Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:27](O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH3:27])[CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Fc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1Cl
Agent: C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCc2c(c(-c3ccc(F)c(Cl)c3)cn2Cc2ccccc2)C1

Procedure:
The title compound (0.03 g) was prepared from 1-benzyl-3-(3-chloro-4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2) and paraformaldehyde as in Example 35. The product was then dissolved in 1/1 EtOAc/CH2Cl2 and treated with 0.03 g (0.15 mmol) of citric acid to afford 0.05 g of the corresponding citrate salt. MS (ESI): exact mass calculated for C21H20ClFN2, 354.13; found, m/z 355.1 [M+H]+, 357.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44-7.22 (m, 1H), 7.34 (t, J=7.7 Hz, 2H), 7.30-7.26 (m, 2H), 7.22 (t, J=9.1 Hz, 1H), 7.19-7.13 (m, 3H), 5.14 (s, 2H), 4.36 (s, 2H), 3.50 (t, J=5.8 Hz, 2H), 2.96 (s, 3H), 2.89 (t, J=5.8, 2H), 2.82-2.71 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](N)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4].N(OCCC(C)C)=O.C[Si](C)(C)[Br:29].C(=O)(O)[O-].[Na+]>BrCBr>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([Br:29])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)=[O:4]
Reactant: C[Si](C)(C)Br
Reactant: COC(=O)c1cnc(N)c(-c2ccc(F)cc2)n1
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCBr
Product: COC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-amino-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester (1.26 g, 5.10 mmol, 1.0 eq) in dibromomethane (25 ml) was added isoamyl nitrite (0.85 ml, 6.29 mmol, 1.2 eq) at room temperature. The resulting suspension was added over 30 minutes at room temperature to a dibromomethane (5 ml) solution of trimethylbromosilane (0.82 ml, 5.90 mmol, 1.15 eq). The mixture was stirred for 2 hours at room temperature after which time the turbid solution was added to aqueous sodium bicarbonate (10%, 15 ml). The phases were mixed, separated and the organic layer dried over magnesium sulfate, concentrated in vacuo and purified by chromatography on silica gel using a gradient of heptane to 10% ethyl acetate in heptane to afford 5-Bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester as white crystals. Yield=0.81 g (51%). 1H NMR (250 MHz, DMSO): δ 3.92 (3H, s), 7.38 (2H, t, J=8.98 Hz), 7.76-7.81 (2H, m), 8.98 (1H, s). HPLC-MS=100%; 2.13 min (MW=311; M+1=313.0).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]/[C:16](=[N:19]/[H])/[NH:17][OH:18])[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.CC[O-].[Na+].[S:31]1[CH:35]=[CH:34][C:33]([C:36](OCC)=O)=[CH:32]1>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[N:19]=[C:36]([C:33]4[CH:34]=[CH:35][S:31][CH:32]=4)[O:18][N:17]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCCC)c1=O)NO
Reactant: CCOC(=O)c1ccsc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCCc2noc(-c3ccsc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 150 °C

Procedure:
A solution of (1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.13 mmol) in EtOH (1 ml) was treated with a 21% solution of NaOEt in EtOH (55 μl, 0.21 mmol) and ethyl 3-thiophenecarboxylate (18 μl, 0.13 mmol). The mixture was heated in the microwave at 150° C. for 10 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous extracted again with EtOAc. The combined extracts were concentrated and purified by the MDAP. The title compound was obtained as an off-white solid (20 mg, 32%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1ccc(C=O)cc1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C2OCCO2)cc1F
Yield: 84.4 %

