Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[N:29]=[C:30]=[O:31]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[NH:29][C:30]([NH:20][C:18]1[CH:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[N:15]=[CH:16][N:17]=1)=[O:31]
Reactant: Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1
Reactant: O=C=Nc1c(F)cccc1F
Product: O=C(Nc1cc(Nc2ccc(N3CCOCC3)cc2)ncn1)Nc1c(F)cccc1F

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(4-morpholin-4-yl-phenyl)-pyrimidine-4,6-diamine and 2,6-difluorophenyl isocyanate. Slightly pink solid, HPLC: tR=3.53 min (purity: 100%, gradient F), ESI-MS: 427.4 [MH]+.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:20][CH2:21][C:22](Br)=[O:23].C(OCC)(=O)C>ClCCl>[Br:20][CH2:21][C:22]([NH:9][C:8]1[CH:10]=[CH:11][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH3:12])=[O:23]
Reactant: Cc1cc(C(C)(C)C)ccc1N
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(C)C)ccc1NC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 g (33.69 mmol) of 4-tert-butyl-2-methylaniline and 3.75 g (37.06 mmol) of triethylamine are initially charged in 150 ml of dichloromethane. At 0°-5° C., 7.48 g (37.06 mmol) of bromoacetyl bromide, dissolved in 90 ml of dichloromethane, are added dropwise, and a light-brown precipitate is formed. The mixture is stirred at room temperature overnight. 150 ml of ethyl acetate are then added to the reaction mixture, which is extracted successively with water, 1 N hydrochloric acid, water, saturated sodium bicarbonate soluton and water. The organic phase is dried over magnesium sulphate and freed from the solvent under reduced pressure. The residue is purified chromatographically. The product is recrystallized from ethyl acetate and n-pentane, filtered off with suction and dried under reduced pressure at 40° C. This gives 6.53 g (68% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[C:6]([OH:24])[CH:5]=1.BrC1C=CC=CC=1O.F[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[C:36]=1[N+]([O-])=O.FC1C=C(C=CC=1[N+]([O-])=O)C#N>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:15][CH2:16]3)[C:39]3[C:38]([O:24][C:6]=2[CH:5]=1)=[C:37]([O:41][CH3:42])[CH:36]=[CH:35][CH:40]=3)=[O:25]
Reactant: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)c(O)c1
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Agent: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Oc1ccccc1Br
Product: COC(=O)c1ccc2c(c1)Oc1c(OC)cccc1N2C1CCN(Cc2ccccc2)CC1

Procedure:
Using an adaptation of the method described in Procedure 1, substituting 4-(1-benzyl-piperidin-4-ylamino)-3-hydroxy-benzoic acid methyl ester, 1d for 2-bromophenol, and 1-fluoro-3-methoxy-2-nitrobenzene for 3-fluoro-4-nitrobenzonitrile, the title compound 10-(1-benzyl-piperidin-4-yl)-6-methoxy-10H-phenoxazine-3-carboxylic acid methyl ester, 2d was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]#[N:11].[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][SH:14].C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:11][C:10]1[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=2[S:14][C:13]=1[C:12]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CS
Reactant: N#Cc1cccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc2c(C#N)cccc2c1N
Yield: 65 %

