Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([NH2:14])=[O:13])=[CH:4]1.[CH2:15]([S:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1)[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[CH2:15]([S:19][C:20]1[N:21]=[C:22]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]([NH2:14])=[O:13])=[CH:4]2)[CH:23]=[CH:24][N:25]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCSc1nccc(Cl)n1
Reactant: NC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCSc1nccc(-n2cc(C(N)=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
NaH (480 mg, 12 mmol, 60% suspension) was added to a solution of 1H-indole-3-carboxylic acid amide (1.6 g, 10 mmol) in DMF (5 mL) at 0° C. and stirred for 20 min. A solution of 2-butylsulfanyl-4-chloro-pyrimidine (2.23 g) in DMF (5 mL) was added at 0° C., and the mixture allowed to warm to RT overnight. Water was added to the mixture, and the resulting white solid filtered off, washed with water (20 mL) and DCM (20 mL) and air-dried overnight to provide 1-(2-butylsulfanyl-pyrimidin-4-yl)-1H-indole-3-carboxylic acid amide (3.224 g, 98.77% yield) as a crude product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[N:22][CH:21]=[CH:20]3)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[S:38](Cl)(=[O:40])=[O:39]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][N:10]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[N:22][CH:21]=[CH:20]3)[CH:16]=1)[S:38]([C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=1)(=[O:40])=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNc1cncc(-c2ccc3cnccc3c2)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCN(c1cncc(-c2ccc3cnccc3c2)c1)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a solution of Example 386B (70 mg, 0.192 mmol) in pyridine (3 mL) was added 2-naphthalenesulfonyl chloride (87 mg, 0.384 mmol) at rt. The formed yellow solution was stirred at rt for 15 h. Pyridine was removed under reduced pressure and the residual oil was purified by flash chromatography (0-15% CH3OH in 2:1 EtOAc/hexane) to provide the desire product (69 mg, 65%). MS (APCI) m/z 555 (M+1)+.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([C:17]([F:20])([F:19])[F:18])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[OH-].[Na+:22]>O>[Na+:22].[C:1]([S:4][CH2:5][CH:6]([C:17]([F:18])([F:19])[F:20])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([O-:13])=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)[O-])C(F)(F)F

Procedure:
A suspension of 1-(3-acetylthio-2-trifluoromethylpropanoyl)-L-proline (1 g.) in water (10 ml.) is adjusted to pH 8 by addition of normal sodium hydroxide. The resulting solution is freeze dried to yield 1-(3-acetylthio-2-trifluoromethylpropanoyl)-L-proline sodium salt.
Reaction SMILES: [OH-].[K+].[CH:3]1([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][N:12]=[C:11]([C:17]([O:19]C)=[O:18])[CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1>O.CO>[CH:3]1([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][N:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cc(OC2CCCC2)c(OC)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cnc(C(=O)O)cc1OC1CCCC1
Reaction time: 45 h
Yield: 36.2 %

Procedure:
A solution of potassium hydroxide (4.71 g) in water (32 mL) is added to a solution of methyl 4-cyclopentyloxy-5-methoxypyridine-2-carboxylate (7.03 g) in methanol (188 mL) and the mixture allowed to stand for 45 hours. After concentrating in vacuo the residue is dissolved in water, washed with ethyl acetate and basefied to pH 5 with concentrated aqueous hydrochloric acid. The mixture is extracted with dichloromethane, the extracts dried (MgSO4) and evaporated to give 4-cyclopentyloxy-5-methoxypyridine-2-carboxylic acid (2.4 g) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH:7]=[CH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]=1.[CH3:23][NH:24][CH3:25].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH:7]=[CH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]=1
Reactant: Cn1c(C=Cc2ccccc2OCCCl)nc2ccccc21
Reactant: CNC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)CCOc1ccccc1C=Cc1nc2ccccc2n1C

Procedure:
2-[o-(β-Dimethylamino-ethoxy)-styryl]-1-methyl-benzimidazole was prepared from 2-[o-(β-chloro-ethoxy)-styryl]-1-methyl-benzimidazole and dimethylamine, and the free base was converted into its dihydrochloride, yielding 18% of theory of the compound of the formula ##STR12## which had a melting point of 208° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:42])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=5)=[CH:27][C:26]=4[NH2:41])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([C:45]1[C:46]([N:54]=[CH:55][N:56]([CH3:58])C)=[N:47][C:48]([CH:51]([CH3:53])[CH3:52])=[CH:49][CH:50]=1)#N>C(O)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:42])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=5)=[CH:27][C:26]=4[NH:41][C:58]4[C:45]5[CH:50]=[CH:49][C:48]([CH:51]([CH3:52])[CH3:53])=[N:47][C:46]=5[N:54]=[CH:55][N:56]=4)=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cn2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: CC(=O)O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cn4)ccc3Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)ncnc2n1
Temperature: 150 °C
Yield: 58.2 %

