Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)[NH2:30]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:24]3[O:25][N:30]=[C:29]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[N:28]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(=NO)c1cccnc1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccnc3)no2)C1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 40.5 mg (0.295 mmol) of N′-hydroxypyridine-3-carboximidamide were reacted according to the General Method 1. Yield: 28.8 mg (21% of theory).
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]3[NH:21][C:20](=S)[CH2:19][N:18]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[C:16]=3[CH:30]=2)=[O:11])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:21]=[C:20]([NH:1][NH2:2])[CH2:19][N:18]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[C:16]=3[CH:30]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)=NCC(=S)N2
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: NNC1=Nc2ccc(C(=O)c3ccc(Cl)cc3)cc2C(c2cccc(Cl)c2)=NC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Hydrazine (1.5 ml) was added to a mixture of intermediate (13) (0.00353 mol) in THF (20 ml). The mixture was stirred at room temperature for 15 min. K2CO3 10% was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 1.5 g (100%) of (4-chlorophenyl)[5-(3-chlorophenyl)-2-hydrazino-3H-1,4-benzodiazepin-7-yl]-methanone (intermediate 14).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)CO.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29]([SH:31])[CH3:30]>C(O)(C)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([S:31][CH2:29][CH3:30])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: OCCO
Solvent: CC(C)O
Product: CCSc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Lit. Org. Lett. 2002, 4(20), 3517-3520. To a stirred suspension of 0.66 mmol 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 5 ml isopropanol were added 1.32 mmol ethylene glycol, 0.07 mmol copper(I) iodide, 1.32 mmol cesium carbonate, 0.13 mmol 1,20-phenanthroline and 3.29 mmol ethyl mercaptan and the reaction mixture was stirred at 120° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid. MS (m/e): 260.0 ({37Cl}[M+H-Me2C═CH2]+, 42%), 258.1 ({35Cl}[M+H-Me2C═CH2]+, 100%).
Reaction SMILES: CN(C)C=O.[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:24])=[N:16]2)[CH2:8][CH2:7]1.Br.Br[CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH:24][CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[N:16]2)[CH2:8][CH2:7]1
Reactant: Nc1nn(CCCN2CCOCC2)c2ccccc12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1nn(CCCN2CCOCC2)c2ccccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 4.21 g of 1-(3-morpholinopropyl)-3-aminoindazole obtained by the same method as described in Example 149, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 3.50 g of 1-(3-morpholinopropyl)-3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 58%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: NCC1CCOCC1
Product: O=[N+]([O-])c1cc(Br)ccc1NCC1CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 4-bromo-1-flouro-2-nitrobenzene (Wako Pure Chemical Industries, Ltd.) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[CH3:12].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=1[CH3:12]
Reactant: COC(=O)c1ccc(CO)cc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a 0° C. solution of 4-hydroxymethyl-2-methyl-benzoic acid methyl ester (0.49 g, 2.7 mmol) in methylene chloride (8.0 mL) is added sodium bicarbonate (0.46 g, 5.4 mmol) and Dess-Martin periodinane (0.14 g, 3.3 mmol) sequentially. The reaction mixture is stirred at room temperature for 1.0 h and quenched with water (2.0 mL). The mixture is partitioned between CH2Cl2 (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to give the title compound as syrup (0.35 g, 72%). 1HNMR (CDCl3) (ppm): 2.6 (3H, s), 3.85 (3H, s), 7.65-8.0 (3H, m), 10.0 (1H, s).
