Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=O)(O)[O-].[Na+]>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:8](=[O:10])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH3:12])=[CH:21][CH:20]=1
Reactant: ClCCCCOc1ccccc1
Reactant: CCC(C(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(C(=O)c1ccc(OCCCCCl)cc1)c1ccccc1
Reaction time: 16 h
Yield: 94.2 %

Procedure:
To a stirred solution of 2-phenylbutyric acid (5.6 g, 34 mmol) in trifluoroacetic anhydrlde (20 ml) was added 4-chlorobutoxybenzene (7.5 g, 41 mmol). After 16 h, the mixture was poured into saturated sodium bicarbonate solution (250 ml), and extracted with ether (2×100 ml). The combined organic layers were dried (MgSO4), and concentrated in vacuo. The residues were purified by flash chromatography (silica; eluant:10-30% ethyl acetate in petrol) to give the title compound as an orange oil (10.6 g, 94% ).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13]([S-])(=[S:17])OCC.[K+]>N1C=CC=CC=1>[S:17]=[C:13]1[NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12]1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C

Procedure:
Methyl 4-amino-3-hydroxybenzoate (16.7 g, 100 mmol, Chemical Abstracts number 63435-16-5, available from Alfa Chemicals, 26 Parkridge Rd, Ward Hill, Mass. 01835-8099) and potassium O-ethyl carbonodithioate (20.8 g, 130 mmol) were combined in pyridine (100 mL) and refluxed for two hours. The reaction mixture was cooled to ambient temperature and the product was filtered, washed with water, and dried in a vacuum oven overnight at 45° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.87 (d, 3 H) 7.34 (d, J=8.33 Hz, 1 H) 7.92 (d, J=1.59 Hz, 1 H) 7.97 (dd, J=12.69, 1.59 Hz, 1 H); MS (ESI−)m/z 207.9 (M−H)−.
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N-:10]=[N+:11]=[N-:12].[Na+]>O>[C:1]([O:7][CH2:8][N:10]=[N+:11]=[N-:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=O)OCN=[N+]=[N-]
Temperature: 90 °C

Procedure:
Chloromethyl pivalate (1.93 ml, 12.9 mmol) and sodium azide (1.27 g, 19.3 mmol) were taken up in water (52 ml). The reaction mixture was heated to 90° C. for 22 hours. The reaction mixture was cooled to ambient temperature, and extracted with ethyl acetate three times. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.COCCOC.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>[Cl:22][C:4]1[C:3](=[CH:2][C:28]2[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=2)[CH:12]=[C:11]2[C:6](=[CH:7][CH:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)[CH:5]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Reactant: O=Cc1ccc(B(O)O)cc1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)C1C=c2cc(Cl)c(=Cc3ccc(C=O)cc3)cc2OC1C(F)(F)F
Temperature: 50 °C
Yield: 47.1 %

Procedure:
The ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (2.0 g, 5.0 mmol) and Pd(PPh3)4 (174 mg, 0.15 mmole) were mixed in DME (50 mL) and the mixture was heated at 50° C. for 10 min. The solution of 4-formylphenylboronic acid (1.12 g, 7.5 mmole) in EtOH/DME (1:1, 4 mL) was added to above mixture and followed by adding 2 M Na2CO3 (5 mL, 10 mmole). The mixture then was heated to 90° C. for overnight. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4 and filtered. The filtrate was concentrated to afford the crude product, which was purified by Biotage chromatography eluted with 5 to 10% EtOAc in hexane to give 1 g the desired product as a yellow solid (47%), which had suitable purity to use without fuirther purification.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16]O)(=[O:4])=[O:3].O=S(Cl)[Cl:20]>C(Cl)Cl>[Cl:20][CH2:16][C:8]1[N:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)CCn1c(CO)nc2ccccc21
Solvent: ClCCl
Product: CS(=O)(=O)CCn1c(CCl)nc2ccccc21
Yield: 33 %

Procedure:
To a solution of crude (1-(2-(methylsulfonyl)ethyl)-1H-benzo[d]imidazol-2-yl)methanol in DCM (30 mL) was added SOCl2 (5 mL). The mixture was heated to reflux and monitored by LCMS. After the reaction completed, the solvents was evaporated. The residue was redissolved in DCM (100 mL) and washed with saturated NaHCO3 (2×30 mL), dried over Na2SO4 and concentrated under vacuum to afford the crude product (600 mg, yield: 33%) as oil. MS obsd. (ESI+) [(M+H)+]: 273.1.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12](OCC)=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][OH:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 102.2 %