Procedure:
2-chloro-1,3-dicyanobenzene (972 mg, 6.0 mmol) was treated with 1 eq of methyl thioglycolate and 1 eq sodium carbonate in methanol as described in Example 41A to give the title compound in 65% yield. 1H NMR (300 MHz, D6-DMSO d 3.83 (s, 3H), 7.38 (bs, 2H), 7.62 (t, J=8 Hz, 1H), 8.10 (d, J=8 Hz, 1H), 8.50 (d, J=8 Hz, 1H). MS (DCI/NH3) m/e 250 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]=[C:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:35])[C:29]=2[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:30]3[CH:31]=[CH:32][CH:33]=[C:34]4[C:29]=3[CH2:28][CH2:27][C:26]4=[CH2:25])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: C=C1CCc2c(O)cccc21
Product: C=C1CCc2c(Oc3nc(C(=O)NC(C)c4cc(F)c(NS(C)(=O)=O)c(F)c4)co3)cccc21
Yield: 77 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 1-methylene-indan-4-ol (38 mg, 0.26 mmol) prepared as in example 30 to give the title compound (49 mg, 77%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[CH:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][Cl:27].[NH4+].[Cl-]>C1COCC1>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCC1
Reactant: ClCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCCCl)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
Under an N2 atmosphere at ˜7° C., BuLi (2.5M in hexanes, 52.8 mL, 132 mmol) was added drop wise to a solution of iPr2NH (18.52 mL, 132 mmol, distilled from NaOH) in dry THF (70 mL) in 10 min. The reaction mixture was allowed to warm to rt, stirred for 0.5 h, cooled to −60° C. and then, ethyl 1-cyclobutanecarboxylate (prepared according to Török, B.; Molnár, Á., J. Chem. Soc. Perkin Trans. 1, 1993, 7, 801-804, 14.05 g, 110 mmol) in dry THF (30 mL) was added dropwise in 20 min. The resulting mixture was allowed to warm to 0° C. in 20 min., cooled again to −60° C. and then, a solution of 1-bromo-4-chlorobutane (19.1 mL, 165 mmol) in dry THF (30 mL) was added dropwise in 20 min, after which the temperature was raised to −20° C. in 15 min. After 1.5 h, the temperature was raised to −10° C. and stirring was continued for 1 h. The reaction mixture was allowed to reach rt, poured into a mixture of aqueous saturated NH4Cl (200 mL) and ice (50 mL) and extracted with Et2O (500 mL). The organic layer was washed with brine (250 mL), dried (Na2SO4) and evaporated in vacuo. The remaining oil was purified by fractional distillation under reduced pressure to give ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (20.53 g, 86%) as a thin, colorless oil. 1H NMR (CDCl3): δ=4.13 (q, J=7.1 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.50-2.32 (m, 2H), 1.96-1.70 (m, 8H), 1.40-1.20 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3): δ=176.6, 60.3, 47.6, 44.8, 37.3, 32.8, 30.1 (2×), 22.4, 15.8, 14.4. HRMS calcd for C11H20(37Cl)O2 (WO: 221.1122, found: 221.1116.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:21]=[C:20]([CH3:22])[C:19]([CH:23]=O)=[CH:18][N:17]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:25]([O:28][CH2:29][CH3:30])([CH3:27])=[O:26].O>C1COCC1>[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:21]=[C:20]([CH3:22])[C:19](/[CH:23]=[CH:27]/[C:25]([O:28][CH2:29][CH3:30])=[O:26])=[CH:18][N:17]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: Cc1nc(NC2CCN(Cc3ccccc3)C2)ncc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(NC2CCN(Cc3ccccc3)C2)nc1C
Temperature: 15 °C

Procedure:
A solution of diethylphosphonoacetcacid ethyl ester (1.79 g) in THF (5 ml) was added dropwise to a mixture of 60% sodium hydride in oil (341 mg) in THF (60 mL) with stirring at 10-20° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinecarbaldehyde (1.58 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-{2-[(1-benzyl-3-pyrrolidinyl)amino]-4-methyl-5-pyrimidinyl}acrylate (1.7 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[C:10]2[CH2:12][CH2:13][CH2:14][C:9]2=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=O)=[CH:18][CH:17]=2)[CH:7]=1.[NH3:28]>CO>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[C:10]2[CH2:12][CH2:13][CH2:14][C:9]2=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH2:28])=[O:25])=[CH:18][CH:17]=2)[CH:7]=1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3ncco3)nc3c2CCC3)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(-c3ncco3)nc3c2CCC3)cc1
Yield: 63 %