Procedure:
A solution of EXAMPLE 17B (2.0 g, 11 mmol), 1,2-ethanediol (1.0 g, 16 mmol), and p-toluenesulfonic acid monohydrate (10 mg) in benzene (10 mL) was heated under reflux with a Dean-Stark apparatus for 6 hours. After cooling, the mixture was partitioned between ethyl acetate and brine and the organic phase washed with 10% sodium hydroxide solution, water and concentrated. The residue was purified by flash chromatography on silica gel (1:5 ethyl acetate/hexane) to give 2.1 g (80%) of the title compound. MS (DCI): m/z 227 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]([C:14]2[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=2)/[CH:17]=[CH:18]/[C:19]([O:21]C)=[O:20])[N:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1>CO.[OH-].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:14]2[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=2)/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[N:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[CH:26][CH:27]=1
Reactant: COC(=O)/C=C/c1cccc(C(c2ccc(Cl)cc2)N2CCN(C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(/C=C/C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
The ester from above (1.05 g, 2.73 mmol) was dissolved in 20 mL of methanol with 8 mL of 1M potassium hydroxide and stirred overnight at room temperature. The methanol was removed in vacuo and the remaining aqueous solution was extracted with two 15 mL portions of ether. The aqueous layer was adjusted to a pH of 7 with 1M hydrochloric acid. The solution was chilled and the white powdery precipitate was collected by filtration to give 504 mg (46%) of (E)-3-(4-chloro-α-(4-methyl-1-piperazinyl)benzyl)cinnamic acid, m.p. 131°-141°. Calc. for C21H23ClN2O2.2H2O: C, 61.99; H, 6.69; N, 6.88; Cl, 8.71. Found: C, 61.98; H, 6.72; N, 6.89; Cl, 8.66.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[N:13]([C:14]([C:16]3([C:19]([F:22])([F:21])[F:20])[CH2:18][CH2:17]3)=[O:15])[CH2:12][C@@H:11](OS(C3C=CC=CC=3)(=O)=O)[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Cl:39][C:40]1[CH:45]=[C:44]([O:46][C@@H:47]([CH3:52])[C:48]([F:51])([F:50])[F:49])[CH:43]=[CH:42][C:41]=1[SH:53].O>CC(N(C)C)=O.O1CCCC1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:10][C@@H:11]([S:53][C:41]3[CH:42]=[CH:43][C:44]([O:46][C@@H:47]([CH3:52])[C:48]([F:49])([F:50])[F:51])=[CH:45][C:40]=3[Cl:39])[CH2:12][N:13]2[C:14]([C:16]2([C:19]([F:20])([F:22])[F:21])[CH2:18][CH2:17]2)=[O:15])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Reactant: C[C@H](Oc1ccc(S)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@H](Oc1ccc(S[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(C(=O)C3(C(F)(F)F)CC3)C2)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 110.5 %

Procedure:
Benzenesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (225 g, 477 mmol) was dissolved in dimethylacetamide (1.125 L) and potassium carbonate (166.5 g, 1.193 mol) was added. At room temperature, a solution of 2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenethiol (142 g, 553.2 mmol) in tetrahydrofuran (135 mL) was added slowly, keeping the internal temperature below 29° C. (ice bath cooling necessary). The mixture was stirred for 5.5 h at room temperature. After addition of ice (700 g) and water (2 L), the mixture was extracted with tert-butyl-methylether (1×1.5 L, 3×750 mL). The combined organic extracts were washed with brine (450 mL) and concentrated in vacuo to yield the title compound as a brown viscous oil (300.4 g). The crude product (containing dimethylacetamide) was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(CCCO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CCCBr)c1
Reaction time: 15 h
Yield: 75.1 %

Procedure:
Compound 16-1 (2.00 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.58 g) and N-bromosuccinimide (2.40 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 15 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.07 g) as a pale-yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20]#[N:21])[CH2:19][CH2:18][CH2:17]2)=[C:12]([O:22][CH3:23])[CH:11]=1.O1C2C=CC=CC=2N=[C:25]1[C:33]1C=CC(C#N)=C(OC)C=1.BrCCCCCBr>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20]#[N:21])[CH2:17][CH2:18][CH2:19][CH2:33][CH2:25]2)=[C:12]([O:22][CH3:23])[CH:11]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C1(C#N)CCC1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1C#N
Agent: BrCCCCCBr
Product: COc1cc(-c2nc3ccccc3o2)ccc1C1(C#N)CCCCC1