Procedure:
To a solution of ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate from Step 1 (3.31 g, 14.5 mmol) in Et2O (80 mL) at 0° C. under N2 was added LiAlH4 (1M in THF, 13.66 mL, 13.66 mmol) in 15 min. The resulting mixture was stirred at 0° C. for another 20 min and quenched by addition of saturated aqueous NH4Cl solution, extracted with EtOAc, dried over Na2SO4. Filtration and evaporation to dryness gave the alcohol as white solid (2.76 g, 100%). LC/MC: 187.1 (MH)+.
Reaction SMILES: O1CCCOC1C1N(C)C(C2SC3C(=NC=CC=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=3[F:32])C=2)=NC=1.[O:33]1[CH2:37][CH2:36][O:35][CH:34]1[C:38]1[CH:39]=[CH:40][C:41]([C:44]2[S:52][C:51]3[C:46](=[N:47][CH:48]=[CH:49][C:50]=3Cl)[CH:45]=2)=[N:42][CH:43]=1>>[O:33]1[CH2:37][CH2:36][O:35][CH:34]1[C:38]1[CH:39]=[CH:40][C:41]([C:44]2[S:52][C:51]3[C:46](=[N:47][CH:48]=[CH:49][C:50]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=3[F:32])[CH:45]=2)=[N:42][CH:43]=1
Reactant: Cn1c(C2OCCCO2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Yield: 72 %

Procedure:
Following the procedure described above for the synthesis of compound 41 (scheme 1) but substituting compound 40 for compound 137, title compound 138 was obtained in 72% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, J=1.8 Hz, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.49 (dd, J=10.4, 2.5 Hz, 1H), 8.47 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.23-8.21 (m, 1H), 8.00 (dd, J=8.2, 2.0 Hz, 1H), 7.73 (t, J=8.5 Hz, 1H), 6.99 (d, J=5.5 Hz, 1H), 5.89 (s, 1H), 4.12-4.06 (m, 2H), 4.04-3.98 (m, 2H). MS (m/z): 440.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:15])[N:11]([CH2:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cccc1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Cn2cccc(OCc3ccccc3)c2=O)cc1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a suspension of 3-benzyloxy-1H-pyridin-2-one (0.22 g, 1.1 mmol) from step A and Cs2CO3 (0.72 g, 2.2 mmol) in dry DMF (5 mL) was added 1-chloromethanesulfonyl-4-methyl-benzene (0.31 g, 1.54 mmol). The reaction mixture was heated at 95° C. overnight and then additional 1-chloromethanesulfonyl-4-methyl-benzene (0.22 g, 1.1 mmol) was added. The reaction mixture was stirred for another 18 h. After the usual work-up, the crude material was purified by chromatography (silica gel, 40% EtOAc/hexanes) to give the product. MS (EI) 370 (M+H)+.
Reaction SMILES: Br[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=1>C(#N)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][CH3:3])=[CH:13][N:12]=1
Reactant: CCBr
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(Br)nc1

Procedure:
2.51 g (22.99 mmol) 1-bromoethane and 1.99 g (14.37 mmol) K2CO3 are added to a mixture of 1.0 g (5.75 mmol) 2-bromo-5-hydroxypyridine in 100 mL ACN. The mixture is stirred at reflux over night. Then the reaction mixture is poured onto water and extracted with TBME. The organic layer is dried with Na2SO4 and the solvent is removed under vacuo. The residue is purified by column chromatography (silica gel, PE/EtOAC 1/1).
Reaction SMILES: [CH:1]([NH:4][C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].NC(N)=O.[CH2:12](Br)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)NC(N)=O
Reactant: CCCCBr
Agent: NC(N)=O
Product: CCCCNC(=O)NC(C)C
Yield: 58 %

Procedure:
N-butyl-N'-isopropylurea was prepared in a yield of 58% as described in Example 1, but using 2.04 g of N-isopropylurea (20 mmol) as the urea and 2.74 g of butylbromide (20 mmol) as the alkylating agent. 1H-NMR (CDCl3 ; 200 MHz; delta): 5.708 (t; 1H; butyl-NH; JCH2NH =5.5 Hz); 5.490 (d; 1H; isopropyl-NH; JCHNH =7.9 Hz), 3.858 (dq; 1H; isopropyl-CH; JCHNH =7.9 Hz; JCHCH3 =6.5 Hz); 3.135 (dse; 2H; butyl-N--CH2 ; JCH2NH =5.5 Hz; JCH2CH2 =6.7 Hz); 1.498-1.275 (m(tt and tq); 4H; butyl-CH2 --CH2); 1.122 (d; 6H; isopropyl-CH3 ; JCHCH3 = 6.5 Hz); 0.906 (t; 3H; butyl-CH3 ; JCH2CH3 =7.0 Hz) ppm.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][CH:13]([N:17]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH3:18])[CH2:12][C:11]=2[C:10]2[N:29]=[CH:30][CH:31]=[CH:32][C:9]1=2)(C)(C)C.CO.[OH-].[Na+].Cl>C1COCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:17]([CH3:18])[CH:13]2[CH2:14][CH2:15][C:16]3[N:8]([CH2:7][C:6]([OH:33])=[O:5])[C:9]4[CH:32]=[CH:31][CH:30]=[N:29][C:10]=4[C:11]=3[CH2:12]2)(=[O:20])=[O:21])=[CH:23][CH:24]=1
Reactant: CN(C1CCc2c(c3ncccc3n2CC(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C1CCc2c(c3ncccc3n2CC(=O)O)C1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 24 h
Yield: 10.6 %

