Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=3[F:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:25][C@@H:26]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[NH:27]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[C@H:26]([CH3:25])[CH2:30][CH2:29][S:28]4(=[O:32])=[O:31])=[CH:19][C:18]=3[F:24])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3F)CC2)c(C)c1
Reactant: C[C@@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 54.3 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](2-fluoro-4-iodophenyl)methanone (439 mg) described in Preparation Example 155 and (R)-3-methylisothiazolidine 1,1-dioxide (135 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (242 mg) was obtained.
Reaction SMILES: Cl.C(O)C.[Cl:5][C:6]1[CH:7]=[C:8]([C@@H:13]2[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C@H:14]2[CH2:27][N:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)[C:29]2=[O:40])[CH:9]=[CH:10][C:11]=1[Cl:12]>C(O)C>[ClH:5].[Cl:5][C:6]1[CH:7]=[C:8]([C@@H:13]2[O:19][CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[CH2:27][N:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]3[NH:38][C:37](=[O:39])[O:36][N:35]=3)[C:29]2=[O:40])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](Cn2cccc(-c3noc(=O)[nH]3)c2=O)C1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c(-c2cccn(C[C@@H]3CNCCO[C@H]3c3ccc(Cl)c(Cl)c3)c2=O)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 186.9 %

Procedure:
A 14 N hydrogen chloride-ethanol solution (2 mL, 28.00 mmol) was added to a solution of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-{[2-oxo-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)pyridin-1(2H)-yl]methyl}-1,4-oxazepane-4-carboxylate (795 mg, 1.48 mmol) in ethanol (8 mL). The reaction mixture was stirred at room temperature for 3 hr, and at 80° C. for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was collected by filtration, and washed with ethanol-hexane to give the title compound (655 mg, 1.383 mmol, 93%).
Reaction SMILES: N([O-])=O.[Na+].FC(F)(F)C(O)=[O:8].N[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C@@H:28]([NH:30][C:31](=[O:33])[CH3:32])[CH3:29])=[CH:22][CH:21]=2)=[N:17][CH:18]=1>S(=O)(=O)(O)O.C(O)(=O)C>[OH:8][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C@@H:28]([NH:30][C:31](=[O:33])[CH3:32])[CH3:29])=[CH:22][CH:21]=2)=[N:17][CH:18]=1
Reactant: CC(=O)N[C@@H](C)CCc1ccc(Oc2ccc(N)cn2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)N[C@@H](C)CCc1ccc(Oc2ccc(O)cn2)cc1

Procedure:
Sodium nitrite (154 mg, 2.23 mmol) was dissolved in 2.68 ml of concentrated sulfuric acid at 0° C. Then, N—{(S)-3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-methylpropyl}-acetamide trifluoroacetate (832 mg, 2.01 mmol) in 5 ml of acetic acid was slowly added dropwise. After 1 h the ice bath was removed and stirring was continued for an hour. The reaction mixture was added dropwise to 100 ml of boiling water, the mixture was stirred for 1 h and, after cooling, extracted with ethyl acetate. The precipitated solid was filtered off and the filtrate was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 153 mg (37%), M+H+: 301.13.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C([O:12][C:13]([CH:15]=[C:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=O)C.CO>C1(C)C=CC=CC=1>[OH:12][CH2:13][CH:15]=[C:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C=C1CCNCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: OCC=C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A solution of 15 ml of DIBAL (1.5 M solution in toluene) in 20 ml of toluene is added dropwise with 0.976 g of 4-(ethoxycarbonylmethylidene)piperidine, dissolved in few milliliter of toluene. The reaction mixture is stirred at room temperature for 2 hours, then it is cooled to 0-5° C. and added dropwise with methanol, until the gaz development is seen. The mixture is concentrated to a little volume and diethyl ether is added: a white solid separates, which is filtered off. The organic phase is concentrated to dryness, redissolved in diethyl ether and again filtered. The clear solution is concentrated to dryness to give 500 mg of the product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O.O>CN(C=O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(O)c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCC(F)(F)F)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a suspension of 2,6-dimethylpyridin-3-ol (5.0 g, 41 mmol) and cesium carbonate (15 g, 47 mmol) in DMF (50 mL) was added 2,2,2-trifluoroethyl trifluoromethane-sulfonate (11 mL, 47 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour. After being stirred at room temperature for 18 hours, the mixture was poured into H2O, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 8.3 g (quantitative yield) of the title compound as a brown oil:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][NH:15]CC2C=CC=CC=2)[C@H:10]([OH:23])[CH2:9]1.[H][H]>CO.[Pd]>[NH2:15][CH2:14][C@@H:11]1[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH:2]2[O:1][CH2:5][CH2:4][O:3]2)[CH2:9][C@H:10]1[OH:23]
Reactant: [H][H]
Reactant: O[C@@H]1CN(CCC2OCCO2)CC[C@H]1CNCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC[C@@H]1CCN(CCC2OCCO2)C[C@H]1O
Yield: 91.4 %

