Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:38]=2)O1>>[N:41]1([CH2:40][CH2:39][N:37]2[CH:38]=[C:34]([C:25]3[CH:2]=[CH:3][C:4]4[O:13][CH2:12][CH2:11][C:10]5[S:9][C:8]([C:14]6[N:15]([CH2:19][C:20]([F:21])([F:22])[F:23])[N:16]=[CH:17][N:18]=6)=[N:7][C:6]=5[C:5]=4[CH:24]=3)[CH:35]=[N:36]2)[CH2:42][CH2:43][O:44][CH2:45][CH2:46]1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cnn(CCN4CCOCC4)c3)cc1-2
Yield: 17 %

Procedure:
8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine were reacted under palladium Suzuki conditions to give 115 (17% yield). LC/MS(ESI+): m/z 532 (M+H). 1H NMR (400 MHz, DMSO) δ 8.48 (d, J=2.1, 0H), 8.30 (s, 0H), 8.07 (s, 0H), 7.76 (s, 0H), 7.49 (dd, J=8.3, 2.2, 0H), 7.09 (d, J=8.3, 0H), 5.89 (q, J=8.6, 0H), 4.38 (t, J=4.9, 0H), 4.25 (t, J=6.6, 0H), 3.61-3.51 (m, 1H), 3.48 (t, J=4.9, 0H), 2.75 (t, J=6.6, 0H), 2.45-2.35 (m, 1H)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:12][O:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[I-].[Na+].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[NH:5]([C:3]([CH2:2][N:19]1[CH2:20][CH2:21][CH:16]([O:15][CH2:14][O:13][CH3:12])[CH2:17][CH2:18]1)=[O:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COCOC1CCNCC1
Reactant: O=C(CCl)Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCOC1CCN(CC(=O)Nc2ccccc2)CC1
Yield: 90.5 %

Procedure:
1.7 ml of chloroacetyl chloride was dropwise added to a solution of 3.0 g of aniline hydrochloride and 7 ml of triethylamine in 30 ml of dichloromethane. The mixture was stirred at room temperature for 3 hours, then washed with water and a saturated aqueous sodium hydrogencarbonate solution in this order, and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was crystallized from ethyl acetate-n-hexane to obtain 2.45 g of N-(2-chloroacetyl)aniline as a light brown solid. A suspension of 2.45 g of the N-(2-chloroacetyl)-aniline, 2.8 g of 4-methoxymethoxypiperidine, 2.45 g of sodium iodide and 2.3 ml of triethylamine dissolved in 30 ml of acetonitrile was refluxed for 1.5 hours. The reaction mixture was diluted with ethyl acetate. The dilution was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: ethyl acetate: n-hexane=1:1) to obtain 3.64 g of 1-(anilinocarbonylmethyl)-4-methoxymethoxypiperidine as a lightyellow oil.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]([C:15]2[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[N:23]1([C:29]([C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>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>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:35]2[CH:36]=[C:31]([C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[CH:32]=[CH:33][CH:34]=2)=[CH:9][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
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: CC(C)n1cc(-c2cc(-c3cccc(C(=O)N4CCOCC4)c3)cnc2N)nn1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
Cs2CO3 (858 mg, 2.64 mmol) was added to a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (250 mg, 0.88 mmol) and (3-(morpholine-4-carbonyl)phenyl)boronic acid (228 mg, 0.97 mmol) in dioxane: water (8 mL: 4 mL) degassed the reaction mixture for 10 min with nitrogen. Then added Pd(PPh3)4 (50 mg, 0.044 mmol), degassed the reaction mixture for additional 10 min with nitrogen, the reaction mixture was heated to 120° C. in microwave for 1 h. After completion of reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). Combined organic layers was dried over Na2SO4 and concentrated under reduced pressure. Crude product was purified by silica (100-200 mesh) column eluted with 80-90% ethyl acetate in pet-ether to afford 210 mg (Yield: 60.34%) of the title compound as a pale yellow solid. Product was converted to its HCl salt by using HCl in ether (2M) to afford 208 mg as an off-white solid.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.CN(C)[CH2:7][CH:8]([CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:13][CH:12]=1)=[O:10].C(O)(=O)C>O>[C:1]([CH2:7][CH:8]([CH3:24])[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=2)=[CH:15][CH:16]=1)=[O:10])#[N:2]
