Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C:12]1[C:13]([NH:15][C:16](=[O:18])[CH:17]=1)=[O:14].[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C(Cl)Cl.N1C=CC=CC=1>[CH2:19]([O:21][CH:22]([O:9][C:6]1[C:5]([F:10])=[C:4]([F:11])[C:3]([C:12]2[C:13]([NH:15][C:16](=[O:18])[CH:17]=2)=[O:14])=[C:2]([F:1])[C:7]=1[F:8])[CH3:23])[CH3:20]
Reactant: C=COCC
Reactant: O=C1C=C(c2c(F)c(F)c(O)c(F)c2F)C(=O)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(C)Oc1c(F)c(F)c(C2=CC(=O)NC2=O)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
3 g of the 2,3,5,6-tetrafluoro-4-hydroxyphenylmaleimide obtained in Example 2 was dissolved in 20 ml of methylene chloride. Thereto was added 2.1 g of ethyl vinyl ether and 58 mg of pyridine salt of p-toluenesulfonic acid. The mixture was stirred at room temperature for 12 hours. 100 ml of ether was added. The mixture was washed with an aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent to obtain 2.8 g of an intended compound (yield: 73%).
Reaction SMILES: [C:1](=[O:14])([O-])[O:2][C:3]1[CH:8]=[CH:7][CH:6]=C(C#CCC)C=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCCCCC>C(OCC)(=O)C>[CH2:3]([O:2][C:1]([N:19]1[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]1)=[O:14])[CH2:8][C:7]#[CH:6]
Reactant: OC1CCNCC1
Reactant: CCC#Cc1cccc(OC(=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#CCCOC(=O)N1CCC(O)CC1
Yield: 101.7 %

Procedure:
10.0 g of 3-butynylphenyl carbonate and 5.8 g of 4-hydroxypiperidine were heated in a solvent-free condition at 100° C. for 30 minutes. After completion of the reaction, silica gel column chromatography (elution solvent: Hexane:ethyl acetate=1:1-1:2) was used for purification to obtain 10.6 g of the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:14])[CH:9]([NH2:13])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl.[CH:16]([O:19][C:20]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:21]=1[C:22](=N)OCC)([CH3:18])[CH3:17].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:14][C:22]([C:21]3[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:20]=3[O:19][CH:16]([CH3:18])[CH3:17])=[N:13][CH:9]2[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(OC)cc1OC(C)C
Reactant: CCCC(N)C(N)c1ccc(Cl)cc1
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCCC1N=C(c2ccc(OC)cc2OC(C)C)NC1c1ccc(Cl)cc1

Procedure:
5-(4-Chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-propyl-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-pentane-1,2-diamine and ethyl 2-isopropoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 387.1840, calculated for C22H28N2O2Cl [(M+H)+]387.1834.
Reaction SMILES: [Br-:1].[Li+].[OH:3][C@@H:4]1[C@H:8]2[N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10][C@@H:11](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:7]2[O:6][CH2:5]1.C(Cl)Cl>CN(C=O)C>[Br:1][C@H:11]1[CH2:10][N:9]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:8]2[C@@H:4]([OH:3])[CH2:5][O:6][C@H:7]12
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](Br)[C@H]2OC[C@H](O)[C@H]21
Temperature: 130 °C
Yield: 52.6 %

Procedure:
Lithium bromide (11.51 g, 132 mmol) was added to a stirred solution of tosylate (35b) (5.28 g, 13.2 mmol) in anhydrous DMF (75 mL) and the mixture heated at 130° C. for 4 hours. The black solution was left to cool to ambient temperature then reduced in vacuo. The residue was taken into DCM (100 mL) and washed with H2O (100 mL). The organic layer was dried (Na2SO4), filtered and reduced in vacuo to leave a black tar (Yield 3.3 g). Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 5:95 to 30:70 gave bromide (111) (2.14 g, 52.6%) as a pale green solid. TLC (Rf=0.4, EtOAc:heptane 3:1), analytical HPLC main peak, Rt=9.34 min., HPLC-MS 252.1/254.1 [M+H−56]+, 308.1/310.1 [M+H]+; 330.0/332.0 [M+Na]+; [α]D22 −90.2° (c=2.33, CHCl3); δC (125 MHz, CDCl3) 28.35/28.44 ((CH3)3C), 48.26/48.75 (BrCHCH), 53.48/54.14 (BocNCH2), 67.78/68.29 (BocNCH), 75.48/75.63 (OCH2CHOH), 75.24/76.08 (OCH2CHOH), 80.78/81.07 ((CH3)3C quaternary), 87.01/87.85 (BrCHCH), 153.83/154.61 (Boc C═O).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 46 %

