Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:20]O>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH3:20])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C(=O)O)c1ccc(N)nc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)c1ccc(N)nc1
Temperature: 25 °C

Procedure:
A solution of 2-(6-aminopyridin-3-yl)-2-methylpropanoic acid hydrochloride (35.0 g, 0.162 mmol) and concentrated H2SO4 (5 mL) in MeOH (250 mL) was heated at reflux overnight. After cooling to ambient temperature, the reaction was quenched cautiously with saturated aqueous NaHCO3 and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organic phase separated and the aqueous phase re-extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue (31.6 g) was judged pure by a combination of TLC and 1H nmr analysis and was used without further purification in the subsequent reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:18]([N:20]([CH:34]([CH3:36])[CH3:35])[C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[O:19])[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=2[O:7][C:6]([CH3:38])([CH3:37])[C:5]1=[O:39].[S:40](S(O)(=O)=O)(O)(=O)=O.[CH3:48][CH2:49][CH2:50]C.C(N(CC)CC)C.CO>O>[CH3:38][C:6]1([CH3:37])[C:5](=[O:39])[N:4]([CH2:3][CH2:2][NH:1][C:50](=[S:40])[CH2:49][CH3:48])[C:9]2[CH:10]=[C:11]([C:18]([N:20]([CH:34]([CH3:35])[CH3:36])[C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:22]3)=[O:19])[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]=2[O:7]1
Reactant: O=S(=O)(O)S(=O)(=O)O
Reactant: CCCC
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(=S)NCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 137.1 %

Procedure:
To tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (100 mg) were added methylpropane dithionate (23 mg), triethylamine (0.050 ml) and MeOH (3 ml), and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (90 mg) as a colorless liquid.
Reaction SMILES: [NH2-].[NH2-].[Ca+2:3].[CH2:4]([CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][OH:8])[CH3:5].N>C1CCCCC1>[CH2:4]([CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:7][O:8][CH2:7][CH:6]([CH2:4][CH3:5])[CH2:9][CH2:10][CH2:11][CH3:12])[CH3:5].[Ca:3]
Reactant: CCCCC(CC)CO
Reactant: [Ca+2]
Agent: N
Agent: [NH2-]
Solvent: C1CCCCC1
Product: CCCCC(CC)COCC(CC)CCCC
Product: [Ca]

Procedure:
To 7.2 g (0.1 mole) of calcium amide slurried in 100 ml of cyclohexane, there is added 23.5 g (28.2 ml, 0.18 moles) of 2-ethyl-1-hexanol gradually over a 10-15 minute period. Ammonia is given off throughout the addition. The mixture is heated to reflux for several hours to remove entrained ammonia, and is then cooled and filtered. The resultant clear, light amber solution is 0.8M in Ca.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][CH2:18]1.[F:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([F:44])[C:30]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[N:17]2[CH2:22][CH2:21][CH:20]([CH:23]([N:25]([CH3:26])[CH3:27])[CH3:24])[CH2:19][CH2:18]2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([F:28])[C:30]([OH:45])=[C:31]([F:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1)N(C)C
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Product: CC(C1CCN(c2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(F)c4)cc23)CC1)N(C)C
Yield: 45 %

Procedure:
Following general procedure F, (6-bromo-4-{4-[1-(dimethylamino)ethyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (60 mg, 0.139 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (39 mg, 0.153 mmol) to afford the desired product (30 mg, 44%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 8.82 (s, 1H), 8.26 (s, 1H), 8.03 (p, J=8.8 Hz, 2H), 7.35 (dd, J=8.0, 1.7 Hz, 2H), 3.56 (t, J=10.3 Hz, 2H), 3.26-3.17 (m, 3H), 2.80 (s, 6H), 2.66-2.53 (m, 1H), 1.96 (d, J=11.2 Hz, 3H), 1.87-1.68 (m, 2H), 1.37-1.22 (m, 8H); ESI MS m/z 480 [C28H31F2N3O2+H]+; HPLC 98.6% (AUC), tR=10.24 min.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].[OH-].[Na+].[C:9]([C:11]1[CH:23]=[CH:22][C:14]2[O:15][C:16]([CH3:21])(C)[CH:17]3[O:19][CH:18]3[C:13]=2[CH:12]=1)#[N:10].[CH2:24](O)C>>[ClH:2].[C:9]([C:11]1[CH:23]=[CH:22][C@@H:14]2[O:15][C@H:16]([CH3:21])[C:17]([CH3:24])([OH:19])[C:18]([NH:6][CH2:5][CH2:4][CH2:3][Cl:2])=[C:13]2[CH:12]=1)#[N:10]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: CCO
Reactant: NCCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H]1O[C@H]2C=CC(C#N)=CC2=C(NCCCCl)C1(C)O
Temperature: 25 °C
Reaction time: 360 h

