Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([CH:11]1[CH2:16][S:15][CH2:14][CH2:13][N:12]1[C:17]([O:19]C(C)(C)C)=O)=[O:10])C(OC)=O.C(O)(C(F)(F)F)=O>ClCCl>[OH:1][CH2:2][C@H:3]1[C:17](=[O:19])[N:12]2[CH:11]([CH2:16][S:15][CH2:14][CH2:13]2)[C:9](=[O:10])[NH:8]1
Reactant: COC(=O)[C@H](CO)NC(=O)C1CSCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N[C@@H](CO)C(=O)N2CCSCC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude 1,1-dimethylethyl 3-({[(1S)-1-(hydroxymethyl)-2-(methyloxy)-2-oxoethyl]amino}carbonyl)-4-thiomorpholinecarboxylate (D118, 3.87 g) in 44 ml of dichloromethane were added under N2, at r.t., 22 ml of TFA. The reaction mixture was stirred at room temperature for 3 hrs. The solvents were removed under reduced pressure and the residue was purified on a SCX cartridge. The fraction eluted with 2M methanolic ammonia was evaporated to dryness and the residue was dissolved in MeOH and refluxed for 20 hrs.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=[C:28]([CH3:36])[CH:27]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:10]([C:37]([OH:39])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:40][OH:41]>>[OH:41][NH:40][C:37]([C@@H:10]1[C@H:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=[C:28]([CH3:36])[CH:27]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1)=[O:39]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCN(C(=O)OC(C)(C)C)CC3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)NO)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 24, Step 3, 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (0.17 g, 0.30 mmol) and hydroxylamine gave a 7:1 mixture of cis- and trans-tert-Butyl (3S,4R)-3-[(hydroxyamino)carbonyl]-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-1-carboxylate as an amorphous white solid (0.025 g, 14.6%) after purification using Biotage Flash 40S chromatography, eluting with 5% methanol in ethyl acetate. Mass Spectrum Found: 571 (M+H)+
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH2:4]1[CH2:10][S:7](=[O:9])(=[O:8])[O:6][CH2:5]1>O1CCCC1>[CH2:1]([NH:3][CH2:5][CH2:4][CH2:10][S:7]([OH:9])(=[O:8])=[O:6])[CH3:2]
Reactant: O=S1(=O)CCCO1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCCCS(=O)(=O)O
Temperature: 5 °C
Yield: 56.9 %

Procedure:
Tetrahydrofuran (THF, 800 mL) was placed a 3 neck 2-L flask (equipped with a condenser) and cooled to 5° C. with an ice-bath. To the cold THF was added aqueous ethylamine (70 wt. % solution in water, 85 mL, 1.07 mol), followed by addition of a cold solution of 1,3-propane sultone (25.08 g, 201 mmol) in THF (100 mL) over 24-min period. The mixture was stirred, while cooled with an ice-bath, for 1 h. The ice-bath was removed and the mixture was stirred at room temperature overnight. It was then heated under reflux for 1 h to distill off the ethylamine. The hot mixture was biphasic. Upon cooling, a solid crystallized at the bottom of the flask. Ether (400 mL) was added and the mixture was cooled to −20° C. The supernatant was decanted. Methanol (about 120 mL) was added to the residue. The mixture was heated to reflux; and complete dissolution of the solid material was achieved. After the solution was cooled to room temperature, precipitates formed. The mixture was cooled in an ice-bath; and the solid material was collected by filtration, rinsed with cold methanol and dried in vacuo (20.66 g, pure by NMR analysis). The solid material was recrystallized from methanol (100 mL). After the mixture was cooled using an ice-bath, the solid was collected by filtration, rinsed with cold methanol, and dried in a vacuum oven at 40° C. Compound CV was obtained as white fine needles (19.12 g, 57%). The 1H and 13C NMR were consistent with the structure.
Reaction SMILES: Br[C:2]1C(C=C)=C(C)C=C2[C:3]=1C=CC(C)=N2.FC(F)(F)S(O[C:22]1[C:23]([Br:37])=[C:24]2[C:29](=[CH:30][C:31]=1[CH3:32])[N:28]=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=[CH:25]2)(=O)=O>>[Br:37][C:23]1[C:22]([CH:2]=[CH2:3])=[C:31]([CH3:32])[CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([C:33]([F:36])([F:35])[F:34])=[N:28]2
Reactant: Cc1cc2nc(C(F)(F)F)ccc2c(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: C=Cc1c(C)cc2nc(C)ccc2c1Br
Product: C=Cc1c(C)cc2nc(C(F)(F)F)ccc2c1Br