Procedure:
A mixture of methyl 6-chloronicotinate (5.0 g), 1-benzyl-3-aminopyrrolidine (6.16 g) and K2CO3 (4.83 g) in DMF (20 ml) was stirred at 100° C. for 10 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (97:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-[(1-benzylpyrrolidin-3-yl)amino]nicotinate (4.17 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[O:13][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[N:15][N:16]=2)=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([C:9]([NH:11][C:12]4[O:13][C:14]([C:17]5[O:18][CH:19]=[CH:20][CH:21]=5)=[N:15][N:16]=4)=[O:10])[CH:3]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[CH3:23]
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(F)cc(Br)c1
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Product: CCc1ccc(-c2ccc(-c3cc(F)cc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-5-fluoro-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]benzenecarboxamide prepared in Reference Example 6 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:30][CH:29]=3)[CH:36]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nnc(OCC2CCN(C(=O)OC(C)(C)C)C2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 mmol, 302 mg) in THF (4.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 1.5 mmol, 60 mg) was added and stirring continued for 10 min at room temperature, then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 1.0 mmol, 352 mg) was added. The resulting mixture was stirred at 50° C. for 1 hour, poured into water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give 3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to provide 4-(4-benzyloxy-phenyl)-3-butyl-6-(pyrrolidin-3-ylmethoxy)-pyridazine dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=[C:11]([CH:24]=O)[C:10]=2[OH:26])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>>[ClH:1].[C:27]([NH:31][CH2:24][C:11]1[CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]=1[OH:26])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N
Reactant: O=Cc1cc(CCCc2ccccc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: CC(C)(C)NCc1cc(CCCc2ccccc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: Cl

Procedure:
3-((tert-Butylamino)methyl)-3′,4′-dichloro-5-(3-phenylpropyl)-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 3′,4′-dichloro-2-hydroxy-5-(3-phenylpropyl)-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH:9]([N:16]1C(=O)C2C(=CC=CC=2)C1=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.NN>C1COCC1.CO>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH:9]([NH2:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Temperature: 65 °C

Procedure:
To a solution of [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (23 g, 63 mmol) in THF (180 mL) and MeOH (180 mL) was added 85% hydrazine hydrate (37 mL, 630 mmol) slowly. The resulting mixture was heated to 65° C. for 15 hours. The reaction mixture was cooled to room temperature, then concentrated to dryness. The residue was purified by column chromatography on silica gel (dichloromethane:MeOH, 100:1, 1% NH3 H2O) to give (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester as a white solid. (Yield 7.4 g, 50%). 1H NMR (300 MHz, CDCl3): δ 7.35-7.24 (m, 5H), 4.81 (brs, 1H), 4.08-4.03 (m, 1H), 3.38-3.21 (m, 2H), 1.44 (s, 9H). LC-MS: [M+H]+ 237.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:11][C:12]([C:14]1[C:15](=[O:28])[N:16]([CH3:27])[C:17]2[C:22]([C:23]=1[OH:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][CH:18]=2)=O)C.C(O)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:12]([C:14]1[C:15](=[O:28])[N:16]([CH3:27])[C:17]2[C:22]([C:23]=1[OH:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][CH:18]=2)=[O:11]
Reactant: CCOC(=O)c1c(O)c2c(OC)cccc2n(C)c1=O
Reactant: CNc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cccc2c1c(O)c(C(=O)N(C)c1ccccc1)c(=O)n2C
Temperature: 25 °C
Yield: 82.8 %

