Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C(C(O)=O)=CN=C([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)N=1.N1(N)C2C(=NC=CC=2)C=C1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([NH:37][C:38]([C:40]1[C:41]([CH3:52])=[N:42][C:43](C3C=CC=CN=3)=[N:44][CH:45]=1)=[O:39])[CH:32]=[CH:31]2>>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([NH:37][C:38]([C:40]1[C:41]([CH3:52])=[N:42][C:43]([C:16]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:44][CH:45]=1)=[O:39])[CH:32]=[CH:31]2
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: Nn1ccc2ncccc21
Product: Cc1nc(-c2cccnc2)ncc1C(=O)Nn1ccc2cc(F)ccc21

Procedure:
Following procedures similar to those of Example 127 but substituting 4-methyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid for 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid, and substituting 5-fluoro-indol-1-ylamine for pyrrolo[3,2-b]pyridine-1-ylamine, there is prepared 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (34%) as a solid. MS: 348 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.85 (s, 3H), 6.57 (m, H), 7.02 (m, H), 7.23-7.46 (m, 2H), 7.62 (m, H), 8.70 (d, H), 8.91 (d, H), 9.17 (s, H), 9.63 (s, H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:17])(=[O:16])[C:5]=2[CH:4]=[C:3]([CH:18]=O)[CH:2]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1(C)C=CC=CC=1>[C:21]1([N:20]=[CH:18][C:3]2[CH:2]=[CH:1][C:11]3[CH:10]=[CH:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[S:6](=[O:17])(=[O:16])[C:5]=3[CH:4]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=S1(=O)c2ccccc2C=Cc2ccc(C=Nc3ccccc3)cc21
Reaction time: 0.17 h

Procedure:
Heat a mixture of 675 mg (2.5 mmoles) of dibenzo[b,f]thiepin-3-carboxaldehyde-5,5-dioxide and 465 mg of aniline (5 mmoles) in 20 ml of toluene, under reflux, with azetropic removal of water for 21 hours. Cool the mixture and filter the insoluble product. Stir the solid in 10 ml of ether containing a few drops of THF for 10 minutes then filter to obtain the pure product, 704 mg, mp: 184°-185°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:14][CH2:15][CH2:16]Cl)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][CH3:28].[I-].[Na+].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:14][CH2:15][CH2:16][N:27]([CH3:28])[CH3:26])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(CCCCl)c2ccc(F)c(Cl)c2)C1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCN(c1ccc(F)c(Cl)c1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
3(S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.24 mmol), 50% dimethylamine solution (1 ml) and sodium iodide (0.37 g, 2.5 mmol) were suspended in DMF (3 ml), followed by stirring at 60° C. for 4 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate was conducted. The organic layer was dried over sodium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate), and the purified product was then concentrated under reduced pressure to thereby obtain 0.36 g of oily colorless 3(S)-[(3-chloro-4-fluorophenyl)-(3-dimethylamino propyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [I:1][CH:2]=[CH:3][CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([Mg]Br)#[CH:12].CCOCC>O1CCCC1>[C:11]([C:4]([OH:10])([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH:2][I:1])#[CH:12]
Reactant: CCCCCC(O)C=CI
Reactant: C#C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC(O)(C=CI)CCCCC
Reaction time: 1 h

Procedure:
As shown in FIG. 1, 1-iodo-1-octen-3-ol (II) is treated with an ethynyl Grignard reagent, conveniently ethynyl magnesium bromide, in a suitable Grignard solvent of the ether type, conveniently tetrahydrofuran, at reduced temperature, conveniently 0° C., while stirring for a short time, conveniently 1 hour, to give dl-3-ethynyl-1-iodo-1-octen-3-ol (III).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:25]([NH:27][CH:28]([CH3:30])[CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH:28]([CH3:30])[CH3:29])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:26]
Reactant: CCNC(C)C
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: CCN(CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1)C(C)C

Procedure:
The product from Example 1C and ethyl(isopropyl)amine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 333 (M+H)+;
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[NH:29][C:28](=[O:30])[CH:27]([CH3:31])[N:8]2[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[N-:32]=[N+:33]=[N-:34].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:1]([C:5]1[N:6]=[C:7]2[NH:29][C:28](=[O:30])[CH:27]([CH3:31])[N:8]2[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:34][N:33]=[N:32][N:25]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2n(c(=O)c1Cc1ccc(-c3ccccc3C#N)cc1)C(C)C(=O)N2
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCc1nc2n(c(=O)c1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C)C(=O)N2
Yield: 45 %

