Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([C@@H:26]1[CH2:30][S:29][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[N:27]1[C:39](=[O:60])[CH2:40][NH:41][C:42](=[O:59])[NH:43][C:44]1[CH:45]=[C:46]([CH:56]=[CH:57][CH:58]=1)[C:47]([O:49]CC[Si](C)(C)C)=[O:48])=[O:25])([CH3:22])([CH3:21])[CH3:20].S(=O)(=O)(O)O>O1CCCC1.[OH-].[Na+]>[C:19]([O:23][C:24]([C@@H:26]1[CH2:30][S:29][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[N:27]1[C:39](=[O:60])[CH2:40][NH:41][C:42](=[O:59])[NH:43][C:44]1[CH:45]=[C:46]([CH:56]=[CH:57][CH:58]=1)[C:47]([OH:49])=[O:48])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1cccc([C@H]2SC[C@@H](C(=O)OC(C)(C)C)N2C(=O)CNC(=O)Nc2cccc(C(=O)OCC[Si](C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cccc([C@H]2SC[C@@H](C(=O)OC(C)(C)C)N2C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.1 %

Procedure:
At a temperature in the vicinity of 25° C., 13.7 cm3 of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution of 4.2 g of 2-trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(3-methoxyphenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoate in 80 cm3 of tetrahydrofuran. The reaction mixture is stirred for 12 hours at a temperature in the vicinity of 25° C., then acidified with 15 cm3 of a 1N aqueous sulphuric acid solution. After extraction with 3 times 50 cm3 of ethyl acetate, the combined organic phases are washed with 60 cm3 of water, then extracted with 2 times 20 cm3 of a 1N aqueous sodium hydroxide solution. The aqueous phases are separated, washed with 2 times 40 cm3 of ethyl ether, acidified to a pH of 4 with a 4N aqueous sulphuric acid solution and extracted with 3 times 50 cm3 of ethyl ether. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 30° C. The solid obtained is dissolved in 10 cm3 of a 0.5N aqueous sodium hydroxide solution. The solution obtained is filtered and acidified with 5 cm3 of a 1N aqueous hydrochloric acid solution. The insoluble product is separated by filtration, washed with 2 times 5 cm3 of water and dried in air. 1.48 g of (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(3-methoxyphenyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoic acid, melting at 125°, are thus obtained, ([α]D20 =+74°±2° (C=0.32%; DMF)) [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 3.8 (s, 3H, OCH3); 6.85 (bd, 1H, O--C6H4 --C in position 4); 7.2 to 7.6 (m, 6H, aromatic); 8.0 (bs, 1H, N--C6H4 -- in position 2). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2975, 2930, 2830, 2600, 1715, 1690, 1655, 1600, 1555, 1490, 1370, 1230, 1150, 1050, 755, 690, 680].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[NH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:21])[N:11]([CH3:24])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1-c1cnc(-c2ccccc2)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cnc(-c2ccccc2)n(C)c1=O

