Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])=[O:9])C.Cl>O>[O:30]=[C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:31])[N:21]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Yield: 92 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-phenyl-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 1, Part C). The mixture was heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 92% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])(O)[C@@H:14]2[C:28]2[CH:33]=[CH:32][C:31]([CH:34]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=2)=[CH:8][CH:9]=1)=[O:4].C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[C:14]2[C:28]2[CH:29]=[CH:30][C:31]([CH:34]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=3)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:32][CH:33]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc([C@@H]2[C@@H](CCCc3ccc(C(=O)OC)s3)CCC2(O)C(C)(C)O[SiH2]C(C)(C)C)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Solvent: c1ccccc1
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(C(C)(C)O[SiH2]C(C)(C)C)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 21 (46 mg, 0.065 mmol) and methyl N-(triethylammoniumsulphonyl)carbamate (Burgess reagent, 62 mg, 0.26 mmol) in benzene (0.9 mL) was heated at 50° C. After 1 h, the reaction was quenched by addition of H2O and the resulting mixture was extracted with dichloromethane (3×20 mL). The combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/hexanes) gave the title compound (31 mg, 68%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2-:14].[Na+]>CN(C)C1C=CC=CC=1>[NH2:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1ccc(-c2ccncc2)cc1
Reactant: [NH2-]
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(-c2ccnc(N)c2)cc1
Temperature: 110 °C
Reaction time: 48 h
Yield: 46.9 %

Procedure:
Under an argon gas, 4-(4-methylphenyl)pyridine (2.74 g) was dissolved in N,N-dimethylaniline (10 ml), followed by the addition of sodium amide (1.40 g) at room temperature. After the resulting mixture was stirred at 110° C. for 2 days, the reaction mixture was cooled to room temperature. Brown powder precipitated by the addition of water was collected by filtration. The powder was further purified by chromatography on a silica gel column (ethyl acetate:toluene=1:1). After concentration of the resulting fraction, hexane was added and powder thus precipitated was collected by filtration and dried, whereby the title compound (1.40 g, 47%) was obtained.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[O:14])[CH:7]=[CH:6]2)#N.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].[OH:27]S(O)(=O)=O>CCCCCC.O>[OH:27][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[O:14])[CH:7]=[CH:6]2
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccc2cc(C=O)ccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Product: O=Cc1ccc2cc(O)ccc2c1
Temperature: -60 °C
Reaction time: 8 h

Procedure:
6-Cyano-2-naphthalenecarbaldehyde (1.0 g, 5.9 mmol) was dissolved in dry hexane (15 mL) under nitrogen. The solution was cooled to −60° C. and a solution of diisobutyl aluminium hydride (DIBAH) (15 mL, 1M in hexane) was added dropwise. After the addition, the solution was left at room temperature overnight. Saturated ammonium chloride solution (20 mL) was added and the mixture was stirred at room temperature for 20 min, subsequently aqueous H2SO4 (10% solution, 15 mL) was added followed by water until all salt was dissolved. The resulting solution was extracted with ethyl acetate (3×), the combined organic phases were dried with MgSO4, evaporated to dryness to afford 0.89 g of 6-hydroxy-2-naphtalenecarbaldehyde.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH2:18][CH:17]([C:19]([OH:21])=O)[CH2:16]3)[CH:9]=2)[N:3]=1.[C:22]1([NH2:29])[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:29][C:19]([CH:17]1[CH2:16][N:15]([C:10]2[CH:9]=[C:8]([N:4]3[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]3)[N:13]=[C:12]([CH3:14])[N:11]=2)[CH2:18]1)=[O:21]
Reactant: Nc1ccccc1N
Reactant: Cc1nc(N2CC(C(=O)O)C2)cc(-n2nc(C)nc2C)n1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CC(C(=O)Nc3ccccc3N)C2)cc(-n2nc(C)nc2C)n1
Temperature: 50 °C

