Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:22]1OC2C=CC(N)=CC=2O1.ClC1N=C(Cl)C2C(=CC=CC=2)N=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Nc2ccc3c(c2)OCO3)c2ccccc2n1
Reactant: Nc1ccc2c(c1)OCO2
Agent: Clc1nc(Cl)c2ccccc2n1
Product: CN(c1ccc2c(c1)OCO2)c1nc(Cl)nc2ccccc12

Procedure:
(2-Chloro-quinazolin-4-yl)-(3,4-methylenedioxyphenyl)-amine: The title compound was prepared from 3,4-methylenedioxyphenylamine and 2,4-dichloroquinazoline by a procedure similar to example 1b and was isolated as solids (45% yield). 1H NMR (CDCl3): 7.81-7.83 (m, 3H), 7.51-7.56 (m, 2H), 7.44 (d, 1H, J=2.1), 6.98 (dd, 1H, J=2.1, 8.1), 6.82 (d, 1H, J=8.1), 6.01 (s, 2H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=[CH:24][CH:23]=4)[C:14]3=[O:32])[CH:11]=2)[C:6]([CH3:34])([CH3:33])[CH2:5]1)(=O)C.Cl>O>[CH3:33][C:6]1([CH3:34])[C:7]2[C:12](=[CH:11][C:10]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=[CH:24][CH:23]=4)[C:14]3=[O:32])=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc5ccccc45)C(C)(C)C3=O)cc21
Agent: Cl
Solvent: O
Product: CC1(C)CNc2cc(N3C(=O)N(Cc4ccnc5ccccc45)C(C)(C)C3=O)ccc21
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
230 mg 3-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione were dissolved in 5 ml water and 5 ml of an aqueous 2 N solution of hydrochloric acid in a process vial. After sealing with a teflon septum the vial was placed in the microwave cavity and the reaction mixture was stirred for 15 minutes at 120° C. by microwave-assisted heating (Emrys Optimizer, Personal Chemistry). The solvent was removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoroacetic acid). Lyophilization of the solution yielded a white solid.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21][NH2:22].C([O-])([O-])OC.[BH4-].[Na+]>CO>[CH3:18][CH:19]([CH3:23])[CH2:20][CH2:21][NH:22][CH2:1][C:3]1[S:7][C:6]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)s2)cc1
Reactant: CC(C)CCN
Agent: COC([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2ccc(C(N)=O)cc2)s1
Reaction time: 3 h

Procedure:
Combine 4-(5-formyl-thiophen-2-yloxy)-benzamide (99 mg, 0.40 mmol) from Example 1 part B, method B, with 3-methyl-butylamine (0.056 mL, 0.48 mmol), methyl orthoformate (0.53 mL) and methanol (0.8 mL). Stir the resulting mixture for 3 hours and then add sodium borohydride in portions. Let stir for few hours. Then, concentrate to remove the methanol. Partition the resulting residue between H2O (4 mL) and CH2Cl2 (6 ml). Dry the organic layer over sodium sulfate, filter and concentrate. Purify through flash chromatography [CH2Cl2/Ammonia (2.0 M in methanol) 20/1] to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:25])=[CH:17][CH:16]=1
Reactant: O=C(O)COc1ccc(-c2ccccc2F)nc1
Reactant: Nc1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccccc2F)nc1)Nc1ccccn1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 90 mg (0.25 mmol) of [6-(2-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 28.1 mg (0.3 mmol) of 2-aminopyridine. Yield: 28 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][NH2:11].[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10]/[N:11]=[C:13](/[CH3:15])\[C:12]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: NNc1cc(F)c(F)cc1Br
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: CCOC(=O)/C(C)=N\Nc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 22 h
Yield: 100.2 %

