Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:23]([O:28][CH2:29][CH3:30])(=[O:27])[C:24]#[C:25][CH3:26].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH2:29]([O:28][C:23](=[O:27])[CH2:24][CH:25]1[S:14][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])=[N:13][CH2:26]1)[CH3:30]
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Yield: 50 %

Procedure:
A solution of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.50 g), ethyl but-2-ynoate (0.40 mL) and tributylphosphine (0.40 mL) in a mixed solvent of tetrahydrofuran (16 mL)-toluene (8 mL) was stirred at 50° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4-1:1) to give the title compound (0.33 g, yield: 50%) as a pale-yellow oil. A part of the oil was crystallized from ethyl acetate-hexane to give pale-yellow crystals. MS:464(MH+). melting point 101-102° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[S:10][C:9]([NH:11][CH3:12])=[N:8][N:7]=1)([CH3:5])[CH3:4].[C-:13]#[N:14].[Na+]>CS(C)=O>[C:13]([CH2:2][C:3]([C:6]1[S:10][C:9]([NH:11][CH3:12])=[N:8][N:7]=1)([CH3:5])[CH3:4])#[N:14]
Reactant: [C-]#N
Reactant: CNc1nnc(C(C)(C)CCl)s1
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1nnc(C(C)(C)CC#N)s1

Procedure:
A 20.5 g. portion of the intermediate prepared in Example 1 and 10 g. of NaCN were added to 50 ml. of dimethylsulfoxide and heated at 110° C. for two hours. The reaction mixture was then cooled and poured into 300 ml. of water, which was then extracted with a total of 1 liter of ethyl ether. The combined ether extracts were dried over anhydrous Na2SO4, filtered, and evaporated to dryness yielding a dark oil. The oil was chromatographed on a silica gel column, eluting with ethyl acetate. The desired intermediate product, 5-(2-cyano-1,1-dimethylethyl)-2-methylamino-1,3,4-thiadiazole, m.p. 65°-67° C., was isolated in the amount of 750 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[K+]>CO.O>[CH:18]1[CH:19]=[CH:20][C:21]2[C:22]([C:23]([OH:27])=[C:14]([C@@H:11]3[CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[C:15](=[O:26])[C:16]=2[CH:17]=1)=[O:25]
Reactant: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 31 °C

Procedure:
The residue obtained (Formula IV) was suspended in 4.5 liter methanol. A solution of potassium hydroxide (225 gm) in water (1550 ml) was added drop-wise under heating over a period of one hour. The reaction mass was then refluxed for 2 hours and cooled to 30-32° C. and filtered. The filtrate was neutralized with 50% aqueous hydrochloric acid to precipitate atovaquone in a cis/trans-isomeric mixture (116 gm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:13]([C:7]1[C:6]([CH3:8])=[CH:5][C:4]([NH:9][C:10](=[O:12])[CH3:11])=[CH:3][C:2]=1[Cl:1])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1cc(C)cc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(C)c(C(C)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A dry CS2 solution (30 mL) containing N-(3-chloro-5-methyl-phenyl)acetamide (5.0 g, 27 mmol) and acetyl chloride (2.9 ml, 40.8 mmol) was slowly added with aluminum chloride (9.1 g, 68 mmol). The reaction mixture was heated at reflux for 30 min, cooled to room temperature, and stand for 4.0 h. The CS2 was decanted and the remaining syrup was poured into icy HCl. The resultant solids were collected, re-dissolved in EtOH, and decolorized by charcoal. The solution was filtered and the filtrate was concentrated under vacuum to give N-(4-acetyl-3-chloro-5-methylphenyl)acetamide (5.2 g) as light yellow solids in 85% yield: 1H NMR (500 MHz, CDCl3) δ 7.48 (s, 1 H), 7.26 (s, 1 H), 7.21 (s, 1 H), 2.52 (s, 3 H), 2.24 (s, 3 H), 2.18 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:27])[C@H:12]([CH:24]([CH3:26])[CH3:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(C)(C)C.FC(F)(F)C(O)=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:54]CI>O1CCOCC1>[Cl:54][CH2:1][O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:27])[C@H:12]([CH:24]([CH3:26])[CH3:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OC(C)(C)C
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(=O)OCCl
Reaction time: 18 h

