Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH2:13](O)C1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:10]([C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)([O:12][CH3:13])=[O:11]
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc2c1OCC2
Yield: 142.6 %

Procedure:
A solution of 0.2 g (1.22 mmol) of 7-dihydrobenzofuran carboxylic acid, 0.13 g (1.22 mmol) of benzyl alcohol, 0.3 g (2.44 mmol) of DMAP and 0.46 g (2.44 mmol) of 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride in 5 mL of CH2Cl2 was stirred at rt for 12 h. The reaction mixture was partitioned between CH2Cl2 and water and the pH was adjusted to pH=1 with 1N HCl solution. The reaction mixture was extracted with CH2Cl2 and the combined organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 6:1) to give 0.31 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:31][CH2:32][Cl:33])(=O)=O)=CC=1>O>[Cl:33][CH2:32][CH2:31][O:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=[N+]([O-])c1cc(OCCCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-nitro-5-(trifluoromethyl)phenol (2.10 g, 10.1 mmol) and cesium carbonate (4.00 g, 12.2 mmol) in acetonenitrile (50 ml) was added 2-chloroethyl p-toluenesulfonate (2.9 g, 12 mmol) slowly. The resulting mixture was stirred at RT for 5 hr, poured into water (100 ml) and then extracted with EtOAc (3×80 ml). The combined organic layer was washed with brine (100 ml) and dried over Na2SO4. Solvent was removed under vacuum and the residue was purified by flash column chromatography on the silica gel (hexane/EtOAc=5 to 25%) to afford the desired compound.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccncc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1.0 g, 0.0052 mol) was suspended in 20 ml of toluene. Isonicotinoyl chloride hydrochloride (0.93 g, 0.0052 mol) was added and then a solution of sodium hydroxide (1.25 g of 50% aqueous NaOH) in 5 ml of water was added dropwise. After stirring at 23° C. for 2 hours, the solids were removed by filtration, washed with water and dried in air. The crude product was chromatographed on silica gel using 5% methanol/methylene chloride as eluant to afford pure N'-t-butyl-N-benzoyl-N'-isonicotinoylhydrazine: m.p. >210° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Pd]>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=Cc1ccccc1
Agent: [Pd]
Product: O=Cc1ccc(C=Cc2ccccc2)cc1
Yield: 72 %

Procedure:
The procedure described in Example 26 is repeated, but using 4.63 g (25 mmols) of 4-bromobenzaldehyde and 3.16 ml (27.5 mmols) of styrene. After a reaction time of 4 hours at 130° C., 3.74 g (18.0 mmols) of 4-formylstilbene are obtained, corresponding to a yield of 72% of theory (conversion figure 7200; Pd content 0.01 mol %).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]([NH:13][C:14](=[NH:17])[NH:15][CH3:16])=[O:12].[CH3:18]OC(OC)N(C)C.Cl.CO>C(#N)C=C.CO>[ClH:1].[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[N:10]1[CH:16]=[N:15][C:14]([NH:17][CH3:18])=[N:13][C:11]1=[O:12]
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CO
Solvent: C=CC#N
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1

Procedure:
To a suspension of 10.0 g. (39.0 m. mol) of 1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride in acrylonitrile (CH3CN) (50 ml.) is added 9.3 g. (78.0 m mol) of dimethylformamide dimethylacetal (DMF-DMA) and the resulting solution, in a bomb, is heated to 100°-105° C. for one hour. After cooling the reaction mixture is placed in a round bottom flask and concentrated under reduced pressure. The residue is partitioned between H2O and CHCl3 and the layers separated. The aqueous layer is extracted with CHCl3 (1×50 ml). The combined CHCl3 extracts are washed with H2O (1×50 ml) dried (MgSO4) and concentrated under reduced pressure. A small amount of the residue is triturated in hexane to give a white solid, having melting point 224. NMR and IR show the product to be identical with that of Example 3. The remainder of the residue is dissolved in MeOH and acidified with HCl/MeOH. The MeOH is removed under vacuum and the residue crystallized from CH3CN to give 6.8 g. (65%) of 1-(2',60'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one hydrochloride, melting point 234°-8° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.O.[C:22]([OH:26])(=[O:25])[CH:23]=O>>[CH2:19]([O:18][C:16]([C:3]1[C:2]([NH:1][CH2:23][C:22]([OH:26])=[O:25])=[CH:7][C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[CH:5][N:4]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: O=CC(=O)O
Solvent: O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCC(=O)O

