Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21](OCC)=[O:22])[CH:14]=2)[CH:7]=1.[NH:29]([CH2:33][CH2:34][OH:35])[CH2:30][CH2:31][OH:32].O>C(O)C>[OH:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][OH:35])[C:21]([CH2:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:8]1[CH:7]=[C:6]([NH:5][C:4]2[CH:26]=[CH:27][CH:28]=[C:2]([CH3:1])[CH:3]=2)[N:11]=[CH:10][N:9]=1)=[O:22]
Reactant: OCCNCCO
Reactant: CCOC(=O)COc1cccc(Nc2cc(Nc3cccc(C)c3)ncn2)c1
Solvent: O
Solvent: CCO
Product: Cc1cccc(Nc2cc(Nc3cccc(OCC(=O)N(CCO)CCO)c3)ncn2)c1
Yield: 39 %

Procedure:
A mixture of 6-(3'-methylanilino)-4-[3'-(ethoxycarbonylmethoxy) anilino]pyrimidine (0.10 g) and diethanolamine (0.06 g) in ethanol (7 ml) was heated at reflux for 72 hours. The mixture was cooled and water (20 ml) added. The ethanol was evaporated and the solid filtered off to give 4-(3'-{N,N-di-(2-hydroxyethyl)carbamoylmethoxy}anilino]6-(3'-methylanilino)pyrimidine in 39% yield, m.p. 112°-113° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@H:12]2[CH2:18][C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:32][CH:33]=O)=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@H:12]2[CH2:18][C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:32][CH2:33][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=CCc1ccc2c(c1)CCC[C@H]2NC(=O)C[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(C[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1)N[C@@H]1CCCc2cc(CCN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step E (63 mg, 0.116 mmol) and piperidine (20 mg, 0.23 mmol) in 1 mL of dichloroethane was added sodium triacetoxyborohydride (49 mg, 0.23 mmol). After stirring overnight at room temperature, the reaction solution was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated to dryness in vaco. Flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:10 to 100:12) afforded the title compound as a white solid. MS: 573.2 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:22]#[N:23])[C:10]([CH3:21])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[F:20])[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:38])[C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:22]#[N:23])[C:10]([CH3:21])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[F:20])[C:12]=3[N:35]3[CH2:36][CH2:37][C@H:33]([N:32]([CH3:38])[CH3:31])[CH2:34]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2F)c(F)c2oc(C3CC3)nc2c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2F)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 90 °C
Reaction time: 10 h

Procedure:
2-Cyclopropyl-7-fluoro-6-(2-fluorophenyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-175) (147 mg, 0.47 mmol) was dissolved in dimethyl sulfoxide (3 ml), then at room temperature, triethylamine (99 μl, 0.71 mmol) and (3S)-3-(dimethylamino)pyrrolidine (78 μl, 0.62 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 10 hours. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][C:16]=1[CH3:24]>>[CH3:24][C:16]1[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(C(=O)O)ccc1Br
Product: Cc1cc(C(=O)O)ccc1-c1ccc(C(F)(F)F)cc1

Procedure:
Production Example 14 was repeated except that 4-(trifluoromethyl)phenylboronic acid and 4-bromo-3-methylbenzenecarboxylic acid were used, to provide the title compound as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[Cu][C:16]#[N:17].O.CO>CN1CCCC1=O>[CH:4]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[C:2]([C:16]#[N:17])[CH:3]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CO
Product: N#Cc1ccc2[nH]c3ccccc3c2c1
Temperature: 200 °C
Yield: 26.3 %

Procedure:
To a solution of 3-bromo-9H-carbazole (4.00 g, 16.3 mmol, 1 equiv) in N-Methyl-2-pyrrolidinone (40 mL) was added copper(I) cyanide (1.6012 g, 17.9 mmol, 1.1 equiv). The mixture was sealed and heated at 200° C. until TLC showed no starting material. The reaction solution was cooled and 60 mL of water was added. The off-white precipitate was filtered off and washed with EtOAc (3×20 mL). This filtrate was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), and then dried over Na2SO4. The solvent was removed under reduced pressure to afford red-brown oil. Methanol was added to the crude oil to afford 0.8251 g off-white precipitate as pure product. The mother liquid from the methanol precipitation was concentrated and purified by chromatography (25% EtOAc/Hex) to provide 0.28 g off-white solid. The combined yield was 35.5%.
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][CH:10]2[C:5](=[C:6]([N+:14]([O-])=O)[CH:7]=[CH:8][CH:9]2[Br:13])[CH2:4]1)[CH3:2].[H][H]>[Ni].CC(C)=O.C1COCC1>[CH2:1]([N:3]1[CH2:12][CH2:11][CH:10]2[C:5](=[C:6]([NH2:14])[CH:7]=[CH:8][CH:9]2[Br:13])[CH2:4]1)[CH3:2]
Reactant: CCN1CCC2C(=C([N+](=O)[O-])C=CC2Br)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCN1CCC2C(=C(N)C=CC2Br)C1
Reaction time: 1 h

