Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]2[C:14](=[O:15])[N:13]([C:16]3[C:21]([CH:22]=[O:23])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:40]=[C:34]6[CH2:35][N:36]([CH3:39])[CH2:37][CH2:38][N:33]6[N:32]=5)[C:27](=[O:41])[N:26]([CH3:42])[CH:25]=4)[CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11][C:4]=2[N:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[BH4-].[Na+]>CO>[F:1][C:2]1[C:3]2[C:14](=[O:15])[N:13]([C:16]3[C:21]([CH2:22][OH:23])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:40]=[C:34]6[CH2:35][N:36]([CH3:39])[CH2:37][CH2:38][N:33]6[N:32]=5)[C:27](=[O:41])[N:26]([CH3:42])[CH:25]=4)[CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11][C:4]=2[N:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(c(F)c7n6CCCC7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(c(F)c7n6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 12.5 °C
Reaction time: 1.5 h
Yield: 14.7 %

Procedure:
To the solution of 241a (54.0 mg, 0.095 mmol) in methanol (5 mL) was added sodium borohydride (28.9 mg, 0.76 mmol) at 0° C. The reaction was stirred at 0-25° C. for 1.5 h. It was then quenched with water (5 mL). The mixture was evaporated under reduced pressure and the residue was extracted with dichloromethane (3×30 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 241 (8.0 mg, 15%) as a white solid. MS-ESI: [M+H]+ 573.3. 1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J=5.0 Hz, 1H), 8.21 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.31 (d, J=5.0 Hz, 1H), 5.88 (s, 1H), 4.87-4.85 (m, 1H), 4.44-4.35 (m, 2H), 4.13-4.08 (m, 1H), 3.92-3.89 (m, 3H), 3.79-3.76 (m, 2H), 3.58 (s, 3H), 3.49 (s, 2H), 2.99-2.94 (m, 2H), 2.79-2.77 (m, 2H), 2.66-2.64 (m, 2H), 2.35 (s, 3H), 1.90-1.78 (m, 2H), 1.75-1.73 (m, 2H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:13])[C:10](O)=[O:11])=O)(C)(C)C.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([C@@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)[CH:15]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:8][C@@H:9]([CH3:13])[C:10]([NH:28][C@H:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH:21]=1)[CH3:27])=[O:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](N)c1cccc(-c2cccnc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](N)C(=O)N[C@@H](C)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2-tert-butoxycarbonylamino-propionic acid (0.083 mmol), (S)-1-(3-pyridin-3-yl-phenyl)-ethylamine (12.7 mg, 0.064 mmol), EDAC.HCl (18.4 mg, 0.096 mmol), HOBT (13 mg, 0.096 mmol and d iisopropylethylamine (33 μL, 0.192 mmol) ) in DMF (2 mL) was stirred at room temperature for 18 h. The reaction mixture was purified by preparative HPLC (Primeshere C18-HC 21.2×100 mm; (5 mM NH4OAc ) 0–100% gradient over 5 min; 20 mL/min flow rate). The solvents were removed through evaporation on the speed-vac, and the crude product was dissolved in CH2Cl2/TFA (1: 1, 2 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated on the speed-vac and purified by preparative HPLC (5 mM NH4OAc buffer; gradient 0% to 100% B in 10 min (A: 10% CH3CN/H2O; B: 90% CH3CN/H2O; column: Primesphere C18 HC 21.2×100 mm) to afford the title product.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]>[Pd].C(O)C>[CH3:1][CH2:2][CH:3]([C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][CH:26]5[CH2:27]4)[O:35][CH2:34][CH2:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48][C:49]([CH3:51])=[O:50])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])[CH3:4]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Agent: [Pd]
Solvent: CCO
Product: CCC(C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4CC5O[C@@H]5OCC[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Yield: 59.1 %

