Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([CH3:10])[CH:4]=1.[Br:11][C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[CH3:10][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:17]([C:15]2[S:16][C:12]([Br:11])=[CH:13][CH:14]=2)(=[O:19])=[O:18])[CH:8]=[C:7]([CH3:9])[N:6]=1
Reactant: Cc1cc(CN)cc(C)n1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(CNS(=O)(=O)c2ccc(Br)s2)cc(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a stirred solution of commercially available 4-aminomethyl-2,6-dimethyl-pyridine [CAS-No. 324571-98-4] (0.24 g, 1.76 mmol) in THF (8 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (0.46 g, 1.76 mmol) dissolved in THF (8 ml) and triethylamine (0.27 ml, 1.94 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) and crystallization from dichloromethane/hexane to yield the title compound (0.33 g, 52%) as a light red solid. MS (ISN) 359.0 [(M−H)−], mp 138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH3-]C#N.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(-c2cccc(Cl)c2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2cccc(Cl)c2)n1

Procedure:
91.87 mg (46.19%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(3-chlorophenyl)-3-propyl-1H-pyrazol-5-yl)propanal (124.75 mg, 0.451 mmol), 1-(2-fluorophenyl)piperazine (92 mL, 0.586 mmol), and NaCNBH3 (85.02 mg, 1.353 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: Cc1cc(Cl)c(Cl)cc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)c(Cl)cc1C
Yield: 97 %

Procedure:
92.1 g (421 mmol) of the 3,4-dichloro-6-methylbenzoic acid obtained in the above step (2) was dissolved in 550 ml of ethanol as both an esterifying agent and a solvent, 20 ml of concentrated sulfuric acid as an acid catalyst was added, and the mixture was refluxed under heat for 7 hours. The ethanol was distilled off under reduced pressure, ice water was added, and the mixture was extracted with ethyl acetate twice. The resultant organic layer was consecutively washed with a sodium carbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 103.4 g (yield 97%) of ethyl 3,4-dichloro-6-methylbenzoate as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:9][C:10]1[CH:15]=[C:14]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[N:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cncc(Br)c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cncc(-c2cccc(F)c2)c1
Temperature: 180 °C
Yield: 83.1 %

Procedure:
To a microwave vial was added 3-amino-5-bromopyridine (LII) (0.400 g, 2.31 mmol), 3-fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 mL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180° C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes→7:3 EtOAc:hexanes) to afford the 5-(3-fluorophenyl)pyridin-3-amine (LIII) (0.360 g, 1.92 mmol, 83% yield) as a yellow-white solid. ESIMS found for C11H9FN2 m/z 189.1 (M+H).
Reaction SMILES: COC1C=CC=C[C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.C([BH3-])#N.[Na+].C[Si](Cl)(C)C>C(#N)C.ClCCl>[CH2:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:10]=1)[CH3:13]
Reactant: COc1ccccc1Oc1ccc(C(C)=O)cc1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCc1ccc(OCOc2ccccc2)cc1
Reaction time: 1 h
Yield: 157 %

