Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[Cl:10]OC(C)(C)C>CO>[Cl:10][N:7]1[C:3]([CH2:2][Cl:1])([CH3:9])[CH2:4][CH2:5][C:6]1=[O:8]
Reactant: CC1(CCl)CCC(=O)N1
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(CCl)CCC(=O)N1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A solution of 5-(chloromethyl)-5-methylpyrrolidin-2-one (302 mg, 2.05 mmol) in methanol (20 mL) was cooled in ice water for 10 min, before neat tert-butyl hypochlorite (0.46 mL, 4.1 mmol, 2 equiv.) was added in one portion. Additional tert-butyl hypochlorite (0.46 mL, 4.1 mmol, 2 equiv.) was added after 45 min. After 1 h, the mixture was concentrated in vacuo and the residue absorbed on silica. Chromatography on silica (0-2.5% MeOH/DCM) afforded the N-chloro-pyrrolidinone as a colorless oil (292 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 3.74 (d, J=11.9 Hz, 1H), 3.50 (J=11.9 Hz, 1H), 2.66-2.57 (m, 1H), 2.54-2.40 (m, 2H), 2.10-2.01 (m, 1H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ171.6 (C), 65.4 (C), 49.1 (CH2), 28.9 (CH2), 27.8 (CH2), 23.1 (CH3); LRMS (ESI/APCI): 182 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:26])=[CH:21][CH:20]=2)[OH:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>O1CCCC1.CC(O)C.[OH-].[Pd+2].[OH-]>[C:31]([O:30][C:28](=[O:29])[NH:27][C@H:25]([C:22]1[CH:23]=[CH:24][C:19]([CH:17]([OH:18])[CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[CH:20][CH:21]=1)[CH3:26])([CH3:32])([CH3:33])[CH3:34]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
To a solution prepared by dissolving 2.98 g of the compound [25-1] in a mixed solvent of 30 mL of tetrahydrofuran and 10 mL of 2-propanol, 750 mg of a carbon catalyst of 20% palladium hydroxide was added, and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure, to obtain 2.3 g of tert-butyl((1S)-1-{4-[hydroxy(piperidin-4-yl)methyl]phenyl}ethyl)carbamate [33-3] (hereinafter, referred to as the compound [33-3]). The compound [33-3] was used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:20]=1[Cl:33].N1C(C)=CC=CC=1C>CN1C(=O)CCC1>[Cl:33][C:20]1[CH:21]=[C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1
Reactant: Clc1cc(OCc2ccccc2)ccc1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Solvent: CN1CCCC1=O
Solvent: Cc1cccc(C)n1
Product: O=C(Nc1ccn(Cc2ccc(OCc3ccccc3)cc2Cl)n1)c1c(F)cccc1F
Temperature: 160 °C

Procedure:
To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(0.961 g, 4.31 mmol) and 1-(bromomethyl)-2-chloro-4-[(phenylmethyl)oxy]benzene (1.21 g, 3.88 mmol) in anhydrous NMP (15 ml) was added 2,6-lutidine (0.5 ml, 4.29 mmol, Aldrich). The reaction vessel (20 ml) was sealed and heated in Biotage Initiator microwave to 160° C. for 30 min. After cooling the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (120 ml) and ethyl acetate (100 ml). The phases were separated and the aqueous phase extracted with ethyl acetate (50 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave a red oil (2.84 g). The residue was loaded in dichloromethane and purified on silica (100 g×2) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (0.778 g); LCMS: (System 4) MH+=454, tRET=3.35 min.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([F:7])[C:4](/[CH:8]=[N:9]/[NH:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:12])=[C:3]([F:19])[CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C1OC=NN1>>[F:19][C:3]1[CH:2]=[CH:1][CH:6]=[C:5]([F:7])[C:4]=1[CH:8]1[N:9]([C:20](=[O:22])[CH3:21])[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[O:12]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N/N=C/c1c(F)cccc1F)c1ccncc1
Agent: C1=NNCO1
Product: CC(=O)N1N=C(c2ccncc2)OC1c1c(F)cccc1F
Yield: 31 %