Procedure:
Following general procedure C, ethyl 2-(4-((2-(oxazol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.047 g, 0.13 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL) to afford the title compound (0.027 g, 63%) as a white solid. MW=334.37. 1H NMR (DMSO-d6, 500 MHz) δ 8.24 (s, 1H), 8.16 (s, 1H), 7.49-7.43 (m, 2H), 7.32-7.25 (m, 3H), 7.17 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 3.37 (s, 2H), 2.90 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.09 (quin, J=7.5 Hz, 2H); APCI MS m/z 335 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[CH2:12][CH3:13]>>[CH2:11]([NH:14][CH2:7][CH:6]([OH:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:12][CH3:13]
Reactant: CCCN
Reactant: Cc1ccc(C2CO2)cc1
Product: CCCNCC(O)c1ccc(C)cc1
Yield: 49.6 %

Procedure:
4-Methyl styrene oxide(1.0 g,8.0 mmol)and 3 ml of propylamine in methanolic solution were charged into a flask. The flask was sealed and put in a refrigerator for 5–7 days. The solution was concentrated and the residue crystallized from ether, the title compound was obtained as white needle crystals, mp. 73.0–75.1 C, yield 49.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][NH:19][CH2:20][CH2:21][NH2:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:22][CH2:21][CH2:20][NH:19][CH3:18])=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: CNCCN
Product: CNCCNC1=Nc2cc(Cl)ccc2Nc2ccccc21
Yield: 25.3 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and N-methylethylenediamine (74 mg, 1.0 mmol) were reacted according to GP4 to give 7.6 mg of the title compound (160FE22). MS (ESI) 301 (MH+). Purity for MH+ (UV/MS) 92/83.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:11]=1.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>C(=S)=S>[CH3:17][CH:16]1[CH2:18][C:10]2[C:11](=[C:6]([CH3:5])[CH:7]=[CH:8][C:9]=2[CH:12]([CH3:14])[CH3:13])[C:15]1=[O:19]
Reactant: Cc1ccc(C(C)C)cc1
Reactant: C=C(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Cc1ccc(C(C)C)c2c1C(=O)C(C)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 1-liter three-necked flask equipped with a 200 ml dropping funnel were charged 87.61 g (0.66 mol) of anhydrous aluminum chloride and 150 ml of carbon disulfide, to which were added at room temperature through a dropping funnel p-cymene (47.0 ml, 0.301 mol) and methacryloyl chloride (33.0 ml, 0.338 mol) diluted with 30 ml of carbon disulfide. After stirring at room temperature for 5 hours, the reaction mixture was slowly poured on 1 kg of ice. After extraction of the reaction mixture with diethyl ether, the resulting organic layer was washed with an aqueous saturated solution of sodium hydrogen carbonate and with saline, and dried over sodium sulfate. Sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([NH:17][C:18]3[NH:22][C:21]4[CH:23]=[C:24]([C:27](=[O:38])[NH:28][C:29]5[CH:37]=[C:36]6[C:32]([CH:33]=[N:34][NH:35]6)=[CH:31][CH:30]=5)[CH:25]=[CH:26][C:20]=4[N:19]=3)[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C>CO.Cl.O1CCOCC1.CCOCC>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([NH:28][C:27]([C:24]3[CH:25]=[CH:26][C:20]4[N:19]=[C:18]([NH:17][C:15]5[S:16][C:10]6[CH2:9][NH:8][CH2:13][CH2:12][C:11]=6[N:14]=5)[NH:22][C:21]=4[CH:23]=3)=[O:38])[CH:37]=2)[CH:33]=[N:34]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3nc4ccc(C(=O)Nc5ccc6cn[nH]c6c5)cc4[nH]3)sc2C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cn[nH]c2c1)c1ccc2nc(Nc3nc4c(s3)CNCC4)[nH]c2c1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 2-[6-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (0.25 mmol; see Example 79) in methanol (1 mL), 4M HCl in dioxane (0.5 mL) was added. The resulting mixture was stirred at room temperature for 5-6 h. The volatiles were removed in vacuo, the residue obtained was suspended in ether. The solid obtained was collected by filtration, washed with ether and dried in vacuo to afford 2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 431 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:12]([O-])=O)=[C:8]([CH2:10][OH:11])[CH:9]=1)[CH3:2].O.NN>CCO.[Pd]>[NH2:12][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]=1[CH2:10][OH:11]
Reactant: CCOc1ccc([N+](=O)[O-])c(CO)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOc1ccc(N)c(CO)c1
Temperature: 90 °C

