Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.CCCCCC.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[CH:19]([O:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25](OC)=[O:26])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH:19]([O:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH3:11])=[CH:17][N:16]=1)=[O:26])([CH3:21])[CH3:20]
Reactant: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ncccc1C
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ncccc2C)nc1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
A 2M solution of trimethylaluminium in hexane (0.404 mL, 0.81 mmol) was added to 5-methylpyridin-2-amine (84 mg, 0.77 mmol) in toluene (22 mL) at 5° C. under nitrogen. The resulting solution was stirred at 5° C. for 20 minutes. (2S)-Methyl 3-isopropoxy-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (300 mg, 0.70 mmol) (Intermediate J5) in toluene (6 mL) was added dropwise at 5° C. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. The solution was allowed to cool to ambient temperature. The reaction mixture was concentrated, diluted with EtOAc (100 mL) and washed sequentially with 1M citric acid (50 mL), then saturated brine (50 mL). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with EtOAc to afford (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (160 mg, 51%). 1H NMR (400 MHz, CDCl3) δ 1.09-1.12 (6H, m), 2.23 (3H, s), 2.26 (3H, s), 3.62-3.68 (1H, m), 4.00-4.09 (2H, m), 5.97 (1H, t), 7.30-7.33 (1H, m), 7.56-7.59 (1H, d), 7.70-7.73 (1H, d), 8.01-8.01 (1H, s), 8.21 (1H, d), 8.44 (1H, s), 8.46 (1H, m) 8.53 (1H, s), 9.5 (1H, broad s); m/z (ESI+) (M+H)+=448; HPLC tR=1.98 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][C:30]=2[C:38]([F:41])([F:40])[F:39])[CH2:24][CH2:23]1)[CH3:21].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:20]([N:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]4[CH:17]=[C:16]5[C:12]([CH2:13][C:14](=[O:18])[NH:15]5)=[CH:11][CH:10]=4)[CH:3]=3)=[O:34])=[CH:31][C:30]=2[C:38]([F:41])([F:39])[F:40])[CH2:26][CH2:27]1)[CH3:21]
Reactant: Nc1cccc(Nc2ccc3c(c2)NC(=O)C3)c1
Reactant: CCN1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)NC(=O)C5)c3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(3-amino-phenylamino)-1,3-dihydro-indol-2-one (120 mg, 0.50 mmol, prepared as described in Example 1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid hydrochloride (213 mg, 0.60 mmol) in DMF (5 mL) is added N,N-diisopropylethylamine (437 μL, 2.5 mmol) followed by addition of HATU (191 mg, 0.50 mmol). The mixture is stirred at ambient temperature overnight. The mixture is diluted with EtOAc and washed with 10% Na2S2O3 aqueous solution and brine. The organic layer is separated, dried over MgSO4, and concentrated. The crude is purified by column chromatography (CH2Cl2/CH3OH=9:1) to give the desired compound. LC-MS: 538.2 (MH+).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:38])(=[O:37])[CH:31]([CH2:33][C:34]([OH:36])=[O:35])[OH:32].C(O)CC>CC(N(C)C)=O>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:33]([C:34]([OH:36])=[O:35])[C@H:31]([OH:32])[C:30]([OH:38])=[O:37]
Reactant: O=C(O)CC(O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCCO
Solvent: CC(=O)N(C)C
Product: O=C(O)C[C@H](O)C(=O)O
Temperature: 25 °C