Procedure:
4-(N-CBz-L-valyloxy) butyric acid t-butyl ester (20 g, 50.8 mmole) was treated with trifluoroacetic acid (30 ml) at 0° C. for 3 h and then evaporated. The residue was coevaporated with toluene several time. The intermediate acid (2.56 g, 7.6 mmole) was dissolved in dioxane (10 ml) and to the solution was added tetrabutylammonium hydroxide (40%, 4.66 ml. 7.2 mmole). The solution was dried and dissolved in dichloromethane (20 ml) and then chloroiodomethane (10 ml, 144 mmole) was added to the solution. After 18 hr, the reaction solution was evaporated and the product was isolated with silica gel column chromatography. Yield 2.1 g.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C.Cl>[C:1]1([S:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCCCSc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCc1ccc(OCCCSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
1.2 g of 4-(3-phenylthiopropyloxy)benzaldehyde were dissolved in 30 ml of ethanol, and the resultant solution was further added with 0.08 g of sodium borohydride and then stirred for 1 hour at room temperature. After completed the reaction, the solvent used was removed by distillation under reduced pressure, and the residue obtained was dissolved in a mixture of ethyl acetate and dilute hydrochloric acid. The ethyl acetate layer resulted was then washed with dilute hydrochloric acid, aqueous solution of sodium hydroxide and water in series. The organic layer resulted was then dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 0.65 g of 4-(3-phenylthiopropyloxy)benzyl alcohol.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].[ClH:26]>CO.O.[C].[Pd]>[ClH:26].[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]2[NH:16][C:15]1=[O:23]
Reactant: O=C1NC2CCCCC2N1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1NC2CCCCC2N1C1CCNCC1

Procedure:
In this reference example, a solution of 6.1 g of 1-benzyl-4-(octahydro-2H-benzimidazol-2-one-1-yl)-piperidine obtained in the same manner as that of Reference Example 18 and 1 g of 5% palladium carbon in 100 ml of methanol, 100 ml of water and 20 ml of 12 N hydrochloric acid is shaken in the atmosphere of hydrogen under 4 to 5 atmosphere in an autoclave. The shaking is ceased when the absorption of hydrogen has been completed. The reaction mixture is subjected to filtration to remove the catalyst and the filtrate is concentrated. The residue is mixed with 20 ml of isopropanol and stirred to crystallize the reaction product. The crystals are dried and recrystallized from ethanol to obtain 3.9 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:28][C:29]([CH3:42])([CH3:41])[CH2:30][NH:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36](Br)[N:35]=1)=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([C:32](=[O:33])[NH:31][CH2:30][C:29]([CH3:41])([CH3:28])[CH3:42])[N:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(C)(C)CNC(=O)c1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C(=O)NCC(C)(C)C)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 6-bromo-pyridine-2-carboxylic acid (2,2-dimethyl-propyl)-amide.
Reaction SMILES: C(OC([NH:6][N:7]=[C:8]([C:18]1[C:19]([Cl:25])=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])=O)C.[S:26](Cl)(Cl)=O>>[Br:24][C:22]1[CH:23]=[C:18]([C:8]2[N:7]=[N:6][S:26][C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])[C:19]([Cl:25])=[N:20][CH:21]=1
Reactant: CCOC(=O)NN=C(Cc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reactant: O=S(Cl)Cl
Product: Clc1cccc(-c2snnc2-c2cc(Br)cnc2Cl)c1Cl
Reaction time: 3.5 h
Yield: 50 %