Procedure:
A stirred solution of (2-bromo-4,5-difluoro-phenyl)-hydrazine (step A) (4.29 g, 19.2 mmol) in ethanol (13.8 ml) was cooled to 0° C. and a solution of ethyl pyruvate (2.39 g, 2.3 ml, 20.0 mmol) in ethanol (4 ml) was added drop wise at 0° C. for 15 min. After the mixture was allowed to stir at room temperature for 22 h it was evaporated to give crude (Z)-ethyl 2-[2-(2-bromo-4,5-difluoro-phenyl)-hydrazono]-propanoate (6.18 g, 100%) as light brown solid, MS (ISP) m/z=323.0 [(M+H)+], mp 78° C., which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([O-:16])=O)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:40]=[CH:39][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=3)[NH:29][C:25]=2[CH:24]=1>>[CH3:37][N:36]([CH3:38])[C:33]1[CH:32]=[CH:31][C:30]([C:28]2[NH:27][C:26]3[CH:39]=[CH:40][C:23]([NH:22][C:14](=[O:16])[C:13]4[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]5[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:21])=[CH:20][CH:19]=5)=[CH:18][CH:17]=4)=[CH:24][C:25]=3[N:29]=2)=[CH:35][CH:34]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(C(=O)[O-])cc2)cc1
Reactant: CN(C)c1ccc(-c2nc3ccc(N)cc3[nH]2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(C(=O)Nc3ccc4[nH]c(-c5ccc(N(C)C)cc5)nc4c3)cc2)cc1

Procedure:
Compound 442 was prepared from 4-(4-dimethylaminobenzamido)benzoate and 5-amino-2-(4-dimethylaminophenyl)benzimidazole by standard conditions. [M+H]+ calcd for C31H30N6O2: 519.24; found: 518.99.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:32])([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:33]([O-])=O)C1C=CC=CC=1>[H][H].[Pd]>[CH3:1][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:32])([CH2:23][NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])=[CH:11][C:10]=1[NH2:33]
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CNC(=O)OC(C)(C)C)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1ccc(C(C)(CNC(=O)OC(C)(C)C)C(=O)N2CCCC2)cc1N

Procedure:
Prepared analogously to Example 1f from 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-tert.butyloxycarbonylamino-1-pyrrolidino-propan-1-one and hydrogen/palladium on activated charcoal.
Reaction SMILES: C([O:5][C:6]1[C:7](=[O:24])[C:8](=O)[C:9]=1[CH:10]=[C:11]1[C:19]([CH3:21])([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH3:22])CCC.Cl.[NH2:26][OH:27].C(N(CC)CC)C>C(O)C>[OH:5][C:6]1[C:7](=[O:24])[C:8](=[N:26][OH:27])[C:9]=1[CH:10]=[C:11]1[C:19]([CH3:21])([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH3:22]
Reactant: CCCCOc1c(C=C2N(C)c3ccccc3C2(C)C)c(=O)c1=O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1C(=Cc2c(O)c(=O)c2=NO)C(C)(C)c2ccccc21

Procedure:
A mixture of 200 mg (0.61 mmol)of 3-butoxy-4-(1,3,3-trimethyl-2,3-dihydro-1H-2-indolylidenmethyl)-3-cyclobutene-1,2-dione (18), 50 mg (0.72 mmol) of hydroxylamine hydrochloride and 90 μl (0.64 mmol) of triethylamine is stirring in 8 ml of absolute ethanol at room temperature for 1 h and 30 min at 40° C. The solvent is removed under reduced pressure by a rotary evaporator. The obtained residue is column purified (Silica gel 60, 0–10% methanol-chloroform) to give 2-hydroxy-4-hydroxyimino-3-(1,3,3-trimethyl-2,3-dihydro-1H-2-indolylidenmethyl)-2-cyclobuten-1-one (19a) as an yellow solid. Yield: 80 mg (46%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[C:18](O)(=[O:20])[CH3:19].C(OC(=O)C)(=O)C>CCOCC>[C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1

Procedure:
A mixture of 11.5 g (50 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 200 ml of acetic acid, and 10.5 ml (110 mmol) of acetic anhydride is heated at reflux for 4.5 hrs. The mixture is cooled and diluted with 150 ml of ether. The solid is filtered, washed with ether, and dried at 60° to give 13.6 g of 6-[4-(acetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>260°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C=O)C.P(Br)(Br)[Br:39].C(OCC)(=O)C>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Br:39])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: BrP(Br)Br
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Br)CS[C@H]12

