Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.CC(O)(C)C.C(OCC)C>[CH:2]([C@@H:3]1[CH2:5][C@@:4]1([CH2:12][N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: CN(C[C@@]1(c2ccccc2)C[C@H]1CO)C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1C=O)C(=O)OC(C)(C)C
Yield: 89.6 %

Procedure:
1,1-dimethylethyl {[(1S,2R)-2-(hydroxymethyl)-1-phenylcyclopropyl]methyl}methylcarbamate (12.02 g, 41.2 mmol), accessed via the method of Preparation 13A, was dissolved in 200 mL DCM with 6.2 mL 2-methylpropan-2-ol and treated with Dess-Martin Periodinane (28.0 g, 66.0 mmol, 1.6 eq) in 200 mL DCM at ambient temperature for 3 h. The reaction mixture was diluted with 1 L diethyl ether and treated with 400 mL 1N NaOH at ambient temperature for 30 min. The organic phase was separated, the aqueous phase extracted twice with diethyl ether, the organic phases combined, washed with brine, dried over MgSO4, filtered and concentrated to a colorless oil. The crude material was purified by flash chromatography (SiO2, eluted with EtOAc/hexanes (1:4)) to give the title compound (10.7, 36.9 mmol, 89%). 1H NMR (400 MHz, CDCl3) δ9.77-9.65 (m, 1H), 7.33-7.23 (m, 5H), 3.75-3.63 (m, 2H), 2.72-2.50 (m, 3H), 2.26-2.19 (m, 1H), 1.87-1.81 (m, 1H), 1.65-1.61 (m, 1H), 1.31-1.18 (m, 9H). LCMS m/z 312.2 (M+Na).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[N:31]1([CH2:36][C:37](O)=[O:38])[CH:35]=[N:34][CH:33]=[N:32]1>>[N:31]1([CH2:36][C:37]([NH:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[O:38])[CH:35]=[N:34][CH:33]=[N:32]1
Reactant: O=C(O)Cn1cncn1
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 55 %

Procedure:
Proceeding as in Example 1, but substituting (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide and 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride, gave Compound 135, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (75 mg, 55%). 1H-NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H), 7.40-7.25 (m, 7H), 7.15-6.90 (m, 6H), 5.00 (s, 2H), 4.79-4.60 (m, 3H), 4.00 (m, 1H), 3.70-3.60 (m, 1H). MS (EI) for C26H23F2N5O4 found 508 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][O:11][CH3:12])[C:5]([CH3:13])=[CH:4][C:3]=1[OH:14].Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][O:11][CH3:12])[C:5]([CH3:13])=[CH:4][C:3]=1[O:14][C:16]1[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH:21]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COCOc1c(C)cc(O)c(Cl)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1c(C)cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c(Cl)c1C
Yield: 75.5 %

Procedure:
By using 5.65 g of 2-chloro-4-methoxymethoxy-3,5-dimethylphenol, 8.88 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 1.35 g of sodium hydride (55% by weight) and 100 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 9.19 g of the title compound were obtained.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]1[CH:33]=[CH:32][N:31]2[N:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:30]2[N:29]=1.O.NN.C1COCC1>CO>[NH2:3][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]1[CH:33]=[CH:32][N:31]2[N:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:30]2[N:29]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCCN3C(=O)c4ccccc4C3=O)nc12
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCCN)nc12
Temperature: 25 °C
Yield: 71.7 %

