Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([C:10]([OH:12])=O)=[N:8][S:9][C:5]=2[CH:4]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=2[C:30]([F:33])([F:32])[F:31])[CH2:18][CH2:17]1.CCN(CC)CC.CCCP(=O)=O>CN(C=O)C>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:29]=[CH:28][C:26]([NH:27][C:10]([C:7]3[C:6]4[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[S:9][N:8]=3)=[O:12])=[CH:25][C:24]=2[C:30]([F:33])([F:31])[F:32])[CH2:18][CH2:17]1
Reactant: COc1ccc2c(C(=O)O)nsc2c1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(C(=O)Nc3ccc(CN4CCN(C)CC4)c(C(F)(F)F)c3)nsc2c1

Procedure:
Prepared analogousely to step 6.1 from 2.0 g (9.57 mMol) 6-methoxy-benzo[d]isothiazole-3-carboxylic acid, 3.9 g (14.3 mMol) 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-aniline, 13.3 ml (95.7 mMol) Et3N and 11.17 ml (50% in DMF; 19.1 mMol) propylphosphonic anhydride in 100 ml of dry DMF: m.p.: 156° C.; MS: [M+1]+=465.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@H:26]2[OH:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:36](Cl)(Cl)=[O:37]>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]2[C@H:25]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:27][CH:26]3[O:34][C:36]2=[O:37])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)OC3Cc4ccccc4[C@@H]32)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 5, using the following starting materials: {2′-[((1S,2R)-2-hydroxy-indan-1-ylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and phosgene (1.9M in toluene).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[CH:7][CH:6]=[CH:5]2.P(Cl)(Cl)([Cl:18])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:18][C:7]1[CH:6]=[CH:5][C:4]2[C:3]([NH2:13])=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1c(Cl)ccc2c1ccc[n+]2[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)ccc2nc(Cl)ccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6-Chloro-5-nitroquinoline 1-oxide (4 g) was added to phosphorus oxychloride (15 mL) at 0° C. The solution was allowed to warm to room temperature and stirred for 12 hours. The excess phosphorus oxychloride was evaporated in vacuo and the residue dissolved in water (100 mL)/dichloromethane (100 mL). The layers were separated and the aqueous layer extracted with dichloromethane (2×50 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. The residue was dissolved in ethanol/water (1:1, 80 mL), ammonium chloride (2.8 g) and iron (2.8 g) added. The mixture was stirred at 65° C. for 4 hours, cooled to room temperature and filtered. The resulting solid was suspended in dimethylsulfoxide (50 mL), methanol (50 mL) and aqueous hydrochloric acid added (2M, 100 mL). The resulting solid was removed by filtration and then treated with ether (50 mL) and isohexane (50 mL). Evaporation of the mixture afforded the sub-title compound as a solid (1 g).
Reaction SMILES: [CH2:1]([C:4]1([O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:24](O)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:5])[CH:2]=[CH2:3].S(Cl)([Cl:40])(=O)=O.ClCCl>N1C=CC=CC=1>[CH2:1]([C:4]1([O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:24]([Cl:40])[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:5])[CH:2]=[CH2:3]
Reactant: C=CCC1(O)O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC1(O)O[C@H](COCc2ccccc2)[C@H](Cl)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 15 h

Procedure:
Allyl-2,3,6-tri-O-benzyl-glucopyranose (as per Example 14) (960 mg) was dissolved in dry pyridine and added 65 μL of sulfuryl chloride at 0° C. dropwise. The reaction mixture was stirred at this temperature for 15 hours. Dichloromethane (150 mL) was added and the resulting solution was washed with sodium bicarbonate (2×150 mL) and water (2×150 mL). Solvent removal left the residue which was purified by chromatography on silica gel using hexane-ethyl acetate (5:1) as eluent to provide compound allyl 4-chloro-4-deoxy-2,3,6-tri-O-benzyl-galactopyranose (550 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])#[N:2].[OH-:21].[Na+].OO>C(O)C>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[NH:2][C:1](=[O:21])[C:3]2[C:4](=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:10]=1
Reactant: COc1ccccc1C(=O)Nc1cc(C)ccc1C#N
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1nc2cc(C)ccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 56 %