Procedure:
A mixture of intermediate (7) (0.019 mol) in methanol (150 ml) was hydrogenated with palladium-on-carbon (10%, 2 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, yielding 4 g of (trans)4-(aminomethyl)-1-[2-(1,3-dioxolan-2-yl)ethyl]-3-piperidinol (intermediate 8).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH2:3].[OH-].[Na+].I[CH2:18][CH:19]([OH:22])[CH2:20][OH:21].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[O:13])[CH:2]=[CH2:3]
Reactant: OCC(O)CI
Reactant: C=CCNc1ccccc1CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: C=CCNc1ccccc1CC(=O)OCC(O)CO

Procedure:
A solution of 7.34 g. of 2-(allylamino)phenylacetic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 2-(allylamino)phenylacetate.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)(O)[O-:13].[Na+].ClCCl.ClC1C=CC=C(C(OO)=O)C=1>O>[O:13]1[CH:6]2[CH:5]1[CH:4]1[CH2:7][CH:1]2[CH:2]([S:8]([NH2:11])(=[O:9])=[O:10])[CH2:3]1
Reactant: O=C([O-])O
Reactant: NS(=O)(=O)C1CC2C=CC1C2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)C1CC2CC1C1OC21
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 63.1 %

Procedure:
To a four-necked flask having an inner volume of 500 ml and equipped with an electromagnetic stirring device, a nitrogen inlet tube, and a thermometer, there were charged 10.0 g (57.7 mmol) of 5-norbornene-2-sulfonamide, 15.1 g (180.0 mmol) of sodium bicarbonate, and 200 g of dichloromethane. After cooling the mixture to 5° C., 14.8 g (60.0 mmol) of 70% m-chloroperbenzoic acid was added thereto over a 20 minute period, and the mixture was stirred at 5° C. for 2 hours. To the reaction mixture was added 100 g of distilled water, and the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed with 40 g of distilled water and concentrated under reduced pressure. By recrystallizing the residue obtained from ethyl acetate, there was obtained 6.89 g (36.4 mmol) of 5,6-epoxy-2-norbornanesulfonamide represented by the following formula (yield 63%):
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=O.Cl.[CH:25]1([C:28]2[CH:29]=[C:30]([CH3:40])[C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:32][CH:33]=2)[CH2:27][CH2:26]1>>[CH:25]1([C:28]2[CH:29]=[C:30]([CH3:40])[C:31]([N:34]3[CH2:35][CH2:36][N:37]([C:9]([C:8]4[CH:13]=[CH:14][C:15]([N:17]5[CH2:21][CH2:20][O:19][C:18]5=[O:22])=[CH:16][C:7]=4[N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:23])=[O:11])[CH2:38][CH2:39]3)=[N:32][CH:33]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc(N2CCOC2=O)cc1N1CCCS1(=O)=O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)cc2N2CCCS2(=O)=O)CC1
Yield: 18.5 %

Procedure:
By reaction and treatment in the same manner as in Example 63 and using methyl 2-(1,1-dioxoisothiazolidin-2-yl)-4-(2-oxooxazolidin-3-yl)benzoate (170 mg) described in Preparation Example 117 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (127 mg) described in Preparation Example 49, the title compound (48.7 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].N1CCCCC1>CCO>[CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[C:22]2[S:18][C:19](=[O:24])[NH:20][C:21]2=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CSC(=O)N1
Reactant: CC1(COc2cccc(C=O)c2)CCCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC1(COc2cccc(C=C3SC(=O)NC3=O)c2)CCCCC1
Yield: 67 %