Procedure:
To a solution of (5-ethoxy-2-nitro-phenyl)-methanol (592 mg, 3.0 mmol) in absolute EtOH (20 mL) at rt was added 150 mg of Pd/C (Aldrich, 10 wt. % on active carbon), followed by slow addition of hydrazine hydrate (1.5 mL). The resulting reaction mixture was refluxed at 90° C. for 1 h. It was then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford crude (2-amino-5-ethoxy-phenyl)-methanol as a pale yellow oil: MS (ESI) 168 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[C:12]([OH:21])(=[O:20])[C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14]>CO>[C:1]([C@:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[C:12]([OH:21])(=[O:20])[C@@H:13]([C@H:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14]
Reactant: C#CC1(O)CN2CCC1CC2
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Product: C#C[C@@]1(O)CN2CCC1CC2

Procedure:
15.1 g of 3-ethynyl-3-quinuclidinol and 15 g of L-(+)-tartaric acid were dissolved under heating in 300 ml of methanol. After cooling as it was, the resulting crystals were collected by filtration and recrystallized from methanol three times, to give 2.07 g of the title compound.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([N:19]=[N:20][C:21](=[C:24]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]#[N:23])=[CH:12][C:13](=[S:16](=[O:18])=[O:17])[CH2:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:47])=O>>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([Cl:47])(=[O:18])=[O:17])=[CH:12][C:11]=1[N:19]=[N:20][C:21](=[C:24]([O:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:22]#[N:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: N#CC(N=NC1=CC(=S(=O)=O)CC=C1OC(=O)c1ccccc1)=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: N#CC(N=Nc1cc(S(=O)(=O)Cl)ccc1OC(=O)c1ccccc1)=C(OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of α-(2-benzoyloxy-5-sulfonylphenylazo)-β-benzoyloxycinnamonitrile (10 g) in 50 ml of thionyl chloride was added 3 ml of dimethylformamide. The reaction mixture was allowed to stir at room temperature for 31/2 hours. The solvent was evaporated to dryness under vacuum at room temperature. The residue was diluted with ethyl ether (50 ml) to form a white precipitate. The product was filtered off and dried to yield 9.4 g, m.p. 153° to 155° C.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([Cl:33])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]3[N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25][CH:19]3[CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)C.C(N(CC)CC)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>ClCCl>[NH2:8][C:9]1[C:10]([Cl:33])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]3[N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25][CH:19]3[CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCC3C(CCN3C(=O)OC(C)(C)C)C2)c1Cl
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC2CN(c3cc(C#N)cc(N)c3Cl)CCC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
tert-butyl 5-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (358 mg, 0.751 mmol) was treated with 25% TFA in dichloroethane (2 ml, 6.49 mmol) at room temperature for 1 h. Solvent was evaporated in vacuo and the residue was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude intermediate was dissolved in dichloromethane (10 mL). Triethylamine (0.209 ml, 1.501 mmol) and BOC anhydride (0.261 ml, 1.126 mmol) were added subsequently. The reaction mixture was stirred at room temperature for 1 h and the reaction was complete. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 10-30% ethyl acetate/hexanes) to give tert-butyl 5-(3-amino-2-chloro-5-cyanophenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (266 mg) as a colorless oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=O)#[N:23].[F:37][C:38]1[CH:39]=[C:40]2[C:44](=[C:45](/[C:47](/[NH:50]O)=[N:48]/[H])[CH:46]=1)[NH:43][CH:42]=[C:41]2[CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:22]([C:24]1[CH:25]=[C:26]([C:27]2[O:29][N:48]=[C:47]([C:45]3[CH:46]=[C:38]([F:37])[CH:39]=[C:40]4[C:44]=3[NH:43][CH:42]=[C:41]4[CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])[N:50]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])#[N:23]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: [H]/N=C(\NO)c1cc(F)cc2c(CCC(=O)OCC)c[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc(F)cc12
Reaction time: 1 h
Yield: 98.6 %