Procedure:
The title compound was prepared from the isonicotinoylhydrazone of 2,6-difluorobenzaldehyde and acetic anhydride, using the General Structural Outline for Oxadiazoline Synthesis in 31% yield, mp 119-121° C.; IR ν 1673, 1624, 1594, 1554, 1334, 1312, 1295, 1209, 1092, 1062, 1008, 988, 974, 886, 825, 790, 730, 703, 663, 632 cm−1; NMR (300 Mhz) δ 8.75 (2H, □□br d, J=6 cps), 7.75 (2H, d, J=6 cps), 7.65-7.15 (4H, m from which emerges singlet at 7.5), 2.2 (3H, s).
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH:2]1[CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1COCC1>[CH3:15][S:16]([O:7][CH2:6][CH:2]1[CH2:1][O:5][CH2:4][O:3]1)(=[O:18])=[O:17]
Reactant: OCC1COCO1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1COCO1

Procedure:
The glycerol formal (Aldrich, 0.26 g, 2.5 mmol), triethylamine (1.1 mL, 8.3 mmol), and methanesulfonyl chloride (0.30 mL, 3.7 mmol) in 20 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].[C:5]([O:10][CH2:11][CH3:12])(=[O:9])[C:6]([CH3:8])=O.C(#N)C.[CH:16](=[N:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:11]([O:10][C:5]([C:6]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=2)[N:23]=[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C(C)=O
Reactant: Oc1ccc(N=Cc2ccccc2)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)nc2ccc(O)cc12
Temperature: 90 °C
Reaction time: 0.45 h
Yield: 20 %

Procedure:
Indium chloride (0.4977 g, 2.25 mmol) and ethyl pyruvate (1.3064 g, 11.3 mmol) were added to an acetonitrile (15.0 mL) solution of 4-benzylideneaminophenol (0.8875 g, 4.50 mmol), and the mixture was heated with stirring at 90° C. for 27 minutes with microwave irradiation. To the reaction solution, water and saturated saline were added. The mixture was subjected to extraction with dichloromethane and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography, and the solvent was distilled off to obtain 6-hydroxy-2-phenyl-4-quinolinecarboxylic acid ethyl ester (0.264 g, 0.900 mmol) as a pale yellow powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:5][CH2:4][CH2:3][CH2:2][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16]
Reactant: ClCCCBr
Reactant: O=C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2c(OCCCCl)cccc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1-Bromo-3-chloropropane (17.3 g) is added to a stirred mixture of 4-hydroxyindanone (14.8 g), potassium carbonate (15.3 g) in DMF/water (150 ml/50 ml) and the reaction mixture stirred at RT for about 4 days. The reaction mixture is partitioned between water and methylene chloride and the organic layer is separated, dried, filtered and evaporated, affording a residue which is chromatographed on a silica gel column to yield the desired product as a white solid.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:11]([OH:27])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH:39]([O:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49][C:50](Cl)=[O:51])=[CH:45][CH:44]=1)([CH3:41])[CH3:40]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:11]([O:27][C:50](=[O:51])[CH2:49][C:46]2[CH:47]=[CH:48][C:43]([O:42][CH:39]([CH3:40])[CH3:41])=[CH:44][CH:45]=2)[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CCCCCC(=O)Oc1ccc(C(=O)CNC(C)(C)C)cc1O
Reactant: CC(C)Oc1ccc(CC(=O)Cl)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)Oc1ccc(CC(=O)Oc2cc(C(=O)CNC(C)(C)C)ccc2OC(=O)CCCCCC(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(7,7-dimethyloctanoyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with p-isopropoxyphenylacetyl chloride there is obtained 3-(p-isopropoxyphenylacetoxy)-4-(7,7-dimethyloctanoyloxy)phenyl tert-butylaminomethyl ketone which reacts with methanesulfonic acid to yield the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-(p-isopropoxyphenylacetoxy)-4-(7,7-dimethyloctanoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[CH3:16][N+:17]([O-:19])=[O:18]>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:10][CH:9]=1
Reactant: COCCOCOc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Solvent: C1CCOC1
Product: COCCOCOc1ccc(/C=C/[N+](=O)[O-])cc1
Yield: 79 %

