Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C(OCC)(=O)C>[CH3:18][S:19]([O:10][CH2:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1)(=[O:21])=[O:20]
Reactant: OCCc1ccnc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccnc(F)c1
Yield: 74.8 %

Procedure:
To a solution of compound 42 (6.50 g, 46.1 mmol) in anhydrous ethyl acetate (250 mL) were added successively at 0° C., under argon, triethylamine (6.40 mL, 46.0 mmol) and dropwise methanesulfonyl chloride (3.60 mL, 46.5 mmol). The mixture was stirred at 0° C. for 10 min before addition of water (200 mL) at room temperature. The mixture was extracted with ethyl acetate (3×200 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (Al2O3, CH2Cl2) to give sulfonate 43 (7.56 g, 34.5 mmol) as a yellow oil. Yield 75%; Rf (Al2O3, CH2Cl2) 0.52; IR (CCl4) ν 1179, 1352, 1414, 1613 cm−1; 1H NMR (200 MHz, CDCl3) δ 2.95 (s, 3H), 3.09 (t, 2H, J=6.4 Hz), 4.45 (t, 2H, J=6.4 Hz), 6.82 (s, 1H), 7.07 (d, 1H, J=5.1 Hz), 8.15 (d, 1H, J=5.1 Hz); MS m/z 219 (M+, 3), 123 (100), 111 (30), 83 (14), 79 (53), 57 (11).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[CH:23]([S:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])([CH3:25])[CH3:24].OC([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)[C@H](N(C)C(=O)CC2)CC3)CC1)C.C(CCCCCCCCCCC(O)=S)C>>[CH:23]([S:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:1][CH:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)=[O:39])([CH3:25])[CH3:24]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(O)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: CC(C)SCCCCCCCCCCCC(=O)O
Agent: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCCCCCCCCCCC(O)=S
Product: CC(C)SCCCCCCCCCCCC(=O)OC1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Employing substantially the same procedure as described in Example 191, but substituting 17-hydroxy-4-methyl-5a-4-azaandrostan-3-one and 12-(isopropylthio)dodecanoic acid for the 20-hydroxy-4-methyl-5α-4-azapregnan-3-one and 11-ethylthioundecanoic acid, respectively, used therein, the title compound was obtained. MS M+ calculated for C34H59NO3S, mw=561.92: observed m/e 561.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[NH2:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([NH:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24])=[O:15])(=[O:10])=[O:11])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: NCCS(=O)(=O)O
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)NCCS(=O)(=O)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.252 g (10 mmol) of 2aminoethanesulfonic acid, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is dissolved in distilled water, extracted with ethyl acetate, and converted into the free acid by treatment with acidic cation exchanger. The title compound is obtained by freeze-drying the aqueous solution.
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:12][C:13](=[O:42])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:31][CH2:30]4)=[N:27][N:28]=3)[N:25]=2)=[CH:16][CH:15]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:9][C:8]([CH3:11])([CH3:10])[C@H:7]([NH:12][C:13](=[O:42])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:30][CH2:31]4)=[N:27][N:28]=3)[N:25]=2)=[CH:18][CH:19]=1)[C:6]([OH:43])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
Tert-butyl-(2S)-3,3-dimethyl-2-({4-[3-(1-quino lin-6-ylcyclopropyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoyl}amino)butanoate was dissolved in methylene chloride (0.7 ml). To the solution was added TFA (0.7 ml). The mixture was stirred for 1.5 h. The volatiles were removed under reduced pressure to yield the desired product. Analytical LCMS: (M+H)+=522.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17].[NH2:20][C:19]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]#[N:17])[CH:18]=1
Reactant: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: Clc1ccccc1
Product: N#CCC(C#N)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Product: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenylhydrazino)succinonitrile (0.323 g) and cupric chloride (0.175 g) was heated in chlorobenzene at 60° C. for 6 hours. After filtration and evaporation, the title compound and 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole were obtained as a 7:1 mixture. Column chromatography on silica gel eluting with dichloromethane gave the pure title compound, obtained as a mixture of syn and anti isomers, NMR (anti isomer) 3.6 (s, 2H), 7.57 (s, 2H), 8.82 (s, 1H, exchangeable with D2O), NMR (syn isomer) 3.56 (s, 2H), 7.59 (s, 2H), 8.27 (s, 1H, exchangeable with D2O).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:12]([NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([N:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[CH3:13]
Reactant: Clc1ncnc2ccccc12
Reactant: CCNCCOc1ccccc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(CCOc1ccccc1C)c1ncnc2ccccc12
Reaction time: 5.5 h
Yield: 54.2 %