Procedure:
A mixture consisting of compound v (0.5 mmol), 2,4-thiazolidinedione (0.6 mmol) and catalytic amounts of piperidine was refluxed in EtOH (5 mL) for 24 h and then concentrated. The oily product was dissolved in ethyl acetate, poured into water and acidified with AcOH. The solution was extracted with ethyl acetate, dried and concentrated. The residue was purified by silica gel chromatography, providing compound 1 in 67% yield. 1H NMR (300 MHz, CDCl3) δ 1.04 (s, 3H), 1.46-1.56 (m, 10H), 3.69 (s, 2H), 6.78-7.28 (m, 2H), 7.08 (d, J=8.40 Hz, 1H), 7.39 (dt, J=2.10, 8.40 Hz, 1H), 7.84 (s, 1H), 8.21-8.78 (br, 1H); HRMS exact mass of (M+Na)+, 354.1140 amu; observed mass of (M+Na)+, 354.113 amu.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:19][CH3:20])[CH:7]([NH:8]C(OCC2C=CC=CC=2)=O)[CH2:6][O:5][CH2:4]1>[Pd].C(O)C>[CH3:1][O:2][C:3]1([O:19][CH3:20])[CH:7]([NH2:8])[CH2:6][O:5][CH2:4]1
Reactant: COC1(OC)COCC1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC1(OC)COCC1N
Reaction time: 12 h

Procedure:
A mixture of 3,3-Dimethoxy4-benzyloxycarbonylamino-tetrahydrofuran (16 g, 57 mmol) and 10% palladium on charcoal (2 g) in ethanol (200 ml) was stirred under an atmosphere of hydrogen (50 psi) for 12 h. The mixture was filtered and concentrated to afford the title compound as a yellow oil, 8 g, 100%.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[NH2:8][CH2:9][C:10]#[N:11].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][N:21]=1)[C:16](Cl)=[O:17].CCOCC>O.C(OCC)(=O)C>[C:10]([CH2:9][NH:8][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][N:21]=[C:13]([Cl:12])[CH:14]=1)#[N:11]
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: N#CCN
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: N#CCNC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
2.4 g (0.056 mol) of sodium hydroxide was dissolved in 24 ml of water. 3.6 g (0.017 mol) of aminoacetonitrile sulfate was added to the solution and the mixture was stirred at room temperature for 1 h and then cooled to 5° C. or below. A liquid mixture of 3.0 g (0.017 mol) of 2-chloroisonicotinoyl chloride and 30 ml of ether was added dropwise thereto at 5° C. or below lest unfavorable heat generation should occur. The mixture was then stirred at room temperature for 2 h to conduct a reaction. Water and ethyl acetate were added thereto to conduct extraction. The extract was washed with a saturated aqueous common salt solution, dried over anhydrous sodium sulfate and concentrated. The resulting crystals were recrystallized from a liquid mixture of n-hexane and ethyl acetate to obtain 2.7 g (yield: 81.2%) of the intended product as white crystals having a melting point of 131° to 132° C.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([N:20]=[C:21]=[S:22])=[O:19].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([CH3:45])[CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([N:20]=[C:21]=[S:22])=[O:19].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:21]([NH:20][C:18](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])=[S:22])=[C:40]([CH3:45])[CH:39]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Agent: O=C(Cl)c1ccccc1F
Agent: O=C(N=C=S)c1ccccc1F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4F)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
2-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Fluoro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (41 mg, yield 52%).
Reaction SMILES: [CH3:1][N+:2]([O-:16])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:5]=1[O:14][CH3:15].[N+:17]([CH:20]=[CH2:21])([O-:19])=[O:18]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:5]1[C:6]([O:12][CH3:13])=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[CH:3]1[CH:20]([N+:17]([O-:19])=[O:18])[CH2:21][O:16][N:2]1[CH3:1]
Reactant: COc1ccc(C=[N+](C)[O-])c(OC)c1OC
Reactant: C=C[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C2C([N+](=O)[O-])CON2C)c(OC)c1OC

