Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C:12]#[CH:13].C([Mg]Br)C.Br[CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O1CCCC1.CCOCC.[Cl-].[NH4+]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][C:12]#[C:13][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCC#CCBr
Reactant: C#CCC#CCOC1CCCCO1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC#CCC#CCC#CCOC1CCCCO1
Reaction time: 2 h

Procedure:
To a stirred solution of 10.8 g (60 mmole) of hexa-2,5-diyn-1-ol tetrahydropyranyl ether [D. Van der Steen et al, Recueil 82, 1015 (1963)] in 100 ml of dry tetrahydrofuran there were added dropwise, under argon atmosphere, at 0°-5° C. 16.9 ml (0.60 mmol) of a 3.5N ethylmagnesium bromide solution in ether, maintaining the temperature at 0°-5° C. The mixture was stirred for 2 hours at 10°-15° C. and then 0.1 g of cuprous chloride were added. After 15 minutes a solution of 5.35 g (26 mmole) of 1-bromo-2-nonyne in 60 ml of dry tetrahydrofuran was added dropwise and the mixture stirred at room temperature for 3 hours. The reaction mixture was diluted with 70 ml of saturated ammonium chloride solution and extracted with methylene chloride. The organic extracts were dried and evaporated, and the residue purified by column chromatography on 450 g of silica gel, using hexane-ethyl acetate (99:1) as eluant, to provide pentadeca-2,5,8-triyn-1-ol tetrahydropyranyl ether.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C1C(=O)N([Br:18])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1csc2ccccc12
Yield: 42.2 %

Procedure:
3-Methylbenzo[b]thiophene (9.9 g, 67 mmol) is heated in carbon tetrachloride (133 ml ) to near reflux in the presence of n-bromosuccinimide (11.9 g, 67 mmol, 1.0 eq.). 2,2′Azobisisobutyronitrile (2.2 g, 13.3 mmol, 0.2 eq.) is added and the resulting mixture is refluxed for two hours. After cooling, the reaction mixture is filtered through a glass-fritted funnel, and the filtrate is concentrated. The residue is triturated with petroleum ether and toluene to afford 6.42 g of 3-Bromomethylbenzo[b]thiophene (42%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([C:10]#[N:11])=[CH:8][N:7]=[C:6]([Cl:12])[N:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=[O:23].Cl>C(OCC)(=O)C.CN(C)C=O>[Cl:12][C:6]1[N:5]=[C:4]2[NH:3][C:22](=[O:23])[N:21]([C:15]3[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:20])[C:10](=[NH:11])[C:9]2=[CH:8][N:7]=1
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
1.12 g of sodium hydride was added to an N,N-dimethylformamide (35 mL) solution of 3.0 g of 4-amino-2-chloropyrimidine-5-carbonitrile, and stirred at room temperature for 5 minutes. 4.38 g of 2,6-dichlorophenyl isocyanate was added to the reaction liquid, and stirred at room temperature for 1 hour. Ethyl acetate and aqueous 1 N hydrochloric acid solution were added to the reaction solution, and the organic layer was separated. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The precipitated solid was solidified with a mixed solvent of methanol/ethyl acetate and taken out through filtration to obtain 3.8 g of the entitled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:4]=1.[CH3:19][O:20]C(Cl)Cl.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:10]([F:12])([F:13])[F:11])([OH:18])[C:14]([F:15])([F:16])[F:17])[CH:6]=[CH:7][C:8]=1[CH:19]=[O:20]
Reactant: COC(Cl)Cl
Reactant: COc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
To a solution of 31.6 g (0.12 mole) of 1-methoxy-3-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzene in 200 ml dichloromethane is added 38 g (0.2 mole) of titanium tetrachloride at 0°-5° with stirring under a nitrogen atmosphere. After the resulting solution is stirred for 15 minutes, 11.5 g (0.1 mole) of α,α-dichloromethyl methyl ether is added dropwise at 0°-5° C. Stirring is continued while the temperature of the solution is allowed to reach 20°-25° during 18 hours. The solution is then added with stirring to a solution of 100 ml 6N hydrochloric acid in 500 ml of ice and water. The resulting organic phase is separated leaving an aqueous phase which is washed with three 300 ml portions of dichloromethane. The combined dichloromethane extracts are washed with 1N hydrochloric acid and then with saturated sodium chloride solution. The dichloromethane solution is dried with anhydrous magnesium sulfate, filtered, and evaporated at reduced pressure to obtain an oily solid which is triturated with chlorobutane, filtered and recrystallized from chlorobutane to give 14.5 g of 2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-(trifluoromethyl)ethyl]benzaldehyde having a melting point of 144°-146°.
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N:13]1([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.CO>C(Cl)(Cl)Cl>[N:13]1([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:5]3[S:1][C:2]4[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=4[CH:4]=3)=[CH:23][N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Brc1ccc(OCCN2CCCC2)nc1
Reactant: OB(O)c1cc2ccccc2s1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: c1ccc2sc(-c3ccc(OCCN4CCCC4)nc3)cc2c1
Yield: 68 %