Procedure:
To a stirred solution of chloropropylamine hydrochloride (2.0 g) and sodium hydroxide pellets (0.5 g) in ethanol (150 ml) was added 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran (2.0 g, prepared as described in U.K. patent 1,511,187, Example 7). The reaction mixture was stirred at room temperature for 15 days and monitored by TLC. The solution was filtered and evaporated, and the resulting gum (1.74 g) chromatographed on 200 g silica gel with elution by ethyl acetate. The early, chromatographically homogeneous fractions were combined (1.16 g), and, dissolved in the minimum quantity of ethanol required, were treated with ethereal anhydrous HCl to give the title compound as a white powder (0.54 g) of mp 250°-253° C.; NMR (in DMSOd6) δ1.11 (s), 1.45 (s), 2.25 (distorted t, J=5, 5 Hz), 3.08 (br multiplet), 3.76 (t, J=5, 5 Hz overlapped with m, 3H), 4.03 (d, J=9 Hz), 4.46 (d, J=9 Hz), 7.03 (d, J=8 Hz), 7.74 (g, J=8, 2 Hz), 8.47 (d, J=2 Hz). Anal. Calcd. for C15H20N2O2Cl2 :C, 54.39; H, 6.09; N, 8,46; Cl, 21.41. Found: C, 54.36; H, 6.19; N, 8.33; Cl, 21.50%.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16](=[O:19])([O-])O.[Na+]>>[CH2:2]([N:3]([CH2:4][CH2:16][OH:19])[S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[CH:2][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13])[CH2:11][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: CCCCCCN(CCO)S(=O)(=O)c1cccc2cnccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 100 ml of ice water was dissolved 10.56 g of 5-isoquinolinesulfonyl chloride hydrochloride, and the pH of the solution was adjusted to 6 with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with 100 ml of dichloromethane. The dichloromethane layer was added dropwise to a 100 ml of dichloromethane solution containing 8.7 g of N-hexylethanolamine and 6.1 g of triethylamine over 20 minutes while cooling with ice. The mixture was stirred at a temperature of 15° C. to 20° C. for 3 hours, washed with water, and dried with anhydrous magnesium sulfate. Then, thedichloromethane was removed under reduced pressure to obtain an oily residue. The thus obtained oily residue was subjected to purification by silica gel column chromatography (Wacogel C-200, 200 g; solvent: a 5% methanol solution in chloroform) to obtain 5.24 g of N-hexyl-N-(2-hydroxyethyl)-5-isoquinolinesulfonamide.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:36][CH3:37])[CH2:25][NH:26]CC2C=CC(OC)=CC=2)[C:5]1=[O:38])[CH:2]=[CH2:3]>C(#N)C.O.[OH-].[Na+].CCOC(C)=O>[CH2:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([CH:24]([CH2:36][CH3:37])[CH2:25][NH2:26])[C:5]1=[O:38])[CH:2]=[CH2:3]
Reactant: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CNCc2ccc(OC)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCC1CC(c2cccc(Cl)c2)C(c2ccc(Cl)cc2)N(C(CC)CN)C1=O

Procedure:
To a solution of (3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((SR)-1-(4-methoxybenzylamino)butan-2-yl)piperidin-2-one (88 mg, 0.160 mmol) in acetonitrile (1899 μL) and water (380 μL) was added ceric ammonium nitrate (350 mg, 0.638 mmol) at 25° C. The reaction was monitored by LCMS and HPLC and on completion was diluted with 0.5 M aq. NaOH and EtOAc and the resulting emulsion was filtered through a pad of Celite® (J. T. Baker, Phillipsberg, N.J., J. T. Baker, Phillipsberg, N.J., diatomaceous earth). The filtrate was extracted with ethyl acetate and the combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to provide the crude product which was used n subsequent steps without further purification.
Reaction SMILES: CN(C=O)C.[CH2:6]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][C:17]=2[C:24]([F:27])([F:26])[F:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:6]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[O:23][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])=[CH:20][CH:19]=[CH:18][C:17]=2[C:24]([F:27])([F:25])[F:26])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrCCCCCCBr
Reactant: Oc1c(Cc2ccccc2)cnc2c(C(F)(F)F)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cccc2c(OCCCCCCBr)c(Cc3ccccc3)cnc12
Yield: 85.8 %

