Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
A nitrogen-flushed, 2.5 L heavy-wall Parr bottle (pressure rated to 60 psi) is charged with 68 g (0.22 mol,) of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate, (A2a), 6.8 g of 10% palladium on carbon, 50% water wet catalyst and 807 g (1020 mL) of methanol. The reaction vessel is inerted three times with nitrogen (ca. 30 psi), evacuating the atmosphere above the reaction mixture each time. The vessel is pressurized twice with hydrogen (ca. 30 psi), evacuating the atmosphere above the reaction mixture each time. The reaction vessel is pressurized to 45 psi with hydrogen. The shaker motor is started. The reaction is exothermic. A temperature rise from 19 to 54° C. over 15 min is observed after which time the hydrogen uptake stops. The mixture is allowed to cool to 30° C. over 1 h at which point the shaker is stopped. The hydrogen atmosphere is replaced with nitrogen as described above (Inert the reaction vessel). The catalyst is removed by filtration through a 10 g pad of filter cel. This entire process is repeated once more, both filtrates are combined and charged to a clean 3 L 4-neck round bottom flask.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(C(O)=O)CC=1.[N+:28]([O-:33])([N+]([O-])=O)=[O:29].O>C(O)(=O)C.C(OCC)C>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:5]2[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]([N+:28]([O-:33])=[O:29])[O:3][C:4]=2[CH:16]=1
Reactant: COc1ccc2c(-c3ccccc3)c(Br)oc2c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C(O)C1CC=CCC1
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1

Procedure:
To a solution of 33.9 g (0.112 mole) of 2-bromo-6 -methoxy-3-phenylbenzofuran in 1 l. of acetic acid is added 21.2 g (0.168 mole) of cyclohexene-4-carboxylic acid, then 15.5 g (0.168 mole) of dinitrogen tetraoxide in 20 ml of acetic acid is added dropwise over 1.5 hours. After 3 additional hours the mixture is poured into cold water to give a yellow gum. The mixture is treated with diethyl ether and the solid residue is collected by filtration. This residue is recrystallized from aqueous ethanol, cyclohexane and ethanol to provide yellow solid 6-methoxy-2-nitro-3-phenylbenzofuran, m.p. 100°-106° C., containing 20 % 7-bromo-6-methoxy-2-nitro-3-phenylbenzofuran.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C([O-])(=O)C.[Na+].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(OCC)(=O)C>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Br)cc1
Temperature: 180 °C
Yield: 22 %