Procedure:
To a solution of 2.5 g (0.015 mole) of 4-chloroquinazoline in toluene were added 2.7 g (0.015 mole) of N-ethyl-2-(2-methylphenoxy)ethylamine and 1.5 g (0.015 mole) of triethylamine. The mixture was then refluxed, with stirring, for 5.5 hours. After completion of the reaction, the toluene was removed from the reaction mixture by evaporation under reduced pressure. Water was then added to the residue and the mixture was extracted with chloroform and the extract was dried. The chloroform was removed by evaporation and the crystals which separated out were recrystallized from isopropanol, giving 2.5 g (54%) of the desired Compound No. 2, in the form of colourless prisms melting at 85°-87° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]3=[O:23])=[CH:9][CH:8]=2)[N:3]=1.[H-].[Na+].Br[CH2:27][CH2:28][Cl:29].O>CN1CCCC1=O>[Cl:29][CH2:28][CH2:27][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:12][CH:11]=2)[C:15]1=[O:23]
Reactant: ClCCBr
Reactant: Cc1nc(-c2ccc(Cn3c(=O)[nH]c4ccccc43)cc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(-c2ccc(Cn3c(=O)n(CCCl)c4ccccc43)cc2)no1
Reaction time: 2 h

Procedure:
1-[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl-1,3-dihydro-2H-benzimidazol-2-one (0.416 g, 1.36 mmol) was added to a suspension of 60% sodium hydride (0.06 g, 1.49 mmol, dispersion in oil) in N-methylpyrrolidinone (3 ml) and stirred for 2 hours. More N-methylpyrrolidinone (2 ml) was added followed by 1-bromo-2-chloroethane (0.203 ml, 0.351 g, 2.44 mmol). The resultant mixture was allowed to stir at room temperature for 16 h then water was added and the mixture extracted with ethyl acetate (2×30 ml). The organic layer was washed with water (4×50 ml), brine (50 ml), dried (MgSO4).filtered and evaporated in vacuo to give a light brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:26]=[CH:25][C:19]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:22](=[O:23])[CH2:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:27])([F:28])[F:14])=[CH:26][CH:25]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC

Procedure:
This compound is prepared by reaction of 3,4-dimethoxyphenylethylamine and 4-(trifluoromethyl)-hydrocinnamic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:13]#[N:14])(C)C.C(N(CC)CC)C>C(#N)C>[C:13]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:14]
Reactant: [O-][n+]1cccc(F)c1
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1F
Yield: 69.5 %

Procedure:
3-Fluoropyridine-1-oxide (10.0 g, 88.4 mmol), trimethylsilylcyanide (26.32 g, 265.3 mmol), and triethylamine (17.89 g, 177 mmol) were reacted in 90 mL of acetonitrile utilizing the procedure described in example 762B. Purification of the crude by silica gel chomatography using CH2Cl2 as eluent gives compound 771B (7.5 g, 70%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=O)([O-:19])=[O:18]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:22]([C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[N+:17]([O-:19])=[O:18])=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2[N+](=O)[O-])o1
Yield: 79 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (2.00 g, 9.12 mmol) was converted using 2-nitro-benzoic acid instead of o-toluic acid to the title compound (2.52 g, 79%) which was obtained as a light-brown solid. MS: m/e=349.1 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH2:27][CH3:28])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:29][O:30][CH2:31][CH2:32][CH2:33]Cl.O>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][CH2:32][CH2:31][O:30][CH3:29])[C:19](=[O:24])[N:18]([CH2:25][CH2:26][CH2:27][CH3:28])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: COCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)n(CCCOC)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.1 g (15.2 mmol) of potassium carbonate were added to a hot solution of 3 g (10.0 mmol) of 7-benzyl-3-butylxanthine from stage a) in 90 ml of dimethylformamide at 60° C. and the mixture was stirred at 60° C. for one hour. 1.3 g (12.0 mol) of 3-methoxypropyl chloride were then added dropwise and the mixture was stirred at 100° C. for 3 hours. It was then allowed to cool to room temperature, and was treated with water and extracted using dichloromethane. The organic phase was washed with water and 1 N sodium hydroxide solution, dried using sodium sulfate and concentrated under reduced pressure. The oily residue was purified by flash chromatography on a silica gel column, toluene/ethanol (39/1)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl.CCOCC>[Br-:1].[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([OH:9])=[O:8]
Reactant: O=C(O)CCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 90.3 %