Procedure:
Raney nickel was refluxed in acetone for 2 hours prior to use to deactivate the metal. The product from Example 26 (0.1 g, 0.35 mmol) was dissolved in THF (10 mL), the Raney nickel added, and the reaction vessel charged with hydrogen gas. After stirring for 1 hour, the Raney nickel was removed by filtration and the solvent removed by filtration to give N-ethyl-5-bromo-8-aminotetrahydroisoquinoline (used without further purification).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.O[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.ClC1C=C(N)C=CC=1OCC1C=CC=CN=1>>[Cl:9][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCc1cccnc1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: Nc1ccc(OCc2ccccn2)c(Cl)c1
Product: Nc1ccc(OCc2cccnc2)c(Cl)c1
Yield: 51.4 %

Procedure:
Compound 2A (0.84 g, 51%) was prepared from 4-amino-2-chloro-phenol (1.0 g, 6.96 mmol), 3-hydroxymethylpyridine (1.52 g, 13.9 mmol) by a route analogous to that used for the preparation of 1C.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:9]([F:10])=[C:8]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[CH:32][CH:31]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 2,3-difluoro-4-trifluoromethylsulfonyloxybenzonitrile in 60 mL of dioxane is admixed under an argon atmosphere with 1.24 g of 4-(tert-butyloxycarbonylamino)phenylboronic acid. A solution of 1.03 g of sodium carbonate in 15 mL of water is added, followed by 0.48 g of tetrakistriphenylphosphinepalladium. The reaction mixture is stirred at 90° C. for 3 hours and then poured into 80 mL of distilled water. Following extraction with ethyl acetate and then washing with saturated sodium chloride solution, the organic phase is concentrated under reduced pressure, to give 0.8 g of 2,3-difluoro-4-(4-tert-butoxycarbonylaminophenyl)benzonitrile, whose characteristics are as follows:
Reaction SMILES: C(O[C:9](=N)[C:10]([Cl:13])([Cl:12])[Cl:11])C1C=CC=CC=1.[C:15]1([NH2:22])[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.O>C(O)(=O)C>[Cl:11][C:10]([Cl:13])([Cl:12])[C:9]1[NH:22][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Solvent: O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
2,2,2-trichloro-acetimidic acid benzyl ester (16) (2.3 g, 9.22 mmol, Alfa Aesar) was added to a solution of Benzene-1,2-diamine (15) (1.0 g, 9.2 mmol) in acetic acid (30 mL), the solution was stirred at RT for 1 h. H2O (20 mL) was added to the mixture and the suspension was filtered. The filter cake was washed with water and dried under vacuum to afford compound (17) (1.90 g yield 88%) which was used directly for the next step without further purification. ESI-MS (M+1): 235 calc. for C8H5Cl3N2 234.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.C(N(CC)CC)C.[I-].C([NH3+])(C)(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: COC(=O)C=CC=CCBr
Reactant: Sc1ccc(Cl)cc1
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C=CC=CCSc1ccc(Cl)cc1
Yield: 63 %