Procedure:
To a solution of 19 g. (40 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 300 ml. of dry DMF was added 15 g. (56 mmole) of phosphorus tribromide and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a mixture of ethyl acetate and water and the organic phase was separated and washed repeatedly with water and dried over magnesium sulfate. The dried organic phase was evaporated in vacuo todryness. The crude reaction product residue weighing about 9 g. was purified by chromatography over 500 g. of silica gel using ethyl acetate-hexane (55:45 v:v) as eluent. The eluate was evaporated to drynessunder reduced pressure and the product, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-bromo-3-cephem-4-carboxylate was obtained crystalline by the triturating the dry residue with diethyl ether.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1F.N1C=CC=CC=1.FC1C=C(S([Cl:48])(=O)=O)C=CC=1>C(Cl)Cl>[ClH:48].[F:2][C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:30][CH2:29][CH2:28][N:27]([CH3:31])[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN1CCCN(c2ccc(NS(=O)(=O)c3ccc(F)c(F)c3)c3ccccc23)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCCN(c2ccc(NS(=O)(=O)c3cccc(F)c3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
To a solution of (intermediate 3 after reduction according to Method A) 4-(4-methyl-1,4-diazepan-1-yl)-1-naphthylamine (0.173 g, 0.676 mmol) and pyridine (450 μL, 4.73 mmol) in CH2Cl2 (3.0 mL) was added 3-fluorobenzenesulfonyl chloride (0.145 g, 0.743 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and the volatiles were evaporated. The crude product was purified by column chromatography (SiO2, CHCl3/MeOH/NH3 9:1:0.4%) to give 240 mg of the product as solid that was triturated with MeOH/ether to give 0.180 g (64%) of the free base which was converted to its HCl-salt: 1H NMR (DMSO-d6) δ 11.07 (br s, 1H), 10.28 (br s, 1H), 8.20-8.16 (m, 1H), 7.98-7.94 (m, 1H), 7.60-7.40 (m, 6H), 7.16-7.12 (m, 1H), 7.06-7.02 (m, 1H), 3.65-3.30 (m, partly obscured by solvent signal, HDO, 6H), 3.26-3.18 (m, 2H), 2.84 (s, 3H), 2.30-2.05 (m, 2H); MS (posES-FIA) m/z=414 (M+H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([N:15]=[C:16]=[O:17])([N:12]=[C:13]=[O:14])(=[O:11])=[O:10]>C1C=CC=CC=1>[CH2:1]([O:8][C:13]([NH:12][S:9]([NH:15][C:16]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17])(=[O:11])=[O:10])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)N=C=O
Reactant: OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(NS(=O)(=O)NC(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h
Yield: 107.2 %

Procedure:
10 g of anhydrous benzyl alcohol are placed in 150 ml of absolute benzene and 7.4 g of sulfuryl diisocyanate are added dropwise accompanied by stirring. The exothermic reaction which takes place leads to a rise in the temperature to 45° C. and shortly after the start a precipitate is formed. Following the temperature drop, stirring is continued for 1 hour at ambient temperature. The resulting precipitate is suction filtered and dried at 60° C. giving a yield of 18.06 g of colorless crystals (99.2% of theory), m.p. 139°-141° C., which can be recrystallized from ethanol.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9]C=C(Cl)[C:3]=1[C:4]([OH:6])=[O:5].OO.C1CCCCC=1.[C:20]([O-:23])([OH:22])=O.[Na+]>CC#N.CCOCC.O>[C:4]([OH:6])(=[O:5])[CH2:3][CH2:2][CH2:10][CH2:9][C:20]([OH:23])=[O:22]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: O=C(O)CCCCC(=O)O
Reaction time: 0.33 h
Yield: 18 %