Procedure:
(R)-ethyl 5-(2-(2-(3-(1,3-dioxoisoindolin-2-yl)prop oxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 0.359 mmol) and hydrazine monohydrate (115 mg, 3.59 mmol) were combined in MeOH (1 mL) and THF (1 mL) in a sealed vessel and heated at 60° C. for 20 minutes. After cooling to ambient temperature, the reaction was concentrated, followed by addition of NaOH (1 N, 2 mL). The mixture was extracted with DCM, and the combined organic extracts were dried (Na2SO4), filtered and concentrated to afford (R)-ethyl 5-(2-(2-(3-aminoprop oxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (110 mg, 72% yield). MS (apci) m/z=428.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:9]([C:24]2[N:28]([CH3:29])[N:27]=[N:26][N:25]=2)/[CH:10]=[CH:11]\[C@H:12]2[O:17]C(C)(C)[O:15][C@@H:14]([CH2:20][C:21](O)=[O:22])[CH2:13]2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:24]2[N:28]([CH3:29])[N:27]=[N:26][N:25]=2)/[CH:10]=[CH:11]/[C@H:12]2[O:17][C:21](=[O:22])[CH2:20][C@H:14]([OH:15])[CH2:13]2)=[CH:31][CH:32]=1
Reactant: Cn1nnnc1C(/C=C\[C@@H]1C[C@H](CC(=O)O)OC(C)(C)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1nnnc1C(/C=C/[C@@H]1C[C@@H](O)CC(=O)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 16 h
Yield: 40.7 %

Procedure:
Cis-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5yl)-1,3-butadienyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid (3.7 g, 7.45 mmol) was dissolved in a solution of THF (90 mL) and 0.2N HCl (60 mL) and allowed to stand for 16 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with brine (2x), dried (Na2SO4), and concentrated under reduced pressure. The residue was dissolved in dry methylene chloride (60 mL) and stirred for 4 hours in the presence of 1-cyclohexyl-3-(2-morpholinomethyl) carbodiimide metho-p-toluenesulfonate (6.6 g, 15.6 mmol). The solution was concentrated under reduced pressure and the residue was partioned between ethyl acetate and water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (1:1/ethyl acetate:diethyl ether). After recrystallization from ethyl acetate-hexane, 1.33 g (40.1%) of the title compound was obtained as a white solid; m.p.=172°-173° C. [α]D25 =+237.8° (c=2.17, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)[CH:9]=1)[C:5]#[N:6].CC([O-])(C)C.[K+].C1COCC1.[Cl:32]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13]([Cl:32])=[N:14][NH:15]3)[CH:9]=1)[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nc(Cl)c23)c1
Reaction time: 0.17 h

Procedure:
To a solution of 3-chloro-5-[(5-chloro-1H-indazol-4-yl)oxy]benzonitrile (100 mg, 0.329 mmol) in DMF (1 mL) was added 1.0M KOtBu in THF (329 μL, 0.329 mmol) and then N-chlorosuccinimide (44 mg, 0.329 mmol). The resulting reaction mixture was then stirred for 10 minutes, after which the mixture was purified on a LUNA column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA) to give the title compound.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[S:6]([O-:10])([OH:9])(=[O:8])=[O:7].[CH3:11][N:12]([C+:14]([N:16]([CH3:18])[CH3:17])Cl)[CH3:13]>O>[S:6]([O-:10])([OH:9])(=[O:8])=[O:7].[CH3:11][N:12]([CH3:13])[C:14]([N:16]([CH3:18])[CH3:17])=[N+:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CN(C)[C+](Cl)N(C)C
Reactant: CCNCC
Agent: O=S(=O)([O-])O
Solvent: O
Product: CC[N+](CC)=C(N(C)C)N(C)C
Yield: 82 %