Reactant: [C-]#N
Reactant: CC(CN(C)C)C(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(CC#N)C(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
Potassium cyanide (0.32 g) was added to a cooled (5° C.) solution of 6-[4-(3-dimethylamino-2-methylpropionyl)phenyl]pyridazin-3(2H)-one hydrochloride (1.28 g) and acetic acid (0.25 ml) in water (30 ml). The solution was stirred for 2 hours at less than 23° C., then cooled and a further amount of potassium cyanide (0.32 g) was added. After stirring for one hour the temperature was raised to 50° C. and the reaction mixture was stirred for 2 hours to afford 6-[4-(3-cyano-2-methylpropionyl)phenyl]pyridazin-3(2H)-one (0.61 g), m.p. 196°-201° C. (dec), ν(C=N) 2240 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][OH:48])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:49][C:50]1[C:55]([F:56])=[CH:54][CH:53]=[C:52]([F:57])[C:51]=1O>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][O:48][C:51]4[C:52]([F:57])=[CH:53][CH:54]=[C:55]([F:56])[C:50]=4[Cl:49])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:37][CH2:38]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Oc1c(F)ccc(F)c1Cl
Reactant: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCOc4c(F)ccc(F)c4Cl)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C

Procedure:
This compound is prepared from compound E9 and 2-chloro-3,6-difluorophenol, according to the above-described procedure A. LC-MS: tR=1.22 min, ES+: 831.36.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([OH:14])=O)[CH2:4][CH2:3]1.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:12]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[S:2](=[O:1])(=[O:15])[CH2:3][CH2:4]2)=[O:14])=[CH:22][CH:23]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCS(=O)(=O)c2ccccc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCS(=O)(=O)c3ccccc32)cc1
Yield: 12.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 1,1-dioxothiochroman-4-carboxylic acid (0.26 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.31 g) as starting materials, N-[(4-dimethylaminophenyl) methyl]-N-(4-isopropylphenyl)-1,1-dioxothiochroman-4-carboxamide (0.07 g) was obtained. melting point: 185-187° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Na+].Br[C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[N:18]([CH3:23])[C:17]3[CH2:24][CH:25]4[NH:29][CH:28]([C:16]=3[C:15]=2[C:14]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[CH3:1][C:2]1[CH:3]=[C:4]([S:8]([C:13]2[CH:21]=[C:20]([CH3:22])[C:19]3[N:18]([CH3:23])[C:17]4[CH2:24][CH:25]5[NH:29][CH:28]([C:16]=4[C:15]=3[C:14]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(S(=O)[O-])c1
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Agent: [Na+]
Product: Cc1cccc(S(=O)(=O)c2cc(C)c3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)c1
Yield: 29 %

Procedure:
Intermediate 10 was coupled to the product of Example 71, step C following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, (8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3-methyl-phenyl)sulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (85 mg, 29%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.97-8.05 (m, 1H), 7.71-7.78 (m, 2H), 7.29-7.38 (m, 3H), 5.23 (br s, 1H), 4.72 (br s, 1H), 3.83 (s, 3H), 3.33 (br s, 1H), 2.74 (s, 3H), 2.45 (d, J=16.2 Hz, 1H), 2.38 (s, 3H), 2.11-2.35 (m, 2H), 1.88-1.97 (m, 1H), 1.55-1.64 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][CH:9]=[C:10]3[C:19](N=C4C(C=CC=C4C(O)=O)=N3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cu][C:24]#[N:25].CN(C)C=[O:29]>O>[C:24]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:19]2=[O:29])#[N:25]
