Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:13]([NH:15][CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38]>O>[CH:18]1([CH2:17][CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:10]([C:9]([NH:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][C:35](=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:3][CH:4]=3)=[O:27])[CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)Nc1ccc(N)nc1
Reactant: CC(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)Nc1ccc(NC(=O)CC(C)C)nc1
Temperature: 0 °C

Procedure:
To a 25 mL round-bottomed flask was added N3-(6-aminopyridin-3-yl)-N1-(2-cyclopentylethyl)-4-methylisophthalamide (0.19 g, 0.52 mmol) and Triethylamine (0.18 ml, 1.3 mmol) to stir at 0° C. Isovaleryl chloride (0.14 ml, 1.0 mmol) was added to the solution dropwise. The reaction was allowed to stir for one hour. At which time was shown to be at completion by LC/MS. DI water was added to the reaction. The reaction was transferred to a separatory funnel, where the aqueous layer was extracted 3 times with DCM. The combined organic layers were washed with brine, saturated NaHCO3, dried with MgSO4, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (25M), eluting with a gradient of 1% to 10% MeOH in CH2Cl2, to provide N1-(2-cyclopentylethyl)-4-methyl-N3-(6-(3-methylbutanamido)pyridin-3-yl)isophthalamide as a white solid. MS (ESI, pos. ion) m/z: 451.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
Preparation B6, Step 1: To a solution of 4-trifluoromethylaniline (5 g, 0.031 mol) in 50 ml of dry benzene was added triethylamine (6.26 g, 8.63 ml, 0.06 mol) at 0° C. Pivaloyl chloride (4.5 g, 0.04 mol) was added slowly and stirred at RT over night. The RM was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. To the solid was triturated with pet-ether and filtered to give N-(4-(trifluoromethyl)phenyl)-pivalamide (6.7 g) as white solid.
Reaction SMILES: [N-:1]=[C:2]=[S:3].[Na+].N1C=CC=CC=1.CS(O[N:16]=[C:17](Cl)[C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)(=O)=O.[CH3:29][C:30]1[C:35]([O:36][C:37]2[C:38]([NH2:50])=[N:39][CH:40]=[C:41]([S:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:42]=2)=[CH:34][CH:33]=[CH:32][N:31]=1>C(#N)C>[CH3:29][C:30]1[C:35]([O:36][C:37]2[C:38]([NH:50][C:2]3[S:3][N:16]=[C:17]([C@H:18]4[CH2:22][O:21][C:20]5([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)[O:19]4)[N:1]=3)=[N:39][CH:40]=[C:41]([S:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:42]=2)=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1N
Reactant: [N-]=C=S
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Temperature: 60 °C
Reaction time: 14 h
Yield: 70.3 %

Procedure:
To 700 mL of acetonitrile was added sodium isothiocyanate (12.5 g, 155 mmol), pyridine (25.2 ml, 309 mmol) and (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (38.4 g, 129 mmol) and the reaction heated to 60° C. for 15 minutes (white solid formed). To the mixture was added 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (32 g, 103 mmol) as a solid and the reaction was stirred for 14 hours at 60° C. The reaction was cooled and concentrated in vacuo. The residue was partitioned between EtOAc and 1N NaOH. The aqueous mixture (basic, about 700 ML) was extracted twice with EtOAc (3000 mL total volume). The combined organic layers were washed with 1 N NaOH (300 mL) and brine (300 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography on about 1 kg of silica gel using 1:1 EtOAc/CH2Cl2 with 1% MeOH as eluent to afford (S)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (38.7 g, 72.4 mmol, 70.2% yield).
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[N:4][N:3]=1.[N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]=[O:24].N(CC([O-])=O)=C=O>C1COCC1.C(OCC)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][NH:22][C:23]([NH:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[N:4][N:3]=1)=[O:24])[CH3:30]
Reactant: Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Reactant: CCOC(=O)CN=C=O
Agent: O=C=NCC(=O)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)Nc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
A suspension of [4-(5-Amino-[1,3,4]oxadiazol-2-yl)-pyridin-3-yl]-(2-fluoro-4-iodo-phenyl)-amine (0.200 g, 0.504 mmol) in dry THF (3 mL) was treated with ethyl isocyanatoacetate (0.077 g, 0.596 mmol). The reaction mixture was stirred at RT overnight. More isocyanatoacetate (0.083 g, 0.643 mmol) was added, and the mixture was stirred for another 72 hrs. The material was diluted with diethyl ether (2 mL), filtered and dried under high vacuum for 2 h to afford a yellow solid product (0.144 g, 0.274 mmol, 54%) LC/MS (Method A) [5.53 min; 527(M+1)]
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[N:12]([O-])=O.[Na+].[Cl:16][Sn]Cl>Cl.O>[ClH:16].[NH:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])[NH2:12]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)cc1NN
Reaction time: 0.75 h