Procedure:
4.20 g (57.4 mmol) of diethylamine are added with stirring and ice-cooling to 6.00 g (25.8 mmol) of bis(dimethylamino)chlorocarbenium hydrogensulfate. The reaction mixture is subsequently stirred for 1 hour at room temperature, and 50 ml of water are subsequently added. The organic phase is separated off, and the aqueous phase is extracted with 50 ml of dichloromethane. The combined organic phases are washed with 20 ml of water, and the solvent is distilled off under reduced pressure. The residue is subsequently dried at 50° C. under reduced pressure (7.0 Pa), giving 5.7 g of viscous N,N,N′,N′-tetramethyl-N″,N″-diethylguanidinium hydrogensulfate, corresponding to a yield of 82.0%.
Reaction SMILES: [F:1][C:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]([F:32])([F:31])[F:30])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([F:4])[CH3:3].[Li+].[OH-]>CCO.O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:2]([F:1])([F:4])[CH3:3])[CH2:10][CH2:9]3)[C:13]=2[C:29]([F:31])([F:32])[F:30])[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
(R)-4-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one (530 mg, 1.16 mmol) was dissolved in EtOH (5 mL). Then LiOH (835 mg, 34.8 mmol, 30.0 eq.) in 2 mL water was added to the mixture. The mixture was heated to 80° C. and stirred for 15 h. Solvent was removed. DCM was added and filtrated. The filtrate was concentrated and purified by silica gel chromatography using DCM/methanol (10/1) to give the title compound (200 mg, 40%) as a slight yellow solid. EDI-MS (M-NH2): 415.2. HPLC: 99.36%. 1H NMR (400 MHz, CD3OD) δ 8.13 (t, 1H), 8.02 (d, 1H), 7.86 (s, 1H), 7.58 (dd, 1H), 7.48 (d, 1H), 4.45-4.41 (m, 1H), 3.85-3.72 (m, 2H), 2.14-2012 (m, 2H), 1.89-1.86 (m, 2H), 1.74-1.68 (m, 4H), 1.51-1.32 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([CH:17]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[OH:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]#[N:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH2:37][CH3:38]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]4)[C:15]([CH:17]([CH:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[O:18][CH2:37][CH3:38])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]#[N:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCI
Reactant: C[C@H]1CC[C@H](Cn2c(C(O)C3CCCC3)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1)C1CCCC1
Temperature: 0 °C