Procedure:
A mixture of 5-(2-methoxyphenyl)-2-phenyl-3H-pyrimidin-4-one (0.4 g, example 9), methyl iodide (0.134 ml), potassium carbonate (0.398 g) and tetrabutylammonium bromide (0.048 g) in toluene (60 ml) and water (10 ml) was refluxed for 2 hours and then evaporated. The residue was taken up in diethyl ether and insolubles were filtered off. The ether solution was evaporated, and the residue was purified by flash chromatography on silica gel (eluent: n-hexane/ethyl acetate 6:4), to give the title compound in a pure form as a white solid (0.22 g).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[CH:18][C:19]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:20]([CH:30]=1)[C:21]([NH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:22].[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][O:15][C:16]1[CH:17]=[CH:18][C:19]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:20]([CH:30]=1)[C:21]([NH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:22]
Reactant: CN(C)CCO
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A solution of DIAD (252 mg, 1.249 mmol) in toluene (1 ml) was added dropwise to a stirred solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 29; 160 mg, 0.50 mmol), 2-(dimethylamino)ethanol (49.0 mg, 0.549 mmol) and Ph3P (328 mg, 1.25 mmol) in toluene (4 ml) under nitrogen at 0° C. The reaction mixture was stirred at 115° C. overnight. The mixture was then cooled and concentrated. The residue was added to water and extracted with ethyl acetate (3×60 ml). The organic phase was washed with saturated brine (30 ml), dried over sodium sulphate and evaporated in vacuo to give crude product. The crude product was added to a silica gel column (40 g) and was eluted with a 20:1 mixture of DCM/methanol (2 l) to yield the title compound as a yellow solid. 50 mg.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[S:8]1[CH:12]=[CH:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:16]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)O)[C:9]1=2.O>C(#N)C>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:17][C:16]2[C:9]3[S:8][CH:12]=[CH:11][C:10]=3[CH:13]=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(C(O)c2cccc3ccsc23)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(Cc2cccc3ccsc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a suspension of sodium iodide (2.0 g) in acetonitrile was added chlorotrimethylsilane (1.5 g) at room temperature. After the mixture was stirred at room temperature for 15 minutes, benzo[b]thiophen-7-yl-p-tolylmethanol (0.68 g) was added to the mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, and the mixture was extracted with hexane. The organic layer washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (0.57 g) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[CH3:13].[CH3:15][C:16]1[N:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:19][C:20]=1[CH:21]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:21][C:20]2[S:19][C:18]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=3)=[N:17][C:16]=2[CH3:15])=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)CCc1ccc(N)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
To a solution of 3-(4-Amino-2-methyl-phenyl)-propionic acid methyl ester (0.14 g, 0.70 mmol) and 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde (0.19 g, 0.71 mmol) in anhydrous CH2Cl2 (5 mL) is added 4 Å molecular sieves followed by acetic acid (50 μL, 0.87 mmol). The mixture is stirred at RT for 2 h. Sodium triacetoxyborohydride (0.22 g, 1.04 mmol) is added, and the mixture is stirred at RT for 12 h. The reaction is quenched with saturated NaHCO3. The organics are separated and washed with saturated NaHCO3 and brine, and dried with MgSO4. The crude material is purified by flash chromatography to yield the title compound (0.21 g, 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([C:21]([OH:28])([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])#[CH:20]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:20]#[C:19][C:21]([OH:28])([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:3]=1)=[O:17]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: CCCC(O)(C#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1)CCC

Procedure:
Coupling of N-(3-(3-bromophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (25) (55.35 g, 169.7 mmol) with 4-ethynylheptan-4-ol (20) (30.13 g, 214.9 mmol) following the method described in Example 1 gave crude 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)propyl)acetamide (26) as a brown oil which was used in the next step without additional purification. Yield (90.32 g, quant.): 1H NMR (400 MHz, DMSO-d6) δ 9.35 (m, 1H), 7.29-7.34 (m, 3H), 7.22-7.26 (m, 1H), 5.39 (d, J=4.4 Hz, 1H), 5.12 (s, 1H), 4.59 (dt, J=8.4, 4.8 Hz, 1H), 3.25 (quint, J=7.6 Hz, 2H), 1.80 (quint, J=8.0 Hz, 2H), 1.44-1.63 (m, 8H), 0.92 (t, J=7.2 Hz, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22]([CH2:23][N:45]6[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]6)=[C:21]([C:27]([F:29])([F:30])[F:28])[CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(C=O)c(C(F)(F)F)c4)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a solution of 4-[3-(1H-indol-5-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-trifluoromethyl-benzaldehyde (0.12 g, 0.214 mmol) in CH2Cl2 (3 mL) was added 1-methylpiperazine (32 mL, 0.32 mmol) and sodium triacetoxyborohydride (136 mg, 0.64 mmol). The reaction mixture was stirred for 1 hr at room temperature, after which it was partitioned between CH2Cl2 and 1 M NaOH. The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in 3:2 MeOH:acetone (5 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 65° C. for 30 min, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to provide a residue that was subjected to silica gel column to yield 3-(1H-indol-5-yl)-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-1H-pyrrolo[2,3-b]pyridine (0.024 g, 24% yield). 1H NMR (CDCl3, 400 MHz): δ 11.89 (s, 1H), 11.07 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.89 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.46 (dd, J=1.8, 6.4 Hz, 2H)), 7.34 (d, J=2.4 Hz, 1H), 6.46 (s, 1H), 3.63 (s, 2H), 3.32 (s, 3H), 2.49-42 (m, 8H), 2.14 (s, 3H); MS ESI (m/z) 490 (M+1)+, calc. 489.53.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10]([Cu])#[N:11].C(N)CN>CC(N(C)C)=O>[NH2:8][C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([C:10]#[N:11])=[CH:7][N:6]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: N#C[Cu]
Solvent: NCCN
Solvent: CC(=O)N(C)C
Product: Cc1cc(N)ncc1C#N
Temperature: 170 °C
Reaction time: 20 h
Yield: 86.9 %