Procedure:
A DMF (3 mL) solution of 3-benzyl-8-(trifluoromethyl)quinolin-4-ol (500 mg, 1.65 mmol), 1,6-dibromohexane (3.22 g, 13.20 mmol), and potassium carbonate (455.7 mg, 3.30 mmol) was stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane:ethyl acetate), and the title compound (660 mg, yield 86%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)=[N:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.[Br:27]Br>C(O)(=O)C>[Br:27][C:21]1[CH:22]=[N:23][C:24]2[C:19]([CH:20]=1)=[CH:18][C:17]([S:16][C:13]1[N:11]3[N:12]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:8]=[CH:9][C:10]3=[N:15][N:14]=1)=[CH:26][CH:25]=2
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc5ncccc5c4)n3n2)cn1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(Br)cc5c4)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.2 %

Procedure:
To a solution of 6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-quinoline (1 g, 2.785 mmol) in glacial acetic acid (20 mL) was added bromine (0.716 mL, 13.93 mmol) dropwise. The reaction mixture was stirred at room temperature for 5 min then at 100° C. for 3 h. The reaction was cooled to room temperature, and the mixture was concentrated in vacuo. The residue was partitioned between 10% aqueous NaOH and 10% methanol/di-chloromethane. The organic layer was separated, washed with 1 M aqueous Na2S2O3, dried over sodium sulfate, filtered, and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-7% methanol/dichloromethane afforded 381 mg of 3-bromo-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-quinoline as a beige solid (31% yield): 1H NMR (DMSO-d6): δ 3.89 (s, 3H), 7.77 (dd, 1H), 7.80 (d, 1H), 7.99 (d, 1H), 8.00 (s, 1H), 8.43 (s, 1H), 8.48 (d, 1H), 8.68 (d, 1H), 8.92 (d, 1H); MS (m/z) 438, 440 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.O>S(Cl)(Cl)=O.C(OCC)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:8]([C:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)=[O:10])=[CH:14][CH:13]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)c1cccc(Cl)n1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: O=C(Nc1ccc(F)cc1)c1cccc(Cl)n1
Yield: 81 %

Procedure:
6-chloropicolinic acid (51.2 g, 0.325 mol) in thionyl chloride (90 ml) was stirred and heated to reflux for 2 hours. The excess thionyl chloride was evaporated in vacuo and diethylether (250 ml) added to the residual 6-chloropicolinoyl chloride. A solution of 4-fluoroaniline (37.5 g, 0.338 mol) in diethylether (100 ml) was added with stirring, maintaining the temperature below 20° C. After the addition, the reaction mixture was stirred overnight at ambient temperature. Water was added to the reaction mixture and the organic layer separated. After a further washing with water and drying with anhydrous magnesium sulphate, the solvent was removed in vacuo to give the title compound as a pale brown solid (66 g, 82%), mp 98° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][C:25](SC)=[N:26][CH:27]=3)[N:6]=[C:5]2[C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:3][CH2:2]1.[OH-:41].[Na+]>CS(C)=O>[CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][C:25]([OH:41])=[N:26][CH:27]=3)[N:6]=[C:5]2[C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH2:3][CH2:2]1
Reactant: CSc1ncc(-c2nc(-c3ccc(OC(F)(F)F)cc3)n(C3CC3)c2C(=O)N2CCC(N3CCCC3)CC2)cn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(c1c(-c2cnc(O)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Yield: 22 %

Procedure:
A solution of 0.06 g (0.1 mmol) of [3-cyclopropyl-5-(2-methylsulfanyl-pyrimidin-5-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 88) and 0.1 ml of 6M sodium hydroxide solution in 0.5 ml of DMSO was heated to 100° C. for 3 h. The DMSO was removed using an Isolute SPE 103 cartridge, and the crude product purified by preparative HPLC affording 0.01 g (22%) of the title compound as a colorless amorphous solid. MS: 543.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.FC1C=CC([NH:35][C:36]([C:38]2([C:41](O)=[O:42])[CH2:40][CH2:39]2)=[O:37])=CC=1.C1(C(O)=O)(C(O)=O)CC1.[F:53][C:54]1[CH:60]=[CH:59][C:57](N)=[CH:56][CH:55]=1.Cl.C(N=C=NCCCN(C)C)C>CC(N(C)C)=O.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:57]5[CH:59]=[CH:60][C:54]([F:53])=[CH:55][CH:56]=5)[C:41]([C:38]5([C:36]([NH2:35])=[O:37])[CH2:39][CH2:40]5)=[O:42])=[CH:20][C:19]=4[F:25])=[C:11]3[CH:10]=[N:9]2)=[CH:26][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc(Cn2ncc3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C1(C(=O)O)CC1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ncc3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred mixture of 4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (73 mg, 0.20 mmol; obtained from Example 1, Step D) and ((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (49 mg, 0.220 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the methods of WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836) in DMA (2 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCI) (77 mg, 0.400 mmol). The reaction was stirred for 1 hour at room temperature. The reaction was diluted with EtOAc (10 mL) and water (10 mL). The phases were separated, and the organic phase washed with water (3×10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified by preparative TLC eluting with 3% MeOH/DCM. The product was obtained as a waxy solid (42 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 8.36 (d, J=5 Hz, 1H), 8.20 (s, 1H), 7.77 (m, 2H), 7.46 (m, 2H), 7.26 (m, 4H), 7.06 (m, 2H), 6.83 (d, J=9 Hz, 2H), 6.40 (d, J=5 Hz, 1H), 5.62 (s, 2H), 3.76 (s, 3H), 1.79 (m, 2H), 1.62 (m, 2H, overlaps with water).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C12CC(CC1)CC2C(O)=O.C([NH-])C1C=CC=CC=1>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C(O)C1CC2CCC1C2
Agent: [NH-]Cc1ccccc1
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 164.4 %