Procedure:
To a solution of 6-bromohexa-2,4-dienoic acid methyl ester (1.03 g, 5 mmol), triethylamine (1.4 mL, 10 mmol) and tert-butylammonium iodide (92 mg, 0.25 mmol) in freshly distilled THF (25 mL) was added 4-chlorothiophenol under an atmosphere of nitrogen. The mixture was stirred at reflux for 2 hours after which it was concentrated under reduced pressure. The oil was dissolved in, ethyl acetate (100 mL) and then washed successively with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL) and brine (50 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (1:9 diethyl ether:40-60° C. petroleum ether). The resulting yellow solid was recrystallised from diethyl ether/40-60° C. petroleum ether to give the title compound (0.85 g, 63%) as a white solid, mp 75-77° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 2-fluorobenzenesulfonyl chloride (380 μl). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(2-fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (891 mg).
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([O:14][CH3:15])[CH:6]=1.CCOC(C)=O>CN(C=O)C>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([S:2][CH3:1])[CH:10]=[CH:9][C:8]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cc(F)ccc1C(C)=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(SC)ccc1C(C)=O
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
Sodium thiomethoxide (3.35 g, 47.8 mmol) was dissolved in dry DMF (35 ml) under a blanket of nitrogen. The solution was cooled to −15° C. and 1-(4-fluoro-2-methoxyphenyl)ethanone (6.7 g, 39.8 mmol) was added in portions. After 10 min at −15° C. the reaction mixture was brought to 0° C. for 1.5 h. EtOAc was added and the organic phase was washed three times with aqueous HCl (10%), dried (Na2SO4) and evaporated under reduced pressure to dryness. Purification by flash column chromatography (isooctane/EtOAc 4:1) gave the pure title compound (6.3 g, 81%). MS m/z (rel. intensity, 70 eV) 196 (M+, 37), 182 (11), 181 (bp), 166 (7), 138 (10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)C(C)C)(C)C.[CH3:28][O:29][CH2:30]Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9](/[N:12]=[C:13]2/[N:14]=[CH:15][N:16]([CH2:28][O:29][CH3:30])[CH:17]=[CH:18]/2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Nc1ccncn1)c1ccc(F)c(Cl)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCn1cc/c(=N\S(=O)(=O)c2ccc(F)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
To 3-chloro-4-fluoro-N-pyrimidin-4-ylbenzenesulfonamide (Preparation 426, 73 mg, 0.25 mmol) in methylene chloride (2 mL) cooled at 0° C. was added N,N-diisopropylethylamine (0.066 mL, 0.38 mmol) and chloromethyl methyl ether (0.025 mL, 0.28 mmol). After stirring at room temperature for 18 hours, the reaction mixture was diluted with ethyl acetate, washed successively with 1N aqueous sodium hydroxide, water, saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 76 mg (90%) of the title compound as an orange oil and a mixture of three regioisomers that were not separated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([C:10]2[S:11][CH2:12]CN=2)[N:3]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])=[O:18]>C(#N)C>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:28][C:29]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]2[S:11][CH2:10][CH2:4][N:3]=2)[N:3]=1)=[O:30])(=[O:26])=[O:27])=[O:18]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(C2=NCCS2)nc(N)n1
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(CSC2=NCCS2)cc(OC)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
7.0 g of 2-amino-4-methoxy-6-(4,5-dihydrothiazol-2-yl)pyrimidine are suspended in 50 ml of abs. acetonitrile, and 6.6 g of 2-methoxycarbonylphenylsulfonylisocyanate are added. There is formed a clear solution with heating, and the product subsequently precipitates in crystalline form. After the reaction mixture has been stirred for 3 hours at 20°-25° C., it is cooled to 0° C. and the solid substance is separated. There is thus obtained N-(2-methoxycarbonylphenyl-sulfonyl)-N'-[4-methoxy-6-(4,5-dihydrothiazol-2-yl)-thiomethyl-pyrimidin-2-yl]-urea, m.p. 135°-145° C. (decomp.).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=1)[C:9]#[N:10])(=[O:5])[CH3:4]>CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH:13]=1)[C:9]#[N:10])=[O:5]
Reactant: BrBr
Reactant: COCCOc1cc(C#N)cc(C(C)=O)c1
Solvent: CCOCC
Product: COCCOc1cc(C#N)cc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
Br2 (31.5 mmol) was dropped into the solution of 3-acetyl-5-(2-methoxyethoxy)benzonitrile (30 mmol) in 150 ml ether at 0° C., then stirred at room temperature for 5 h. The solution was washed with brine, dried (MgSO4), filtered, and concentrated to afford 3-(2-bromoacetyl)-5-(2-methoxyethoxy)benzonitrile (94.2%).
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[C:10]([CH2:27][CH3:28])=[N:11][N:12]([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][C:18]=2[F:26])[C:13]=1[CH2:14][CH3:15])=[O:7])(C)(C)C.C(N(C(C)C)CC)(C)C.[NH2:38][C:39]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][N:40]=1.C(O)(=O)C>CN(C)C=O>[CH2:27]([C:10]1[C:9]([CH2:8][C:6]([OH:5])=[O:7])=[C:13]([CH2:14][CH3:15])[N:12]([CH2:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]3[NH:38][C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:44]4[N:45]=3)=[CH:19][C:18]=2[F:26])[N:11]=1)[CH3:28]
Reactant: Nc1cccnc1N
Reactant: CCc1nn(Cc2ccc(C(=O)O)cc2F)c(CC)c1CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nn(Cc2ccc(-c3nc4cccnc4[nH]3)cc2F)c(CC)c1CC(=O)O
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
To a stirred solution of 4-(4-tert-butoxycarbonylmethyl-3,5-diethylpyrazol-1-ylmethyl)-3-fluorobenzoic acid (19 mg) in dimethylformamide (2 ml) at room temperature is added diisopropylethylamine (50 μl). After 10 min, the solution is added to 2,3-diaminopyridine (7 mg). After 2 days, glacial acetic acid (2 ml) is added and the reaction is heated to 130° C. After 15 h, the reaction is allowed to cool to room temperature and concentrated in vacuo. The residue is dissolved in dichloromethane and trifluoroacetic acid (200 μl) and water (200 μl) are added. After 15 h, the reaction mixture is concentrated in vacuo. The residue is purified by HPLC to yield (3,5-diethyl-1-[2-fluoro-4-(3H-imidazo[4,5-b]pyridin-2-yl)benzyl]-1H-pyrazol-4-yl)acetic acid (10 mg; [M+H]=429; HPLC retention time 1.34 min (Method A)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:29])=[C:9]([C:25]([O:27][CH3:28])=[O:26])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[Cl:24])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(O)(O)(=O)=O.CS[C:37](=[NH:39])[NH2:38].C(N(CC)CC)C>C(O)CC>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:25]([O:27][CH3:28])=[O:26])=[C:8]([CH3:29])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:37]([NH2:39])=[NH:38])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CCCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(COCCNC(=N)N)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 74.9 %

