Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:71]1[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]2([OH:85])[CH2:84][CH2:83][S:82][CH2:81][CH2:80]2)=[C:73]([CH3:86])[CH:72]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[C:57]([CH3:70])[CH:56]=1)[CH2:53][CH3:54])[CH3:51]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:58]2[CH:59]=[CH:60][C:55]([C:52]([CH2:53][CH3:54])([C:71]3[CH:76]=[CH:75][C:74](/[CH:77]=[CH:78]/[C:79]4([OH:85])[CH2:84][CH2:83][S:82][CH2:81][CH2:80]4)=[C:73]([CH3:86])[CH:72]=3)[CH2:50][CH3:51])=[CH:56][C:57]=2[CH3:70])[CH:10]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
(5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 35 mg, 0.14 mmol), palladium acetate (2.2 mg, 0.01 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (7.9 mg, 0.019 mmol), potassium phosphate (61 mg, 0.29 mmol) and water (0.2 mL) were added to a solution of 4-[(E)-2-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-vinyl]-tetrahydro-thiopyran-4-ol (Example 138-(3); 50 mg, 0.096 mmol) in toluene (2 mL). The mixture was stirred in a nitrogen atmosphere at 110° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:2) to give the title compound (20 mg, 38%).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:22]1[CH2:24][CH:23]1[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:24][CH:23]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[OH:22])[C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: c1cc(C2CO2)ccn1
Reactant: CN1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(OC(F)(F)F)ccc3n2CC(O)c2ccncc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of 2-methyl-8-trifluoromethoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 3.70 mmol) in DMF (10 mL) was added sodium hydride (445 mg, 11.12 mmol) under nitrogen at 0° C. After stirring for 10 min, 4-(oxiran-2-yl)pyridine (806 g, 6.66 mmol) was added dropwise under nitrogen and the reaction mixture was stirred at RT for 12 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (5×50 mL) and dried over anhydrous sodium sulfate, concentrated and re-crystallized in diethyl ether to yield 2-(2-methyl-8-trifluoromethoxy-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.58 (d, 2H), 7.17-7.21 (m, 4H), 7.0 (d, 1H), 4.6 (m, 1H), 4.0 (m, 2H), 3.38 (dd, 2H), 2.8 (m, 1H), 2.7 (m, 2H), 2.6 (m, 1H), 2.18 (s, 3H). Separation by chiral HPLC provides enantiomers II-67a-b.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1I.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([CH3:20])[CH:22]=[CH:23]2
Reactant: CCOC(=O)c1c(O)c2cc(I)c(Cl)cc2[nH]c1=O
Reactant: Cn1ccc2cc(B(O)O)ccc21
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(O)c2cc(-c3ccc4c(ccn4C)c3)c(Cl)cc2[nH]c1=O
Temperature: 120 °C
Yield: 65.5 %

Procedure:
To a solution of ethyl 7-chloro-4-hydroxy-6-iodo-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Intermediate 100) (300 mg, 0.762 mmol) in 1,4-dioxane (7 mL) and water (3.5 mL) were added (1-methyl-1H-indol-5-yl)boronic acid (Combi-Blocks, 140 mg, 0.800 mmol), cesium carbonate (373 mg, 1.143 mmol) and tetrakis(triphenylphosphine)palladium (8.81 mg, 7.62 μmol). The reaction vessel was sealed and heated to 120° C. for 20 min in a microwave. After cooling, the mixture was filtered, evaporated to dryness and the resulting residue was acidified with 1N HCl. The precipitate was filtered and dried to give ethyl 7-chloro-4-hydroxy-6-(1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydro-3-quinolinecarboxylate (198 mg, 0.499 mmol, 65.5% yield) as off-white solid. LCMS: (M+H)+=397; Rt=2.79 min. HRMS: calculated for C21H18ClN2O4 (M+H)+: 397.0955. found: 397.0927.
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.[O:10]1[CH2:15]COC[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH3:11][O:10][CH2:15][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1ccc(Br)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COCc1ccc([N+](=O)[O-])s1
Temperature: 100 °C
Reaction time: 6 h
Yield: 11 %