Procedure:
This compound was prepared from ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate and glyoxylic acid monohydrate employing methods similar to those described in Example 11, Step 1 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 13.1 (1H, br), 7.91 (1H, t, J=5 Hz), 7.78 (1H, d, J=1 Hz), 7.29 (2H, dd, J=9, 6 Hz), 7.09 (1H, t, J=9 Hz), 7.02 (1H, s), 4.25 (2H, q, J=7 Hz), 3.92 (2H, d, J=5 Hz), 3.90 (2H, s), 1.27 (3H, t, J=7 Hz); ES+ MS: 333 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[CH3:23])(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[CH3:23])(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccncc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cnccc2C)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (127 mg) in ethyl acetate (2 mL) and 2-propanol (0.5 mL) was added 4N hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine as a pale-yellow oil (yield 97 mg, 97%). A solution of the obtained 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (30 mg) in ethanol (2 mL) and concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 103 mg, 81%).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:7][C:6]=1[CH3:28])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[N:7][C:6]([CH3:28])=[C:5]([CH:10]=2)[C:4]([OH:29])=[O:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1C(=O)O
Reaction time: 16 h

Procedure:
A solution of 1.6 g of 5-(4-Chloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid ethyl ester and 136 mg of LiOH in 5 ml of THF and 5 ml of water was stirred at room temperature for 16 h. After 16 h, the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was codistilled twice with dichloromethane and twice with toluene The isolated crude product was used in the next reaction step. Yield: 1.6 g.
Reaction SMILES: [OH-].[CH2:2]([N+:9]([CH3:12])([CH3:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13]1([NH:19][C:20](=[O:26])/[CH:21]=[CH:22]\[C:23]([OH:25])=[O:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>CO>[CH2:2]([N+:9]([CH3:12])([CH3:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13]1([NH:19][C:20](=[O:26])/[CH:21]=[CH:22]\[C:23]([O-:25])=[O:24])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)/C=C\C(=O)Nc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C([O-])/C=C\C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.1 %

Procedure:
48.2 g (0.1 mole) of benzyltrimethylammonium hydroxide solution (34.7% in methanol) is added to 19.1 g (0.1 mole) of N-phenylmaleamic acid in 100 ml of methanol, and the reaction mixture is stirred for one hour at room temperature. The pH-value is adjusted to about 7.0 with acetic acid, and the solvent is removed in vacuo in a rotary evaporator to leave 36.8 g of N-phenylmaleamic acid benzyltrimethyl-ammonium salt in the form of yellow oil, which crystallises after prolonged standing.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C.O>[NH2:12][C:10]([C:3]1[C:2]([F:1])=[C:7]([CH:6]=[CH:5][C:4]=1[F:9])[O:8][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:11]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(F)c(C(N)=O)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2,6-difluoro-3-hydroxybenzenecarboxamide (1.2 g, 7 mmol, 1 equiv.), K2CO3 (2.87 g, 21 mmol, 3 equiv.) and methyl bromoacetate (0.69 ml, 7.35 mmol, 1.05 equiv.) in DMF (30 ml) was stirred at r.t. for 18 h. The mixture was diluted with water and extracted with EtOAc (4×80 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness under reduced pressure. The product was used crude on the next step. HPLC-MS (method 1): m/z 246 [M+H]+, Rt=2.08 min.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1>CN(C=O)C.O>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([O:1][C:2]2[CH:14]=[C:13]3[C:5]([C:6]4[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][C:11]=4[NH:12]3)=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(O)ccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(Oc3ccc([N+](=O)[O-])cc3)ccc12
Temperature: 140 °C
Yield: 44.8 %