Procedure:
960 mg of 1-[4-(2-methoxyphenoxy)phenyl]ethanone 69 are dissolved in 20 ml of acetonitrile and cooled in an ice bath, and 1.05 g of sodium cyanoborohydride and 2.01 ml of trimethylsilyl chloride are added. After 1 h, the mixture is diluted with dichloromethane and filtered through Celite, and the organic phase is extracted with sodium chloride solution, dried over sodium sulfate and concentrated. The residue is purified by chromatography (heptane:ethyl acetate 7:1). 710 mg of the desired product are obtained. C15H16O2 (228.29) MS (ESI): 246.20 (M+NH4+).
Reaction SMILES: [C:1]([C@H:3]([CH3:27])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[N:14]3[CH2:18][CH2:19][N:20](COCC)[C:13]3=[N:12][C:11]=2[N:10]([CH3:25])[C:9]1=[O:26])#[N:2].Cl>C(O)C>[C:1]([C@H:3]([CH3:27])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[N:14]3[CH2:18][CH2:19][NH:20][C:13]3=[N:12][C:11]=2[N:10]([CH3:25])[C:9]1=[O:26])#[N:2]
Reactant: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)C#N)c(=O)n1C
Agent: Cl
Solvent: CCO
Product: C[C@@H](C#N)CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A mixture of (R)-3-(5-cyanohexyl)-7,8-dihydro-8-ethoxymethyl-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione and concentrated hydrochloric acid (1.0 ml) and ethanol (5 ml) was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate-methanol (3:1) to provide (R)-3-(5-cyanohexyl)-7,8-dihydro-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (CT-30255) (61 mg, 50% yield) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[F:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[CH2:62][NH:61][CH2:60][CH2:59]2>ClCCl.O>[F:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[CH2:62][N:61]([C:19](=[O:20])[CH2:18][O:17][CH:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:23])([F:25])[F:24])[CH:6]=3)[CH2:16][CH2:15]1)[CH2:60][CH2:59]2
Reactant: Fc1ccc2c(c1)CCNC2
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCc2cc(F)ccc2C1
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
To a solution of 2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetic acid (144 mg, 0.40 mmol) in dichloromethane (15 ml) was added EDAC.HCl (114 mg, 0.59 mmol), HOBt (80 mg, 0.59 mmol) and triethylamine (120 mg, 1.19 mmol) with stirring for 30 minutes. Then 6-fluoro-1,2,3,4-tetrahydroisoquinoline (60 mg, 0.40 mmol) was added to the reaction mixture and the contents were stirred overnight at room temperature. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×80 ml). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to give a residue, which was purified by silica gel column chromatography using 5% ethyl acetate in dichloromethane to afford 1-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethan-1-one as a yellow solid (93.8 mg, 48%); (ES, m/z): [M+H]+ 496.00; 1H NMR (300 MHz, CDCl3): δ 8.01 (d, J=9.0 Hz, 1H), 7.09 (m, 1H), 6.95-6.82 (m, 3H), 6.65 (d, J=9.0 Hz, 1H), 4.69 (m, 2H), 4.28 (s, 2H), 3.84-3.70 (m, 2H), 3.48-3.33 (m, 2H), 2.93-2.83 (m, 2H), 2.16-2.13 (m, 4H), 1.52-1.40 (m, 2H), 1.34-1.16 (m, 2H).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C:33]1=[O:41].ClCCl>CO.O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:34][C:33]3=[O:41])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: O=C1Cc2ccccc2N1CCCCl
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCN3C(=O)Cc4ccccc43)c2CC1
Temperature: 25 °C

Procedure:
Add potassium hydroxide (899 mg, 16.64 mmol) in one portion to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.52 mmol) in methanol (10 mL). Heat the reaction to 50° C. under nitrogen for 24 h, then cool to room temperature and add 1-(3-chloro-propyl)-1,3-dihydro-indol-2-one (217 mg, 1.04 mmol). Stir the reaction at room temperature for 4 days. Remove solvents in vacuo, add dichloromethane (20 mL) and water (20 mL). Remove the organic layer and dry using an ISCO® phase separator then concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as orange powder. MS (ES+) m/z: 509 (M+Na)+.
Reaction SMILES: O[C@@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1.C(Br)(Br)(Br)[Br:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:23][C@H:2]1[CH2:21][N:5]2[C:6](=[O:20])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH2:8][C@@H:4]2[CH2:3]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@H](O)CN12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](Br)CN12
Yield: 84 %

Procedure:
To the solution of (6S,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 20, step a) (1.47 g, 4.36 mmol) and CBr4 (3.3 g, 8.72 mmol) in anhydrous THF (30 mL) was added PPh3 (2.3 g, 8.72 mmol) in THF (10 mL). Then the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate=10:1) to yield 1.50 g (84%) of the title compound as white solid. 1H NMR (300 MHz, CDCl3): δ 7.58 (d, 2H, J=9 Hz), 7.17 (d, 2H, J=9 Hz), 4.59-4.55 (m, 1H), 4.43-4.37 (m, 1H), 4.25-4.22 (m, 1H), 4.07 (t, 1H, J=9 Hz), 3.76 (dd, 1H, J1=3 Hz, J2=9 Hz), 3.62-3.56 (d, 1H, J=18 Hz), 2.43 (dd, 1H, J1=6 Hz J2=12 Hz), 1.99-1.92 (m, 1H). LC-MS: 365 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][CH:5]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:8]=2[NH:7][C:6]1=[O:19].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:40])=[CH:24][N:23]=1>>[CH3:1][O:2][C:3](=[O:20])[NH:4][CH:5]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[CH:14]=[CH:15][C:16]([NH:18][C:22]3[N:27]=[C:26]([NH:28][C:29]4[C:30]([C:31](=[O:32])[NH:33][CH3:34])=[CH:35][CH:36]=[CH:37][C:38]=4[F:39])[C:25]([Cl:40])=[CH:24][N:23]=3)=[CH:17][C:8]=2[NH:7][C:6]1=[O:19]
Reactant: COC(=O)NC1CC(C)(C)c2ccc(N)cc2NC1=O
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)OC)CC3(C)C)ncc1Cl