Reactant: N#C[Cu]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc2nc3ccc4c(Br)cccc4c3nc12
Solvent: O
Product: N#Cc1cccc2c1CCCC2=O
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5-bromotetralone (see Reference Example 1C)(5.0 g) in N,N-dimethylformamide (20 mL) was added copper (1) cyanide (6.39 g) and the reaction mixture heated to reflux for 20 hours. The reaction mixture was then cooled to 80° C. and a solution of FeCl3.6H2O (24 g) in water (38 mL) was added. After stirring for a further 45 minutes the reaction mixture was cooled, diluted with water, extracted into toluene, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 5-cyano-1-tetralone as a yellow solid.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:31]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:30])[NH:17][S:18]([C:21]1[C:28]([CH3:29])=[CH:27][C:25]([CH3:26])=[CH:24][C:22]=1[CH3:23])(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH:52]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:53]([C:58](ON1C(=O)CCC1=O)=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56].CN1CCOCC1.NCCN1CCNCC1>CN(C)C=O.[Pd]>[NH:52]([C:68]([O:70][C:71]([CH3:73])([CH3:72])[CH3:74])=[O:69])[C@H:53]([C:58]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:31]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:30])[NH:17][S:18]([C:21]1[C:28]([CH3:29])=[CH:27][C:25]([CH3:26])=[CH:24][C:22]=1[CH3:23])(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:59])[CH2:54][CH:55]([CH3:57])[CH3:56]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: Cc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)O)c(C)c1
Agent: [Pd]
Agent: NCCN1CCNCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O)c(C)c1
Reaction time: 5 h
Yield: 90.1 %

Procedure:
In 120 ml of dimethylformamide are dissolved 9.5 g (13 millimoles) of Z-Gln-Arg(Mts)-Leu-OH obtained according to the process of Example 20 and 5.2 g (16 millimoles) of Boc-Leu-OSu, and 1.43 ml of N-methylmorpholine is added to the solution. Then 0.5 g of 10% Pd-C is added to the mixture, and the mixture is stirred for 5 hours in a current of H2. The N-(2-aminoethyl)piperazine is added to the mixture, the mixture is stirred for 1 hour. The 10% Pd-C is recovered by filtration, and the mixture is cancentrated under reduced pressure. The residue is added to a liquid mixture of 100 ml of ethyl acetate and 200 ml of a dilute aqueous solution of citric acid. The mixture is sufficiently stirred, and the ethyl acetate layer is recovered, washed with water, dried and concentrated under reduced pressure. Ether is added to the concentrate and the precipitate is recovered by filtration to obtain 9.5 g of intended Boc-Leu-Gln-Arg(Mts)-Leu-OH (the yield being 86.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH:7]3[CH:11]([C:12](=[O:13])[C:4]=2[CH:3]=1)[CH2:10][N:9]([CH3:14])[CH2:8]3.[CH3:17][Li].[Cl-].[NH4+].O>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH:7]3[CH:11]([C:12]([CH3:17])([OH:13])[C:4]=2[CH:3]=1)[CH2:10][N:9]([CH3:14])[CH2:8]3
Reactant: CN1CC2Cc3ccc(Cl)cc3C(=O)C2C1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN1CC2Cc3ccc(Cl)cc3C(C)(O)C2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 43 g of 6-chloro-3a,4,9,9a-tetrahydro-2-methylbenz[f]isoindolin-4-one in 430 ml of tetrahydrofuran is added dropwise at room temperature with stirring to 170 ml of a ca. 5% solution of methyl lithium in ether in a nitrogen atmosphere and the mixture is stirred for 51/2 hours at room temperature. Thereafter, saturated ammonium chloride solution and water are added and the mixture extracted with methylene chloride. The organic phase is dried over sodium sulphate and evaporated. The residue is crystallised from ether/petroleum ether to yield 6-chloro-3a,4,9,9a-tetrahydro-2,4-dimethylbenz[f]-isoindolin-4-ol. M.P. 125°-130°.