Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[O:4][CH2:3]1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:1][CH:2]1[CH2:7][O:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[O:4][CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: OC1COC(c2ccccc2F)OC1
Agent: [H-]
Agent: [Na+]
Product: Fc1ccccc1C1OCC(OCc2ccccc2)CO1
Yield: 46.6 %

Procedure:
5-Hydroxy-2-(2-fluorophenyl)-1,3-dioxane (18.0 g, 0.09 mole) was reacted with sodium hydride and benzyl chloride (13.0 g, 0.09 mole) as described in Example 2, except that the slurry was heated at 80°-100° C for 12 hours. The product was isolated in the manner described in Example 2 to give 12.1 g of oil which was distilled under 1 × 10-5 mm to give a product (6.2 g) which distilled at a pot temperature of 165°-170° C. VPC analysis of this product indicated it to contain 32% cis-5-benzyloxy-2-(2-fluorophenyl)-1,3-dioxane.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH2:28])[CH:18]=[CH:19][CH:20]=1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH:28][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(-c2ccc(C)cc2N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: COc1cccc(-c2ccc(C)cc2Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (0.065 g, 0.36 mmol) was reacted with the product from Example 217b (0.072 g, 0.34 mmol) for 96 h at 100° C. following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing a trifluoroacetic acid salt (0.102 gm, 64%). 1H NMR (300 MHz, DMSO-d6) ppm: 2.43 (s, 3H) 2.72 (s, 3H) 3.62 (s, 3H) 6.29 (d, J=7.35 Hz, 1H) 6.77 (dd, J=7.91, 2.02 Hz, 1H) 6.87-7.00 (m, 2H) 7.17 (t, J=7.91 Hz, 1H) 7.36 (s, 1H) 7.41-7.46 (m, 1H) 7.51-7.56 (m, 1H) 7.75 (d, J=8.46 Hz, 1H) 8.32 (d, J=7.35 Hz, 1H) 8.91 (d, J=8.82 Hz, 1H) 11.99-12.22 (s, 1H); MS (ESI+) m/z 356.0 (M+H)+; (ESI−) m/z 354.0 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[N:24][N:23]([CH3:26])[C:22]=2[CH:27]=1>>[CH3:26][N:23]1[C:22]2[CH:27]=[C:18]([CH2:17][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[N:11]3[CH:15]=[N:14][N:13]=[CH:12]3)[CH:19]=[CH:20][C:21]=2[N:25]=[N:24]1
Reactant: Cn1nnc2ccc(CCl)cc21
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Product: Cn1nnc2ccc(CN(c3ccc([N+](=O)[O-])cc3)n3cnnc3)cc21

Procedure:
Starting Compounds: 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole and 6-chloromethyl-1-methyl-1H-benzotriazole
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH:26][CH2:27][CH:28]([OH:30])[CH3:29].[P:31]([OH:36])([O:34]C)[O:32]C>CO>[P:31]([OH:36])([OH:34])[OH:32].[CH2:14]([S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:26][CH2:27][CH:28]([OH:30])[CH3:29]
Reactant: COP(O)OC
Agent: CCCCCCCCCCCCSCCCCCCCCCCCC
Solvent: CO
Solvent: CC(O)CO
Product: OP(O)O

