) was cooled to 0° C. and treated with 1 M borane-tetrahydrofuran complex (24.5 mL, 24.5 mmol) and the resulting solution was stirred at room temperature for 4 h. Then, 12 mL of 3 N NaOH solution was added slowly to the stirring reaction solution followed by the addition of 6 mL of 30% aqueous hydrogen peroxide. After stirring for 30 min, the resultant mixture was diluted with 500 mL of ethyl acetate and washed by brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated, and the residue was purified on silica gel (30% ethyl acetate\hexane) to give 5 as a white solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:46])([O:28][C:29]([F:45])([F:44])[C:30]([F:43])([F:42])[O:31][C:32]([F:41])([F:40])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:24]([F:27])([F:26])[F:25].BrCCCCBr>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([O:31][C:30]([F:42])([F:43])[C:29]([F:44])([F:45])[O:28][C:23]([F:22])([F:46])[C:24]([F:25])([F:27])[F:26])([F:41])[F:40])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: FC(F)(COCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Solvent: BrCCCCBr
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.995 g, 7.01 mmol) and 4-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromobutane (3.44 g, 7.36 mmol; prepared by combining 1,4-dibromobutane with 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethanol). The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with 15 volume percent ethyl acetate/hexane, to yield 4.12 g of purified product.
Reaction SMILES: CC1(C)O[CH:5]([N:7](C)[C:8](=[O:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16](=[O:18])[CH3:17])[CH2:4][O:3]1.FC(F)(F)[C:24](O)=[O:25]>ClCCl>[OH:3][CH:4]([CH2:24][OH:25])[CH2:5][NH:7][C:8](=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccccc1C(=O)N(C)C1COC(C)(C)O1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)NCC(O)CO
Reaction time: 0.5 h

Procedure:
The solution from 2-acetoxybenzoic acid 2,2-dimethyl-[1,3]dioxolan-4-yl-methylamide (184 mg, 0.63 mmol) in dichloromethane (5 ml) is treated with trifluoroacetic acid (1 ml). After 0.5 h at room temperature, the mixture is concentrated, the residue is taken up in toluene (10 ml) and the solution is concentrated. The residue is purified by column chromatography (dichloromethane/methanol=10/1). Yield: 132 mg.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH3:30][N:31]([CH2:33][CH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)[CH3:32].O>C1COCC1>[CH3:30][N:31]([CH2:33][CH:34]1[CH2:39][CH2:38][CH:37]([CH:2]=[O:3])[CH2:36][CH2:35]1)[CH3:32]
Reactant: CN(C)CC1CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1CCC(C=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (25.7 g, 75 mmole) was suspended in absolute THF (100 ml) under argon, potassium tert-butylate (8.42 g, 75 mmole) dissolved in absolute THF (70 ml) was added dropwise, and then stirred for 15 minutes at 0° C. The corresponding 4-[dimethylaminomethyl]-cyclohexanone 8 (50 mmole), dissolved in absolute THF (75 ml), was then added dropwise to the above solution and stirred overnight at RT. The mixture was hydrolysed by adding dropwise water (38 ml) and 6N HCL 112 ml) while cooling with iced water. After stirring for one hour at RT the mixture was extracted with ether (10×50 ml), the aqueous phase was adjusted to pH 11 with 5N NaOH, shaken with ethyl acetate (3×50 ml), dried over Na2SO4, and concentrated by evaporation in vacuo. The crude product was purified by flash chromatography with ethyl acetate/cyclohexane (1:1). As a rule two diastereomers were obtained in different ratios.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH2:18].Br[CH2:23][CH2:24][CH2:25][CH2:26]Br.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[N:18]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(N)CC2
Reactant: BrCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(N1CCCC1)CC2

Procedure:
1-(3-Chlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine (6 g, 19.88 mmol) was dissolved in acetonitrile (150 mL). 1,4-Dibromobutane (2.61 mL, 21.87 mmol) and triethylamine (6.1 mL, 43.7 mmol) were added and the reaction mixture heated under reflux for 3 h. The reaction mixture was poured on ice and extracted with dichloromethane. The combined organic extracts were successively washed with water and brine, dried (MgSO4) and the solvent was evaporated in vacuo. The crude product (6.6 g) was used for the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Cc1cc(Cl)ccn1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccnc(C)c2)cc1C=O
Temperature: 85 °C