Procedure:
Using the procedure described in Example 5, treatment of L-proline-L-isoleucine benzylamide (100 mg, 0.32 mmol) with 2-norbornyl α-chloromethyl ketone (82 mg, 0.48 mmol, 1.5 eq; prepared from 2-norbornanecarboxylic acid by the method described in Example 1) provided 69 mg of L-isoleucine, N-[1-(2-bicyclo[2.2.1]hept-2-yl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.C(Cl)Cl>[O:9]1[C:13]2([CH2:18][CH2:17][CH:16]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1
Reactant: Nc1ccccc1O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Oc1ccccc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A mixture of 2-aminophenol (2 g, 18.327 mmol), 1,4-dioxa-spiro[4.5]decan-8-one (3.721 g, 23.825 mmol), and sodium triacetoxyborohydride (5.826 g, 27.491 mmol) in DCE (20 ml) and acetic acid (0.2 ml) was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM and washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and the solvent was evaporated in vacuo. The solid residue was triturated with diisopropyl ether to yield D19 (3.78 g) as a white solid.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[F:55][CH:56]1[CH2:59][N:58]([S:60]([NH2:63])(=[O:62])=[O:61])[CH2:57]1>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]3([CH3:49])[CH2:42][CH2:43][C:44]([F:47])([F:48])[CH2:45][CH2:46]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:63][S:60]([N:58]2[CH2:59][CH:56]([F:55])[CH2:57]2)(=[O:62])=[O:61])=[O:35])[CH2:27][CH2:28]1
Reactant: NS(=O)(=O)N1CC(F)C1
Reactant: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CCC(F)(F)CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(COc2cc(F)c(C(=O)NS(=O)(=O)N3CC(F)C3)cc2C2CC2)CCC(F)(F)CC1

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with 3-fluoroazetidine-1-sulfonamide, the title compound was obtained (0.06 g, 20%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.81-8.63 (m, 1H), 7.70-7.58 (m, 1H), 6.66-6.50 (m, 1H), 5.45-5.13 (m, 1H), 4.59-4.29 (m, 4H), 3.77 (s, 2H), 2.09-1.74 (m, 7H), 1.69-1.60 (m, 2H), 1.17 (s, 3H), 1.01-0.89 (m, 2H), 0.71-0.60 (m, 2H); MS (ES+) m/z 479.1 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[Cl:3][CH2:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[ClH:3]
Reactant: OCc1cccc2nccn12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution consisting of 58.4 ml (800 mmol) of thionyl chloride and 100 ml of methylene chloride was added 23.68 g (160 mmol) of 5-hydroxymethylimidazo[1,2-a]pyridine with small portions. The reaction mixture was stirred for one hour at room temperature. Then, the solvent and excess amount of thionyl chloride were distilled off under reduced pressure. To the resulting white solid residue was added 100 ml of toluene. The mixture was shaken sufficiently, then the solvent was distilled off under reduced pressure. This process was repeated twice to give 31.85 g (98.0%, white solid) of a crude product.
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1.[CH3:12][N:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22])[CH3:14].[Cl-].[NH4+]>O1CCCC1>[ClH:9].[CH3:14][N:13]([CH:15]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[OH:22])[CH3:12]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(CC2(O)CCCCC2C(c2ccccc2)N(C)C)cc1
Product: Cl
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
0.38 g (15.6 mmole) of magnesium turnings was stirred in 15 ml of tetrahydrofuran of analysis purity. 2.44 g (15.6 mmole) of 4-methoxybenzyl chloride dissolved in 15 ml of tetrahydrofuran were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further 1.5 hours at 65° C. 3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl) cyclohexanone prepared according to Example 1 were dissolved in 15 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to the Grignard reagent, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and extracted three times at RT with 20 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.26 g of crude base (93.0% of theory) were obtained, from which 2.87 g of 2-(di-methylaminophenylmethyl)-1-(4-methoxybenzyl)cyclohexanol, hydrochloride (56.8% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 130° C.