Procedure:
To a round bottom flask containing Compound 9 (80 mg, 0.268 mmol) in DMF (2 mL) was added potassium carbonate (74.1 mg, 0.536 mmol) and 4-fluoro-nitrobenzene (41.6 mg, 0.295 mmol). The reaction mixture was heated for 20 min at 140° C. After cooling down to rt, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The organic layers were dried, concentrated. The residue was purified on a silica gel column (EtOAc:Hexanes=3:7) to afford Compound 10 as a yellow solid (50 mg, 0.12 mmol, 44% yield). 1H NMR (400 MHz, CDCl3) δ: 8.22 (d, J=9.2 Hz, 2H), 8.10 (br, 1H), 8.00-7.90 (m, 3H), 7.12 (s, 1H), 7.06-6.90 (m, 4H), 6.70 (br, 1H), 1.56 (s, 9H); LRMS for C23H21N3O5+H+, calc'd: 420.2. found: 420.2 (M+H+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11].Cl.C1C(=O)N([O:23][C:24]([O:26][CH2:27][CH:28]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)=O)C(=O)C1>C(=O)([O-])O.[Na+].COCCOC>[NH:8]([C:24]([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:23])[C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11]
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
Under cooling on ice, sodium hydride (3.19 g, 133 mmol) was added to a solution of Boc-Ser (12.3 g, 53.9 mmol) in DMF (300 ml) and stirred at room temperature for 1.5 hours. Octane iodide (11.0 ml, 60.9 mmol) was added thereto and stirred at room temperature for 16 hours. After water (40 ml) was added dropwise to the reaction solution under cooling on ice, the solvent was evaporated under vacuum. The resulting residues were purified by applying them to silica gel column chromatography (gel; Art9385, Merck Co., Ltd, eluent; dichloromethane:methanol:acetic acid=120:10:1), to give 6.88 g Boc-Ser (C8H17) (yield, 36.2%) as pale yellow oily matter. Trifluoroacetic acid (120 ml) was added to this product, Boc-Ser (C8H17) (6.88 g, 21.7 mmol), under cooling on ice and stirred for 0.5 hour at room temperature. After the trifluoroacetic acid was evaporated, the resulting residues were dissolved in diethyl ether (120 ml), and 4N HCl-dioxane (22 ml) was added thereto and stirred for 1 hour under cooling on ice. The precipitated crystals were recovered by filtration to give 5.23 g H-Ser (C8H17) HCl (yield, 96.3%) as colorless crystals. After triethylamine (1.40 ml, 10 mmol) was added to a suspension (50 ml) of this product H-Ser (C8H17).HCl (2.54 g, 10.0 mmol) in 10% sodium hydrogen carbonate, a solution of Fmoc-Osu (5.00 g, 14.8 mmol) in 1,2-dimethoxyethane (20 ml) was added dropwise thereto over the period of 10 minutes and stirred at room temperature for 16 hours. The insolubles were filtered off, then dichloromethane was added to the filtrate, and the organic phase was separated and washed with 13% NaCl solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residues were purified by applying them to silica gel column chromatography (gel; BW-300, Fuji Silicia Co., Ltd, eluent; dichloromethane:methanol=93:7), to give 2.75 g Fmoc-Ser (C8H17) (yield: 62.6%) as colorless crystals. Rf=0.45 (CHCl3: MeOH=9:1, Silica gel 60F254, MERCK CO., Ltd). Fmoc-DSer(C8H17): Rf=0.45 (CHCl3: MeOH=9:1, Silica gel 60F254, MERCK Co., Ltd).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A153) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.N.[CH3:13][C:14](=O)[CH3:15]>>[CH3:13][C:14]1([CH3:15])[CH2:9][C:8](=[O:10])[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:7]=2)[O:11]1
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(F)ccc1O
Agent: N
Product: CC1(C)CC(=O)c2ccccc2O1

Procedure:
The title compound was prepared according to the procedure of Example 1A, substituting 1-(2-hydroxyphenyl)ethanone for 1-(5-fluoro-2-hydroxyphenyl)ethanone and using propan-2-one. MS (DCI/NH3) m/z 194 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].Br[C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>C(#N)C>[O:20]=[C:19]1[C:18]([CH3:23])([CH3:22])[C:12]2[C:11](=[C:10]([S:9][S:8][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]4[C:2]=3[NH:1][C:19](=[O:20])[C:18]4([CH3:23])[CH3:22])[CH:15]=[CH:14][CH:13]=2)[NH:16]1
Reactant: CC(C)(Br)C(=O)Cl
Reactant: Nc1ccccc1SSc1ccccc1N
Solvent: CC#N
Product: CC1(C)C(=O)Nc2c(SSc3cccc4c3NC(=O)C4(C)C)cccc21
Temperature: 40 °C
Yield: 55.2 %