Procedure:
HOBT (672 mg) and EDCI (841 mg) were added to a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (450 mg) in THF (10 mL). The resulting solution was stirred for 1 hour. Ethyl 3-{5-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D136) (717 mg) in THF (5 mL) was added, and the reaction mixture was stirred at RT for 2 hours. TBAF (2.34 g) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 1.5 hours. After cooling, the reaction was quenched with water, and extracted with EA for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D138) (1.00 g) as a yellow solid. MS (ES): C25H23FN4O4 requires 462; found 463.2 (M+H+).
Reaction SMILES: NC1C=CC(OC2C=CN=C3C=C(C4C=CC(O)=CC=4)SC=23)=CC=1.F[C:26]1[CH:27]=[C:28]([NH:49][C:50]([NH:52][C:53](=[O:61])[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[S:51])[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40]([C:42]3[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=3)[S:41][C:34]=12>>[OH:48][C:45]1[CH:46]=[CH:47][C:42]([C:40]2[S:41][C:34]3[C:35](=[N:36][CH:37]=[CH:38][C:33]=3[O:32][C:31]3[CH:30]=[CH:29][C:28]([NH:49][C:50]([NH:52][C:53](=[O:61])[CH2:54][C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)=[S:51])=[CH:27][CH:26]=3)[CH:39]=2)=[CH:43][CH:44]=1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)c(F)c1
Agent: Nc1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)cc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(O)cc4)sc23)cc1
Yield: 3 %

Procedure:
Starting from the compound 199 and following the procedure described above for the compound 155a (scheme 28, example 109), title compound 200 was obtained in 3% yield. 1H NMR (400 MHz, DMSO-d6 ppm: 12.38 (s, 1H), 11.74 (s, 1H), 9.94 (s, 1H), 8.46 (d, 1H, J=5.3 Hz), 7.81 (s, 1H), 7.72 (d, 2H, J=9.0 Hz), 7.69 (dd, 2H, J=6.7/1.8 Hz), 7.34-7.27 (m, 7H), 6.86 (dd, 2H, J=6.7/1.8 Hz), 6.61 (d, 1H, J=5.5 Hz), 3.82 (s, 2H). LRMS (M+1) 512.1 (100%).
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:9][CH2:8]1.C(N(CC)CC)C.[F:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH:30]([F:32])[F:31])[C:25]=1[C:33](Cl)=[O:34]>O1CCCC1>[CH:7]1([N:6]([CH2:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[Si:2]([CH3:15])([CH3:14])[CH3:1])[C:33]([C:25]2[C:26]([CH:30]([F:32])[F:31])=[N:27][N:28]([CH3:29])[C:24]=2[F:23])=[O:34])[CH2:8][CH2:9]1
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1F
Reactant: C[Si](C)(C)c1ccccc1CNC1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nc(C(F)F)c(C(=O)N(Cc2ccccc2[Si](C)(C)C)C2CC2)c1F
Yield: 66.1 %

Procedure:
To 175 mg (0.80 mmol) of N-[2-(trimethylsilyl)benzyl]cyclopropanamine in 5 ml of dry tetrahydrofurane was added 0.234 ml (1.68 mmol) of triethylamine, followed by a solution of 187 mg (0.88 mmol) of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride in 3 ml of tetrahydrofurane. The reaction mixture was stirred under reflux for 3 hours. After cooling down, the reaction mixture was filtered, and the filtrate was evaporated under vacuum. The residue was dissolved in ethyl acetate/water. The aqueous phase was further extracted with ethyl acetate. The combined organic phase were dried and evaporated under vacuum to give 209 mg of the expected product.