Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[(R)-3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=425.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17]O)[N:3]=1.C(N(S(F)(F)[F:25])CC)C>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH2:17][F:25])[N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(CO)n1
Product: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(CF)n1
Temperature: -10 °C

Procedure:
Fluorination of racemic 2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxymethyl pyrimidine can be effected using diethylaminosulphur trifluoride (DAST). That may be carried out in dichloromethane at, initially, -78° C. followed by warming to -10° C. for four and a half hours, to afford racemic 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH2:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH2:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: COC(=O)C(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CNc1ccc(F)cc1[N+](=O)[O-]
Reaction time: 15 h
Yield: 60.7 %

Procedure:
To a solution of 1,4-difluoro-2-nitrobenzene (14.3 g, 90 mmol) in tetrahydrofuran (250 mL) was added methyl 3-amino-2-methylpropanoate (10.5 g, 90 mmol) and potassium carbonate (24.8 g, 180 mmol). The reaction mixture was heated to reflux and stirred for 15 hours. Then the mixture was concentrated in vacuo, and the residue was dissolved in water (250 mL), extracted with ethyl acetate (100 mL*3). The combined organic layers was separated, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to afford methyl 3-(4-fluoro-2-nitrophenylamino)-2-methylpropanoate as a red solid (14.0 g, 61%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH3:21])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:27])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:35]1([CH2:38][NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:37][CH2:36]1>CO>[CH:40]1([N:39]([CH2:38][CH:35]2[CH2:36][CH2:37]2)[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH3:21])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:27])=[O:9])[CH:3]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: COC(=O)CN(C)S(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Reactant: C1CCC(NCC2CC2)CC1
Solvent: CO
Solvent: CC(C)NC(C)C
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Temperature: 160 °C

Procedure:
A solution of methyl 2-(4-(6-chloropyrimidine-4-carboxamido)-N,3-dimethylphenylsulfonamido)acetate (Intermediate 36, 123 mg; 0.30 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in methanol (4 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (45.3 mg; 0.37 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and then the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give methyl 2-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-N,3-dimethylphenylsulfonamido)acetate which was used directly without any further purification. The residue was redissolved in methanol (10 ml) and THF (10 ml) and treated with 5 N NaOH (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with concentrated HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N+:15]([O-])=[C:14]([CH3:19])[C:13]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:24][CH2:19][C:14]1[C:13]([CH3:20])=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][N:15]=1)(=[O:23])[CH3:22]
Reactant: Cc1c(OCCOCc2ccccc2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1nccc(OCCOCc2ccccc2)c1C
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture comprising 6.5 g of 4-(2-benzyloxyethoxy-2,3-dimethylpyridine N-oxide and 56 ml of acetic anhydride was stirred at 80 to 90° C. for one hour and distilled to remove the acetic anhydride. The obtained residue was made weakly basic with an aqueous solution of sodium carbonate and extracted with methyl ethyl ketone. The extract was dried over magnesium sulfate and distilled to remove the methyl ethyl ketone. Thus, 7.0 g of 2-acetoxymethyl-4-(2-benzyloxyethoxy)-3-methylpyridine was obtained. This intermediate was dissolved in 90 ml of ethanol, followed by the addition of 1.43 g of sodium hydroxide. The obtained mixture was stirred at 40° C. for one hour, followed by the addition of water. The mixture was extracted with methyl ethyl ketone. The obtained extract was dried over magnesium sulfate to obtain 5.4 g of 4-(2-benzyloxyethoxy)-2-hydroxymethyl-3-methylpyridine.
Reaction SMILES: Br[CH:2]([CH3:11])/[C:3](/OC)=[CH:4]\[C:5]([O:7][CH3:8])=[O:6].[C:12]([NH2:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:11][C:2]1[O:19][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:20][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: NC(=O)c1ccccc1
Reactant: COC(=O)/C=C(/OC)C(C)Br
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C

Procedure:
reacting methyl (E)-4-bromo-3-methoxy-pent-2-enoate with benzamide to give methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N:10]([O-])=O.[Na+]>S(=O)(=O)(O)O.O.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][NH2:10])[CH:7]=[CH:8][CH:9]=1
Reactant: O=N[O-]
Reactant: COc1cccc(N)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cccc(NN)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A stirred solution of 50.0 g (0.41 mole) of 3-methoxyaniline in 60 mL of concentrated sulfuric acid and 100 mL of water was cooled to -5° C., and a solution of 28.0 g (0.41 mole) of sodium nitrite in water was added slowly while maintaining the temperature of the reaction mixture below 0° C. The mixture was stirred at 0° C. for 1 hour, then added slowly to a chilled, stirred solution of 100 g (0.44 mole) of stannous chloride dihydrate in 300 mL of concentrated hydrochloric acid. After complete addition, the reaction mixture was allowed to warm to ambient temperature and stand for 16 hours. The reaction mixture was filtered and the filter cake made basic. The basic material was extracted with diethyl ether. The reaction mixture filtrate was also made basic and extracted with diethyl ether. The ether extracts were combined and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to give 49.1 g of product as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]4[CH:22]=[N:23][N:24]([CH2:26][C@H:27]5[O:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]5)[CH:25]=4)[N:15]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Br-].[C:41]1([CH:47]([Zn+])[CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.C(OCC)(=O)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:41]1([CH:47]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]5[CH:22]=[N:23][N:24]([CH2:26][C@H:27]6[O:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]6)[CH:25]=5)[N:15]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH3:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(Br)cn5)CC4)n3)cn2)C1
Reactant: CC([Zn+])c1ccccc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(c1ccccc1)c1cnc(N2CCN(c3ncnc(Nc4cnn(C[C@@H]5CN(C(=O)OC(C)(C)C)CCO5)c4)n3)CC2)nc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 2-((4-(4-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (100 mg, 0.17 mmol) and Pd(Amphos)Cl2 (11.7 mg, 0.17 mmol) in THF (2 mL, dried) was dropwise added a solution of (1-phenylethyl)zinc(II) bromide in THF (7.0 mL, 0.5 M, 3.4 mmol). The reaction mixture was stirred at 70° C. for 1 hour under N2, then cooled to room temperature and diluted with ethyl acetate (50 mL). After filtration, the filtrate was concentrated to afford (2S)-tert-butyl 2-((4-(4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate as a white solid (130 mg, crude), which was directly used in the next step without further purification. MS (ES+) C32H41N11O3 requires: 627, found: 628 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:47])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](N(C(C2N(OCC3C=CC=CC=3)C(C3CCCCC3)NC=2COC23CC4CC(CC(C4)C2)C3)=O)N)=O)[CH:5]=1.[C:48]12([O:58][CH2:59][C:60]3[NH:64][CH:63]([CH:65]4[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]4)[N:62]([O:71]CC4C=CC=CC=4)[C:61]=3[C:79]([NH:81][NH2:82])=[O:80])[CH2:57][CH:52]3[CH2:53][CH:54]([CH2:56][CH:50]([CH2:51]3)[CH2:49]1)[CH2:55]2.C12(OCC3NC(C4CCCCC4)=NC=3C(NN)=O)CC3CC(CC(C3)C1)C2>>[C:48]12([O:58][CH2:59][C:60]3[NH:64][CH:63]([CH:65]4[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]4)[N:62]([OH:71])[C:61]=3[C:79]3[O:80][C:10]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:47])=[O:2])=[N:82][N:81]=3)[CH2:55][CH:54]3[CH2:56][CH:50]([CH2:51][CH:52]([CH2:53]3)[CH2:57]1)[CH2:49]2
Reactant: NNC(=O)C1=C(COC23CC4CC(CC(C4)C2)C3)NC(C2CCCCC2)N1OCc1ccccc1
Reactant: COC(=O)c1cccc(C(=O)N(N)C(=O)C2=C(COC34CC5CC(CC(C5)C3)C4)NC(C3CCCCC3)N2OCc2ccccc2)c1
Agent: NNC(=O)c1nc(C2CCCCC2)[nH]c1COC12CC3CC(CC(C3)C1)C2
Product: O=C(O)c1cccc(-c2nnc(C3=C(COC45CC6CC(CC(C6)C4)C5)NC(C4CCCCC4)N3O)o2)c1

Procedure:
3-{N1-[5-(Adamantan-1-yloxymethyl)-3-benzyloxy-2-cyclohexyl-1H-imidazole-4-carbonyl]-hydrazinocarbonyl}-benzoic acid methyl ester. The title compound was prepared essentially using the procedure in Example 8, step b, with the modification that 5-(Adamantan-1-yloxymethyl)-3-benzyloxy-2-cyclohexyl-1H-imidazole-4-carboxylic acid hydrazide. was used instead of 5-(Adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid hydrazide. 1H NMR (CDCl3) 11.16 (1H, d), 9.21 (1H, br s), 8.51 (1H, s), 8.20 (1H, d), 8.12 (1H, d), 7.54 (1H, t), 7.46 (2H, m), 7.38 (3H, m), 5.33 (2H, s), 4.74 (2H, s), 3.94 (3H, s), 2.60 (1H, m), 2.17 (3H, br s), 1.90 (6H, s), 1.79 (2H, m), 1.62 (11H, m), 1.26 (3H, m).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][CH:6]([NH:13][CH2:14][CH2:15][CH3:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:21](OCC)(OCC)(OCC)[CH3:22]>>[ClH:1].[CH3:21][C:22]1[N:13]([CH2:14][CH2:15][CH3:16])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[N:2]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCNC(Cc1ccccc1N)c1ccccc1
Agent: Cl
Product: CCCN1C(C)=Nc2ccccc2CC1c1ccccc1

Procedure:
90 ml of Ethanolic hydrogen chloride is added dropwise to a stirred suepnsion of 9.00 g of 2-amino-α-phenyl-N-proylphenethylamine in 90 ml of triethyl orthoacetate. After complete addition, the mixture is refluxed for 2 hours. The ethanol is slowly distilled from the mixture and additional ethanolic hydrogen chloride (50 ml) is added. The mixture is then distilled to a volume of 20-30 ml. 100 ml of ether is added causing precipitation of the hydrochloride salt. The salt is collected, washed with ether (100 ml) and dried to give white crystals, mp 272°-275° C. of 4,5-dihydro-2-methyl-4-phenyl-3-propyl-3H-1,3-benzodiazepine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]2[NH:17][CH:18]=[C:19]([CH3:20])[C:12]=12.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=1.Cl.[OH-].[Na+]>O>[Cl:21][C:22]1[N:23]=[C:24]([NH2:29])[N:25]=[C:26]([NH:8][C:6]2[CH:5]=[C:4]([F:9])[C:3]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[NH:17][CH:18]=[C:19]([CH3:20])[C:12]=34)=[C:2]([F:1])[CH:7]=2)[CH:27]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1c[nH]c2nccc(Nc3c(F)cc(N)cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2nccc(Nc3c(F)cc(Nc4cc(Cl)nc(N)n4)cc3F)c12
Temperature: 100 °C

Procedure:
27 mg (0.10 mmol) of 2,6-difluoro-N1-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene-1,4-diamine and 23 mg (0.14 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 0.14 ml of 1 M hydrochloric acid is added, and the mixture is heated at 100° C. overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off and washed with water. The crude product is purified by preparative HPLC.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:23]=[C:22]3[C:14]([N:15]4[C:20](=[CH:21]3)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]4)=[N:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:25][O:26][CH2:27][CH2:28]Br.[H-].[Na+]>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:23]=[C:22]3[C:14]([N:15]4[C:20](=[CH:21]3)[C:19](=[O:24])[N:18]([CH2:28][CH2:27][O:26][CH3:25])[CH2:17][CH2:16]4)=[N:13][CH:12]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2cnc3c(c2)cc2n3CCNC2=O)CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCN1CCn2c(cc3cc(OC4CCN(C(C)C)CC4)cnc32)C1=O
Yield: 72 %

Procedure:
The title compound was synthesized in analogy to example 17, from 7-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 84), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a colorless oil (72%).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)=[O:7]>CO.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[CH:5]([S:2][CH3:1])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:12]=1)#[N:17]
Reactant: C[S-]
Reactant: N#Cc1ccc(CNC(=O)C(Br)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CSC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of sodium methanethiolate (0.43 g) at rt in methanol (15 ml) were added the (RS)-2-bromo-N-(4-cyano-benzyl)-2-phenyl-acetamide (0.5 g, example 81.1) and a catalytic amount of tetrabutyl ammonium iodide. The mixture was then stirred at rt for 1 hr. The mixture was concentrated. The residue was taken up in EtOAc, washed with 1.0 N and brine, dried over MgSO4, filtered and concentrated. The product was isolated by chromatography (silica gel, cyclohexane/EtOAc 2:1) to give (RS)-N-(4-cyano-benzyl)-2-methylsulfanyl-2-phenyl-acetamide (0.36 g). Colorless solid. MS 297.2 ([M+H]+)
Reaction SMILES: C([C@H]([C@@H](C(OCC)=O)O)O)(OCC)=[O:2].[CH3:15][C:16]([Si:19]([CH3:38])([CH3:37])[O:20][C@@H:21]1[C@@H:25]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:24]([CH2:35][OH:36])=[CH:23][CH2:22]1)([CH3:18])[CH3:17].C(OO)(C)(C)C.COC(C)(C)C>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:18][C:16]([Si:19]([CH3:38])([CH3:37])[O:20][CH:21]1[CH2:22][CH:23]2[C:24]([CH2:35][OH:36])([O:2]2)[CH:25]1[CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:15])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC=C(CO)[C@@H]1COCc1ccccc1
Reactant: CCOC(=O)[C@@H](O)[C@H](O)C(=O)OCC
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC1CC2OC2(CO)C1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 250-mL oven dried three necked round bottomed flask was equipped with a magnetic stir bar, argon inlet, and temperature probe charged with oven dried powdered molecular sieves 4A° (9.0 g). DCM (30 mL) was added to the flask and the resulting suspension was stirred room temperature for 5 minutes. Diethyl D-tartrate (2.13 g, 10.32 mmol) in DCM (18 mL) was added at room temperature and the mixture was cooled to −30° C. Keeping the temperature at −30° C., titanium (IV) isopropoxide (2.665 mL, 9.03 mmol) was added. The reaction mixture was stirred at −30° C. for 30 minutes followed by 15 minutes at −15° C. The mixture was cooled to −30° C. To this mixture, a solution of compound 16 (4.5 g, 12.9 mmol) in DCM (18 mL) was added. The mixture was stirred for 30 minutes at −30° C. followed by addition of a solution of tert-butyl hydroperoxide (5.0–6.0 M; 9.40 mL, 5.176 mmol). The reaction mixture was stirred between −30° C. to −20° C. for 3 hours to complete the reaction. The reaction was quenched by addition of water (45 mL). The reaction mixture was stirred with vigorous mixing and allowed to warm up to room temperature (15 to 20° C). When the temperature reached ˜15° C., 30% sodium hydroxide solution (10 mL) was added slowly to give a milky white slurry. This slurry was added into a 3.0-L Erlenmeyer flask containing tert-butyl methyl ether (1100 mL). The mixture was stirred for 30 minutes and then filtered on a bed of diatomaceous earth (Celite®). The aqueous layer was separated from the filtrate and discarded. The organic layer was washed with 10% aqueous sodium thiosulfate (100 mL) and water (2×160 mL). The combined organic layer was washed with water (100 mL), brine (50 mL), and dried over magnesium sulfate. The organic layer was concentrated in vacuo to give the title compound in quantitative yield (5.47 g) as an oil.
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([OH:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1.C(OC(C)C)(C)C>CO>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:29]([O-:42])(=[O:41])/[CH:30]=[CH:31]/[C:32]1[CH:40]=[CH:39][C:37]([OH:38])=[C:34]([O:35][CH3:36])[CH:33]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COc1cc(/C=C/C(=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sitagliptin free base (0.5 gms) and ferulic acid (0.25 gms) were dissolved in methanol (3 ml) at 60° C. to 65° C. and the solution was cooled to room temperature. Isopropyl ether (25 ml) was added to the clear solution and stirred for 2 hours. Filtered the precipitated solids and allowed for suck dry for 30 minutes to obtain the title compound. Yield: 0.42 gms.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH:15]=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Br:17][C:18]1[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1>ClCCCl.CC(O)=O>[Br:17][C:18]1[N:19]=[CH:20][C:21]([NH:24][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)=[N:22][CH:23]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1ccc(-c2ccccc2C=O)cc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(-c2ccccc2CNc2cnc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
Sodium tiracetoxyl borohydride (215 mg, 1.02 mmol) was added to the solution of 4′-methyl-biphenyl-2-carbaldehyde and 5-bromo-pyrazin-2-ylamine in 5 ml of DCE, 0.1 ml of HOAc was added and the mixture was stirred overnight at room temperature, followed by addition of 5 ml of DCE. The organic phase was washed with water, and purified with column (silica gel, hexane:EtOAc 6:1) to give 100 mg of (5-bromo-pyrazin-2-yl)-(4′-methyl-biphenyl-2-ylmethyl)-amine, yield 55%.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][CH:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.Cl[CH2:14][CH:15]1[O:17][CH2:16]1>>[O:17]1[CH:15]([CH2:14][O:1][C:2]2[CH:12]=[CH:11][C:5]3[CH2:6][CH2:7][CH:8]([CH3:10])[O:9][C:4]=3[CH:3]=2)[CH2:16]1
Reactant: ClCC1CO1
Reactant: CC1CCc2ccc(O)cc2O1
Product: CC1CCc2ccc(OCC3CO3)cc2O1

Procedure:
Starting from 7-hydroxy-2-methyl-3,4-dihydro-2H-1-benzopyrane, using 1-chloro-2,3-epoxypropane reagent and following the process of example 9 (b), 1,2-epoxy-3-(2-methyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-propane was obtained (m.p. 67°-69° C.).
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:26][C:27]1[CH:44]=[CH:43][C:42]([C@H:45]2[C@H:50]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@@H:49]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C@H:48]([O:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:47]([CH2:75][O:76][CH2:77][C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[O:46]2)=[CH:41][C:28]=1[CH2:29][C:30]1[CH:40]=[CH:39][C:33]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(Cl)Cl.CCN(CC)CC>[Cl:26][C:27]1[CH:44]=[CH:43][C:42]([C@H:45]2[C@H:50]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C@@H:49]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[C@H:48]([O:67][CH2:68][C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[C@@H:47]([CH2:75][O:76][CH2:77][C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)[O:46]2)=[CH:41][C:28]=1[CH2:29][C:30]1[CH:40]=[CH:39][C:33]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:1](=[O:3])[CH3:2])=[CH:32][CH:31]=1
Reactant: CC(=O)O
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CNC2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(Cc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of acetic acid (0.11 g) and Et3N (0.14 mL) in CH2Cl2 (1 mL) at room temperature, EDCI (96 mg) and HOBt (68 mg) was added. The mixture was stirred for 30 min at room temperature. A solution of N-(4-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)cyclopropanamine (Intermediate AQ) (40 mg) in CH2Cl2 (0.2 mL) was added dropwise. The reaction was monitored by LC-MS. After the starting material was consumed, CH2Cl2 was added to dilute the solution. The resulting mixture was then washed with H2O, 1N HCl, aqueous NaHCO3 and brine. CH2Cl2 was removed under reduced pressure, and the crude product was purified by preparative TLC to give intermediate AR (20 mg). MS ESI (m/z): 836 (M+H)+, 853 (M+NH4)+.