Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH2:24])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.C(Cl)Cl>[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[S:33]([NH:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([O:7][CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:9]=3[N:17]=2)[CH:19]=1)(=[O:35])=[O:34]
Reactant: Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCOCC4)c3n2)c1)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of 5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine (Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) was slowly added 2-bromo-4-fluorobenzene-1-sulfonyl chloride (0.0510 g, 0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, the reaction mixture was diluted with DCM and quenched with 1N. aq HCl. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from EtOAc-Hexane to give 2-bromo-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.0400 g, 46%) as a purple solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.02-2.11 (2H, m), 2.24-2.28 (2H, m), 3.69-3.75 (2H, m), 4.11-4.16 (2H, m), 5.65-5.71 (1H, m), 7.08-7.13 (1H, m), 7.46-7.49 (1H, m), 8.14-8.18 (1H, m), 8.22 (1H, d, J=8.8 Hz), 8.38 (1H, d, J=8.8 Hz), 8.55 (1H, s), 8.62 (1H, s), 8.84 (1H, s), 9.16 (1H, s). m/z=562.0 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Si]([O:28][CH2:29][CH:30]1[CH2:34][C:33]([CH2:35]Br)=[CH:32][CH2:31]1)(C(C)(C)C)(C)C>>[OH:28][CH2:29][CH:30]1[CH2:34][C:33]([CH2:35][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:32][CH2:31]1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC=C(CBr)C1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2=CCC(CO)C2)c1
Yield: 33.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and (4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide were reacted by the same way with the example 6 to obtain the titled compound (73 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=3[C:6]=2[CH2:7][CH2:8][CH2:9]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.00 g (0.032 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 50 ml of pyridine and 6.75 g (0.048 mol) of benzoyl chloride were added dropwise thereto at 0°. After stirring at room temperature overnight the mixture was extracted with water and chloroform, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 1:1) and crystallization (chloroform-hexane) gave 4-benzoyl-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]-quinoline as white crystals of melting point 194°-196°.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C[O-].[Na+].[C@:9]12([C:22](OCC)=O)[CH2:14][C@H:13]1[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2>CC1CCCO1>[CH3:2][C:1]1[N:3]=[C:22]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)[O:5][N:4]=1
Reactant: CC(N)=NO
Reactant: CCOC(=O)[C@]12C[C@H]1CN(C(=O)OC(C)(C)C)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: Cc1noc([C@]23C[C@H]2CN(C(=O)OC(C)(C)C)C3)n1
Yield: 56.5 %

Procedure:
2-Methyl-tetrahydrofuran (40 mL), acetamide oxime (0.93 g, 0.0125 mol) and sodium methoxide (1.1 g, 0.020 mol) were added to (1R,5R)-3-tert-butyl 1-ethyl 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylate (142) (1.27 g, 0.0050 mol) and the mixture was heated to reflux for 3 hrs. Upon cooling the suspension was partitioned between ethyl acetate (100 mL) and water (25 mL). The organic layer was washed with water (25 mL), saturated sodium chloride (25 mL) and dried over Na2SO4. The mixture was concentrated and the residue was chromatographed over 25 g of silica gel with 15-25% ethyl acetate/hexanes, to obtain 0.75 g of clear colorless oil. MS (ESI) m/z 304 [M+K]+. 1H NMR (CDCl3) δ 1.16-1.17 (m, 1 H), 1.46 (s, 9 H), 1.60 (s, 1 H), 1.72-1.75 (m, 1 H), 2.36 (s, 3 H), 3.49-3.51 (m, 1 H), 3.65-3.79 (dd, 1 H), 3.91-4.00 (m, 2 H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](N)=[O:5].[OH2:14]>>[NH2:2][C@H:3]([C:4]([OH:14])=[O:5])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O
Reactant: NC(=O)C(N)Cc1ccccc1
Agent: Cl
Product: N[C@@H](Cc1ccccc1)C(=O)O
Yield: 50 %

