Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(/C=C/c2nc3ccccc3s2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(C=Cc2nc3ccccc3s2)cc1
Yield: 9.3 %

Procedure:
A mixture of 2-(4-nitrophenylethenyl)benthiazole 11 (500 mg, 1.7 mmol) and tin (II) chloride dihydrate (1.18 g, 5.2 mmol) in anhydrous ethanol (20 ml) was refluxed under N2 for 4 hrs. Ethanol was removed by vacuum evaporation. The residue was dissolved into ethyl acetate (20 ml), washed with NaOH solution (1 N, 3×20 ml) and water (3×20 ml), and dried over MgSO4. Evaporation to dryness gave 40 mg (8.0%) of product 12.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[CH3:34][C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1>C(Cl)Cl>[CH3:15][C:14]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:22][C:42](=[O:43])[N:41]([C:37]2[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][CH:38]=2)[CH2:12][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(O)c2ccccc2)cc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccc(N2CCC(C)(c3ccccc3)OC2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxy-3-phenylbutyl 4-methylbenzenesulfonate (1 g, 3.12 mmol) and DBU (1.4 g, 9.26 mmol) in CH2Cl2 (15 mL) was added a solution of 3-methylphenyl isocyanate (623 mg, 4.68 mmol) in CH2Cl2 (5 mL) at 0° C. over 0.5 h. The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography and then by preparative HPLC to afford 6-methyl-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one. LC-MS Method 2, tR=2.706 min, m/z=282. 1H NMR (CDCl3) 1.75 (s, 3H), 2.30 (s, 3H), 2.35-2.50 (m, 2H), 3.30 (m, 1H), 3.50 (m, 1H), 6.95 (m, 2H), 7.05 (m, 1H), 7.20-7.30 (m, 1H), 7.35 (m, 1H), 7.42-7.50 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C(C)(C)C)=[C:5]([CH3:16])[C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].Cl.[OH-].[Na+].CCOC(C)=O>CCO>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:18])([F:19])[F:20])[C:5]=1[CH3:16]
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(N)ccc(C#N)c1C(F)(F)F
Temperature: 70 °C

Procedure:
The crude N-[4-cyano-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide from Example 191B was dissolved in EtOH (5 mL) and conc. HCl (5 mL). The resulting mixture was heated to 70° C. for 20 min. The cooled reaction's pH was adjusted to ca. 8 with 6 N NaOH. EtOAc (20 mL) was added and the isolated organic portion was dried (Na2SO4), filtered, and concentrated to afford the title compound: MS (ES) m/z 201 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:15][C:14](=[O:16])[O:13][C:11](=[O:12])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][C:11]([N:18]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:17])=[O:12])[CH2:15][C:14]([OH:13])=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNCCc1ccccc1
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)CC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCc1ccccc1)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,4-Dichlorophenyl)glutaric anhydride (3.4 g) in CH2Cl2 (50 mL) at 0° C. was treated sequentially with N-methylphenethylamine (2.4 mL), triethylamine (2.3 mL) and N,N-dimethylaminopyridine (162 mg). The mixture was stirred at 0° C. for two hours then allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was washed with 1N HCl (1×100 mL) and brine (1×100 mL). The organic layers were dried over MgSO4, filtered and concentrated to afford the title compound (4.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19]C(Cl)C(OC)=O)[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:26]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:26][CH2:19][C:14]1[CH:13]=[C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(Cl)Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cnc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1

Procedure:
A solution of 9.6 g (31.4 mmol) of 3-chloro-2-(4-chloro-3-methylphenyl)5-trifluoromethylpyridine (prepared as in Example 16) and 5.6 g (31.5 mmol) of N-bromosuccinimide in 150 ml of tetrachloromethane was irradiated with a 150 W high-pressure Hg lamp for one hour. For the workup, the precipitated succinimide was removed, and the filtrate was concentrated under reduced pressure. The residue was taken up in cyclohexane. The solids were removed and discarded, and the cyclohexane solution was concentrated again. The crude product was purified by chromatography on silica gel (mobile phase: n-pentane/methyl tert-butyl ether 20:1). Yield: 6.2 g (51%) of colorless crystals of melting point 71°-72° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[CH:4][CH:3]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)C>[OH:14][CH2:13][CH2:15][NH:16][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: NCCO
Solvent: CCO
Product: Nc1ccc(C(=O)NCCO)cc1