Procedure:
A mixture of 4-((2-methoxyethoxy)methoxy)benzaldehyde (Intermediate I, 1.86 g, 8.85 mmol) and NH4OAc (0.75 g, 9.73 mmol) in dry THF (15 mL) and CH3NO2 (15 mL) was refluxed for 20 h and allowed to reach room temperature. The volume of the reaction was reduced to aprox. ⅓, by rotatory evaporation; the resulting solution was poured into water (15 mL) and extracted with AcOEt (2×15 mL). The organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residual brown oil was purified by column chromatography on silica gel (15-30% EtOAc/Hexanes) affording 1.77 g of (E)-1-((2-methoxyethoxy)methoxy)-4-(2-nitrovinyl)benzene [Rf=0.7 (50% AcOEt/Hexanes), yellow solid, 79% yield].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2CCC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(C)cc1
Yield: 79 %

Procedure:
A mixture of 3-[5-(4-methylphenyl)-4-isoxazolyl]propionic acid (4.00 g), conc. sulfuric acid (2 ml) and methanol (80 ml) was refluxed for 1 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-methylphenyl)-4-isoxazolyl]propionate (3.35 g, yield 79%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:7, volume ratio). NMR (CDCl3) δ: 2.41 (3H, s), 2.63 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.5 Hz), 3.68 (3H, s), 7.30 (2H, d, J=8 Hz), 7.59 (2H, d, J=8 Hz), 8.20 (1H, s).
Reaction SMILES: [CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[CH:1]([N:4]([CH3:27])[C:5]1[C:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2N(C)C(C)C)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(isopropyl(methyl)amino)-2-(4-methoxyphenyl)quinoxaline-6-carboxylate (40 mg, 0.11 mmol, 1.00 equiv) in methanol (10 mL). Then a solution of sodium hydroxide (21.9 mg, 0.55 mmol, 5.00 equiv) in water (1 mL) was added. The resulting solution was stirred for 5 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 20 mL of water. The pH value of the aqueous solution was adjusted to 4-5 with aq. 1N hydrogen chloride. The resulting solids were collected by filtration. This resulted in 25 mg (65%) of 3-(isopropyl(methyl)amino)-2-(4-methoxyphenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>CO.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:34]([NH:33][CH2:31][CH3:32])=[O:35])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Reactant: CCN=C=O
Solvent: CC#N
Solvent: CO
Product: CCNC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 74.3 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.159 g of ethyl isocyanate according to the general procedure of Example 37 to give 0.86 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido-[2,3-d]pyrimidin-7-yl}-3-ethyl-urea, MS (ES+20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=517; mp 82°-90° C.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][CH:9](CC(C)=O)[CH3:10]>>[CH3:6][C:5](=[CH:4][C:2](=[O:1])[CH:3]=[C:9]([CH3:10])[CH3:8])[CH3:7]
Reactant: CC(=O)CC(C)C
Reactant: CC(=O)C=C(C)C
Product: CC(C)=CC(=O)C=C(C)C

Procedure:
Mesityl oxide isomer→MIBK→MIBC  (7)
Reaction SMILES: C12BC(CCC1)CCC2.CC1[C@H]2C(C)(C)[C@H](C2)CC=1.[CH:20]1([C:26](=[O:29])[C:27]#[CH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[CH:20]1([C@H:26]([OH:29])[C:27]#[CH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C#CC(=O)C1CCCCC1
Agent: B1C2CCCC1CCC2
Agent: CC1=CC[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Product: C#C[C@@H](O)C1CCCCC1
Temperature: 0 °C
Yield: 69 %