Procedure:
A mixture of potassium methoxymethyl trifluoroborate (33 mg, 0.22 mmol), 2-bromo-5-nitrothiophene (30 mg, 0.14 mmol), 1,4-dioxane (1.5 ml), water (0.15 ml), cesium carbonate (235 mg, 0.72 mmol), palladium (II) acetate (3.2 mg, 0.014 mmol), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (9.0 mg, 0.014 mmol) was stirred at 100° C. (external temperature) for 6 hours. After the reaction mixture was cooled at room temperature, water and ethyl acetate were added to the mixture, followed by filtration using Celite. The organic layer was washed with an aqueous saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (2.7 mg, 0.016 mmol, 11%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:10]#[CH:11])[CH2:3][O:4][CH:5]1[CH2:9][CH2:8][O:7][CH2:6]1.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19](I)=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)[C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])=[O:16].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:11]#[C:10][C:2]([CH3:12])([CH3:1])[CH2:3][O:4][CH:5]2[CH2:9][CH2:8][O:7][CH2:6]2)=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:33][CH2:34][CH:35]([OH:38])[CH2:36][CH2:37]1)[C:23]([CH:25]1[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])=[O:16]
Reactant: COC(=O)c1sc(I)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Reactant: C#CC(C)(C)COC1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C#CC(C)(C)COC2CCOC2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Yield: 75.8 %

Procedure:
A solution of 3-(2,2-dimethyl-but-3-ynyloxy)-tetrahydro-furan (169 mg, 1.00 mmol), 3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-iodo-thiophene-2-carboxylic acid methyl ester (404 mg, 0.80 mmol) and triethylamine (1.2 mL, 8.61 mmol) in DMF (1.2 mL) was degassed for 10 minutes with nitrogen. PdCl2(PPh3)2 (25 mg, 0.036 mmol) and CuI (6.0 mg, 0.031 mmol) was added and the resulting mixture was degassed with nitrogen for an additional 5 minutes after which the reaction was placed in a 65° C. oil bath and heated for 2.5 h. The reaction was cooled and partitioned between ethyl acetate and sat. NaHCO3. The organic layer was separated, washed with 5% LiCl, brine, dried over Na2SO4 and concentrated to give a dark brown foam. Purification by flash column chromatography on silica gel using 50% ethyl acetate in hexanes then 5% methanol in ethyl acetate provided 5-[3,3-dimethyl-4-(tetrahydro-furan-3-yloxy)-but-1-ynyl]-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (331 mg, 75%) as a pale yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12](Cl)=[C:11]([OH:17])[C:10]=2[N+:18]([O-:20])=[O:19])=[O:5])[CH3:2].[CH2:22](OC(C1C(=O)OC2C(C=1)=CC(CC)=C(O)C=2)=O)[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH2:22][CH3:23])=[C:11]([OH:17])[C:10]=2[N+:18]([O-:20])=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Cl)c(O)c([N+](=O)[O-])c2oc1=O
Reactant: CCOC(=O)c1cc2cc(CC)c(O)cc2oc1=O
Product: CCOC(=O)c1cc2cc(CC)c(O)c([N+](=O)[O-])c2oc1=O