Procedure:
Compound 107-2 (584 mg, 2.03 mmol), benzene-1,2-diamine (263 mg, 2.43 mmol), HOBt (465 mg, 3.04 mmol), EDC (582 mg, 3.04 mmol) and DIEA (1.77 mL, 10.1 mmol) were combined in degassed DMF (10 mL) and heated at 50° C. for 18 h. The mixture was cooled to room temperature, poured into sodium bicarbonate (200 mL, aqueous saturated) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc (containing 10% MeOH)/hexanes), providing 107-3 as a pale green solid. MS: m/z=379.3 (M+H).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][CH:7]=[CH:6]1)(=O)[CH3:2].[CH2:10](O)[CH2:11]CC.CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:5]1([O:4][CH2:1][CH2:2][CH2:10][CH3:11])[CH2:9][CH2:8][CH:7]=[CH:6]1
Reactant: CC(=O)OC1C=CCC1
Reactant: CCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CC(C)=O
Solvent: O
Product: CCCCOC1C=CCC1

Procedure:
2-Cyclopentenyl acetate (0.30 g) and n-butanol (0.40 g) were mixed and stirred vigorously at 40° C. for 4 hours with a solution of 0.020 g of tetrabutylammonium hydrogen sulfate in 0.25 g of water. At the end of the reaction period acetone was added to give a single phase, and the solution was analyzed by gas chromatography using an Apiezon column programmed at 60°-220° C. Peaks for the cyclic compounds had the following relative areas.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[C:8]([OH:10])[CH:9]=1.C(N(CC)CC)C.CO[CH:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH:33]=2)[C:28](=[O:40])[NH:27][C:26]1=[O:41]>CN(C)C=O>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:3][NH:2][CH:24]=[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]3[CH:39]=[CH:38][CH:37]=[CH:36]3)[CH:33]=2)[C:28](=[O:40])[NH:27][C:26]1=[O:41]
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Reactant: CCCOc1ccc(CN)cc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCOc1ccc(CNC=C2C(=O)NC(=O)c3ccc(-n4cccc4)cc32)cc1O
Reaction time: 0.25 h

Procedure:
A mixture of 5-aminomethyl-2-propoxy-phenol hydrochloride (109 mg, 0.50 mmole), 4 mL of N,N-dimethylformamide and triethylamine (75 μL, 0.54 mmole) is stirred for 15 minutes. Then (4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione (134 mg, 0.50 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, taken up in 5% methanol in chloroform and passed through a short pad of Florisil eluting with 5% methanol in chloroform. The eluate is evaporated in vacuo and treated with acetonitrile, filtered and dried to give a beige solid, 94 mg, (45%), mp 215-216° C. dec; MS (ES+): m/z 418.2 (M+H).
Reaction SMILES: [Cl-].[CH:2]1([CH2:9][NH2+:10][CH2:11][CH2:12]Cl)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[N:10]([CH2:9][CH:2]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:11][CH2:12][S:26]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: ClCC[NH2+]CC1CCCCCC1
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cycloheptylmethyl bromide according to Method B2a to give N-cycloheptylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cycloheptylmethyl)-1,3-thiazolidine.
Reaction SMILES: BrC1C=CC2OCCC3N(N=C(C4N(C(C)C)N=CN=4)C=3)C=2C=1.C[N:25](C)[CH:26]=[N:27][C:28]([C:30]1[CH:31]=[C:32]2[N:38]([N:39]=1)[C:37]1[CH:40]=[C:41]([Br:44])[CH:42]=[CH:43][C:36]=1[O:35][CH2:34][CH2:33]2)=O.[F:46][C:47]([F:52])([F:51])[CH2:48][NH:49]N>>[Br:44][C:41]1[CH:42]=[CH:43][C:36]2[O:35][CH2:34][CH2:33][C:32]3[N:38]([N:39]=[C:30]([C:28]4[N:49]([CH2:48][C:47]([F:52])([F:51])[F:46])[N:25]=[CH:26][N:27]=4)[CH:31]=3)[C:37]=2[CH:40]=1
Reactant: CN(C)C=NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Reactant: NNCC(F)(F)F
Agent: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(Br)ccc1OCC2
Product: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(Br)ccc1OCC2

Procedure:
Following the procedure for 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene, 9-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylaminomethylideneamide was reacted with trifluoroethyl hydrazine (70% aqueous) to give 9-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene as a white solid. LCMS RT=4.49 min, M+H+=414/416.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]1[N:11]=[C:10]([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[O:9][N:8]=1.[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[S:39](Cl)(=[O:41])=[O:40]>>[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[S:39]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]1[N:11]=[C:10]([CH2:12][O:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:18][CH2:19]2)[O:9][N:8]=1)(=[O:40])=[O:41]
Reactant: O=C(OCc1ccccc1)N1CCC(OCc2nc([C@@H]3CCCCN3)no2)CC1
Reactant: O=S(=O)(Cl)c1nc2ccccc2[nH]1
Product: O=C(OCc1ccccc1)N1CCC(OCc2nc([C@@H]3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)CC1