Procedure:
Utilizing the general procedure outlined for the synthesis of 1-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]cyclobutanecarbonitrile, 4-(1,3-benzoxazol-2-yl)-2-methoxybenzonitrile (250 mg, 0.95 mmol) was reacted with 1,5-dibromopentane (160 μL, 1.1 mmol) to afford the desired 1-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]cyclohexanecarbonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.83–7.75 (m, 3H), 7.59–7.56 (m, 1H) 7.45–7.43 (d, 1H), 7.38–7.34 (m, 2H), 4.04 (s, 3H), 2.41–2.38 (d, 2H), 1.92–1.15 (m, 8H). MS (ESI) 333 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:11][CH2:12][O:13][CH2:14]CBr.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: BrCCOCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1cc(F)cc(Br)c1
Reaction time: 8 h

Procedure:
3-Bromo-5-fluoro-phenol (5.0 g, 26.2 mmol), 2-bromoethylether (4.0 g, 28.8 mmol) and K2CO3 (4.4 g, 31.4 mmol) are mixed in 50 ml DMF and stirred at 50 C overnight. Addition of aqueous NaHCO3 solution and extraction into ethyl acetate yields the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH:22][C:23](=[O:41])[CH2:24][N:25](C(OC(C)(C)C)=O)[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>CO>[ClH:42].[ClH:42].[ClH:42].[F:33][C:28]1[CH:27]=[C:26]([NH:25][CH2:24][C:23]([NH:22][C:17]2[CH:16]=[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:20]=[CH:19][C:18]=2[CH3:21])=[O:41])[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)CN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Agent: Cl
Solvent: CO
Product: Cc1ccc(CN2CCNCC2)cc1NC(=O)CNc1ccc(F)c(F)c1
Yield: 51 %

Procedure:
To a solution of 4-(3-{2-[tert-butoxycarbonyl-(3,4-difluoro-phenyl)-amino]-acetylamino}-4-methyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.100 g) in MeOH (3 ml) was added HCl (2ml of 4M solution in dioxane). After standing for several hours, a solid was filtered off, washed with acetone and dried in vacuo. The solid was re-suspended in acetone, sonicated for 5 min filtered and dried to afford the title compound (0.043 g, 51%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].Br[CH2:14][C:15](=O)[CH2:16][CH3:17]>C1(C)C=CC=CC=1.O1CCOCC1>[CH2:16]([C:15]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=2)[O:7][CH:14]=1)[CH3:17]
Reactant: CCC(=O)CBr
Reactant: COc1cc(C(N)=O)ccc1O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCc1coc(-c2ccc(O)c(OC)c2)n1
Temperature: 125 °C
Yield: 63.4 %

Procedure:
To a solution of the amide prepared in Example 171 (460 mg, 2.75 mmol) in toluene (3 mL) and 1,4-dioxane (3 mL) was added 1-bromo-2-butanone (623 mg, 4.13 mmol), and the solution was heated to 125° C. for 18 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc:hexane (v/v)=4:1) gave 382 mg (73%) of the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 7.78 (s, 1H), 7.39 (d, 1H), 7.36 (dd, 1H), 6.83 (d, 1H), 3.79 (s, 3H), 2.45 (m, 2H), 1.18 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23]([O:25]C)=[O:24])[CH:22]=3)[NH:19][N:18]=[CH:17]4)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:27].[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[C:16]4[C:20](=[C:21]([C:23]([OH:25])=[O:24])[CH:22]=3)[NH:19][N:18]=[CH:17]4)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:27]
Reactant: COC(=O)c1cc(-c2cccnc2-c2ccc(F)c(C)c2)cc2cn[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ncccc2-c2cc(C(=O)O)c3[nH]ncc3c2)ccc1F
Yield: 115.2 %