Procedure:
A mixture made from 10 g (49.5 mmol) of 2-bromo nitrobenzene, 13 g (163 mmol) of sodium acetate and 10 g (59 mmol) of 4-bromo aniline was stirred with heating at the temperature of 180° C. under the atmosphere of nitrogen gas for 8 hours. The reacted solution was cooled down to room temperature, diluted with ethyl acetate and filtered. After concentrating the filtrate, and by washing the residue with methanol 3.8 g of (4-bromophenyl)-(2-nitrophenyl) amine was obtained as orange crystals (yield: 22%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][C:12]3[CH:13]=[C:14]([CH2:22][OH:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=3)[CH:8]=2)[CH2:3]1.[CH3:24][S:25](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:27])=[O:26].N1CCCN2CCCCCC=12>C1COCC1>[OH:23][CH2:22][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=1)[CH2:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][C@H:2]([NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10]2
Reactant: N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Reactant: CS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)N[C@H]1Cc2ccc(Cc3cc(CO)cc(C(F)(F)F)c3)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (S)-(3-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)phenyl)methanol (50, mg, 0.16 mmol) in THF (1 mL) was added perfluorophenyl methanesulfonate (39 mg, 0.15 mmol) followed by 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (34.1 mg 0.22 mmol). The reaction was allowed to stir at RT overnight before removing the solvent in vacuo. The sample was redissolved in DMSO (500 μL) before purifying by reverse phase preparative HPLC-MS to give the title compound as a clear film (11 mg, 17.2%). MS (ESI): m/z [M+H]+ 400.1
Reaction SMILES: CN[C:3]([C:5]1SC=C(C)C=1NC1C(Cl)=CN=C(Cl)N=1)=O.[CH3:20][NH:21][C:22]([C:24]1[S:25][CH:26]=[C:27]([CH3:53])[C:28]=1[NH:29][C:30]1[C:35]([Cl:36])=[CH:34][N:33]=[C:32]([NH:37][C:38]2[CH:39]=[CH:40][C:41]3[CH2:47][N:46]([C:48](=[O:50])[CH3:49])[CH2:45][C:44](=[O:51])[NH:43][C:42]=3[CH:52]=2)[N:31]=1)=[O:23]>>[CH3:20][NH:21][C:22]([C:24]1[S:25][CH:26]=[C:27]([CH3:53])[C:28]=1[NH:29][C:30]1[C:35]([Cl:36])=[CH:34][N:33]=[C:32]([NH:37][C:38]2[CH:39]=[CH:40][C:41]3[CH2:47][N:46]([C:48](=[O:50])[CH3:49])[CH2:45][C:44](=[O:51])[N:43]([CH2:3][CH3:5])[C:42]=3[CH:52]=2)[N:31]=1)=[O:23]
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(C(C)=O)C3)ncc1Cl
Reactant: CNC(=O)c1scc(C)c1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CN(C(C)=O)Cc2ccc(Nc3ncc(Cl)c(Nc4c(C)csc4C(=O)NC)n3)cc21

Procedure:
Following a procedure analogous to Example 1741e, 4-acetyl-1-ethyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazopin-2-one and 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-thiophene-2-carboxylic acid methylamide were converted to 3-[2-(4-acetyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide: 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 8.2 (s, 1H), 7.8 (s, 1H), 7.38 (dd, 2H), 7.22 (d, 1H), 7.1 (d, 1H), 6.08 (d, 1H), 4.55 (s, 2H), 4.12 (s, 2H), 3.85 (br, 2H), 3.05 (d, 3H), 2.30 (s, 3H), 2.18 (s, 3H), 1.15 (t, 3H); MS (m/e): 528.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11](COCC[Si](C)(C)C)[CH:12]=2)[N:5]2[CH:21]=[CH:22][N:23]=[C:4]2[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[N:11][NH:10][CH:9]=2)[N:5]2[CH:21]=[CH:22][N:23]=[C:4]2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2nc(Cl)cc3nccn23)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Clc1cc2nccn2c(-c2cn[nH]c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of 7-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation G; 0.250 g, 0.715 mmol) in 3.5 mL of DCM was added 2,2,2,-trifluoroacetic acid (2.2 mL, 28.6 mmol) and allowed to stir at ambient temperature for 1 hour before the reaction mixture was diluted with 5 mL of toluene and then concentrated under reduced pressure. The resulting residue was dissolved in 2 mL of 7M ammonia in methanol and stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography eluting with a gradient of 2-5% methanol in DCM with 1% ammonium hydroxide to afford 7-chloro-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.107 g, 0.468 mmol, 65.5% yield). MS (apci) m/z=220.1 (M+H).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:66])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:64])[CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:65])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:66])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:64])[CH2:57][C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:65])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Cc4ccccc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Cc4ccccc4)cc3)cc2C1=O
Yield: 90 %

Procedure:
The compound of example 659 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 658.
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH:10][C:11](=[S:13])[S-:12])[C:5](=[S:7])[S-:6].[Na+].[Na+].[Na].[Mn:17](Cl)(Cl)=O>O>[SH:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH:10][C:11](=[S:12])[S-:13])[C:5](=[S:6])[S-:7].[Mn+2:17]
Reactant: O=[Mn](Cl)Cl
Agent: S=C([S-])NCCN(CCS)C(=S)[S-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: [Mn+2]

