Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:37])[CH2:9]1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:38][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:37][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A solution of acryloyl chloride (64 μL, 0.79 mmol) in CH2Cl2 (4 mL) was added dropwise over 10 minutes to 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 153, 336 mg, 0.76 mmol) in CH2Cl2 (11 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h, and was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat.NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (296 mg, 79%) as an orange solid after trituration with diethyl ether; 1H NMR: 1.70-1.81 (1H, m), 2.05-2.13 (1H, m), 2.18 (6H, s), 2.68-2.76 (1H, m), 3.17-3.27 (3H, m), 3.35-3.42 (1H, m), 3.84 (3H, s), 5.67 (1H, dd), 6.17 (1H, dd), 6.51 (1H, dd), 6.56 (1H, s), 7.05 (1H, dd), 7.21 (1H, d), 7.40-7.45 (1H, m), 7.84 (1H, s), 8.02 (1H, s), 8.30 (1H, d), 8.46 (1H, d), 8.76 (1H, s), 8.78 (1H, d), 9.35 (1H, s); m/z: ES+ MH+ 499.69.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].Cl.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.CO>[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][CH2:34][NH:35][C:13]([C:4]3[CH:5]=[C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:2]([CH3:1])[C:3]=3[CH3:16])=[O:15])[CH2:30][CH2:31]2)[CH:23]=[CH:24][CH:25]=1
Reactant: NCCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: Cc1c(C(=O)O)cc(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1c(C(=O)NCCCN2CCN(c3cccc(Cl)c3)CC2)cc(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
To the mixture of 1,2-Dimethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.46 mmol) and 3-(4-(3-chlorophenyl) piperazin-1-yl)propan-1-amine dihydrochloride (152 mg, 0.46 mmol) in methylene chloride (5 ml) was added EDCI (178 mg, 0.92 mmol), HOBT (130 mg, 0.9 mmol) and NMM (0.3 ml, 1.8 mmol) continuously. After stirring for 1 day at room temperature, MeOH was added to the resulting solution, and filter off. After evaporation under reduced pressure, the residue was purified by reverse phase preparative HPLC to provided title compound (149 mg, 71%) as white solid.
Reaction SMILES: [C:1]([C:3]([OH:24])([CH2:5][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14]C(=O)C)[C:10]([CH3:18])=[C:9]([CH3:19])[C:8]=1[O:20]C(=O)C)[CH3:4])#N.[CH3:25][OH:26].Cl.[OH2:28]>>[OH:20][C:8]1[C:9]([CH3:19])=[C:10]([CH3:18])[C:11]([OH:14])=[C:12]([CH3:13])[C:7]=1[CH2:6][CH2:5][C:3]([OH:24])([CH3:4])[C:1]([O:26][CH3:25])=[O:28]
Reactant: CC(=O)Oc1c(C)c(C)c(OC(C)=O)c(CCC(C)(O)C#N)c1C
Reactant: CO
Reactant: O
Agent: Cl
Product: COC(=O)C(C)(O)CCc1c(C)c(O)c(C)c(C)c1O
Reaction time: 8 h