Procedure:
2 g of sunitinib base were suspended in 6 ml of DMA under stirring at RT. 0.673 g of Malic acid were added to the mixture and the temperature was set at 40° C. 40 ml n-propanol were dropped in 3 minutes, the suspension was cooled to 0° C., filtered and washed with 10 ml n-propanol. Dried at 70° under vacuum for 16 h.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([N+:10]([O-:12])=O)=[C:6]([CH:9]=1)[CH:7]=O.[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.[C-:24]#[N:25].[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]2[C:6](=[C:7]([C:24]#[N:25])[N:21]([C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][CH:19]=3)[N+:10]=2[O-:12])[CH:9]=1
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [C-]#N
Reactant: Nc1ccc(F)cc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N#Cc1c2cc(Br)c([N+](=O)[O-])cc2[n+]([O-])n1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
To a stirred suspension of 5-bromo-2,4-dinitrobenzaldehyde (6.5 g, 0.024 mol) in acetic acid (120 mL) was added 4-fluoroaniline (9.28 g, 0.054 mol) and the reaction mixture was heated to 60° C. to get a clear solution. To this was added sodium cyanide portionwise (6.0 g, 0.123 mol) and the reaction mixture was stirred at 60° C. for 5 min. Acetic anhydride (1.9 mL, 0.020 mol) was added and the reaction mixture was stirred for 5 min at the same temperature. Sodium cyanide (6.0 g, 0.123 mol) was then added at the same temperature at which time the product precipitated out. After stirring for 30 min, the mixture was cooled to RT, diluted with water (50 mL), filtered and washed with ethanol to afford crude product, which was purified by flash column chromatography eluting with PE/EtOAc (100/1) to give pure 5-bromo-3-cyano-2-(4-fluorophenyl)-6-nitro-2H-indazole 1-oxide (5.0 g, 56%). 1H-NMR (CDCl3, 400 MHz) δ 8.40 (s, 1H), 8.15 (s, 1H), 7.67˜7.70 (m, 2H), 7.38˜7.42 (m, 2H). MS (M+H)+: 377/379.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[CH:16][CH:17]=3)[C:12]2=[O:22])=[CH:7][CH:6]=1)[CH3:4].I[CH3:24]>C(#N)C.O.C(OCC)(=O)C.[Ag]=O>[CH3:21][O:20][C:15]1[CH:14]=[C:13]2[C:18]([CH2:19][N:11]([C:8]3[CH:7]=[CH:6][C:5]([CH:3]([CH3:4])[CH2:2][O:1][CH3:24])=[CH:10][CH:9]=3)[C:12]2=[O:22])=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1ccc(C(C)CO)cc1)C2
Reactant: CI
Agent: O=[Ag]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCC(C)c1ccc(N2Cc3ccc(OC)cc3C2=O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 72 %

Procedure:
A mixture of 2-(4-(1-hydroxypropan-2-yl)phenyl)-6-methoxyisoindolin-1-one (0.042 g, 0.14 mmol), silver oxide (0.196 g, 0.42 mmol), iodomethane (0.070 mL) and 4 Å molecular sieves (0.050 g) in acetonitrile (2 mL) was stirred for 96 h at room temperature. After this time, the mixture was diluted with water (10 mL) and ethyl acetate (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an off-white solid Purification by flash chromatography (silica, 1:1 ethyl acetate/hexanes) afforded 6-methoxy-2-(4-(1-methoxypropan-2-yl)phenyl)isoindolin-1-one (0.031 g, 72%) as a white solid: mp 116-118° C.; 1H NMR (300 MHz, CDCl3) δ 7.78 (dd, J=8.7, 2.0 Hz, 2H), 7.40-7.38 (m, 2H), 7.29 (dd, J=8.6, 1.9 Hz, 2H), 7.15 (dd, J=8.3, 2.4 Hz, 1H), 4.78 (m, 2H), 3.89 (s, 3H), 3.55-3.41 (m, 2H), 3.34 (s, 3H), 3.04 (q, J=7.0 Hz, 1H), 1.29 (d, J=7.0 Hz, 3H); ESI MS m/z 312 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].[H-].[Na+].[CH3:28]I>CN(C)C=O.CCOCC>[CH3:28][O:18][CH:17]([C:5]1[N:4]([CH2:3][CH:2]([CH3:25])[CH3:1])[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)Cn1c(C(O)c2ccccc2)nc2cnc3ccccc3c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(c1ccccc1)c1nc2cnc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
1-(2-Methylpropyl)-α-phenyl-1H-imidazo[4,5-c]quinoline-2-methanol (5.0 g; 15 mmol, Example 45) was dissolved in N,N-dimethylformamide (25 mL) then added to a cooled (0-5° C.) suspension of sodium hydride (0.5 g; 16.6 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was stirred at room temperature for about one hour then combined with methyl iodide (1.4 mL; 22.6 mmol). Stirring was continued until the reaction was complete as indicated by thin layer chromatography. The reaction mixture was diluted with ether then quenched with water. The ether layer was separated, washed twice with water, dried over magnesium sulfate then evaporated under vacuum. The residue was triturated with methylene chloride/hexane to provide 4.5 g of a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]=[C:18]([NH2:20])[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[CH2:26](N)[CH2:27]N>O.C(O)CCCC>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]1[NH:20][CH2:26][CH2:27][N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(N)=Nc1nc2ccccc2n1Cc1ccccc1
Reactant: NCCN
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCO
Product: c1ccc(Cn2c(NC3=NCCN3)nc3ccccc32)cc1