Procedure:
A stirred suspension of 3-formyl-4-methoxybenzeneboronic acid (700 mg, 3.89 mmol), 4-chloro-2-picoline (494 mg, 3.89 mmol), potassium carbonate (1.45 g, 10.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (225 mg, 0.19 mmol) in 1,2-dimethoxyethane (14 mL) and water (5 mL) is degassed at RT with N2 for 15 minutes then warmed for 16 h at 85° C. The reaction mixture is then cooled to RT and 2 M HCl (15 mL) added. The aqueous layer is washed with TBME (15 mL) then basified to pH 10 with aqueous K2CO3 and extracted into EtOAc (3×50 mL); The combined organic phases are dried over Na2SO4 and the solvents removed in vacuo to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: ClCCCCCCBr
Product: CC(=O)c1cccc(OCCCCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 1-(3-hydroxyphenyl)ethanone and 1-bromo-6-chlorohexane.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([OH:14])[C:11]([OH:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1.Br[CH2:20][CH2:21]Br>CN(C=O)C.C(OCC)(=O)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[C:11]2[O:15][CH2:21][CH2:20][O:14][C:12]=2[CH:13]=1
Reactant: O=[N+]([O-])c1cc(F)cc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc2c1OCCO2
Reaction time: 2 h

Procedure:
K2CO3 (15.27 g, 110.6 mmol) was added to a solution of 5-fluoro-3-nitrobenzene-1,2-diol (5 g, 28.9 mmol) in DMF (35 mL) followed by the addition of 1,2-Dibromoethane (13.63 g, 6.25 mL, 72.5 mmol) and stirring was continued at 80° C. for 2 h. Reaction mixture was diluted with ethyl acetate, washed with cold water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by MPLC (silica gel, Mobile Phase: ethyl acetate in n-Hexane 0 to 5% as eluant) to afford 7-fluoro-5-nitro-2,3-dihydrobenzo[b][1,4]dioxine (Int-51) as pale yellow solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.3-7.2 (1H, dd), 6.9-6.8 (1H, dd), 4.4 (4H, s).
Reaction SMILES: [C:1]([O:5][SiH:6]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:17]([Si:19]([O:28][CH:29]([CH3:31])[CH3:30])([O:24][CH:25]([CH3:27])[CH3:26])[O:20][CH:21]([CH3:23])[CH3:22])=[CH2:18]>C1(C)C(C)=CC=CC=1>[C:8]([O:7][Si:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:18]=[CH:17][Si:19]([O:20][CH:21]([CH3:23])[CH3:22])([O:24][CH:25]([CH3:27])[CH3:26])[O:28][CH:29]([CH3:31])[CH3:30])([CH3:11])([CH3:10])[CH3:9]
Reactant: C=C[Si](OC(C)C)(OC(C)C)OC(C)C
Reactant: CC(C)(C)O[SiH](OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1C
Product: CC(C)O[Si](C=C[Si](OC(C)(C)C)(OC(C)(C)C)OC(C)(C)C)(OC(C)C)OC(C)C
Temperature: 225 °C

Procedure:
Into a 45 cc Parr bomb was added 2.5 g (0.010 mol) tritertbutoxysilane, 4.7 g (0.020 mol) vinyltriisopropoxysilane, 1.0 g xylene and 2000 ppm Ru3CO12 (29 mg) as a catalyst. The reaction was heated to 225° C. for 3 hours in a fluidized sand bath. A single product, 1-tritertbutoxysilyl-2-triisopropoxysilylethylene was formed.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]2[S:13][C:12]([C:14]([F:17])([F:16])[F:15])=[N:11][CH:10]=2)[C:6](=[O:18])[N:5]=[C:4](SC)[N:3]=1.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=2)=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:34][CH2:33][N:32]([C:4]3[N:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]4[S:13][C:12]([C:14]([F:17])([F:16])[F:15])=[N:11][CH:10]=4)[C:6](=[O:18])[N:5]=3)[CH2:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: CSc1nc(C)n(Cc2cnc(C(F)(F)F)s2)c(=O)n1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CC=C(c3ccc(F)cc3)CC2)nc(=O)n1Cc1cnc(C(F)(F)F)s1
Yield: 61.5 %

Procedure:
To a 1,4-dioxane solution (500 μL) of 6-methyl-4-(methylthio)-1-{[2-(trifluoromethyl)thiazol-5-yl]methyl}-1,3,5-triazin-2(1H)-one (38.7 mg, 0.120 mmol) synthesized in Reference Synthesis Example 374, 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (30.8 mg, 0.144 mmol) and N,N-diisopropylethylamine (41.1 μL, 0.240 mmol) were added and the resultant mixture was stirred under reflux by heating for 1 day. After the completion of the reaction, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→0/1) to obtain the title compound (33.3 mg, yield: 61%).