Procedure:
4-(5-chloropyridin-3-yl)-2-(cyclopentyl(hydroxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (240 mg, 0.517 mmol) was dissolved in THF (5.2 mL) and cooled to 0° C. in a flask under nitrogen before adding sodium hydride (41.4 mg, 1.034 mmol). Upon cessation of gas evolution, iodoethane (0.125 μL, 1.552 mmol) was added, and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with sat. aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/0-40% EtOAc) to afford racemic 4-(5-chloropyridin-3-yl)-2-(cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. The racemic material was then purified by chiral supercritical fluid chromatography (Chiralpak IC, 21×250 mm, 2-Propanol +0.25% Dimethyl Ethyl Amine in CO2) to afford 4-(5-chloropyridin-3-yl)-2-(R)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile and 4-(5-chloropyridin-3-yl)-2-((S)-cyclopentyl(ethoxy)methyl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. 1H NMR (600 MHz, CD3OD) δ 8.78 (d, J=2.3, 1H), 8.75 (d, J=1.5, 1H), 8.29 (t, J=2.0, 1H), 8.24 (s, 1H), 4.65 (d, J=8.5, 1H), 4.08-3.97 (m, 2H), 3.59-3.34 (m, 2H), 2.65-2.54 (m, 1H), 1.88-1.77 (m, 1H), 1.73-1.54 (m, 6H), 1.49 (d, J=13.2, 2H), 1.30-1.25 (m, 1H), 1.17 (t, J=7.0, 3H), 1.15-1.08 (m, 1H), 1.01-0.95 (m, 1H), 0.91-0.76 (m, 4H), 0.75 (d, J=6.6, 3H), 0.56-0.45 (m, 2H). MS ESI calc'd. for C28H34ClN5O [M+H]+ 492. found 492.
Reaction SMILES: [N:1]1C=CC=[CH:3][CH:2]=1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)([O-:9])=[O:8].BrCC#N>C(COC)OC>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=1[CH2:3][C:2]#[N:1])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: c1ccncc1
Agent: N#CCBr
Solvent: COCCOC
Product: N#CCc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
Cuprous chloride (2.97 g, 30 mmol) is added to a goose neck additional funnel fitted to a 500 mL four neck round bottom flask with a rubber septum, thermometer, and magnetic stir bar. The flask is attached to a vacuum line and flame dried under vacuum. It is then allowed to cool to ambient temperature under argon. Potassium t-butoxide (42 mmol, 1M THF solution) is then added via syringe. The THF is carefully removed under vacuum to afford potassium t-butoxide as a white solid, and argon is reintroduced. Anhydrous dimethoxyethane (180 mL) is added via syringe, followed by the cuprous chloride (with stirring) in one portion, giving a dark mixture. Stirring is continued at ambient temperature for 45 min. Anhydrous pyridine (12 mL) is then added to the dark stirred mixture followed by 1,3-dinitrobenzene (2.02 g, 12 mmol) in 30 mL of anhydrous dimethoxyethane. After cooling the reaction to an internal temperature of −20° C., bromoacetonitrile (1.44 g, 12 mmol) in 30 mL of anhydrous dimethoxyethane is added via cannula with stirring over the course of 15 min. During the addition, the internal temperature is maintained at −20° C. and the reaction is stirred at this temperature for another 2 h and warms to ambient temperature for 30 min and then quenched with the addition of 60 mL of 3M HCl solution. The reaction mixture is then added to 600 mL of water and extracted with eight 50 mL portions of diethyl ether. The combined ether extracts are dried over sodium sulfate, filtered and evaporated to afford a dark oil of 2,6-dinitrophenyl acetonitrile whose 1H NMR (CDCl3) is in concert with the literature spectrum.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH2:10]=[CH2:11].[CH3:12][CH:13]([CH3:16])[CH:14]=O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O.ClCCCl>[CH3:10][C:11]1[C:5](=[O:8])[CH2:6][CH2:7][C:13]([CH3:16])([CH3:14])[CH:12]=1
Reactant: CCC(=O)Cl
Reactant: CC(C)C=O
Reactant: C=C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CC1=CC(C)(C)CCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
Aluminium chloride (60.6 g, 0.454 moles) Was added to 1,2-dichloroethane (200 ml) and the mixture cooled to about 0° C. Propanoyl chloride (40 g, 0.432 moles) was then added over a period of 20 minutes and the temperature of the reaction mixture allowed to rise to 20° C. to give a clear pale orange solution. This solution was stirred for 30 minutes and ethene (12 g, 0.432 moles) was then bubbled into the solution over a period of about 11/2 hours. The mixture was then quenched in a mixture of concentrated hydrochloric acid (65 ml) and ice (330 ml) and the organic phase separated and backwashed with water (2×50 ml). 2-Methylpropanal (22 g, 0.3 moles) and para-toluenesulphonic acid (1.65 g, 8.64 mmoles) were then added and the mixture refluxed with azeotropic water removal until no more water separated. The organic phase was then washed with 10% (w/v) sodium hydroxide (200 ml) and the solvent removed. Distillation gave 30 g 2,4,4-trimethylcyclohex-2-en-1-one, b.pt. 40° C. at 0.3 mm Hg. (Yield: 72%)
Reaction SMILES: [CH2:1]([N:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].C([O-])(=O)/C=C/C([O-])=O>CN(C)C=O.C(O)CC>[C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:9]2[CH2:8][CH2:7][CH:6]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)(=[O:14])[CH3:12]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCN(CC)C1CCNCC1
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: CN(C)C=O
Product: CCN(CC)C1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 52.3 %

