Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)=[O:3].[CH3:11][C:12](C)([O-:14])C.[K+].C(OCC)(=O)C>C1COCC1>[Cl:10][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][C:12](=[O:14])[CH3:11])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 3-chloroacetophenone (1.30 mL, 10.0 mmol) in 20 mL THF was added Potassium tert-butoxide (11.0 mL of a 1.0 M solution in THF, 11.0 mmol) and then anhydrous ethyl acetate (1.05 mL, 10.7 mmol). The reaction was stirred at room temperature for 2 hours and then at 50° C. for 15 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 50% ethyl acetate in heptanes) to yield 0.75 g (38%) of 1-(3-chlorophenyl)butane-1,3-dione. LCMS (ESI) m+H=197.2.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:21](=[O:24])[CH:22]=[CH2:23])=[CH:14]\[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:25][CH:26]([C:31]1[CH:32]=[CH:33][C:34]([CH:37]=[O:38])=[N:35][CH:36]=1)[C:27]([OH:30])([CH3:29])[CH3:28].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10](/[C:13](=[CH:14]\[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)/[C:21](=[O:24])[CH2:22][CH2:23][C:37]([C:34]3[CH:33]=[CH:32][C:31]([CH:26]([OH:25])[C:27]([OH:30])([CH3:28])[CH3:29])=[CH:36][N:35]=3)=[O:38])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C=CC(=O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)(O)C(O)c1ccc(C=O)nc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(O)C(O)c1ccc(C(=O)CCC(=O)/C(=C/C2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Yield: 10.8 %

Procedure:
A mixture of (1E)-2-[4-(cyclopropylsulfonyl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)penta-1,4-dien-3-one (4.16 g), 5-(1,2-dihydroxy-2-methylpropyl)pyridine-2-carbaldehyde (2.58 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (0.32 g), triethylamine (0.84 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and the title compound (0.70 g, yield 79%) was obtained as yellow crystals from a fraction eluted with ethyl acetate. melting point 102-104° C.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[NH:30][C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)=[N:28][N:27]=4)[CH2:22][CH2:21]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].C1C=C[C:46]2[N:51](O)[N:50]=[N:49][C:47]=2[CH:48]=1.N1C=C(C(O)=O)N=N1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C.C(O)(=O)C>[C:37]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]5[NH:30][C:29]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)=[N:28][N:27]=5)[CH2:24][CH2:25]4)=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][N:12]4[C:48]([C:47]5[N:49]=[N:50][NH:51][CH:46]=5)=[N:2][N:1]=[C:3]4[C:4]=3[CH:5]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: On1nnc2ccccc21
Agent: O=C(O)c1c[nH]nn1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: c1ccc(-c2cc3c(ccn4c(-c5c[nH]nn5)nnc34)nc2-c2ccc(CN3CCC(c4nnc(-c5ccccn5)[nH]4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 9-3 (2.0 g, 3.6 mMol), HOBT (0.5 g, 3.9 mMol), and 1H-1,2,3-triazole-4-carboxylic acid (0.4 g, 3.9 mMol) in anhydrous DMF (20 mL) was added DIEA (1.2 mL, 7.2 mMol) followed by EDC (0.76 g, 3.9 mMol). The solution was stirred at ambient temperature overnight. The solution was then treated with 2 mL of acetic acid and was heated to 80° C. for 3 hrs. Upon cooling to room temperature, the solution was filtered through a syringe filter and purified on a C18 reverse phase HPLC to give 9-4 as a solid. Mass (M+1) calculated: 631.2789 observed: 631.2778
Reaction SMILES: [H-].[Na+].[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[N:21][C:15]=3[NH:14][C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]2=3)=[O:10])=[CH:5][CH:4]=1.[CH3:32]I>CCCCCC.ClCCl>[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[N:21][C:15]=3[N:14]([CH3:32])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]2=3)=[O:10])=[CH:7][CH:8]=1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccnc2Nc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CN1c2ccccc2N(C(=O)c2ccc(-c3ccccc3)cc2)Cc2cccnc21
