Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11](CC2C=CC(OC)=CC=2OC)[CH2:10][C:9]2[S:23][N:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:8]=2[C:7]1=[O:32])=[O:5])[CH3:2].O=S(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:32])=[C:8]2[C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:24][S:23][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)c2c(-c3ccccc3)nsc2CN1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncc2snc(-c3ccccc3)c2c1O
Temperature: 25 °C
Yield: 71.1 %

Procedure:
To a solution of 6-(2,4-dimethoxy-benzyl)-4-oxo-3-phenyl-4,5,6,7-tetrahydro-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (5.42 g, 11.99 mmol) in CH2Cl2 was added SOCl2 (1.31 mL, 17.98 mmol) and the mixture was stirred at r.t. After 3 h the mixture was filtered and the filter cake was washed with hexanes/CH2Cl2(4/1, 12 mL). The solid was then suspended in sat. NaHCO3 (200 mL) and the mixture extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, water, dried over MgSO4, and concentrated in vacuo to give the title compound as yellow solid (2.56 g): MS (m/z) 301.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([NH2:23])=[S:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31](=O)[CH3:32]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:26]=[CH:25][CH:24]=[C:20]([C:21]5[S:22][CH:30]=[C:31]([CH3:32])[N:23]=5)[CH:19]=4)[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Solvent: CCO
Product: Cc1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamide (Example 149) (97 mg, (0.25 mmol) in ethanol (5 mL) was added chloroacetone (0.1 mL, 1.25 mmol) and the mixture was heated at reflux. After 1 h and after 5 h of heating, more chloroacetone (2 times 0.1 mL, 1.25 mmol) was added. After 20 h the mixture was cooled to 0° C. and stirred for 0.5 h, and the title compound was isolated by filtration as light yellow solid (61 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15](=[O:29])[CH2:16][CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:19]=2[CH2:18]1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:29])[CH2:16][CH:17]1[CH2:23][CH2:22][CH2:21][C:20]2[CH:24]=[CH:25][C:26]([O:28][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])=[CH:27][C:19]=2[CH2:18]1)[CH3:13]
Reactant: CCOC(=O)CC1CCCc2ccc(O)cc2C1
Reactant: CC(C)(C)OC(=O)NCCBr
Product: CCOC(=O)CC1CCCc2ccc(OCCNC(=O)OC(C)(C)C)cc2C1

Procedure:
The title compound is prepared according to the procedure of Example 19 except that (2-bromo-ethyl)-carbamic acid tert-butyl ester is used in place of (3-bromo-propyl)-carbamic acid tert-butyl ester and (3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-acetic acid ethyl ester is used in place of (7-hydroxy-1,2,3,4-tetrahydro-napthalene-2-yl)-acetic acid ethyl ester.
Reaction SMILES: C([O:8][C:9]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[CH:17]=[CH:16][C:10]=1[C:11](=[NH:15])[O:12][CH2:13][CH3:14])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:10]=1[C:11](=[NH:15])[O:12][CH2:13][CH3:14]
Reactant: [H][H]
Reactant: CCOC(=N)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=N)c1ccc(O)cc1O
Yield: 75 %

Procedure:
2,4-Dibenzyloxybenzoic acid was reacted with oxalyl chloride in toluene and DMF at 0-25° C. to give an acid chloride. The acid chloride was reacted with aqueous ammonia in methylene chloride to yield 87% (over 2 steps) of 2,4-dibenzyloxybenzamide. 2,4-Dibenzyloxybenzamide was reacted with triethyloxonium hexafluorophosphate in methylene chloride to yield 69% of ethyl 2,4-dibenzyloxybenzimidate. The ethyl 2,4-dibenzyloxybenzimidate was hydrogenated over a palladium/carbon catalyst with 1 atmosphere of hydrogen gas in ethanol, to yield 75% of ethyl 2,4-dihydroxybenzimidate. The overall yield for the reaction sequence was 34% for six steps.
Reaction SMILES: [Cl:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][C:13]([OH:15])=O)([CH2:5]3)[CH2:3]1)[CH2:9]2.S(Cl)([Cl:18])=O>>[Cl:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([CH2:12][C:13]([Cl:18])=[O:15])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC12CC3CC(CC(Cl)(C3)C1)C2
Product: O=C(Cl)CC12CC3CC(CC(Cl)(C3)C1)C2
Yield: 98.3 %

