Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:19]1[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=1)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7]2)([CH3:3])=[CH2:2]>C1COCC1.CO.[C].[Pd]>[NH:22]1[CH:23]=[C:19]([C:14]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=3)[CH:10]=2)([OH:18])[CH:15]([CH3:17])[CH3:16])[N:20]=[CH:21]1
Reactant: C=C(C)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 167.4 %

Procedure:
1-(6-Isopropenylnaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.70 g) was dissolved in THF-methanol (2:1) (12 ml). To the solution were added 10% palladium carbon (170 mg), and the mixture was stirred at room temperature for 2 h under hydrogen atmosphere. The catalyst was filtered and washed with THF. The filtrate was concentrated and the obtained residue was purified by silica gel chromatography (eluent, hexane:THF=1:1). Crystallization from isopropyl ether-hexane gave the titled compound (1.60 g) as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:3][C:4]#[CH:5].[C:15]1([CH:21]2[CH2:26][CH:25]3[CH2:27][CH:22]2[CH2:23][NH:24]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:28]=O>O1CCOCC1>[CH3:1][C:2]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])=[O:8])([CH3:28])[C:3]#[C:4][CH2:5][N:24]1[CH2:23][CH:22]2[CH2:27][CH:25]1[CH2:26][CH:21]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C#CCC(C)S(=O)(=O)c1ccccc1
Reactant: C=O
Reactant: c1ccc(C2CC3CC2CN3)cc1
Solvent: C1COCCO1
Product: CC(C)(C#CCN1CC2CC1CC2c1ccccc1)S(=O)(=O)c1ccccc1

Procedure:
A solution of 4-methyl-4-(phenylsulphonyl)butyne (208 mg, 1 mmol), 5-phenyl-2-azabicyclo[2.2.1]heptane (207 mg, 1.2 mmol), and paraformaldehyde (36 mg, 1.2 mmol) in dioxane (3 ml) was degassed three times. Cuprous chloride (10 mg) was added and the mixture was heated under reflux conditions for 1 h. The mixture was cooled and evaporated in vacuo. The residue was purified by chromatography on silica using 1–7% methanol in dichloromethane. The resulting brown oil was re-purified on alumina (grade III) using 25–50% ethyl acetate in i-hexane as eluant. The resulting oil was dissolved in ethyl acetate and ethereal hydrogen chloride added dropwise to give a white crystalline solid.
Reaction SMILES: [CH2:1]([C:4]1[C:14]([OH:15])=[C:13]([C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[O:10][CH2:9]1)[CH2:2][CH3:3].[SH:19][CH2:20][CH:21]1[CH2:25]S[C:23]2([CH2:29][CH2:28][CH:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]2)[S:22]1.C(=O)([O-])[O-:37].[K+].[K+]>C(C(C)=O)C>[C:16]([C:13]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH2:9][S:19][CH2:20][CH:21]2[S:22][C:23]3([CH2:29][CH2:28][CH:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:26]3)[O:37][CH2:25]2)=[C:4]([CH2:1][CH2:2][CH3:3])[C:14]=1[OH:15])(=[O:18])[CH3:17]
Reactant: CCOC(=O)CC1CCC2(C1)SCC(CS)S2
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCC2CO2)ccc(C(C)=O)c1O
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCC(O)CSCC2COC3(CCC(CC(=O)OCC)C3)S2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(2-n-Propyl-3-hydroxy-4-acetylphenoxy)-1,2-epoxypropane (1.5 g, 0.006 mol) (described in U.S. Pat. No. 4,565,882) is dissolved in 20 ml of methyl ethyl ketone. To this solution is added the mercaptan of Example G (1.75 g, 0.006 mol) and anhydrous potassium carbonate (2.5 g) and the reaction mixture is refluxed with stirring under a nitrogen atmosphere for 24 hrs. The reaction is cooled to room temperature, filtered and the filtrate is concentrated on a rotary evaporator. The residue is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the titled compound.