Procedure:
165.2 parts of ethyl p-aminobenzoate are dissolved in 150 parts of ethanolamine and ethanol is then distilled off at 160° C. The volatile constituents are subsequently stripped off in vacuo and the resulting residue is recrystallised from isopropanol. p-Aminobenzoic acid β-hydroxyethylamide of melting point 116° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Yield: 42.5 %

Procedure:
A N,N-dimethylformamide solution (2.2 mL) of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (280 mg, 0.99 mmol), and tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (300 mg, 1.08 mmol) is heated at 90° C. for 0.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with N,N-dimethylformamide and ether to give 222 mg (42%) of the title compound as a yellow solid. MS (ESI) m/z 527.529 (M+H)+1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:23]([C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)[CH3:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([O:23][CH3:24])[C:30]=4[O:31][CH3:32])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc(B(O)O)c1OC
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Product: COc1cccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1OC
Yield: 82 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.783 mmol) with (2,3-dimethoxylphenyl)boronic acid (0.427 g, 2.35 mmol) generally according to the procedure described for Intermediate 184 provided 0.283 g (82%) of (±)-[7-(2,3-dimethoxylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[C:16](Cl)=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CCN(CC)CC>C(Cl)Cl.[Cu]I>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[C:19]([C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cl)nc1Cl
Reactant: C#CCCCCCC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC#Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Yield: 78 %

Procedure:
A mixture of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-chloro-6-chloropyridine from Example 69a (400 mg, 1.02 mmol), 1-octyne (0.23 mL, 1.54 mmol), Pd(PPh)3Cl2 (36 mg), CuI (catalytic amount) and NEt3 (2.5 mL) in CH2Cl2 (8 mL) was heated at reflux for 16 h. Heating was continued until no starting material remained. The solvent was removed, and the residue was washed with 10% NaOH then extracted with CH2Cl2. The organic extract was dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; hexane:EtOAc, 3:1) to afford the title compound (335 mg, 72% yield): 1H NMR (CDCl3, 300 MHz) δ 0.91 (t, J=7.5 Hz, 3H), 1.23-1.40 (m, 4H), 1.48 (s, 9H), 1.56-1.69 (m, 2H), 1.81-2.06 (m, 5H), 2.46 (t, J=7.5 Hz, 2H), 3.27-3.47 (m, 2H), 3.98-4.21 (m, 4H), 7.29 (br, s, 1H), 7.98 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 421 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[NH:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[Br:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[N:12]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:11]=2)=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)nc2)c2c1-c1ccsc1C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
At 0° C., NaH (60 percent, 0.6 g, 12.0 mmol) was added to a THF solution (15 mL) containing 6-(6-Bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.1 g, 9.7 mmol). Then SEM-Cl (2.5 mL, 12 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% ETOAc in hexane) to give 6-(6-Bromo-pyridin-3-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.0 g, 6.7 mmol) as brown solid in 70% yield.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][CH:18]([C:29]([OH:31])=[O:30])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>>[C:29]([CH:18]([NH:17][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)([OH:31])=[O:30]
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1NC(Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with DL-tryptophan to provide the title compound in good yield.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][N:26]3[CH2:27][CH2:28][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:24][CH2:25]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN2CCN(CCCc3cc(-c4ccccc4)no3)CC2)cc1
Yield: 54.5 %

Procedure:
About 2 min after dissolving 3-(3-phenylisoxazol-5-yl)propanal (20 mg, 0.10 mmol) and 1-benylpiperazine (17.4, 0.10 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (64 mg, 0.30 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 4.1 hr and followed the same processes as in Example 1 to obtain 19.7 mg (54.5%) of the target compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13][CH2:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:21][C:20]2[C:15]([CH2:14][OH:13])=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ncccc1O
Reactant: BrCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: OCc1ncccc1OCCCCCc1ccccc1