Procedure:
Compound 7D was prepared following the procedure used to prepare compound 5B of Example 5, except that 5-bromo-7-methyl-2-(trifluoromethyl)quinolin-6-yl trifluoromethanesulfonate (7C) was used instead of compound 5A. LCMS-ESI+ (m/z): 316.1, 318.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21]OS(C)(=O)=O)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]([CH3:29])[CH3:28]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][N:27]([CH3:29])[CH3:28])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)CC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 24.5 %

Procedure:
In a sealed vial, (R)-benzyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)-butanoate (130.8 mg, 0.34 mmol) was stirred at rt in a THF solution of Me2NH (2.0 M, 10 mL, 20 mmol) for 3 d. Then the reaction was concentrated under reduced pressure and purified by preparative TLC (0.5% MeOH in DCM, and then 5% MeOH/DCM) to afford the title compound as a colorless gum (28 mg, 25%). 1H NMR (300 MHz, CDCl3): δ=7.85-7.25 (m, 5H), 5.25-5.00 (m, 2H), 4.15 (br s, 1H), 2.58-2.50 (m, 4H), 2.41 (br s, 6H), 1.39 (s, 9H); MS ESI [M]+, calcd for [C18H28N2O4+H]+ 336.4 found m/z 337.2 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:41][S:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=2)(=[O:39])=[O:40])=[O:26])=[CH:28][CH:29]=1)[CH3:20])=[O:17]
Reactant: COc1cccc(S(N)(=O)=O)c1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Product: COc1cccc(S(=O)(=O)NC(=O)c2ccc([C@H](C)NC(=O)c3cc(Cl)cnc3Oc3ccc(F)cc3)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 3-methoxybenzenesulfonamide: 1H-NMR (CDCl3) δ 8.51 (1H, d, J=2.8 Hz), 8.13 (1H, d, J=2.8 Hz), 8.09 (1H, d, J=7.0 Hz), 7.73 (2H, d, J=8.4 Hz), 7.70–7.64 (2H, m), 7.49–7.39 (3H, m), 7.21–7.08 (5H, m), 5.37–5.25 (1H, m), 3.88 (3H, s), 1.56 (3H, d, J=6.8 Hz); MS (ESI) m/z 584 (M+H)+, 582 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 5 h
Yield: 82.4 %

Procedure:
A mixture of 2.00 g of 10,11-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 15 ml of ethyl alcohol and 15 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is dissolved in methylene chloride, passed through silica gel and the pad washed with 3:1 ethyl acetate-hexane. The filtrate is concentrated in vacuo to give 1.5 g of the desired product as a yellow solid, m.p. 166°-168° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][N:9]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[NH:21][CH:20]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:19](=[O:27])[N:18]([CH3:28])[CH2:17][C:16]=3[CH:29]=2)=[O:11])=[CH:3][CH:2]=1>O=[Pt]=O.CO>[NH:35]1[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][N:9]([CH2:8][CH2:7][CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[NH:21][CH:20]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:19](=[O:27])[N:18]([CH3:28])[CH2:17][C:16]=3[CH:29]=2)=[O:11])[CH2:33][CH2:34]1
Reactant: COC(=O)CC1Nc2ccc(C(=O)N(CCc3ccncc3)CCc3ccncc3)cc2CN(C)C1=O
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)CC1Nc2ccc(C(=O)N(CCC3CCNCC3)CCC3CCNCC3)cc2CN(C)C1=O
Reaction time: 5 h
Yield: 179.7 %

Procedure:
A mixture of methyl (±)-7-[[bis[2-(4-pyridinyl)ethyl]amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.35 g, 0.65 mmole), PtO2 (0.11 g, 0.48 mmole), 1.0 N HCI (1.3 mL, 1.3 mmole), and MeOH (30 mL) was hydrogenated at 45 psi in a Parr apparatus. After 5 h, the reaction mixture was filtered through celite® and concentrated to give the crude title compound (0.6 g) which was used without further purification. MS(ES) m/e 514.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH2:12][O:13][CH:14]=[CH:15][CH:16]=2)[CH:4]([CH2:17][O:18][Si](C2C=CC=CC=2)(C2C=CC=CC=2)C(C)(C)C)[O:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]1([CH3:36])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH2:12][O:13][CH:14]=[CH:15][CH:16]=2)[CH:4]([CH2:17][OH:18])[O:3]1
Reactant: CC1(C)OC(CCCCC2=CC=COC2)C(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)OC(CO)C(CCCCC2=CC=COC2)O1
Yield: 78.4 %