Procedure:
N-Methylaniline (2.7g, 0.025 mol) was dissolved in 80 ml of toluene and about 30 ml of the solvent was distilled off in order to obtain a dry solution. 1,2-Dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxylic acid ethyl ester (2.7 g, 0.01 mol) was added to the boiling solution. The ethanol formed during the reaction was distilled off together with some toluene for about 4 hours. The mixture was cooled to room temperature. The precipitate was collected, washed with cold toluene and hexane and dried to give the title compound (2.8 g), yield 83%.
Reaction SMILES: CN1CCOCC1.[CH3:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:12]2[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 0 °C

Procedure:
N-methylmorpholine (60 g, 65 mL, 0.6 mol) is dissolved in DCM (100 mL), to which 1-methylpiperazine (30.5 g, 0.3 mol) is added. The reaction is cooled to 0° C., after which a solution of 4-bromo-benzenesulfonyl chloride (75.8 g, 0.296 mol) in DCM (100 mL) is added dropwise. The reaction is allowed to warm to RT overnight. The reaction mixture is then concentrated and water (1 L) is added. The solids that are formed are filtered and the filtrate is extracted with EtOAc (500 mL). The organic layer is washed with saturated brine, dried over MgSO4, filtered and concentrated to afford 1-(4-bromo-benzenesulfonyl)-4-methyl-piperazine as a pale yellow solid: LC/MS 321.0 (M+1); 1H NMR (400 MHz, CDCl3) δ 2.3 (s, 3 H) 2.5 (m, 4 H) 3.0 (m, 4 H) 7.6 (dt, J=8.8, 2.0 Hz, 2 H) 7.7 (dt, J=8.8, 2.1 Hz, 2 H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.ClC1[N:12]=[C:13]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:14]2[S:19][C:18]([CH2:20][N:21]3[CH2:30][CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)=[CH:17][C:15]=2[N:16]=1.NC1C=CC=CC=1N>>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][N:21]1[CH2:20][C:18]1[S:19][C:14]2[C:13]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[N:12][C:2]([NH:3][C:4]3[C:5]([NH2:1])=[CH:6][CH:7]=[CH:8][CH:9]=3)=[N:16][C:15]=2[CH:17]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCc4ccccc4C3)cc2n1
Agent: Nc1ccccc1N
Product: Nc1ccccc1Nc1nc(N2CCOCC2)c2sc(CN3CCc4ccccc4C3)cc2n1

