Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.C(Cl)(=O)C([Cl:15])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][Cl:15]
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1ccc(Cl)nc1Cl
Yield: 113.1 %

Procedure:
A solution of 2,6-dichloronicotinic acid (3.84 g), oxalyl chloride (2.0 g), and 1 drop of dimethylformamide in dichloromethane (25 ml), was stirred at room temperature for 18 hours. The solution was concentrated in vacuo to give 3.50 g of 2,6-dichloronicotinyl chloride which was added portionwise in dichloromethane (25 ml) to an ice cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (2.15 g) and diisopropylethylamine (2.03 g) in dichloromethane (50 ml). The mixture was stirred at room temperature for 18 hours and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate and filtered through a short column of anhydrous sodium magnesium silicate. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield 2.65 g of the title as an amorphous solid. m.p. 115-130° C. MS, m/z: 358.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C@@H:8]1[CH2:17][N:16]2[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]2)[CH2:10][N:9]1CC1C=CC=CC=1)([CH3:4])[CH3:3].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:4][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C@@H:8]1[CH2:17][N:16]2[C@H:11]([CH2:12][O:13][CH2:14][CH2:15]2)[CH2:10][NH:9]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Temperature: 80 °C
Reaction time: 1.25 h
Yield: 94.7 %

Procedure:
To a stirred solution of (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-8-(phenylmethyl)octahydropyrazino[2,1-c][1,4]oxazine (D106, 22.2 g, 0.059 moles) in 660 ml of methanol at room temperature under nitrogen, palladium on carbon (10 wt %, wet, 6.28 g, 0.006 moles) and ammonium formate (37.2 g, 0.59 moles) were added. The resulting mixture was stirred at 80° C. for 1-1.5 hours. The resulting mixture was then allowed to cool down to room temperature and filtered over Celite. The filtrate was concentrated under vacuum to afford the title compound (16 g) as pale yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[S:3])[NH2:2].Br[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21]>O1CCOCC1>[F:21][C:20]([F:23])([F:22])[C:19]1[N:2]=[C:1]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[S:3][CH:18]=1
Reactant: COC(=O)C(C)c1ccc(NC(N)=S)cc1
Reactant: O=C(CBr)C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)C(C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
In a 250 ml round-bottomed flask equipped with condenser and magnetic stirrer, a solution of methyl 2-[4-(carbamothioylamino)phenyl]propanoate (10.7 g, 48.4 mmol) in 1,4-dioxane (200 ml) was treated at room temperature with 3-bromo-1,1,1-trifluoro-propan-2-one (5 ml, 48.4 mmol) and the reaction mixture was refluxed for 2 h. After cooling at room temperature, the solvent was distilled under vacuum, the residue dissolved in CH2Cl2 (200 ml), washed with a saturated solution of NaHCO3 (3×100 ml), dried over anhydrous Na2SO4 and evaporated under vacuum to give pure methyl 2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate (12.8 g, 38.7 mmol) as yellow oil (80%).
Reaction SMILES: I[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH2:16])[C:10]([CH3:15])=[C:11]([CH:12]([CH3:14])[CH3:13])[C:5]=2[O:4]1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH:12]([C:11]1[C:5]2[O:4][C:3]([CH3:18])([CH2:2][N:28]3[CH2:29][CH2:30][CH:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[CH2:7][C:6]=2[C:8]([CH3:17])=[C:9]([NH2:16])[C:10]=1[CH3:15])([CH3:14])[CH3:13]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CI)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CN1CCC(c3ccccc3)CC1)O2
Yield: 45.8 %

Procedure:
A suspension of 2,3-dihydro-2-(iodomethyl)-7-isopropyl-2,4,6-trimethyl-5-benzofuranamine (1.1 g), 4-phenylpiperidine (0.87 g) and potassium carbonate (0.83 g) in N,N-dimethylacetamide (6 mL) was refluxed for 4.5 hours. The mixture was diluted with water and the product was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtrated and evaporated in vacuo. The residue was purified with basic silica gel column chromatography (hexane:ethyl acetate=30:1 to 10:1) and recrystallized from hexane/ethyl acetate to afford 0.55 g of the title compound. Yield 47%.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[C:44]2[O:43][CH2:42][CH2:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[C:44]5[O:43][CH2:42][CH2:41][C:40]=5[CH:39]=[CH:38][CH:37]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc2c1OCC2
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1cccc2c1OCC2
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2,3-dihydrobenzofuran-7-sulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:26][NH2:27])[CH3:25]>CO>[CH2:24]([O:26]/[N:27]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][N:14]=2)[N:17]=1)\[CH3:22])[CH3:25]
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: CCON
Solvent: CO
Product: CCO/N=C(\C)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 46.1 %