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Sodium hydride (60% suspension, 0.10 g, 2.5 mmol) washed with hexane and dried under nitrogen, was suspended in dry N,N-dimethylformamide (15 mL). Following addition of 1,1′-biphenyl-4-yl-(5,11-dihydro-benzo[b]pyrido[2,3-e][1,4]diazepin-6-yl)-methanone of Example 4 (0.76 g, 2.0 mmol), methyl iodide (0.15 mL, 2.4 mmol) was added. After stirring for 1 hour, the reaction was quenched with water and extracted with dichloromethane The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow solid. Purification of the residue by flash chromatography using a solvent gradient from 25% to 35% of ethyl acetate in hexane gave a white foam which was redissolved in dichloromethane, concentrated in vacuo to a foam, then crystallized by sonication from ethyl acetate/hexane to provide the title compound (0.48 g, 61.3%) as a white solid, m.p. 220-223° C.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:23])[CH2:4][O:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].N1C=CC=CC=1.[C:30](Cl)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][CH2:2][CH:3]([O:23][C:30](=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:4][O:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:20])[CH3:21])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(CBr)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-bromo-2-hydroxy-1-(N-CBZ-L-valyloxy)-propane (7.9 g, 20 mmol) and pyridin (3.2 g, 40 mmol) in 250 ml dichloromethane was added dropwise a solution of stearoyl chloride (9.1 g, 30 mmol) in 50 ml dichloromethane between 10° C. and 15° C. The solution was stirred overnight at room temperature. 150 ml of 5% sodium hydrogen carbonate solution was added and the mixture stirred for 30 minutes. The organic phase was separated and the water phase was extracted two times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by silica gel column chromatography.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].OC1C2N=NNC=2C=CC=1.[NH2:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH2:43])=[O:42])=[O:38].Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([NH:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH2:43])=[O:42])=[O:38])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCC(=O)NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)NCC(N)=O
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
40 mL of Dimethyl formamide was added to 2.52 g (7.47 mmol) of Z-Glu(OtBu)-OH, 1.3 g (8.49 mmol) of hydroxybenzotriazole, 1.3 g (7.76 mmol) of H-Gly-GlyNH2, and 1.52 g (7.93 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. 2.5 mL (14.3 mmol) of diisopropyl ethyl amine was added and the reaction was stirred over night. The reaction mixture was purified in three equal portions by direct injection on a preparative 5 cm×25 cm C18 HPLC column. The column was run at 100 mL/min with deionized water containing 0.3% formic acid with 5% acetonitrile for 10 min followed by a 15 min linear gradient from 5% acetonitrile to 90% acetonitrile. Product fractions (retention time 18-20 min) were combined and solvent was removed by rotary evaporation under vacuum to give 2.9 g (83%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.79-7.68 (m, 1H), 7.64 (s, 1H), 7.27 (q, J=4.9, 5H), 6.90 (s, 1H), 6.42 (s, 1H), 6.35 (d, J=6.8, 1H), 5.08 (d, J=12.0, 1H), 4.98 (d, J=12.2, 1H), 4.20 (dd, J=12.9, 7.6, 1H), 3.84-3.95 (m, 2H), 3.83 (d, J=5.0, 2H), 2.42-2.19 (m, 2H), 2.07 (d, J=6.9, 1H), 1.96-1.83 (m, 1H), 1.39 (s, 9H). 13C NMR (101 MHz, DMSO) δ 171.79, 171.65, 170.82, 168.87, 163.04, 156.08, 136.86, 128.31, 127.74, 79.64, 65.58, 53.96, 42.17, 41.81, 31.25, 27.73, 27.01.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[O:17].Cl.C(N=C=NCCCN(C)C)C.O[C:42]1[C:50]2[N:49]=N[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:47][C:46]1[CH:45]=[CH:44][CH:43]=[CH:42][C:50]=1[NH2:49])=[O:25])=[O:17]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
5-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)pentanoic acid (382 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (382 mg, 81% yield) as a brown solid. LC-MS (m/z) 473 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O.CS(C)=O>CCOCC.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccc(Cl)c(OCc2ccccc2)c1
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1ccc(Cl)c(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
4-Chloro-3-(phenylmethoxy)phenyl methan-1-ol (82c) (2.74 g, 11.06 mmol) was dissolved in 25 mL ether. Triethylamine (TEA) (7.74 mL, 55.3 mmol) was added and the mixture was cooled to 0° C. A suspension of sulfur trioxide-pyridine (5.27 g, 22.18 mmol) and dimethylsulfoxide (6.3 mL, 88.48 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was then diluted with dichloromethane, washed with 1N hydrochloric acid, sodium bicarbonate and brine and concentrated to dryness. The crude product was purified by preparative HPLC using hexane/ethyl acetate to give the 1.9 g (71% yield) of the title compound (82d).