Procedure:
A solution of the crude (±)-2-cyano-4-(2,5-diacetoxy-3,4,6-trimethylphenyl)butan-2-ol prepared in Example 60 in 2000 ml. of anhydrous methanol was cooled in a dry ice-ethanol bath. When the internal temperature reached -50°, HCl gas was passed rapidly into the solution. Over the next 45 minutes, the external and internal temperatures were allowed to come to -20° and +5°, respectively. These temperatures were maintained until the solution was saturated with HCl The clear, dark brown solution was kept at +2° overnight, stripped of solvent at reduced pressure, diluted with 2000 ml. of H2O, heated at 40° under N2 for 2.0 hours, cooled and extracted with ethyl acetate and ether. The organic solutions were washed with saturated brine, dried over Na2SO4 and stripped of solvent to give (±)-methyl 4-(2,5-dihydroxy-3,4,6-trimethylphenyl)-2-hydroxy-2-methylbutanoate as a dark green-black oil. TLC indicated that under these conditions, virtually no (±)-methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylate had been formed.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)[C:10]2=[O:29])=[N:6][C:5]=1[CH3:30])(=O)[CH3:2].COC(OC)[N:34]([CH3:36])C.O.[NH2:40]N>CN(C)C=O.C(OCC)(=O)C>[CH3:30][C:5]1[N:6]=[C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:22])=[CH:19][CH:20]=3)[C:10]2=[O:29])[S:8][C:4]=1[C:1]1[NH:40][N:34]=[CH:36][CH:2]=1
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(=O)N4CCCCC4)cc3)C2=O)nc1C
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(Cc3ccc(C(=O)N4CCCCC4)cc3)C2=O)sc1-c1ccn[nH]1
Temperature: 110 °C
Yield: 54 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(piperidine-1-carbonyl)benzyl)imidazolidin-2-one (0.43 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added N,N-dimethylformamide dimethyl acetal (0.20 mL, 1.50 mmol). The reaction mixture was heated for 20 hours at 110° C., and hydrazine monohydrate (0.25 mL, 5.14 mmol) was added. The reaction mixture was heated for another 10 minutes at 110° C., then cooled to ambient temperature, diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound as a colorless solid in 54% yield (0.26 g): mp 156-157° C. (ethyl acetate): 1H NMR (300 MHz, CDCl3) δ 7.45-7.22 (m, 4H), 4.50 (s, 2H), 4.15-4.01 (m, 2H), 3.69-3.32 (m, 6H), 2.60 (s, 3H), 2.40 (s, 3H), 1.71-1.20 (m, 6H): MS (ES+) m/z 427.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[CH:9][N:10]=[C:11]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)[N:4]2[N:3]=1.[I:22]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]2=[C:9]([I:22])[N:10]=[C:11]([C@H:12]3[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]3)[N:4]2[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)[C@H]1CC[C@H](c2ncc3c(=O)[nH]c(N)nn32)CC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]c(N)nn32)CC1

Procedure:
A solution of methyl trans-4-(2-amino-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.200 g, 0.000686 mol) and N-iodosuccinimide (0.278 g, 0.00124 mol) in anhydrous DMF (4.0 mL) was stirred at rt for 48 h. The reaction was concentrated in vacuo then partitioned between H2O and EtOAc. The aqueous material was re-extracted with EtOAc (3×) and the combined organic fractions were washed with H2O (2×), Na2S2O3 (2×) and brine (1×). The aqueous was re-extracted with CHCl3 and combined with the EtOAc fractions dried over Na2SO4, filtered and concentrated in vacuo resulting in 229 mg, (79.9% yield) of the title compound as a light orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.65 (m, 4H), 1.88-2.06 (m, 4H), 2.33-2.45 (m, 1H), 2.91-3.01 (m, 1H), 3.61 (s, 3H), 6.17 (s, 2H) and 10.82 (br. s., 1H); MS (ES+): m/z 417.82 [MH+].
Reaction SMILES: [C:1](N(CCO)CC[OH:8])(C)(C)[CH3:2].[CH2:12]1[CH:17]([CH2:18][CH:19]2[CH2:24][CH2:23][CH:22](N=C=O)[CH2:21][CH2:20]2)[CH2:16][CH2:15][CH:14](N=C=O)[CH2:13]1>>[CH:13]1[C:14]([OH:8])=[CH:15][CH:16]=[C:17]([CH3:18])[CH:12]=1.[CH:1]([C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:18]=[CH2:17])=[CH2:2]
Reactant: O=C=NC1CCC(CC2CCC(N=C=O)CC2)CC1
Reactant: CC(C)(C)N(CCO)CCO
Product: C=Cc1ccccc1C=C
Product: Cc1ccc(O)cc1