Procedure:
To a mixture of [Mn2O3(Me3-TACN)2] (PF6)2.H2O (16.2 mg, 20 μmol, 0.2 mol %) and 2,6-dichlorobenzoic acid (57.3 mg, 0.30 mmol, 3.0 mol %) in CH3CN (7 ml) was added H2O2 (30 μl of a 50% aq. solution, 0.53 mmol) at room temperature and the resulting mixture was stirred for 20 min. Subsequently cyclohexene (0.805 g, 9.70 mmol) was added together with CH3CN (2 ml) and water (1 ml). H2O2 (5.67 ml of a 50% aq. solution, 100 mmol, 10.0 equiv.) was then added at 60° C. using a syringe pump (0.7 ml/h). New batches of [Mn2O3(Me3-TACN)2] (PF6)2.H2O (16.2 mg, 20 μmol, 0.2 mol % per batch) were added to the reaction mixture 1.5, 3.5, 5 and 7 hours after the addition of H2O2 had commenced. When the addition of H2O2 was completed, the mixture was stirred for additional 15 hours. Water (10 ml) and Et2O (10 ml) were added and the pH of the aqueous layer was set to pH >9 by adding some saturated NaHCO3 (aq.). The organic layer was separated and the aqueous layer was washed with Et2O (3×15 ml). The pH of the aqueous layer was subsequently set to pH <2 with some 10% HCl (aq.) and was extracted with Et2O (3×20 ml). The combined organic extracts were dried over anhydrous Na2SO4. The solvents were removed in vacuo yielding 473 mg of a solid with a purity of circa 56% (determined by 1H NMR), 18% yield of adipic acid. N.B. NMR showed other compounds as well, including 2,6-dichlorobenzoic acid.
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].Cl[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:8]=1.O>CN(C)C=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:9]2[N:8]=[C:7]([O:2][CH3:1])[CH:12]=[C:11]([CH3:13])[N:10]=2)=[CH:16][CH:17]=1
Reactant: CO
Reactant: Cc1cc(Cl)nc(Nc2ccc(Cl)cc2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)nc(Nc2ccc(Cl)cc2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A 28% methanol solution of sodium methylate (1.5 g) was added to a solution of 1.5 g of 4-chloro-2-(4-chloroanilino)-6-methylpyrimidine in 50 ml of dimethylformamide and the mixture was stirred for 2 hours at 70° C. After completion of the reaction, the reaction mixture was poured into water, extracted with 150 ml of toluene, washed with water, dried over Glauber's salt, and the toluene layer was concentrated by evaporation. The residue was purified by silica gel column chromatography to obtain 1.3 g (yield: 88%) of 2-(4-chloroanilino)-4-methoxy-6-methylpyrimidine having a melting point of 101°-103° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:18][C:19]1[C:20]2[CH2:28][N:27]([C:29]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:30]=3[C:31]#[N:32])[CH2:26][CH2:25][C:21]=2[N:22]=[CH:23][N:24]=1)[C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.CCOC(C)=O>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:29]([N:27]2[CH2:26][CH2:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([NH:18][C@@H:10]([C:11]4[CH:16]=[N:15][C:14]([CH3:17])=[N:13][CH:12]=4)[CH2:9][OH:8])[C:20]=3[CH2:28]2)=[C:30]([CH:33]=1)[C:31]#[N:32]
Reactant: Cc1ncc([C@@H](CO[Si](C)(C)C(C)(C)C)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-(4-(2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-chlorobenzonitrile (60 mg, 0.11 mmol) in THF (10 mL) was added 1M TBAF in THF (5 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then treated with water and EtOAc. The organic layer was washed with aq. NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was washed by ethyl ether and water (to completely remove TBAF) and dried to yield the final product as a light colored solid.
Reaction SMILES: C(OC([O:11][C:12]1([CH2:50][CH3:51])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:49])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:44])([CH3:43])[CH2:33][CH2:34][CH2:35][O:36][C:37]([CH:39]2[CH2:42][CH2:41][CH2:40]2)=[O:38])=[C:23]2[CH:45]=[CH:46][CH:47]=[CH:48][C:22]2=[N:21][C:20]3=1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:50]([C:12]1([OH:11])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:49])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:44])([CH3:43])[CH2:33][CH2:34][CH2:35][O:36][C:37]([CH:39]2[CH2:42][CH2:41][CH2:40]2)=[O:38])=[C:23]2[CH:45]=[CH:46][CH:47]=[CH:48][C:22]2=[N:21][C:20]3=1)[CH3:51]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)C1CCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)C1CCC1