Procedure:
2.1 g (13.25 mmol) of 4-(N,N-diethylamino)piperidine, 1.8 g (13.25 mmol) of 4-fluoroacetophenone and 7.3 g of potassium carbonate in 100 ml of dimethylformamide/n-propanol (1:1) were refluxed for 20 h. 1.9 g of 1-(4-acetylphenyl)-4-(N,N-diethylamino)piperidine were obtained as crystalline fumarate. Melting point 125°-127° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].[CH3:12][S:13](Cl)(=[O:15])=[O:14].Cl>O>[CH3:12][S:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)NCCCCCC(=O)O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
6-aminohexanoic acid (904 mg, 6.89 mmol) and NaOH (415 mg, 10.34 mmol) were dissolved in H2O (30 mL) and cooled to 0-5° C. Methanesulfonyl chloride (0.586 mL, 7.58 mmol) was added dropwise and the reaction mixture stirred for 2 h, then warmed to ambient temperature and stirred for an additional 2 h. The mixture was acidified with HCl (1 N) and extracted with EtOAc (3×15 mL). The extracts were combined, washed with H2O, then brine, dried over MgSO4, and filtered. Evaporation under reduced pressure gave 69 as a white crystalline solid (207 mg, 0.99 mmol, 14%). 1H-NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 6.91 (t, 1H), 2.90 (dt, 2H), 2.87 (s, 3H), 2.20 (t, 2H), 2.48 (m, 2H), 2.43 (m, 2H), 1.27 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=O)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:17]([NH:16][C:12]2[C:8]3[CH:9]=[CH:10][N:11]=[C:3]([C:2]([NH2:7])=[O:1])[C:4]=3[N:5]=[CH:6][N:14]=2)[CH2:18][NH:19][CH3:32])=[CH:34][C:35]=1[C:40]([F:41])([F:42])[F:43]
Reactant: CN(C[C@@H](N)c1ccc(Cl)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)nccc12)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Compound 42 was prepared following general synthesis scheme 8 wherein a mixture of 4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) and 4-Hydroxy-pyrido[3,4-d]pyrimidine-8-carboxylamide (H) was reacted with N—[(S)-2-Amino-2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride. LC/MS [425 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.28 (s, 1H), 9.00 (d, J=4.5 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.77 (d, J=7.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 5.64-5.44 (m, 1H), 3.20-3.09 (m, 1H), 3.04-2.88 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]#[N:18])=[N:9][CH:8]=1.FC(F)(F)C(O)=O>>[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]#[N:18])=[N:9][CH:8]=1
Reactant: COc1ccc(CNc2cnc(C#N)c3ccccc23)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc(N)c2ccccc12
Yield: 88.7 %

Procedure:
Compound 470C (50 mg, 0.16 mmol) was treated with trifluoroacetic acid (0.5 mL) for 1 h. The highly colored mixture was partitioned between ethyl acetate (30 mL) and 1N NaOH (30 mL). After washing with brine (15 mL), the organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 24 mg (92%) of compound 470D as a yellow solid. HPLC: 99% at 1.09 min (retention time) (Phenomenex C-18, 5 micron column, 4.6×30 mm, eluting with 10–90% aqueous methanol over 2 min containing 0.1% TFA, 4 mL/min, monitoring at 254 nm). MS (ES+): m/z 170.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]([O:7][C:8]([CH:10]1[CH2:15][CH2:14][C:13](=O)[CH:12](Br)[CH2:11]1)=[O:9])[CH3:6]>C(O)C>[CH2:5]([O:7][C:8]([CH:10]1[CH2:15][CH2:14][C:13]2[N:1]=[C:2]([NH2:4])[S:3][C:12]=2[CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)C1CCc2nc(N)sc2C1
Temperature: 25 °C
Yield: 80 %

Procedure:
Thiourea (0.672 g, 8.835 mmol) was taken in ethanol (30 mL). To this stirred solution was added 3-Bromo-4-oxo-cyclohexane carboxylic acid ethyl ester (2.2 g, 8.835 mmol). The reaction was refluxed for 2 hrs. The reaction mixture was allowed to cool to room temperature and ethanol was evaporated under reduced pressure, the residue was partitioned between water and ethyl acetate. The water layer was collected and basified using sat. sodium bicarbonate solution, extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to afford 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester (1.6 g)
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[N:31]=1>CN(C)C=O>[CH3:37][O:36][C:32]1[N:31]=[C:30]([CH2:29][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: COc1cccc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 85.9 %

Procedure:
Tetrahydrofuran (3 mL) and a 5N sodium hydroxide aqueous solution (22.4 μL, 0.11 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 5-1-1, which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of the 2-chloromethyl-6-methoxy-pyridine (21.2 mg, 0.13 mmol) described in Manufacturing Example 99-1-2, which was stirred for 12 hours at 60° C. This reaction mixture was cooled to room temperature and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and this residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1) to obtain the title compound (36.7 mg, 84%).