Procedure:
A mixture of the product from Example 17D (23.9 g, 37.4 mmol) and N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine (9.71 g, 44.9 mmol, 1.2 eq) in 450 mL of glacial acetic acid was heated in an oil bath at 150° C. for 2 h and then cooled to room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in approximately 70 mL of dichloromethane. This material was purified by silica gel chromatography using a Biotage Flash 75M cartridge, eluting first with 1:4 ethyl acetate/dichloromethane followed by 98:2 dichloromethane/methanol. The resulting product triturated with dichloromethane and filtered to provide the title compound as a white solid (17.6 g, 58%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11]([OH:13])=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.ClC(OCC(C)C)=O.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[O:4]1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([C:11]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH2:29][CH2:30]3)=[O:13])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)C1CCCC2(C1)OCCO2
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: O=C(C1CCCC2(C1)OCCO2)N1CCN(c2ccccn2)CC1
Yield: 58.2 %

Procedure:
From 1,4-dioxaspiro[4.5]decane-7-carboxylic acid (Example A, Step A) (10 g), triethylamine (8 g), isobutyl chloroformate (7.9 g) and 1-(2-pyridyl)piperazine (8.3 g) using the procedure of Example A, Step B is obtained 9.8 g of the title compound as an oil.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C.[C:53]([O:57][C:58]([N:60]1[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62][C@H:61]1[C@H:67]([C:71]1[CH:76]=[CH:75][C:74]([Cl:77])=[CH:73][C:72]=1[F:78])[C:68](O)=[O:69])=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl>[Cl:77][C:74]1[CH:75]=[CH:76][C:71]([C@@H:67]([C@H:61]2[N:60]([C:58]([O:57][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:59])[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62]2)[C:68]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:69])=[C:72]([F:78])[CH:73]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Cl)cc2F)CCC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
(5R,7R)-5-Methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.109 g, 0.356 mmol; see Example 3, Step 12), HATU (0.123 g, 0.324 mmol), and collidine (0.171 mL, 1.30 mmol) were added to a solution of (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chloro-2-fluorophenyl)acetic acid (0.125 g, 0.324 mmol; prepared analogously to that described in Example B) in DCM (25 mL). The reaction was stirred overnight at room temperature. The reaction was partitioned between water (20 mL) and DCM (50 mL), and the layers were separated. The organics were washed with water (2×10 mL). The aqueous portion was back extracted with DCM (25 mL), dried (MgSO4) and concentrated to an oil that was purified by flash chromatography (5% MeOH/DCM) to give (S)-tert-butyl 5-((S)-1-(4-chloro-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.116 g, 0.193 mmol, 59.5% yield). LC/MS=3.79 minutes, (APCI+) m/z=602 [M+H]+.
Reaction SMILES: C([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([N:22]([CH3:24])[CH3:23])=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:25])[C:11]1=[O:26])(=O)C.[OH-].[K+]>O.CO>[CH3:25][N:12]1[C:13]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([N:22]([CH3:24])[CH3:23])[C:14]=2[C:15](=[O:16])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:27])[C:11]1=[O:26]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(N(C)C)cc(C)nc2n(C)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(N(C)C)c2c(=O)n(CCCC[C@@H](C)O)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To crude (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-(N,N-dimethylamino)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was added a solution of potassium hydroxide (100 mg) in 10% water-methanol (2.2 ml). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was treated with saturated aqueous sodium chloride solution (10 ml) and ethyl acetate (10 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford (R)-1,7-dimethyl-5-(N,N-dimethylamino)-3-(5-hydroxyhexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (55 mg, 79% yield for 2 steps) as an oil. 1H NMR (300 MHz, benzene d6) δ 1.13 (d, 3H), 1.20-1.50 (m, 4H), 1.56-1.72 (m, 2H), 2.11 (s, 3H), 3.40 (s, 3H), 3.55 (m, 1H), 3.90 (t, 2H), 6.21 (s, 1H), 7.15 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:4](OCC)=[O:5].O.[NH2:20][NH2:21]>C(O)C>[CH3:1][O:2][CH:3]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:4]([NH:20][NH2:21])=[O:5]
Reactant: NN
Reactant: CCOC(=O)C(OC)c1cccc2ncccc12
Solvent: CCO
Solvent: O
Product: COC(C(=O)NN)c1cccc2ncccc12
Temperature: 85 °C
Yield: 76.7 %

