Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[C:15]([NH2:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:23]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:22][CH:2]=2)=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: NC(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Product: CS(=O)(=O)c1ccc(-c2coc(-c3ccccc3)n2)cc1
Yield: 27.8 %

Procedure:
The mixture of the 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone (2 g, 7.2 mmol) and benzamide (0.87 g, 7.2 mmol) was heated to 140˜180° C. for 4 hours. When TLC showed that the reaction had completed, the mixture was cooled, and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice, and the combined organic layers were washed with water and brine, dried over MgSO4. After concentration, the residue was purified by column (eluted by PE:EA=10:1) to afford 0.6 g (yield 30%) of 4-[4-(methylsulfonyl)phenyl]-2-phenyl-1,3-oxazole.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(Oc2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Oc5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenoxy-pyridine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]1[CH2:17][CH2:16][CH2:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].C(O)C>[C:13]1([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: C1=CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCO
Product: CCOC(=O)c1cccc(C2=CCCC2)c1
Temperature: 80 °C

Procedure:
The following are successively introduced into a round-bottomed flask: 7 g of ethyl 3-iodobenzoate (25 mmol), 11.2 ml of cyclopentene (127 mmol), 21 ml of ethanol, 1.16 g of Pd2dba3 complex (1.27 mmol), 8.8 g of potassium carbonate (63 mmol) and 8.17 g of nBu4NBr (25 mmol). The medium is heated at 80° C. for 16 hours and then the black mixture is filtered on celite. The precipitate is washed with ethyl acetate. The filtrate is washed with water and then with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The title product, which is isolated by bulb to bulb distillation (5.2 g), is obtained in the form of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.Cl[C:13]1[N:18]=[N:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][N:18]3[C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C(O)c1ccc(Cl)nn1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2nc3ccc(Cl)cc3c(=O)n2n1
Yield: 54.3 %

Procedure:
A mixture of 5-chloroanthranilic acid (5.4 g, 31.6 mmol) and 6-chloropyridazine-3-carboxylic acid (5.0 g, 31.6 mmol) is heated at reflux in acetic acid (50 ml) for 80 hrs. The mixture is cooled and the precipitate which formes is collected to give 4.73 g of crude product, m.p. 253°-300° C. (dec.). Recrystallization of this material from pyridine gives the analytical material, m.p. 260°-262° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].Cl.[NH2:10][OH:11].C(N(CC)CC)C.Cl.C(N(CC)CC)C>CO>[OH:11][N:10]=[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)[NH2:2]
Reactant: NO
Reactant: N#Cc1cncnc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=NO)c1cncnc1
Temperature: 0 °C
Yield: 52.2 %