Procedure:
Approximately 100 g of the above 1,2-dihydroxypropane dodecyl sulfide was reacted with 15 g dimethyl hydrogen phosphite as generally described in Example 1 until methanol evolution ceased. The product was vacuum-distilled to remove volatile materials.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11]Br)=[O:4].[F:26][C:27]1([F:35])[CH2:31][NH:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28]1.CCN(C(C)C)C(C)C>ClCCCl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][N:30]1[CH2:31][C:27]([F:35])([F:26])[CH2:28][C@H:29]1[C:32]([OH:34])=[O:33])=[O:4]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)C1=C(CN2CC(F)(F)C[C@H]2C(=O)O)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a stirred solution of (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.049 g, 0.11 mmol) and (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid (0.044 g, 0.17 mmol) in 1,2-dichloroethane (5 mL) was added dropwise DIPEA (0.078 mL, 0.45 mmol). The reaction mixture was stirred at room temperature until the disappearance of starting material which was checked by LC/MS. The mixture was diluted with EtOAc (50 mL) and washed successively with saturated aqueous NH4Cl solution and brine. The organic layer was separated and dried over Na2SO4. The solvent was concentrated in vacuo and the crude product was purified by prep-HPLC to give (R)-6-((S)-2-carboxy-4,4-difluoro-pyrrolidin-1-ylmethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Example 2) as a light yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:27]=[CH:26][C:10]([CH2:11][O:12][N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH2:24][CH3:25])[CH:17]=3)[CH3:15])=[CH:9][C:8]=2[C:28]([F:31])([F:30])[F:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1.CCN(CC)CC.[BH3-]C#N.[Na+]>O1CCOCC1.O=[Mn]=O>[CH:1]1([C:7]2[CH:27]=[CH:26][C:10]([CH2:11][O:12][N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:32]4[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]4)=[C:18]([CH2:24][CH3:25])[CH:17]=3)[CH3:15])=[CH:9][C:8]=2[C:28]([F:29])([F:30])[F:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(C(C)=NOCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)ccc1CO
Reactant: O=C(O)C1CNC1
Agent: O=[Mn]=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCc1cc(C(C)=NOCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)ccc1CN1CC(C(=O)O)C1
Temperature: 50 °C

Procedure:
To a suspension of MnO2 (10 eq) in dioxane is added 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime (1 eq). The resulting mixture is refluxed for 10 minutes. After filtration and concentration, the residue is dissolved in MeOH and treated with azetidine-3-carboxylic acid (2 eq) and Et3N (1.5 eq). The resulting mixture is heated at 50° C. for 30 minutes. After cooling to room temperature, NaBH3CN (3 eq) is added in portions. Purification by preparative LCMS results in 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid; 1H NMR (400 MHz, CD3OD) δ 1.24 (t, 3H), 1.30-1.60 (m, 5H), 1.74-1.92 (m, 5H), 2.28 (s, 3H), 2.79 (q, 2H), 2.92 (m, 1H), 3.68 (m, 1H), 4.32 (m, 4H), 4.51 (s, 2H) 5.22 (s, 2H), 7.38 (d, 1H), 7.50-7.68 (m, 5H). MS: (ES+): 517.3 (M+1)+.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.C=O.O.[OH-].[Na+]>C(#N)C.C(Cl)(Cl)Cl>[CH3:30][N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25][CH2:26]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNCC3)cc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CN1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Reaction time: 2.5 h
Yield: 101.4 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(piperidin-4-yloxy)-1H-indazole (57.7 mg, 0.142 mmol) in acetonitrile was treated in three portions with odium triacetoxyborohydride (54 mg, 0.26 mmol) and 37% formaldehyde in water (0.1 mL, 1.3 mmol), stirred at ambient temperatures for 2.5 hours and poured into excess chloroform and 1.0 N sodium hydroxide. The phases were separated. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography with 0.5% ammonium hydroxide/5.0% methanol in chloroform to give 5-(1-methylpiperidin-4-yloxy)-3-(1-naphthylsulfonyl)-1H-indazole (47.9 mg, 0.144 mmol) as a light orange foam. The foam was dispersed in methanol and chloroform, treated with isopropanolic HCl and concentrated in vacuo at 82° C. in for 10 hours to yield the title product as a light orange solid, mp 252-4° C.; Mass spectrum (+EI, [M+H]+) m/z 422. 1HNMR (300 MHz, DMSO-d6): δ14.16 (s, 1H), 10.06-10.17 (m*, 1H), 8.73-8.75 (m, 1H), 8.54-8.56 (m, 1H), 8.26-8.28 (m, 1H), 8.02-8.05 (m, 1H), 7.72 (t, 1H, J=7.81 Hz), 7.55-7.63 (m, 3H), 7.29-7.37 (m*, 1H), 7.10-7.20 (m*, 1H), 4.58-4.77 (m*, 1H), 3.45-3.50 (m, 1H), 3.07-3.20 (m, 2H), 2.75 (s, 3H), 1.70-2.20 ppm (m*, 4H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([CH2:17][CH2:18][OH:19])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:20]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>COCCOC.C(OCC)(=O)C>[CH3:28][S:29]([O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:8]2[NH:7][C:6]3[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:11](=[O:12])[NH:10][C:9]=2[CH:13]=1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1Nc2cc(CCO)ccc2Nc2cc(Cl)ccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CS(=O)(=O)OCCc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
A mixture of Example 204A (1.8 g, 5.58 mmol) in DME (30 mL) was treated with triethylamine (2.33 mL, 16.7 mmol), followed by methanesulfonyl chloride (648 μL, 8.4 mmol) and stirred at ambient temperature for one hour. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated to give the title compound (2 g, 98% yield). MS (ESI) m/e 367 (M+H)+; 1H NMR (300 MHz, DMSO-d.6 □ 9.89 (s, 1H), 8.03 (s, 1H), 7.68 (d, J=8.5 Hz, 1H). 7.06 (d, J=2.0 Hz, 1H), 6.85-6.94 (m, 4H), 4.33 (t, J=6.6 Hz, 2H), 3.11 (s, 3H), 2.86 (t, J=6.6 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[C:11](Cl)(=O)[CH3:12].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(N(CC)CC)C>[CH3:11][C:12]1[O:10][C:4]2[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=2[N:2]=1
Reactant: Nc1ccc(O)cc1O
Reactant: CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Product: Cc1nc2ccc(O)cc2o1