Procedure:
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from benzo[b]thiophene-2-boronic acid and 5-bromopyrid-2-yl 2-(1-pyrrolidinyl)ethyl ether (Part A) in 68% yield as an oil following flash chromatography (SiO2; gradient of 0-4% MeOH in CHCl3).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[N:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[C:22]2[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O.O>CN(C)C=O>[C:38]([O:37][C:36]([NH:35][CH2:34][C:23]1[N:24]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:25](=[O:29])[C:26]2[C:21]([C:22]=1[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[CH:20][C:19](/[CH:17]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:28][CH:27]=2)=[O:42])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C=O)ccc2c1=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (1.0 mL, 5 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (0.20 g, 5 mmol) (60% in oil), and the mixture was stirred at room temperature for 10 min. To the obtained mixture was added a solution of tert-butyl (6-formyl-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (2.17 g, 5 mmol) in N,N-dimethylformamide (20 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give ethyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenate (2.03 g, 71.7%) as an amorphous.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][C@H:16]([CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[C:17](O)=[O:18])=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:3]1.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[CH3:37][N:38]1[CH2:39][CH2:40][CH:41]([N:44]2[CH2:49][CH2:48][N:47]([C:17](=[O:18])[C@H:16]([NH:15][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([N:6]4[C:2](=[O:1])[NH:3][C:4]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[N:5]4)[CH2:8][CH2:9]3)=[O:14])[CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH2:46][CH2:45]2)[CH2:42][CH2:43]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=C(O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(n2nc(-c3ccccc3)[nH]c2=O)CC1
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3ccc4c(c3)CCCC4)NC(=O)N3CCC(n4nc(-c5ccccc5)[nH]c4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 54c) from 300 mg (0.61 mmol) (R)-2-{[4-(5-oxo-3-phenyl-4,5-dihydro-[1,2,4]triazol-1-yl)-piperidine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionic acid and 120 mg (0.66 mmol) 1-(1-methyl-piperidin-4-yl)-piperazine.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:14]=2)[C:9]1=[O:22])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:14]=2)[C:9]1=[O:22]
Reactant: CC=CCC1Cc2ccc(OS(C)(=O)=O)cc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)Oc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.92 h
Yield: 85 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 55 minutes while stirring through a solution, cooled to -70°, of 11.3 g of (RS)-2-(2-buten-1-yl)-6-mesyloxy-1-indanone in 300 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.51 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 250 ml of dichoromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 4 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 9.38 g (85%) of (RS)-2-(2-oxoethyl)-6-mesyloxy-1-indanone were obtained as a light brown solid with m.p. 85°-87°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:33])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=[C:22]3[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]3=[O:32])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1.[CH2:34](O)[CH3:35].O1CCOCC1.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:33])[NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16](=[C:22]3[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O:31][CH2:34][CH3:35])=[O:30])[C:23]3=[O:32])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=S)Nc2ccc(Cl)cc2)n1
Reactant: CCO
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CN1C(=O)C(=C(C(=O)OCC)c2csc(NC(=S)Nc3ccc(Cl)cc3)n2)SC1=S
Reaction time: 108 h