Procedure:
{8-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl}-carbamic acid methyl ester was prepared from (8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-carbamic acid methyl ester and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1d. Title compound was isolated as a pale yellow solid (30 mg, 19%) LCMS 558 (M+H), HNMR (DMSO) 9.51 (s, 1H), 9.39 (s, 1H), 9.34 (s, 1H), 8.51 (d, 1H), 8.19 (s, 1H), 7.49-7.46 (m, 2H), 7.39-7.25 (m, 3H), 7.15 (s, 1H), 7.09 (m, 1H), 3.93-3.90 (m, 1H), 3.50 (s, 3H), 2.74 (d, J=3.8 Hz, 3H), 2.09-2.06 (m, 1H), 1.95-1.89 (m, 1H), 1.32 (s, 3H), 1.22 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C(OC([N:21]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]2)[CH2:23][CH2:22]1)=O)(C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][CH:29]1[CH2:30][CH2:31][C:24]3([CH2:25][CH2:26][NH:21][CH2:22][CH2:23]3)[CH2:27][CH2:28]1)[CH:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Reactant: COc1ccc2cc(O)ccc2c1
Product: COc1ccc2cc(OC3CCC4(CCNCC4)CC3)ccc2c1

Procedure:
Was prepared according to method A from 6-methoxy-2-naphthol and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:6]([CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:25])[CH2:11][CH2:10]1)=[O:7].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:8][N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:25])[CH2:13][CH2:14]2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C(=O)CN2CCC(N3Cc4ccccc4NC3=O)CC2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)CN2CCC(N3Cc4ccccc4NC3=O)CC2)cc1OC
Temperature: 25 °C
Yield: 66.1 %

Procedure:
In this example 2.80 g of 1-(3,4-dimethoxybenzoylmethyl)-4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine and 150 ml of methanol are mixed and stirred at room temperature. Then, 460 mg of sodium borohydride is added to the stirred mixture over a period of 30 minutes. Thereafter, the mixture is stirred overnight at room temperature. The white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 2.02 g of a crude product. The crude product is crystallized from hot ethanol to obtain 1.86 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([Br:12])=[CH:4][CH:3]=1.[Br:13]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([Br:12])=[CH:4][C:3]=1[Br:13]
Reactant: COC(=O)c1nc(N)ccc1Br
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(N)c(Br)cc1Br
Reaction time: 16 h

Procedure:
A solution of methyl 6-amino-3-bromopyridine-2-carboxylate (20.62 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623–4633) in chloroform (570 ml) was treated dropwise over 2 hours with bromine (4.62 ml) in chloroform (115 ml) and stirred 16 hours. The solution was washed with excess aqueous sodium bicarbonate, dried and evaporated. Crystallisation from EtOAc/hexane gave a solid (13.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH:14]=O)[O:10][C:9]=2[C:8]([O:16][CH3:17])=[CH:7][CH:6]=1)=[O:4].C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1.Cl>C1(C)C=CC=CC=1>[CH3:17][O:16][C:8]1[C:9]2[O:10][C:11](/[CH:14]=[CH:19]\[C:20]([OH:22])=[O:21])=[CH:12][C:13]=2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: COC(=O)c1ccc(OC)c2oc(C=O)cc12
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC)c2oc(/C=C\C(=O)O)cc12
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To a well stirred solution of Methyl-2-formyl-7-methoxybenzo[b]furan-4-carboxylate (from step 7) (2.0 g, 8.53 mmol) in toluene (50.0 mL) was added malonic acid (1.33 g, 12.80 mmol) and Piperidine (0.5 ml). The reaction mixture was then refluxed for 3-4 hours. Reaction mixture was cooled to room temperature, acidified with 10% aqueous HCl solution and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×100 mL0 and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (1.8 g) as light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[N:6]1[C:15]2C(=[CH:11][CH:12]=[CH:13][CH:14]=2)N=C[CH:7]=1.[S:16]([O:21]C)([O:19][CH3:20])(=[O:18])=[O:17]>CCOCC>[CH3:20][O:19][S:16]([O-:21])(=[O:18])=[O:17].[CH3:1][N+:2]1[C:5]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=[CH:7][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: c1ccc2nccnc2c1
Reactant: CN(C)C=O
Solvent: CCOCC
Product: COS(=O)(=O)[O-]
Product: C[n+]1ccnc2ccccc21
Temperature: 25 °C
Yield: 68 %