Procedure:
A solution of 0.2 g of 7-butyl-6-((2'-cyanobiphenyl-4-yl)methyl]-3-methylimidazo[1,2-a]pyrimidin-2,5-dione in 4 ml of toluene and 1 ml of DMF is added with 38 mg of sodium azide and 0.17 ml of tributylstannyl chloride. After 72 h under reflux, the solvent is evaporated under reduced pressure and the residue is taken up in a NaOH diluted solution and extracted with toluene. The aqueous phase is acidified to pH 5 with AcOH, to separate a white solid which is filtered off and washed first with H2O, and then with a mixture of hexane-toluene to obtain g 0.1 of a white solid, after crystallization (45% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CCOC(C)=O>[CH:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:16]=1[C:2]1[N:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2ccc3ccccc3c2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.9 %

Procedure:
To a solution of 2-bromo-5-hydroxypyridine (1.04 g, 6 mmol) in 25 mL anhydrous THF was added 2-naphthylboronic acid (1.03 g, 6 mmol) and 2 M aq. sodium carbonate (9 mL, 18 mmol). To this reaction mixture was added palladium tetrakistriphenylphosphine (0.7 g, 0.6 mmol) and the mixture was stirred at rt for 15 h under nitrogen. The reaction mixture was diluted with EtOAc, the organic layer was washed with water (50 mL), brine (50 mL) and dried over anhydrous Na2SO4. Removal of solvent gave a white powder which was purified by column chromatography (Silica Gel 230-400 mesh; 3% MeOH in DCM) to give 6-naphthalen-2-yl-pyridin-3-ol (0.225 g, 17%). MS (ES) m/z: 222.96 (M+1), 221.93 (M); Mp. 168-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:38]([S:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:39]#[CH:40].CCO>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:40]=[C:39]([CH2:38][S:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Reactant: C#CCSc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(CSc3ccccc3)cc3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and Cu (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and phenyl propargyl sulfide (0.082 mL). The reaction is stirred at room temperature for 7 days. The reaction mixture is diluted with dichloromethane and partitioned against dilute aqueous sodium bicarbonate. The aqueous. phase is extracted with two portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 1% to 3% methanol in ethyl acetate. Product containing fractions are combined and condensed to afford a mixture of cyclized and uncyclized materials. To a flask is added the mixture, EtOH (2 mL), and Et3N (0.12 mL). The suspension is heated at 75° C. overnight tightly capped. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, adsorbed onto silica, and flash column chromatographed eluting with 1% to 4% methanol in ethyl acetate. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid. The solid is crystallized from acetonitrile to give 0.16 g of the title compound as light tan product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[C:9]([Cl:18])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Fc1ccc(-c2csc3ncnc(Cl)c23)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Fc1ccc(-c2c(Cl)sc3ncnc(Cl)c23)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 16.5 %

Procedure:
To a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (1 g, 4.06 mmol) in acetic acid (15 mL), N-chlorosuccinimide (1.08 g, 8.1 m. mol) was added and the mixture was stirred at 90° C. for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (30 mL) and washed with sat. NaHCO3 solution (3×20 mL). The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by column chromatography to get the title product (200 mg, 16%) as pale yellow solid. 1H NMR (400 MHz, CDCl3 and CDCl3): δ 8.85 (s, 1H), 7.35 (m, 2H), 7.20 (m, 2H). MS (ESI) m/z: Calculated: 297.95; Observed: 299.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH2:11]O)=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH2:11][Cl:19])=[O:8])=[C:4]([Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1
Reactant: C[Si](C)(C)c1cc(Cl)sc1C(=O)NCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C[Si](C)(C)c1cc(Cl)sc1C(=O)NCCCl
Temperature: 0 °C

Procedure:
A solution of the compound of Example 263 (0.4 g) and 1 mL thionyl chloride in 6 mL CH2Cl2 was refluxed for 1 h, then cooled and poured into ice-water. Additional CH2Cl2 was added. The organic layer was separated, washed with brine, dried and concentrated. Flash chromatography of the residue with 5% ethyl acetate-hexane as eluent gave 0.4 g of the desired product as a white solid. m.p. 68°-72° C.
Reaction SMILES: CO[C:3]1C(OC)=CC2C(C3C=CC=CC=3)=NNC(=O)CC=2[CH:20]=1.[S:23]1[C:27]([C:28]2[C:34]3[CH:35]=[C:36]([O:42][CH2:43][CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[CH:38][C:33]=3[CH2:32][C:31](=[O:45])[NH:30][N:29]=2)=[CH:26][C:25]2[CH:46]=[CH:47][CH:48]=[CH:49][C:24]1=2>>[S:23]1[C:27]([C:28]2[C:34]3[CH:35]=[C:36]([O:42][CH2:43][CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[CH:38][C:33]=3[CH2:32][C:31](=[O:45])[N:30]([CH2:3][CH3:20])[N:29]=2)=[CH:26][C:25]2[CH:46]=[CH:47][CH:48]=[CH:49][C:24]1=2
Reactant: CCOc1cc2c(cc1OCC)C(c1cc3ccccc3s1)=NNC(=O)C2
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NNC(=O)C2
Product: CCOc1cc2c(cc1OCC)C(c1cc3ccccc3s1)=NN(CC)C(=O)C2
Yield: 72 %