Procedure:
Following General Procedure J for Multi-Step Benzimidazole Formation by Buchwald coupling, 4-(2-chloro-6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine and 1,2-diaminobenzene were reacted to give N1-(6-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)benzene-1,2-diamine which was cyclized with acetic acid to give 204. LCMS m/z: 497.6 (MH+)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2([C:16]#[N:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][CH:4]=1.C(O)(=[O:22])C.C(N(C(C)C)C(C)C)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][C:35]=1[O:42][CH2:43][CH3:44].C([BH3-])#N.[Na+]>C(O)C>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2([C:16]([NH2:17])=[O:22])[CH2:11][CH2:12][N:13]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([Cl:33])=[C:35]([O:42][CH2:43][CH3:44])[CH:36]=3)[CH2:14][CH2:15]2)=[O:8])=[CH:5][CH:4]=1
Reactant: N#CC1(NC(=O)c2ccc(Cl)cc2)CCNCC1
Reactant: CC(=O)O
Reactant: CCOc1cc(C=O)ccc1Cl
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(Cl)cc3)(C(N)=O)CC2)ccc1Cl
Temperature: 55 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
To a solution of 4-chloro-N-(4-cyano-piperidin-4-yl)-benzamide hydrochloride (45.03 mg, 0.15 mmol, 1.0 equiv) in ethanol (1 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 4-chloro-3-ethoxy-benzaldehyde (33.2 mg, 0.18 mmol, 1.2 equiv; intermediate B1) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 9.7 mg (14%) of the title compound. MS (ISP): 450.2 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[CH2:16][C@@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[C:1]([N:9]1[CH2:16][C@@H:15]([OH:17])[CH2:14][C@H:10]1[C:11]([O:13][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCc1ccccc1)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of (cis)-1-benzoyl-4-hydroxy-L-proline (7.074 gm, 30.1 mmole) in acetone was treated dropwise with 1,8-diazabicyclo[5.4.0]- undec-7-ene (5.4 ml, 36.1 mmole) while cooling with a water bath. After stirring under argon for 10 minutes, benzyl bromide (4.3 ml, 36.1 mmole) was added dropwise. After stirring for 3 hours at room temperature, an additional aliquot (0.25 ml) of benzyl bromide was added. The reaction was stirred overnight and the acetone removed in vacuo. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with additional HCl, sodium bicarbonate solution, brine, and dried (sodium sulfate). Filtration, followed by concentration in vacuo afforded a solid which was recrystallized from ethyl acetate. The yield of the title compound was 8.77 gm (90%).
Reaction SMILES: Cl/C(=C\C)/[C:3]#[N:4].[C:7]1(C)C=CC(S(Cl)(=O)=O)=C[CH:8]=1.[Na].[Cl:19][C:20]1[N:36]=[CH:35][CH:34]=[CH:33][C:21]=1[C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[C:30](O)=O)=O>ClCCCl.C(N(CC)CC)C>[CH3:7][C:8]1[C:30]([C:3]#[N:4])=[C:25]2[N:24]([C:22]=1[C:21]1[C:20]([Cl:19])=[N:36][CH:35]=[CH:34][CH:33]=1)[CH2:29][CH2:28][CH2:27][CH2:26]2
Reactant: O=C(O)C1CCCCN1C(=O)c1cccnc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C/C=C(\Cl)C#N
Agent: [Na]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1c(C#N)c2n(c1-c1cccnc1Cl)CCCC2
Temperature: 35 °C

Procedure:
3.75 g of 2-chlorocrotononitrile are added to a solution of 5.16 g of para-toluenesulphonyl chloride in 120 cm3 of 1,2-dichloroethane. The solution obtained is clear. 4 g of the sodium salt of N-(2-chloronicotinoyl)piperidine-2-carboxylic acid are added with stirring. The addition causes a rise in temperature from 20° C. to 28° C. and the mixture is kept stirred for one hour at ambient temperature. 3.8 cm3 of triethylamine are then added dropwise and the temperature increases to 35° C. The solution is heated to 40° C. for one hour and 30 minutes. After cooling, the reaction mixture is concentrated at reduced pressure (2.7 kPa) at a temperature close to 60° C. A mixture of products is thus obtained which is chromatographed on a column of 1.8 cm diameter containing 90 g of silica (0.04-0.0063). Elution is carried out with chloroform at a pressure of 1.5 bar, 20-cm3 fractions being collected. The homogeneous fractions are combined and concentrated at reduced pressure (2.7 kPa) at a temperature close to 60° C. 2.81 g of 2-methyl-3-(2-chloro-3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile are thus obtained in the form of cream crystals melting at about 134° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]([NH2:16])([C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[CH:5]([CH3:7])[CH3:6].C1COCC1.[Li+].[OH-]>CO.O>[CH3:6][CH:5]([CH3:7])[C:4]([NH2:16])([C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[C:3]([OH:17])=[O:2]
Reactant: COC(=O)C(N)(C(=O)c1cccnc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)C(N)(C(=O)O)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 3-methyl-2-[pyridine-3-carbonyl]-amino-butyric acid methyl ester (1.5 g, 6.3 mmol), in methanol (15 mL), THF (9 mL) was added LiOH (1.3 g, 31.7 mmol) dissolved in water (3 mL). The mixture was allowed to stir at room temperature (25° C.) over 2 h. Solvent was evaporated from reaction mixture, dissolved in water (15 mL), acidified with 1.5N HCl extracted with ethyl acetate (150 mL), dried over sodium sulphate and concentrated to obtain product as yellow colour solid (1.38 g, 99%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]1([CH3:13])[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:4][C:8]1[CH:7]=[C:6]([CH3:13])[C:11]([OH:12])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccccc1O
Product: Cc1cc(Cl)ccc1O
Yield: 84 %

