Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:13])=[CH:4][CH:3]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+].CC#N>CCOC(C)=O.O.CN(C=O)C>[CH2:28]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:12]([O:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNc1ccc(Br)cc1)C(=O)OC1CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCN(Cc1ccccc1)c1ccc(Br)cc1)C(=O)OC1CCCC1
Temperature: 60 °C
Yield: 188.8 %

Procedure:
To a mixture of cyclopentyl(2S)-4-[(4-bromophenyl)amino]-2-[(tert-butoxycarbonyl)amino]butanoate (0.66 g, 1.495 mmol), benzyl bromide (1.023 g, 5.98 mmol) and K2CO3 (0.620 g, 4.49 mmol) was added MeCN (15 ml) and DMF (1 ml). The suspension was heated overnight at 60° C. The reaction was then poured onto a mixture of water and EtOAc, the layers separated and the aqueous layer extracted with EtOAc. The combined organics were washed with water and brine, then dried (MgSO4), filtered and evaporated in vacuo to give an oil (˜1.5 g) which was subjected to column chromatography eluting with 5 to 10% EtOAc in hexanes to give the product (550 mg, 1.1 mmol, 69% yield). LCMS purity 95%: m/z 532 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:15][CH:16]=2)[N:11]([CH3:26])[C:10]1=[O:27]>Br>[NH:19]([C:14]1[N:13]=[C:12]2[N:11]([CH3:26])[C:10](=[O:27])[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccccc1N1Cc2cnc(Nc3ccccc3)nc2N(C)C1=O
Agent: Br
Product: CN1C(=O)N(c2ccccc2O)Cc2cnc(Nc3ccccc3)nc21
Yield: 82.3 %

Procedure:
A solution of 50 mg (0.14 mmol) of 3-(2-methoxyphenyl)-7-anilino-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one in 15 ml of 48% aqueous hydrobromic acid was heated at reflux for 1 hour. The mixture was cooled and evaporated and the residue was triturated in hexane. The resultant solid was filtered off and dried to give 40 mg (82%) of 7-anilino-3,4-dihydro-3-(2-hydroxyphenyl)-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as an off-white solid of melting point 192° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.CCCCCC.CO>C(O)C.ClCCl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:1][CH2:2][C:3]2[NH:4][C:5](=[O:13])[C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=3[N:8]=2)=[CH:17][CH:18]=1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: Fc1ccc(CBr)cc1
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(CNCc2ccc(F)cc2)nc2c1COCC2
Yield: 83.8 %

Procedure:
A mixture of 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (150 mg, 0.83 mmol) and 1-(bromomethyl)-4-fluorobenzene (83 μL 0.66 mmol) was heated via microwave in ethanol (5 mL) at 120° C. for 5 minutes. The reaction mixture was concentrated in vacuo and the residue was purified via flash column chromatography (ethyl acetate:hexane, 20:80 to 100:0 and then methanol: dichloromethane, 1:99 to 30:70) to provide the title compound (160 mg, 67% yield). MS m/z 290.2 (M+1), retention time=1.04 min
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].CN(C1C=CC=CN=1)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>Cl>[C:21]([O:5][C:4]1[C:6]([O:7][CH3:8])=[CH:9][CH:10]=[CH:11][C:3]=1[CH:2]=[O:1])(=[O:23])[CH3:22]
Reactant: COc1cccc(C=O)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Agent: Cl
Product: COc1cccc(C=O)c1OC(C)=O
Reaction time: 8 h

Procedure:
To a solution of o-vanillin (10.1 g) and a catalytic quantity (0.8 g) of dimethylaminopyridine in N-diisopropylethyl amine (23 mL) at 0° C. was added acetic anhydride (8 mL). The solution was stirred overnight, poured into 2N hydrochloric acid (100 mL), extracted with dichloromethane and the solvent removed in vacuo to afford a yellow solid. Recrystallization from ethanol yielded yellow crystals (10.9 g, 85%): m.p. 75.4-76.2° C., lit17 m.p. 76° C.; EIMS m/z 194 (M+), 152, 106, 43.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][C:5]1=[O:11])[CH2:2][CH3:3].C([O-])(=O)C.[NH4+:16]>>[NH2:16][C:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:11])[CH:6]=1
Reactant: CCCC1CCC(=O)CC1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CCCC1CCC(N)=CC1=O