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:15][C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:29](=O)[CH:30]([CH3:32])[CH3:31].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:15]([C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:29][CH:30]([CH3:32])[CH3:31])=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccccc1Nc1cc2c(cc1C)N(C(C)C)CCC2(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1ccccc1N(CC(C)C)c1cc2c(cc1C)N(C(C)C)CCC2(C)C
Yield: 34.4 %

Procedure:
Ethyl [(1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (Compound 20, 0.12 g, 0.32 mmol) was dissolved in a 10% acetic acid in acetonitrile solution (2.0 mL). The solution was treated with isobutyraldehyde (0.10 mL, 1.1 mmol) and then sodium cyanoborohydride (22 mg, 0.35 mmol) and the reaction stirred at room temperature for 7 hours. 1 M aqueous NaOH was added until pH=6 was reached and the solution was extracted with ether (2×), washed with brine, and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the residue purified using flash column chromatography (10% ethyl acetate in hexanes) to give the title compound (48 mg) as an oil.
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]([CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[O:21]=[C:22]1[N:28]([CH2:29][CH2:30][CH2:31][CH:32]=O)[CH2:27][CH2:26][CH2:25][O:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:3]([CH:4]([CH3:20])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:14])=[O:13])=[CH:10][CH:11]=1)[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:27][CH2:26][CH2:25][O:24][CH2:23][C:22]1=[O:21])[CH3:2]
Reactant: O=CCCCN1CCCOCC1=O
Reactant: CCN[C@@H](C)Cc1ccc(S(=O)(=O)c2nccs2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCCCN1CCCOCC1=O)C(C)Cc1ccc(S(=O)(=O)c2nccs2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of ethyl-{(S)-1-methyl-2-[4-(thiazole-2-sulfonyl)phenyl]ethyl}-amine (0.326 g, 1.02 mmole), 4-(3-oxo-[1,4]oxazepan-4-yl)-butyraldehyde (0.22 g, 1.2 mmole), and sodium triacetoxyborohydride (0.3 g, 1.4 mmole) in 1,2-dichloroethane (10 mL) was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the residue was partitioned between 5% hydrochloric acid and diethyl ether. The aqueous phase was brought to pH 12 with 25% sodium hydroxide and the mixture was extracted with dichloromethane. The organic phase was dried (magnesium sulfate) and concentrated to give 4-(4-{ethyl-[2-(4-thiazole-2-sulfonylphenyl)-1-methylethyl]amino}butyl)-[1,4]oxazepan-3-one, 145, as an oil. Anal.: Calcd. for C23H34ClN3O4S2.1H2O: C, 51.72; H, 6.79; N, 7.87%. Found C, 51.71; H, 6.49 N, 7.82%.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[S:9]1[C:13]2[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1.O>CS(C)=O>[S:9]1[C:13]2[C:14]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nnsc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a suspension of 60% sodium hydride (1.34 g, 30.7 mmol) in dimethyl sulfoxide (20 mL) was added a solution of trimethylsulfoxonium iodide (6.76 g, 30.7 mmol) in dimethyl sulfoxide (50 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl(2E)-3-(1,2,3-benzothiadiazol-7-yl)acrylate (6.00 g, 25.6 mmol) in dimethyl sulfoxide (130 mL) at 0° C., and the mixture was stirred at room temperature for 6 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (3.00 g, yield 47%).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[O:9]=[CH:10][C:11]([OH:13])=[O:12].[O:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1>CN(C)C=O>[O:9]=[C:10]([C:15]1[O:14][CH:18]=[CH:17][CH:16]=1)[C:11]([O:13][CH3:3])=[O:12]
Reactant: c1ccoc1
Reactant: O=CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(=O)c1ccco1