Procedure:
By replacing 7,8-dimethoxy-1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIaa in example IIIag by 1-(2-benzo[b]thienyl)-7,8-diethoxy-3,5-dihydro-4H-2,3-benzodiazepin-4-one VIab and proceeding in the same manner, the abovenamed product is obtained. Yield: 72%. M: 100–103° C. 1H-NMR (200 MHz, CDCl3): d 1.26 (t, J=7.1, 3H, CH3), 1.44 (t, J=7.0, 3H, CH3), 1.52 (t, J=7.1, 3H, CH3), 3.29–3.56 (m, 2H, 5-CH2), 3.85–4.25 (m, 6H, 3×CH2CH3), 6.87 (s, 1H Ar), 7.15 (s, 1H Ar), 7.32–7.44 (m, 3H Ar), 7.71–7.89 (m, 2H Ar).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC1C(Cl)=NC2C(=CC=CC=2)N=1.N.[Br:26][CH2:27][C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(O)C.C(COC)OC>[Br-:26].[NH2:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[CH2:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:34]
Reactant: Nc1nc2ccccc2nc1Cl
Reactant: CCOC(=O)C(=O)CBr
Agent: Clc1nc2ccccc2nc1Cl
Agent: N
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)C(=O)C[n+]1c(N)c(Cl)nc2ccccc21
Product: [Br-]

Procedure:
A solution of 9 g of 2-amino-3-chloro-quinoxaline [prepared by heating under pressure 2,3-dichloro-quinoxaline and ammonia in ethanol by method of Saikachi et al (Chem. Pharm. Bull. Tokyo (1961), Vol. 9, p. 941], 12 g of ethyl bromopyruvate and 180 ml of dimethoxy ethane was stirred overnight and was filtered to obtain 5.33 of 2-amino-1-carbethoxycarbonylmethyl-3-chloro-quinoxalinium bromide in the form of a pale yellow crystalline solid. The filtrate was held in a refrigerator for 2 days to obtain 2 more crops of 1.20 and 3.62 g of product for a total yield of 10.22 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[N:15]=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[N:13]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:44])[CH:42]=[CH2:43]>O1CCCC1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:41](=[O:44])[CH:42]=[CH2:43])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[N:17]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(OCCO)cc3O)n2)c(C)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCCOc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(O)c1
Yield: 88.8 %