Procedure:
A mixture comprising 4.8 g of 5-{1-[2-(3-p-chloro-phenylthioureido)thiazol-4-yl]-1-ethoxycarbonylmethylene}-rhodanine-3-acetic acid, 10 g of ethanol and 50 ml of a 4N dioxane solution of hydrogen chloride was left to stand at room temperature for 4.5 days. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, and was then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was recrystallized from a circa 1:1 by volume mixture of hexane and ethyl acetate. The resulting product was an orange powder having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([CH3:22])=[CH:17][N:16]=1>CO>[Cl:14][C:15]1[N:20]=[C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[S:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=3[CH:13]=2)[C:18]([CH3:22])=[CH:17][N:16]=1
Reactant: CN1C(=O)CSc2ccc(N)cc21
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CO
Product: Cc1cnc(Cl)nc1Nc1ccc2c(c1)N(C)C(=O)CS2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
A mixture of 1.3 g of 6-Amino-4-methyl-3-oxo-benzo[1,4]thiazine and 3.3 g of 2,4-Dichloro-5-methylpyrimidine in 100 mL methanol was stirred at RT overnight and was reduced in volume by rotary evaporation. The solution was filtered and the filtrate diluted with water and neutralized with sodium bicarbonate. The precipitate was collected by suction filtration washed with water and dried on the funnel to yield 660 mg 13% of the desired product 2-Chloro-5-methyl-N4-(4-methyl-3-oxo-benzo[1,4]thiazin-6-yl)-4-pyrimidineamine 1H NMR (DMSO-d6): δ 8.93 (s, 1H), 8.06 (m, 2H), 7.62 (s, 1H), 7.37 (s, 1H), 3.51 (s, 2H), 2.16 (s, 3H) purity 97%; MS (m/e) 321 (MH+).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[Cl:8][C:9]1[C:10]([N:15]2[C:19]3=[N:20][CH:21]=[N:22][C:23]([O:24][C@@H:25](CCO)[C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=4)=[O:27])=[C:18]3[CH:17]=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:8][C:9]1[C:10]([N:15]2[C:19]3[N:20]=[CH:21][N:22]=[C:23]([O:24][C@H:25]([C:26]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=4)=[O:27])[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:18]=3[CH:17]=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(NC(=O)[C@H](CCO)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 45.8 %

Procedure:
Acetic anhydride (0.035 mL, 0.38 mmol) was added to (2S)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-4-hydroxy-N-(5-methylpyridin-2-yl)butanamide (Example 143) (150 mg, 0.34 mmol), N,N-Diisopropylethylamine (0.089 mL, 0.51 mmol) and 4-dimethylaminopyridine (4.17 mg, 0.03 mmol) in DCM (2 mL) at 0° C. over a period of 5 minutes under nitrogen. The resulting solution was stirred at 0° C. for 25 minutes. The volatiles were removed under reduced pressure and the crude product was purified by flash silica chromatography, eluting with 0 to 100% ethyl acetate in isohexane to afford the product (75 mg, 45.6%). 1H NMR (400 MHz, CDCl3) δ 1.95 (3H, s), 2.29 (3H, s), 2.54 (2H, q), 4.31-4.39 (2H, m), 6.00 (1H, t), 7.45-7.49 (1H, m), 7.53 (1H, d), 8.00-8.02 (1H, m), 8.10-8.14 (2H, m), 8.43 (1H, s), 8.61 (1H, q), 8.64 (1H, s), 8.80 (1H, s); m/z (ES+) (M+H)+=482; HPLC tR=2.04 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[P:7](Cl)([O:11][CH3:12])([O:9][CH3:10])=[S:8].[C:14]([C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][C:20]=1[OH:21])#[N:15]>CC(C)=O>[C:14]([C:16]1[S:17][C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][C:20]=1[O:21][P:7]([O:11][CH3:12])([O:9][CH3:10])=[S:8])#[N:15]
Reactant: N#Cc1sc(-c2ccccc2)cc1O
Reactant: COP(=S)(Cl)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COP(=S)(OC)Oc1cc(-c2ccccc2)sc1C#N
Temperature: 20 °C
Reaction time: 15 h
Yield: 79 %

Procedure:
7 g of potassium carbonate and 8 g of O,O-dimethyl chlorothiophosphate were added to a solution of 10.5 g of 2-cyano-3-hydroxy-5-phenyl-thiophene in 120 ml of acetone and the mixture was stirred at 20° C. for 15 hours and was then filtered. The filtrate was evaporated to dryness and the crystal residue was empasted with petroleum ether. The crystals were then crystallized from isopropyl ether to obtain 12.8 g of 2-cyano-3-(dimethoxythiophosphoryloxy)-5-phenylthiophene melting at 95° C.
Reaction SMILES: [CH3:1][C:2]([NH:10][OH:11])=[C:3]1[CH:9]=[CH:8][C:6](=[O:7])[CH:5]=[CH:4]1.[CH3:12][C:13](C1C=CC(O)=CC=1)=[O:14].O[NH2:23]>S(Cl)(Cl)=O>[C:13]([NH:23][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[CH:8][CH:9]=1)(=[O:14])[CH3:12].[CH3:1][C:2]([NH:10][OH:11])=[C:3]1[CH:9]=[CH:8][C:6](=[O:7])[CH:5]=[CH:4]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NO
Agent: CC(NO)=C1C=CC(=O)C=C1
Solvent: O=S(Cl)Cl
Product: CC(=O)Nc1ccc(O)cc1