Reaction time: 72 h
Yield: 38.7 %

Procedure:
Methyl iodide (3.34 ml) was added to a stirred mixture of potassium carbonate (7.4 g) and furan α-oxoacetic acid (5 g) (Fluka) in dimethylformamide (70 ml). The mixture was stirred for 3 days and then partitioned between ethyl acetate and water. The organic phase was washed three times with water, then brine, dried over magnesium sulphate and evaporated. The product (2.1 g) was isolated by column chromatography using gradient elution (Kieselgel:3:1 going to 1:1 hexane:ethyl acetate. δH (250 MHz, CDCl3), 3.96 (3H, s), 6.62-6.65 (1H, m), 7.75-7.78 (2H, m).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][C@H:3]([C:7]([O:9]C)=O)[CH2:2]1.Cl.[O:19]([C:21]#[N:22])[K]>O1CCOCC1.O>[O:9]=[C:7]1[C@@H:3]2[CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][N:4]2[C:21](=[O:19])[NH:22]1
Reactant: N#CO[K]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)NC(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-tert-butyl 3-methyl (3S)-piperazine-1,3-dicarboxylate (AA3) (1.0 eq.) and 6 N aq. HCl sol. (1.0 eq.) in 1,4-dioxane (1 M) was added a sol. of KOCN (2.0 eq.) in H2O (2 M). The reaction mixture was stirred at RT for 2 h, then the organic solvent was removed under reduced pressure. The desired product precipitated from H2O: it was filtered off, washed with cold water and dried at the high vacuum pump. Mother liquors were extracted with EtOAc, the organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10-100% EtOAc/petroleum ether to afford the desired product (H1) as a white powder which was combined with the previously isolated precipitate. 1H-NMR (300 MHz, DMSO-d6, 300K) δ 10.95 (1H, bs), 4.15-4.00 (2H, m), 3.97-3.75 (2H, m), 2.97-2.67 (3H, m), 1.42 (9H, s). MS (ES) C11H17N3O4 requires: 255, found: 256 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[SH:11][CH2:12][CH2:13][CH2:14][SiH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18].C(N(CC)CC)C>C1CCCCC1>[C:1]([S:11][CH2:12][CH2:13][CH2:14][SiH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COC(OC)[SiH2]CCCS
Reactant: CCCCCCCC(=O)Cl
Solvent: C1CCCCC1
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)SCCC[SiH2]C(OC)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
Octanoyl chloride (18.0 g, 0.111 mol) is added dropwise over 30 minutes to a solution of 3-mercaptopropyldimethoxymethylsilane F with CAS number [31001-77-1] (20.0 g, 0.111 mol) and triethylamine (11.2 g, 0.111 mol) in cyclohexane (200 mL) kept at 5° C. under an inert atmosphere. The temperature of the reaction medium remains between 5 and 8° C. The reaction medium is then stirred for 15 hours at room temperature. The precipitate of triethylamine hydrochloride Et3N.HCl is filtered over celite. After evaporating the solvents under reduced pressure at 25° C., S-octanoylmercaptopropyl-dimethoxymethylsilane G with CAS number [828241-23-2] (32.6 g, 0.106 mol) is obtained in the form of a colourless oil with a yield of 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])OC(C)(C)C)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:33]([N:36]=C=O)[CH2:34][CH3:35].C(OC(=O)C)C.C(O)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][C:26]([NH:36][CH2:33][CH2:34][CH3:35])=[O:32])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCCN=C=O
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCCNC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Reaction time: 0.5 h

Procedure:
2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethanamine (example 1, 100 mg, 0.28 mmol) was dissolved in dichloromethane (2 ml) and 1-propyl isocyanate (33.5 mg, 0.39 mmol) was added. The mixture was stirred for 30 min and then the solvent was reduced. After addition of ethylacetate and isopropanol the product precipitated as colourless solid (120 mg, 0.27 mmol, 97%).