Procedure:
4-Aminoresorcinol hydrochloride (2.0 g, 12.4 mM), acetyl chloride (1.0 g, 12.6 mM), triethylamine (1.38 g, 13.6 mM) and pyridinium-p-toluenesulfonate (PPTS, 800 mg, 3.2 mM) were refluxed in xylenes (50 mL) for about 18 hours. Additional PPTS (300 mg) was added and the mixture was then refluxed about 48 hours. The reaction mixture was concentrated and the residue dissolved in ethyl acetate (200 mL) and washed with H2O (3×150 mL). The combined aqueous layer was back extracted with ethyl acetate (200 mL) and the combined organic layers were dried over MgSO4. Filtration and concentration provided 1.36 g. Filtration through a silica gel column eluted with 10% methanol/methylene chloride provided an orange solid, 0.3 g; m.p., 94-96° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH3:13].F>C1(C)C=CC=C(C)C=1>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:13].[CH3:8][C:7]1[CH:6]=[C:5]([C:9]([CH3:11])([CH3:10])[CH3:12])[CH:4]=[C:3]([CH3:13])[CH:2]=1
Reactant: Cc1cc(C(C)(C)C)cc(C)c1Br
Agent: F
Solvent: Cc1cccc(C)c1
Product: Cc1cc(C)cc(C(C)(C)C)c1
Product: Cc1cccc(C)c1Br

Procedure:
contacting the 2-bromo-1,3-dimethyl-5-tertiary-butylbenzene with meta-xylene in the presence of hydrogen fluoride at a temperature of from about 30° C. to about 60° C. and a pressure of from about 20 psig to about 100 psig to form 2-bromo-1,3-dimethylbenzene and 1,3-dimethyl-5-tertiary-butylbenzene;
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:14].Cl.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][SH:35])[CH2:28][CH2:27]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:16].[ClH:14].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[SH:35][CH2:34][CH2:33][CH2:32][N:29]2[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:27][CH2:28]2)[OH:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: SCCCN1CCN(CCCc2ccc(Cl)cc2)CC1
Reactant: CCCCc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(NC(O)=[SH]CCCN2CCN(CCCc3ccc(Cl)cc3)CC2)cc1