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].[C:5]1([P:11](C2C=CC=CC=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[Cl:2][P:1]([Cl:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:2][P:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClP(Cl)Cl
Product: ClP(Cl)c1ccccc1
Product: ClP(c1ccccc1)c1ccccc1

Procedure:
A mixture of 60 g (=0.4364 mole) of freshly distilled phosphorus trichloride and 40 g (=0.1527 mole) of triphenylphosphane (→molar ratio of 2.86 to 1) is added dropwise in the course of 30 minutes to the apparatus which has been described in Example 6 and which is at 620° C. The subsequent distillation gives 38 g (=0.1212 mole) of dichlorophenylphosphane and 16.5 g (0.075 mole) of chlorodiphenylphosphane (→molar ratio of 2.83 to 1), unconverted phosphorus trichloride and unconverted triphenylphosphane. The yield relative to the starting amount of triphenylphosphane is 52% of theory in dichlorophenylphosphane and 38% of theory in chlorodiphenylphosphane, with an 87% conversion.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](C)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16](C)C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.[NH2:21]N.[CH2:23]([OH:25])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:23])=[C:6]([C:7]2[NH:21][N:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:19]=1
Reactant: CCO
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1C
Reactant: NN
Product: CCOC(=O)c1cn[nH]c1-c1cc(Cl)ccc1OC
Yield: 100 %

Procedure:
A solution of ethyl 2-(5-chloro-2-methylbenzoyl)-3-(dimethylamino)acrylate (2.87 g, 9.70 mmol) and hydrazine (0.50 mL, 16.0 mmol, 1.6 equiv) in 30 mL ethanol was heated at 70° C. for 2 hours. Solvent and excess hydrazine were then evaporated to provide 2.57 g (100%) of ethyl 5-(5-chloro-2-methoxyphenyl)-1H-pyrazole-4-carboxylate, which was used without further purification. LCMS (ESI) m+H=265.2.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:17]([F:20])([F:19])[F:18])([OH:16])[C:4]=2[CH:3]=1.[OH2:21].[Mn]([O-])(=O)(=O)=[O:23].[K+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]([OH:23])=[O:21])[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:16])([C:17]([F:18])([F:19])[F:20])[C:4]=2[CH:3]=1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(Cl)cc2c1-c1ccccc1C2(O)C(F)(F)F
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1cc(Cl)cc2c1-c1ccccc1C2(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a mixture of 2-chloro-4-methyl-9-trifluoromethyl-9H-fluoren-9-ol (2.987 g), pyridine (6 ml) and water (24 ml) was added potassium permanganate (7.902 g) at 100° C., and the mixture was stirred for 2 hr. To this mixture were added further potassium permanganate (4.70 g) and pyridine (6 ml) and the mixture was stirred at 100° C. for 2 hr. Potassium permanganate (4.70 g) was further added and the mixture was stirred at 100° C. for 2 hr. This operation was repeated twice. The reaction mixture was cooled to room temperature, and the insoluble material was filtered off and washed with water (50 ml). The filtrate was adjusted to pH 1 with 6N hydrochloric acid, and extracted with ethyl acetate (200 ml). The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was treated with hexane/ethyl acetate mixed solution (hexane:ethyl acetate=9:1) (30 ml). This slurry was filtered, and the obtained solid was dried to give the title compound (2.509 g, 76%).