Procedure:
A solution of 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (41.2) (30 mg, 0.099 mmol) and O-ethylhydroxylamine (18.12 mg, 0.297 mmol) in 5 mL of MeOH was stirred at rt overnight. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA) to give 15.8 mg (46.1%) of the title compound as a white TFA salt. 1H-NMR (400 MHz, MeOH-d4 δ ppm 9.05 (s, 1H), 8.85 (d, 1H), 8.23 (s, 1H), 8.12 (m, 3H), 7.98 (d, 1H), 7.89 (m, 1H), 4.91 (s, 2H), 4.36 (q, 2H), 2.30 (s, 3H), 1.36 (t, 3H). LC-MS (method B): [MH]+=347.1.1, tR=2.50 min.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6][N:7]=1.S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[NH2:1][C:2]1[NH:7][CH2:6][CH:5]([C:8]([O:10][CH3:15])=[O:9])[CH2:4][N:3]=1
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NC1=NCC(C(=O)O)CN1
Product: COC(=O)C1CN=C(N)NC1
Product: Cl

Procedure:
2-Amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid (0.1 g, 0.5 mmol) and thionyl chloride (0.2 mL, 1.4 mmol) were refluxed in methanol for 24 h, and then evaporated to dryness in vacuo to give 2-amino-5-methyloxycarbonyl-1,4,5,6-tetrahydropyrimidine hydrochloride. 2-Amino-5-methyloxycarbonyl-1,4,5,6-tetrahydropyrimidine hydrochloride (0.1 g, 0.6 mmol) and N,N-dimethylhydrazine 98% (0.4 mL, 5.3 mmol) were refluxed in anhydrous methanol (20 mL) for 2 h, then evaporated to dryness in vacuo to give a white residue. Recrystallization of the residue from absolute ethanol and diethyl ether gave crystals (40 mg, 58%) of 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic-(N,N-dimethyl)hydrazide as the hydrochloride salt: mp 192°-193° C.; 1H NMR (D2O): δ2.8 (s, 1H), 3.0 (m, 1H), 3.50 (d, 4H), 3.65 (s, 6H); MS m/z 156 (M+ of free base). Anal. (C7H16N5OCl) C, H, N.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][NH:20][CH3:21])[C:10]2=[O:22])[CH2:7][CH2:6][C:5](=[O:23])[NH:4]1.[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl.O>[C:24]([NH:28][C:29](=[O:30])[N:20]([CH2:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17](=[O:18])[N:9]([CH:8]1[CH2:7][CH2:6][C:5](=[O:23])[NH:4][C:3]1=[O:2])[C:10]2=[O:22])[CH3:21])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N=C=O
Reactant: CNCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a suspension of 2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dione hydrochloride (0.65 g, 1.93 mmol) and t-butyl-isocyanate (0.26 mL, 2.31 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.47 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was added water (40 mL) and 1N HCl (40 mL). The mixture was quenched with MeOH and extracted with H2O (40 mL), then with 1N HCl (40 mL). The organic layer was washed with brine (40 mL) and concentrated on rota-vap. The resulting oil was purified on silica gel column to give 3-tert-butyl-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.59 g, 76%): mp 188-190° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.14 (96%); 1H NMR (DMSO-d6): δ 1.28 (s, 9H), 2.08 (m, 1H), 2.64-2.50 (m, 2H), 2.85 (s, 3H), 2.87-2.95 (m, 1H), 4.87 (s, 2H), 5.14-5.18 (dd, J=5.3, 12.6 Hz, 1H), 5.71 (s, 1H), 7.50-7.52 (m, 1H), 7.79-7.88 (m, 2H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 29.13, 30.90, 34.81, 47.02, 48.82, 50.07, 121.70, 127.45, 131.73, 132.49, 134.78, 139.63, 157.40, 166.95, 167.61, 169.80, 172.73. Anal Calcd for C20H24N4O5: C, 59.99; H, 6.04; N, 13.99. Found: C, 59.87; H, 6.01; N, 13.83.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.C([N:34]1[CH2:38][CH2:37][NH:36][C:35]1=[O:39])(=O)C>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[CH2:38][CH2:37][NH:36][C:35]4=[O:39])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 16 %

Procedure:
Using [4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 166 and 1-acetylimidazolidin-2-one (96 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (40 mg) was obtained.
Reaction SMILES: C(C[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](=[O:16])[CH3:15])#N.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[C:18]([CH2:19][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14](=[O:16])[CH3:15])([OH:21])=[O:20]
Reactant: CC(=O)O
Reactant: CC(=O)CCc1ccccc1CCCC#N
Agent: Cl
Product: CC(=O)CCc1ccccc1CCCC(=O)O