Procedure:
N-acetyl-para-aminophenol is prepared by subjecting 4-hydroxyacetophenone oxime to a Beckmann rearrangement in the presence of a thionyl chloride catalyst and an alkyl alkanoate as the reaction solvent. An integrated process is disclosed wherein 4-hydroxyacetophenone is reacted with a hydroxyl amine salt and a base to obtain the ketoxime of the ketone, e.g., 4-hydroxyacetophenone oxime, extracting the ketoxime product from the reaction with alkanoate ester and subjecting the ketoxime dissolved in the ester to a Beckmann rearrangement in the presence of a thionyl chloride catalyst.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.Br[C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][O:29][C:27](=[O:28])[C@H:26]([N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)[C@H](Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 70.7 %

Procedure:
A mixture of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (400 mg, 1.21 mmol, 1 equiv), (R)-methyl 2-bromo-2-phenylacetate (276.6 mg, 1.21 mmol, 1 equiv) and potassium carbonate (418.1 mg, 3.025 mmol, 2.5 equiv) in N,N-dimethylformamide was stirred at 65° C. for 3.5 hours. The reaction mixture was cooled to ambient temperature and the mixture was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.4, gradient—5%-20% ethyl acetate/hexanes) to afford (R)-tert-butyl 3-(2-methoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as an oil (410 mg, 71.1%). MS for C27H33N3O5 m/z 479.57 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[C:14]3[C:19](=[N:20][CH:21]=2)[N:18]=CN(C)[C:15]3=[O:23])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[OH-:24].[Na+]>CO>[NH2:18][C:19]1[C:14]([C:15]([OH:23])=[O:24])=[N:13][C:12]([N:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)=[CH:21][N:20]=1
Reactant: [OH-]
Reactant: CCS(=O)(=O)N1CCN(c2cnc3ncn(C)c(=O)c3n2)CC1
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 6-(4-ethylsulfonylpiperazin-1-yl)-3-methyl-pteridin-4-one (5 g, 14.78 mmol) in methanol (51.00 mL) was treated with sodium hydroxide (45.92 mL of 10% w/v, 114.8 mmol) and the reaction mixture stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue diluted with water and neutralised with formic acid. The resulting precipitate was filtered off and the filtrate acidified to pH4 by the addition of formic acid and extracted with dichloromethane. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo to give the product as a bright yellow solid (4.66 g, 52% Yield). 1H NMR (400.0 MHz, CDCl3) d 1.45 (3H, t), 3.05 (2H, q), 3.54 (8H, m), 6.05 (2H, br s), 8.21 (1H, s) ppm; MS (ES+) 316
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH:14]=[O:15])[CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH3:27])=O>O>[CH2:26]([O:25][C:23]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH2:11][N:12]([CH:14]=[O:15])[CH3:13])[CH:9]=[CH:10][C:2]=2[N:1]=1)[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: CN(C=O)Cc1ccc(N)c(C(=O)O)c1
Solvent: c1ccncc1
Solvent: O
Product: CCOc1nc2ccc(CN(C)C=O)cc2c(=O)o1

Procedure:
To 6.0 g of 2-amino-5-(N-formyl-N-methylamino-methyl)-benzoic acid, there was added 30 mL of pyridine and then 11.1 mL of ethyl chloroformate was dropwise added to the mixture while ice-cooling the same. After the elapse of a night, 20 mL of water was dropwise added to the mixture to separate out a solid material, the solid was then isolated through filtration under reduced pressure and washed with 20 mL of water. Then the solid thus separated was dried under reduced pressure to give 3.97 g of the intended compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=O)[CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:6])[CH3:2].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:3]([CH2:4][CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:6])[CH2:17][CH3:18])[CH3:2]
Reactant: CCN(CC)C(=O)C(C)Nc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CC(C)Nc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
2.31 g of N,N-diethyl 2-(3,4-dichloroanilino)propionamide were dissolved in 15 ml of dry tetrahydrofuran. This solution was added dropwise in 5 minutes to a stirred suspension of 0.61 g of lithium-aluminium-hydride in 25 ml of dry tetrahydrofuran. The reaction mixture was refluxed for 6 hours and was left to stand overnight. The next day 0.6 ml of water, 1.5 ml of 15% sodium hydroxide solution and 1.5 ml of water were added successively. After filtration the organic layer was washed with water, dried and filtered. After evaporating the solvent, 2.06 g of the desired product were obtained; identification by means of thin-layer chromatography. The product was purified by means of columnchromatography (acetone as an eluent), after which 1.41 g or an orange oil was obtained; nD25 =1.5404.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Reactant: C#CC(O)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (58.9 mg, 0.7 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and Cul (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 10 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 64 mg, 70%).