Procedure:
To a mechanically stirred suspension of N-(2-cyano-5-methylphenyl)-2-methoxybenzamide (180 g, 0.67 mol) in 1.8 L ethanol under an N2 atmosphere was added 6 N sodium hydroxide solution (310 g in 1.25 L water). To the above mixture, 30% hydrogen peroxide (350 mL, 3.64 mol) was slowly added. The solution was then slowly heated to 80° C. and maintained at this temperature for 4 h. The reaction mixture was concentrated under reduced pressure to remove ethanol, giving a suspension, which was quenched with ice-cold water (1.8 L) and acidified with acetic acid to pH 5-6 to give a solid residue. The solid was filtered and washed with water, then dissolved in 5.5 L CH2Cl2 and washed with water (2×18 L). The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure to give a light yellow solid (100 g, 54%). mp 165-170° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=2[O:4][CH2:3]1.[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH:15]1([NH:1][C@@H:2]2[CH2:7][C:6]3[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=3[O:4][CH2:3]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCC1
Reactant: COc1ccc(F)c2c1C[C@@H](N)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(F)c2c1C[C@@H](NC1CCCC1)CO2
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of (R)-3-amino-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (0.7 g, 3.4 mmol), cyclopentanone (0.7 g, 8.3 mmol) and HOAc (0.2 g, 3.5 mmol) in methanol (25 mL), NaCNBH3 (0.7 g, 10 mmol) was added in portions at room temperature. The solution was stirred at room temperature over night. The methanol was evaporated. The residue was dissolved in EtOAc and washed with water. The organic layer was dried with Na2SO4 and the solvent was evaporated to give 0.9 g (100% yield) of the title compound as a colourless oil. GC indicated 99.6 purity. GC/MS (70 eV) M=265 (30%).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][C:7]=1[OH:14].O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(O)(=O)C>ClCCl>[F:13][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([NH:5][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[C:7]([OH:14])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cc(N)c(O)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(O)cc1F
Temperature: 100 °C
Yield: 106.9 %

Procedure:
Polymer supported sodium cyanoborohydride (794 mg, 3.41 mmol) was added to a solution of commercially available 2-amino-5-fluoro-4-methylphenol (241 mg, 1.71 mmol), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (350 mg, 1.76 mmol) and acetic acid (0.489 mL, 8.53 mmol) in dichloromethane (10 mL). The mixture was heated by microwave at 100° C. for 30 min before being filtered and concentrated by rotary evaporation to give a green oil. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 1,1-dimethylethyl 4-[(4-fluoro-2-hydroxy-5-methylphenyl)amino]-1-piperidinecarboxylate (593 mg, 73% purity, 78% yield) as a brown oil.
Reaction SMILES: CSC.B.[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][C:15](O)=[O:16])[CH:10]=[C:11]([CH3:13])[CH:12]=1>C1COCC1>[Br:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:14][CH2:15][OH:16])[CH:10]=[C:11]([CH3:13])[CH:12]=1
Reactant: Cc1cc(CBr)cc(CC(=O)O)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cc(CBr)cc(CCO)c1
Reaction time: 0.17 h

Procedure:
Borane dimethyl sulfide complex (2M in THF, 8.6 mL) was added dropwise to a solution of 2-(3-(bromomethyl)-5-methylphenyl)acetic acid [Aromatic Intermediate 23, step a] (2.1 g) in THF (50 mL) at 0° C. and the mixture stirred for 10 minutes at this temperature and then at room temperature for 1 hour. The reaction mixture was quenched by dropwise addition of methanol, the solvents were evaporated under reduced pressure and the residue was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Fractions containing the product were evaporated to dryness to afford the titled compound. Yield 1.40 g.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10]CC)=O.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C1(C)C(C)=CC=CC=1>CN(C)C=O>[OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:10]
Reactant: Nc1cccnc1
Reactant: CCOC(=O)c1c(O)c2sccc2[nH]c1=O
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1c(O)c2sccc2[nH]c1=O
Temperature: 140 °C
Yield: 53.2 %