Procedure:
Azadirachtin (30mg, 0.042mmol) and 0.5ml of ethanol was stirred with 20mg of 5% palladiumon alumina at 20° C. under hydrogen (10 atm) for 3 hours. The reaction mixture was then filtered and rotary evaporated in vacuo. The crude product was purified by silica gel preparative HPLC (solvent=2-propanol:n-hexane, 17:83, v/v), followed by ODS preparative HPLC (solvent=methanol:water, 1:1, v/v) to give 2',3',22,23-tetrahydroazadirachtin (18mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12](OC)[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[CH:4][CH:3]=1.[CH3:31][S-:32].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][S:32][CH3:31])[C:26]=2[Cl:27])=[O:21])=[CH:6][CH:7]=1
Reactant: C[S-]
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1NC(=O)c1scc(CCl)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCc1csc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.52 g, 1.1 mmol) in DMF (12 mL) was added sodium thiomethoxide (0.39 g, 5.5 mmol) and the reaction mixture stirred at ambient temperature. After 16 hours, the mixture was poured into water (100 mL) and extracted with ethyl acetate (2×80 mL). The combined organics were washed with water (2×80 mL), 1M hydrochloric acid (2×80 mL) and brine (80 mL), dried over MgSO4 and concentrated of all volatiles in vacuo. Purification of the resulting solid by flash chromatography on silica gel afforded 0.36 g (68% yield) of N-(4-chlorophenyl)-2-[((3-chloro-4-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a pale yellow solid; NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 7.9 (d, 1), 7.8 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 3.7 (s, 2), 2.0 (s 3) ppm.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:42][CH:43]2[CH2:45][CH2:44]2)[C:6]2[C:15]([CH2:16][N:17]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[C:18]3[N:19]=[N:20][N:21]([CH2:23][CH2:24][OH:25])[N:22]=3)=[CH:14][C:13]3[C:8](=[C:9]([CH3:41])[CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O.[CH3:49]SC>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C(Cl)Cl>[F:36][C:33]([F:34])([F:35])[C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([C:37]([F:39])([F:40])[F:38])[CH:30]=1)[CH2:26][N:17]([CH2:16][C:15]1[C:6]([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:42][CH:43]2[CH2:45][CH2:44]2)=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:41])[C:18]1[N:19]=[N:20][N:21]([CH2:23][CH2:24][O:25][CH3:49])[N:22]=1
Reactant: CSC
Reactant: Cc1cccc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(CCO)n3)c(N(CC3CC3)CC3CC3)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCCn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc3cccc(C)c3nc2N(CC2CC2)CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 367.6 %

Procedure:
To the 2-{5-[[2-(bis-cyclopropylmethyl-amino)-8-methyl-quinoline-3-ylmethyl]-(3,5-bistrifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethanol (0.08 g, 0.126 mmol), (example 93), was added NaOH (0.010 g, 0.25 mmol) and water (1 mL). The reaction was stirred at room temperature for 15 min and then DCM (1 mL) was added followed by the addition of DMS (0.019 g, 0.15 mmol) and TBAB (0.002 g, 0.006 mmol). The reaction was continued for overnight. The solvent was evaporated and the aqueous layer was back extracted with DCM (2×10 mL). The combined organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated on rotavapor. The residue obtained was purified by preparative thin layer chromatography and eluted with 15% ethyl acetate and petroleum ether to get the desired product (0.30 g, 56%).
Reaction SMILES: [N+](=[CH:3][Si](C)(C)C)=[N-].[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32]([C:33]([C@@H:35]3[CH2:38][C@H:37]([C:39]([OH:41])=[O:40])[CH2:36]3)=[O:34])[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:42][CH3:43])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14]2.O.C(OCC)(=O)C>C1COCC1.CO>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@@H:23]2[N:32]([C:33]([C@@H:35]3[CH2:38][C@H:37]([C:39]([O:41][CH3:3])=[O:40])[CH2:36]3)=[O:34])[CH2:31][CH2:30][C:29]3[N:28]=[C:27]([O:42][CH3:43])[CH:26]=[CH:25][C:24]2=3)=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:18])([CH3:19])[CH2:15][CH2:14]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](C(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](C(=O)OC)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Diazomethyl)trimethylsilane (0.6M hexane solution) (0.404 mL, 0.24 mmol) was added to a mixture of cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6 (5H)-yl)carbonyl)cyclobutanecarboxylic acid (60 mg, 0.12 mmol) in THF (1 mL) and MeOH (1 mL) at 5° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added water and ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→50% ethyl acetate/hexane) to give the title compound (50 mg, 0.098 mmol, 81%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16](B(O)O)[CH:17]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=2)[CH:13]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: COc1ccc(F)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)N)cc1
Temperature: 200 °C