Procedure:
5-Cyanopyrimidine (J. Org. Chem. 1962, 27, 2264) (0.64 g, 6.1 mmol) was dissolved in methanol (20 mL), the solution was cooled to 0° C. then hydroxylamine hydrochloride (0.42 g, 6.1 mmol) and triethylamine (0.84 mL, 6.1 mmol) were added and the mixture was heated to reflux overnight. The mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was pre-absorbed onto silica gel, and purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonia—95:5:0.5 as eluant) to give a yellow solid which was contaminated with triethylamine hydrochloride. Recrystallisation from ethanol gave the title compound as a white solid (0.44 g).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12].[CH3:14]OC(OC)(C)C>CO>[C:11]([CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)([O:13][CH3:14])=[O:12]
Reactant: O=C(O)C1CCc2ccccc2C1
Reactant: COC(C)(C)OC
Solvent: CO
Product: COC(=O)C1CCc2ccccc2C1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Dissolve 1,2,3,4-tetrahydro-2-naphthoic acid (10 g, 57 mmol) in methanol (100 mL) and add dimethoxypropane (3 mL). Cool to 5° C. and saturate with hydrogen chloride gas. Allow to stand overnight then evaporate the solvent in vacuo. Take the residue up in ethyl ether, wash with saturated sodium hydrogen carbonate and dry (MgSO4). Evaporate the solvent in vacuo and distill to give 2-carbomethoxy-1,2,3,4-tetrahydronaphthalene; bp 90°-96° C.@0.25 mm Hg).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[Cl:11][C:12]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: O=C(O)Cn1ccnn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2Cl)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 2, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2-chloro-4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 7.79-7.75 (m, 2H), 7.43-7.39 (m, 2H), 7.25-7.13 (m, 2H), 7.03-6.86 (m, 7H), 5.32 (d, 1H), 5.18 (d, 1H), 4.77 (d, 1H), 3.76-3.70 (m, 1H), 3.36 (t, 1H), 3.08-2.96 (m, 1H), 2.94-2.88 (m, 2H), 2.60-2.53 (m, 1H), 1.82-1.73 (m, 1H). MS (EI) for C28H25ClF2N5O3 found 552 (MH+).
Reaction SMILES: [F:1][C:2]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][C:19]=2[N+:28]([O-:30])=[O:29])[CH2:7][CH2:6][C:5]2(OC3C=CC=CC=3[O:8]2)[CH2:4][CH2:3]1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[F:1][C:2]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][C:19]=2[N+:28]([O-:30])=[O:29])[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCC3(CC2)Oc2ccccc2O3)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NS(=O)(=O)c1ccc(OCC2(F)CCC(=O)CC2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 363A (860 mg) in ethanol (30 mL) was added concentrated HCl (10 mL) and the mixture was stirred at 100° C. for 3 hours. The mixture was neutralized with solid Na2CO3 and extracted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(#N)C.[Pt]>[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2
Reactant: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)NNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reaction time: 17 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl N′-(7-benzyloxy-3-nitroquinolin-4-yl)hydrazinecarboxylate (20.00 g, 48.73 mmol) in 200 mL of methanol and 200 mL of acetonitrile was treated with platinum on carbon (2.00 g, 0.51 mmol) and shaken under an atmosphere of hydrogen (3.8×105 Pa). After 17 h, the mixture was filtered through a pad of CELITE filter agent and rinsed with MeOH:MeCN (1:1) until the filtrate ran clear. The filtrate was concentrated under reduced pressure to yield 18.21 g of tert-butyl N′-(3-amino-7-benzyloxyquinolin-4-yl)hydrazinecarboxylate as a red/orange solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[CH2:30]([O:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Cl)=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCCCCC.C(OCC)(=O)C.O.CN(C)C(=O)C>[CH2:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:42][C:12]([CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:44][CH:45]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CCCc1ccccc1)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
0.48 g of sodium hydride (55% oil suspension) was added to a mixture of 2.78 g of diethyl 2-(3-phenylpropyl)malonate, 20 ml of toluene and 10 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 30 minutes. Then, 2.45 g of 4-benzyloxybenzyl chloride was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes and then at 60° C. for 30 minutes. After the reaction, ethyl acetate and water were added to the reaction mixture, and then the ethyl acetate layer was separated. The extract thus obtained was dried over anhydrous magnesium sulfate and concentrated. The residue thus obtained was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 3.91 g of the desired compound as a syrup.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=[O:4].C1COCC1.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:43]1[C:48](=[O:49])[CH2:47][CH2:46][C:44]1=[O:45])=[N+](C)C)C>CCOC(C)=O>[NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([O:5][N:43]1[C:48](=[O:49])[CH2:47][CH2:46][C:44]1=[O:45])=[O:4]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)OCc1ccccc1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Z-Gly-OH (1.0 g, 4.78 mmol) was added THF (10 ml), DIEA (0.98 ml, 5.74 mmol), and TSTU (1.7 g, 5.74 mmol) and the resulting mixture was stirred at room temperature for 2 hours. AcOEt (100 ml) was added and the mixture was washed with 0.2N hydrochloric acid (100 ml) and water (2×100 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo to afford 1.34 g (92%) of Z-Gly-OSu as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:18])([CH3:17])[C:6]=1[OH:19])=[S:4].O1CCCC1.[BH4-].[Na+]>CO>[CH3:1][NH:2][C:3]([C@H:5]1[C:10]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:17])([CH3:18])[C@H:6]1[OH:19])=[S:4]
Reactant: CNC(=S)C1=C(O)C(C)(C)Oc2ccc(C#N)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=S)[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h
Yield: 7.1 %