Procedure:
A solution of {8-[(4-fluoro-benzenesulfonyl)-methyl-amino]-6,7,8,9-tetrahydro-pyrido[3,2-b]indol-5-yl}-acetic acid tert-butyl ester (43 mg, 0.9 mmol) was dissolved in THF (1 mL), MeOH (1 mL) and 1N NaOH (0.2 mL). After 24 hours, the reaction mixture was neutralized with 1N HCl and concentrated to afford 40 mg of {8-[(4-fluoro-benzenesulfonyl)-methyl-amino]-6,7,8,9-tetrahydro-pyrido[3,2-b]indol-5-yl}-acetic acid. Mass spectrometric data [M+H]+=418.
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH:16]2[O:28][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)cc3F)cc2)C(O)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccc(F)cc4F)cc3)cc21

Procedure:
Analogously to Method D, 0.600 g of tert-butyl 4-{4-[3-(2,4-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.391 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.17 (1:2 EtOAc-heptane); Rt=5.80.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:14]([C:11]2[CH:12]=[N:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][CH:10]=2)=[O:16])=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: O=C(O)c1cnc(Oc2ccccc2)nc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cnc(Oc3ccccc3)nc2)c(O)n1
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A solution of 2-phenoxypyrimidine-5-carboxylic acid (300 mg, 1.4 mmol) in dichloromethane (15.0 mL) was added N-hydroxybenzotriazole (270 mg, 2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (384 mg, 2 mmol), triethylamine (202 mg, 2 mmol). Then the mixture was stirred for 30 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (270 mg, 2 mmol) was added and the mixture was stirred at room temperature 24 hours. The mixture was washed with water (50 mL), and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulphate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, methanol/dichloromethane=1:20, 1% NH3) to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-phenoxypyrimidine-5-carboxamide (200 mg, 46%) as white solid. LRMS (M+H+) m/z: calcd 350.14. found 350. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, CD3OD): δ 8.93 (s, 2H), 7.46-7.16 (m, 5H), 6.10 (s, 1H), 4.48 (s, 2H), 2.35 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:19]1[C:20]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:21]=2[S:22](=[O:32])[C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:20]2[C:19]([O:1][C:2]3[CH:3]=[CH:4][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[S:22](=[O:32])[C:21]=2[CH:33]=1
Reactant: COc1ccc(C2=C(Br)c3ccc(OC)cc3S2=O)cc1
Reactant: CCOC(=O)/C(C)=C/c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of (E)-ethyl 3-(4-hydroxyphenyl)-2-methylacrylate (92 mg, 0.445 mmol) in DMF (2.0 mL) was added sodium hydride (60% suspension in oil, 17.79 mg, 0.445 mmol), the resulting mixture was allowed to stir for 30 min at room temperature. To the solution was added 3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (125 mg, 0.342 mmol) as a suspension in DMF (2.0 mL). The reaction was heated to 80° C. for 15 h. Upon completion the reaction was cooled to room temperature, quenched with water and extracted with EtOAc. The combined organic layers were then washed with water, sat. aq. NaHCO3, brine and then collected (phase separator) and concentrated in vacuo to afford the crude product. The crude material was purified by column chromatography (SiO2, 0-70% EtOAc/Heptane) to afford (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate (144 mg, 0.294 mmol, 86% yield). LC/MS (m/z, MH+): 491.3
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:25]2[CH2:24][CH2:23][CH:22]([N:21]([CH3:28])[C:19](=[O:20])[CH2:18][O:17][C:4]3[N:3]=[C:2]([CH3:1])[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:6]([CH3:16])[N:5]=3)[CH2:27][CH2:26]2)=[CH:32][CH:31]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: Fc1ccc(CBr)cc1
Product: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccc(F)cc3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 4-fluorobenzyl bromide in the same manner as in Example 32.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([CH2:6][N:7]([CH3:9])[CH3:8])=[CH2:5].CO[CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]([C:4]1([CH2:6][N:7]([CH3:9])[CH3:8])[CH2:5][CH2:13][N:14]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15]1)=[O:10]
Reactant: C=C(CN(C)C)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(CN(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.8 %