Procedure:
Methyl 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylate (300 mg, 0.55 mmol) was saponified by LiOH (0.12 g,) in THF/H2O (1:1, 8 mL) for 2 days. The reaction mixture was concentrated to dryness, diluted with water (4 mL) and neutralized by the addition of aq. 2N HCl. The solid formed after the neutralization was filtered and suction dried to obtain the title compound as a white solid (220 mg). 1H NMR (DMSO-d6): δ 13.15 (s, 1H),8.67 (app dd, 1H, J=1.4 and 4.7 Hz), 8.17 (s, 1H), 7.97-7.92 (m, 2H), 7.68 (d, 1H, J=1.7 Hz), 7.51 (dd, 1H, J=4.7 and 7.6 Hz), 7.38 (d, 1H, 7.6 Hz), 6.93-6.90 (m, 2H), 2.12 (s, 3H).19F NMR (DMSO-d6): δ −118.43 (s).LCMS: 97%, MS (m/e) 348 (MH+).
Reaction SMILES: BrCCOC1C=C(S(C)(=O)=O)C=C(Cl)C=1.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].[F:21][C:22]1[CH:23]=[C:24]([CH:32]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:34]=1)[O:25][CH2:26][CH2:27]NCCC>C(O)C>[F:21][C:22]1[CH:23]=[C:24]([CH:32]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:34]=1)[O:25][CH2:26][CH2:27][NH:20][CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CCCNCCOc1cc(F)cc(S(C)(=O)=O)c1
Reactant: CC(C)CN
Agent: CS(=O)(=O)c1cc(Cl)cc(OCCBr)c1
Solvent: CCO
Product: CC(C)CNCCOc1cc(F)cc(S(C)(=O)=O)c1

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-chloro-5-methylsulfonyl-benzene (0.05 g, 0.16 mmol) and isobutylamine (0.2 ml, 1.3 mmol) in ethanol (5 ml). MS m/z (relative intensity, 70 eV) 289 (M+, 1), 246 (bp), 138 (2), 86 (70), 56 (17).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:13][CH:14]=[CH2:15])[CH:10]=[CH:9]2)([OH:3])=O.N1C2C(=CC=CC=2C([N:27]2[CH2:31][C@@H:30]([CH:32]3[CH2:34][CH2:33]3)[C@H:29]([CH2:35][N:36]3[CH2:41][CH2:40][CH:39]([C:42]4[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=4)[CH2:38][CH2:37]3)[CH2:28]2)=O)C=C1>>[CH2:13]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[C:1]([N:27]2[CH2:31][C@@H:30]([CH:32]3[CH2:33][CH2:34]3)[C@H:29]([CH2:35][N:36]3[CH2:37][CH2:38][CH:39]([C:42]4[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=4)[CH2:40][CH2:41]3)[CH2:28]2)=[O:3])[CH:9]=[CH:10]1)[CH:14]=[CH2:15]
Reactant: C=CCn1ccc2cccc(C(=O)O)c21
Reactant: O=C(c1cccc2cc[nH]c12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Product: C=CCn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](C4CC4)C3)c21

Procedure:
The title compound was prepared from 7-carboxy-N-allylindole and 3-(S)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine (Example 11) as described in Example 11. Mass Spectrum (EI) m/e 486 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:23]([NH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[Br:15])=[O:24]
Reactant: Nc1ccc(-c2ccccc2)cc1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccc(-c2ccccc2)cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 4-phenyl aniline(0.185 g, 1 mmol) and 2-bromophenylisocyanate(0.198 g) by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane(215 mg, 56%). EI-MS m/z 383(M+H)+.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26])=[O:22])[C@@H:11]([CH3:20])[O:12]CC1C=CC=CC=1)=[O:8]>C(O)(=O)C.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26])=[O:22])[C@@H:11]([CH3:20])[OH:12])=[O:8]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@H]1C(N)=O
Yield: 59.6 %