Procedure:
2-(1-Benzylbenzimidazolyl)guanidine (3.65g, 0.0143 mol) was dissolved in water (600 ml) containing 5N hydrochloric acid (5.5 ml). The solution was cooled to 0° to 5°C and treated portionwise with sodium nitrite (1.0g) each hour for 3 hours. After a further 4 hours the reaction mixture was filtered and the microcrystals so obtained were heated under reflux in amyl alcohol (15 ml) with ethylenediamine (3 ml) for 6 hours. The cooled reaction mixture was evaporated to dryness. The resulting semi-solid was crystallised from amyl alcohol was then recrystallised from ethanol to yield 2-(1-benzylbenzimidazolyl)amino-2-imidazoline (1.0g) as colourless microcrystals m.p. 165°-166°C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1.[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30]Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[NH2:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:30][O:29][CH2:28][CH2:27][O:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([Cl:17])[N:9]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: O=C(OCCOCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Reaction time: 0.33 h
Yield: 19.6 %

Procedure:
A suspension of potassium carbonate (4.1 g) and 2-amino-6-chloropurine (5.0 g) in dry dimethylformamide (120 ml) was stirred for 20 minutes. 2-Benzoyloxyethoxymethyl-chloride (6.3 g) was added and the resulting pink suspension stirred at room temperature for 6 days. The reaction mixture was then poured into a mixture of ice and water (210 ml) with vigorous stirring. The aqueous mixture was extracted with chloroform (3+200 ml), and the chloroform solution obtained was washed with a 5% acetic acid solution and then twice with water. The chloroform solution was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was redissolved in a minimal amount of chloroform and the resulting solution applied to a column containing silica gel (200 g) in chloroform. The column was eluted with 2% methanol/98% chloroform and the eluant collected in 30 ml cuts. The fractions containing 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (determined by TLC) were combined, evaporated and the residue recrystallized from benzene to give 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl) purine (2.0 g., m.p. 130°-133.5° C.).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:14]1[N:19]=[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=2)[CH:17]=[CH:16][N:15]=1.[F:30][C:31]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:34]([NH2:35])=[C:33]([O:41][CH3:42])[CH:32]=1>CC(O)CCC>[F:30][C:31]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:34]([NH:35][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
p-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol) was added in one portion to a mixture of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate 130, 24.27 g, 99.58 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 18.54 g, 99.58 mmol) in 2-pentanol (500 mL). The resulting mixture was stirred at 105° C. for 2.5 h. and then cooled to r.t. The resulting precipitate was collected by filtration, washed with 2-pentanol (50 mL) and dried under vacuum to give some of the desired product as a yellow solid. The filtrate was cooled and the resulting precipitate was collected by filtration and washed with 2-pentanol (10 mL). The two crops of product were combined and triturated with CH3CN to give a solid which was collected by filtration and dried under vacuum to give the title compound (37.4 g, 95%) as a yellow solid; 1H NMR: 3.92 (3H, s), 4.01 (3H, s), 7.13 (1H, dd), 7.27-7.36 (1H, m), 7.40-7.51 (2H, m), 7.59 (1H, d), 8.26 (1H, t), 8.35 (1H, d), 8.61 (1H, s), 8.85 (1H, d), 9.46 (1H, s); m/z: ES− M− 392.
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6](=O)[CH2:7][C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[CH:12][CH:13]=1)C.O>C1COCC1>[N:14]1([C:11]2[N:10]=[CH:9][C:8]([CH2:7][CH2:6][OH:5])=[CH:13][CH:12]=2)[CH:18]=[N:17][N:16]=[N:15]1
Reactant: CCOC(=O)Cc1ccc(-n2cnnn2)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc(-n2cnnn2)nc1
Reaction time: 12 h