Procedure:
A 5.88 g (26.1 mmol) portion of N-methyl-C-(2,3,4-trimethoxyphenyl)nitrone was added to 50 mL of 0.76 molar (38 mmol) nitroethylene in toluene. The mixture was heated at reflux for 2 h. The solvent was removed in vacuo to leave a brown tar which was purified by flash chromatography on a column of 50 g of silica gel eluted successively with 100 mL portions of 0, 10, 20, 30, 40 and 50% ether in hexanes to yield 4.53 g of an orange oil. This material was crystallized from 20 mL of ice-cold 1:1 ether:hexanes to give 3.16 g of 2-methyl-4-nitro-3-(2,3,4-trimethoxyphenyl)-isoxazolidine (Example 38) as a low melting solid.
Reaction SMILES: [C:1]([CH:3]([C:14]#[N:15])[C:4]1[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=O)[CH:5]=1)#[N:2].P(Cl)(Cl)([Cl:18])=O>O>[Cl:18][C:6]1[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:10])[C:4](=[C:3]([C:14]#[N:15])[C:1]#[N:2])[CH:5]=1
Reactant: Cn1c(C(C#N)C#N)cc(=O)n(C)c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN1C(=O)N(C)C(=C(C#N)C#N)C=C1Cl

Procedure:
To 6.1 g (0.03 mol) of the resulting 6-dicyanomethyl-1,3-dimethyluracil was added 1.5 ml of water, and 40 ml of phosphorus oxychloride was added dropwise thereto. After heating the mixture at reflux for 1.5 hours, the phosphorus oxychloride was removed by distillation under normal pressure, and the residue was poured onto ice. The precipitated crystals were collected by filtration. The filtrate was extracted three times with chloroform and dried over anhydrous sodium sulfate. The chloroform was distilled away and the resulting residue was combined with the above obtained crystals. Recrystallization from water-methanol yielded 6.15 g of 6-chloro-1,3-dimethyl-2-oxo-4-dicyanomethylenepyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([NH:6][CH:7]=[C:8]([C:22]#[N:23])[C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([Cl:20])=[CH:14][C:13]=2[Cl:21])=O)=[CH:4][C:3]=1[O:26][CH3:27].CO.P(Cl)(Cl)(Cl)=O>C(#N)C>[Br:1][C:2]1[CH:25]=[C:24]2[C:5](=[CH:4][C:3]=1[O:26][CH3:27])[N:6]=[CH:7][C:8]([C:22]#[N:23])=[C:9]2[NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([Cl:20])=[CH:14][C:13]=1[Cl:21]
Reactant: COc1cc(NC(=O)C(C#N)=CNc2ccc(Br)c(OC)c2)c(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: CC#N
Product: COc1cc(Nc2c(C#N)cnc3cc(OC)c(Br)cc23)c(Cl)cc1Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a suspension of (5.13 g, 11 mmol) of 4-bromo-3-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide in 400 mL of acetonitrile was added 1.5 mL of methanol. The mixture was heated to reflux and phosphorous oxychloride (4.10 mL, 44.0 mmol) was added dropwise. The resulting mixture was heated at reflux for 26 hours. Additional phosphorous oxychloride (2.1 mL) and methanol (0.75 mL) were added and the mixture was heated at reflux for 21 hours. After cooling to 0-5° C. in an ice-bath, the solid was collected by filtration, washed with cold acetonitrile (100 mL) and then suspended in tetrahydrofuran (100 mL). To the tetrahydrofuran suspension was added concentrated ammonium hydroxide and the mixtures were stirred for 1 hour. Water (300 mL) was added and stirring was continued for 1 hour. The solid was collected by filtration, washed with hot water (46° C.), acetonitrile and dried in vacuo overnight to recover 2.1 g of 4-bromo-3-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide. The acetonitrile filtrate and washing were combined and concentrated aqueous ammonium hydroxide was added. The resulting acetonitrile mixture was stirred for 1 hour. Water was added and stirring was continued for 1 hour. The solid was collected by filtration, washed with water, ethyl acetate and ether, then dried in vacuo to provide 1.92 g (39%) of 6-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-methoxy-3-quinolinecarbonitrile as a yellow solid, mp 256-257° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 4.04 (s, 3H), 7.37 (s, 1H), 7.46 (s, 1H), 7.75 (s, 1H), 8.56(s, 1H), 8.89 (s, 1H), 9.93 (s, 1H); MS (ES) m/z451.9, 454.0 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][C:6]=1[O:7][CH2:8][CH2:9]O)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:54][O:55][C:56](=[O:62])[C@@H:57]1[CH2:61][CH2:60][CH2:59][NH:58]1>ClCCl.C(#N)C>[CH3:54][O:55][C:56]([CH:57]1[CH2:61][CH2:60][CH2:59][N:58]1[CH2:9][CH2:8][O:7][C:6]1[CH:11]=[C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]4[C:31]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:13]=[CH:14][C:5]=1[C:1]([CH3:2])([CH3:4])[CH3:3])=[O:62]
Reactant: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1OCCO
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCN1CCOc1cc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Mix 2-(2-tert-butyl-5-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin4-ylamino]-phenoxy}-ethanol (24 mg, 0.05 mmol) and triethyl amine (6 mg, 0.06 mmol) in dichloromethane 1 ml and add methanesulfonyl chloride (6 mg, 0.05 mmol). Stir the solution at room temperature for 1 hour and evaporate to dryness. Re-dissolve the residue in acetonitrile (2 ml), transfer to a sealed tube, add potassium carbonate (13 mg, 0.1 mmol) and L-proline methyl ester (13 mg, 0.1 mmol) and heat the mixture at 80° C. for 8 hours. Partition the residue between ethyl acetate and sodium bicarbonate solution and extract with further ethyl acetate. Dry the combined extracts (MgSO4) and concentrate under reduced pressure. Purify the residue by flash chromatography on silica gel (ethyl acetate) to give the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.CON(C)[C:24]([C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:25]>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:24]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:25])[C:17]([F:20])=[N:18][CH:19]=1
Reactant: COc1cccnc1C(=O)N(C)OC
Reactant: Fc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cccnc1C(=O)c1cc(Br)cnc1F
Temperature: -20 °C
Yield: 63.1 %