Procedure:
A mixture of (R)-1-(4-bromophenyl)ethylamine (0.10 g, 0.5 mmol), 5-fluoro-2-methoxyphenyl boronic acid (0.17 g, 1 mmol), and palladium (II) acetate (0.011 g, 0.05 mmol) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The mixture was then poured onto an SCX column, washed with dichloromethane/methanol, and the intermediate amine eluted using 1M ammonia in methanol (50 ml). Evaporation of solvents under reduced pressure gave (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. To a solution of (R)-1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (0.25 g, 0.1 mmol) in dichloromethane (1 ml) was added triethylamine (0.025 g, 0.25 mmol) and 2,4 difluorophenyl-sulfonyl chloride (0.043 g, 0.2 mmol). The solution was stirred overnight and then quenched with acetic acid (0.5 ml). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound: 1H NMR (400 MHz, DMSO): δ 8.58 (d, 1H), 7.64 (q, 1H), 7.30-6.98 (m, 9H), 4.44 (dq, 1H), 3.74 (s, 3H), 1.36 (d, 3H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[N:17][CH:18]=2)=[O:11])=[C:5]([C:23]([F:26])([F:25])[F:24])[CH:4]=1.C1COCC1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=2)=[O:11])=[C:5]([C:23]([F:25])([F:26])[F:24])[CH:4]=1
Reactant: COC(=O)c1ccc(NC(=O)Cc2ccc(OC)cc2C(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)O)nc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
Prepared using General Procedure 9: To a stirred solution of methyl 5-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)picolinate INT-14 (74 mg, 0.2 mmol) in MeOH (1 mL) and THF (4 mL) was added 2 N NaOH (1 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was diluted with water (1 mL) and acidified with 1 N HCl to a pH of 2. The resulting precipitate was isolated by filtration and the filter cake was washed with water. Crude product was dried under vacuum to afford 48 mg (67%) of 5-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)picolinic acid INT-15 which was used in the next step without purification. LCMS-ESI (m/z) calculated C16H13F3N2O4: 354; found 355, tR=2.66 min (Method 1). 1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.18 (dd, J=8.6, 2.5 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.29-7.10 (m, 2H), 3.92 (s, 2H), 3.82 (d, J=5.3 Hz, 3H), 3.35 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[C:18]2Cl>CN1CCCC1=O.C(OCC)C>[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=3)[NH:3][C:2]=1[CH3:1])[CH:19]=[CH:18]2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Cc1cccc2c(Cl)ccnc12
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1ccc2[nH]c(C)c(-c3ccc4cccc(C)c4n3)c2c1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
2,5-Dimethylindole (290 mg) and 8-methyl-4-chloroquinoline (360 mg) were suspended in N-methylpyrolidinone (0.5 ml), and maintained under a nitrogen atmosphere. The reaction was heated to 140° C. with stirring for 45 minutes. On cooling a deep red precipitate formed, the mixture was diluted with diethylether and the solid collected by filtration, and dried to give the sub-title compound (570 mg).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[C:15]1([CH3:29])[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[C:26](O)=[O:27])[CH:16]=1>>[F:13][C:10]([F:12])([F:11])[C:9]([NH:8][CH2:7][C@H:2]1[N:3]([C:26]([C:25]2[CH:24]=[CH:23][S:22][C:21]=2[C:17]2[CH:16]=[C:15]([CH3:29])[CH:20]=[CH:19][CH:18]=2)=[O:27])[CH2:4][C@H:5]2[C@@H:1]1[CH2:6]2)=[O:14]
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Reactant: Cc1cccc(-c2sccc2C(=O)O)c1
Product: Cc1cccc(-c2sccc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c1

Procedure:
prepared by reaction of N-[(1S,2S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-2-yl)methyl]-2,2,2-trifluoro-acetamide with 2-m-tolyl-thiophene-3-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:26]3[CH2:27][CH2:28][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:24][CH2:25]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(N1CCN(Cc2ccccc2)CC1)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 2 h
Yield: 79 %

