Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[N:3]=1.[O:22]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC>[O:19]1[C:15]2([CH2:20][CH2:21][CH:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:32]4[CH:33]=[CH:34][C:29]([O:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[CH:30][CH:31]=4)=[N:3]3)[CH2:13][CH2:14]2)[O:16][CH2:17][CH2:18]1
Reactant: Nc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.8 %

Procedure:
3-bromo-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Intermediate X) (4.0 g, 11.3 mmol), 4-phenoxyphenylboronic acid (Intermediate V) (2.66 g, 12 mmol), sodium carbonate (2.87 g, 27 mmol), palladium tetrakis(triphenyphosphine) (0.78 g, 0.6 mmol) in dimethoxyethane (120 mL)/water (60 mL) mixture was heated at 85° C. under nitrogen for 4 hrs. Cool to room temperature and stand for 72 hrs. The solid which precipitated was filtered and washed with water and diethylether (100 mL of each). Dry in vacuo for 3 hrs to furnish 4.2 g of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as a beige solid (87%). 1H NMR (400 MHz, d6-DMSO) 8.24 (1H, s), 7.67 (2H, m), 7.45 (2H, m), 7.19 (5H, m), 4.78 (1H, m), 3.90 (4H, m), 2.25 (2H, m), 1.71-1.84 (6H, m) Mass Spec.: MH+=444.2
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:45])[NH2:26])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Yield: 86 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 86% of theory, C27H29N7O3 (499.6); Rf value: 0.09 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=500.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:35][CH:33]([CH3:34])[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:12]=3[CH:11]=[CH:10][N:9]4[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=3)[CH2:20][CH2:21]2)[CH:26]=1)=[O:36]
Reactant: Cc1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: Cc1cccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methylbenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 466.3 (M+H)+.
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:27](OC(C)(C)C)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=O.Cl>C(O)C>[F:24][C:22]([F:25])([F:23])[C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:14][C:10]2[N:9]3[C:5](=[CH:6][N:7]=[C:8]3[CH:13]=[CH:12][CH:11]=2)[C:27]1=[O:28])=[O:26]
Reactant: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Agent: Cl
Solvent: CCO
Product: O=C1c2cnc3cccc(n23)CN1CCCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 2.60 g (4.64 mmol) of 3-trichloro acetyl-5-[N-tert-butoxycarbonyl-N-(4-trifluoroacetamidobutan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 20 ml of ethanol was added 1.90 ml (23.22 mmol) of 12N HCl. The mixture was stirred for one hour at room temperature. The solvent and excess volume of hydrochloric acid were distilled off under reduced pressure. The residue was dissolved in a mixture of 20 ml of purified water and 20 ml of ethanol. To this solution was added a 2N aqueous solution of sodium hydroxide to neutralize. This solution was extracted with 100 ml of dichloromethane. The organic layer was washed with 100 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to afford 1.26 g of the desired compound (75.9%, pale yellow amorphous).
Reaction SMILES: Cl.[CH3:2][C:3]([C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[OH:12])=[O:4].[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[O:22])=[CH:19][CH:20]=1>C(O)C>[OH:11][C:9]1[CH:10]=[C:5]2[C:6](=[CH:7][CH:8]=1)[O:12][CH:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=1)[CH2:2][C:3]2=[O:4].[OH:12][C:6]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=1[CH:3]=[CH:2][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=1)=[O:22]
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2cc(O)ccc2O)cc1
Product: COc1ccc(C2CC(=O)c3cc(O)ccc3O2)cc1

Procedure:
HCl is passed for 4 hours, with stirring, into a solution of 15.2 g of 2,5-dihydroxyacetophenone and 27.2 g of anisaldehyde in 1,500 ml of ethanol. 3-p-Methoxybenzylidene-6-hydroxy-4'-methoxyflavanone is precipitated, m.p. 199°-201°. 6-Hydroxy-4'-methoxyflavanone and 2,5-dihydroxy-p-methoxybenzylideneacetophenone are formed as intermediates.
Reaction SMILES: CC(C)=[O:3].[OH:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(N(CC)CC)C>[OH:5][N:6]1[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]2[C:10]1=[O:11].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O-:27])(=[O:3])=[O:26])=[CH:21][CH:20]=1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)=O
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Product: C=Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 20 °C