Procedure:
The treatment of a solution at 5% of 2-amino-3-phenyl propionamide hydrochloride in water (pH included between 6.5 and 8.5) is effected by a suspension of cells of strain A4 at 20 to 40 g of dry matter per liter. One obtains quantitatively L-phenylalanine (50%) and the corresponding D-amide (50%). This D amide can either be hydrolized in D-phenylalanine by action of strain R 312 (CBS 717.73) or racemized and recycled in regard to preparation of L-phenyl-alanine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:71][CH3:72])[CH2:42][CH2:43][C@@H:44]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH2:63])(=[O:62])=[O:61])=[CH:56][C:55]=1[S:64]([C:67]([F:70])([F:69])[F:68])(=[O:66])=[O:65])[CH2:45][S:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH2:71][CH3:72])[CH2:42][CH2:43][C@@H:44]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH:63][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[OH:30])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)(=[O:61])=[O:62])=[CH:56][C:55]=1[S:64]([C:67]([F:68])([F:69])[F:70])(=[O:66])=[O:65])[CH2:45][S:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:34]([CH3:37])([CH3:35])[CH3:36])([CH3:33])[CH3:32]
Reactant: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Reactant: CCN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CCO[Si](C)(C)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
(R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 2.15 g, 5.10 mmol), (R)-4-(4-((2-(tert-butyldimethylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 65, 3.41 g, 5.10 mmol), DMAP (1.87 g, 15.29 mmol) and EDC (1.954 g, 10.19 mmol) were dissolved in DCM (17 ml). The reaction mixture was stirred at r.t. overnight, diluted with DCM (50 ml) and washed with NH4Cl solution (saturated, aq., 20 ml), saturated aq. NaHCO3 (20 ml) and brine (20 ml). The collected organic layer was dried over Na2SO4 and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 12 g silica gel, eluted with 0→20% MeOH in EtOAc) to provide the title compound (3.41 g, yield: 62%).
Reaction SMILES: C([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][O:17][CH2:18][O:19][CH3:20])(OCC1C=CC=CC=1)=O.[H][H]>CO.[C].[Pd]>[CH3:20][O:19][CH2:18][O:17][CH2:16][CH:12]1[CH2:13][CH2:14][CH2:15][NH:11]1
Reactant: [H][H]
Reactant: COCOCC1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCOCC1CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-carbobenzoxy-2-methoxymethoxymethylpyrrolidine (prepared in the above (2)) 3.9 g in methanol 80 ml is added palladium-carbon 1 g at argon atmosphere. Hydrogen gas is blown through the mixture and the mixture is stirred at room temperature for 3 hours. After reaction catalyst is removed by filtration and the filtrate is concentrated in vacuo to give 2-methoxymethoxymethylpyrrolidine 2.02 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[N:14]([CH2:29][CH2:30][CH3:31])[C:13]=2[CH:32]=1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[N:14]([CH2:29][CH2:30][CH3:31])[C:13]=2[CH:32]=1)[CH2:39][C:35]1[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=1
Reactant: CCCN(CCC)CCCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2n1CCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
The compound (8.8 mg) obtained in Example 48-6 was dissolved in methanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (2.6 mg) and sodium cyanoborohydride (2.5 mg). After the solution was adjusted to pH 4 with acetic acid, the whole was stirred at room temperature for 18 hours. After the solvent was distilled off, the resultant was neutralized with a saturated aqueous sodium hydrogen carbonate solution and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (9.3 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][C@@H:33]([C:35]([OH:37])=[O:36])[NH2:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([NH:31][CH2:32][C@@H:33]([C:35]([OH:37])=[O:36])[NH:34][CH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[N:9]=[CH:8][N:7]=[C:6]2[NH:5][C:4]1[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[C:3]=1[F:23])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: CC(C)(C)OC(=O)NC[C@H](N)C(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN[C@@H](CNC(=O)OC(C)(C)C)C(=O)O

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 3-[(tert-butoxycarbonyl)amino]-L-alanine (Tetrahedron Letters (1993), 34(20), 3201-4) using an analogous method to that described for the equivalent step in Example 1 to give 3-[(tert-butoxycarbonyl)amino]-N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.32 (s, 9H); 3.26 (m, 3H); 3.86 (d, 1H); 3.97 (m, 4H); 6.73 (s, 1H); 7.21 (s, 1H); 7.27 (t, 1H); 7.47 (t, 1H); 7.54 (t, 1H); 8.40 (s, 1H); 8.44 (s, 1H); 9.86 (s, 1H); Mass Spectrum: (M+H)+ 520.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccnc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ncccc1CBr
Reaction time: 16 h
Yield: 52.1 %