Procedure:
2.04 g (3.7 mmoles) of Z-Glp-Thr(Bzl)-Pro-NH2 are dissolved in 40 ml of acetic acid, 0.4 g of a 10% palladium-on-carbon catalyst are added, and hydrogen is bubbled through the mixture for 4 hours. The catalyst is filtered off, the filtrate is evaporated, and the residue is triturated with ether. The resulting 1.31 g of amorphous crude product are applied onto the top of a column filled with 30 g of silica gel (particle size: 0.063-0.2 mm), and the column is eluted with solvent mixture (3). The main fractions which contain the pure substance are combined, evaporated, and the product is isolated with ether. 0.72 g (59.5%) of Glp-Thr-Pro-NH2 are obtained; Rf4 =0.16, [α]D25 =-90.0° (c=1%, in acetic acid). Amino acid analysis: Glu: 1.00 (1.0), Thr: 0.99 (1.0), Pro: 1.03 (1.0).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)O1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Agent: OBO
Product: N#Cc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile as a boronic acid, the desired compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]3[N:21](C4C=CC(S(C)(=O)=O)=CC=4F)[N:22]=[CH:23][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])C.Cl.Cl.[F:37][C:38]1[CH:43]=[C:42]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:41]=[CH:40][C:39]=1N1C2=NC=NC(SC3CCNCC3)=C2C=N1.C(N(CC)CC)C.ClC(OC(C)C)=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14]([C:39]2[CH:40]=[CH:41][C:42]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:43][C:38]=2[F:37])[C:15]2[N:20]=[CH:19][N:18]=[C:17]3[NH:21][N:22]=[CH:23][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCNCC4)ncnc32)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Agent: CC(C)OC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC([SH](c2ccc(S(C)(=O)=O)cc2F)c2ncnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester (3.54 g, 6.97 mmol) was treated with 4M HCl in 1,4-dioxanes (40 mL). After 2 hours stirring at room temperature, 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride was collected by filtration. To a mixture of 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (3.0 g, 6.76 mmol) in DMF (27 mL) was added triethyl amine (2.05 g, 20.28 mmol). After 30 minutes stirring, isopropyl chloroformate (7.44 mmol) as a 1.0M solution in toluene was added to the reaction and reaction was stirred for two hours. HCl salts had crashed out and were removed by filtration. Filtrate was extracted with ethyl acetate (100 mL) and washed with water (4×100 mL). Organic was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield Compound A214 as a white solid. 1H NMR(CDCl3, 400MHz) δ 1.27 (d, J=6.3 Hz, 6H), 1.77 (2H, m), 2.18 (2H, m), 3.13 (3H, s), 3.21 (2H, m), 4.04 (2H, m), 4.48-4.40 (1H, m), 4.99-4.90 (1H, m), 7.98-7.92 (3H, m), 8.30 (1H, s), 8.79 (1H, s). Exact mass calculated for C21H24FN5O4S2 493.1, found 494.3 (MH+).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[C:7]([CH3:36])=[C:8]([C:27]([O:34][CH3:35])=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([O:19]CC2C=CC=CC=2)[CH:11]=1.[H][H]>[Pd].O1CCOCC1>[CH3:4][O:5][C:6]1[C:7]([CH3:36])=[C:8]([C:27]([O:34][CH3:35])=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([OH:19])[CH:11]=1
Reactant: [H][H]
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(O)c2)c(OC)c(OC)c1OC
Yield: 75.4 %

Procedure:
10% Pd—C (50 mg) was added to an ethanol (10 ml) and dioxane (10 ml) mixed solution of 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (150 mg, 0.3554 mmol) and the resulting solution was stirred at room temperature for 16 hours in a hydrogen stream. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with hexane to obtain the titled compound (97 mg, 0.2679 mmol, 75%).
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][CH2:20][NH:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)C1(N)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCNC1(C(=O)OCC)CCCCC1
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-aminocyclohexanecarboxylate (669 g), potassium carbonate (683.1 g) and ethyl 4-bromobutyrate (558 ml) was stirred at 130° C. for 18 hours, then cooled to ambient temperature and poured onto ice-water (3 l). The product was extracted into dichloromethane and the combined extracts were dried over sodium sulphate and the solvent was removed in vacuo to yield ethyl 1-(3-ethoxycarbonylpropylamino)cyclohexanecarboxylate as a brown/orange oil. Yield 943.2 g.