Procedure:
50 ml of acetone was added to 3.3 g of N-hydroxyphthalimide and 4.1 g of p-styrenesulfonyl chloride. 2.0 g of triethylamine was dropwise added to the mixture under stirring at room temperature (about 20° C.). The mixture was stirred at room temperature for additional 1 hr. and poured into 200 g of ice/water. The precipitate thus formed was recrystallized from a solvent mixture of benzene/ethanol to obtain 4.6 g of N-hydroxyphthalimide-p-styrenesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25](O)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Reactant: C1COCCN1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Yield: 53.2 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 184 μmol) and morpholine (16 μl, 184 μmol) as starting materials. The reaction affords 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (44 mg, 53.2%) as white solid. mp.: 212-214° C., MS: m/z=450.0 (M+H+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[CH2:9][C@@H:10]2[C@H:14]([CH2:15]\1)[C@@H:13]([CH2:16][CH2:17][CH:18]([OH:25])[CH:19]([F:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:11]2)([OH:3])=[O:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>C(O)(C)C>[C:1]([CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[CH2:9][C@@H:10]2[C@H:14]([CH2:15]\1)[C@@H:13]([CH2:16][CH2:17][C:18](=[O:25])[CH:19]([F:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:11]2)([OH:3])=[O:2]
Reactant: CCCCC(F)C(O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCCCC(F)C(=O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 0.67 h

Procedure:
(1S,2R,3R,5S)-7(E)-(4-Carboxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxyoctyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (13) (0.184 g) was oxidized with Jones reagent between about -15° and -5° C. After stirring for 40 minutes, isopropyl alcohol (0.43 ml) was added, and treated by a usual work-up. Obtained crude product was purified on column chromatography (hexane/ethyl acetate=15/1-10/1) using silica gel treated with an acid (CC-4: available from Mallineckrodt Co., Ltd.) to give (1S,2R,3R,5S)-7(E)-(4-carboxybutylidene)-2-[4(RS)-fluoro-3-oxooctyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (14) as a colorless oily product. Yield: 0.072 g (40%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Yield: 51.6 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 1-aminonaphthalene (0.22 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.26 g, 3.09 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (gradient from 2:1 to 1:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.29 g, 51%) as a white solid. 1H NMR (DMSO-d6, HMDSO), 6:3.69 (3H, s); 6.56 (1H, d, J=16.0 Hz); 7.16 (1H, dd, J=7.0 and 1.4 Hz); 7.27-8.14 (11H, m); 10.25 (1H, s).
Reaction SMILES: [CH2:1]([CH:3]([C:7]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:8]=1[C:9]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=O)[C:4]([CH3:6])=O)[CH3:2].S(=O)(=O)(O)O.O.[NH2:37][NH2:38].C([O-])(O)=O.[Na+].C>C(O)(C)C>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:9]2[C:8]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:7]=3[CH:3]([CH2:1][CH3:2])[C:4]([CH3:6])=[N:38][N:37]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: NN
Reactant: CCC(C(C)=O)c1cc(OC)c(OC)cc1C(=O)c1cc(OC)c(OC)c(OC)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCC1C(C)=NN=C(c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
1.40 g (3.36 mmoles) of 2-(1-ethylacetonyl)-3',4,4',5,5'-pentamethoxybenzophenone are dissolved in 5.4 ml of isopropanol, and 0.175 ml of concentrated sulfuric acid are added dropwise to the solution. The reaction mixture is heated to boiling, stirred at this temperature for one hour, thereafter the mixture is cooled to 60° C. and 0.41 ml (8 mmoles) of 98% hydrazine hydrate are added. The resulting mixture is stirred for a further hour. 0.154 g of sodium hydrocarbonate are added in portions to the mixture, the mixture is heated to boiling, decolorized with charcoal, filtered, the filtrate is evaporated, and the residue is passed onto a filter with a total amount of 25 ml of water. 0.835 g (60.5%) of the title compound are obtained; m.p.: 152°-155° C. When recrystallized from a small amount of isopropanol the product melts at 160°-162° C. C23H28N2O5 =412.5.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]([O:17][CH3:18])([O:15][CH3:16])OC.[CH2:19]([O:21][C:22]([CH:24]1[C:31](=[O:32])[CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]2[CH:25]1[CH2:26]C(=O)[CH2:28]2)=[O:23])[CH3:20].C(=O)(O)[O-].[Na+]>CO>[CH2:36]([O:35][C:33]([CH:30]1[C:31](=[O:32])[CH:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH:25]2[CH:29]1[CH2:28][C:12]([O:15][CH3:16])([O:17][CH3:18])[CH2:26]2)=[O:34])[CH3:37]
Reactant: COC(OC)OC
Reactant: CCOC(=O)C1C(=O)C(C(=O)OCC)C2CC(=O)CC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1C(=O)C(C(=O)OCC)C2CC(OC)(OC)CC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 25° C., 330 mg of p-toluenesulfonic acid and 1.6 ml of trimethyl orthoformate are added to a solution of 9.6 g of 2,4-bisethoxycarbonylbicyclo[3.3.0]octane-3,7-dione (preparation: Reference Example 1) in 330 ml of methanol. The mixture is stirred for 3 hours at 25° C., combined with 80 ml of 5% strength sodium bicarbonate solution, extracted three times with respectively 300 ml of methylene chloride, dried over sodium sulfate, and evaporated under vacuum. The residue is purified by chromatography on silica gel. With ethyl acetate/hexane (1+1), 7 g of the title compound is obtained as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][C@:11]([NH:34]C(=O)OC(C)(C)C)([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:18]=2)[C:10]1=[O:42].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:34][C@:11]1([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[N:18]=2)[CH2:12][CH2:13][N:9]([CH3:8])[C:10]1=[O:42]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@@]2(N)CCN(C)C2=O)n1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Trifluoroacetic acid (2 mL, 26.92 mmol) was added to a solution of tert-butyl N-[(3R)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 13) (482 mg, 0.99 mmol) in DCM (10 mL) at 20° C. and the reaction was stirred for 1 hour. Solid K2CO3 was added to quench the TFA present (care: gas evolved) and the resultant solid was filtered off and washed five times with DCM. The solvent was evaporated to give (3R)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (D14) (343 mg, 0.883 mmol, 89.5% yield) as a yellow oil. 300 MHz NMR δH (CDCl3) 1.95 (2H, br.s), 2.07-2.17 (1H, m), 2.44-2.53 (1H, m), 2.63 (3H, s), 2.72-2.88 (2H, abq), 2.94 (3H, s), 3.38-3.53 (2H, m), 7.53 (1H, s), 7.78 (2H, d), 8.20 (2H, d).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH3:6])[CH3:5].Cl.[OH-].[Na+].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1>C(O)C>[CH3:5][N:4]([CH2:3][CH2:2][S:17][C:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=1)[CH3:6]
Reactant: CN(C)CCCl
Reactant: Sc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCSc1ccc(Br)cc1
Reaction time: 0.03 h
Yield: 86 %