Procedure:
An intimate mixture of 6-bromohexanoic acid (19.5 g) and triphenylphosphine (26.3 g) was heated at 150° for three hours in a closed flask. After the reaction was cooled, the crude product was dissolved in chloroform (200 mL) and the resulting solution was diluted just to the cloud point with ether. The mixture was stored at 0° C. for several hours, then the solids were collected by filtration, washed with ether and dried in vacuo to yield 41.3 g of (5-carboxypentyl)triphenylphosphonium bromide, mp 197°-198° C. Anal. Calculated for C24H26BrO2P: C, 63.03; H, 5.73; Br, 17.47. Found: C, 63.00; H, 5.76; Br, 17.54.
Reaction SMILES: [NH2:1][C:2](=[N:20][N+:21]([O-:23])=[O:22])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:10])[NH2:8].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(O)(=O)C>[C:24]([NH:8][C@@H:7]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)=[O:10])[CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:20][N+:21]([O-:23])=[O:22])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1ccc(O)cc1
Solvent: CC(=O)O
Product: CC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1ccc(O)cc1
Temperature: 50 °C

Procedure:
0.3 g (0.925 mMol) of (R)-N5 -[amino(nitroimino)methyl]-N-[(4-hydroxyphenyl)methyl]-ornithinamide were dissolved in 3 ml of glacial acetic acid and after the addition of 3 ml (0.032 Mol) of acetic anhydride the mixture was heated to a reaction temperature of 50° C. for 30 minutes. The product remaining after the volatile components had evaporated off was further processed without purification.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[C:15]([F:22])[CH:14]=1.C[O-].[Na+]>C(O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:3]=[N:2][N:1]([C:4]3[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)[C:20]=2[NH2:21])=[C:15]([F:22])[CH:14]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: COc1ccc(N=[N+]=[N-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(Cl)cc3F)c2N)cc1
Temperature: 0 °C
Yield: 3.3 %

Procedure:
To a stirred and ice-cooled solution of 1-azido-4-methoxy-benzene (2.000 g, 13.4090 mmol) and commercial (4-chloro-2-fluoro-phenyl)-acetonitrile (2.729 g, 16.0909 mmol) in absolute ethanol (30 ml), an ice-cooled solution of sodium methoxide (1.087 g, 20.1136 mmol) in absolute ethanol (20 ml) is added drop-wise. The resulting reaction mixture is evaporated and the residue is dissolved in methylene chloride and washed with water, brine, dried over MgSO4, filtered and evaporated to afford ˜4.3 g of crude material as brownish solid. This crude product is purified by column chromatography eluting with 25-35% ethyl acetate in hexane, to obtain the title compound as a yellow solid (0.140 g, 3.25% yield). M.p. 147.9-149.5° C. LC-ESI-HRMS of [M+H]+ shows 319.0779 Da. Calc. 319.076192 Da, dev. 5.4 ppm
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: CC=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC=C(CC)C1N(CC(=O)NC(C)(C)CO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 68.6 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-fluorocarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.24 mmol) prepared in example 82a was reacted with 2-amino-2-methyl-propan-1-ol (73 mg, 0.82 mmol), N-methylmorpholine (0.2 g, 1.98 mmol) and 4-dimethylaminopyridine (2 mg, 0.016 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-hydroxy-1,1-dimethylethyl)aminocarbonylmethyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 92 mg, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:18]=[C:19]1[O:23][C:21](=[O:22])[CH2:20]1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:21](=[O:22])[CH2:20][C:19](=[O:23])[CH3:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Solvent: CC#N
Product: CC(=O)CC(=O)Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 50 °C
Yield: 43.8 %