Procedure:
A solution of 2,2-dimethyl-4-[3-oxa-4-phenyl butyl]-5-[3,3-diphenyl-3-t-butyl-2-oxa-3-silapropyl]-1,3-dioxacyclopentane [490 mg, 0.97 mmol] prepared in Part F in THF [5 mL] was treated with tetra-n-butylammonium fluoride [1M in THF, 3 mL] at ambient temperature for two hours. The solvent was removed and the resulting residue was diluted with ether, washed with saturated sodium chloride and dried [MgSO4 ]. The crude product was purified by flash column chromatography to give 204 mg of 2,2-dimethyl-4-[3-oxa-4-phenyl butyl]-5-hydroxymethyl-1,3-dioxacyclopentane. NMR [CDCl3 ]: δ7.33 [s, 5H], 4.52 [s, 2H], 4.30-4.00 [m, 2H], 3.60 [t, 4H], 2.18 [t, 1H, --OH], 1.86 [dt, 2H], 1.43 [s, 3H], 1.33 [s, 3H].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:23]45[CH2:32][CH:27]6[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]6)[CH2:24]4)[CH2:30]5)=[C:17]([OH:22])[CH:18]=3)[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[OH:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([C:23]45[CH2:24][CH:25]6[CH2:26][CH:27]([CH2:28][CH:29]([CH2:31]6)[CH2:30]4)[CH2:32]5)=[C:17]([O:22][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:18]=3)[CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCCI
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1O
Product: CCCCCCOc1cc2ccc(-c3ccc(C(=O)OC)c(O)c3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 54.6 %

Procedure:
Following the basic procedure of Example 11, by reacting 430 mg (1 mmol) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 180 μl (1.2 mmol) of 6-iodohexane, 280 mg (55%) of methyl 2-hydroxy-4-[7-(1-adamantyl)-6-hexyloxy-2-naphthyl]benzoate were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32]S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:65]1([C@H:71](O)[CH2:72][CH3:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32][C@H:71]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:72][CH3:73])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC[C@@H](O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-3-{(R)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.7 g) was dissolved in 10 mL dry THF and 1320 mg triphenylphosphine and 691 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 minutes, then 992 μL DIAD was added dropwise. The reaction was stirred at room temperature for 3 hours and was evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc). The resulting residue was dissolved in 20 mL dry DMF, then 526 μL mercaptoacetic acid and 2.5 mL DBU were added at room temperature. The reaction was stirred for 30 minutes and was partitioned between saturated aqueous NaHCO3 and diethyl ether. The aqueous layer was washed again with diethyl ether and the organic layers were combined. The organic layer was washed with aqueous NaHCO3, dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc (first column)) and (hexanes to 1:1 DCM-hexanes to DCM to 9:1 DCM-EtOAc (second column)) to give 1.05 g of the product after drying.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][N:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4].[CH2:22](I)[CH3:23].O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][CH2:22][CH3:23])=[CH:16][N:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cnn(-c2ccc(CO)cn2)c1C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1ccc(-n2ncc(C(=O)OCC)c2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (175 mg) was added at room temperature to a solution of 1-[5-(hydroxymethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (935 mg) described in Reference Example 41(3) in N,N-dimethylformamide (18 ml), and stirred at the same temperature for 30 minutes. Ethyl iodide (0.6 ml) was added and the mixture was stirred at 80° C. for two hours. Then, Sodium hydride (175 mg) and ethyl iodide (0.6 ml) were added and stirred at 80° C. for two hours. After the reaction, the reaction solution was cooled to room temperature, water was added and extracted with ethyl acetate four times. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified with a silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[5-(ethoxymethyl)pyridin-2-yl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (223 mg) as a white solid.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Al+3].[Cl-].[Cl-].[Cl-].[Br:20]Br>C(Cl)Cl>[Br:20][CH:2]([CH2:3][CH3:4])[C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5]
Reactant: CCCC(=O)c1ccc(NC(C)=O)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(Br)C(=O)c1ccc(NC(C)=O)cc1
Reaction time: 0.17 h