Procedure:
In a stream of nitrogen, 12.4 g of bis(2-aminophenyl)disulfide was added to 100 ml of acetonitrile, and further added thereto was 18.6 g of α-bromo-α-methylpropionic acid chloride. The resulting mixture was heated under reflux for 3 hours. After removal of acetonitrile, 100 ml of ethylene chloride was added to the reaction product, and gradually added thereto was 28 g of anhydrous aluminium chloride at room temperature. After the conclusion of the additional materials, the mixture was heated for 2 hours at 40° C. with vigorous stirring. The reaction mixture was poured into 200 g of ice-cold water containing concentrated hydrochloric acid in order to decompose the aluminium chloride. After the decomposition, 100 ml of chloroform was added to the reaction mixture, and the organic phase was washed with saturated sodium chloride solution three times. The chloroform-ethylene chloride phase was removed, and concentrated to dryness. The product was purified by column chromatography on silica gel to obtain 10.6 g of bis(2-oxo-3,3-di-methyl-7-indolinyl)disulfide.
Reaction SMILES: C1(C2CC(=O)NN=2)CCCCC1.ClC1C2C(=CC=CC=2)[N+]([O-])=CC=1.Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29]/[C:28](=[C:36]2/[C:37]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[N:38][NH:39][C:40]/2=[O:41])/[CH:27]=1.[C:48]([NH:51][C:52]1[CH:57]=[CH:56][C:55]([SH:58])=[CH:54][CH:53]=1)(=[O:50])[CH3:49]>C(OC(=O)C)(=O)C.C(O)C>[CH:42]1([C:37]2=[N:38][NH:39][C:40](=[O:41])/[C:36]/2=[C:28]2\[NH:29][C:30]3[C:35]([C:26]([S:58][C:55]4[CH:54]=[CH:53][C:52]([NH:51][C:48](=[O:50])[CH3:49])=[CH:57][CH:56]=4)=[CH:27]\2)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=C1NN=C(C2CCCCC2)/C1=C1\C=C(Cl)c2ccccc2N1
Agent: O=C1CC(C2CCCCC2)=NN1
Agent: [O-][n+]1ccc(Cl)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3C3CCCCC3)Nc3ccccc32)cc1
Temperature: 180 °C

Procedure:
3-Cyclohexyl-3-oxo-propionic acid ethyl ester (0.5 g, 2.52 mmol) was stirred in ethanol and acetic acid (10:1, 2:0.2 mL), and treated with hydrazine (0.095 mL, 3.03 mmol). After 18 hrs, the resulting solid was filtered off and washed with a minimum amount of ethanol to yield 3-cyclohexyl-1H-pyrazol-5(4H)-one. Then, the 3-cyclohexyl-1H-pyrazol-5(4H)-one (0.2 g, 1.23 mmol) and 4-chloroquinoline N-oxide (1.23 mmol) were stirred in acetic anhydride (20 mL) at ambient temperature for 60-90 minutes. The reaction mixture was concentrated and the resulting solid filtered off and washed with a minimum amount of ether. (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-cyclohexyl-1H-pyrazol-5(4H)-one (0.05 g, 0.13 mmol) was dissolved in ethanol (1.5 mL) and 4-acetamidothiophenol (0.023 g, 0.13 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The solid was filtered and washed with ethanol to yield Example 48. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88-1.00 (m, 2H) 1.26-1.38 (m, 2H) 1.58 (d, J=10.61 Hz, 6H) 2.10 (s, 3H) 2.33 (t, J=9.47 Hz, 1H) 6.87 (s, 1H) 7.62-7.72 (m, 3H) 7.89 (t, J=7.83 Hz, 4H) 8.17 (d, J=8.34 Hz, 1H) 10.37 (s, 1H); ESI-MS: m/z calc'd for C26H26N4O2S 458.58. found 459.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[C:31]([Cl:56])=[C:32]([N:38]2[CH2:43][CH2:42][C@@H:41]([O:44][Si](C(C)(C)C)(C)C)[C@H:40]([NH:52][C:53](=[O:55])[CH3:54])[CH2:39]2)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1>>[Cl:56][C:31]1[C:30]([NH:29][C:7]2[N:6]=[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=2)=[CH:35][C:34]([C:36]#[N:37])=[CH:33][C:32]=1[N:38]1[CH2:43][CH2:42][C@@H:41]([OH:44])[C@H:40]([NH:52][C:53](=[O:55])[CH3:54])[CH2:39]1
Reactant: CC(=O)N[C@@H]1CN(c2cc(C#N)cc(N)c2Cl)CC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Product: CC(=O)N[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1O

Procedure:
(+/−)-N-((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl amino) imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-hydroxypiperidin-3-yl)acetamide was prepared starting from 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 2) and (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-4-((tert-butyldimethylsilyl)oxy) piperidin-3-yl)acetamide using a method analogous to that used to prepare Example 171.