Procedure:
The title compound was prepared by a similar method to Example 1 from benzyl 4-(3-[(2S)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)-1-piperidinecarboxylate [see Preparation 95] and 1H-benzo[d]imidazol-2-sulfonyl chloride [see Preparation 8]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20 changing to 0:100, by volume, hexane:ethyl acetate, in 5% increments, to afford benzyl 4-(3-[(2S)-1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)-1-piperidinecarboxylate as a clear oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4][N:3]1[OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1C=CC=CC=1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4][N:3]1[O:12][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1c2ccccc2nnn1O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CS(=O)(=O)On1nnc2ccccc2c1=O
Yield: 73.3 %

Procedure:
In benzene (30 ml) are dissolved 4-oxo-3,4-dihydro-3-hydroxy-1,2,3-benzotriazine (2.4 g) and triethylamine (2.1 ml) and thereto is added dropwise methanesulfonyl chloride (1.7 g), whereby faint exotherm occurs and crystals are precipitated. The reaction mixture is extracted with ethyl acetate (80 ml). The extract is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate and then distilled to remove the solvent. The resulting residue is washed with ether-petroleum ether and dried to give 4-oxo-3,4-dihydro-3-methanesulfonyloxy-1,2,3-benzotriazine (2.6 g), melting point: 132°-134° C. Infrared spectrum: 1720, 1380, 1175 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-2-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.542 min, m/z=430.23; 1H NMR (CDCl3) 1.02-1.15 (d, 6H), 1.50 (d, 3H), 2.09-2.21 (m, 6H), 2.32 (m, 1H), 2.78 (m, 1H), 5.65 (m, 1H), 6.98 (d, 2H), 7.15-7.30 (m, 6H), 7.55 (m, 1H), 7.70 (d, 1H), 8.60 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Nc1ccccc1Cl
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Nc1ccccc1Cl)C(=O)OCC
Reaction time: 10 h
Yield: 35.6 %

Procedure:
o-Chloroaniline (15.9 g) was dissolved in dry toluene (20 ml), and diethyl bromomalonate (12.0 g) was added. The mixture was heated under reflux with stirring for 10 hours. The reaction mixture was washed with dilute hydrochloric acid, then with water three times, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using benzene as an eluent to give 5.1 g (yield 36%) of diethyl o-chloroanilinomalonate which had the following NMR data.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1.[C:17]([CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22])(=O)[CH3:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:14]([NH:15][C:17](=[C:20]2[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH3:18])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(C)c(-c2ncccc2N)c(C)c1
Reactant: CC(=O)C1CCOC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Nc1cccnc1-c1c(C)cc(C)cc1C)=C1CCOC1=O
Yield: 64.4 %