Procedure:
To a suspension of 3-amino-4-methylbenzoic acid (5.0 g, 33 mmol) in concentrated HCl (31 mL) cooled to below −5 ° C. was added a solution of NaNO2 (2.4 g, 35 mmol) in water (12 mL) at such rate that the temperature remained below −4 ° C. After stirring for 45 min, the suspension was transferred to a cold stirred solution of SnCl2 (28 g, 124 mmol) in concentrated HCl (18 mL) via pipette. The resulting solid was collected via vacuum filtration and washed first with cold water and then with Et2O. The solid was recrystallized from water/2-propanol (10:1) to provide 3-hydrazino-4-methyl-benzoic acid hydrochloride. (2.23 g, 33%) as a pink solid. ESI MS m/z 167 [C8H10N2O2+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][CH2:13][CH2:14][CH:15]1[C:20](=[O:21])[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[S:16]1)=O)C.O>CCOCC>[OH:9][CH2:10][CH2:12][CH2:13][CH2:14][CH:15]1[C:20](=[O:21])[NH:19][C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[S:16]1
Reactant: CCOC(=O)CCCC1Sc2ccccc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: O=C1Nc2ccccc2SC1CCCCO
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a suspension of 0.46 g of lithium aluminum hydride in 50 ml of ether was added dropwise, with ice-cooling, a solution of 1.6 g of 2-(3-ethoxycarbonylpropyl)-2H-1,4-benzothiazin-3(4H)-one in ether (30 ml). After the mixture was stirred for one hour, water was added dropwise thereto. The resultant white precipitates were filtered off, and the filtrate was dried (MgSO4). The solvent was evaporated off, and the residue was subjected to a column chromatography on silica-gel (70 g). From the eluate with hexane-ethyl acetate (1:1, v/v) was obtained 0.75 g (55.6%) of 2-(4-hydroxybutyl)-2H-1,4-benzothiazin-3(4H)-one. Recrystallization from ethyl acetate gave prisms, m.p. 101°-102° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:18]3[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cccc(-c2csc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Yield: 51.1 %

Procedure:
A solution of 2-bromo-4-(3-methoxyphenyl)-1,3-thiazole (3.70 g, 13.7 mmol), tert-butyl piperazine-1-carboxylate (3.83 g, 20.5 mmol) and potassium carbonate (1.89 g, 13.7 mmol) in dimethylformamide (50 ml) was stirred at 120° C. for 7 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.63 g (51.2%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH3:5][C@H:6]1[CH2:10][CH2:9][C@H:8]([CH3:11])[N:7]1[CH2:12][C:13](OC)=[O:14]>>[NH2:3][C:2]([NH2:4])=[N:1][C:13](=[O:14])[CH2:12][N:7]1[C@@H:8]([CH3:11])[CH2:9][CH2:10][C@@H:6]1[CH3:5]
Reactant: N=C(N)N
Reactant: COC(=O)CN1[C@@H](C)CC[C@@H]1C
Product: C[C@H]1CC[C@H](C)N1CC(=O)N=C(N)N