Procedure:
A mixture of 2.43 g (10.2 mmols) of ethyl 4,5-dihydro-7-hydroxy-5-oxothieno[3,2-b]pyridine-6-carboxylate [J. Chem. Res. (S), 6 (1980); J. Chem. Res. (M), 113 (1980)], 1.00 g (10.6 mmols) of 3-aminopyridine, 50 ml of xylene and 10 ml of dimethylformamide was heated at 140° C. for an hour. After completion of the reaction, insoluble matters were filtered and recrystallized from dimethylformamide to give 1.56 g (yield: 54%) of Compound 1.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[O:35][C:36]([C:39](Cl)=[O:40])=[CH:37][CH:38]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]2[O:35][C:36]([C:39](=[O:40])[NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)=[CH:37][CH:38]=2)=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.29 g (1.8 mmol) of 4-trifluoromethylaniline were initially charged in 20 ml of THF1 0.14 g (1.8 mmol) of pyridine were added and a solution of 0.5 g (1.5 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise at RT. After 0.5 h, the mixture was poured into ice-water and the precipitate was filtered off with suction and recrystallized from isopropanol. This gave 0.47 g (69%) of the title compound. m.p.: 205-206° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:2]=[CH2:3].[NH2:22][C:23]([NH2:25])=[S:24].C(O)C.[ClH:29]>O>[ClH:29].[Si:15]([O:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:1][CH2:2][CH2:3][NH:25][C:23](=[NH:22])[SH:24])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: NC(N)=S
Reactant: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1c(CCCNC(=N)S)ccc2ccccc12
Yield: 86 %

Procedure:
A mixture of the product of Example 122 Part C (1.55 g, 0.004 mole), thiourea (0.31 g, 0.004 mole), and absolute ethanol (8.0 mL) was heated at reflux for 7 hours. The cooled solution was treated with water (5.0 mL), cooled to 0°, and treated with concentrated hydrochloric acid (5.0 mL). The precipitated solid was isolated by filtration, rinsed with water and air-dried to provide the title compound (1.45 g, 86%) as a white powder, mp 190°-194°.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([N:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)[CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][CH2:26][C@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28].C([BH3-])#N>CN(C=O)C.C(O)(=O)C>[NH2:1][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][CH:21]([NH:25][CH2:26][C@H:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[OH:28])[CH2:22][CH2:23]4)[CH:13]=[C:14]([CH2:15][CH2:16][CH3:17])[C:8]=3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCc1cc(N2CCC(=O)CC2)nc2sc3c(N)ncnc3c12
Reactant: NC[C@@H](O)c1ccccc1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCc1cc(N2CCC(NC[C@@H](O)c3ccccc3)CC2)nc2sc3c(N)ncnc3c12
Reaction time: 16 h
Yield: 56.2 %

Procedure:
1-(4-Amino-9-propyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-7-yl)-piperidin-4-one (Example 4) (341 mg, 1.00 mmol) and (S)-2-amino-1-phenylethanol (142 mg, 1.00 mmol) was dissolved in 10 mL of dry DMF. MP-Cyanoborohydride (0534 mg, 1.20 mmol) was added followed by 10 drops of glacial acetic acid. This mixture was shaken for 16 h. The resin was removed by filtration and washed with MeOH and dichloromethane. The filtrate was evaporated. The residue was treated with 2 M sodium carbonate solution. The resulting solid was collected by filtration and recrystalized from MeOH/acetonitrile to give the title compound as a pale-colored solid (0.260 g, 56%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.N1C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine is dissolved in methylene chloride and pyridine, and the mixture is cooled in an ice bath. Methanesulfonyl chloride is added dropwise, and the reaction mixture is stirred at ice bath temperature, then allowed to warm to room temperature. The reaction mixture is quenched by addition of water and extracted with methylene chloride. The organic layer is washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to give N-(6-benzenesulfonyl-naphthalen-1-ylmethyl)-methanesulfonamide.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[ClH:19]>C(Cl)Cl.CCOCC>[Cl:19][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: Cl
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCO)CC2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(N2CCN(CCCl)CC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
1-(2-Hydroxyethyl)-4-(4-nitrophenyl)piperazine (5 g, 0.02 mol) was dissolved in 50 mL of DCM and treated with HCl (40 mL of a 1M solution in Et2O) under a drying tube for 90 min. The solvent was evaporated, the residue dissolved in thionyl chloride (60 mL) and the mixture refluxed at 80° C. After 5 h, the reaction was complete as shown by LCMS and the thionyl chloride was removed under reduced pressure redissolving in DCM and evaporating three times to give the title compound as the HCl salt. LCMS: 93%, t=0.88 min, [MH+]=270.23.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([OH:18])[C:10](=[CH:16][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4].[I-:19].[Na+]>CC(C)=O>[I:19][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([OH:18])[C:10](=[CH:16][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4]
Reactant: [I-]
Reactant: CCOC(=O)c1ccc(CNC(=O)CCl)cc1O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(CNC(=O)CI)cc1O
Temperature: 25 °C
Yield: 130.8 %