Procedure:
A mixture of Compound 61 (70 mg, 0.1 mmol), 10% palladium on carbon (20 mg, 20%) in 20 mL of ethanol was hydrogenated for 18 hours at a balloon pressure of hydrogen at 21° C. The catalyst was removed by filtration over celite and the filtrate was evaporated to give a crude product, which was chromatographed to give the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([NH:21][C@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]3[OH:28])=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C>C(OCC)(=O)C.CO.[Pd]>[OH:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]1[NH:21][C:19]([C:11]1[CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:20]
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2cccnc2)c2ccccc2n1
Reaction time: 18 h

Procedure:
To a solution of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (A) (0.15 g, 0.38 mmol) in 3.5 mL ethyl acetate and a few drops of methanol to increase solubility was added triethylamine (0.053 mL, 0.38 mmol) and palladium on carbon (10 mol %). The reaction mixture was placed under a H2 (g) atmosphere with a balloon for 18 h. The reaction mixture was filtered through Celite, washed with excess methanol, and concentrated. The resulting residue was subjected to purification via reverse phase HPLC to afford the title compound that gave a mass ion (ES+) of 362.1866 for M+H+. 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.49 (dd, J=1.3, 4.8 Hz, 1H), 8.27 (d, J=7.7 Hz, 1H), 8.17 (s, 1H), 8.15 (dd J=0.7, 8.6 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.78-7.74 (m, 1H), 7.63-7.52 (m, 1H), 7.44-7.42 (m, 1H), 7.19 (dd, J=4.9, 7.9 Hz, HA 4.51 (s, 2H), 3.93-3.84 (m, 1H), 3.62-3.54 (m, 1H), 3.36 (d, J=4.2, 1H), 2.17-2.12 (m, 2H) 1.82-1.79 (m, 2H), 1.52-1.34 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][NH:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:17]2[CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:16]2)=[O:14])=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2Cc3ccccc3C2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added isoindoline (5.9 mg, 0.050 mmol, 1.1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C19H16N2O2: 304.1212, found 304.1222.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C@H:17]3[C@H:15]([O:16]3)[C@H:14]([CH3:18])[C@H:13]([OH:19])[C@@H:12]([CH3:20])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.[Si:29](OS(C(F)(F)F)(=O)=O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].CO>C(Cl)Cl>[C:1]1([S:7]([C:10]2[C@H:17]3[C@H:15]([O:16]3)[C@H:14]([CH3:18])[C@H:13]([O:19][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@@H:12]([CH3:20])[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C[C@@H]1[C@H](O)[C@@H](C)C=C(S(=O)(=O)c2ccccc2)[C@@H]2O[C@H]12
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: C[C@H]1[C@H]2O[C@H]2C(S(=O)(=O)c2ccccc2)=C[C@H](C)[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Yield: 95.6 %

Procedure:
A mixture of alcohol α36 (62 mg, 0.21 mmol) and 2,6-lutidine (50 μL, 0.43 mmol) in CH2Cl2 (2 mL) was cooled to −78° C., and 63 μL (0.27 mmol) of TBSOTf was added. The stirred cold solution was warmed to 0° C. over 5 h. MeOH (40 μL, 1 mmol) was then added to quench the excess TBSOTf. The resulting mixture was concentrated via rotary evaporation, and the crude residue was purified by flash column chromatography (EtOAc/hexanes; 1:5) to afford 82 mg (95%) of α37 as a white solid. mp 89.0-90.0° C.; [α]20D=−30.5 (c=0.61, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.93-7.97 (m, 2H), 7.55-7.70 (m, 3H), 7.09 (d, J=5.1 Hz, 1H), 3.70 (dd, J=8.4 Hz, 2.1 Hz, 1H), 3.67 (d, J=4.8 Hz, 1H), 3.37 (dd, J=7.2 Hz, 4.2 Hz, 1H), 2.60 (m, 1H), 2.49 (m, 1H), 1.26 (d, J=7.2 Hz, 3H), 0.90 (s, 9H), 0.74 (d, J=7.2 Hz, 3H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 146.0, 140.2, 136.1, 133.7, 129.3, 128.4, 74.5, 56.8, 48.7, 40.9, 36.9, 25.9, 18.4, 18.1, 9.7, −4.3, −4.4; Analytical. Calculated for C21H32O4S: C, 61.72; H, 7.89. Found: C, 61.39; H, 7.59.