Procedure:
(3-Chloroadamantan-1-yl)acetic acid (607.5 mg, 2.66 mmol) was dissolved in thionyl chloride (5 mL, 68.5 mmol). The reaction mixture was heated at reflux for 5 hours. The reaction mixture was cooled and then concentrated in vacuo to provide the title compound as a white solid (646.4 mg, 98%) that was used without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C)C=O>[Si:15]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][CH:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: OCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a solution of 3-bromobenzylalcohol (18.7 g) in dimethylformamide (100 ml) was added imidazole (13.6 g) and t-butyidimethylsilylchloride (15.8 g). The mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water (300 ml) and then extracted with a mixture of hexane and ethyl acetate (1:1, 100 ml×2). The extract was washed with 0.5N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, successively, dried over anhyrous sodium sulfate and concentrated to give the title compound (30.1 g) having the following physical data.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:28]=4[O:27][CH3:26])=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: Cl
Product: COc1ccc(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,4-dimethoxybenzoyl chloride as starting compounds. The crude product is purified by column chromatography (silica gel and EA/PE=2:1) to yield the title compound.
Reaction SMILES: [N:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.OS(O)(=O)=O>O>[CH2:13]([O:11][C:10]([C:2]1[N:1]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[CH:4][CH:3]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cccc(C(=O)O)n1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cccc(C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.8 %

Procedure:
A mixture of 2,6-pyridinedicarboxylic acid (10 g, 0.06 mol) and benzyl alcohol (68 mL, 0.66 mol) were taken in water (25 mL), and concentrated H2SO4 (3.5 mL) was added. The reaction mixture was refluxed for 10 h and further allowed to stir at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and the organic product was extracted with CHCl3. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5% MeOH in CH2Cl2) to afford 6-((benzyloxy)carbonyl)picolinic acid (4.6 g, yield 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.54 (br s, 1H), 8.29-8.24 (m, 2H), 8.20-8.16 (m, 1H), 7.52-7.50 (m, 2H), 7.44-7.36 (m, 3H), 5.43 (s, 2H). MS (ESI) m/z: Calculated for C14H11NO4: 257.07. found: 258.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([CH:15]([NH2:18])[CH2:16][CH3:17])[CH3:14]>CS(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CCC(N)CC
Solvent: CS(C)=O
Product: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.8 %

Procedure:
A mixture of 2,4-dichloro-6-methyl-3-nitro-pyridine (250 mg, 1.21 mmol) and 1-ethyl-propyl amine (105 mg, 1.21 mmol) in DMSO (4 ml) was stirred at room temperature for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 280 mg of yellow oil. The oil was purified through silical gel column chromatography using 65% chloroform in hexane as eluent to give 110 mg (35%) of the title compound as a yellow crystal, mp 82-84° C. 1H NMR (CDCl3) δ 6.57 (d, 1H), 6.46 (s, 1H), 3.39 (m, 1H), 2.42 (s, 3H), 1.4-1.8 (m, 4H), 0.94 (t, 6H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:28]1[N:29]=[C:30]([NH:33]C=O)[S:31][CH:32]=1)[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>CO.O>[C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(N)n1
Reaction time: 1.5 h
Yield: 77.4 %

Procedure:
To a solution of 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (65.9 g) in ethyl acetate (300 ml) and tetrahydrofuran (200 ml) was dropwise added a solution of diphenyldiazomethane in ethyl acetate (1 m mol/ml, 200 ml) at ambient temperature and the mixture was stirred for an hour. The resultant mixture was washed with saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The solution was evaporated to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (99.3 g). To the solution of benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer) (99.0 g) in methanol (500 ml) was added conc. hydrochloric acid (41.6 g) at ambient temperature and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into a solution of sodium bicarbonate (33.6 g) in water (2.5 l) and extracted with ethyl acetate. The extracts were washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was pulverized with ether to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (72.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[NH2:25][OH:26].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:25][OH:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: NO
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ONCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 15, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with a cold mixture of hydroxylamine and sodium hydride in dimethylformamide to give 8-chloro-1-[(hydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo [4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.C[O:15][C:16](=O)[C:17]1[C:22]([I:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:24][C:20]1[CH:19]=[C:18]2[C:17](=[C:22]([I:23])[CH:21]=1)[C:16](=[O:15])[N:9]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:5][CH:6]=1)[CH2:25]2
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
A mixture of 4-trifluoromethoxy-benzyl amine (0.092 mL, 0.6 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.181 g, 0.49 mmol), and K2CO3 (0.138 g, 1 mmol) in toluene was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.080 g, 36%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.19 (s, 2H), 4.79 (s, 2H), 7.06-7.38 (m, 5H), 7.67 (d, 1H). GC-MS: m/z 451 (M)+, 382 (M−69)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH:10]=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[CH2:13]=[C:14]1[CH2:17][C:16]2([CH2:20][CH2:19][CH2:18]2)[CH2:15]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:13][C:14]3([CH2:17][C:16]4([CH2:20][CH2:19][CH2:18]4)[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON=CC#Cc1cccc(Cl)c1
Reactant: C=C1CC2(CCC2)C1
Product: Clc1cccc(C#CC2=NOC3(C2)CC2(CCC2)C3)c1