Procedure:
Compound 233 was prepared following the preparation of compound 241, except that 3-ethoxycarbonyl-6-ethyl-7-hydroxy-coumarin was nitrated to give the title compound 233.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[N:6]([CH3:11])[CH:7]=[N:8][C:9]=2[N:10]=1.[H-].[Na+].I[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:16]([N:3]1[C:4](=[O:12])[C:5]2[N:6]([CH3:11])[CH:7]=[N:8][C:9]=2[N:10]=[C:2]1[Cl:1])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: Cn1cnc2nc(Cl)[nH]c(=O)c21
Agent: [H-]
Agent: [Na+]
Product: CCCCn1c(Cl)nc2ncn(C)c2c1=O
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a suspension of 2-chloro-7-methyl-1,7-dihydro-6H-purin-6-one [Ber., 30, 2400 (1897)] (6.68 g, 0.0362 mol) was added 2.03 g (0.0507 mol) of 60% sodium hydride, and the mixture was stirred for 30 minutes. To the mixture was added 8.24 ml (0.0724 mol) of iodobutane. The mixture was stirred at an external temperature of 65° C. for further 30 minutes. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=20:1) to afford 5.38 g (61.8%) of Compound j as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13])[CH:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:6][CH2:5]2.F[B-](F)(F)F.[O:29]=[N+:30]=[O:31]>ClCCl>[Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[C:10]([N+:30]([O-:31])=[O:29])[CH:11]=1)[N:8]([C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13])[CH:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:6][CH2:5]2
Reactant: CCOC(=O)C(=O)N1C2=CC=C(Br)CC2CCC1CC(=O)OC
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1C2=C([N+](=O)[O-])C=C(Br)CC2CCC1CC(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A solution of 6-bromo-2-methoxycarbonylmethyl-N-ethoxalyltetrahydroquinoline (56.0 g, 0.146 mol) in dichloromethane (500 mL) was added dropwise to a suspension of nitronium tetrafluoroborate (25.0 g, 0.179 mol) in dichloromethane (500 mL) at 0° C. The mixture was stirred for 3 h at 0° C., poured into ice-water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 3:1 to 2:1 hexane/ethyl acetate to give 52.0 g of the title compound (83%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:9])[CH2:4][CH2:3]1.Cl[CH2:32][CH2:33][CH:34]1[O:38][CH2:37][CH2:36][O:35]1.C(N(CC)CC)C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:26][CH2:27][N:28]([CH2:32][CH2:33][CH:34]3[O:38][CH2:37][CH2:36][O:35]3)[CH2:29][CH2:30]2)=[O:9])[CH2:6][CH2:7]1
Reactant: ClCCC1OCCO1
Reactant: CN1CCN(C(=O)c2c(N3CCNCC3)n(-c3ccccc3)c3ccccc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2c(N3CCN(CCC4OCCO4)CC3)n(-c3ccccc3)c3ccccc23)CC1

Procedure:
A stirred mixture of 8 g (0.02 mol) of 1-phenyl-2-(1-piperazinyl)-indole 3-carboxylic acid (4-methyl)-piperazide, 9.45 g (0.07 mol) of 2-(2-chloroethyl)-1,3-dioxolane and 9.7 ml of triethylamine in 60 ml of toluene was maintained at the boil for 40 hours. After cooling, the mixture was diluted with 200 ml of chloroform, washed three times with water, and the solvent was eliminated in vacuo. The resinous residue of the organic phase was chromatographed using silica gel 60 (0.06-0.2 mm, deactivated by 10% of water, column size: 3 × 100 cm) with chloroform containing 10% methanol. The base was eluted as a resin. The yield amounted to 6.6 g (66% of the theoretical yield). The dihydrochloride melted at 215°-217° C.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].C(O[CH:9]([CH:20]1[CH2:22][C:21]1([F:24])[F:23])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)(=O)C.[CH3:25][S:26]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[NH:37][CH:36]=[CH:35]2)(=[O:28])=[O:27].C(=O)(O)[O-].[Na+]>ClCCCl.C(OCC)(=O)C>[F:24][C:21]1([F:23])[CH2:22][CH:20]1[CH:9]([C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)[C:35]1[C:34]2[C:38](=[C:30]([CH2:29][S:26]([CH3:25])(=[O:28])=[O:27])[CH:31]=[CH:32][CH:33]=2)[NH:37][CH:36]=1
Reactant: CC(=O)OC(c1ccc(C(F)(F)F)cc1)C1CC1(F)F
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C3CC3(F)F)c[nH]c12