Procedure:
Then, for the antioxidant, a 2:1 mixture of (Dupont Methacrole™ 2462, c1) produced by reacting t-butyl diethanol amine and methylene-bis-(4-cyclohexyl isocyanate) and Dupont Methacrole™ 2390, c2) produced by condensation polymerization of p-cresol and divinyl benzene were prepared in a DMAc solution as an antioxidation agent (concentration 35 wt %), and this was added with other additives to solution C1 (55 wt %)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([NH2:19])=[C:12]2[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC[C:24]([NH2:26])=[O:25]>CCOCC.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:24](=[O:25])[NH2:26])[C:13]([NH2:19])=[C:12]2[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([NH2:19])=[C:12]2[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(N)c(C#N)c2cc(OCc3ccccc3)ccc21
Reactant: NC(=O)CI
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1c(N)[nH]c2ccc(OCc3ccccc3)cc12
Product: N#Cc1c(N)n(CC(N)=O)c2ccc(OCc3ccccc3)cc12

Procedure:
Using the general method of selective N-alkylation described for 5-benzyloxy-2-amino-1-methyl-1H-indole-3-carbonitrile in Example 25, using iodoacetamide (222 mg; 1.2 mmol), 5-benzyloxy-1-carbamoylmethyl-2-amino-1H-indole-3-carbonitrile (163 mg) was obtained as a white solid from 5-benzyloxy-2-amino-1H-indole-3-carbonitrile (263 mg; 1.0 mmol) after trituration with Et2O/CH2Cl2.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.[CH2:25]([CH:32]1[CH2:37][CH2:36][N:35]([CH:38]([CH3:48])[C:39]([C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)=[O:40])[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)C>[CH2:25]([CH:32]1[CH2:33][CH2:34][N:35]([CH:38]([CH3:48])[C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:43][CH:42]=2)=[O:40])[CH2:36][CH2:37]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C(=O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)Oc1ccc(C(=O)C(C)N2CCC(Cc3ccccc3)CC2)cc1
Reaction time: 5 h

Procedure:
6.5 g of palmitoyl chloride are added to 40 ml of pyridine containing 7 g of 2-(4-benzylpiperidino)-4'-hydroxypropiophenone and the mixture is stirred for 5 hours. It is diluted with 100 ml of diethyl ether and left to stand overnight. The precipitate is then collected by filtration, washed and dried. 11 g of a product which melts at 185°-192° C. with decomposition are thus isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@@H:31]([NH2:36])[CH2:32][C:33]([OH:35])=[O:34])=[CH:22]1.C([BH3-])#N.[Na+]>CO.C1COCC1.C(OCC)(=O)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@@H:31]([NH:36][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:32][C:33]([OH:35])=[O:34])=[CH:22]1
Reactant: N[C@@H](CC(=O)O)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCN[C@@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1

Procedure:
Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamine (5.03 g, 19.0 mmol) and (R)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((R)-tryptophan methyl ester hydrochloride salt) (4.9 g, 19.42 mmol) in methanol (50 mL) and stir for 30 minutes. Add sodium cyanoborohydride in solution (15.0 mL, 1M in THF, 15.0 mmol) and stir under an inert atmosphere for 16.5 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 50% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.[C:14]([S-:16])#[N:15].[K+].BrBr.[CH3:20][OH:21]>>[CH3:20][O:21][C:9](=[O:13])[CH2:8][CH2:7][C:6]1[CH:5]=[C:4]([S:16][C:14]#[N:15])[C:3]([O:2][CH3:1])=[CH:12][C:11]=1[OH:10]
Reactant: CO
Reactant: COc1ccc2c(c1)OC(=O)CC2
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: COC(=O)CCc1cc(SC#N)c(OC)cc1O
Reaction time: 2 h