Procedure:
In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 4-propylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=1.Cl[CH2:13][C:14]([OH:16])=[O:15]>CN(C)C=O>[CH3:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][O:11][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(O)CCl
Reactant: Cc1ccc(CCO)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCOCC(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.3 %

Procedure:
Sodium hydride (0.622 g) was suspended in dry dimethylformamide (5 ml) and treated dropwise with a solution of 2-(5-methyl-2-thienyl)ethanol (1.0 g) in dry dimethylformamide (5 ml). The mixture was stirred at room temperature under nitrogen for 2 hours then a solution of chloroacetic acid (0.664 g) in dry dimethylformamide (5 ml) added. The mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue quenched with water and extracted with ethyl acetate. The aqueous layer was adjusted to pH 2 using dilute hydrochloric acid and then extracted with ethyl acetate. This extract was washed with water, brine then dried (MgSO4). The solvent was removed in vacuo to give a brown oil (1.51 g) which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1.N1C=CN=C1.[C:28]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C.C(OCC)C>[Si:32]([O:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C@H:4]1[CH2:17][C:18]1[N:19]=[CH:20][S:21][CH:22]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO)OC1(C)C
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reaction time: 2 h

Procedure:
(4S,5S)-Tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (0.096 g, 0.29 mmol) was dissolved in DMF (1 mL) with 1H-imidazole (0.026 g, 0.38 mmol) and tert-butylchlorodimethylsilane (0.053 g, 0.35 mmol). The reaction was stirred 2 hrs, diluted with diethyl ether and washed twice with water and once with brine. The organic layer was dried over magnesium sulfate and concentrated to furnish the title compound, which was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH2:24][OH:25])[CH2:19]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.[ClH:36]>C(Cl)Cl.CO>[ClH:36].[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:21]2[CH2:22][CH2:23][N:18]([C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][N:10]=3)[CH2:19][C@@H:20]2[CH2:24][OH:25])=[O:35])=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: OC[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2nnc(-c3ccc(F)cc3)c3ccccc23)C[C@@H]1CO
Yield: 97.7 %

Procedure:
Treat a solution of (R)-(4-(4-(4-fluorophenyl)phthalazin-1-yl)piperazin-2-yl)-methanol (0.15 g, 0.44 mmol) in CH2Cl2 (3 ml) with 1-fluoro-4-isocyanatobenzene (0.04 g, 0.31 mmol). Stir the reaction at ambient temperature for 30 min and then concentrate the reaction mixture. Purify the resulting residue by flash silica gel chromatography (0-50% EtOAc in hexanes, then switch to 3% MeOH in CH2Cl2) to yield a solid. Dissolve the solid in MeOH (1 mL) and treat with 1 N aqueous HCl (0.13 mL, 0.13 mmol). Concentrate the solution to obtain the title compound as a solid (0.065 g, 29%). ES/MS m/z 476.0 (M+1).
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C@@:13]1([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([OH:23])=[C:15]([C:24]2[NH:29][C:28]3[CH:30]=[CH:31][C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:27]=3[S:26](=[O:40])(=[O:39])[N:25]=2)[C:14]1=[O:41])=[O:12])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>CO>[OH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@:13]([C:11]([N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[CH2:5][OH:4])=[O:12])([CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[C:14](=[O:41])[C:15]=1[C:24]1[NH:29][C:28]2[CH:30]=[CH:31][C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:27]=2[S:26](=[O:40])(=[O:39])[N:25]=1
Reactant: CC(=O)OC[C@H]1CCCN1C(=O)[C@]1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)CC[C@@]1(C(=O)N2CCC[C@@H]2CO)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 171G (0.15 g, 0.22 mmol) in methanol (2 mL) was added K2CO3 (68 mg, 0.5 mmol). The resulting mixture was stirred at r.t. for 3 hrs, and then poured into N HCl (10 mL), extracted with ethyl acetate (3× 10 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using 5% methanol in chloroform, and the title compound was obtained as a lt. yellow solid (0.134 g, 97%). 1H NMR (300 MHz, DMSO-d6): δ 0.45 (m, 1H), 0.63 (d, J=6.62 Hz, 3H), 0.69 (d, J=6.62 Hz, 3H), 0.94 (m, 1H), 1.27 (m, 1H), 1.61 (m, 3H), 1.99 (m, 1H), 2.23 (m, 2H), 2.89 (m, 1H), 3.03 (s, 3H), 3.20 (m, 1H), 3.65 (dd, J=9.93, 3.68 Hz, 1H), 3.98 (m, 1H), 7.13 (m, 1H), 7.52 (m, 5H), 8.11 (m, 1H), 10.07 (br s, 1H), 14.18 (br s, 1H); MS (ESI) m/z=631 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]([CH3:20])[C:16]([CH3:19])=[CH:17][N:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:20][N:15]1[C:16]([CH3:19])=[CH:17][N:18]=[C:14]1[N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cnc(N2CCN(c3ccc(N)cc3)CC2)n1C
Product: Cc1cnc(N2CCN(c3ccc(NS(C)(=O)=O)cc3)CC2)n1C