Procedure:
A mixture of 1.6 liters 0.5M 9-borabicyclo[3.3.1]nonane in tetrahydrofuran and 122.6 g (-)-α-pinene was heated at reflux under nitrogen for 4 hr., at which time the excess (-)-α-pinene and tetrahydrofuran were removed under vacuum to leave a thick oil. The contents of the flask were cooled to 0° C. and 80 g of 1-cyclohexyl-2-propyn-1-one, prepared according to Preparation 4, was added with stirring. The resulting mixture was allowed to warm to 23° C. and it was stirred at that temperature for 16 hr. Excess S-Alpine borane was destroyed by adding 44 ml propionaldehyde and stirring at 23° C. for 1 hr. The liberated (-)-α-pinene was removed by vacuum distillation. The resulting mixture was diluted with 400 ml tetrahydrofuran followed by 300 ml 3N sodium hydroxide. To this stirred mixture was added in dropwise fashion 300 ml 30% hydrogen peroxide over 1 hr. The mixture was heated at 40° C. for 3 hr. After cooling, the mixture was extracted with diethyl ether and this extract was dried over magnesium sulfate. Evaporation of the solvent and purification of the residue by silica gel flash chromatography using 5% ethyl acetate-hexane gave 56 g of (S)-3-cyclohexyl-1-propyn-3-ol, which by nmr analysis was shown to be 90% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=2)[N:11]=1)[C:5]#[N:6].[N-:21]=[N+:22]=[N-:23].[Na+].[Li+].[Cl-]>COCCOCCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:21]=[N:22][NH:23][N:6]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:20])[CH:16]=2)[N:11]=1
Reactant: N#Cc1ccc(-c2ccc3cc(O)ccc3n2)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: COCCOCCO
Product: Oc1ccc2nc(-c3ccc(-c4nn[nH]n4)cc3Cl)ccc2c1
Yield: 12.1 %

Procedure:
A mixture of 3-chloro-4-(6-hydroxyquinolin-2-yl)benzonitrile (230 mg, 0.819 mmol), NaN3 (55 mg, 0.820 mmol) and LiCl (70 mg, 1.64 mmol) in diethylene glycol monomethyl ether (5 mL) was refluxed for 4 hours. The resulting mixture was cooled, filtered through silica gel pad and purified by prep-HPLC (0.1% TFA as additive) to give Compound 23 (32 mg, yield 12%). 1H NMR (CD3OD, 400 MHz): δ 8.52 (d, J=8.4 Hz, 1H), 8.34 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.04 (d, J=9.2 Hz, 1H), 7.92-7.82 (m, 2H), 7.54 (dd, J=9.2, 2.0 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H). MS (ESI): m/z 323.6 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1N1CCCNCC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To 2.03 g (6.62 mmol) of 4-(2-methoxy-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester in 30 mL CH2Cl2 at 23° C. was added 5 mL trifluoroacetic acid. After stirring at 23° C. for 30 min, 4 additional mL of trifluoroacetic acid were added. After a total of 1 h, the reaction solution was poured into 200 mL of saturated aqueous NaHCO3 and extracted with 3×100 mL of EtOAc. The combined organics were washed with 1×200 mL H2O, 1×200 mL brine, dried over Na2SO4, filtered and evaporated to give 1.01 g (4.90 mmol, a 74% yield) of the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3): δ1.99 (pent, J=4.5 Hz, 2H), 2.82 (brs, 1H), 3.06 (t, J=4.4 Hz, 2H), 3.08-3.13 (m, 2H), 3.29-3.36 (m, 4H), 3.84 (s, 3H), 6.83-6.96 (m, 4H); IR (KBr, cm−1): 3335w;, MS (ES) m/z (relative intensity): 207 (M++H, 100).
Reaction SMILES: [C:1]12([C:14]([OH:16])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([C:11]([OH:13])=[O:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:17]N1C(=O)C2=CC=CC=C2C1=O>[Co+2].C(O)(=O)C>[OH:17][C:5]12[CH2:4][C:3]3([C:11]([OH:13])=[O:12])[CH2:9][CH:7]([CH2:8][C:1]([C:14]([OH:16])=[O:15])([CH2:2]3)[CH2:10]1)[CH2:6]2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Agent: [Co+2]
Solvent: CC(=O)O
Product: O=C(O)C12CC3CC(O)(C1)CC(C(=O)O)(C3)C2
Temperature: 80 °C
Reaction time: 24 h
Yield: 52.5 %