Procedure:
Compound 14A (3 g), KSCN (4.9 g) were dissolved in MeOH (125 mL) at 0° C., Br2 (3 g) was added, then stirred for 2 h. The reaction mixture was quenched with water (200 mL) and ethyl acetate (200 mL). The ethyl acetate was separated and washed with water, brine, dried (MgSO4), concentrated, to afford compound 14B (3.5 g). mp 105-016° C.; MS: 268 (M+1)+. Preparation of 6-Mercapto-7-methoxy-chroman-2-ol (Compound 14C)
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]([Sn]([Cl:20])(CCCC)CCCC)[CH2:8][CH2:9]C.[Cl-:21].[Cl-].[Cl-].[Cl-].[Zr+4:25]>C(Cl)Cl>[Cl-:20].[Cl-:21].[Cl-:20].[CH:3]1([Zr+3:25])[C:2]2[C:6](=[CH:7][CH:8]=[CH:9][CH:1]=2)[CH:5]=[CH:4]1
Reactant: CCCCCC
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: [Zr+3]C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
After adding litiumidenide (IndLi) powder (17.52 g, 0.144 mol) and hexane (300 ml) into a 500 mL flask under nitrogen atmosphere, tributyltin chloride (41 ml, 0.145 mol) was injected into the above mentioned flask with syringe slowly. The mixture is stirred at room temperature for 48 hours. Yellowish oil type product was obtained by a series of processes, such as separating the organic liquid by filtering reaction mixture and removing volatile from filtrate. Then the obtained yellowish oil type product was diluted with methylenedichloride (200 ml), and zirconium tetrachloride (ZrCl4, 33.03 g, 0.142 mol) was added. The mixture is stirred at room temperature for 48 hours. Indenylzirconium trichloride (IndZrCl3, 39.5 g, yield: 88%) was obtained by a series of processes, such as removing the volatile from reaction mixture, slurrifying by adding hexane (200 ml), filtering, collecting scarlet colored solid powder and drying.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18]1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:15]([NH:14][S:11]([C:18]2[O:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]=2)(=[O:13])=[O:12])=[O:16])[N:3]=1
Reactant: c1ccc2occc2c1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)c2cc3ccccc3o2)n1
Temperature: -10 °C

Procedure:
A suspension of 2.59 g of 2-amino-4,6-dimethylpyrimidine in 50 ml of nitromethane was cooled to -10° C. and treated with 2.0 ml of chlorosulfonyl isocyanate. After stirring for 0.5 hour at -10° C. a solution of 2.0 ml of benzofuran in 10 ml of nitromethane was added dropwise followed by 2.8 g of aluminum chloride. The mixture was stirred and heated at reflux until TLC monitoring indicated the disappearance of starting material. The mixture was cooled, poured into water, extracted with methylene chloride, the extract washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to a dark oil. Trituration with dichloromethane followed by washing with acetonitrile gave the desired product as a mixture of 2- and 3-positional isomers, m.p. 206°-218° C. dec. The product exhibited IR bands at 3300 (NH), 1710 (C=O, 1340 (SO2) and 1140 (SO2) cm-1 and NMR absorptions at δ 2.4 (s, pyrimidine methyls) and 6.3-8.0 (m, aromatic and pyrimidine H's).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 3-fluoro-benzenesulfonyl chloride (73 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-3-fluoro-benzenesulfonamide (141 mg, 94.6%) as a white solid. MS (ESI+APCI) M+1=479.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Cl)ccc1CBr