Procedure:
1.9 g (6.01 mmol) of phenylpentyl bromide, 1.00 g (8.00 mmol) of 2-hydroxymethyl-3-pyridinol and 1.2 g (8.8 mmol) of potassium carbonate are heated at reflux overnight. The mixture is taken up in ethyl acetate, washed with water, 2N aqueous sodium hydroxide solution and water, dried and concentrated under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:10]=2[CH:11]=1.N1C=CN=C1.[Si:27](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.C(OCC)(=O)C>[Si:27]([O:1][CH2:2][C:3]1[NH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:10]=2[CH:11]=1)([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)c1cccc2[nH]c(CO)cc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cc2c(C(=O)OCc3ccccc3)cccc2[nH]1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a solution of benzyl 2-hydroxymethylindole-4-carboxylate (456 mg) and imidazole (364 mg) in N,N-dimethylformamide (10 ml) was added tert-butyldiphenylsilyl chloride (802 mg) and the solution was stirred at ambient temperature for 2 hours. The resulting mixture was diluted with ethyl acetate (30 ml) and washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified be silica gel column chromatography (eluent; n-hexane:ethyl acetate=15:1) to give benzyl 2-tert-butyldiphenylsilyloxymethylindole-4-carboxylate (810 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9]2)[N:5]=[C:4]([NH:17][CH3:18])[N:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[N:8]1([C:6]2[N:5]=[C:4]([NH:17][CH3:18])[N:3]=[CH:2][N:7]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CNc1nc(Cl)nc(N2CCc3ccccc32)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CNc1ncnc(N2CCc3ccccc32)n1
Temperature: 50 °C
Yield: 39.2 %

Procedure:
A mixture of 2-chloro-4-indolin-1-yl-6-methylamino-1,3,5-triazine (5.0 g, 19.1 mM), ammonium formate (6.02 g, 95.6 mM), 10% w/w palladium on charcoal (1.0 g) and methanol (100 ml) was heated at 50° C., under argon, for 6 hours. The mixture was cooled, basified, and filtered. The solid collected by filtration was heated at reflux with ethanol, and the mixture refiltered. The filtrates were combined and the solvent evaporated. The residual solid was washed with water and then purified by flash column chromatography (silica, Merck 9385), eluting with ethyl acetate/hexane (1:3). This gave a solid which was recrystallised from ethyl acetate. There was thus obtained 2-(indolin-1-yl)-4-methylamino-1,3,5-triazine (1.7 g, 39% yield); m.p. 185°-187° C.: micro analysis, found: C, 62.8; H, 6.1; N, 30.3%; C12H13N5. 1/4 H2O requires: C, 62.2; H, 5.8; N, 30.2 %.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]3[O:13][CH2:14][CH2:15][O:16][C:11]=3[C:10]=2[S:19]([NH2:22])(=[O:21])=[O:20])[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[NH:31][CH3:32].Cl>C(O)(C)C>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][C:12]4[O:13][CH2:14][CH2:15][O:16][C:11]=4[C:10]=3[S:19]([NH2:22])(=[O:21])=[O:20])[CH:5]=[CH:4][N:3]=2)=[CH:26][C:25]=1[NH:31][CH3:32]
Reactant: NS(=O)(=O)c1c(Nc2ccnc(Cl)n2)ccc2c1OCCO2
Reactant: CNc1cc(N)ccc1C
Agent: Cl
Solvent: CC(C)O
Product: CNc1cc(Nc2nccc(Nc3ccc4c(c3S(N)(=O)=O)OCCO4)n2)ccc1C