Procedure:
A solution of 23.5 g of chloroethyldimethylamine.HCl in 75 ml of ethanol was added to 160 ml of sodium hydroxide solution formed by dissolving 20 g of sodium hydroxide pastilles in 500 ml of ethanol. A solution of 30 g of 4-bromothiophenol in 100 ml of ethanol was added to 160 ml of the said sodium hydroxide solution and the first solution was added thereto over 2 minutes at 20° C. The mixture was refluxed for 3 hours and was evaporated to dryness. Water was added to the residue and the mixture was extracted with methylene chloride. The organic phase was washed with aqueous 0.1N sodium hydroxide solution, then with water, dried and evaporated to dryness. The residue was distilled to obtain 35.5 g of 4-(N,N-dimethylaminoethylthio)-bromobenzene boiling at 110° C. at 0.1 mm Hg.
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][N:13]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:14](=[O:25])[CH2:15][CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([NH:19][CH3:20])=[O:18])=[O:11])C1C=CC=CC=1.[K+].[Br-]>>[OH:8][NH:9][C:10]([CH2:12][N:13]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:14](=[O:25])[CH2:15][CH:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:17]([NH:19][CH3:20])=[O:18])=[O:11]
Reactant: CNC(=O)C(CC(=O)N(CC(=O)NOCc1ccccc1)CC(C)C)CC(C)C
Agent: [Br-]
Agent: [K+]
Product: CNC(=O)C(CC(=O)N(CC(=O)NO)CC(C)C)CC(C)C