Procedure:
Treatment of 1-(4-aminophenyl)-4-(1,5-dimethylimidazol-2-yl)piperazine with methanesulphonylchloride followed by chromatography as described in Example 5(v) gave the title compound, m.p. 257° C. (decomp). Found: C,55.00; H,6.70; N,19.55. C16H23N5O2S requires: C,54.99; H,6.63; N,20.04%.
Reaction SMILES: C(S[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[N:8]=1)C.[CH3:16][NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1>C1COCC1>[CH3:16][N:17]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[N:8]=1
Reactant: CNC1CCN(C)CC1
Reactant: CCSc1nc2cc([N+](=O)[O-])ccc2o1
Solvent: C1CCOC1
Product: CN1CCC(N(C)c2nc3cc([N+](=O)[O-])ccc3o2)CC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
Dissolve 2-ethylsulfanyl-5-nitro-benzooxazole (1.17 g, 5.23 mmol) in anhydrous THF (10 mL) in a reaction tube and blow nitrogen into the vessel for 10 s. Add methyl-(1-methyl-piperidin-4-yl)-amine (1.37 mL, 9.42 mmol) to the solution. Quickly seal the vessel and immerse into a pre-heated oil bath (100° C.) and stir for 24 h. Concentrate the reaction mixture in vacuo, wash with 1.0M NaOH (aq) (2×50 mL), dry over Na2SO4, filter, and concentrate in vacuo. Subject the residue by silica gel flash column chromatography, eluting with 2N NH3 in MeOH/CH2Cl2, to yield the desired product (0.608 g, 40%). MS (ES+) 291.0 (M+1)+.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:31]([CH3:33])[CH3:32])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Br:30])[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>ClCCl.O>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Br:30])[N:8]2[CH2:2][CH2:3][N:4]([CH:31]([CH3:32])[CH3:33])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 41.9 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylicacid(2-hydroxyethyl)-isopropylamide (379) (1.0 g, 1.873 mmol) and triphenyl phosphine (1.717 g, 6.554 mmol) in dichloromethane (120 mL), diisopropyl azodicarboxylate (1.114, 5.618 mmol) was added over 10 h (dilution 0.19 M; rate 3 ml/h) at 0° C. The reaction was monitored by silica thin layer chromatography (3% methanol in dichloromethane; Rf=0.4). After completion of the reaction, 50 mL water were added and the mixture was extracted with dichloromethane (2×100 mL). The organic part was dried over sodium sulphate and concentrated. The resulting crude product was column purified (using amine bound silica) to get 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (0.406 g, 41.95%) as a white solid.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][N:22]=[CH:21][C:20]=4Br)=[N:13][C:12]=3[C:11]([O:27][CH3:28])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.COCCNC1C=C(C=CN=1)C(NC1SC2C(N3CCOCC3)=CC=C(OC)C=2N=1)=O>>[O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][N:22]=[C:21]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)[CH:20]=4)=[N:13][C:12]=3[C:11]([O:27][CH3:28])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccncc3Br)nc12
Reactant: C1CCNC1
Agent: COCCNc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccnc(N4CCCC4)c3)nc12