Procedure:
To a mixture of 1.4 g of N-methyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide, 15 ml of tetrahydrofuran, and 15 ml of methanol was added 0.23 g of sodium borohydride (NaBH4) at -10° C. with stirring, followed by stirring at -10° C. for 2 hours and then at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure, ice-water added to the residue, and the mixture made acidic with acetic acid and extracted with diethyl ether and ethyl acetate. The organic layer combined was dried over Na2SO4, followed by distillation. The residue was subjected to silica gel column chromatography (developing solution: CH2Cl2 :AcOEt=2:1). From the first fraction was obtained 0.1 g of cis-N-methyl-6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22])[OH:15]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:17]([O:24][CH3:25])=[N:18][CH:19]=[C:20]([Cl:23])[C:21]=1[CH3:22])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(OC)ncc(Cl)c2C)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(OC)ncc(Cl)c2C)c(OC)c1OC
Yield: 91.7 %

Procedure:
4 g of active manganese dioxide was added to a toluene 15 ml solution of 0.64 g (1.7 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(5-chloro-2-methoxy-4-methyl-3-pyridyl)methanol, followed by stirring under reflux with heating for 1 hour. The reaction solution was subjected to filtration on the pad of celite, and the solvent was distilled off under reduced pressure to obtain 0.57 g (yield: 90%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-5-chloro-2-methoxy-4-methylpyridine (melting point 94.5 to 95.5° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:46])[CH2:42][CH2:43][NH:44][CH3:45]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:44]([CH2:43][CH2:42][N:41]([CH3:46])[CH3:40])[CH3:45])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CNCCN(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N(C)CCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 25.6 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (40 mg, 0.073 mmol) in THF (3 mL) and DMF (0.5 mL) were added N,N,N′-trimethyl-1,2-ethanediamine (0.047 mL, 0.364 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (11 mg, 26%). LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) δ 2.18 (s, 6H), 2.40 (m, 5H), 3.02 (m, 3H), 3.50 (m, 2H), 4.17 (s, 2H), 7.15 (m, 4H), 7.52 (m, 2H), 7.71 (m, 2H), 7.82 (s, 1H), 7.97 (d, 1H).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21]>C(N(CC)CC)C>[Br:18][CH:19]([CH3:23])[C:20]([NH:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)=[O:21]
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Br)C(=O)Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Into 50 ml of tetrahydrofuran, were added 3.5 g of 2-amino-4-phenylthiazole and 2.0 g of triethylamine. The mixture was cooled to 0°--5° C. Then, 4.3 g of α-bromopropionylbromide was dropped to the solution mixture. After the completion of the dropwise addition, the solution mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. The residue was taken up in chloroform and washed with water. Upon removal of chloroform, a crude reaction product was obtained. It was thereafter subjected to silica gel chromatography and then eluted with a chloroform/methyl alcohol (40:1) mixed solvent. It was then recrystallized from an ether/cyclohexane mixed solvent, thereby obtaining 4.2 g of 2-(α-bromopropionylamino)-4-phenylthiazole.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O.[C:21]([O-:24])(=[S:23])[CH3:22].[K+].O>CS(C)=O>[C:21]([S:23][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)(=[O:24])[CH3:22]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)SC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 61.6 %