Procedure:
A solution of 2.9 g (0.01 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahyfrofuran was treated while stirring with the dropwise addition of 1.8 g (0.01 mole) of 1-benzylpiperazine. After stirring for 2 hr, the reaction mixture was diluted with water (200 ml) and 1.4 g of potassium carbonate was added. The solid precipitate was collected by filtration (5.2 g). Recrystallization from benzene/ligroin yielded 3.4 g (79.1%) of white crystals, m.p. 133°-135° C.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:19][N:20]1[C:24]([C:25](O)=[O:26])=[C:23]([C:28]([F:31])([F:30])[F:29])[C:22]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:21]1.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([Cl:55])=[C:44]([CH:54]=1)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50].O>C1COCC1>[Cl:55][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:25]([C:24]2[N:20]([CH3:19])[N:21]=[C:22]([C:32]([F:37])([F:38])[C:33]([F:35])([F:36])[F:34])[C:23]=2[C:28]([F:30])([F:31])[F:29])=[O:26])=[CH:54][C:44]=1[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ccc1Cl
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(CNC(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 40.9 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (=DMTMM, see Tetrahedron 1999, 55, 13159-13170) (1.25 g, 4.51 mmol, 1.1 eq.) was added to 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (1.28 g, 4.1 mmol; preparation according to WO2010/051926) and tert-butyl (5-amino-2-chlorobenzyl)carbamate (1.05 g, 4.1 mmol, 1.0 eq.) in THF (15 ml), and the mixture was left at room temperature for 18 h. Water (30 ml) was added, the mixture was extracted with ethyl acetate (3×30 ml) and the extracts were dried over MgSO4. After concentration under reduced pressure, the product was purified by column chromatography on silica gel (hexane/ethyl acetate), giving tert-butyl [2-chloro-5-({[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzyl]carbamate (924 mg, 41%).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1>>[F:17][C:18]([F:27])([F:28])[C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[CH2:25][NH:26][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: NCc1cccc(C(F)(F)F)c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3cccc(C(F)(F)F)c3)ccc12
Yield: 20.6 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 448 using 6 (230 mg, 1.0 mmol) and (3-(trifluoro-methyl)phenyl)methanamine (350 mg, 1.00 mmol) to provide 451 (76 mg, 20% yield) as a white powder. LC-MS (M+H=370, obsd.=370). 1H NMR (400 MHz, DMSO-D6) δ 11.51 (s, 1H), 8.59 (d, J=8.1, 1H), 8.42 (dd, J=1.6, 4.7, 1H), 8.00 (d, J=8.8, 1H), 7.70 (m, 2H), 7.60 (d, J=6.9, 2H), 7.41 (d, J=2.1, 1H), 7.25 (dd, J=4.7, 8.0, 1H), 6.97 (dd, J=2.2, 8.8, 1H), 4.63 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24]3)=[CH:18][CH:17]=2)[CH2:10][C:11]([O:13]CC)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].[OH-].Cl>C1COCC1.C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24]3)=[CH:20][CH:21]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CC(c1ccc(OC2Cc3ccccc3C2)cc1)c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)CC(c1ccc(OC2Cc3ccccc3C2)cc1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(+/−)3-(3,5-Difluoro-phenyl)-3-[4-(indan-2-yloxy)-phenyl]-propionic acid ethyl ester 35 (25 mg) was dissolved in 3 mL THF-EtOH-H2O (1/1/1), and LiOH (20 mg) was added. The mixture was stirred at room temperature for 6 hours. 1N HCl was added to acidify the mixture to pH 2-3. The mixture was extracted with EtOAc (2×20 mL). The organic solution was washed with water and brine, dried over Na2SO4, concentrated, and flash chromatographed (0-60% EtOAc in hexane). (+/−)-3-(3,5-Difluorophenyl)-3-(4-(2,3-dihydro-1H-inden-2-yloxy)phenyl) propanoic acid 36 was obtained as a colorless oil. MS ESI (neg.) m/e: 393 (M−H). 1H NMR (500 MHz) (CDCl3) δ 7.25-7.31 (m, 2H); 7.20-7.22 (m, 2H); 7.14 (d, J =8.4 Hz, 2H); 6.87 (d, J=8.4 Hz, 2H); 6.78 (d, J =6.5 Hz, 2H); 6.67 (t, J =8.9 Hz, 1H); 5.16 (m, 1H); 4.47 (t, J=7.8 Hz, 1H); 3.38 (dd, J =16.7, 6.3 Hz, 2H); 3.19 (dd, J=16.7, 2.6 Hz, 2H); 3.06 (d, J =7.9 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][Cl:13])=[C:6]([N+:14]([O-])=O)[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][Cl:13])=[C:6]([NH2:14])[CH:5]=1
Reactant: COC(=O)c1ccc(NCCCl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(NCCCl)c(N)c1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of 4-(2-chloroethylamino)-3-nitro-benzoic acid methyl ester (12.7 g, 0.0492 mol) in methanol (500 mL) was added 10% Pd/C (1.3 g) under a N2 atmosphere. The reaction mixture was hydrogenated in a Parr apparatus at 3 kg pressure for 2 h. The catalyst was filtered over celite and the filtrate was concentrated affording 11.0 g (98%) of 3-amino-4-(2-chloroethylamino)-benzoic acid methyl ester as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:13]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=3)[N:19]=2)=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)[CH:2]([CH3:4])[CH3:3].P(S)(OCC)(OCC)=[S:29]>O.ClCCl>[CH2:1]([O:5][C:6]1[N:7]=[CH:8][C:9]([C:10](=[S:29])[NH2:11])=[CH:12][C:13]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=2)[N:19]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOP(=S)(S)OCC
Reactant: CCCc1c2nc(-c3cc(C#N)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Solvent: O
Solvent: ClCCl
Product: CCCc1c2nc(-c3cc(C(N)=S)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Temperature: 25 °C

Procedure:
Water (2 drops) was added to a stirred suspension of 6-isobutoxy-5-(2-methyl-7-oxo-3-propyl-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-5-yl)-nicotinonitrile (Example 36) (150 mg, 0.41 mmol) in (EtO)2P(S)SH (0.5 mL). The mixture was stirred at room temperature. After 5 h more (EtO)2P(S)SH (0.5 mL) was added and dichloromethane (5 mL) added to aid stirring. After 14 h the reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. After filtration and separation of the phases the organics were washed again with saturated sodium bicarbonate solution and brine, dried (MgSO4) and concentrated. The product was purified by flash column chromatography (gradient elution from 100% dichloromethane to 96% dichloromethane:methanol) to give 80 mg product.