Procedure:
The product of Step (d) (0.5 g, 2.2 mmol) was dissolved in acetonitrile (1 ml). In a separate flask, diketene (0.17 ml, 2.2 mmol, stabilized with copper sulfate) was dissolved in acetonitrile (1 ml). The diketene solution was added to the amine suspension In three portions, the reaction mixture was sealed and heated to 50° C. for 18 hours. The solvent was evaporated to dryness and purified by silica gel chromatography (5% MeOH/CH2Cl2) to afford the title compound, (0.3 g, 44%); MS (ES+) m/e 313 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C:7](Cl)=[O:8])[CH2:4][O:3]1.Cl.[NH:12]1[CH2:17][CH2:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][N:30]4[N:34]=[N:33][CH:32]=[N:31]4)[O:26][C:25]3=[O:35])=[CH:20][C:19]=2[F:36])=[CH:14][CH2:13]1.N1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C:7]([N:12]2[CH2:17][CH2:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][N:30]5[N:34]=[N:33][CH:32]=[N:31]5)[O:26][C:25]4=[O:35])=[CH:20][C:19]=3[F:36])=[CH:14][CH2:13]2)=[O:8])[CH2:4][O:3]1
Reactant: O=C1O[C@@H](Cn2ncnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3ccc(N4C[C@H](Cn5ncnn5)OC4=O)cc3F)CC2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
(4S)-2,2-Dimethyl-1,3-dioxolane-4-carbonyl chloride (350 mg, 2.10 mM) was added dropwise to a stirred suspension of (5R)-3-(4-(1,2,5,6-tetrahydropyridin-4-yl)-3-fluoro-phenyl)-5-(tetrazol-2-ylmethyl)oxazolidin-2-one hydrochloride (500 mg, 1.31 mM) and pyridine (0.52 g, 6.57 mM) in dichloromethane (20 ml) with ice/water cooling. The reaction was allowed to warm to room temperature and stirred 1 hour. The resulting solution was washed with water and saturated brine, dried (magnesium sulfate) and evaporated to a small volume. Addition of diethyl ether gave the title compound (600 mg) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C@@:17]1([C:31]2([OH:35])[CH2:34][CH2:33][CH2:32]2)[CH2:21][CH2:20][C@@H:19]([NH:22][C@@H:23]2[C@H:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][CH2:24]2)[CH2:18]1)=[O:16])=O)(C)(C)C.[ClH:36]>O1CCOCC1.CO>[ClH:36].[ClH:36].[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]([C@@:17]1([C:31]2([OH:35])[CH2:34][CH2:33][CH2:32]2)[CH2:21][CH2:20][C@@H:19]([NH:22][C@@H:23]2[C@H:28]([O:29][CH3:30])[CH2:27][O:26][CH2:25][CH2:24]2)[CH2:18]1)=[O:16]
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)(C2(O)CCC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C[C@H]2CN3)(C2(O)CCC2)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To 902 mg (1.827 mmol) of 1,5-anhydro-3-{[(1R,3S)-3-{[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(1-hydroxycyclobutyl)cyclopentyl]amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol was added 10 mL of 4 M HCl in dioxane, and a few drops of methanol sufficient to give a clear solution. The solution was stirred at ambient temperature for 45 minutes, then concentrated under reduced pressure to give 973 mg of the intermediate salt as a foam. 1H NMR (400 MHz, MeOD) δ ppm 1.57-1.70 (m, 1H) 1.73-1.93 (m, 4H) 1.93-2.10 (m, 4H) 2.14-2.28 (m, 2H) 2.29-2.44 (m, 3H) 2.46-2.59 (m, 2H) 3.35-3.77 (m, 12H) 3.98 (dd, J=11.6, 4.4 Hz, 1H) 4.26 (d, J=13.3 Hz, 1H) 4.45 (s, 1H) 5.21 (br. s., 1H). LC-MS ES+ 394.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@:13]2([CH2:16][CH2:17][OH:18])[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCO)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=1.887 min, m/z=450.2; 1H NMR (CDCl3) 1.54 (d, 3H), 2.07-2.29 (m, 2H), 2.34 (m, 3H), 2.97 (m, 1H), 3.55 (m, 1H), 3.74 (m, 1H), 4.06 (d, 3H), 5.64 (m, 1H), 6.93 (m, 1H), 6.95-7.11 (m, 2H), 7.26-7.37 (m, 2H), 7.90 (m, 1H), 8.38 (m, 1H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C=O.[NH:11]1[C:20](=O)[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13]>O>[NH2:13][C:12]1[N:14]=[C:15]2[C:19]([NH:18][CH:17]=[N:16]2)=[C:20]([Cl:3])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
46.0 g (0.3 mol) of phosphorus oxychloride was added to 73.1 g (1.0 mol) of N,N-dimethylformamide, and 15.1 g (0.1 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd.) was then added, followed by stirring at 100° C. for 4 hours. After cooling, 100 ml of water was carefully added at 20° C. After stirring at room temperature for 24 hours, the precipitating crystal was collected by filtration and dissolved in 100 ml of 25% aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure, and the precipitating crystal was collected by filtration to yield 9.3 g (0.055 mol) of a white crystal of 2-amino-6-chloropurine (yield 55%).