Procedure:
To a solution of 3-methylpicolinonitrile (1.0 g, 8.47 mmol) in CCl4 (43 ml) was added NBS (1.81 g, 10.16 mmol) and benzoyl peroxide (32 mg, 1.27 mmol) and the mixture stirred at relux for 16 hours. The reaction was concentrated in vacuo to afford a black oil. Purification via column chromatography on silica gel (EtOAc:hexane, 1:9, v/v) afforded 3-bromomethyl-pyridine-2-carbonitrile as a white solid (0.87 g, 48%). 1H NMR (CDCl3) δ 4.64 (s, 2H), 7.53 (dd, 1H, J=4.4, 4.0 Hz), 7.94 (dd, 1H, J=6.1, 1.8 Hz), 8.66 (dd, 1H, J=2.6, 1.8 Hz).
Reaction SMILES: [CH:1]1([N:4]([CH3:24])[C:5]2[N:9]=[C:8]([CH:10]=[CH:11][C:12]3[N:22]=[C:15]4[N:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[N:14]4[N:13]=3)[N:7]([CH3:23])[N:6]=2)[CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]1([N:4]([C:5]2[N:9]=[C:8]([CH2:10][CH2:11][C:12]3[N:22]=[C:15]4[N:16]=[C:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[N:14]4[N:13]=3)[N:7]([CH3:23])[N:6]=2)[CH3:24])[CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=Cc3nc(N(C)C4CC4)nn3C)nc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C)n2nc(CCc3nc(N(C)C4CC4)nn3C)nc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
N-cyclopropyl-5-(2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)vinyl)-N,1-dimethyl-1H-1,2,4-triazol-3-amine (10 mg, 30.8 μmol, Eq: 1.00) was stirred in Ethyl acetate (6 ml) using 5% Pd on Ba2SO4 (3 mg, 30.8 μmol, Eq: 1.00) as catalyst in a hydrogen atmosphere. The mixture was stirred at room temperature for 4 h. No reaction. Palladium on activated charcoal 10% (5 mg, 30.8 μmol, Eq: 1.00) was added an stirring was continued for 4 h. TLC showed new product but still starting material left. Palladium on activated charcoal 10% (4 mg, 30.8 μmol, Eq: 1.00) was added and stirring was continued for 4 h again. TLC showed nearly complete conversion. The crude material was applied on silica gel an purified by column chromatography using ethyl acetate/methanol (0-5% methanol) as eluent to give Cyclopropyl-{5-[2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-methyl-amine (8.4 mg, 83.5%) as off-white semisolid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1.O=S(Cl)[Cl:19]>ClCCCl>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-n2ccccc2=O)cc1
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(-n2ccccc2=O)cc1

Procedure:
4-(2-oxopyridin-1(2H)-yl)benzoic acid (1 g, 4.6 mmol) was ]mixed with 10 mL of 1,2-dichloroethane. To this suspension was added SOCl2 (6 mL), and the mixture was refluxed for 1.5 h. The mixture was reduced in vacuo. The remaining traces of SOCl2 were removed by adding 1,2-dichloroethane (2×5 mL) and evaporating to dryness to yield 4-(2-oxopyridin-1(2H)-yl)benzoyl chloride as a white solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Br:12][C:13]1[CH:14]=[N:15][C:16]2[C:17]3[N:25]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[C:24]([CH2:31][O:32][CH2:33][CH3:34])=[N:23][C:18]=3[CH:19]=[N:20][C:21]=2[CH:22]=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:36][C:19]1[C:18]2[N:23]=[C:24]([CH2:31][O:32][CH2:33][CH3:34])[N:25]([CH2:26][C:27]([CH3:28])([OH:29])[CH3:30])[C:17]=2[C:16]2[N:15]=[CH:14][C:13]([Br:12])=[CH:22][C:21]=2[N:20]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
mCPBA (35.5 g of 77% purity, 158 mmol) was added to a stirred solution of 1-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol (15 g, 0.040 mol) in chloroform (400 mL), and the reaction was stirred at room temperature for 2.5 hours. Concentrated ammonium hydroxide (200 mL) was added, and then p-toluenesulfonyl chloride (18.9 g, 98.9 mmol) was added over a period of five minutes. The reaction mixture was stirred at room temperature for 2.5 hours, and an analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material. Additional p-toluenesulfonyl chloride (11 g) was added, and the reaction mixture was stirred at room temperature for one hour. An analysis by LC/MS indicated the reaction was still incomplete. Additional ammonium hydroxide (100 mL) and p-toluenesulfonyl chloride (10 g) were added, and the mixture was stirred for 30 minutes at room temperature. The aqueous layer was separated and extracted with dichloromethane (2×300 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (41.4 g) was purified by automated flash chromatography (FLASH 65I cartridge, eluting with ethyl acetate:methanol in a gradient from 97:3 to 85:15) to provide 5.96 g of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[NH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][NH2:34])=[O:32])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([N:33]=[N:34][C:3]2[C:2]([CH3:1])=[C:8]([OH:9])[C:7]3[N:10]4[CH2:11][CH:12]5[NH:23][CH:13]5[C:14]4([O:21][CH3:22])[CH:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=3[C:4]=2[OH:5])=[O:32])=[CH:29][CH:28]=1
Reactant: NNC(=O)c1ccc(N)cc1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC12C(COC(N)=O)c3c(O)c(N=NC(=O)c4ccc(N)cc4)c(C)c(O)c3N1CC1NC12
Yield: 40.2 %

