Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[CH:7]=[N:8][OH:9].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:22]=[C:23]([C:28]([C:30]([F:33])([F:32])[F:31])=[CH2:29])[CH:24]=[C:25]([Cl:27])[CH:26]=1.C(=O)([O-])O.[K+]>COCCOC.C(OCC)(=O)C.O>[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2([C:30]([F:33])([F:31])[F:32])[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][C:3]([Cl:11])=[C:2]([Cl:1])[CH:10]=3)[CH2:29]2)[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: ON=Cc1cnc(Cl)c(Cl)c1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2cnc(Cl)c(Cl)c2)=NO1
Temperature: 70 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
In a solution of 2.1 g of 5,6-dichloronicotine aldehyde oxime in 30 mL of 1,2-dimethoxyethane, 2.3 g of N-chlorosuccinimide was added, and stirred at 70° C. for 4 hours. Then, the reaction mixture was left and cooled to room temperature, 2.5 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 1, 1.4 g of potassium hydrogen carbonate and 2.0 mL of water were added and continued to stir at room temperature further for 20 hours. After the completion of the reaction, the reaction mixture was diluted with 70 mL of ethyl acetate, washed with water (50 mL×1), and the organic was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with medium pressure preparative liquid chromatography (medium pressure collection apparatus: YFLC-Wprep manufactured by Yamazen Corporation) that was eluted with ethyl acetate-hexane (gradient of 1:10 to 1:5) to obtain 1.7 g of the aimed products as white crystal.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][N:11]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:11]=1
Reactant: Brc1ccccc1/C=C/c1n[nH]c2ccccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccccc1C=Cc1nn(C2CCCCO2)c2ccccc12
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A solution of (E)-3-[2-(2-bromophenyl)vinyl]-1H-indazole (0.35 g, 1.2 mmol) obtained in Step 1 of Example 133, 3,4-dihydro-2H-pyrane (0.21 mL, 2.3 mmol) and p-toluenesulfonic acid monohydrate (22 mg, 0.12 mmol) in THF was stirred at 80° C. for 8 hours. After cooling to room temperature, the reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was reslurried with diisopropylether to obtain 3-[2-(2-bromophenyl)vinyl]-1-(tetrahydropyran-2-yl)-1H-indazole (0.39 g, 86%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([N:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=O)=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:20]([C:17]1[CH:16]=[CH:15][C:14]([N:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][CH:18]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(Cc2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 85.5 %

Procedure:
Lithium aluminum hydride (1.6 g, 43.0 mmol) was dissolved in purified tetrahydrofuran (30 mL) under a nitrogen atmosphere, and the reaction solution was stirred. A solution prepared by dissolving (4-(diphenylamino)phenyl) (phenyl)methanone (5.0 g, 14.3 mmol) in purified tetrahydrofuran (100 mL) was slowly added thereto at 0° C. The reaction mixture solution was stirred at room temperature for 2 hours, and then distilled water (30 mL) was added to the reaction mixture solution, followed by addition of aqueous sodium hydroxide solution (100 mL). The reaction solution was subjected to extraction with dichloromethane, the solvent was removed from the extracted material, and then the residue material was dried in vacuum to thereby obtain a white solid (4.1 g, yield: 86%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=[O:13].C1CCN2C(=NCCC2)CC1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:26]([O:13][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccc2ccccc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccc2ccccc2c1)OCc1ccccc1
Yield: 100.5 %

Procedure:
To a stirred solution of 2-naphthylacetic acid (1 g, 5.4 mmol) in acetonitrile (10 mL) were added DBU (0.97 mL, 6.4 mmol) and benzyl bromide (0.77 mL, 6.4 mmol). After 3 hours the mixture was concentrated, and the residue was taken up in ethyl acetate. The organic phase was washed with 10% citric acid, 10% NaHCO3 and brine, dried (MgSO4), and concentrated to give 2-naphthylacetic acid benzyl ester as a white solid (1.5 g, 100%).
Reaction SMILES: Br.C(O[NH:7][CH:8]([CH3:20])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH2:19])(C)(C)C.C(N(CC)CC)C.[CH3:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C(Cl)Cl>[NH2:7][CH:8]([CH3:20])[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[NH:19][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([CH3:28])=[CH:30][CH:31]=1
Reactant: CC(Cn1c(N)nc2ccccc21)NOC(C)(C)C
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2nc3ccccc3n2CC(C)N)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-tert-butoxyaminopropyl)-2-aminobenzimidazole hydrobromide (1.00 g, 2.70 mmol) and triethylamine (1.9 mL, 3.79 mmol) in CH2Cl2 (50 mL) was added 4-methylbenzoyl chloride (0.46 g, 29.73 mmol) at 0° C. This mixture was stirred at 0° C. for 1 h and at room temperature overnight. The volatiles were evaporated and the residue was purified by flash chromatography using ethyl acetate-hexane (1:1). The fractions collected were concentrated in vacuo and the residue was dissolved in trifluoroacetic acid (5 ml) and stirred overnight. The trifluoroacetic acid was evaporated and the residue was dissolved in ethyl acetate and washed with a saturated solution of bicarbonate. Ethyl acetate was evaporated and the residue was purified by flash chromatography using CH2Cl2-MeOH (9.5: 0.5). The oil recovered after evaporation of solvent was transformed to the hydrochloride salt. MS 308 (M+1). 1HNMR (DMSO): δ 1.3(d, 3H), 2.37 (s, CH3), 3.80 (m, 1H), 4.45 (m, 2H), 7.26 (m, 4H), 7.55 and 7.62 (2d, 2H), 8.15 (d, 2H), 11.61 (bs, NH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][C@@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][C@@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccc(F)c(F)c1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@H](Cc3ccc(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Yield: 22.2 %