Procedure:
In 50 ml of water, 13 g (0.02 mole) of an aqueous 48% sodium N-(2-mercaptoethyl)-ethylenebisdithiocarbamate was stirred at 45° to 50° C. The remaining part of the procedure was performed under a current of nitrogen gas. To the resultant sodium salt solution, 9.5 g (0.02 mole) of an aqueous 26.5% manganous chloride solution was gradually added dropwise at temperatures of 40° to 50° C. After the dropwise introduction, the resultant mixture was stirred at 45° C. for one hour. The crystals which consequently educed in the solution were separated by filtration and washed with water. The washed crystals were dried under a vacuum to produce manganese N-(2-mercaptoethyl)-ethylenebisdithiocarbamate (61). The compounds produced by this procedure were as follows:
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:35])[CH:11]=2)[CH:6]=1.[OH-].[Li+]>C1COCC1.O>[F:35][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([S:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])(=[O:23])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)Cc3ccccc3[N+](=O)[O-])CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)Cc2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
To a light yellow solution of {6-fluoro-3-methyl-4-[1-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (100 mg, 0.194 mmol) in THF (4 mL) was added a solution of lithium hydroxide (93.1 mg, 3.89 mmol) in water (1 mL) at room temperature. The resulting light brown solution was stirred for 15 hours at room temperature. The THF was evaporated off under vacuum and the basic aqueous layer was neutralized with 1.0 N HCl. The resulting solids were filtered using filter paper and washed with water and hexanes. The white solid (82 mg) was dissolved in ethyl acetate (˜5 mL) with heating and the mixture was diluted with hexanes. During the dilution some precipitate was formed. Cooling in the refrigerator precipitated additional solids. {6-Fluoro-3-methyl-4-[1-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (88 mg, 90%) was isolated as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (br. s, 1H), 8.08 (d, J=8.03 Hz, 1H), 7.90 (dd, J=8.91, 6.65 Hz, 1H), 7.74-7.86 (m, 3H), 7.64-7.73 (m, 2H), 7.36 (t, J=8.03 Hz, 1H), 4.97 (s, 2H), 3.52-3.90 (m, 7H), 2.42 (br. s, 3H), 1.60-184 (m, 4H). MS cald. for C25H25FN2O6S [(M+H)+] 500, obsd. 501.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[CH3:2].Br[CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:16][CH2:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH:6]=1)[CH3:2]
Reactant: FC(F)(F)CCCBr
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(OC)c(OCCCC(F)(F)F)c1
Reaction time: 8 h

Procedure:
A suspension of 3-hydroxy-4-methoxy-benzoic acid ethyl ester (1.00 g, 5.10 mmol), 1-bromo-4,4,4-trifluorobutane (1.12 g, 5.86 mmol) and anhydrous K2CO3 (2.14 g, 15.3 mmol) in MeCN (10 mL) is refluxed with stirring overnight. After cooling, the mixture is filtered, and the filtrates are evaporated to drying to give the title compound as white solid. TLC, Rf (hexane/AcOEt 1:1)=0.62. MS: 307.0 [M+H]+. 1H-NMR (CDCl3): δ 1.42 (m, 3H), 2.1-2. (m, 2H), 2.3-2.45 (m, 2H), 3.95 (s, 3H), 4.14 (m, 2H), 4.39 (m, 2H), 6.93 (dd, 1H), 7.58 (d, 1H), 7.74 (dd, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.Cl.[C:20]([C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:27][NH2:28])=[CH:24][CH:23]=1)#[N:21].C(N(CC)CC)C>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:27]([CH2:26][C:25]2[CH:29]=[CH:30][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[N:28]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: N#Cc1ccc(CNN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1ccc(Cn2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1

Procedure:
5.0 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, 3.9 g of 4-cyanobenzylhydrazine hydrochloride and 6 ml of triethylamine are boiled under reflux for 3 h in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethanol/water. After drying, 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-ylmethyl]benzonitrile remains as colorless crystals of m.p. 147-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[C:25]([C:24]1[CH:23]=[CH:22][C:21]([NH:18][C:19]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:20])=[CH:28][CH:27]=1)#[N:26]
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: N#Cc1ccc(NC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 85.3 %