Procedure:
2.05 g (9.27 mmol) of indium(III) chloride were added to 2.50 g (8.50 mmol) of the compound from Example 192A and 1.62 g (7.72 mmol) of the compound from Example 86A in 31 ml of 1,2-dichloroethane under argon and reflux, and the mixture was heated under reflux for 2.5 h. A further 2.00 g (9.04 mmol) of indium(III) chloride were added, and the mixture was heated under reflux for a further 2 h. This was followed by addition of ethyl acetate and saturated aqueous sodium bicarbonate solution, separation of the phases, drying of the organic phase and concentration. The residue was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1/1) and by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 13.0 mg (0.3% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:22]2[CH:9]3[CH2:10][C:11]4[CH:18]=[C:17]5[O:19]C[O:21][C:16]5=[CH:15][C:12]=4[CH2:13][CH2:14][N:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(O)C.Cl>[CH:23]1[C:22]2[CH:9]3[CH2:10][C:11]4[CH:18]=[C:17]([OH:19])[C:16]([OH:21])=[CH:15][C:12]=4[CH2:13][CH2:14][N:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([OH:2])[CH:24]=1
Reactant: COc1ccc2c(c1)CCN1CCc3cc4c(cc3CC21)OCO4
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCO
Product: Oc1ccc2c(c1)CCN1CCc3cc(O)c(O)cc3CC21
Reaction time: 4 h
Yield: 108.1 %

Procedure:
The title compound was prepared as described in Example 22 by the treatment of 5,6,8,9,15,15a-hexahydro-3-methoxy-[1,3]dioxolo[4,5-h]isoquino[1,2-b][3]benzazepine (XIIIb, Ex. 19) (0.9 g, 2.8 mmole) with boron tribromide. The reaction time was shortened to 4 hours. Evaporation of ethyl acetate extracts on a rotary evaporator afforded a solid residue which was dissolved in hot ethanol solution with ethanolic hydrogen chloride solution. When the mixture was warmed on a steam bath with an additional amount of ethanol (15 ml), a crystalline product was separated. The mixture was chilled in a refrigerator, and the precipitate was collected on a filter and washed with ethanol to give the titled product (0.9 g, 97%). An analytical sample was obtained by dissolving the product in a mixture of ethanol and a small amount of water, and precipitation by an addition of a large amount of anhydrous ether. The product started to char at 282° and decomposed completely at 286°. Mass spec (CI) m/z 298 (M+1) and 247.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>N1C=CC=CC=1>[N:12]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: C1CCCNCC1
Solvent: c1ccncc1
Product: O=C1CCc2cc(N3CCCCCC3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Fluoroindan-1-one (5 g, 33.3 mmol) and azepane (9.92 g, 100 mmol) were dissolved in pyridine (20 ml) and heated at reflux for 3 hours, stirred at ambient temperature for 16 hours, and then heated at reflux for an additional 6 hours. The solvent was removed under vacuum and the residue partitioned between methylene chloride and water. The organic layer was washed with 1N aqueous sodium hydroxide, dried with magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was filtered through a pad of silica gel with 1:1 ethyl acetate:hexanes, and the solvent evaporated under vacuum to provide the title compound which was used without further purification. 1H NMR (CDCl3) δ 1.56 (m, 4H), 1.81 (m, 4H), 2.62 (m, 2H), 3.02 (m, 2H), 3.55 (t, 4H), 6.59 (d, 1H), 6.68 (dd, 1H), 7.61 (d, 1H); MS (DCI) 230 (M+H)+.
Reaction SMILES: CCN(CC)CC.[C:8]1([C:14]2[N:15]=[C:16]([C:19]3([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[S:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:27]([C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)#[N:28]>C(Cl)Cl>[C:27]([C:29]1[CH:30]=[C:31]([S:35]([NH:26][CH2:25][C:19]2([C:16]3[S:17][CH:18]=[C:14]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:15]=3)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)#[N:28]
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(S(=O)(=O)NCC2(c3nc(-c4ccccc4)cs3)CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
Et3N (0.15 mL, 1.43 mmol) was added dropwise to an ice cold solution of (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (130 mg, 0.48 mmol) in dry CH2Cl2 (3 mL). The resulting reaction mixture was stirred at 0° C. for 5 min, then a solution of 3-cyanobenzene-1-sulfonyl chloride (105 mg, 0.52 mmol) in dry CH2Cl2 (2 mL) was added dropwise. The reaction mixture was further stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 35% EtOAc in petroleum ether) to afford compound 3-cyano-N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)benzenesulfonamide (0.13 g, yield 61%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.03-7.98 (m, 2H), 7.85-7.76 (m, 3H), 7.59-7.54 (m, 1H), 7.50-7.38 (m, 4H), 3.87-3.79 (m, 2H), 3.74-3.66 (m, 2H), 3.36 (s, 2H), 2.27-2.19 (ddd, J=13.5 Hz, 6.7 Hz, 3.5 Hz, 2H), 2.01-1.93 (ddd, J=13.8 Hz, 7.5 Hz, 3.7 Hz, 2H). MS (ESI) m/z: Calculated for C22H21N3O3S2: 439.10. found: 440.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:13]=[N:12][C:5]2[NH:6][C:7](=[O:11])[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:14]([O:18]C(C)(C)C)(=[O:17])[CH:15]=[CH2:16].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:11]=[C:7]1[NH:6][C:5]2[N:12]=[CH:13][C:2](/[CH:16]=[CH:15]/[C:14]([OH:18])=[O:17])=[CH:3][C:4]=2[C:9](=[O:10])[NH:8]1
Reactant: O=c1[nH]c(=O)c2cc(Br)cnc2[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C(O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Yield: 103.6 %