Procedure:
A mixture of 5-bromo-4-methyl-pyridin-2-ylamine (500 mg, 2.67 mmol), CuCN (478 mg, 5.34 mmol) and DMA (2 mL) was stirred under nitrogen for 20 h at 170° C. The reaction mixture was cooled and added to 50 mL of a 20% aqueous solution of ethane-1,2-diamine. The layers were separated and the aqueous layer was extracted 3× with EtOAc. The combined organics were washed with water followed by brine and dried over MgSO4. Concentration in vacuo afforded compound 851A (309 mg, 87%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][SH:23])[CH3:16].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][S:23][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2)[CH3:16]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Brc1ccc2c(ccc3nnnn32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nnnn32)c1
Temperature: 130 °C

Procedure:
9d (233 mg, 0.88 mmol) and 3-mercaptopropionic acid 2-ethylhexyl ester (86 mg, 0.38 mmol) were dissolved in 1,4-dioxane (10 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.33 mL, 1.80 mmol) was added, followed by Pd2dba3 (20 mg, 0.02 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol). The reaction was sealed and heated overnight at 130° C., and then cooled to room temperature and diluted with EtOAc and water. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-20% MeOH in EtOAc) to give the desired product, 9e.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:18]2[O:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[CH:23]=2)[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[O:13]C.C(O)C>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([C:18]2[O:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22](=[O:24])[CH:23]=2)[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[OH:13]
Reactant: COc1cc(-c2cc(=O)c3ccccc3o2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: O=c1cc(-c2cc(O)c(O)c([N+](=O)[O-])c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 ml of boron tribromide in 50 ml of methylene chloride are added dropwise within 30 minutes at -10° to a solution of 1.0 g of 2-(3,4-dimethoxy-5-nitrophenyl)-4H-1-benzopyran-4-one in 100 ml of methylene chloride under an argon atmosphere, whereupon the mixture is stirred at room temperature overnight. After cooling to -20°, 20 ml of ethanol are added dropwise thereto. The mixture is then evaporated in a water-jet vacuum. The yellow residue obtained is extracted with water/ethyl acetate. The organic phase is washed with water, dried over sodium sulfate and evaporated. After recrystallization from ethanol/ethyl acetate, there is obtained 2-(3,4-dihydroxy-5-nitrophenyl)-4H-1-benzopyran-4-one in the form of yellow crystals of m.p. >240° (dec.).
Reaction SMILES: [NH3:1].[N:2]1([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[C:16]4[C:17]5[C:22]([S:23][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:21][CH:20]=[C:19]([CH2:28][C:29]([O:31]CC)=O)[CH:18]=5)[CH2:10][CH2:9]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1>C(O)C>[N:2]1([CH:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]3[C:16]4[C:17]5[C:22]([S:23][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:21][CH:20]=[C:19]([CH2:28][C:29]([NH2:1])=[O:31])[CH:18]=5)[CH2:12][CH2:13]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)Cc1ccc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c2c1
Reactant: N
Solvent: CCO
Product: NC(=O)Cc1ccc2sc3ncnc(NC4CCC(N5CCOCC5)CC4)c3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Into a saturated solution of ammonia (gas) in ethanol (50 mL) was added ethyl 2-(3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0 [2,7]]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl)acetate (100 mg, 0.22 mmol, 1.00 equiv) and the resulting solution was sealed and stirred overnight at room temperature. After completion, the solvent was removed under reduced pressure. The residue was applied onto a silica gel column with dichloromethane/methanol/NH4OH (15:1:0.05) to provide the resulted 2-(3-[[4-(morpholin-4-yl)cyclohexyl]amino]-8-thia-4,6-diazatricyclo[7.4.0.0 [2,7]]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl)acetamide (38.5 mg, 41%) as a off-white solid. LC/MS: (ES, m/z) 426 [M+H]+. 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.93-7.91 (d, 1H), 7.75 (s, 1H), 7.45-7.40 (t, 1H), 5.46-5.42 (d, 2H), 5.35-5.32 (d, 2H), 4.31-4.16 (m, 1H), 3.81-3.79 (m, 6H), 2.64-2.60 (d, 3H), 2.46-2.40 (d, 3H), 2.07-1.98 (m, 2H), 1.58-1.55 (m, 2H), 1.48-1.42 (m, 2H).
Reaction SMILES: C(O[C:4]([S-])=[S:5])C.[K+].[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[NH2:18])[C:14]([CH3:20])([CH3:19])[C:13](=[O:21])[C:12]2([CH3:23])[CH3:22].C(O)(=O)C>O>[SH:5][C:4]1[NH:18][C:17]2[CH:16]=[C:15]3[C:11](=[CH:10][C:9]=2[N:8]=1)[C:12]([CH3:23])([CH3:22])[C:13](=[O:21])[C:14]3([CH3:19])[CH3:20]
Reactant: CCOC(=S)[S-]
Reactant: CC1(C)C(=O)C(C)(C)c2cc(N)c(N)cc21
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Temperature: 20 °C
Yield: 78.8 %