Procedure:
Step-2: A solution of N-(4-butyryl-phenyl)acetamide (3.47 g, 16.9 mmol) in 100 mL of anhydrous DCM was cooled to 0° C. under N, and treated with AlCl3 (180 mg, 1.35 mmol). Approximately 10 mL of Br2 was added and the mixture was stirred for 10 min. The reactor was removed from the cooling bath and the remaining Br2 was added dropwise via syringe over 0.5 min. After 3 hr, the dark orange color of Br2 had faded and by 3¼ hr a precipitate had formed. The reaction was quenched with saturated NaHCO3. The phases were separated and the aqueous phase extracted three times with DCM. The combined extracts were dried over Na2SO4, filtered through a Celite® pad and concentrated in vacuo to give N-(4-(2-bromobutanoyl)phenyl)acetamide which was used without purification. MS ESI: m/z 284.10 [M+].
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:3]1=2.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:3]1=2
Reactant: NC(=O)c1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Yield: 82.4 %

Procedure:
From 3.2 g (0.01 mol) of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxamide (Example 25), 90 ml of phosphorus oxychloride and 50 ml of chloroform and refluxing for twenty-four hours, following the procedure of Example 27, there is obtained 2.5 g of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carbonitrile; mp 349°-351° C. after recrystallization from pyridine.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([O:14][CH2:15][CH3:16])[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:22].C(OCC)(=O)C>C(Cl)Cl>[CH2:15]([O:14][C:5]1[CH:4]=[C:3]([S:2]([CH3:1])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(SC)cc1OCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S(C)=O)cc1OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.7 %

Procedure:
To a cooled solution of ethyl 4-methylthio-2-ethoxybenzoate (1.1 g, 4.6 mmol) in methylene chloride (40 mL) was added 3-chloroperoxybenzoic acid (1.1 g, 4.5 mmol, 77%) in several portions. The reaction mixture was stirred at 0° C. for 15 min, after which TLC (50% ethyl acetate in hexanes) showed consumption of starting material. The reaction mixture was quenched with a solution of sodium thiosulfate and neutralize with a solution of sodium bicarbonate. The product was extracted three times with methylene chloride. The organic layer was washed with sodium bicarbonate, dried over magnesium sulfate, and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 50% ethyl acetate in hexanes) gave ethyl 2-ethoxy-4-methanesulfinylbenzoate as a yellow oil (0.70 g, 58%). LC-MS: 257.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1.CO.[BH4-].[Na+]>CCOC(C)=O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3F)CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(O)c3ccccc3F)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a 50-mL round-bottomed flask charged with N-(3-{1-[7-(2-fluorophenyl)-7-oxoheptyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.0 mmol) and methanol (20 mL) was added NaBH4 (7.5 mmol) at 0° C. in an ice-bath. The reaction mixture was warmed to 25° C. and stirred for 2 h. The reaction was monitored by TLC (EtOAc:MeOH 95:5). If necessary, another 5.0 mmol of NaBH4 was added to the reaction mixture and the reaction mixture was refluxed for 1 h. The reaction was quenched with water (5.0 mL) and diluted with EtOAc (10 mL). The organic layer was separated, washed with saturated NaHCO3 solution (10 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (EtOAc:MeOH 97:3) to give the desired product (90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
Part A. A solution of 4-chloro-6-methyl-3-nitropyridone (5.0 g, 26.5 mmol) in acetonitrile (93 mL) was treated with benzylamine (2.89 mL, 26.5 mmol) and diisopropylethylamine (5.54 mL, 31.8 mmol). The mixture was heated to reflux for 4 hrs., then cooled to ambient temperature and allowed to stir for 12 hrs. The mixture was partitioned between dichloromethane and water (200 mL each), and the aqueous layer was extracted with dichloromethane (200 mL). The extracts were washed in sequence with water (200 mL) and combined, and the resulting precipitate was collected by filtration. The filtrate was dried over sodium sulfate, refiltered and evaporated to afford a second crop of crystalline product, 4-benzylamino-6-methyl-3-nitropyridone (6.74 g total, 26.0 mmol, 98%). m.p. 246-247° C. TLC RF 0.35 (10:90 isopropanol-ethyl acetate). 1H NMR (300 MHz, CDCl3): d 10.48 (1H, br s), 9.69 (1H, br s), 7.41-7.26 (5H, m), 5.66 (1H, s), 4.57 (2H, d, J=5.5 Hz), 2.26 (3H, s). MS (NH3-CI): m/e 261 (10), 260 (70), 226 (100).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([Cl:17])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[Cl:17][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]1[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=1)[C:6]([C:4]([OH:3])=[O:5])=[C:14]2[O:15][CH3:16]
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1OC
Reactant: BrCc1cccc2ccccc12
Product: COc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(Cl)cc12

Procedure:
Using general procedure B, 5-chloro-3-methoxy-1H-indole-2-carboxylic acid ethyl ester (Lit. 9) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 364.1 ([M−H]−).