Procedure:
(2S,4S)-Methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (45 mg, 0.13 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 1 mL, 5.71 mmol) and the mixture stirred at room temperature. After 17 h more hydrogen bromide (33% in acetic acid, 0.5 mL, 2.85 mmol) was added and the reaction continued at room temperature for a total of 24 h. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4S)-2-(3,4-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (8.5 mg, 22%). 1H NMR (600 MHz, cd3od) δ 1.71-1.79 (m, 1H), 1.96-2.04 (m, 1H), 2.04-2.12 (m, 2H), 2.79-2.92 (m, 2H), 2.95-3.03 (m, 1H), 3.14-3.36 (m, 3H), 5.51 (s, 1H), 7.00-7.04 (m, 1H), 7.13-7.24 (m, 2H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1276
Reaction SMILES: C(N=C=S)C1C=CC=CC=1.C(NC(=S)NN)C1C=CC=CC=1.ClC(OCC)=O.[CH2:29]([N:36]1[C:40]([SH:41])=[N:39][N:38]=[C:37]1[OH:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Br[C:44]1[S:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][N:48]=1>>[CH2:29]([N:36]1[C:40]([S:41][C:44]2[S:45][C:46]([N+:49]([O-:51])=[O:50])=[CH:47][N:48]=2)=[N:39][N:38]=[C:37]1[OH:42])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Oc1nnc(S)n1Cc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: CCOC(=O)Cl
Agent: NNC(=S)NCc1ccccc1
Agent: S=C=NCc1ccccc1
Product: O=[N+]([O-])c1cnc(Sc2nnc(O)n2Cc2ccccc2)s1
Yield: 17.8 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 5 starting with benzyl isothiocyanate. The intermediate 4-benzyl-3-thiosemicarbazide (1.81 g) was treated with ethyl chloroformate (1.09 g) as in Example 5. The reaction product 4-benzyl-3-hydroxy-5-mercapto-1,2,4-triazole (1.04 g) was reacted with 1.05 g of 2-bromo-5-nitrothiazole as in Example 5. Crystallization from ethanol and water gave 0.3 g of 4-benzyl-3-hydroxy-5-[(5-nitrothiazol-2-yl)mercapto]1,2,4-triazole, a yellow solid, MP 221°-224° C.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:28])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([CH2:21][S:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]=2[CH3:27])[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:30]([O:32][NH2:33])[CH3:31]>>[CH2:23]([S:22][CH2:21][C:15]1[C:14]([CH3:27])=[C:13]([CH:9]2[CH2:10][C:11](=[O:12])[C:6]([C:1](=[N:33][O:32][CH2:30][CH3:31])[CH2:2][CH2:3][CH3:4])=[C:7]([OH:28])[CH2:8]2)[C:18]([CH3:19])=[CH:17][C:16]=1[CH3:20])[CH2:24][CH2:25][CH3:26]
Reactant: CCON
Reactant: CCCCSCc1c(C)cc(C)c(C2CC(=O)C(C(=O)CCC)=C(O)C2)c1C
Agent: Cl
Product: CCCCSCc1c(C)cc(C)c(C2CC(=O)C(C(CCC)=NOCC)=C(O)C2)c1C