Procedure:
The title compound was prepared following the procedure described for Compound 3c, using Compound 31e instead of Compound 3b and Compound 97a instead of Compound 3a. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP01®TM-Biotage; Petroleum Ether-EtOAc 97:3; then DCM 100%) to give the title compound as a white-yellowish solid. Yield: 20.7%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH2:45][CH2:44]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 47.9 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.21 mmol), 2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (60 mg, 0.19 mmol), and p-toluenesulfonic acid (98 mg, 0.51 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.091 mmol, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.39 (d, J=2.01 Hz, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.19 (s, 1H), 8.01-8.07 (m, 1H), 7.78-7.83 (m, 1H), 7.68-7.75 (m, 1H), 7.56-7.63 (m, 1H), 7.36-7.47 (m, 3H), 7.16-7.23 (m, 2H), 6.93-7.01 (m, 1H), 6.67 (s, 1H), 6.45 (d, J=4.40 Hz, 2H), 3.79 (s, 3H), 3.31-3.36 (m, 2H), 3.10-3.18 (m, 4H), 3.03 (s, 3H), 2.71-2.78 (m, 2H), 2.53-2.61 (m, 4H). MS (ESI): 739 [M+H]+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:35])[CH2:18][CH:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[C:16]2[CH:29]=[C:30]([C:33]#[N:34])[CH:31]=[CH:32][C:15]=2[O:14]1>ClCCl>[C:33]([C:30]1[CH:31]=[CH:32][C:15]2[O:14][C:13]([CH3:35])([CH3:12])[CH2:18][CH:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N+:20]=3[O-:9])[C:16]=2[CH:29]=1)#[N:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccc3ccccc3n2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2ccc3ccccc3[n+]2[O-])c2cc(C#N)ccc2O1
Reaction time: 2 h
Yield: 69.7 %