Procedure:
LiBH4 (0.48 mL, 0.96 mmol, 2 M in THF) was added to a stirred solution of ethyl[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetate (0.150 g, 0.64 mmol) in THF (20 ml) at 0° C. The resulting solution was stirred for 12 h. Water (5 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure to yield the product after flash chromatography (eluted with 10-50% ethyl acetate in hexanes) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.51 (s, 1H), 8.43 (br s, 1H), 8.01 (dd, J=2.7, J=2.7 Hz, 1H), 7.91 (dd, J=2.1, J=2.0 Hz, 1H), 3.99 (br s, 2H), 3.00 (t, J=6.1, J=6.2 Hz, 2H). LC-MS (IE, m/z): 164.1 [(M+1)+−28].
Reaction SMILES: [CH2:1]([N:8]([S:48]([CH2:51][CH2:52][CH2:53][Cl:54])(=[O:50])=[O:49])[C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[C:16]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:17]2[CH2:20][C:21]([N:23]([CH3:35])[CH2:24][CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[O:22])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:54].[CH2:1]([N:8]([S:48]([CH2:51][CH2:52][CH2:53][Cl:54])(=[O:49])=[O:50])[C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:42]3[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]3)=[C:16]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:17]2[CH2:20][C:21]([N:23]([CH3:35])[CH2:24][CH2:25][NH:26][CH3:27])=[O:22])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)N(Cc3ccccc3)S(=O)(=O)CCCCl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCN(C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)N(Cc3ccccc3)S(=O)(=O)CCCCl)cc21
Product: Cl
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of the crude tert-butyl {2-[{[6-({benzyl[(3-chloropropyl)sulfonyl]amino}carbonyl)-3-cyclohexyl-2-phenyl-1H-indol-1-yl]acetyl}(methyl)amino]ethyl}methylcarbamate in DCM) (0.09 M) was treated with TFA (140 eq) at 0° C. The reaction was allowed to reach RT in about 1 h. The solvent was then removed in vacuo, a 2 M solution HCl in Et2O was added and the volatiles removed in vacuo. MeCN was added and the precipitate was collected by filtration to afford clean compound (30%). (ES+) m/z 677 (M+H)+
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Cl.C(O)(=O)C>C1COCC1.O.O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Mn+3]>[CH2:1]([NH:8][C:9](=[O:17])[C:10]1[C:15]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:26])=[CH:14][C:13]([Cl:16])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)c1ccc(Cl)nc1
Reactant: Cc1ccccc1[Mg]Cl
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1-c1cc(Cl)ncc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89.1 %

Procedure:
A solution of 0.5 g (2.0 mMol) N-benzyl-6-chloro-nicotinamide in 5.0 ml THF was added over 25 minutes to 10.1 ml (10.1 mMol) of o-tolylmagnesium chloride solution (1M in THF) cooled to 0° C. After 2.5 hours stirring at room temperature, the reaction mixture was cooled again to 0° C. and 4.0 ml acetic acid were added over 15 minutes followed by 1.1 g (4.1 mMol) manganese triacetate dihydrate. After stirring for 1 hour at room temperature, the reaction mixture was filtered and the filtrate was poured onto 20 ml deionized water. Sodium bicarbonate was added portionwise to bring the pH to 7 and the phases were separated. The aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with water, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluent ethyl acetate/n-hexane 2:1) to yield 0.6 g (88%) N-benzyl-6-chloro-4-o-tolyl-nicotinamide as an orange resin.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[C:35]=O.[CH3:47][O:48][C:49]1[CH:50]=[CH:51][C:52]2[CH:53]=[C:54]3[CH2:61][NH:60][CH2:59][CH2:58][N:55]3[C:56]=2[CH:57]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:35]([N:60]1[CH2:59][CH2:58][N:55]3[C:56]4[CH:57]=[C:49]([O:48][CH3:47])[CH:50]=[CH:51][C:52]=4[CH:53]=[C:54]3[CH2:61]1)[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc2cc3n(c2c1)CCNC3
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCn3c(cc4ccc(OC)cc43)C2)N1c1cccc(C(F)(F)F)c1