Reaction SMILES: Br.[NH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:12][C:13](=[O:14])[N:8]2[CH2:7][CH2:6][CH2:5]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([O:31][CH3:32])[CH:23]=1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][CH2:3][CH:4]2[C:9]3=[N:10][C:11]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][N:16]=4)=[CH:12][C:13](=[O:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)=[O:27])=[C:24]([O:31][CH3:32])[CH:23]=1
Reactant: NCC1CCCn2c1nc(-c1ccncn1)cc2=O
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: Br
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1C(=O)NCC1CCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a solution of 0.067 g (0.20 mmol) of 9-aminomethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one hydrobromide (1:1) dissolved in 2.00 mL of dimethylformamide were added 0.053 g (0.20 mmol) of 4-chloro-2-methoxy-benzoic acid, 0.030 mL (0.20 mmol) of diethylcyanophosphonate and 0.140 mL (1.00 mmol) of triethylamine. The resulting mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added, the mixture was extracted with ethyl acetate and the organic phase was washed with a saturated solution of ammonium chloride, dried over sodium sulfate and concentrated. A purification on silica gel (eluant: dichloromethane with 5% of methanol) gave 0.049 g (57%) of pure product obtained in the form of free base as a solid.
Reaction SMILES: C[O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([C:24]2[NH:28][C:27]([C:29]3[O:30][CH2:31][C@@H:32]([C@@H:34]([OH:36])[CH3:35])[N:33]=3)=[CH:26][CH:25]=2)[CH:10]=[C:11]([O:13][C:14]2[CH:19]=[N:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=2)[CH:12]=1)[CH3:5].B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[OH:36][C@H:34]([C@@H:32]1[CH2:31][O:30][C:29]([C:27]2[NH:28][C:24]([C:9]3[CH:8]=[C:7]([CH:12]=[C:11]([O:13][C:14]4[CH:19]=[N:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][N:15]=4)[CH:10]=3)[O:6][C@@H:4]([CH3:5])[CH2:3][OH:2])=[CH:25][CH:26]=2)=[N:33]1)[CH3:35]
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[C@H](O)[C@@H]1COC(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)CO)c3)[nH]2)=N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
(1S)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{[5-(methylsulfonyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (204 mg, 0.395 mmol) synthesized in Example (112d) was dissolved in methylene chloride (5.0 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.80 mL, 0.80 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 1.5 hours under nitrogen atmosphere. To this reaction solution, a 1N aqueous sodium hydroxide solution (10 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-5%) to afford the desired compound (159 mg, yield 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:17][C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=2[F:27])=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:61][N:62]1[CH2:68][CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[O:17][C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:65]3[CH2:66][CH2:67][CH2:68][N:62]([CH3:61])[CH2:63][CH2:64]3)=[O:23])=[CH:20][C:19]=2[F:27])=[CH:15][CH:14]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(C(=O)O)cc2F)o1
Reactant: CN1CCCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCCN(C(=O)c2ccc(-c3ccc(C=C4C(=O)Nc5ccc(Cl)cc54)o3)c(F)c2)CC1
Temperature: 25 °C

Procedure:
To 4-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)-3-fluorobenzoic acid (40 mg, 0.104 mmol) in DMF was added HBTU (60 mg, 0.157 mmol) and DIEA (55 μL, 0.313 mmol). The mixture was stirred at room temperature then was added 1-methylhomopiperazine (16 μL, 0.125 mmol) and allowed to stir at room temperature. The solid formed was isolated by filtration and purified by HPLC to yield 5-chloro-3-((5-(2-fluoro-4-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=480).
Reaction SMILES: [O:1]=[C:2]1[C@@H:6]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4][O:3]1.S(=O)(=O)(O)O.[C:23](=O)([O-])[OH:24].[Na+]>CO>[CH2:10]([O:9][C:8]([NH:7][C@@H:6]([CH2:5][CH2:4][OH:3])[C:2]([O:24][CH3:23])=[O:1])=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(N[C@H]1CCOC1=O)OCc1ccccc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](CCO)NC(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To the compound (500 mg) obtained in Step 1 were added methanol (5 ml) and conc. sulfuric acid (30 μl), and the mixture was stirred overnight at 60° C. To the reaction mixture was further added sodium hydrogen carbonate (250 mg), and the mixture was stirred at room temperature for 2 hrs. After celite filtration of the reaction mixture, the solvent was evaporated to give the title compound as a crude product.