Procedure:
A suspension of 6-bromo-1H-pyrido[2,3-d]pyrimidine-2,4-dione (430 mg, 1.59 mmol) in propionitrile (8 mL) and DMF (2 mL) was treated with tert-butyl acrylate (0.93 mL, 6.4 mmol), (i-Pr)2EtN (0.6 mL, 3.3 mmol) and P(o-tol)3 (100 mg, 0.32 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (36 mg, 0.16 mmol) was added and the mixture was deoxygenated with a stream of Ar for 10 min. The mixture was heated to reflux for 17 h, then allowed to cool. The resulting precipitate was isolated by filtration to give the title compound (384 mg, 83%) as a gray solid: 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 11.54 (s, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.53 (d, J=2.2 Hz, 1H), 7.65 (d, J=16.1 Hz, 1H), 6.72 (d, J=16.1 Hz, 1H), 1.49 (s, 9H); ESI MS m/e 290 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[NH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19]>>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[S:3][CH:4]=2)=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(-c2csc(Br)n2)cc1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 175 °C
Yield: 68.2 %

Procedure:
2-Bromo-4-(4-nitrophenyl)-1,3-thiazole (1.0 g, 3.5 mmol), prepared in the previous step, and 2-amino-2-methyl-propan-1-ol (2.0 mL, 21.0 mmol) were placed in a sealed tube and heated to 175° C. for 18 h. The crude product was pre-adsorbed onto silica gel and purified using a stepwise gradient of 1-5% methanol:methylene chloride to give 2-{[4-(4-nitrophenyl)-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol (700 mg, 69%), MS (ES) m/z 294[M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]3[O:28][CH2:29][CH2:30][O:31][C:26]=3[CH:25]=2)[CH3:22])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([CH2:23][N:21]([CH3:22])[CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: CN(Cc1ccc2c(c1)OCCO2)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.6 %

Procedure:
Trifluoroacetic acid (591 μL, 7.67 mmol, 15.0 eq) is added at 0° C. to a stirred solution of 4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (195 mg, 0.51 mmol, 1.0 eq) in dichloromethane (10 mL). After 3 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and water (10 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-piperidin-4-yl-amine as a light yellow solid (148 mg, 99% yield).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.[ClH:29]>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@@H:13]([NH2:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:29]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(OC2CCCC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cccc(OC2CCCC2)c1
Reaction time: 1 h

Procedure:
(S)-tert-butyl 1-(3-(cyclopentyloxy)phenyl)ethylcarbamate (75.1 mg, 0.246 mmol) was dissolved in 4M HCl in dioxane (1 ml, 4.00 mmol) and the resulting mixture was allowed to sit for 1 hour, then concentrated to yield (S)-1-(3-(cyclopentyloxy)phenyl)ethanamine as an HCl salt (yield assumed quantitative). LCMS m/z 206.1 (M+H)+, Rt 0.61 min.