Procedure:
A solution of ethyl-2-(1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)ethylidene)hydrazinecarboxylate (3.03 mmol) was stirred in thionyl chloride (20 mL). The solution was heated from 0° C. to RT and stirred for 3.5 hours. The solvent was evaporated to give a yellow oil which was adsorbed onto Celite™ and purified by silica gel chromatography (5-40% EtOAc/hexanes) to give 5-bromo-2-chloro-3-(5-(2,3-dichlorophenyl)-1,2,3-thiadiazol-4-yl)pyridine as a yellow solid (640 mg, 50% yield over 2 steps).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:11][C:10]([S:12]([N:15]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24]OC4CCCCO4)=[O:23])=[CH:16]3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.C[OH:33]>>[OH:33]/[C:21](=[CH:20]/[C:17]1[CH:18]=[CH:19][N:15]([S:12]([C:10]2[S:11][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][CH:9]=2)(=[O:14])=[O:13])[CH:16]=1)/[C:22]([NH2:24])=[O:23]
Reactant: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)s2)cn1
Reactant: CO
Product: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C(/O)C(N)=O)c3)s2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.099 g (E)-3-{1-[5-(1-methyl-1H-pyrazol-4-yl)-thiophene-2-sulfonyl]-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide with 3.0 ml methanol and 6.0 ml 1M aqueous HCL is stirred at ambient temperature for 24 h. The suspension is filtered and washed with water and ethyl acetate. The title compound is dried in vacuo. By this method 0.037 g light pink solid are obtained. Melting point: 163-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.Cl[C:37]1C=C2C(C3N=C(NC4CCCC(=O)C4)C(F)=CN=3)=CN(S(C3C=CC=CC=3)(=O)=O)C2=NC=1.C[Mg]Br>C1COCC1.C(OCC)(=O)C.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][C:20]([CH3:37])([OH:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Reactant: O=C1CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)ncc2F)C1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(O)CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 28a, (0.47 g, 0.92 mmol) in THF (5 mL) was added methylmagnesium bromide (3.30 ml of 1.4M solution, 4.58 mmol). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with ethyl acetate and aqueous saturated NH4Cl solution. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The products were purified by silica chromatography with DCM and methanol, two products were eluded with 95% DCM and 5% methanol no separation. The two diastereomers were taken on as a mixture without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:11][OH:12].C[O-].[Na+]>CO>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[N:11][OH:12])[NH2:5]
Reactant: NO
Reactant: N#Cc1ccccc1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1ccccc1O

Procedure:
2-Hydroxybenzonitrile (10 grams), hydroxylamine HCl (7 g.) in 150 ml. methanol, and sodium methoxide (9.0 grams) were refluxed for about 18 hours. The reaction mixture was then filtered and the ethanol evaporated. Next water was added and the product extracted into ethyl acetate. Drying and evaporation of the solvent left an oily product which solidified upon standing. The identity of the final product was confirmed by NMR and IR analysis.
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:10]=1)[C:7](O)=O.[Cl:24][C:25]1[C:26]([O:35][CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][C:39]([CH3:44])([CH3:43])[CH2:38]2)=[CH:27][C:28]([F:34])=[C:29]([CH:33]=1)[C:30]([OH:32])=[O:31]>>[Cl:24][C:25]1[C:26]([O:35][CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][C:39]([CH3:44])([CH3:43])[CH2:38]2)=[CH:27][C:28]([F:34])=[C:29]([CH:33]=1)[C:30]([O:32][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:31]
Reactant: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Reactant: CC1(C)CCCC(COc2cc(F)c(C(=O)O)cc2Cl)C1
Product: CC1(C)CCCC(COc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)C1