Procedure:
To a suspension of 2.9 g (7.2 mmol) 6-(2-chloro-pyrimidin-4-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-sulfonic acid amide and 2.0 g 4, N3-dimethyl-benzene-1,3-diamine (compound of Example 102f)) in 50 ml isopropanol is added 5 ml conc. HCl and the reaction mixture is heated to reflux for 2 hours. Then the reaction mixture is partitioned between 1 l ethyl acetate and 1 l water. The aqueous layer is adjusted to slightly basic pH by adding NaHCO3. The water layer is extracted a second time with 300 ml ethyl acetate, the combined organic phases are dried with Na2SO4 and evaporated. The crude product is purified by chromatography on silica gel eluting with ethyl acetate to give in the order of elution a mixture of the two starting materials and the title compound. The mixture of starting materials is again subjected to the reaction conditions and workup giving another 1.21 g (37% yield) of desired product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:12])=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[CH3:13][N:14]=[C:15]=[O:16]>C(Cl)Cl.C(N(CC)CC)C>[Cl:12][C:5]1[N:4]=[N:3][C:2]([NH:1][C:15]([NH:14][CH3:13])=[O:16])=[CH:7][C:6]=1[C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(N)nnc1Cl
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Nc1cc(C(C)(C)C)c(Cl)nn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 1.3 g of (0.007 mole) of 3-amino-6-chloro-5-(1,1-dimethylethyl)pyridazine in 65 ml of methylene chloride was added one drop of triethylamine and 0.8 g (0.014 mole, 2.0 equivalents) of methyl isocyanate. The mixture was stirred at room temperature for about 18 hours. Additional methyl isocyanate (0.8 g, 0.140 mole, 2.0 equivalents) was added and about 3 hours later, the solution was diluted to 400 ml using methylene chloride. The solution was washed with four 40-ml portions of 1.0N hydrochloric acid and 50 ml of water, and was then dried with magnesium sulfate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.O>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=C1CCOCC1
Reactant: C1COCCN1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(N2CCOCC2)CCOC1
Reaction time: 5 h

Procedure:
650 mg of tetrahydro-4H-pyran-4-one together with 950 mg of morpholine were dissolved in 10 ml of toluene and the mixture was heated under reflux in a light water separator for 5 hours. Subsequently, the mixture was concentrated under reduced pressure, and residue (1.3 g) was used further without further workup.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:14](I)[CH3:15]>C1COCC1>[CH2:14]([O:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[CH3:15]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
Sodium hydride (506 mg, 12.65 mmol) was added to a solution of 1,4-Dioxa-spiro[4.5]decan-8-ol (2 gm, 12.65 mmol) in dry THF (20 mL) at 0° C. After 15 minutes, ethyl iodide (2 gm, 12.65 mmol) was added and the mixture was allowed to stir at RT overnight. After removing the THF under reduced pressure, the mixture was poured into ice cold water and extracted into ethyl acetate. The crude product was purified by flash column chromatography (EtOAc:Hexane 5:95) to isolate the title compound (1.3 gm, 55%). 1H NMR (CDCl3, 500 MHz): δ 1.2 (t, 3H, J=7), 1.45-1.92 (m, 8H), 3.4 (m, 1H), 3.45 (m, 2H), 3.98 (m, 4H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[OH-].[Na+].Cl>CN(C=O)C.O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
To a mixture of hydroquinone(24 g, 0.22 mol) and ethyl bromoacetate(24 mL, 0.22 mol) in DMF(300 mL) was added 10 M aq. NaOH(22 mL, 0.22 mol). The mixture was stirred at 0° C. for 1 h, diluted with H2O, acidified with 6M aq. HCl and extracted with EtOAc. The EtOAc extract was dried(anhydrous MgSO4) and concentrated in vacuo. The residue was swished with Et2O to give ethyl 4-hydroxyphenoxy-acetate(5.8 g) as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14](O)=[O:15])[CH:9]=2)=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20].C(Cl)CCl.C1C=[N:30]C2N(O)N=NC=2C=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][NH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:30])=[O:15])[CH:9]=2)=[CH:5][C:4]=1[N+:19]([O-:21])=[O:20]
Reactant: CNc1ccc(Oc2ccnc(C(=O)O)c2)cc1[N+](=O)[O-]
Reactant: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNc1ccc(Oc2ccnc(C(N)=O)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-[4-(methylamino)-3-nitrophenoxy]pyridine carboxylic acid in tetrahydro-furan was added EDC (2 eq) and HOAT (1.5 eq) and ammonium chloride (2 eq). The resulting mixture was stirred at ambient temperature for 16 h. The mixture was concentrated and partitioned between ethylacetate and water. A solid crashes out in the aqueous layer which was filtered and was found to be the product on LC/MS. The organic layer was then dried with sodium sulfate and concentrated. Purification on silica gel gave 4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxamide.