Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:20][C:21]1[C:26]2[N:27]=[C:28]([CH2:35][CH2:36][CH3:37])[N:29]([CH2:30][CH2:31][CH2:32][CH2:33]O)[C:25]=2[C:24]([CH3:38])=[C:23]([CH3:39])[N:22]=1.[C:40]([O:44][C:45]([O:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:46])([CH3:43])([CH3:42])[CH3:41].N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C>[NH2:20][C:21]1[C:26]2[N:27]=[C:28]([CH2:35][CH2:36][CH3:37])[N:29]([CH2:30][CH2:31][CH2:32][CH2:33][N:48]([O:47][C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:25]=2[C:24]([CH3:38])=[C:23]([CH3:39])[N:22]=1
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
Triphenylphosphine (0.845 g, 3.22 mmol, 1.1 eq), 4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butan-1-ol (0.81 g, 2.93 mmol), and tert-butyl N-(tert-butoxycarbonyloxy)carbamate (0.751 g, 3.22 mmol) were dissolved in DMF and cooled to 0° C. Diisopropyl azodicarboxylate (0.634 mL, 3.22 mmol) was added dropwise over 10 minutes to the reaction mixture and was allowed to warm to ambient temperature and stirred overnight. Analysis by HPLC indicated the reaction was incomplete. An additional amount of reagents (0.5 eq) were added to the reaction mixture (cooled to 0° C. before addition of the diisopropyl azodicarboxylate) and stirred for an additional 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate (150 mL), washed with a water and brine mixture (1:1, 4×30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on a BIOTAGE HORIZON High-Performance Flash Chromatography instrument (silica gel, eluting with 2-30% CMA in chloroform) and concentrated under reduced pressure to provide 1.19 g of tert-butyl 4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl[(tert-butoxycarbonyl)oxy]carbamate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[F:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[F:15][C:16]1[N:21]=[C:20]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1cccc(F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Temperature: 120 °C
Yield: 48.6 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (0.737 g, 3.76 mmol) and 6-fluoropicolinaldehyde (0.470 g, 3.76 mmol) in N,N-dimethylacetamide (20 mL), NaHSO3 (58.5% SO2 content, 1.0 g, 5.63 mmol) and p-toluenesulfonic acid monohydrate (0.143 g, 0.75 mmol) were added. The reaction was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (50 mL) and saturated NaHCO3 solution was added to adjust the pH to 8. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.550 g, 49%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.28-8.33 (m, 1H), 8.19-8.27 (m, 1H), 7.47 (dd, J=8.01, 1.76 Hz, 1H), 6.82 (d, J=2.34 Hz, 1H), 6.62 (d, J=2.34 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −68.08 (d, J=8.03 Hz); ESI MS m/z 302 [M+H]+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]([C:13]1[CH:14]=[C:15](I)[CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][N:19]=[C:18]2[NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.C1COCC1>[NH2:10][C:11]([C:13]1[CH:14]=[C:15]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][N:19]=[C:18]2[NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c(C(N)=O)cc(I)cc23)C1
Reactant: OB(O)c1ccccc1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c(C(N)=O)cc(-c4ccccc4)cc23)C1
Reaction time: 0.33 h

Procedure:
Combined phenylboronic acid (16.18 mg; 0.13 mmol; 1.20 eq.), tert-butyl (3S)-3-{[8-(aminocarbonyl)-6-iodoquinazolin-4-yl]amino}piperidine-1-carboxylate (55.00 mg; 0.11 mmol; 1.00 eq.), and bis(tri-tert-butylphosphoranyl)palladium (5.67 mg; 0.01 mmol; 0.10 eq.) in a microwave tube. Then added THF (0.70 ml) followed by cesium carbonate (0.22 ml; 2.00 M; 0.44 mmol; 4.00 eq.). Heated reaction in the microwave at 130 deg C. for 20 minutes. LCMS: M+1=448 major peak (266 present). Concentrated reaction. Purified by silica gel chromatography (Biotage; 10 g column; 15 mL/min; 1-10% MeOH/CH2Cl2). Concentrated product to give an oil. LCMS: M+1=448 major peak.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[S:20][C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:22]([CH3:25])[C:23]=2[Br:24])[O:7][C@@H:6]1[CH2:35][O:36]C(=O)C)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Br:24][C:23]1[C:22]([CH3:25])=[C:21]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=2)[S:20][C:19]=1[C@H:8]1[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:35][OH:36])[O:7]1
Reactant: CCc1ccc(Cc2sc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(Br)c2C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(Cc2sc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(Br)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a suspension of acetate (56) (200 mg, 0.320 mmol) in MeOH (5 mL) was added NaOMe (25 wt % in MeOH, 0.1 mL) at room temperature. The mixture was stirred at room temperature for 1 hr. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (C18) to provide the title compound 58 (80 mg, 55%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:19][C:18]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(=O)C>ClCCl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:18]2[N:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:35])[N:17]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2nc(-c3ccc(F)cc3)nc2-c2ccc(F)cc2)CC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
3.1 g 4-(2-(3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl)-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 20 ml dichlormethane and 20 mL trifluor acetic acid was added. The reaction was stirred 24 h at RT and the solvent was evaporated. 10% potassiumcarbonate solution was added to the residue. The precipate was filtered and crystallized with a mixture of acetonitrile and isopropylether to give 2.3 g of the desired compound. (M+H)+: 384
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CC(N(C)C)=O.[C:17]12([CH2:27][NH2:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:17]12([CH2:27][NH:28][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH2:1])[N:7]=3)=[O:10])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: Nc1cccc(C(=O)O)n1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Nc1cccc(C(=O)NCC23CC4CC(CC(C4)C2)C3)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 6-aminopyridine-2-carboxylic acid (10 g, 72.4 mmol) in DMF (200 mL) at RT, is sequentially added 25.2 mL of DMA (144.8 mmol), 12 g of 1-admantylmethylamine (72.4 mmol) and 38.4 g of BOP (86.88 mmol). The resulting mixture is stirred at RT for 16 h. The reaction mixture is added to 400 mL of ice/water. Filtration affords the title compound which is used in subsequent reactions without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:4]([C@@H:5]([CH2:31]C)[C@@H:6]([OH:30])[C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH2:3]1.[OH-].[Na+].Cl>CCO>[OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:4]([C@@H:5]([CH3:31])[C@@H:6]([OH:30])[C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: CCOC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)[C@H](CC)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1[C@@H](O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Yield: 43.2 %

Procedure:
Ethyl 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oate (4) (0.10 g, 0.22 mmol) was dissolved in 15 ml of 96% EtOH and added to 10% NaOH in 96% EtOH (2 ml, 5 mmol). The mixture was refluxed for 4 hours. The mixture was acidified with 3N HCl and extracted with ethyl acetate (3×20 ml). The combined organic fractions were washed with a saturated NaCl solution (1×50 ml), dried with Na2SO4 and evaporated under vacuum. The residue was chromatographed on silica gel column; elution by CHCl3:MeOH (95:5) yielded 3α,7α-dihydroxy-6α-methyl-5β-cholan-24-oic acid (6) (0.04 g, 0.095 mmol, 43% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:9])=[N:4][CH:5]=[N:6][C:7]=1[SH:8].[C:10](OCC(Cl)=O)(=[O:12])[CH3:11]>N1C=CC=CC=1>[SH:8][C:7]1[C:2]2[N:1]=[C:11]([CH2:10][OH:12])[S:9][C:3]=2[N:4]=[CH:5][N:6]=1
Reactant: Nc1c(S)ncnc1S
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: OCc1nc2c(S)ncnc2s1
Temperature: 115 °C

Procedure:
A cooled (ice bath) suspension of 5-aminopyrimidine-4,6-dithiol (Intermediate 41) (40.0 g) in pyridine (500 mL) was stirred under an inert atmosphere atmosphere. Acetoxyacetyl chloride (38 mL) was added over 10 minutes, the ice bath was removed and the mixture stirred at ambient temperature overnight. The mixture was concentrated in vacuo and azeotroped three times with toluene (200 mL). The residue was suspended in 2N HCl, and heated at 115° C. for 5 hours, and allowed to cool to ambient temperature overnight. The resulting suspension was filtered, washed with water (200 mL) and ether (200 mL) to give the title compound as a pale brown solid (48.3 g, 97%) (containing 10% of (7-mercapto[1,3]thiazolo[5,4-d]pyrimidin-2-yl)methyl acetate);
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:12][C:13]([CH3:23])([CH2:21][CH3:22])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:12][C:13]([CH3:23])([CH2:21][CH3:22])[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CCC(C)(Cc1ccc(Cl)c(NCc2ccccc2)c1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C)(Cc1ccc(Cl)c(N)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.20 g (about 5.67 mmol) of (+/−)-tert-butyl 2-[3-(benzylamino)-4-chlorobenzyl]-2-methylbutanoate were dissolved in 130 ml of ethyl acetate, and 100 mg of palladium on carbon (10%) were added. At RT, the reaction mixture was stirred under an atmosphere of hydrogen at atmospheric pressure overnight. The reaction mixture was then filtered off with suction through kieselguhr, the residue was washed thoroughly with ethyl acetate and the combined filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1 to 30:1). This gave 924 mg (54.7% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.CN(C)C1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO>[C:22]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1)(=[O:24])[CH3:23]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(N)n1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(C)cc(C)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-amino-4,6-dimethyl-3-nitropyridine (14.91 g) and N,N-dimethylaniline (80 ml) was heated at 70° C. To the solution was added dropwise acetyl chloride at 70° C. and the mixture was stirred at 70° C. for 2.5 hours. To the reaction mixture was added ethyl acetate(500 ml). The organic layer was separated. and washed with water three times and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was dissolved in hot isopropyl ether (200 ml), and cooled to ambient temperature. After the mixture was cooled in an ice bath for an hour, the resulting solid collected by filtration, was washed with cold isopropyl ether, purified by flash column chromatography on silica gel eluted by a mixture of ethyl acetate and n-hexane (1:9 then 2:1) to yield a brown oil and the oil was dissolved methanol(40 ml). To the solution was added saturated sodium bicarbonate (10 ml), and stirred at room temperature for 70 minutes. The mixture was diluted with ethy acetate, organic layer was separated, and the aqueous layer was extracted with ethy acetate. The combined ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentated in vacuo. To the residue was added diisopropyl ether (50 ml). After cooling, the solid was collected by filtration and washed diisopropyl ether to give 2-acetylamino-4,6-dimethyl-3-nitropyridine(5.56 g) as colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=3)[N:9]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[NH2:61][CH:62]1[CH2:67][CH:66]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:65][N:64]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:63]1>CN(C=O)C>[C:68]1([CH:66]2[CH2:67][CH:62]([NH:61][C:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]([C:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:8]=[C:7]4[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[O:17])[CH2:63][N:64]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[CH2:65]2)[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1
Reactant: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)CC(c2ccccc2)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CC(c2ccccc2)C1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a microwave vial equipped with a stir bar was added 3-pyridin-4-yl-1-trityl-1H indazole-5-carboxylic acid (155.4 mg, 0.323 mmol), HOBT (74.1 mg, 0.484 mmol), EDC (93 mg, 0.484 mmol), DIPEA (225 μl, 1.291 mmol), tert-butyl 3-amino-5-phenylpiperidine-1-carboxylate (89 mg, 0.323 mmol), and DMF (3227 μl). The vial was sealed and heated to 45° C. The LCMS taken after 4 hours indicates formation of the desired product. The material was filtered through a column pre-packed with celite and was concentrated under reduced pressure. A column was run from 100% hexanes to 100% ethyl acetate. The desired product eluted and fractions were collected and concentrated in vacuo. The material was dissolved in acetonitrile and water and was dried on the lyophilizer.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]4)=[CH:17][C:15]3=2)[CH:10]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl.CCCCCC>[CH3:5][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]4)=[CH:17][C:15]3=2)[CH:10]=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)c1cc2ccc3cc4ccccc4cc3c2[nH]1
Reactant: COS(=O)(=O)OC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc3cc4ccccc4cc3c2n1C
Yield: 96.2 %

Procedure:
Using the procedure outlined in Example 34A except that dimethyl sulfate was used as the alkylating agent, ethyl 1H-naphth[2,3-g]indole-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 96.2% yield of ethyl 1-methyl-1H-naphth[2,3-g]indole-2-carboxylate, mp 165°-165.5°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[CH:18]1([P:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([SH:26])=[S:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([P:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([S:26][CH2:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=2)=[S:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(CSP(=S)(C2CCCCC2)C2CCCCC2)cc(C(C)(C)C)c1O

Procedure:
3,5-di-t-butyl-4-hydroxybenzyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain 3,5-di-t-butyl-4-hydroxybenzyl dicyclohexylphosphinodithioate, m.p. 129°-131° C, which on testing lasted 475 hours* longer than the control. The total number of hours required to reach failure was 1.9 times that of the control.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[N:11][C:5]2[S:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:12]=[N:11][C:5]2[S:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1
Reactant: O=C1CSc2ncc(Cl)cc2N1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Clc1cnc2c(c1)NCCS2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-Chloro-1H-pyrido[2,3-b][1,4]thiazin-2(3H)-one (1.2 g, 5.98 mmol) was suspended in THF (5.0 mL), cooled to 0° C. and treated with BH3-THF (47.8 mL, 47.8 mmol, 1.0M in THF). The reaction was stirred at rt for 30 min and heated at 45° C. for 2 h. At this time more BH3-THF (47.8 mL, 47.8 mmol, 1.0M in THF) was added and the reaction was heated at 45° C. for 16 h. The reaction was then treated with 100 mL of MeOH and it was refluxed for 30 min. After this time the reaction was cooled to rt and acidified to pH 2 with aqueous HCl. The reaction was then basified to pH 14 with aqueous NaOH and the mixture was then extracted with EtOAc (3×80 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. The resulting white solid was triturated with hot EtOAc and the mixture was allowed to cool to rt for 20 min. After filtration, the precipitate was dried over MgSO4 and evaporated in vacuo to give 7-chloro-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.60 (1H, d, J=2.3 Hz), 6.85 (1H, d, J=2.2 Hz), 6.52 (1H, t, J=3.0 Hz), 3.43-3.50 (2H, m), 3.04-3.15 (2H, m). Mass Spectrum (ESI) m/e=187.0 (M+1).
Reaction SMILES: [CH:1]([S:4][C:5]1[C:10]([CH2:11][OH:12])=[CH:9][N:8]=[C:7]([CH3:13])[N:6]=1)([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23](O)=[C:22]([F:28])[CH:21]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:12][CH2:11][C:10]2[C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([CH3:13])=[N:8][CH:9]=2)=[C:22]([F:28])[CH:21]=1)[CH3:15]
Reactant: Cc1ncc(CO)c(SC(C)C)n1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: CCOC(=O)CCc1cc(F)c(OCc2cnc(C)nc2SC(C)C)c(F)c1
Yield: 73.1 %

Procedure:
(4-Isopropylsulfanyl-2-methyl-pyrimidin-5-yl)-methanol (0.006 g, 0.03 mmol) obtained in Step B of Preparation Example 40 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.007 g, 0.03 mmol) obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 24 to obtain the title compound (0.009 g, 72%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=1)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:1][NH:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=CNc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
0.338 g (0.001 mol) of 1-benzyl-piperidin-4-yl 4-formamido-benzoate was dissolved in 10 ml of THF, treated with 4.5 ml (0.0045 mol) of 1M BH3 -THF solution and boiled at reflux for 18 hrs. The reaction mixture was treated with 9 ml of 1N aqueous HCI and stirred at room temperature for 1 hr. The mixture was made basic with sat. sodium carbonate solution, extracted with ethyl acetate and the organic phase was subsequently extracted with sat. sodium chloride solution. It was dried over sodium sulfate and concentrated and the residue was chromatographed over silica gel with ethyl acetate/toluene (1:2). 0.105 g (32%) of 1-benzyl-piperidin-4-yl 4-methylamino-benzoate was obtained as a colorless oil.