Reaction SMILES: C(OC1C=CC(N2CCNCC2)=CC=1F)C1C=CC=CC=1.C(Br)CCCCCCC.[F:31][C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([F:40])=[CH:34][C:33]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.[CH:47]1([CH2:53][CH2:54][CH2:55]Cl)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[CH:47]1([CH2:53][CH2:54][CH2:55][N:44]2[CH2:45][CH2:46][N:41]([C:33]3[CH:34]=[C:35]([F:40])[C:36]([O:38][CH3:39])=[CH:37][C:32]=3[F:31])[CH2:42][CH2:43]2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: ClCCCC1CCCCC1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Solvent: CCCCCCCCBr
Product: COc1cc(F)c(N2CCN(CCCC3CCCCC3)CC2)cc1F
Yield: 97.1 %

Procedure:
Production Example 38 was repeated except that 1-(4-benzyloxy-3-fluorophenyl)piperazine and n-octyl bromide were replaced with 1-(2,5-difluoro-4-methoxyphenyl)piperazine (228 mg) and 3-cyclohexylpropyl chloride (161 mg). The resulting crude product was purified on silica gel column chromatography (eluent, ethyl acetate) to provide 1-(3-cyclohexylpropyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (342 mg).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>CN(C)C=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:1][C:2]2[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:22][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(C=O)cccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 80.9 %

Procedure:
To a solution of 2-hydroxy-3-nitrobenzaldehyde (3 g) in dimethylformamide (20 mL) were sequentially added potassium carbonate (3.72 g), tetra-n-butylammonium fluoride (331 mg) and 1-(chloromethyl)-4-methoxybenzene (3.37 g), and the mixture was stirred for 11 hours at room temperature. The reaction mixture was poured into ice-water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was washed with tert-butyl methyl ether to give the title compound (4.17 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8](=[O:14])[CH:9]=[CH:10][C:11]=1[CH2:12]Br)=[O:5])[CH3:2].[CH3:22][O:23][C:24](=[O:37])[CH2:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8](=[O:14])[CH:9]=[CH:10][C:11]=1[CH2:12][N:26]([CH2:25][C:24]([O:23][CH3:22])=[O:37])[S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CBr)ccc(=O)n1Cc1ccccc1
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CN(CC(=O)OC)S(=O)(=O)c2ccc(C)cc2)ccc(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
A mixture of 1-benzyl-3-bromomethyl-6-oxo-1,6-dihydro-pyridine-2-carboxylic acid ethyl ester (147 mg, 0.42 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (112 mg, 0.46 mmol), sodium iodide (126 mg, 0.84 mmol) and potassium carbonate (116 mg, 0.84 mmol) in DMF (4 mL) was stirred at r.t. for 16 h. Brine (20 mL) were added, and the mixture was extracted with EtOAc. The organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes) to give 140 mg of the title compound. MS: (+) m/z 513.34 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[C:6]([OH:18])(C)[C:5](O)([CH3:19])[C:4]=2[CH:3]=1.F[C:22](F)(F)C(O)=O>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]([CH3:19])([CH3:22])[C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1(O)c2cc(Br)ccc2-c2ccc(Br)cc2C1(C)O
Solvent: CC(=O)O
Product: CC1(C)C(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
132.8 g (294 mmol) of 2,7-dibromo-9,10-dihydroxy-9,10-dimethyl-9,10-dihydrophenanthrene were suspended in 420 ml of acetic acid and 210 ml of trifluoroacetic acid under argon, and the mixture was stirred for 3 h under reflux. After the mixture had been stirred overnight at room temperature, it was filtered with suction, the residue was washed with water and methanol and dissolved in toluene, the solution was filtered through silica gel, and the solvent was removed, giving 89.9 g (80.4% of theory) of the product, which was used without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]#[N:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1C[CH2:24][CH2:23][CH2:22]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(Br)C=C>C(OCC)(=O)C.CCCCCC.O.CN(C)P(N(C)C)(N(C)C)=O>[Si:1]([O:8][CH2:9][CH2:10][C:11]([CH2:24][CH:23]=[CH2:22])([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:12]#[N:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCC(C#N)Cc1ccccc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC(C#N)(CCO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 