Procedure:
2-(2-Aminoethoxymethyl)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (5.0 g) and S-methylisothiourea sulphate (3.45 g) was suspended in n-propanol (120 ml) and triethylamine (30 ml) and refluxed for 17 hours. After evaporation to dryness, the residual oil was partitioned between aqueous sodium bicarbonate and methylene chloride. The organic layer was dried (MgSO4), filtered and evaporated. The resultant beige solid was triturated with hexane to give the title compound (4.1 g), N.M.R. (CDCl3, 60 MHz): 3H 1.15(t), 3H 3.55(s), 4H 3.7(m), 2H 4.0(q), 2H 4.7(s), 1H 5.45(s), 8H 7.25(m).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]1([CH:20]2[CH2:25][CH2:24][C:23](=[CH:26][C:27]#[N:28])[CH2:22][CH2:21]2)[N:9]=[N:10][N:11]2[C:16]=1[C:15]1[CH:17]=[CH:18][NH:19][C:14]=1[N:13]=[CH:12]2.O>CS(C)=O>[C:8]1([CH:20]2[CH2:21][CH2:22][C:23]3([CH:26]([C:27]#[N:28])[CH2:2]3)[CH2:24][CH2:25]2)[N:9]=[N:10][N:11]2[C:16]=1[C:15]1[CH:17]=[CH:18][NH:19][C:14]=1[N:13]=[CH:12]2
Reactant: N#CC=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1CC12CCC(c1nnn3cnc4[nH]ccc4c13)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 36.8 %

Procedure:
Trimethylsulfonium iodide (59.0 μL, 0.269 mmol) in dimethyl sulfoxide (1 mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil, 12.0 mg, 0.269 mmol) at room temperature for 30 minutes. The reaction mixture was mixed with 2-[4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexylidene]acetonitrile (15.0 mg, 0.0539 mmol) obtained in Synthetic Examplea 434 and then stirred at room temperature for 15 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1 (v/v)) to give the title compound as a colorless solid (5.80 mg, yield 37%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][CH2:26][CH2:27]I>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:27][CH2:26][F:25])[C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Reactant: FCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(F)c(F)cc2n(CCF)c(=O)n1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 1.0 g, 3.2 mmol) in 20 mL of DMF was added to a suspension of sodium hydride (0.16 g, 3.9 mmol) in 20 mL of DMF and stirred for 30 minutes. 2-Fluoroethyl iodide (1.1 g, 6.4 mmol) was added, and the mixture was warmed to 50° C. for 18 hours. The reaction was quenched with 1 mL of water and concentrated to an oil. The residue was dissolved in chloroform, washed with water, brine and dried over magnesium sulfate. The solution was concentrated to give 0.73 g of the title compound as a solid, mp 145-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([F:13])[F:12].[H-].[Na+].Br[CH2:17][C:18]([NH2:20])=[O:19].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]([NH2:20])=[O:19])[C:6](=[O:11])[C:5]2([F:13])[F:12]
Reactant: O=C1Nc2ccc(Cl)cc2C1(F)F
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CN1C(=O)C(F)(F)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-chloro-3,3-difluoro-1,3-dihydro-2H-indol-2-one 4 (2.55 g, 12.5 mmol) is dissolved in dry DMF (20 ml) under a nitrogen atmosphere. The solution is cooled at 0° C. and NaH (0.547 g, 13.8 mmol, 60% dispersion) is carefully added portionwise. When the nitrogen evolution ceases, bromoacetamide (2.05 g, 15.0 mmol) is added. After 30 minutes, the mixture is poured into cold water and the solid is filtered off and washed with water. The crude material is directly recrystallized in acetone/water affording of 2-(5-chloro-3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide 12 as a pink solid.