Procedure:
To a cold solution of 2-dimethylaminomethyl-acrylic acid methyl ester (0.266 g, 1.86 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzyl-amine (1.43 ml, 5.59 mmol) in dichloromethane (25 ml) was added at 0° C. trifluoroacetic acid (83 μl, 1.12 mmol). The resulting solution was warmed to room temperature and stirred for 72 hours. Saturated aq. NaHCO3 (60 ml) was added to the reaction mixture and stirred for 10 minutes. Diluted with dichloromethane (50 ml) and the organic layer was separated. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexanes (1:2) followed by CH2Cl2/MeOH/NH4OH (9/1/0.01) to give the title compound (400 mg, 78%).
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[C:10]1=[O:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F-].[NH4+]>C(OCC)(=O)C.CCCCCC>[CH3:1][C@H:2]([N:9]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)([CH2:14][CH2:15][OH:16])[C:10]1=[O:32])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](c1ccccc1)N1CCC(CCO[Si](C)(C)C(C)(C)C)(Cc2ccc(F)cc2)C1=O
Agent: [F-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@@H](c1ccccc1)N1CCC(CCO)(Cc2ccc(F)cc2)C1=O

Procedure:
Prepare by the method of Example 17.4 using 1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine (1.7 g, 3.73 mmol) and ammonium fluoride (0.83 g, 22.4 mmol) to give, after chromatography on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound as diastereomers: Rf=0.49 and 0.27 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:27](O)=[O:28]>>[CH:27]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:28]
Reactant: O=CO
Reactant: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1cccc(N)c1
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1cccc(NC=O)c1

Procedure:
2,6 g of cis-6-(3-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine are heated to 100° for 21/2 hours in 50 ml of 90% formic acid. The reaction solution is evaporated to dryness in a vacuum, the resulting residue is made alkaline with a dilute potash solution and this aqueous phase is extracted with methylene chloride. After drying and concentrating the organic phase by evaporation, the title compound is obtained as yellowish foam and crystallizes after the addition of acetone in the form of yellowish prisms having a melting point of 209°-210°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1.[OH-].[Na+]>[C:12]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of 4-(methylamino)benzoic acid (1.50 g) in THF (30 mL) and 1 mol/L aqueous sodium hydroxide solution (30 mL) was added dropwise benzoyl chloride (1.20 mL) under ice-cooling, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was adjusted to pH=1-2 by the addition of dilute hydrochloric acid, and extracted with ethyl acetate (50 mL×2). The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was washed with a chloroform/hexane mixture and collected by filtration to give the title compound (1.81 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:13][CH2:14][CH2:15][CH2:16][O:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCCBr)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-methoxy-4-nitrophenol (Intermediate 18 in EP-A-494623) (2.4 g), 1,3-dibromopropane (7.5 ml) and potassium carbonate (2.2 g) in DMF (30 ml) was stirred at room temperature for 24 h. The mixture was filtered and the filtrate was evaporated to dryness. The residue was treated with water and extracted with dichloromethane. The organic extract was then washed with 5% sodium hydroxide solution and brine, dried and concentrated in vacuo to give the title compound (3.5 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.ICS[C:20]1[NH:21][CH2:22][CH2:23][N:24]=1>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH:15][C:20]3[NH:24][CH2:23][CH2:22][N:21]=3)=[N:10][C:9]=2[CH3:16])=[CH:6][CH:7]=1
Reactant: ICSC1=NCCN1
Reactant: Cc1nc(NN)nnc1-c1ccc(Cl)cc1
Solvent: CCCCO
Product: Cc1nc(NNC2=NCCN2)nnc1-c1ccc(Cl)cc1
Yield: 17 %

Procedure:
A mixture of 6-(4-chlorophenyl)-3-hydrazino-5-methyl-1,2,4-triazine (7 g), 2-iodomethylthio-2-imidazoline (8.11 g) and n-butanol (50 ml) was refluxed for 3 hours with stirring. After cooling, the mixture was evaporated under reduced pressure and the residue was dissolved in 1N hydrochloric acid. The solution was washed with ethyl acetate and made alkaline with an aqueous solution of potassium carbonate. The resultant precipitates were collected by filtration, washed with water, dried and recrystallized from methanol and then from ethanol to give dark red crystals of 6-(4-chlorophenyl)-3-[2-(2-imidazolin-2-yl)hydrazino]-5-methyl-1,2,4-triazine (1.53 g), m.p. 230°~231° C. (decomp.).