Reaction SMILES: O.O[O:3][S:4]([O-:6])=O.[K+].[CH2:8]1[CH:15]2[C:11]3([C:17]([NH:19][C:20]4[S:28][C:23]5[CH2:24][O:25][CH2:26][CH2:27][C:22]=5[C:21]=4[C:29]([NH:31][CH2:32][CH2:33]SC)=[O:30])=[O:18])[CH2:12][CH:13]([CH2:16][CH:9]1[CH2:10]3)[CH2:14]2.[CH3:36]O>>[CH2:14]1[CH:15]2[C:11]3([C:17]([NH:19][C:20]4[S:28][C:23]5[CH2:24][O:25][CH2:26][CH2:27][C:22]=5[C:21]=4[C:29]([NH:31][CH2:32][CH2:33][S:4]([CH3:36])(=[O:6])=[O:3])=[O:30])=[O:18])[CH2:10][CH:9]([CH2:16][CH:13]1[CH2:12]3)[CH2:8]2
Reactant: CSCCNC(=O)c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1CCOC2
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)CCNC(=O)c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1CCOC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 50-mL round-bottomed flask containing a magnetic stir bar were added water (2 mL) and OXONE® (155 mg, 0.252 mmol). The flask was cooled in an ice bath. A solution of Example 201 in methanol (11 mL) was added and the resulting slurry was stirred at 0° C. for 30 minutes. The mixture was allowed to warm to room temperature over 3 hours. The mixture was extracted with dichloromethane (3×5 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator. The crude material was recrystallized from ethyl acetate/hexanes to afford the title compound. 1H NMR (dimethylsulfoxide-d6, 300 MHz) δ 1.62-1.67 (m, 4H), 1.76-1.88 (m, 4H), 1.98-2.02 (m, 2H), 2.33 (br s, 2H), 2.59-2.63 (m, 1H), 2.84 (t, J=4.8 Hz, 2H), 3.05 (s, 3H), 3.39 (t, J=6.6 Hz, 2H), 3.69-3.75 (m, 2H), 3.84 (t, J=5.4 Hz, 2H), 4.65 (br s, 2H), 7.48 (t, J=5.8 Hz, 1H), 11.94 (br s, 1H). MS (ESI+) m/z 453.1 (M+H)+. Anal. calcd. for C21H28N2O5S2: C, 55.73; H, 6.24; N, 6.19. Found: C, 55.76; H, 6.25; N, 6.10.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1F.[CH3:17][C:18]1[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:19]=1[NH2:29].Cl>C(OCC)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:29][C:19]1[CH:20]=[CH:21][C:22]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:23][C:18]=1[CH3:17]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Reactant: Cc1cc(OC(F)(F)F)ccc1N
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccc(OC(F)(F)F)cc1C
Temperature: 140 °C

Procedure:
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (0.50 g, 2.15 mmol) is suspended in xylenes (3 mL) and 2-methyl-4-trifluoromethoxy-phenylamine (1.00 g, 5.23 mmol) is added. The reaction mixture is stirred at 140° C. under N2. After stirring for 7 days, the reaction is a mixture of starting material and product. The reaction mixture is cooled to room temperature. The reaction mixture is poured into a separatory funnel and diethyl ether and 10% aqueous HCl are added and the layers separated. The aqueous phase is extracted with three portions of diethyl ether. The combined diethyl ether layers are dried (MgSO4) and concentrated under reduced pressure. The residue is redissolved in methylene chloride and flushed through a plug of silica gel eluting with methylene chloride. The filtrate is concentrated under reduced pressure to give a bright yellow solid. The solid is washed with diethyl ether and the filtrate is concentrated under reduced pressure and the residue is further purified by FCC (eluting with 100% methylene chloride) to yield 0.39 g (45%) of the desired pure product as a yellow solid. MS APCI (−) m/z 402 (M−1) detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[CH3:20][O:21][CH2:22][C:23]([NH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2)=[O:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=[C:29]2[C:28]3[C:32](=[CH:33][CH:34]=[C:26]([NH:25][C:23](=[O:24])[CH2:22][O:21][CH3:20])[CH:27]=3)[NH:31][C:30]2=[O:35])=[CH:6][CH:7]=1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Reactant: COCC(=O)Nc1ccc2c(c1)CC(=O)N2
Product: COCC(=O)Nc1ccc2c(c1)C(=Cc1[nH]c3c(c1-c1ccc(F)cc1)C(=O)NCC3)C(=O)N2
Yield: 68.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 2-methoxy-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide as starting materials to give N-{3-[3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-2-methoxy-acetamide (46 mg, 68.7%) as a red solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22](=O)[NH2:23])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.P(Cl)(Cl)([Cl:27])=O>CN(C)C=O>[ClH:27].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([C:22]#[N:23])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)c(C(N)=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: N#Cc1c(F)ccc2onc(OCCN)c12
Temperature: 5 °C
Yield: 105.4 %

Procedure:
To a solution of 3-(2-(N-t-butoxycarbonylamino)ethoxy)-4-carbamoyl-5-fluoro-1,2-benzisoxazole (0.25 g) in dimethylformamide (2.0 ml) was added phosphorus oxychloride (0.12 g) with stirring at 5° C., and the mixture was then stirred at the same temperature for 15 minutes. The reaction mixture was poured into ice water (20 ml), extracted with ethyl acetate (twice each with 20 ml) and the combined extracts were dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (4/1) as an eluent, to give the title compound (0.20 g, 87% yield) as a colorless powder.