Procedure:
N-(7-[1,4]Dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-bromo-isonicotinamide and pyrrolidine were reacted as described for 2-(2-methoxy-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in WO03/043636. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown solid. MS: m/e=455(M+H+).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][C:6]1[CH:11]=[C:10](Br)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1>C1COCC1.O>[Br:5][C:6]1[CH:11]=[C:10]([NH:4][CH:1]([CH3:3])[CH3:2])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Br
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Nc1cc(Br)ncc1[N+](=O)[O-]
Reaction time: 5.5 h

Procedure:
A solution of isopropylamine (17 ml, 34.0 mmol) in THF (14 ml) was added dropwise over 1 h to a mixture of 2,4-dibromo-5-nitropyridine (4.94 g, 17.0 mmol) in THF (85 ml) at room temperature. After 5.5 h, the reaction mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and evaporated to give the crude title compound as a yellow solid. (UPLC-MS 6) tR 1.03; ESI-MS 260.0/262.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:13]([CH:14]=[CH:15][CH:16]=1)=[C:12]1[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]1)=[N:6][C:5]=2[CH3:17].[BH4-].[Na+].FC(F)(F)C(O)=O.C1C=CC2C3C=CC=CC=3NCC=2C=1.C(N(CC)CC)C.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1>O1CCCC1.ClCCl>[CH:16]1[CH:15]=[CH:14][C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][CH2:5][C:4]=2[CH:3]=1.[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[CH:5]([CH3:17])[N:6]([S:56]([C:53]1[CH:52]=[CH:51][C:50]([O:49][CH3:48])=[CH:55][CH:54]=1)(=[O:58])=[O:57])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=12
Reactant: COc1cccc2c1c(C)nc1ccccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2c(c1)CNc1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3cccc(OC)c3C2C)cc1

Procedure:
The intermediate dihydrophenanthridine was prepared from 7-methoxy-6-methylphenanthridine, (Example 36, Step b, 0.61 g, 2.7 mmol), by treatement with sodium borohydride (0.62 g, 16 mmol) and trifluoroacetic acid (0.84 mL, 10.8 mmol) in tetrahydrofuran (12 mL). In a separate, second step, the dihydrophenanthridine was treated with triethylamine (0.77 mL, 5.5 mmol) and 4-methoxybenzenesulfonyl chloride (0.57 g, 2.8 mmol, 2 equivalents) in dichloromethane (3 mL) according to the procedure and in the same manner as described in Example 32, Method A, Step d. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient), to yield 7-methoxy-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine as a white solid (0.17 g, 33% from the dihydrophenanthridine);
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([Cl:19])[CH:13]=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:19])[C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1c(Cl)cccc1CBr

Procedure:
N-Bromosuccinimide (4.67 g, 26.23 mmol) was added to a stirred solution of 6-methyl-2-chloro-1-nitrobenzene (4.5 g, 26.23 mmol) in distilled carbon-tetrachloride. Benzoyl peroxide (0.01 g) was added to the reaction mixture and the mixture was refluxed for 8 h. The solid separated was filtered. The filtrate was concentrated to get the crude product, which was purified by using column chromatography (silica gel, pet.ether 60-80° C.) to obtain the title compound. Yield: 2.69 g, (41%); MS: m/e (Cl) 253 (M+1).
Reaction SMILES: O[C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.S(Cl)([Cl:21])=O>>[Cl:21][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cc([N+](=O)[O-])cnc1Cl
Temperature: 80 °C
Yield: 68 %