Procedure:
Example 25 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 4-isocyanatobenzonitrile (0.0196 g) to give the title compound (0.0325 g). LC-MS (System A): Rt 2.29 mins, Mass Spectrum m/z 419 [MH+].
Reaction SMILES: [F:1][C:2]([F:17])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)CCN(C)C.[CH:52]([O:54][CH2:55][CH2:56]Cl)=[CH2:53]>CS(C)=O>[F:17][C:2]([F:1])([S:13]([O-:16])(=[O:15])=[O:14])[C:3]([F:11])([F:12])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[CH:52]([O:54][CH2:55][CH2:56][O:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[CH2:53]
Reactant: C=COCCCl
Reactant: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CS(C)=O
Product: C=COCCOc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
4-Hydroxyphenyldiphenylsulfonium perfluorobutanesulfonate salt (52.2 g), potassium carbonate (18.0 g), and N,N,N′,N′-tetramethylethylenediamine (1.05 g) were dissolved in dimethyl sulfoxide (26.1 g). Chloroethyl vinyl ether (13.9 g) was added to the solution, followed by heating to 80° C. The reaction mixture was stirred for 15 hours and cooled to 30° C. or lower. After removal of solid through filtration, water (100 g) was added to the filtrate, and the aqueous layer was washed three times with hexane (100 g). To the washed aqueous layer, dichloromethane (209 g) and water (260 g) were added under stirring, whereby the target substance was extracted to the dichloromethane layer. The organic layer was repeatedly washed with distilled water until the pH of the separated aqueous layer was shifted to 7. The solvent was removed by means of a rotary evaporator, to thereby yield 69.9 g of an oily substance. Through 1H-NMR and ion chromatography, the substance was identified to be 4-vinyloxyethoxyphenyldiphenylsulfonium perfluorobutanesulfonate salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8].[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](O)=[O:21].CCN=C=NCCCN(C)C.Cl>N1C=CC=CC=1.O.C(Cl)Cl>[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])=[O:21]
Reactant: COC(=O)/C=C/c1cccc(N)c1
Reactant: Cn1cccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)/C=C/c1cccc(NC(=O)c2cccn2C)c1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 73.8 %

Procedure:
A mixture of methyl (E)-3-aminocinnamate (9) (1.20 g, 6.77 mmol), 1-methylpyrrole-2-carboxylic acid (0.89 g, 7.11 mmol) and EDCI.HCl (1.56 g, 8.14 mmol) in pyridine (8 mL) was stirred at 50° C. for 2.5 h and then cooled and diluted with water. The precipitated semi-solid was dissolved in CH2Cl2, the solution was washed with 0.5 N HCl (2×) and water (2×) and then dried and concentrated under reduced pressure below 30° C. The residue was chromatographed on silica gel, eluting with CH2Cl2/EtOAc (10:1), to yield a solid which was triturated with i-Pr2O/petroleum ether to give thermally unstable methyl (E) -3- (l-methylpyrrole-2-carboxamido)cinnamate (10) (1.42 g, 74%), mp 89-90° C. 1H NMR [(CD3)2SO] δ9.83 (s, 1 H, NH), 8.01 (d, J=1.4 Hz, 1 H, H-2), 7.76 (dt, J=7.8, 1.4 Hz, 1 H, H-4), 7.63 (d, J=16.0 Hz, 1 H, PhCH═CH), 7.45-7.35 (m, 2 H, H-5,6), 7.05 (dd, J=4.0, 1.7 Hz, 1 H, H-pyrrole), 7.03 (t, J=2.0 Hz, 1 H, H-pyrrole), 6.54 (d, J=16.0 Hz, 1 H, Ph CH═CH), 6.11 (dd, J=3.8, 2.6 Hz, 1 H, H-pyrrole), 3.89 (s, 3 H, NCH3), 3.74 (s, 3 H, CO2CH3).
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>CO.N1CCCCC1>[I-:1].[CH3:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH2:13][CH:12]([O:23][CH3:24])[O:11][CH3:10]
Reactant: Cc1cccc[n+]1C
Reactant: COC(COc1ccccc1C=O)OC
Agent: [I-]
Solvent: C1CCNCC1
Solvent: CO
Product: COC(COc1ccccc1C=Cc1cccc[n+]1C)OC
Yield: 86.6 %