Procedure:
The chlorination of aromatic compounds with sulfuryl chloride is generally known. For example, DuBois in Z. F. Chem. 705 (1866) reported that treatment of molten phenol with an equal molar amount of sulfuryl chloride yields only p-chlorophenol. Sulfuryl chloride was first reported as a chlorinating agent for o-cresol by Sah and Anderson in J. Am. Chem. Soc. 63, 3164 (1941). Their data showed that o-cresol reacted with sulfuryl chloride to yield 84% of the 4-chloro-o-cresol.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[C@H:36]([OH:37])[C@@H:23]5[O:24][CH:25]([C:28]6[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=6)[O:26][CH2:27][C@@H:22]5[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:38]1[CH:43]=[CH:42][C:41]([O:44][C:45](Cl)=[S:46])=[CH:40][CH:39]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:45](=[S:46])([O:44][C:41]1[CH:42]=[CH:43][CH:38]=[CH:39][CH:40]=1)[O:37][C@@H:36]1[C@@H:23]2[O:24][CH:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[O:26][CH2:27][C@@H:22]2[CH2:21][C@H:20]1[N:17]1[C:13]2[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[C:12]=2[CH:19]=[CH:18]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@H]6CCc7ccccc76)ncnc54)[C@H](O)[C@@H]3O2)cc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@H]6CCc7ccccc76)ncnc54)[C@H](OC(=S)Oc4ccccc4)[C@@H]3O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-ol (4.00 g, 8.02 mmol) was dissolved in DCM (169 mL) under an atmosphere of argon and 4-(dimethylamino)-pyridine (2.94 g, 24.1 mmol) was added followed by phenyl chlorothionocarbonate (2.22 mL, 16.0 mmol). The mixture was stirred at rt for 1 hour. The solvent was concentrated in vacuo and purified via silica gel chromatography eluting with a gradient of 20 to 100% EtOAc in hexanes on a column pre-treated with 1% TEA in hexanes to afford the title compound (5.00 g, 99%). LC/MS: Rt=2.34 min, ES+ 636 (AA standard).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[CH:17]=[C:18]3[C:24]([CH3:25])=[N:23][N:22](CC4C=CC(OC)=CC=4)[C:19]3=[N:20][CH:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[CH:17]=[C:18]3[C:24]([CH3:25])=[N:23][NH:22][C:19]3=[N:20][CH:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1
Reactant: COc1ccc(Cn2nc(C)c3cc(Nc4ccc(N5CCN(C)CC5)c(F)c4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2ncc(Nc3ccc(N4CCN(C)CC4)c(F)c3)cc12
Temperature: 60 °C

Procedure:
To a stirred solution of N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine (169) (30 mg, 0.063 mmol) in CHCl3 (15 mL) was added trifluoroacetic acid (6 mL) and the reaction mass heated to 60° C. overnight. After completion of the reaction the solvents were completely distilled off and diluted with water and the pH was adjusted to 9 and extracted with chloroform twice. The combined organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed and the crude material was passed through 100-200 mesh silica gel, eluting with 8% MeOH/CH2Cl2 obtained pure N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine 170 as a pale yellow colored solid (10 mg). 1H NMR (400 MHz, CDCl3) δ: 8.36 (s, 1H), 7.71 (s, J=2.31, 1H), 6.90 (m, 1H), 6.71 (m, 2H), 5.56 (s, 1H), 3.07 (bs, 4H), 2.62 (bs, 4H), 2.54 (bs, 3H), 2.36 (s, 3H); MS m/z 341.0 (M+H)+.