Procedure:
In a similar manner to that described in Example 17, mitomycin A (302 mg), 4-aminobenzoylhydrazine (389 mg) and potassium carbonate (150 mg) are used to obtain the desired product (163 mg) with a yield of 40.5%.
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.[CH3:10][O:11][CH:12]([O:20][CH3:21])[CH2:13][NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18].Cl[CH2:23][C:24]([CH2:26][F:27])=[CH2:25]>O>[F:27][CH2:26][C:24](=[CH2:23])[CH2:25][N:14]([CH2:13][CH:12]([O:11][CH3:10])[O:20][CH3:21])[C:15](=[O:19])[O:16][CH2:17][CH3:18]
Reactant: C=C(CF)CCl
Reactant: CCOC(=O)NCC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(CF)CN(CC(OC)OC)C(=O)OCC
Temperature: 90 °C
Reaction time: 1 h

Procedure:
8 g (0.26 mol) of sodium hydride (80% pure) are initially introduced into 200 ml of toluene and 35.8 g (0.2 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added dropwise at 90° C. The mixture is then stirred for one hour at 90° C. and 32.6 g (0.3 mol) of 1-chloro-2-fluoromethylprop-2-ene are then added dropwise. The mixture is stirred overnight at 90° C., salts are dissolved in water, and the aqueous phase is separated off and extracted with toluene. The organic phases are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1>CN(C=O)C>[CH3:1][NH:2][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1
Reactant: CN
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: CNc1ccc(C#N)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Methylamine was bubbled into a solution of 6-chloronicotinonitrile (2 g, 14.4 mmol) in DMF (150 mL) at room temperature for 4 min. The reaction mixture was then stirred at 50° C. for 1 hour. The DMF was removed under reduced pressure. The residue was taken up in water and extracted with diethyl ether. The organic layer was washed with water and dried over Na2SO4. The solvent was evaporated in vacuo to give the title compound as a white solid (1.9 g, 99%). 1H NMR (250 MHZ, CDCl3) δ(ppm):8.3 (d, 1H); 7.55 (dd, 1H); 6.35 (d, 1H); 5.4 (brd, 1H); 2.9 (d,3H).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[N:6]1[C:7]2[N:8]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:9]=[CH:10][C:11]=1O>ClCCCl.CN(C=O)C>[Br:3][C:11]1[CH:10]=[CH:9][N:8]2[C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=[C:7]2[N:6]=1
Reactant: Oc1ccn2c(n1)nc1ccccc12
Reactant: O=P(Br)(Br)Br
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Brc1ccn2c(n1)nc1ccccc12
Temperature: 100 °C
Yield: 100 %

Procedure:
Phosphorus oxybromide (25 g, 87 mmol) was added to a suspension of benzo[4,5]imidazo[1,2-a]pyrimidin-2-ol (5.2 g, 28.1 mmol) in DCE (Ratio: 1.000, Volume: 93 ml) and DMF (Ratio: 0.01, Volume: 0.927 ml). Heated the reaction mixture to 100° C. for 3 hours. Cooled the reaction to room temperature and concentrated. Diluted with ice water and quenched to pH ˜8 with concentrated ammonium hydroxide. The resulting residue was filtered and washed with water followed by ethyl ether. Dried under vacuum to afford crude 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (6.97 g, 28.1 mmol, 100% yield).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH:10]([OH:26])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][C:49](O)=[O:50]>ClCCl>[C:27]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]3[CH:12]([CH2:13][NH:14][CH:15]3[C:49](=[O:50])[CH2:48][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[O:41][CH3:40])[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH:10]([OH:26])[CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)C1NCC2C1C(c1ccccc1)(c1ccccc1)CC(O)C2(O)c1ccccc1OC
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
To a solution of 4.5 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol hydrochloride in 100 cm3 of dichloromethane, cooled to 0° C., are added 4.2 cm3 of triethylamine, followed by 2.4 g of (2-methoxyphenyl)acetic acid in 50 cm3 of dichloromethane. Stirring is carried out at room temperature for 90 minutes; the reaction mixture is washed with twice 10 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The crystallized solid is taken up with 100 cm3 of diisopropyl ether and then filtered, washed with 50 cm3 of saturated sodium bicarbonate solution and then with 50 cm3 of diisopropyl ether. 4.35 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-(2-methoxyphenyl)acetylperhydro-4,5-isoindolediol are obtained, in the form of a light beige solid melting at 278° C.