2-(2-(t-butyldimethylsilyloxy)ethyl)-3-phenylpropionitrile (1.32 g,4.55 mmol) and tetrahydrofuran (8 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of lithium bis(trimethylsilyl)amide (9.1 mL, 1 M in THF, 9.1 mmol). After 30 minutes, add hexamethylphosphoramide (0.25 mL) and allyl bromide (1.10 g, 9.1 mmol). Warm slowly to ambient temperature. After 12 hours, add water and separate the layers. Extract the aqueous layer three times with ethyl acetate. Combine the organic layers and extract with aqueous 1 M hydrochloric acid solution. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give the title compound: Rf=0.83 (silica gel, 1/4 ethyl acetate/hexane).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH2:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[CH2:11]([N:17]=[C:18]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:11]([NH:17][C:18]([NH:10][CH:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NC1CCCc2sccc21
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)NC1CCCc2sccc21

Procedure:
In the manner described in Example 1, 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is allowed to react with n-hexyl isocyanate to give 1-(n-hexyl)-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 122° C. to 124° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:16])[N:13]=[C:12]([O:14][CH3:15])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=[C:22]([Cl:24])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3([CH3:16])[N:13]=[C:12]([O:14][CH3:15])[CH2:11][O:10][CH2:9]3)[CH:3]=2)[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: COC1=NC(C)(c2cccc(Br)c2)COC1
Reactant: CC1(C)OB(c2cc(Cl)cc(Cl)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC1=NC(C)(c2cccc(-c3cc(Cl)cc(Cl)c3)c2)COC1
Temperature: 105 °C

Procedure:
A degassed solution of (RS)-3-(3-bromo-phenyl)-5-methoxy-3-methyl-3,6-dihydro-2H[1,4]oxazine (intermediate XI-1) (200 mg, 0.7 mmol) in 1,2-dimethoxyethane (3 ml) and 2-(3,5-dichloro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (288 mg, 1.1 mmol) was treated consecutively with a solution of sodium carbonate (2M, 0.6 ml), triphenylphosphine (38 mg, 0.1 mmol), and palladium(II)acetate (16 mg, 0.1 mmol). The mixture was heated overnight in a sealed tube at 105° C. For the workup, the reaction mixture was evaporated at reduced pressure and the residue directly purified by chromatography on a silica-amine phase using a gradient of heptane/ethylacetate=100/0 to 60/10 as the eluent. The (RS)-3-(3′,5′-dichloro-biphenyl-3-yl)-5-methoxy-3-methyl-3,6-dihydro-2H-[1,4]oxazine was obtained as a colorless oil (160 mg, 65% of theory). MS (ISP): m/z=350.2 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:17])[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1)(=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-:39]#[N:40].[K+]>CC#N.Cl.O.CC(C)=O.CCOCC.[Zn]>[C:39]([C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:17])[CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1)#[N:40]
Reactant: [C-]#N
Reactant: O=C1CCOc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: Cl
Agent: [K+]
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc2c(c1)OCCC2=O
Temperature: 60 °C

Procedure:
7-[[(Trifluoromethyl)sulfonyl]oxy]-4-chromanone (27.8 g, 94 mmol) and PPh3 (2.5g, 9.6 mmol) were dissolved in degassed CH3CN (350 mL). KCN (6.8 g, 105 mmol), (PPh3)2NiBr2 (3.5 g, 4.7 mmol) and acid washed (stirred in 0.5 N HCl 1 min, washed successively with H2O, acetone, and Et2O) zinc dust (2.0 g, 31 mmol) were added and the reaction was purged with N2. The reaction was heated in a 60° C. bath for 6 h. The reaction was cooled, poured into H2O (400 mL) and extracted with EtOAc (3×300 mL). The organic layers were combined and washed with H2O (200 mL) and brine (150 mL). The solution was dried over MgSO4, filtered and concentrated in vacuo to provide a residue which was purified on a plug of silica (CH2Cl2 eluant) to provide the title compound.