Reaction SMILES: [CH:1]#[CH:2].C(=O)=O.CO.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH3:25])=[O:17]>O1CCCC1>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[C:16]([C:10]1[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH3:8])([OH:17])[C:1]#[CH:2]
Reactant: C#C
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2C)c(C)c1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CO
Product: C#CC(O)(c1ccc(C)cc1C)c1ccc(C)cc1C
Reaction time: 8 h

Procedure:
0.5 g of Fe(NO3)3.9H2O and 49 g of sodium are added to liquid ammonia (1.5 ) to produce sodium amide. Then acetylene gas is introduced into the reaction mixture at a temperature of -40° C. to -65° C. (whilst cooling using dry ice-methanol) for one hour while stirring. Then, an anhydrous tetrahydrofuran solution containing 476 g of di-(2,4-dimethylphenyl) ketone is added dropwise to the reaction mixture while cooling and stirring. After further stirring for 2 hours, the mixture is left at room temperature overnight. After removal of ammonia from the reaction solution by evaporation, 3N diluted HCl (300 ml) is added to the solution. After extraction with ether, the ether layer is washed with water and dried. After removal of ether by evaporation, 1,1-bis(2,4-dimethylphenyl)-2-propyn-1-ol is obtained as colourless oily product with a yield of 450 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[CH:26][C:7](/[CH:8]=[C:9]2/[C:10](=[O:25])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[C:12](=[O:14])[S:13]/2)=[CH:6][CH:5]=1)[CH3:2].[Sn](Cl)Cl>C(Cl)(Cl)Cl.C(O)C.ClCCl>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:11]2[C:10](=[O:25])/[C:9](=[CH:8]/[C:7]3[CH:26]=[CH:27][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)/[S:13][C:12]2=[O:14])=[CH:17][CH:18]=1
Reactant: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc([N+](=O)[O-])cc3)C2=O)cc1
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOc1ccc(/C=C2\SC(=O)N(Cc3ccc(N)cc3)C2=O)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of compound 28n (100 mg, 0.26 mol) in 10 mL of chloroform-ethanol co-solvent (ratio, 4:1) was added tin(II) chloride.dihydrate (293 mg, 1.30 mmol). The reaction mixture was stirred at 45° C. overnight. The reaction mixture was diluted with dichloromethane and washed with sat'd aqueous NaHCO3, collected the organic layer, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (10% ethyl acetate in dichloromethane) to afford 88 mg (97.0%) of pure 28o as a yellow-orange solid.
Reaction SMILES: [NH3:1].O.[C@@H:3]1([N:12]2[C:22]3[N:21]=[C:19]([NH2:20])[NH:18][C:16](=O)[C:15]=3[N:14]=[CH:13]2)[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]1[OH:5].Cl[Si](C)(C)C>O>[NH2:20][C:19]1[N:21]=[C:22]2[C:15]([N:14]=[CH:13][N:12]2[C@@H:3]2[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]2[OH:5])=[C:16]([NH2:1])[N:18]=1
Reactant: N
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: C[Si](C)(C)Cl
Solvent: O
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
This variation of the procedures of Robins, et al. supra, eliminated the need to utilize liquid ammonia in the reaction mixture since the ammonia molecule is generated in situ from the silazane reagent and the water of hydration of the guanosine hydrate starting material. Further, the use of chlorotrimethylsilane was not necessary nor was it necessary to conduct the reaction under anhydrous conditions, do a preliminary evaporation, or open and re-seal the Parr bomb under a dry nitrogen atmosphere.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[C@@H:9]([CH3:31])[C:10]([NH:12][C@@H:13]([CH:28]([CH3:30])[CH3:29])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:57][C:58]1[CH:64]=[CH:63][C:62]([CH3:65])=[CH:61][C:59]=1[NH2:60].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[F:57][C:58]1[CH:64]=[CH:63][C:62]([CH3:65])=[CH:61][C:59]=1[NH:60][C:25]([C@H:17]1[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:31])[CH:28]([CH3:30])[CH3:29])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18]1)=[O:27]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)O
Reactant: Cc1ccc(F)c(N)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)c1
Reaction time: 0.08 h
Yield: 79.4 %

Procedure:
To a solution of (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-3-methylbutanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Intermediate 8) (50 mg, 111 μmol, Eq: 1.00) and diisopropylethylamine (58.4 μL, 334 μmol, Eq: 3) in DCM (1.5 mL) was added diphenylphosphinic chloride (58.0 mg, 46.7 μL, 245 μmol, Eq: 2.2). After stirring for 5 min, 2-fluoro-5-methylaniline (21 mg, 167 μmol, Eq: 1.5) was added and the resulting solution was stirred at rt for 2 days. The reaction mixture was poured into 0.1 M aqueous KHSO4 (20 mL) and extracted with EtOAc. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 40% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-5-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate as a colorless oil (49 mg), m/z=556 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][S:36][CH2:37][CH2:38]O.CCOC(/N=N/C(OCC)=O)=O>O>[CH3:35][S:36][CH2:37][CH2:38][O:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:6][CH:7]=1
Reactant: CCCCCC(=O)Nc1ncc(O)cn1
Reactant: CSCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCCCCC(=O)Nc1ncc(OCCSC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
N-(5-Hydroxypyrimidin-2-yl)hexanamide (8.18 g, 39 mmol) and triphenylphosphine (20.5 g, 78 mmol) were mixed, and dried under reduced pressure, and then the atmosphere was substituted with argon. These substances were dissolved by heating in anhydrous N,N-dimethylformamide (80 mL), and the solution was cooled to room temperature, and then added with 2-methylthioethanol (5.4 g, 58.6 mmol). The reaction mixture was added with DEAD (2.2 M solution in toluene, 26.6 mL, 58.6 mmol) on an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with water (300 mL), and the mixture was stirred for 15 minutes, and then and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, the resulting residue was dissolved in saturated ammonia in methanol (60 mL), and the solution was left at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→hexane:acetone=2:1), and the concentrated residue was dissolved in chloroform by heating. The crystals obtained by ice cooling of the solution were removed, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to obtain N-{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}hexanamide (6.8 g, 61%) as pale dark brown solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1>[CH2:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][CH:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[CH2:13][CH2:14]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C1CCN(C2CCCN(C(=O)OCC)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCC(N2CCC(C(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 147.9 %

Procedure:
Ethyl 4-[4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (1.10 g, 3.4 mmol) was dissolved in THF (60 mL) at rt and 1M LiOH sol. (10 mL) was added. The reaction mixture was stirred at rt for 5 d. The pH was carefully adjusted to pH 6 by addition of concentrated hydrochloric acid, the solvents were removed in vacuo, to give 1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid (1.5 g) as a viscous pale yellow oil, Intermediate 2, which was used crude in subsequent reactions.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A process as described in claim 1 where 4-(3,5-di-t-butyl-4-hydroxyphenyl)-butane-2-one is reacted with lithium aluminum hydride to yield 4-(3,5-di-t-butyl-4-hydroxyphenyl)-butane-2-ol.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C@@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[OH:10][CH:9]([C@@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:13][CH2:12]1)[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(=O)CCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(O)CCc2ccccc2)CC1
Reaction time: 2 h
Yield: 104.8 %

Procedure:
To a solution of tert-butyl {[cis-4-(3-phenylpropanoyl)cyclohexyl]-methyl]carbamate (3.45 g, 10.0 mmol) in ethanol (65 ml) under nitrogen cooled in an ice-bath was added sodium borohydride (0.78 g, 21 mmol). The mixture was stirred two hours at ice-bath temperature. The reaction was quenched by addition saturated sodium bicarbonate solution (30 ml). The mixture was concentrated under reduced pressure to remove ethanol. The aqueous residue was diluted with water (15 ml) and extracted with ethyl acetate (3×60 ml). The extract was washed with water (20 ml), and brine (20 ml), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give crude (±)-tert-butyl {[cis-4-(1-hydroxy-3-phenylpropyl)cyclohexyl]methyl)carbamate (3.64 g, theoretical yield 3.48 g) as a colorless gum. MS: 348.3 (M+1).