Procedure:
2-Hydroxy-5-nitro-nicotinic acid (2.7 mmol) in a mixture of N,N-dimethylformamide (2.7 mmol) and thionyl chloride (5 ml) was heated at 80° C. for 1 h. The mixture was allowed to cool and concentrated in vacuo. To the resulting residue was added ice-water (20 ml) and with vigorous stirring a precipitate formed. The precipitate was filtered off and dried in a vacuum oven to give a white solid (68%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH3:5])[CH:7]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNCCC(O)c1ccccc1
Agent: Cl
Product: CNCCC(Oc1cccc(C)c1)c1ccccc1

Procedure:
Under stirring, while maintaining the temperature between about 15° and about 25° C. with an ice-water bath, 8.55 g of 36% aqueous hydrogen chloride are dropped on the filtered organic phase, resulting in the crystallization and suspension of the 3-ATM Hydrochloride (mw 291.82). The suspension is stirred at about 20° C. for 1 hour, the solid is collected by filtration, washed twice with 35 ml of n-butyl acetate, and dried for 18 hours under vacuum at about 50° to about 60° C., yielding about 19.6 g of product, having a melting point of about 159° to about 160° C., and 1H-NMR data of 9.58 ppm, bs, 2H, 7.35-7.20 ppm, m, 5H, 7.01 ppm, t, 1H; 6.68-6.65 ppm, m, 2H, 6.59 ppm, dd, 1H, 5.30 ppm, dd, 1H; 3.10 ppm, quint, 2H; 2.57 ppm, t, 3H, 2.41 ppm, m, 2H, 2.22 ppm, s, 3H. The yield is 28 percent by weight based on the starting N-methyl-3-hydroxy-3-phenylpropylamine. The 3-ATM HCl is determined to be a mixture of enantiomers, with relative ratio: 99/1 by chiral HPLC.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12][CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: c1ccccc1
Product: CCOC(=O)C1=CC=CC=CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
Ethyl diazoacetate (43.4 g, 0.38 mol) was added slowly (syringe pump) over a period of 7 hours to a mixture of benzene (594.32 g, 7.61 mol) and tetrakis(perfluorobenzoato) dirhodium(II) (0.84 g, 00.16 mol). After stirring at room temperature for 16 hours, the solvent was removed and the oily residue distilled in vacuo to give 50.44 g (81%) of ethyl 1,3,5-cycloheptatriene-1-carboxylate: bp 90°-96° C. 2 4-3.0 mm Hg); 1H NMR (CDCl3) δ6.6 (m, 2H), 6.2 (m, 2H), 5.3 (m, 2H), 4.2 (q, 2H OCH2CH3), 2.5 (t, 1H), 1.3 (t, 3H CH2CH3)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:15].CCN(CC)CC>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[Cl:15]
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Clc1ncnc2ccc(Br)cc12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Next, to a dioxane solution containing 6-bromo-3H-quinazolin-4-one (B, 15.0 g, 66.7 mmol, 1.0 equiv) is added POCl3 (20.0 mL, d=1.67, 33.4 g, 219 mmol, 3.3 equiv). Et3N (30.0 mL, d=0.726, 21.8 g, 215 mmol) is then added dropwise to the solution. The reaction mixture is heated at reflux for 12 h. The solution is cooled to room temperature and poured into an ice-water mixture. Then, the resultant precipitate is collected by filtration, washed with H2O (100 mL), and dried under vacuum to provide the desired 6-bromo-4-chloro-quinazoline (C, 15.4 g, 63.2 mmol) in 95% yield: ESI-MS m/z 243.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[C:3]=1[CH2:10][OH:11].N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[Si:21]([O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:10][OH:11])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Cl)c1CO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Cl)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of 3-chloro-1,2-benzenedimethanol (described in J. Chem. Soc., p. 5050 (1952); 3.02 g, 17.5 mmol) in tetrahydrofuran (40 ml) was cooled to 0° C., and then imidazole (1.19 g, 17.5 mmol) and tert-butylchlorodimethylsilane (2.64 g, 17.5 mmol) were added thereto. The mixture was stirred at room temperature for 1 hour, then water was added thereto, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to give a residue. The residue was subjected to chromatography on a silica gel (100 g) column (eluent; ethyl acetate:hexane=1:5) to afford the title compound (3.69 g, 73% yield) as a colorless oil.