Procedure:
To a solution of ethyl 2-methoxy-2-(quinolin-5-yl)acetate (0.9 g, 3.67 mmol) in absolute ethanol (25 mL) was added hydrazine hydrate (1.0 mL, 20.5 mmol) and the mixture was heated at 85° C. for 18.5 hours. After cooling to room temperature, the mixture was poured into ice-water (˜150 mL) then concentrated in vacuo. The residue was taken up in EtOAc, washed with diluted brine once, water twice then brine. The organics were dried over Na2SO4 and concentrated in vacuo to give 2-methoxy-2-(quinolin-5-yl)acetohydrazide as an off-white foam (0.651 g, 77% yield) that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][O:20][C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.ClC1C=C(C=CC=1)C(OO)=[O:31].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][O:20][C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11](=[O:31])[CH2:10][CH2:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1N1CCSCC1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S1CCN(c2ccc(C3=NOC(COc4ccon4)C3)cc2F)CC1
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a stirred solution of (5RS)-3-(3-fluoro-4-thiomorpholin-4-ylphenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (174 mg, 0.48 mM) in dichloromethane (5 ml) was added dropwise a solution of 3-chloroperoxybenzoic acid (80%, 124 mg, 0.57 mM) in dichloromethane (5 ml) at ambient temperature, and stirring continued for 1 hour. Aqueous sodium metabisulfite (5%, 5 ml) was added, and after stirring for 5 minutes the organic phase was separated. After further extraction with dichloromethane (2×10 ml), the combined extracts were washed with aqueous sodium bicarbonate solution (2×15 ml) and dried (magnesium sulfate). Crude product was chromatographed on a 10 g silica Mega Bond Elut® column, eluting first with a gradient from 0–50% ethyl acetate in dichloromethane (to remove sulfone, 10 mg), then with a gradient from 0–2.5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (128 mg).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([OH:7])=[O:6].[CH:13]1[CH:18]=CC=C[CH:14]=1.O>C(O)(C)C>[ClH:1].[NH2:2][C@@H:3]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:4]([OH:8])[C:5]([O:7][CH:13]([CH3:18])[CH3:14])=[O:6]
Reactant: c1ccccc1
Reactant: CC(C)C[C@H](N)C(O)C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC(C)C[C@H](N)C(O)C(=O)OC(C)C

Procedure:
Hydrogen chloride was passed into a solution of 4.0 g of (2RS, 3S)-3-amino-2-hydroxy-5methylhexanoic acid in 50 ml of isopropyl alcohol with stirring under ice-cooling. To the reaction solution was added 100ml of benzene, and the mixture was heated under reflux for 10 minutes with removal of water as formed during the reaction using a molecular seives. The reaction mixture was evaporated under reduced pressure to obtain 5.7 g of isopropyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[O:19][N:18]=[C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][N:22]([C:24](=[O:26])[CH3:25])[CH3:23])[CH:16]=1)(C)(C)C>C(Cl)Cl>[NH2:14][C:15]1[O:19][N:18]=[C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][N:22]([CH3:23])[C:24](=[O:26])[CH3:25])[CH:16]=1
Reactant: CC(=O)N(C)CC(C)(C)c1cc(NC(=O)OC(C)(C)C)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(C)CC(C)(C)c1cc(N)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
Trifluoroacetic acid (0.108 mL, 1.4 mmol) is added to a solution of {3-[2-(acetyl-methyl-amino)-1,1-dimethyl-ethyl]isoxazol-5-yl}-carbamic acid tert-butyl ester (87.0 mg, 0.28 mmol) in DCM (1 mL). The reaction mixture is stirred at room temperature for 1 h. More trifluoroacetic acid (0.20 mL, 2.59 mmol) is added to the reaction mixture and the reaction mixture is stirred for another hour. After this time, the reaction mixture is diluted with DCM and quenched with saturated aqueous NaHCO3 solution. The layers are separated and the aqueous layer is extracted with DCM twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide 28.0 mg of the title compound. Yield: 47%. LC-MS Retention time: 0.94 mins. ESI+ion mode. Zorbax SB-C18 column (3.5 μm, 4.6×30 mm). Gradient: 5% B to 80% B (0 min to 1.7 mins), 80% B to 95% B (1.7 mins to 2 mins), 95% B to 95% B (2 mins to 2.1 mins). Flow rate: 2.5 mL/min. A=(Water+0.1% Formic Acid) B=(Acetonitrile+0.1% Formic Acid). Diode Array Detector; m/z 212 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(CNC(=O)Nc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Yield: 83 %

Procedure:
Intermediate 8 (1.9 g) was stirred in 4.0M hydrogen chloride in 1,4-dioxane (40 ml) at 22° C. for 30 min. The solvent was removed in vacuo and the residue was purified by solid phase extraction (Isolute SCX sulphonic acid column), eluting with methanol followed by 10% 0.880 NH3 solution in methanol, to give the title compound as a cream foam (1.15 g). LC/MS (System A) Rt 2.03 min, Mass Spectrum m/z 270 [MH+].
Reaction SMILES: C([O-])(O)=O.[Na+].C(#[N:8])C.[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15](Cl)=[O:16])([O-:11])=[O:10]>O>[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15]([NH2:8])=[O:16])([O-:11])=[O:10]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The L-malic salt (5 mg, 14 μm) was dissolved in a mixture of 1 ml H2O, 3.5 mg (3 meq) NaHCO3, and 1 ml acetonitrile and 3.2 mg (14 μm) of 3,5-dinitrobenzoyl chloride was added and the reaction stirred for 16 hr at room temperature. After 5 ml H2O was added, the reaction was vacuum filtered and washed with H2O (2×1 ml portions), cold isopropanol (2×1 ml portions) and diethyl ether (2×2 ml) to isolate 2.5 mg of the 3,5-dinitrobenzamide, "DBN", (85 area % by gradient reverse phase HPLC).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:28][C@@H:29]1[CH2:34][O:33][CH2:32][CH2:31][NH:30]1>CC(O)CC.C(Cl)Cl>[CH3:28][C@@H:29]1[CH2:34][O:33][CH2:32][CH2:31][N:30]1[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:3]=1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: CCC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc[nH]c2n1
Temperature: 180 °C
Reaction time: 100 h

Procedure:
2-Chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (1.02 g, 4 mmol), diisopropylethylamine (1.40 mL, 8 mmol), and (R)-3-methylmorpholin hydrochloride (826 mg, 6 mmol) were stirred in 2-butanol (5 mL) in a closed microwave tube under argon at 50° C., until all ingredients were dissolved. The reaction was then stirred at 180° C. for 100 hours. The reaction mixture was then cooled to room temperature and diluted with 200 mL of CH2Cl2.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[CH2:25][CH2:26][CH2:27][CH:28]=[O:29])[C:5]1=[O:32])[CH:2]=[CH2:3].[CH3:34][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:33])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:25][CH2:26][CH2:27][CH:28]([OH:29])[CH3:34])[CH2:30][CH3:31])[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC=O)C1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CCCC(C)O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-5-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)heptanal prepared above in Step A (138 mg, 0.284 mmol) in THF (2.8 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (608 μL, 0.851 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 2 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a colorless film.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3]2=[O:20])=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2cccc(Cl)c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 233°-234° C.
Reaction SMILES: [I:1]Cl.[CH3:3][CH:4]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])[CH3:5].C([O-])(=O)C.[Na+]>C(O)(=O)C>[I:1][C:11]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([CH:4]([CH3:5])[CH3:3])[CH:12]=1
Reactant: ClI
Reactant: CC(C)c1ccccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(I)ccc1N
Reaction time: 1 h

Procedure:
Iodine monochloride (12.9 cm3) was added at room temperature to a stirred solution of 2-[prop-2-yl]-aniline (27.0 g) and sodium acetate (16.4 g) in acetic acid (250 cm3). After 1 hour, volatile material was removed in vacuo and the residue was partitioned between ethyl acetate (200 cm3) and 10% sodium carbonate solution (50 cm3). The dried (MgSO4) organic extract was filtered and evaporated in vacuo to afford an oil which was chromatographed on silica (Merck "MK 60.9385") eluting with hexane. Combination and evaporation of the product containing fractions gave the product as a crude dark unstable oil (38 g) which was not characterised fully but was used directly in Preparation 84.
Reaction SMILES: [H-].[Na+].C1(S([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=O)(=O)=O)C=CC=CC=1>CS(C)=O>[C:15]12[CH2:14][CH2:13][CH:12]=[C:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 79.8 %

Procedure:
0.144 g (6 mmole) of NaH and 10 ml of DMSO were first heated at 80° for 30 min. Once the hydrogen evolution was terminated, 0.728 g (2 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone were added to the above mixture and the resulting reaction mixture further heated at 100° for 4 hours. After the treatments of extraction and distillation mentioned hereinabove, there were isolated 0.326 g (80% yield) of the desired compound.