Procedure:
The procedure described in Example 2 was followed, using 2.5 g of 4-n-butylphenyl isocyanate, 5.0 g of 3-{4-[3-(4-chlorophenyl)propyl]piperazin-1-yl}propanethiol dihydrochloride, 1.4 g of triethylamine and 50 ml of methylene chloride, to give 2.7 g (34% of theory) of N-(4-n-butylphenyl-S-{3-[4-[3-(4-chlorophenyl)propyl]piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, m.p. 270°-272° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].[H-].[Na+].[CH2:25](Br)[C:26]#[CH:27]>CN(C=O)C>[CH3:17][N:18]([CH3:20])[CH:19]=[N:12][S:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([O:1][CH2:27][C:26]#[CH:25])[CH:14]=[CH:13][C:5]=2[N:6]=1)(=[O:11])=[O:10]
Reactant: COC(OC)N(C)C
Reactant: C#CCBr
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc2nc(S(=O)(=O)N=CN(C)C)sc2c1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
To a 100 mL round bottomed flask equipped with a magnetic stir bar, rubber septum, and argon inlet containing DMF (25 mL) in an ice bath was placed 1 (17.5 g, 76.1 mmol) and the reaction was stirred at rt until the solid dissolved. To this solution was added N,N-dimethylformamide dimethyl acetal (60 g) and the mixture was heated at 40° C. for 4 h. Solvent was removed in vacuo at 42° C. and the residue was dissolved in anhydrous DMF (60 mL). To this solution at 0° C. was added portion wise NaH (4.56 g, 60% in oil, 114 mmol) and the reaction was stirred at 0° C. for 30 min. To this mixture was added propargyl bromide (18 g, 80% toluene solution, 121.7 mmol) dropwise. Ice bath was removed and the mixture was stirred at rt for 1 h. The residue was poured into a mixture of water and EtOAc (200 mL/200 mL). The mixture was filtered and solid was collected and dissolved in DCM (300 mL) and washed with saturated NaHCO3 (3×200 mL) and water (200 mL). To this solution was added 100 g of silica gel and dried in vacuo. The solid mixture was loaded on silica gel column and eluted with 10% EtOAc in DCM to afford compound 2 as a yellow solid (9.2 g, 37.4%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:46][C:47]1[CH:48]=[C:49]([C:54]2[O:58][C:57]([CH2:59][CH2:60][NH2:61])=[CH:56][CH:55]=2)[CH:50]=[CH:51][C:52]=1[Cl:53]>C(Cl)Cl>[Cl:46][C:47]1[CH:48]=[C:49]([C:54]2[O:58][C:57]([CH2:59][CH2:60][NH:61][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:8]=3)=[O:14])=[CH:56][CH:55]=2)[CH:50]=[CH:51][C:52]=1[Cl:53]
Reactant: O=C(O)C1=NN=C(c2ccncc2)C1
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(-c2ccncc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
To a stirred solution of 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid (1.78 g, 9.42 mmol) in DCM (10 ml) was added DIPEA (2.46 ml, 14.1 mmol), EDCI (2.71 g, 9.42 mmol) and HOBt (1.91, 14.1 mmol). 2-(5-(3,4-dichlorophenyl)furan-2-yl)-ethanamine hydrochloride (2.75 g, 9.42 mmol) was dissolved in DCM (15 ml) and DIPEA (1.64 ml, 9.42 mmol). The resulting solution was added to the reaction mixture, which was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution and water. The organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, silica column, eluent 0-15% MeOH/DCM). Product containing fractions were collected, evaporated and crystallized from DCM and re-crystallized from 2% MeOH/DCM and heptane. Thus, 1.18 g (29%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 2.97 (t, 2H), 3.59 (q, 2H), 6.35 (d, 1H), 7.03 (d, 1H), 7.33 (s, 1H), 7.62 (d, 2H), 7.75 (m, 2H), 7.84 (t, 1H), 8.57 (br s, 1H), 8.63 (m, 2H), 13.95 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:20]=[C:19]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[CH3:34])[N:18]=2)[CH:13]=[CH:14][C:15]=1[F:16].CCN(C(C)C)C(C)C.CC(N(C)C)=O>CCOC(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2[N:18]=[C:19]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[CH3:34])[N:20]=[C:21]([N:23]3[CH2:24][CH2:25][N:26]([C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=4)[CH2:27][CH2:28]3)[CH:22]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: Clc1ncc(Br)cn1
Reactant: CC1CCCN1c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCNCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC1CCCN1c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncc(Br)cn3)CC2)n1