Procedure:
N4 -(Benzyloxycarbamoyl-methyl)-2,N4 -diisobutyl-N1 -methyl-succinamide (0.30 g, 0.74 mmol) was deprotected by catalytic hydrogenolysis as described in Example 30 (Step 1) then purified by column chromatography (silica gel, 5% methanol in dichloromethane) to give the product as a white hygroscopic solid. m.p. 60.5-61.5° C. 1H-NMR; δ(CD3OD), 4.16-3.62 (2H, br m), 3.31-2.82 (2H, br m), 2.69 (1H, m), 2.58 (4H, m), 2.30 (1H, m), 1.82 (1H, m), 1.42 (2H, m), 1.18 (1H, m) and 0.78 (1 2H, br m). 13C-NMR; δ(CD3OD), 178.6, 178.4, 174.7, 174.5, 168.3, 167.9, 57.5, 55.4, 48.6, 43.1, 43.0, 42.6, 42.3, 37.0, 32.7, 28.9, 28.0, 27.0, 26.3, 23.6, 23.3, 22.6, 20.5, 20.3 and 14.4. IR (KBr) νmax 3309, 2957, 2871, 1681, 1636, 1560 and 1490 cm-1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN(C)[CH:22]=[O:23]>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[CH:22]=[O:23]
Reactant: Clc1ccncc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cnccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of diisopropylamine (18.2 mL, 0.13 mol) in THF (200 mL, 0.5 M) at −78° C. was added n-butyl lithium (2.5 M in hexane, 52 mL, 0.13 mol) dropwise. After 30 min, 4-chloropyridine from Step A in THF (10 mL) was added and the reaction mixture was stirred at −78° C. for 1 h. To the resulting reddish-brown solution at −78° C. was added N,N-dimethylformamide (12.4 mL, 0.16 mol). The reaction mixture was allowed to warm slowly to room temperature over a 15 h period, and then the reaction was quenched with water (150 mL). The THF was removed in vacuo and the aqueous layer was extracted with isopropyl acetate (3×150 mL). The organic layers were combined, dried over sodium sulfate, filtered and the solvent was removed in vacuo to give the crude product as a brown oil. This residue was purified by silica gel chromatography (using 5% EtOH in EtOAc) to afford 3.97 g of the title intermediate as a yellow solid (Rf=0.6, 28% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([S:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[S:22][CH:23]=1)(=[O:10])[CH3:9].Br[CH:33]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[F:45])[C:34]([CH:36]1[CH2:38][CH2:37]1)=[O:35].C(N(CC)CC)C>C(#N)C>[C:8]([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:33]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[C:34]([CH:36]2[CH2:37][CH2:38]2)=[O:35])[CH2:14]/[C:13]/1=[CH:18]\[C:19]1[N:20]=[C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[S:22][CH:23]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)SC1CCNC/C1=C\c1csc(NC(=O)OC(C)(C)C)n1
Reactant: O=C(C1CC1)C(Br)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1csc(NC(=O)OC(C)(C)C)n1
Yield: 48.5 %

Procedure:
Following a procedure similar to that described in Example 132-(g), (E)-4-(acetylsulfanyl)-3-{[2-(t-butoxycarbonylamino)-1,3-thiazol-4-yl]methylidene}piperidine hydrogen trifluoroacetate (420 mg) was subjected to the reaction with 2-bromo-2-(2-fluorophenyl)-1-cyclopropylethanone (340 mg) and triethylamine (310 μl) in acetonitrile (5 ml). The product obtained by usual extraction was purified by silica gel chromatography (eluent: hexane/ethylacetate=2/1˜2/3) to afford (E)-4-(acetylsulfanyl)-3-{[2-(t-butoxycarbonylamino)-1,3-thiazol-4-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidine (230 mg) as a pale yellow amorphous solid.
Reaction SMILES: [F:1][CH:2]([F:41])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH2:31][CH2:32][CH2:33]O)[S:27]([CH3:30])(=[O:29])=[O:28])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1.C[CH2:43][N:44](CC)[CH2:45]C.CS(Cl)(=O)=O.CNC>C(Cl)Cl>[NH3:4].[F:41][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH2:31][CH2:32][CH2:33][N:44]([CH3:45])[CH3:43])[S:27]([CH3:30])(=[O:28])=[O:29])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1
Reactant: CCN(CC)CC
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(CCCO)S(C)(=O)=O)CC2)n1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(CCCN(C)C)S(C)(=O)=O)CC2)n1
Product: N
Reaction time: 0.75 h
Yield: 63 %

Procedure:
The above alcohol (305 mg, 0.51 mmol) in CH2Cl2 (15 mL) was treated with Et3N (0.3 mL) and methanesulfonyl chloride (0.2 mL, 2.5 mmol) at 0° C. The reaction mixture was stirred at this temp for 45 min and 40% aqueous solution of dimethylamine (5 mL) was then added. Stirring was continued for 2 days at 20° C., and the CH2Cl2 was evaporated. The residue was diluted with water, and the resulting precipitate was washed with water and dried. Chromatography on neutral alumina, eluting with CH2Cl2/MeOH (98:2), followed by chromatography on silica, eluting with CH2Cl2/MeOH/aq. NH3 (96:3:1) gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]methanesulfonamide (200 mg, 63%). The amine was converted to the hydrochloride salt by combining with 1.25 M HCl in MeOH. Recrystallization from MeOH/isopropanol gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-[3-(dimethylamino)propyl]methanesulfonamide hydrochloride: mp 187-191° C.; 1H NMR (DMSO-d6) δ9.83 (br s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.84-4.73 (m, 2H), 3.98 (s, 3H), 3.92-3.85 (m, 1H), 3.80 (m, 4H), 3.70 (m, 4H), 3.16 (t, J=7.4 Hz, 2H), 3.11-2.96 (m, 7H), 2.71 (s, 6H), 1.91-1.83 (m, 4H), 1.73-1.68 (m, 2H); Anal. Calcd. for C27H40ClF2N9O4S.H2O: C, 47.8; H, 6.2; N, 18.6; Cl, 5.2. Found: C, 47.9; H, 6.2; N, 18.6; Cl, 5.0%.