Procedure:
In 6 ml of methanol, 1.50 g of 1,2-dimethylpyridinium iodide and 1.50 g of o-(2,2-dimethoxyethoxy)benzaldehyde. The resultant solution, with two drops of piperidine added thereto, was refluxed for five hours and then left to stand and cool off. The crystals which deposited consequently were collected and thoroughly washed with acetone. Consequently, there was obtained 2.36 g of 1-methyl-2-[o-(2,2-dimethoxyethoxy)-styryl]pyridinium iodide which melted at 169°~173° C. This product showed the highest absorption at 353 nm (ε=1.78×104). The infrared absorption spectrum (KBr) showed peaks at 1630, 1610, 1595, 1567, 1515, 1500, 1450, 1280, 1248, 1130, 1065, 971, 780, 760 and 750 cm-1. The yield was 87%.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:31][O:32][C:33](Cl)=[O:34]>>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][N:21]([C:33]([O:32][CH3:31])=[O:34])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCNC2
Reactant: COC(=O)Cl
Product: COC(=O)N1CCc2c(nc(-c3ccc(NC(=O)NC4CC4)cc3)nc2N2CCOC[C@@H]2C)C1

Procedure:
Method as example 34 using (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 15) and methylchloroformate as starting materials.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH3:30])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1>CC(O)=O.[Zn]>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:12]2[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:8]([C:5]3[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=3)[C:9]3[C:10](=[N:27][N:28]([CH3:30])[CH:29]=3)[N:11]=2)=[CH:25][CH:24]=1
Reactant: Cn1cc2c(-c3ccc(Cl)nc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cn1cc2c(-c3cccnc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Yield: 3.1 %

Procedure:
To a solution of 4-(6-chloropyridin-3-yl)-6-(4-fluorophenyl)-2-methyl-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (74 mg, 0.2 mmol, obtained in example 193) in AcOH (1 mL), Zn (72 mg, 1.1 mmol) was added under argon atmosphere and the mixture was heated to reflux overnight. It was allowed to cool and concentrated. The residue was treated with saturated NaHCO3 and it was extracted with CHCl3. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc-MeOH mixtures of increasing polarity, to afford 2.4 mg of the title compound (yield: 4%)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:25])[O:18][C:17](=[O:19])[C:16](=[CH:20]OCC)[C:15](=[O:24])[O:14]1>CN(C)C=O>[CH3:12][C:13]1([CH3:25])[O:14][C:15](=[O:24])[C:16](=[CH:20][NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[C:17](=[O:19])[O:18]1
Reactant: CCOC=C1C(=O)OC(C)(C)OC1=O
Reactant: Nc1ncnc2ccccc12
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C(=CNc2ncnc3ccccc23)C(=O)O1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
A mixture of 4-aminoquinazoline (2.9 g) and 2,2-dimethyl-5-ethoxymethylene-1,3-dioxane-4,6-dione (4.46 g) in N,N-dimethylformamide (20 ml) was stirred for 1 hour and 10 minutes at 110° C. The resultant mixture was cooled to ambient temperature and allowed to stand overnight to give crystals, which were separated by filtration and washed with a mixture of ethyl acetate and hexane to give crystalline 2,2-dimethyl-5-[(4-quinazolinyl)amino]methylene-1,3-dioxane-4,6-dione (4.1 g).