Procedure:
Starting with 182 mg (0.4 mmol) of the iminophosphorane from Example 12A, 134 mg (0.4 mmol) of 1-isocyanato-3-(trifluoromethyl)benzene and 81 mg (0.4 mmol) of 7-methoxy-1,2,3,4-tetrahydropyrazino[1,2-a]indole from Example 35A, the general procedure [M] gives 140 mg (62% of theory) of product.
Reaction SMILES: [CH:1]1([NH:5][CH2:6][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[OH:8])[CH2:4][CH2:3][CH2:2]1.[N:17]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)=[C:18]=[O:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:16][C:10]1[C:11]([Cl:15])=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]([OH:8])[CH2:6][N:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:18](=[O:19])[NH:17][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:30])[CH3:28])=[CH:32][CH:33]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(N=C=O)cc1
Reactant: OC(CNC1CCC1)c1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(NC(=O)N(CC(O)c2cccc(Cl)c2Cl)C2CCC2)cc1
Reaction time: 1.5 h

Procedure:
To a test tube containing 0.3 mmol 2-cyclobutylamino-1-(2,3-dichlorophenyl)ethanol in 1 ml CH2Cl2 was added 314 μl of a 0.1 M solution of N-(4-isocyanato-benzyl)-2,2-dimethyl-propionamide and 0.43 μl triethylamine. The solution was allowed to stand for 1.5 h, then saturated sodium bicarbonate (1 ml) was added and the resulting mixture extracted with 1 mL EtOAc. The EtOAc extract was washed with water (2×1 ml), and the solvent removed by vacuum centrifugation over 48 h. The resulting solid was dissolved in 450 ml DMF and purified by reverse phase preparatory HPLC (Zorbax 2.5×7 cm C8 column, linear gradient 5-100% CH3CH/H2O (0.1% TFA), 15 mL/Min). The desired fractions were combined and the solvent removed by vacuum centrifugation to give. The desired fractions were combined and placed on a speed vacuum overnight for 15 h to give N-(4-{3-[2-(2,3-Dichloro-phenyl)-2-hydroxy-ethyl]-3-cyclobutyl-ureido}-benzyl)-2,2-dimethyl-propionamide. 1H NMR δH (CD3OD) 7.67-7.66 (d, 1H, J 1.22 Hz), 7.64-7.63 (d, 1H, J 1.23 Hz), 7.38-7.36 (t, 1H, J 7.94 Hz), 7.28-7.25 (d, 2H, J 8.55 Hz), 7.20-7.17 (d, 2H, J 8.24 Hz), 5.33-5.31 (t, 1H, J5.5 Hz), 4.38-4.31 (m, 4H), 3.59-3.57 (d, 2H, J 5.5 Hz), 2.20-1.99 (m, 4H), 1.68-1.56 (m, 3H), 1.20 (s, 9H).
Reaction SMILES: S(=O)=O.[CH2:4]([N:8]([CH2:11][CH2:12][CH2:13][CH3:14])[S:9]Cl)[CH2:5][CH2:6][CH3:7].[CH3:15][NH:16][C:17](=[O:30])[O:18][C:19]1[C:27]2[O:26][C:25]([CH3:29])([CH3:28])[CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CCCCCC.O>[CH2:4]([N:8]([CH2:11][CH2:12][CH2:13][CH3:14])[S:9][CH2:15][NH:16][C:17](=[O:30])[O:18][C:19]1[C:27]2[O:26][C:25]([CH3:28])([CH3:29])[CH2:24][C:23]=2[CH:22]=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CCCCN(CCCC)SCl
Agent: O=S=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCCCCC
Product: CCCCN(CCCC)SCNC(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 9.5 °C
Reaction time: 18 h

Procedure:
Sulfur dioxide was passed through 30.2 g of a 50% solution of dibutylaminosulfenyl chloride (0.077 mole) in hexane until the solution had gained 2.8 g (0.044 mole). 2,3-Dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate (98%, 15.5 g, 0.069 mole) was added followed by dropwise addition of triethylamine (12.4 g, 0.123 mole) over a period of 28 minutes with stirring. Stirring was continued for about 18 hours. The mixture was cooled to 9.5° C., 31 ml of water and 40 ml of hexane were added, and the layers were separated. The organic layer was concentrated to yield 27.4 g of 94% (by hplc) 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (dibutylaminothio)methylcarbamate (98% chemical yield).