Procedure:
A solution of 50 g (0.23 mol) of 4-[2-(3-cyanopropyl)phenyl]-2-butanone, 8 in 125 ml glacial acetic acid and 125 ml concentrated HCl was refluxed overnight. The solution was evaporated and the residue diluted with H2O. The precipitate was recrystallized from benzene-petroleum either to give 42.5 g of the keto acid 9, mp 59°-61° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(Cl)Cl.[CH3:11][Si:12]([CH3:15])(Cl)Cl>>[CH3:1][SiH2:2][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][SiH2:12][CH3:15]
Reactant: C[Si](C)(Cl)Cl
Reactant: C[Si](Cl)(Cl)c1ccccc1
Product: C[SiH2]C
Product: C[SiH2]c1ccccc1

Procedure:
The procedure of Reference Example 2 was followed, but using a mixture of 60 g methylphenyldichlorosilane and 90 g dimethyldichlorosilane in place of the methylphenyldichlorosilane used in Reference Example 2. The product was a methylphenylsilanedimethylsilane copolymer with an average molecular weight of 40,000 and a softening point of 125 degrees Centigrade.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:49][CH2:48][CH:47]=[CH:46][CH2:45][N:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:41][C@H:42]1[CH2:49][CH2:48][CH:47]=[CH:46][CH2:45][N:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:43]1=[O:56])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCC=CCN(c2ccccc2)C1=O
Agent: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC/C=C\CN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N21
Agent: N[C@H]1CC/C=C\CN(c2ccccc2)C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCC=CCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S,Z)-2-oxo-1-phenyl-1,2,3,4,5,8-hexahydroazocin-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (11 mg, 0.019 mmol) and Intermediate 63 (5.6 mg, 0.022 mmol) to give a white solid (3.5 mg, 25% yield). Anal. Calcd. for C44H52N4O6S m/z 764.4. found: 765.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.09 (16H, m), 7.00 (1H, d, J=7.1 Hz), 5.98-5.87 (1H, m), 5.60 (1H, d, J=11.5 Hz), 5.34 (1H, t, J=4.7 Hz), 5.11-5.05 (1H, m), 5.04-4.84 (3H, m), 4.06-3.97 (1H, m), 3.66 (3H, s), 3.08-2.99 (1H, m), 2.87-2.70 (5H, m), 2.49-2.33 (4H, m), 2.13-1.96 (3H, m), 1.88-1.73 (3H, m), 1.71-1.51 (7H, m), 1.38-1.28 (1H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]([CH2:8]Cl)=[C:6]([CH3:10])[S:5][C:4]=1[CH3:11].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:4]1[S:5][C:6]([CH3:10])=[C:7]2[CH2:8][N:21]([S:18]([C:15]3[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=3)(=[O:19])=[O:20])[CH2:2][C:3]=12
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1sc(C)c(CCl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3c(C)sc(C)c3C2)cc1
Yield: 63.6 %

Procedure:
A solution of 10 g (0.048 mol) of 3,4-bis(chloromethyl)-2,5-dimethylthiophene and 8.22 g of p-toluenesulphonamide in 600 ml of dry dimethylformamide is added dropwise, over 6 h, to a stirred suspension, heated to 100°-110° C., of 180 g of potassium carbonate in 900 ml of dimethylformamide. After the end of the addition, the mixture is maintained at the same temperature for 30 min, and then filtered. The solid is washed with dimethylformamide. The filtrate is concentrated under vacuum, and the residue is treated with 100 ml of ethanol, and filtered. The solid residue remaining is washed with ethanol and dried. 9.39 g of product are obtained. Melting point: 163°-164° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11]3=[C:12]([C:14]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]=4[N:10]3[CH2:9][CH2:8][CH2:7]2)[CH:13]=1)([O-])=O>[Pd].C(O)C>[CH:13]1[C:12]2[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[N:10]3[C:11]=2[C:6]([CH2:7][CH2:8][CH2:9]3)=[CH:5][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reaction time: 48 h
Yield: 10.2 %