Procedure:
A solution of 4-[4-(methanesulfonyloxy)piperidin-1-yl]nitrobenzene (2.0 g), and potassium thioacetate (1.14 g) in dimethylsulfoxide (DMSO) (20 ml) was stirred at 100-110° C. for 3 hours. The reaction mixture was poured into water (100 ml) and extracted twice with ethyl acetate (100 ml). The extracts were collected, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting precipitates were washed with IPE (50 ml), collected by filtration and dried in vacuo to give 4-(4-acetylthiopiperidin-1-yl)nitrobenzene (1.15 g).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]([OH:43])[CH2:21][NH:22][C:23]([CH3:42])([CH3:41])[CH2:24][CH2:25][N:26]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]([CH2:38][CH3:39])([CH2:36][CH3:37])[O:28][C:27]2=[O:40])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:38]([C:29]1([CH2:36][CH3:37])[O:28][C:27](=[O:40])[N:26]([CH2:25][CH2:24][C:23]([NH:22][CH2:21][CH:20]([OH:43])[C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:19])[NH:16]3)([CH3:41])[CH3:42])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]1=2)[CH3:39]
Reactant: [H][H]
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3[nH]c(=O)ccc23)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2cc(O)cc3[nH]c(=O)ccc23)c2ccccc21

Procedure:
A suspension of 1-{3-[2-(7-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-hydroxyethylamino]-3-methylbutyl}-4,4-diethyl-1,4dihydrobenzo[d][1,3]oxazin-2-one (152 mg, 0.338 mmol) and Pd/C (10%) (40 mg) in MeOH (12 mL) is hydrogenated at room temperature (RT) and 1 bar hydrogen pressure for 4 hours. The catalyst is filtered off through CELITE® filter aid and washed with MeOH (5 mL). The organic phase is evaporated down, the residue is triturated with EtOAc and the precipitate formed is filtered off and dried in vacuo. Yield: 76 mg (46%); Rf=0.3 (silica gel, dichloromethane/MeOH/saturated aqueous ammonia 90:10:0.5); ESI-MS: [M+H]+=494.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:14]1[CH2:19]O[CH2:17][O:16][CH2:15]1.CS(O)(=O)=O>C(O)(=O)C.O>[N:13]1([S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:17][O:16][CH2:15][O:14][CH2:19]1
Reactant: C1OCOCO1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2COCOC2)cc1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 34.8 %

Procedure:
4-Nitrobenzenesulphonamide (2.02 g, 10 mmol) was added to a solution of 1,3,5-trioxane (1.96 g, 20 mmol) in acetic acid (5 ml). The mixture was cooled for 5 minutes ated methanesulphonic acid (10 ml) was added slowly. The mixture was then stirred at 35° C. for 20 minutes, cooled to 0° C., diluted with water and extracted with ethyl acetate. The combined extracts were washed twice with water and twice with 5% aqueous sodium hydrogen carbonate solution, then dried and the volatiles removed by evaporation. The residue was recrystallized from ethanol to give the title compound (955 mg, 35%). NMR: 4.87 (s, 2H), 5.30 (s, 4H), 8.20 (d, 2H), 8.42 (d, 2H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[N:32][C:27]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: Brc1ncccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3ncccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and 2-bromopyrimidine.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([N:18]1[CH2:24][CH:23]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:22]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([Cl:41])[CH:35]=2)[O:21][CH2:20][C:19]1=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>C(OCC)C.C1COCC1>[CH2:11]([N:18]1[CH2:24][CH:23]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:22]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([Cl:41])[CH:35]=2)[O:21][CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)C(=O)COC1c1ccc(F)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)CCOC1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of aluminum(III) chloride (1.12 g) in diethyl ether (85 mL)-THF (40 mL) was added, under a nitrogen stream, lithium aluminum hydride (960 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C., a solution of (6RS,7SR)-4-benzyl-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(3-chloro-4-fluorophenyl)-1,4-oxazepan-3-one (6.72 g) in THF (60 mL) was added dropwise, and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added 1 N aqueous sodium hydroxide solution (14 ml) at −78° C., the mixture was stirred at room temperature for 2 hr, and filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (4.16 g).