Procedure:
Ethyl N-chloroacetyl4-aminomethylsalicylate (0.11 g, 0.40 mmoles) was dissolved in acetone (5 mL) and sodium iodide (0.06 g, 0.40 mmoles) was added. The solution was refluxed for 2.5 hours, then cooled to room temperature and filtered. The filtrate was evaporated to dryness to afford a white solid of ethyl N-iodoacetyl4-aminomethylsalicylate (0.19 g, 100% yield) (m.p. 105°-108° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].CCN(CC)CC.[Na+].[Cl-]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][C@@H:4]([NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(S)-tert-Butyl 4-hydroxy-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate was dissolved in 60 mL DCM and cooled to 0° C. MsCl (773 mL, 10 mmol) and Et3N (1.67 mL, 12 mmol) were added and the reaction was stirred for 1.5 hours at 0° C. NaCl (saturated, aqueous) was added, and the mixture was extracted with DCM (3×100 mL), dried over MgSO4 and evaporated. The title compound was obtained as an off-white solid and used without further purification in the next step. LCMS (API-ES) m/z (%): 411.1 (100%, M++H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH:29][C@@H:24]2[CH2:25][CH2:26][N:28]([CH3:27])[CH2:23]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)c(F)cc1N
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1N
Reaction time: 2 h

Procedure:
4-amino-2-fluoro-5-methoxybenzoic acid (Intermediate 183; 500 mg, 2.70 mmol), HATU (1.55 g, 4.05 mmol) and (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 631 mg, 3.31 mmol) were stirred in DMF (7.5 mL) and diisopropylethylamine (2.36 ml, 13.50 mmol) added. The reaction mixture was stirred for 2 hours and then absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by column chromatography (2.5% ammonia in methanol/DCM) to yield the title compound as a viscous brown oil. (662 mg, 92%).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([CH:11]=[C:12]1[NH:17][CH2:16][CH2:15][CH2:14][S:13]1)([O-:10])=[O:9].[Cl:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[Cl:18][CH2:19][CH2:20][CH2:21][S:22]([N:17]1[CH2:16][CH2:15][CH2:14][S:13][C:12]1=[CH:11][N+:8]([O-:10])=[O:9])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])C=C1SCCCN1S(=O)(=O)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 ml of triethylamine was added to a solution of 4.8 g of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine in 100 ml of dichloromethane at -15° C. under nitrogen. Then a solution of 5.9 g of 3-chloropropylsulfonyl chloride in 50 ml of dichloromethane was added drop-by-drop over 25 minutes. The resulting mixture was allowed to warm to room temperature, stirred for one hour and washed with 2% hydrochloric acid solution. The organic phase was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with methanol to give N-(3-chloropropylsulfonyl)-2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (1A), as a solid, m.p.: 99°-99° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([O-:19])=[O:18]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])c1ccccc1F
Product: O=[N+]([O-])c1ccccc1N1CCc2ccccc21
Temperature: 120 °C

Procedure:
11.0 g (0.10 mole) of indoline and 28.2 g of 1-fluoro-2-nitrobenzene are combined and the resultant solution is stirred and heated to 120° C. and kept at that temperature 18 hours. The reaction mixture is then cooled to room temperature and partitioned between chloroform and water. The chloroform layer is separated, washed with water, dried and concentrated in vacuum. The residue is dissolved in isopropylether from which 1-(2-nitrophenyl)indoline, m.p. 62°-64° C., precipitates on standing.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][NH:55][CH2:56][CH2:57][CH2:58]O>C(Cl)Cl>[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:58][CH2:57][CH2:56][NH:55][CH3:54])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Reactant: CNCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNCCCOc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Diethyl azodicarboxylate (522 mg, 3 mmol) was added dropwise to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (364 mg, 1 mmol), (prepared as described for the starting material in Example 48), triphenylphosphine (786 mg, 3 mmol) and 3-methylamino-1-propanol (178 mg, 2 mmol), (J.Am.Chem.Soc., 1954, 76, 2789), in methylene chloride (4 ml) under nitrogen. The mixture was stirred for 1 hour at ambient temperature, neutral alumina (˜20 g) was added to the reaction mixture and the solvent was removed by evaporation. The powder was poured onto a column of neutral alumina and was eluted with a mixture of methylene chloride/methanol (95/5 followed by 90/10 and 80/20). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(3-methylaminopropoxy)quinazoline (220 mg, 50%).