Procedure:
p-Toluenesulfonic acid monohydrate (39 mg, 0.20 mmol) was added to a solution of 2-mesityl-3-pyridinamine (3.9 g, 18 mmol) and α-acetyl-γ-butyrolactone (4.7 g, 37 mmol) in toluene (80 mL). The mixture was heated under reflux for seven days while removing water using Dean-Stark apparatus. The mixture was evaporated, and the resulting crystals were washed with 60% diethyl ether/ethyl acetate, to give the title compound (3.74 g) as white crystals.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O-]CC.[Na+].[CH:21]12[O:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]2.Cl>C(O)C>[CH3:13][C:12]([C:7]1[CH:8]=[C:9]([S:11][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[OH:27])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[OH:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C1CCC2OC2C1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (12.8 g, 0.054 moles) was added to a solution of sodium ethoxide [prepared from sodium (2.5 g, 0.108 mole)] in ethyl alcohol (75 ml). Cyclohexene oxide (5.15 g, 0.0525 mole) was added and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into 10% hydrochloric acid (250 ml) and the mixture was extracted twice with 200 ml of ethyl ether. The combined ethyl ether extracts were washed twice with 25 ml of water, dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow oil. The product was purified by silica get chromatography and recrystallized from methyl alcohol/water, m.p. ca 91° C. The structure was supported by NMR, infrared spectroscopy, and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH:12]([NH2:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH:12]([NH:14][C:22](=[O:23])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)CCCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CCCc1ccc(Cl)c(Cl)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
Intermediate 18A (0.500 g, 2.15 mmol) and sodium carbonate (0.50 g, 4.7 mmol) were combined in THF (10 mL) and treated with benzyl chloroformate (0.31 mL, 2.2 mmol) drop wise over 15 min. The reaction mixture was stirred at rt for 18 h. The mixture was concentrated in vacuo, diluted with DCM and washed with saturated Na2CO3 twice, brine and the organic portion dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-50%, column 40 g) to give benzyl 5-(3,4-dichlorophenyl)pentan-2-ylcarbamate (440 mg, 1.20 mmol, 56.0%) as a clear oil. HPLC/MS (HPLC Method L): RT=2.32 min, [M+1]+ =366.0. The racemates were separated on chiral prep HPLC (chiral AD 10 micron 4.6×250 mm, 15 min 5% isocratic. A=EtOH/MeOH (50/50). B=Heptane; retention time=9.8 min) to afford Intermediate 18B (220 mg, 0.600 mmol, 28.0%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07 (3H, d), 1.32-1.41 (2H, m), 1.51-1.62 (2H, m), 2.42-2.57 (2H, m), 3.62-3.75 (1H, m), 4.42 (1H, br. s.), 5.02 (2H, s), 6.91 (1H, d, J=7.5 Hz), 7.17 (1H, br. s.), 7.23-7.31 (6H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH:11]=[CH:12][CH2:13]C.C1(C)C=CC=CC=1>O>[CH2:12]([C:11]1[C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[C:3]=2[O:9][CH:10]=1)[CH3:13]
Reactant: CCC=CCOc1ccc(F)cc1Br
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1coc2c(Br)cc(F)cc12

Procedure:
Beginning with pent-2-en-1-yl 2-bromo-4-fluorophenyl ether, the title compound was prepared essentially as described in Preparation XVII, except that Amberlyst 15™ resin in refluxing toluene was used in place of sulfuric acid, and water was removed by azeotropic distillation with a Dean-Stark trap.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:65]=[C:64]([Cl:66])[C:63]([Cl:67])=[C:62]([Cl:68])[CH:61]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].[NH2:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76]>C(Cl)Cl.O>[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:61]=[C:62]([Cl:68])[C:63]([Cl:67])=[C:64]([Cl:66])[CH:65]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46]([NH:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:76])([CH3:78])[CH3:77])=[O:47]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)NCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
PyBOP (420 mg, 0.82 mmol) and DIPEA (0.410 mL, 2.46 mmol) were added to a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) and tert-butyl 2-aminoethylcarbamate (130 mg, 0.82 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at ambient temperature for 18 h. Water was added to the reaction mixture and extracted with CH2Cl2 (25 mL). The organic layer was washed with 2N HCl followed by saturated NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 40% EtOAc in petroleum ether to afford the title compound as a brown solid (200 mg, 39%): 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J=5.2 Hz, 1H), 7.91-7.89 (m, 3H), 7.58 (d, J=6.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.99 (dd, J=15.6, 9.2 Hz, 1H), 6.84 (t, J=6.0 Hz, 1H), 6.76 (t, J=15.6 Hz, 1H), 4.84-4.80 (m, 1H), 3.24-3.20 (m, 2H), 3.11-3.08 (m, 2H), 1.30 (s, 9H); ESIMS m/z 628.80 ([M+H]+); IR (thin film) 3365, 1701, 1167, 699, 555 cm−1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[C:6]([Cl:25])[CH:5]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[C:6]([Cl:25])[CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)cc(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cc(Cl)cc(Cl)c31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) was added to a solution of tert-butyl 7,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate (0.94 mL, 8.4 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (3:1) to give 1.8 g (98%) of a white solid: mp 117.0-120.0° C.; IR (diffuse reflectance) 2972, 1744, 1690, 1464, 1409, 1377, 1366, 1349, 1294, 1222, 1204, 1190, 1167, 1111, 861 cm−1; MS (EI) m/z 440 (M+), 440, 386, 385, 384, 339, 311, 310, 300, 298, 57; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 56.97; H, 5.97; N, 6.19.