Procedure:
A mixture of 2-nitro-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinoline (0.30 g, 11 mmol) and 5% palladium on carbon (0.10 g) in ethanol (35 mL) was shaken on a Parr hydrogenator under an atmosphere of hydrogen (45 PSI) for 48 h. The reaction mixture was filtered through Celite® and the filter bed was washed with ethanol. The filtrate was concentrated to provide 0.27 g of 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine.
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8][C:9]1[C:10]([CH3:28])=[CH:11][C:12]([C:26]#[N:27])=[C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[NH:22]C(=O)[O-])[CH:14]=1>C(O)C>[NH2:22][C@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:16]1[NH:15][C:13]1[CH:14]=[C:9]([Cl:8])[C:10]([CH3:28])=[CH:11][C:12]=1[C:26]#[N:27]
Reactant: Cc1cc(C#N)c(N[C@H]2CCCC[C@@H]2NC(=O)[O-])cc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)c(N[C@H]2CCCC[C@@H]2N)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4 M Hydrogen chloride/ethyl acetate (20 ml) was added to an ethanol solution of {(1S,2S)-2-[(5-chloro-2-cyano-4-methylphenyl)amino]cyclohexyl}carbamate, followed by stirring at room temperature for 12 hours. By concentrating the reaction liquid under a reduced pressure, 2-{[(1S,2S)-2-aminocyclohexyl]amino}-4-chloro-5-methylbenzonitrile was obtained.
Reaction SMILES: Cl.[N:2]1(N=C2CCCC(O)=C2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.Cl.[CH3:21][C:22]([OH:24])=O>>[CH:9]1[CH:8]=[CH:7][C:6]2[CH2:5][CH2:4][CH2:3][N:2]3[C:11]=2[C:10]=1[C:3]1[C:22](=[O:24])[CH2:21][CH2:6][CH2:5][C:4]=13
Reactant: OC1=CC(=NN2CCCc3ccccc32)CCC1
Reactant: CC(=O)O
Agent: Cl
Product: O=C1CCCc2c1c1cccc3c1n2CCC3
Temperature: 25 °C
Yield: 33 %

Procedure:
3-(3,4-Dihydro-1(2H)-quinolinylimino)-1-cyclohexen-1-ol hydrochloride (4.78 g, 17 mmol) was mixed with AcOH (37 mL) and conc. HCl (6.1 mL). The reaction mixture was refluxed for lh and cooled to RT. The reaction mixture was concentrated in vacuo then the residue was dissolved in CH2Cl2. The organic solution was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel (hex:EtOAc 1:1) to give 5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one (1.25 g, 33%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1(C)[C:6](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:20]1[C:21]([N:42]2[CH2:47][CH2:46][CH2:45][C@@H:44]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:43]2)=[C:22]2[C:28]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])=[CH:27][N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:23]2=[N:24][CH:25]=1.CC#N.O>O1CCOCC1.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>[C:52]([O:51][C:49]([NH:48][C@@H:44]1[CH2:45][CH2:46][CH2:47][N:42]([C:21]2[C:20]([C:2]([CH3:6])=[CH2:1])=[CH:25][N:24]=[C:23]3[N:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:27]=[C:28]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[C:22]=23)[CH2:43]1)=[O:50])([CH3:54])([CH3:53])[CH3:55]
Reactant: CC(C)C(=O)Nc1cn(C(=O)OC(C)(C)C)c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1cnc2c(c(NC(=O)C(C)C)cn2C(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 50.3 %

Procedure:
4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (174 mg, 1.03 mmol), PS-palladium tetrakis (470 mg, 0.0517 mmol, 0.10 mmol/1 g) and 2N sodium carbonate (775 μL, 1.55 mmol) were added to (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (300 mg, 0.517 mmol; Example 81, Step A) in degassed dioxane (1 mL). The reaction was heated to 120° C. for 1 hour under microwave irradiation. 4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (174 mg, 1.03 mmol) and 2N sodium carbonate (775 μL, 1.55 mmol) were added, and the reaction was heated to 120° C. for an additional 2 hours. The reaction mixture was then cooled down and filtered. The filtrate was diluted with DCM washed with water. The layers were separated. The organic phase was dried (MgSO4) and concentrated, and the resulting residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-100% CH3CN/water) to yield (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (141 mg, 50% yield) as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>C1(C)C=CC=CC=1>[C:22]([NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)C(=O)Cl
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NCCC[Si](OCC)(OCC)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
A solution of 3-aminopropyltriethoxysilane (20.0 g) in toluene (200 ml) was added to a 500 ml three neck flask equipped with magnetic stir bar, addition funnel, and nitrogen inlet. A total of 9.11 g of triethylamine was added to the solution and the solution was cooled to 0° C. in an ice bath. A total of 9.41 g of methacryloyl chloride was added dropwise to the reaction by the addition funnel at a rate such that the temperature did not exceed 5° C. The reaction was stirred overnight with gradual warming to room temperature. The reaction mixture was then washed 4 times with 200 ml of ice water, dried over magnesium sulfate and concentrated under vacuum. The yield was 38.4 percent and the reaction product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:11]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:23]#[N:24].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10][CH2:11][C:23]#[N:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC#N)c1ccccc1
Yield: 107.6 %

Procedure:
A solution of methanesulfonic acid (S)-3-tert-butoxycarbonylamino-3-phenylpropyl ester (2.0 g) and sodium cyanide (0.97 g) in DMF (10 ml) was stirred at 70° C. for 16 hours. The reaction mixture was partitioned between water (50 ml) and ethyl acetate (50 ml), and the aqueous phase was reextracted (2×50 ml). The combined organic phases were dried over magnesium sulfate and concentrated. This gave the product (1.7 g) with a molecular weight of 260.3 g/mol (C15H20N2O2); MS (ESI): m/e=261 (M+H+).