Procedure:
20 ml of water and 17.0 g of purified potassium ethylxanthate were added to 20.0 g of 5,6-diamino-1,1,3,3-tetramethyl-2-indanone, dissolved in 200 ml of alcohol, in a 750 ml sulfonation flask equipped with stirrer, thermometer, reflux condenser. The mixture was left to boil at reflux overnight, then diluted with 200 ml of water, neutralized with 20 ml of glacial acetic acid and stirrer at 60°-70° C. for an additional 1 hour. After cooling to 20° C., were removed by filtration under suction. There were obtained 18.8 g (78.9% of theory) of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno(5,6-d)-imidazol-6(1H)-one with a melting point above 300° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:34]CCCCC.C([Li])CCC.CI>C1COCC1>[C:16]1([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]2[CH:14]=[C:10]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH3:34])[N:11]=[CH:12]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCC
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of diethyl(1-triphenylmethylimidazol-4-yl)methylphosphonate (690 mg, 1.5 mmol) in THF (20 ml) was added 1.6M hexane solution of n-butyllithium (0.94 ml, 1.5 mmol) dropwise over 10 minutes at −72° C. under argon flow, followed by adding a solution of methyl iodide (213 mg, 1.5 mmol) in THF (5 ml) dropwise over 10 minutes. After stirring at the same temperature for 30 minutes, the reaction mixture was heated to room temperature, and then stirred at room temperature for 2 hours. The reaction was quenched with water (1 ml), and then the THF was removed under reduced pressure. Saturated brine (40 ml) was added to the residue, and the mixture was extracted 3 times with ethyl acetate (40 ml). The resultant organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product as a light yellow solid. It was purified through chromatography on silica gel column using methanol-ethyl acetate (1:9) to provide the titled compound (690 mg, 97%) as a white powder (m.p. 124-126° C.). This powder was recrystallized from a mixture of ethyl acetate and hexane to provide the title compound as a small needle crystal (m.p. 125-128° C.).
Reaction SMILES: [F:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[CH:6](Cl)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[F:1][C:2]1[C:17]([F:18])=[CH:16][C:5]2[CH:6]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Fc1cc2c(cc1F)C(Cl)Cc1ccccc1S2
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2Cc3ccccc3Sc3cc(F)c(F)cc32)CC1

Procedure:
A mixture of 7,8-difluoro-10-chloro-10,11-dihydrodibenzo(b,f)thiepine (5.08 g), 1-methylpiperazine (4 ml) and chloroform (5 ml) was refluxed for 7 hours. Chloroform was evaporated and the residue shaken with water and benzene. The organic layer was washed with water and shaken with dilute (1:2) hydrochlorid acid (50 ml). The formed suspension was filtered and the thus-obtained solid hydrochloride added to the aqueous layer of the filtrate. Addition of 15% sodium hydroxide solution liberated the desired base which was extracted with benzene, m.p. 106°-108° C. (acetone). Neutralization of this base with methanesulfonic or maleic acid in ethanol, followed by the addition of ether, yields the corresponding salts, i.e., the methanesulfonate (m.p. 244°-247° C.) or maleate (hemihydrate, m.p. 161°-163° C.), which were purified by crystallization from a mixture of ethanol and ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](O)=[S:12])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][O:23][N:22]([CH3:21])[C:11]([C:6]1[NH:7][C:8]2[C:4]([C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[S:12]
Reactant: CNOC
Reactant: OC(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=S)c1[nH]c2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared from 5-chloro-3-phenylthioindole-2-carboxylic acid (1.0 g, 3.30 mmol)) N,O-dimethylhydroxylamine hydrochloride (0.64 g, 6.6 mmol), triethylamine (1.0 mL, 7 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (1.64 g, 3.6 mmol) in dimethylformamide according to the general procedure described in Example 1 for the preparation of N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1COCC1>[CH3:16][S:17]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)(=[O:19])=[O:18]
Reactant: OCCn1cccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCn1cccc1

Procedure:
The 1-(2-hydroxyethyl)pyrrole (TCI-US, 0.138 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.