Reaction SMILES: FC(F)(F)C(O)=O.COC[O:11][CH2:12][CH2:13][CH:14]1[O:18][C:17]2=[N:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][N:16]2[CH2:15]1>C(Cl)Cl>[OH:11][CH2:12][CH2:13][CH:14]1[O:18][C:17]2=[N:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][N:16]2[CH2:15]1
Reactant: COCOCCC1Cn2cc([N+](=O)[O-])nc2O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cn2c(n1)OC(CCO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Trifluoroacetic acid (2 ml) was added to a solution of 2-(2-methoxymethoxyethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 25 (0.2 g, 0.822 mmol) in methylene chloride (10 ml) followed by stirring at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1), and crystallized from methanol-diisopropyl ether to afford 2-(2-hydroxyethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (0.11 g, yield 65%) as a light yellow powder.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>C1C=CC=CC=1>[F:22][C:2]([F:1])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[CH3:30])[CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:19])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1
Reactant: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C#CC(C)(C)N1CCC(OC(=O)c2ccccc2C)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol- 2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methylbenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1 -(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop- 2-ynyl)-6-(2-methylbenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: C1(C)C=CC=CC=1.S(Cl)([Cl:10])=O.[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[O:26][CH:27]([F:29])[F:28])[C:20](O)=[O:21])[CH2:14][CH2:13]1>CN(C=O)C>[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[O:26][CH:27]([F:29])[F:28])[C:20]([Cl:10])=[O:21])[CH2:14][CH2:13]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
A reaction vessel is charged with toluene, a catalytic amount of DMF (1-5% by weight of the amount of thionyl chloride employed) and 1 equivalent of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. While stirring, 1 to 4 equivalents of thionyl chloride are slowly added at 70 to 90° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:35])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]34[CH2:34][CH:29]5[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]5)[CH2:26]3)[CH2:32]4)[CH:19]=2)=[CH:14][CH:13]=1.Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C>[CH3:7][O:8][C:9](=[O:35])/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[C:20]([C:25]34[CH2:34][CH:29]5[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]5)[CH2:26]3)[CH2:32]4)[CH:19]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(-c2ccc(OCCN3CCOCC3)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
K2CO3 (265 mg, 1.92 mmol) was added to a solution of (E)-3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)-acrylic acid methyl ester (250 mg, 0.64 mmol) in DMF (2.5 ml) and the mixture was stirred at RT for 30 min. 4-(2-Chloroethyl)-morpholine hydrochloride (155 mg, 0.83 mmol) was added and the solution was heated to 60° C. for 14 h. The reaction was quenched by addition of water and was extracted with EtOAc. The organic layer was washed with a saturated solution of NaHCO3, water and brine, dried over Na2SO4 and evaporated under reduced pressure to obtain (E)-3-[3′-adamantan-1-yl-4′-(2-morpholin-4-yl-ethoxy)biphenyl-4-yl]-acrylic acid methyl ester (193 mg, 60%) after purification on silica gel (EtOAc:hexane 50:50).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:11])([CH:8]1[CH2:10][CH2:9]1)[C:6]#[N:7])(=[O:3])[CH3:2].[OH-].[Na+]>[Cl-].[Na+]>[C:1]([O:4][C@:5]([CH3:11])([CH:8]1[CH2:10][CH2:9]1)[C:6]#[N:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C#N)C1CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)O[C@@](C)(C#N)C1CC1
Temperature: 10 °C
Reaction time: 118 h
Yield: 15 %

Procedure:
(Warning: Highly toxic hydrogen cyanide is formed in the experiment; use adequate protection). 119.8 g (782 mmol) racemic α-(acetyloxy)-α-methyl-cyclopropaneacetonitrile was emulsified in 7.0 L 0.1 M sodium chloride/3.8 mM sodium phosphate buffer pH 7.0 by stirring. The emulsion was cooled to 10° C. and the hydrolytic reaction started by adding 8.0 g of triacylglycerol lipase from wheat germ (Sigma L-3001) and the pH maintained at 7.0 by the controlled addition of 1.0 N sodium hydroxide solution under vigorous stirring at 10° C. After a consumption of 605.8 mL solution (corresponding to 78% conversion), after 118 h, the reaction was stopped by adding 6 L dichloromethane under vigorous stirring. The emulsion was allowed to stand overnight for phase separation. The organic phase was removed (the turbid part was filtered through silicon-treated Phase Separator (1PS; Whatman) and the filtrate stirred with ca. 1 L of Speedex filter aid). The aqueous phase was extracted again with 2×6 L dichloromethane. The combined organic phases were concentrated in vacuo down to a volume of ca. 40 mL and distilled (final temp. 68-69° C./4 mbar) to give 17.88 g (117 mmol; 15%) of (R)-α-(acetyloxy)-α-methyl-cyclopropaneacetonitrile as a colorless oil. Analysis: purity >99% GC; 98.0% ee (column: BGB-176; 30 m×0.25 mm; 100-140° C. with 2° C./min; H2; 90 kPa; Inj. 200° C.; Det. 210° C.); αD20:+32.92° (c=1.00; EtOH).
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([F:29])[CH:27]=3)[N:22]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:21]=2)[CH:14]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])(=O)=O.[C:40]([O-])(=[S:42])[CH3:41].[K+].O>CN(C=O)C>[C:40](=[S:42])([O:5][CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([F:29])[CH:27]=3)[N:22]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:31])=[O:32])[CH:21]=2)[CH:14]=1)[C:8]([CH3:10])([CH3:9])[CH3:11])[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=S)OC[C@@H](Nc1cc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutyl methanesulfonate, 55a, (10.5 g, 18.11 mmol) in dry DMF (200 mL) was added potassium thioacetate (3.1 g, 27.1 mmol). The brown solution was heated with stirring at 80° C. for 1 hour. The thick brown suspension was poured into water and extracted with EtOAc (3×100 mL). The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 6.8 g of the desired product, 56a, as a pale brown solid: 1H NMR (400 MHz, CDCl3) δ 8.41 (m, 2H), 8.23 (s, 1H), 8.01 (m, 3H), 7.23-7.16 (m, 2H), 4.99 (d, J=10.1 Hz, 1H), 4.37 (m, 1H), 3.21 (dd, J=13.8, 2.3 Hz, 1H), 3.09-2.95 (m, 1H), 2.31 (s, 3H), 2.16 (s, 3H), 1.02 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 560.99 (M+H) RT=4.14 minutes.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=O)[C:6]2[CH:11]=[CH:10][S:9][C:7]=2[N:8]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:6]2[CH:11]=[CH:10][S:9][C:7]=2[N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: CSc1nc2sccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nc(Cl)c2ccsc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Methylsulfanyl-3H-thieno[2,3-d]pyrimidin-4-one (12 g, 60.5 mmol) was combined with POCl3 (56 mL), and the resulting mixture was heated to reflux for about 1 hour. The reaction mixture was concentrated under reduced pressure at 50° C. The residue was diluted with ethyl acetate (700 mL) at 0° C. Saturated sodium bicarbonate solution (600 mL) was added slowly. The resulting mixture was stirred vigorously at 0° C. for one hour and the layers were separated. Saturated sodium bicarbonate solution (600 mL) was added to the organic layer at 0° C., and the mixture was stirred vigorously for 20 minutes. The layers were separated. Brine (600 mL) was added to the organic layer and stirred vigorously for 5 minutes, and the layers were again separated. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (10.7 g) as a dark tan powder (M+=216, M.P.=105.0–107.4° C.).