Procedure:
Diisopropylamine (0.50 ml, 3.54 mmol) and tetrahyrofuran (40 ml) were combined and cooled to −20° C. with stirring. n-Butyl lithium (1.41 ml, 2.5 M in hexanes, 3.53 mmol) was slowly added and stirred at this temperature for 30 minutes. The temperature was decreased to −78 C and neat 5-bromo-2-fluoropyridine (0.38 ml, 3.69 mmol) was added (internal temperature was not allowed to exceed −68 C). The reaction mixture was stirred at −78° C. for 40 minutes. The reaction mixture was added to a solution of 3-methoxy-pyridine-2-carboxylic acid methoxy-methyl-amide (685 mg 3.49 mmol) in tetrahydrofuran (10 ml). This was stirred at −78 C for 1 hour. The reaction mixture was slowly warmed to room temperature, and quenched with saturated aqueous ammonium chloride. The reaction mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography (0-50% ethyl acetate in hexanes) to give 685 mg (63%) of (5-bromo-2-fluoro-pyridin-3-yl)-(3-methoxy-pyridin-2-yl)-methanone. MS: m/z 310.6+312.9 (M+H+).
Reaction SMILES: CC1C(C[N:8]([CH2:10][C:11]2[S:15][CH:14]=[C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:28]3[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]3)[CH:12]=2)[CH3:9])=C(C)NN=1.[CH3:40][C:41]1C(CNC)=C(C)N[N:42]=1>>[C:41]([CH2:40][N:8]([CH2:10][C:11]1[S:15][CH:14]=[C:13]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:28]2[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])[CH2:30][CH2:29]2)[CH:12]=1)[CH3:9])#[N:42]
Reactant: CNCc1c(C)n[nH]c1C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)Cc5c(C)n[nH]c5C)c4)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CC#N)c4)cc23)CC1
Yield: 12.7 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[[(3,5-dimethyl-1H-pyrazol-4-yl)methyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, substituting (methylamino)acetonitrile (320 μmol) for 1-(3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine to afford 6.36 mg of the title compound (12.7%).