Procedure:
Heat a solution of 5-bromo-2-chloropyrimidine (Lancaster Chemicals, 565 mg), 4-(3-chloro-4-fluorophenyl)-2-(2-methylpyrrolidin-1-yl)-6-piperazin-1-yl-pyrimidine (1000 mg), DIEA (500 mg) and DMA (5 mL) at 110° C. for 3 h under nitrogen. Dilute with EtOAc (15 mL), wash with water (3×10 mL), dry (Na2SO4), and evaporate. Purify by silica gel chromatography, eluting with 1:1 hexanes:EtOAc to provide the title compound.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:17][CH2:18][O:19][C:20]([CH:22]1[CH2:28][CH2:27][C:25](=O)[CH2:24][CH2:23]1)=[O:21]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:18]([O:19][C:20]([CH:22]1[CH2:28][CH2:27][C:25]2([O:4][CH2:1][CH2:2][O:3]2)[CH2:24][CH2:23]1)=[O:21])[CH3:17]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 73.1 %

Procedure:
Ethylene glycol (18.2 g) and p-toluenesulfonic acid monohydrate (2.37 g) were added to a solution of 4-cyclohexanonecarboxylic acid ethyl ester (25 g) in toluene (500 ml) and stirred under reflux for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (23 g) as a colorless oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[S:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:9]1[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:6][CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: c1ccc2c(c1)CNCCS2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCSc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulphonyl chloride (3.3 g) in dichloromethane (15 ml) was added dropwise at room temperature to a stirred solution of 2,3,4,5-tetrahydro-1,4-benzothiazepine (4.8 g, prepared as described in the first paragraph of Example 6 above) and triethylamine (2.9 g) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine which was recrystallised from hexane. Yield 3 g. (m.p. 98°-100° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[CH3:16])=O)[O:5][C:6]=1[CH3:7].[NH3:17]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[CH3:16])=[N:17][C:6]=1[CH3:7]
Reactant: Cc1ccncc1C(=O)c1cc(C)c(C)o1
Reactant: N
Solvent: CO
Product: Cc1ccncc1-c1nc(C)c(C)cc1O
Temperature: 160 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(4-methylpyridin-3-yl)-methanone (150 mg), methanol (2 ml), and a 28% aqueous ammonia solution (2 ml) were placed in a sealed tube and was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give 5,6,4′-trimethyl-[2,3′]bipyridin-3-ol (30 mg, yield 20%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)CC)(C)C>C1COCC1>[C:27]([O:26][C:24]([N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[CH2:17][NH:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ccnc(Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (300 mg, 1.25 mmol) and tert-butyl 2-(aminomethyl)-piperidine-1-carboxylate (540 mg, 2.50 mmol) in THF (10 mL) is added diisopropylethyl-amine (0.43 mL, 2.50 mmol). The reaction is heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 268 mg (51% yield) of the desired compound: MS (ESI, pos. ion) m/z: 418 (M+1).