Procedure:
Bromination of 4-chloro-2-methoxytoluene by means of N-bromosuccinimide in boiling carbon tetrachloride in the presence of dibenzoyl peroxide produces 4-chloro-2-methoxybenzyl bromide as a colourless liquid which has a boiling point of 140°-145° C./13 mm Hg. Reaction of this compound with triethyl phosphite in boiling xylene turns it into diethyl 4-chloro-2-methoxybenzylphosphonate; this is a colourless, viscous liquid which has a boiling point of 132° C./0.1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23]>>[ClH:1].[CH3:28][O:27][C:25]1[CH:24]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc(OC)c1
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,5-dimethoxyaniline (44 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (29 mg, 38%). 1H NMR (DMSO-d6): 10.32 (s, 1H), 9.48-9.46 (m, 1H), 8.76-8.74 (m, 1H), 8.62-8.58 (m, 1H), 7.63-7.58 (m, 1H), 7.14 (s, 1H), 7.06 (s, 2H), 6.32 (s, 1H), 3.80 (s, 6H).
Reaction SMILES: C([O:3][C:4](=[O:28])/[CH:5]=[C:6](\[CH3:27])/[CH:7]=[CH:8]/[C:9](/[Br:26])=[C:10](\[C:12]1[CH:21]=[CH:20][C:19]2[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=2[CH:13]=1)/[CH3:11])C.[OH-].[Na+]>CCO.C1COCC1>[Br:26]/[C:9](=[C:10](/[C:12]1[CH:21]=[CH:20][C:19]2[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=2[CH:13]=1)\[CH3:11])/[CH:8]=[CH:7]/[C:6](/[CH3:27])=[CH:5]/[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C(Br)=C(/C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(/C=C/C(Br)=C(/C)c1ccc2c(c1)C(C)(C)CCC2(C)C)=C\C(=O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
472 mg of (2E,4E,6E)-6-bromo-3-methyl-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-octa-2,4,6-trienoic acid ethyl ester were dissolved in 10 ml of EtOH/THF=1:1 and treated with 2.65 ml of 2N aq. NaOH. The reaction mixture was stirred for 22 hours at ambient temperature in the dark. It was then poured onto crushed ice, extracted with AcOEt, washed with brine and H2O, and dried over Na2SO4. Evaporation of the solvent and twofold crystallization (hexane/AcOEt=8:2) yielded finally 168 mg of (2E,4E,6E)-6-bromo-3-methyl-7-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-octa-2,4,6-trienoic acid as yellow crystals of m.p. 189°-190° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: NCc1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1NCc1cccc(Br)c1
Yield: 81.6 %

Procedure:
2,4-Difluoronitrobenzene (2.9 g, 18.1 mmol), 3-Bromobenzylamine (2.6 g, 18.1 mmol) and N,N-diisopropylethylamine (2.4 g, 18.1 mmol) were stirred in acetonitrile (25 mL) at room temperature for 2 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated in vacuo to collect the title compound (4.8 g, 95% yield). 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.25 (dd, 1H), 7.32-7.21 (m, 4H), 6.41 (m, 2H), 4.50 (d, 2H).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][Cl:5].[CH2:6]([OH:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].B(F)(F)F>>[CH2:6]([O:18][CH2:1][CH2:2][CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:4]([Cl:5])/[CH:2]=[CH:1]\[OH:3]
Reactant: CCCCCCCCCCCCO
Reactant: ClCC1CO1
Agent: FB(F)F
Product: CCCCCCCCCCCCOCCCCCCCCCCCC
Product: O/C=C\CCl

Procedure:
185 g of glycerol epichlorhydrin are reacted with 1 mole, i.e., 186 g of dodecanol at 75°-80° C in the presence of 1.5 ml of an acetic acid complex containing 36% BF3. Dodecyl ether of polyepichlorohydrin having the following formula is obtained:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].[OH-:13].[Na+].O=[C:16]([CH3:20])[C:17]([O-:19])=[O:18].Cl>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([C:5]([OH:12])=[O:13])[CH:20]=[C:16]2[C:17]([OH:19])=[O:18]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: [OH-]
Reactant: CC(=O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1cc(C(=O)O)c2cc(F)ccc2n1
Temperature: 110 °C

Procedure:
To 5-fluoroindoline-2,3-dione (0.454 g, 2.75 mmol) was a 3M NaOH (5.46 mL, 16.52 mmol) solution added. The reaction mixture was heated until refluxing, and 2-oxopropanoate (0.364 g, 3.30 mmol) was added. After refluxing at 110° C. for 4 h, the mixture was cooled to room temperature. The pH was adjusted to 3-4 with 1M HCl, and the precipitate was filtered and washed with water to yield whitish crystals