Procedure:
Following the procedure as described in Example 158 step 2 and making variations as required to replace 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)benzoic acid with 5-chloro-4-((3,3-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid, the title compound was obtained as pale yellow oil (3.20 g, 99%): MS (ES−) m/z 316.9 (M−54).
Reaction SMILES: [CH3:1][C@:2]([NH:26]C(=O)OC(C)(C)C)([C:5](=[O:25])[NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH:17]([CH3:24])[CH2:18][O:19]3)=[CH:11][CH:12]=1)[CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[NH2:26][C@:2]([CH3:1])([CH2:3][CH3:4])[C:5]([NH:6][C:7]1[CH:8]=[N:9][C:10]([O:13][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH:17]([CH3:24])[CH2:18][O:19]3)=[CH:11][CH:12]=1)=[O:25]
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2CC(C)CO3)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2CC(C)CO3)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
In a 50 mL round-bottomed flask tert-butyl N-[(1R)-1-methyl-1-[[6-(3-methylchroman-5-yl)oxy-3-pyridyl]carbamoyl]propyl]carbamate (Intermediate 146, 55.8 mg, 0.104 mmol) was dissolved in Dichloromethane (3 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. and TFA (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was evaporated in vacuo to give the crude product as a yellow oil. The sample was charged on a 2 g SCX cartridge. It was then flushed with 36 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated in vacuo affording the title compound (32.9 mg) as pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:28])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]#[N:27])[CH2:20][CH2:19]4)[C:12]=3[C:11]([CH3:29])=[C:10]2[CH3:30])=[C:4]([CH3:31])[CH:3]=1.[OH:32]S(O)(=O)=O.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:28])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]([NH2:27])=[O:32])[CH2:20][CH2:19]4)[C:12]=3[C:11]([CH3:29])=[C:10]2[CH3:30])=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1nc(N2CCC(CCC#N)CC2)c2c(C)c(C)n(-c3c(C)cc(Br)cc3C)c2n1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N2CCC(CCC(N)=O)CC2)c2c(C)c(C)n(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propionitrile (0.40 g), H2SO4 (4 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice, and then was made to alkaline by adding 4 M aqueous NaOH solution. The mixture was extracted with ethyl acetate and the organic phase and the organic phase was dried over Na2SO4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: CHCl3:methanol=60/1) to obtain an oil. The oily product was crystallized from diethylether to obtain the title compound (0.33 g) as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1>[Pd].C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:20])[CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(O)(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
A solution of 3.18 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid in 30 ml. of acetic acid is hydrogenated, at 20° and under normal pressure, on 0.2 g. of 10% Pd/C in the presence of 0.01 ml. of HClO4. The mixture is filtered and the filtrate is diluted with water to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.[Cl-]>ClCCl>[CH3:14][Si:15]([CH3:17])([CH3:16])[C:18]#[C:19][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C#C[Si](C)(C)C)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1 g 5-bromo-1,2,3-trimethoxybenzene, 1.14 mL of trimethylsilylacetylene, 1.4 mL of diisopropylethylamine (DIPEA) and 290 mg of triphenylphosphinpalladium(II) chloride and 39 mg Cu(I)iodide were placed in a dried flask under argon. The mixture was stirred for 1 h at 80° C., after cooling diluted with dichloromethane (DCM) and filtered through a plug of silica. The filtrate was extracted with aqueous ammonia, saturated brine and concentrated. The residue was purified via flash chromatography (SiO2:cyclohexane→cyclohexane/ethylacetate 9:1) to give trimethyl((3,4,5-trimethoxyphenyl)ethynyl)silane.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.Cl.[C:9](=N)(OCC)[CH2:10][CH2:11][CH2:12][CH3:13]>C(O)C>[CH2:10]([C:9]1[NH:7][C:6]2[C:2](=[CH:3][S:4][CH:5]=2)[N:1]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Nc1cscc1N
Reactant: CCCCC(=N)OCC
Agent: Cl
Solvent: CCO
Product: CCCCc1nc2cscc2[nH]1
Reaction time: 1.5 h

Procedure:
A mixture of 3,4-diaminothiophene (1.7 g) and ethyl valeroimidate hydrochloride (3.0 g) in ethanol (30 ml) was stirred at room temperatures for 1.5 hour. 10 The reaction mixture was concentrated and the residue was dissolved in a mixture of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by silica gel column chromatography to give crystals. Recrystallization from isopropyl ether afforded colorless crystals (0.72 g, 27%), m.p. 118°-120° C. 1H-NMR(200 MHz, CDCl3)δ: 0.95(3H,t), 1.35-1.54(2H,m), 1.73-1.88(2H,m), 2.79(2H,t), 6.75(2H,br s), 8.50(1H,br s). IR(KBr)cm-1 :3200-2200, 1530, 1480, 1440, 1390, 1240, 1230, 1160, 830, 815, 760, 740.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1)=[O:6].[H-].[Na+].O>CN(C)C=O>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17])=[CH:10][CH:9]=1
Reactant: COC(=O)/C=C/c1ccc(NC(=O)CCCBr)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(N2CCCC2=O)nc1
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of methyl (E)-3-[6-(4-bromobutyramido)-pyridin-3-yl]acrylate (90 mg) in dimethylformamide was added sodium hydride (6.93 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give methyl (E)-3-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]acrylate (65 mg).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].[OH-].[Na+]>C(Cl)Cl>[CH:1]([NH:4][C:6](=[O:7])[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)NC(=O)Oc1ccccc1
Reaction time: 2 h

Procedure:
Using the same procedure as in Example 4, isopropylamine (2.36g, 0.04 mole) was reacted with phenyl chloroformate (6.0g, 0.038 mole) in methylene chloride (35 ml) and with aqueous sodium hydroxide. The reaction mixture was stirred for two hours, then allowed to separate. The organic layer was dried over anhydrous magnesium sulfate, then gravity filtered. The filtrate was stripped of solvent on the Rotovap, leaving pure white crystals weighing 6.66g, MP 81°-82° C.