Procedure:
5-[3-(n-Butylthiomethyl)-2,4,6-trimethylphenyl]-2-[1-(ethoxyimino)butyl]-3-hydroxycyclohex-2-en-1-one (59) was prepared from 2-butyryl-5-[3-(n-butylthiomethyl)-2,4,6-trimethylphenyl]-3-hydroxycyclohex-2-en-1-one and ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1, part (iv).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.Cl.[CH3:23][O:24][CH2:25][C:26]1[N:30]=[C:29]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[NH:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:35][C:34]3[CH:33]=[CH:32][C:31]([C:29]4[NH:28][N:27]=[C:26]([CH2:25][O:24][CH3:23])[N:30]=4)=[CH:37][CH:36]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: COCc1n[nH]c(-c2ccc(N)cc2)n1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Agent: Cl
Product: COCc1n[nH]c(-c2ccc(NC(=O)C(C)n3ccc(-c4cc(Cl)ccc4C#N)cc3=O)cc2)n1

Procedure:
90 mg (purity 93%, 0.28 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 80 mg (0.33 mmol) of 4-[3-(methoxymethyl)-1H-1,2,4-triazol-5-yl]aniline monohydrochloride were reacted according to General Method 1. Yield: 45 mg (33% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[N:20]=[C:19]([N:21]([CH3:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:18]([C:28]#[N:29])=[C:17]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][OH:39])=[CH:32][CH:31]=4)[C:16]=3[C:40]#[N:41])[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[NH2:29][C:28]1[C:18]2[C:19](=[N:20][C:15]([S:14][CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[S:9][CH:10]=3)=[C:16]([C:40]#[N:41])[C:17]=2[C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][OH:39])=[CH:34][CH:35]=2)[N:21]([CH3:27])[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1c(N)c2c(-c3ccc(OCCO)cc3)c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc2n1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
21 mg (0.035 mmol) of the compound from Example 21A were initially charged in 0.69 ml of acetonitrile, and 45 mg (0.139 mmol) of cesium carbonate were added. The reaction mixture was stirred at 50° C. for 2 h and then cooled. The solid was filtered off and then washed with acetonitrile. The filtrate was concentrated and the residue was dried under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14](=[O:31])[CH:15]([NH2:30])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14](=[O:31])[CH:15]([NH:30][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)C(N)Cc1ccc(-c2cccc(O)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc(-c2cccc(O)c2)cc1)NC(=O)c1cc(Cl)ccc1N
Yield: 36 %

Procedure:
A solution of 2-amino-5-chloro-benzoic acid (1.95 g, 11.38 mmol) in DMF (10.0 mL) was reacted with 2-amino-3-(3′-hydroxy-biphenyl-4-yl)propionic acid methyl ester (3.50 g, 11.38 mmol), HBTU (3.98 g, 10.50 mmol), and DIEA (6.08 mL, 34.15 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silical gel using DCM (+15% hexane) and increasing the gradient to DCM and finally DCM (+0.25% methanol) to give 1.75 g, (36%) of 2-(2-amino-5-chloro-benzoylamino)-3-(3′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester as a white solid. LCMS: 425 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:15](I)[C:16]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:17]=3[N:18]=2)=[N:6]1.[F:30][C:31]([F:36])([F:35])[CH2:32][CH2:33][NH2:34]>CN1C(=O)CCC1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:15]([NH:34][CH2:33][CH2:32][C:31]([F:36])([F:35])[F:30])[C:16]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:17]=3[N:18]=2)=[N:6]1
Reactant: NCCC(F)(F)F
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(I)c21
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(NCCC(F)(F)F)c21
Temperature: 150 °C

Procedure:
40 mg (0.07 mmol) of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 33A) was dissolved in 1 ml of absolute NMP and 334 mg (2.96 mmol) of 3,3,3-trifluoropropan-1-amine was added. The mixture was heated in the microwave for 2 h at 150° C. and 1 h at 150° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 27 mg (purity 93%, 70% of theor.) of the target compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18](F)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Fc1cc2c(Nc3ccc(Cl)c(Br)c3)ncnc2cn1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(Cl)c(Br)c4)ncnc3cn2)cc1
Temperature: 59 °C
Yield: 73.2 %