Procedure:
To a one-neck, round bottom flask connected with a condensor was charged with dimethyl formamide solution (100 ml) of quinoxaline oligomers (50 mmol) and dimethyl sulfate (7.6 g, 60 mmol, 1.2 equivalence). The mixture was stirred at 90° to 110° C. for at least 10 hours. After being cooled to room temperature, it was added into an ether solution (600 ml) to complete the precipitation of the product. The precipitates were fiItered, washed with ether and dried in vacuum to give a brownish-red solid of methyl quinoxalinium methylsulfate oligomers in 68% yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[S:13](Cl)(=[O:16])(=[O:15])[NH2:14]>CN(C=O)C>[S:13](=[O:16])(=[O:15])([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[NH2:14]
Reactant: NS(=O)(=O)Cl
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)OCCc1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 57.1 %

Procedure:
A mixture of 2.95 g (0.015 mole) of 4-bromophenethyl alcohol in 10 ml DMF was added dropwise to a suspension of sodium hydride 0.90 g, 60% in oil; 0.065 mole) in 35 ml DMF at 0°-5° C. The suspension was stirred for 20 min under argon after which sulfamoyl chloride (2.09 g, 0.018 mole) was added portionwise at 0°-5° C. After stirring for 20 min, the resultant suspension was poured into ice and extracted twice with Et2O. The combined organic phases were washed with saturated brine, dried over potassium carbonate and concentrated in vacuo to a white solid which was recrystallized in EtOAc/hexane to give 2.40 g (59%) of the title compound as a white solid, mf 109°-110° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:35])[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(-c4ccccc4)cc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(-c4ccccc4)cc3)c2c1
Yield: 105.1 %

Procedure:
480 mg of 2-[4-(biphenyl-4-ylamino)-quinazolin-6-ylcarbamoyl]-ethyl-carbamic acid t-butylester (prepared in accordance with the procedure of Example 80) dissolved in 10 ml of methylene chloride was reacted with 10 ml of trifluoroacetic acid at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 50 ml of saturated aqueous sodium bicarbonate for 30 mins, filtered under a reduced pressure, and dried to obtain the title compound (400 mg, 99%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[CH2:13]([O:15][C:16](=[O:28])[CH2:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH3:14]>O.C(O)(=O)C>[CH2:13]([O:15][C:16](=[O:28])[C:17](=[N:1][NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[Cl:5])[C:18](=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)[CH3:14]
Reactant: O=N[O-]
Reactant: Nc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NNc1ccccc1Cl)C(=O)Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (3.4 g, 50.4 mmol) in water (15 ml) was added dropwise over an hour period to a cooled (0° C.), stirred solution of 2-chloroaniline (6.4 g, 50.4 mmol) in acetic acid (50 ml)/water (7 ml). Then a solution of 4-(4-chloro-phenyl)-3-oxo-butyric acid ethyl ester (10 g, 42 mmol) in acetic acid (30 ml) was added dropwise over a 30-minutes period to produce an orange slurry (20 ml of water added to aid stirring). After an additional hour, the mixture was filtered, solids washed with water and air-dried. Solids slurried in ethanol (75 ml) for 30 minutes, filtered, solids washed with methanol and dried in vacuo to afford the title compound (I-2b) as an orange solid, 11.0 g.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[I:7][C:8]1[N:9]=[N:10][C:11](I)=[CH:12][CH:13]=1.O>C1COCC1>[I:7][C:8]1[N:9]=[N:10][C:11]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:12][CH:13]=1
Reactant: Ic1ccc(I)nn1
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(I)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.50 mL (6.6 mmol) isopropanol are added to 289 mg (7.23 mmol) sodium hydride (60%) in 100 mL THF and the mixture is stirred for 30 min at rt. After that time, 2.0 g (6.0 mmol) 3,6-diiodo-pyridazine are added and the mixture is stirred for 14 h at rt and for 14 h at 50° C. After that time, the mixture is poured into water and extracted with EtOAc. The organic layer is washed with water (2×) and dried over sodium sulphate. The solvent is removed in vacuo and the residue is purified by column chromatography (silicia gel; heptane:EtOAc gradient 0 to 50%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.Br>>[N:9]1([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: COc1ccc(-n2cncn2)cc1
Agent: Br
Product: Oc1ccc(-n2cncn2)cc1
Yield: 74 %

Procedure:
A mixture of 8 parts of 1-(4-methoxyphenyl)-1H-1,2,4-triazole and 150 parts of a hydrobromic acid solution 48% is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is triturated in 2-propanone. The product is filtered off and crystallized from ethanol, yielding 5.5 parts (74%) of 4-(1H-1,2,4-triazol-1-yl)phenol; mp. 255.4° C.