Procedure:
A mixture of 1.92 mol of 1,3-adamantanedicarboxylic acid, 192 mmol of N-hydroxyphthalimide, 1.83 mmol of cobalt (II) acetylacetonato and 1290 ml of acetic acid was stirred at 80° C. under an oxygen atmosphere (1 atm) for 24 hours. The reaction mixture was concentrated and then separated by the addition of ethyl acetate and water. Sodium chloride was added to the aqueous layer and the layer was extracted with ethyl acetate; the organic layer was dried on anhydrous magnesium sulfate and was concentrated. The caked crude purified product was washed with ethyl acetate to give 5-hydroxy-1,3-adamantanedicarboxylic acid (yield: 52.5%) at a conversion rate from 1,3-adamantanedicarboxylic acid of 75%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.CN(C)[CH:31]=[O:32]>>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH:31]=[O:32])=[CH:17][CH:16]=2)[C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[CH:26][CH:25]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(N(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(N(c2ccc(C=O)cc2)c2ccc(OC)cc2)cc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1.76 g (11.5 mmols) of phosphorus oxychloride was dropped in anhydrous dimethylformamide under agitation at room temperature, into which 25 ml of anhydrous dimethylformamide solution of 1.75 g of N,N-di(4-methoxyphenyl)aniline ((36)-2) was further dropped, following by raising the reaction temperature and agitating at 70° C. for 90 minutes.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[CH3:24][C:25]1([NH2:29])[CH2:28][O:27][CH2:26]1>>[CH3:24][C:25]1([NH:29][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:10][CH:11]=2)[CH2:28][O:27][CH2:26]1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Reactant: CC1(N)COC1
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 93 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (80 mg, 0.26 mmol) was converted, using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran, to the title compound (91 mg, 93%) which was obtained as an off white solid. MS: m/e=381.2 [M+H]+.
Reaction SMILES: C(NC1SC(S(NC2C=CC(CC([NH:24][C:25]3[C:26](=[O:45])[N:27]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])[C:28](=[O:36])[N:29](CC4CC4)[C:30]=3[NH2:31])=O)=CC=2)(=O)=O)=C(C)N=1)(=O)C.Cl.CN(C)CCCN=C=NCC.[Cl:58][C:59]1[N:63]([CH3:64])[N:62]=[C:61]([CH3:65])[C:60]=1[S:66]([NH:69][C:70]1[CH:71]=[CH:72][C:73]([CH2:76][C:77]([OH:79])=O)=[N:74][CH:75]=1)(=[O:68])=[O:67].NC1C(=O)N(CC2C=CC=CC=2F)C(=O)NC=1N>CO.C(Cl)(Cl)Cl>[NH2:31][C:30]1[NH:29][C:28](=[O:36])[N:27]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:26](=[O:45])[C:25]=1[NH:24][C:77](=[O:79])[CH2:76][C:73]1[CH:72]=[CH:71][C:70]([NH:69][S:66]([C:60]2[C:61]([CH3:65])=[N:62][N:63]([CH3:64])[C:59]=2[Cl:58])(=[O:67])=[O:68])=[CH:75][N:74]=1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)O)nc1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2ccc(CC(=O)Nc3c(N)n(CC4CC4)c(=O)n(Cc4ccccc4F)c3=O)cc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1[nH]c(=O)n(Cc2ccccc2F)c(=O)c1N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)nc1
Yield: 42 %

Procedure:
Prepared as for 2-[4-(2-acetylamino-4-methyl-thiazole-5-sulfonylamino)-phenyl]-N-[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (example 10, step 1) except that the coupling was performed using 1 [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride as the coupling reagent and [5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetic acid and 5,6-diamino-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione were used as the coupling partners. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 10/90 methanol/chloroform) afforded N-[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetamide (42%) as an off white solid; LRMS for C29H29ClFN7O4S (M+H)+ at m/z=577/579.