Procedure:
A mixture of compound 205 (3.09 g, 8.74 mmol) and 4-methoxybenzylamine (11.5 mL, 87.4 mmol) in dry DMSO (20 mL) was stirred under a nitrogen atmosphere at 58-60° C. (bath temperature) for a week. The solution was then cooled and petroleum ether (300 mL) was added. It was stirred at room temperature for 20 min. The layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated once more with petroleum ether (300 mL). Water (250 mL) was added and the mixture was stirred at room temperature for 20 h. The yellow/orange solid was collected by filtration and washed with water (5×20 mL), then with petroleum ether (3×30 mL). The sticky yellow/orange solid was dissolved in acetone (150 mL) at 45° C. (bath temperature). It was filtered to remove insoluble impurities. To the filtrate was added water (400 mL) and stirred at room temperature for 1 h. The solid was collected by suction-filtration, washed with water (5×25 mL), petroleum ether (3×30 mL), and dried in vacuum over silica-gel/KOH to give pure N4-(3-bromo-4-chlorophenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (214) (3.01 g, 73%) as a greenish yellow solid, mp 207-210° C.; 1H NMR δ [(CD)2SO] 9.74 (s, 1H), 8.77 (s, 1H), 8.41 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.96 (dd, J=8.8, 2.4 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.38-7.25 (m, 3H), 7.17 (s, 1H), 6.92-6.85 (m, 2H), 4.49 (d, J=6.3 Hz, 3.71 (s, 3H). Anal. Calcd for C21H17BrClN5O: C, 53.58; H, 3.64; N, 14.88%. Found C, 53.84; H, 3.55; N, 14.63%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[N+:8]([O-:19])[C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc([N+](=O)[O-])cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.5 g of 5-nitro-2-picoline are dissolved in 60 ml of methylene chloride and 4.05 g (20 m mole) of 85% m-chloroperbenzoic acid are added while stirring at room temperature. Stirring is continued overnight and the mixture is washed twice with aqueous sodium bicarbonate and then with water. It is dried, evaporated and the residue crystallized from acetonitrile, to yield the 5-nitro-2-picoline-N-oxide melting at 149°-153°.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([CH:24]=[C:25]3[NH:29][C:28](=[O:30])[NH:27][C:26]3=O)[CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]3[N:21]=[C:26]4[NH:27][C:28](=[O:30])[NH:29][C:25]4=[CH:24][C:17]=3[CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2cc(N3CCN(C(=O)c4ccccc4)CC3)ccc2[N+](=O)[O-])N1
Solvent: CO
Product: O=C(c1ccccc1)N1CCN(c2ccc3nc4[nH]c(=O)[nH]c4cc3c2)CC1

Procedure:
This compound, m.p. >300° C. (obtained as a methanol solvate by crystallization from dimethylformamidemethanol), was prepared analogous to Example 4 from 1-benzoyl-4-[3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenyl)piperazine.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#[CH:13]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:13]#[C:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#CC(=O)OCC
Product: CCOC(=O)C#Cc1ccc([N+](=O)[O-])cc1

Procedure:
According to the method of (Reference Example 3), from 1-iodo-4-nitrobenzene (5.0 g) and ethyl propiolate (6.1 mL), the subject compound (2.94 g) was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:2]1[O:4][CH2:3]1.[OH2:11]>C(O)(=O)CCCCCCCCCCC.[OH-].[K+]>[CH2:1]([O:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:2]([CH2:3][OH:11])[OH:4]
Reactant: CC(C)CCOCC1CO1
Reactant: O
Agent: CCCCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Product: CC(C)CCOCC(O)CO
Temperature: 157 °C
Yield: 99.7 %

Procedure:
The crude isoamyl glycidyl ether (140 g), water (140 g; 7.78 mol), lauric acid (7.64 g; 0.038 mol) and potassium hydroxide (2.14 g; 0.038 mol) were placed in a 2-l autoclave, and the mixture was heated up to 157° C. while stirring it. The mixture was stirred for 5 hours as it was, and was then allowed to cool down to room temperature. The mixture was extracted with ethyl acetate (500 ml), and the extract was washed twice with water (300 ml). The solvent was then distilled off to obtain 157 g of crude monoisoamyl glyceryl ether. This crude product was purified by vacuum distillation (2 mmHg, 114-115° C.) to obtain 103 g of monoisoamyl glyceryl ether as a colorless transparent oil (total yield: 71%). Quenching of a proton signal (methylene in an epoxy ring) at δ=2.60, 2.80 was observed by 1H-NMR (200 MHz), thereby identifying the compound. The purity of the compound was found to be at least 99% by GLC.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37](Cl)[CH:38]1[O:42][CH2:41][CH2:40][CH2:39]1>CN(C)C(=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][N:17]([CH2:37][CH:38]3[CH2:39][CH2:40][CH2:41][O:42]3)[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Reactant: ClCC1CCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(CC3CCCO3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
To a stirred solution of N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1, 52 mg) in N,N-dimethylacetamide (0.9 mL) were added cesium carbonate (54 mg), tetrahydrofurfuryl chloride (20 mg) and tetrabutylammonium iodide (4 mg). The mixture was stirred for 3 days at r.t. and for 1 day at 50° C. Tetrahydrofurfuryl chloride (20 mg) was added and the mixture was heated to 100° C. in the microwave oven for 10 min. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 95:5 to 1:1) to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-N-(tetrahydro-furan-2-ylmethyl)-2-trifluoromethyl-benzenesulfonamide (37 mg) as a light yellow oil. MS: 576.7 ([M+NH4]+)