Procedure:
22.1 g (0.05 mol) of 2-(2-hydroxy-4-hydroxyethoxy-phenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine (prepared as described in U.S. Pat. No. 3,244,708, Example 18), are dissolved in 300 ml of tetrahydrofurane at 40° C. and 21 ml (0.15 mol) of triethylamine are added. A solution of 5.05 ml (0.053 mol) of acrylic acid chloride in 20 ml THF is added dropwise with stirring and with cooling the reaction mixture to 25°-30° C. After further stirring of two hours the precipitated ammonium salt is filtered off, the filtrate is evaporated and the residue recrystallized from toluene-hexane mixture to obtain 22 g (88.7% yield) of 2-(2-hydroxy-4-acryloyloxyethoxy-phenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine as slightly yellow crystals (compound No. 25), m.p. 128°-129° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[S:6][C:5]2[CH:7]=[C:8]3[S:12][C:11]([CH3:14])([CH3:13])[S:10][C:9]3=[CH:15][C:4]=2[S:3]1.C([Li])CCC.[C:22](=[O:24])=[O:23].[C:25](=O)([O-])[O-].[K+].[K+].CI>CCOCC.CN(C=O)C>[CH3:25][O:23][C:22]([C:15]1[C:4]2[S:3][C:2]([CH3:16])([CH3:1])[S:6][C:5]=2[CH:7]=[C:8]2[S:12][C:11]([CH3:14])([CH3:13])[S:10][C:9]=12)=[O:24]
Reactant: O=C=O
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Sc2cc3c(cc2S1)SC(C)(C)S3
Agent: [K+]
Agent: [Li]CCCC
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1c2c(cc3c1SC(C)(C)S3)SC(C)(C)S2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dithiole (2.0 g, 6.98 mmol) was dissolved in dry ether (50.0 mL) in a dry, argon filled reaction flask. n-Butyllithium (3.07 mL, 2.5M in hexane) was added and the reaction mixture was stirred for 30 min. The solution was poured onto solid carbon dioxide and, after stirring overnight, the ether was filtered off. The solid residue was washed with chloroform and dried under vacuum. The crude product was mixed with potassium carbonate (0.97 g, 6.98 mmol) in dry DMF (20.0 mL) and was stirred for 1.5 h at 60° C. After cooling to ambient temperature, methyl iodide (0.435 mL, 6.98 mmol) was added. The stirring was continued overnight. The mixture was filtered, the solution evaporated and the residue was dissolved in dichloromethane and water. The organic phase was washed with water (2*30 mL), dried (Na2SO4) and evaporated to give after additional drying under vacuum a bright green-yellow crystalline pure product. Yield 1.56 g (65%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH:24]([O:27][CH3:28])[O:25][CH3:26])[CH:16]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>O.C1COCC1.C(Cl)Cl>[CH2:39]([O:38][C:36](=[O:37])[N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([CH:24]([O:25][CH3:26])[O:27][CH3:28])[CH:16]=2)[CH:9]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COC(OC)c1cc(Oc2cccc(NC3CCCCC3)c2)ccc1[N+](=O)[O-]
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(OC)c1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
A mixture of cyclohexyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-amine (0.00868 mol) and Na2CO3 (0.02083 mol) in H2O (15 mL) and THF (75 mL) was stirred at 5° C. A solution of benzyl chloroformate (0.0104 mol) in THF (25 mL) was added dropwise over 15 min at 5° C. The resultant reaction mixture was stirred for 21 hours at room temperature. This mixture was extracted with diisopropyl ether. The separated organic layer was dried (MgSO4) and filtered, and the solvent was evaporated. The residue (0.00633 mol A) was reacted again with benzyl chloroformate (1.3 g, 0.0076 mol) and TEA (1.53 g, 0.0152 mol) in DCM (70 mL) under the same conditions as above. The residue was purified by column chromatography over silica gel (eluent: 95:5 CH2Cl2:hexane). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[O:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:34][CH2:35][CH2:36][O:32]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: C1CNOC1
Product: O=C1N=C(N2CCCO2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-isoxazolidin-2-yl-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and isoxazolidine following General Procedure B.
Reaction SMILES: NC1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)N=1.[NH2:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([O:18][CH3:19])[N:12]=1.C[O-].[Na+].[CH3:23][C:24]([CH3:26])=O>CO>[NH2:10][C:11]1[N:16]=[C:15]([NH:7][C:6]2[CH:5]=[CH:4][CH:26]=[CH:24][CH:23]=2)[CH:14]=[C:13]([O:18][CH3:19])[N:12]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)=O
Reactant: COc1cc(Cl)nc(N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Nc2ccccc2)nc(N)n1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
2-Amino-4-anilino-6-methoxypyrimidine was synthesized using 2-amino-4,6-dichloropyrimidine as a starting material through 2-amino-4-chloro-6-methoxypyrimidine. A solution of sodium methoxide in 28% methanol (43 mL) at an internal temperature of 20° C. or less was dropwise added to a mixture of 2-amino-4,6-dichloropyrimidine (32.8 g) and acetone (700 mL) under ice cooling. The reaction was further continued at an internal temperature of 40° C. for 4 hours, and the solution was concentrated under reduced pressure, followed by addition of 500 mL of water. The precipitated solid was collected by filtration and was used without purification for the subsequent step. The crude product of 2-amino-4-chloro-6-methoxypyrimidine, aniline (26.7 mL), methoxyethanol (150 mL), and hydrochloric acid (0.2 mL) were mixed, followed by stirring with heating at 120° C. for 3 hours. After cooling, the reaction solution was added to aqueous sodium bicarbonate (500 mL)/ethyl acetate under ice cooling to extract the product with ethyl acetate. After the concentration, purification by column chromatography (ethyl acetate/n-hexane) was performed to yield 14 g of 2-amino-4-anilino-6-methoxypyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl.C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:28])[N:6]2[C@H:21]1[CH2:22][CH2:23][C@H:24]([O:27][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)[CH2:25][CH2:26]1
Reactant: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](O)CC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1[C@H]1CC[C@H](OC2CCCCO2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one (0.8 mmol) and dihydropyran (15 equiv.) in anhydrous chloroform/THF (30 mL/15 mL) containing p-TsOH (0.1 equiv.) was stirred at 50° C. for 1 day (LCMS indicative of complete reaction). The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on neutral alumina to give the desired product. MS (EI) m/z 487.3 (MH)+.