Procedure:
203 mg of m-chloroperbenzoic acid were added at room temperature to a solution of 314 mg of 3,4-dihydro-2,2-dimethyl-4-(2-quinolyl)-2H-1-benzopyran-6-carbonitrile in 10 ml of dichloromethane. After stirring for 2 hours the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was recrystallized from diethyl ether to give 230 mg of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-quinoline-1-oxide of melting point 183°-185° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:42])[CH:10]([CH2:31][C:32]1[CH:40]=[C:39]([CH3:41])[CH:38]2[CH:34]([CH:35]=[N:36][NH:37]2)[CH:33]=1)[CH2:11][C:12](=[O:30])[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:15][CH2:14]1.[CH:43](=O)[CH3:44].[BH4-].[Na+]>CO>[CH2:43]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:42])[CH:10]([CH2:31][C:32]1[CH:40]=[C:39]([CH3:41])[CH:38]2[CH:34]([CH:35]=[N:36][NH:37]2)[CH:33]=1)[CH2:11][C:12](=[O:30])[N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:17][CH2:18]1)[CH3:44]
Reactant: CC=O
Reactant: CC1=CC(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)Nc2ccccc2N)=CC2C=NNC12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNc1ccccc1NC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)CC1=CC2C=NNC2C(C)=C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(2-aminophenyl)-2-((7-methyl-3a,7a-dihydro-1H-indazol-5-yl)methyl)-4-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)butanamide (0.24 mmol) in methanol (5 mL) was treated with acetaldehyde (1 mL) at room temperature. The mixture was stirred for 2 h at room temperature before the solvent was removed in vacuo. The residue was taken up in methanol (5 mL) and then sodium borohydride (0.48 mmol) was added. After 30 min, the methanol was removed in vacuo and the residue was taken up in methylene chloride (15 mL). The final product was obtained by filtration through a pad of celite and concentration of the filtrate. (95%) MS(ESI)[M+H]+=594.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>CCOCC>[C:21]([C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=[CH:3][N:2]([CH3:1])[CH3:14])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CN(C)C=Cc1ccccc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)C(=CN(C)C)c1ccccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To a stirred solution of 3.84 g. of β-dimethylamino-2-nitrostyrene and 1.61 ml. of pyridine in 20 ml. of ether, was added dropwise a solution of 1.42 ml. of acetyl chloride in 5 ml. of ether. The mixture was stirred for 3 hours at 0° and filtered. The gummy solid was partitioned between methylene chloride and water. The organic phase was washed with dilute hydrochloride, dried and concentrated to a dark oil. The nmr spectrum was in agreement with the proposed structure. This product, i.e., α-acetyl-β-dimethylamino-2-nitrostyrene was used without further purification in the next step.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]2[CH:49]=[CH:48][C:24]([C:25]([NH:27][C:28]3[CH:29]=[C:30]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:31]=[CH:32][C:33]=3[NH:34]C(=O)OC(C)(C)C)=[O:26])=[CH:23][CH:22]=2)[CH2:17]1)=O)(C)(C)C>C(Cl)Cl>[NH2:34][C:33]1[CH:32]=[CH:31][C:30]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:29][C:28]=1[NH:27][C:25](=[O:26])[C:24]1[CH:48]=[CH:49][C:21]([N:18]2[CH2:19][CH2:20][C@H:16]([NH2:15])[CH2:17]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
TFA (1 mL) was added to a solution of 326 (370 mg, 0.65 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 24 h, concentrated and the residue was partitioned between EtOAc and NaHCO3. The aqueous layer was extracted with fresh EtOAc and the comb organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified using the Biotage system, (cartridge Biotage Si 25+M), eluent MeOH/DCM (10% to 40%) to afford the title compound 327 (161 mg, 67% yield).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:8]=2)[N:3]=1.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.N1C(C)=CC=CC=1C>O1CCOCC1>[CH:13]1([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[CH:8]=3)[N:3]=[C:2]([NH:29][C:26]3[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=3)[N:11]=2)[CH2:15][CH2:14]1
Reactant: Cn1ccc(N)n1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(NC4CC4)c3c2)cc1
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: Cn1ccc(Nc2nc(NC3CC3)c3cc(-c4ccc(F)cc4)ccc3n2)n1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
To a solution of [2-Chloro-6-(4-fluoro-phenyl)-quinazolin-4-yl]-cyclopropylamine (150 mg, 0.48 mmol) and 1-Methyl-1H-pyrazol-3-ylamine (70 mg, 0.72 mmol) in 1,4-dioxane (5 ml) was added 2,6-lutidine (2 equiv.; 102 mg, 0.96 mmol). The solution was heated to 100° C. for 3 hours, then cooled and purified by RP HPLC with a gradient of H2O, 0.1% TFA-acetonitrile, to provide the desired product (140 mg, 0.287 mmol, 60% yield). The product was characterized as follows: MS (m/z): 375 ([M+H]+, 100); HPLC Rt=1.60 minutes (Method B).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C@H:14]1[CH2:18][C@@H:17]([C:19]([O:21][CH3:22])=[O:20])[N:16](C)[CH2:15]1)=[O:12].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C@H:14]1[CH2:18][C@@H:17]([C:19]([O:21][CH3:22])=[O:20])[NH:16][CH2:15]1)=[O:12]
Reactant: COC(=O)[C@@H]1C[C@H](OC(=O)N2CCc3ccccc3C2)CN1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](OC(=O)N2CCc3ccccc3C2)CN1
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Compound 6 (1.45 g, 3.6 mmol) dissolved in DCM (20 ml) was treated with TFA (10 ml) at 0° C. After 2 hr, volatiles are evaporated. The residue is treated with sat. sodium bicarbonate aqueous solution and extracted with DCM. Compound 7 (0.86 g, 79%) is obtained as a pale yellow powder after the evaporation of solvent.