Procedure:
By a procedure analogous to Example 7, guanidine is reacted with methyl (trans-2,5-dimethyl-pyrrolidin-1-yl)acetate to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][O:7][CH2:8][C:9](N(OC)C)=[O:10].O1CCCC1.[O:29]1[CH2:34][CH2:33][CH2:32][O:31][CH:30]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[Mg]Br>>[O:29]1[CH2:34][CH2:33][CH2:32][O:31][CH:30]1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=1[C:9](=[O:10])[CH2:8][O:7][CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=1
Reactant: Br[Mg]c1ccccc1C1OCCCO1
Reactant: CON(C)C(=O)COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C1OCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3,5-bis(trifluoromethyl)benzyloxy)-N-methoxy-N-methylacetamide (5.0 g, 14 mmol) in tetrahydrofuran (20 mL, 247 mmol) at −78° C. was added (2-(1,3-dioxan-2-yl)phenyl)magnesium bromide (0.25M in tetrahydrofuran) (64 mL). The ice bath was replaced with a 0° C. bath and stirring continued for 1 h. The reaction was quenched by addition of saturated ammonium chloride. The mixture was diluted with pentane and the layers separated. The organics were washed with water, then brine, dried over magnesium sulfate, and concentrated. Flash chromatography (12% EtOAc/Hex) gave 3.20 g (49%) as a white crystalline solid. 1H-NMR (CDCl3, 300 MHz) δ 7.80 (s, 2H), 7.78 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.44 (m, 1H), 7.33 (m, 2H), 5.87 (s, 1H), 4.70 (s, 2H), 4.61 (s, 2H), 4.16 (dd, J=11.3, 4.9 Hz, 2H), 3.92 (m, 2H), 2.11 (m, 1H), 1.38 (d, J=13.7 Hz, 1H); 13C-NMR (CDCl3, 126 MHz) δ 202.2, 140.7, 136.9, 136.1, 131.7 (q, J=33.6 Hz), 130.9, 128.4, 127.7, 126.7, 123.4 (q, J=273 Hz), 121.7, 98.7, 75.2, 71.6, 67.4, 25.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[I-].[NH2:23][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]3[N:23]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccccn2)c(OC)c1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(-c3ccccn3)c(OC)c2)nn2ccccc12

Procedure:
A solution of ethyl(2E)-3-(3-methoxy-4-pyridin-2-ylphenyl)prop-2-enoate (55 mg, 0.2 mmol) and 1-aminopyridinium iodide (86 mg, 0.4 mmol) in DMF (1 mL) was stirred at rt for 2 days open to the atmosphere. The deep purple reaction mixture was diluted with CH2Cl2 (25 mL) and washed with a saturated solution of sodium thiosulfate (25 mL) and brine (25 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 3:2) to afford the desired ethyl 2-(3-methoxy-4-pyridin-2-ylphenyl)pyrazolo[1,5-a]pyridin-3-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(OC(=O)C)(=O)C.CC([O-])=O.[K+].[N:26](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Cl:13][C:9]1[CH:10]=[C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[NH:1][N:26]=[CH:12]2
Reactant: COC(=O)c1cc(Cl)cc(C)c1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(Cl)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Methyl 2-amino-5-chloro-3-methylbenzoate (6.6 g, 33.1 mmol) was dissolved in CHCl3 (90 mL) then cooled in an icebath while acetic anhydride (7.2 mL, 76.1 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for ca. 1 h, then KOAc (650 mg, 6.6 mmol) was added, followed by isoamyl nitrite (9.7 mL, 72.8 mmol). The reaction mixture was heated under reflux until the reaction was complete by TLC (overnight). While cooling to room temperature, precipitation was observed. The precipitate was collected and dried to afford methyl 5-chloro-1H-indazole-7-carboxylate as a yellow solid (4.83 g, 69%): 1H NMR (300 MHz, CDCl3) δ 11.25 (s, 1H), 8.10 (s, 1H), 8.05 (s, 3H), 7.97 (s, 1H), 4.09 (s, 1H); MS (ESI+) m/z 211 (M+H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH:12]1[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][N:13]=1>CN(C)C=O>[ClH:2].[Cl-:1].[NH2:11][C:5]1[C:4]([CH2:3][N+:13]2[CH:14]=[CH:15][C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=3[CH:12]=2)=[CH:9][N:8]=[C:7]([CH3:10])[N:6]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1cc2c(cn1)CCCC2
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ncc(C[n+]2ccc3c(c2)CCCC3)c(N)n1
Product: [Cl-]
Reaction time: 16 h
Yield: 84 %

Procedure:
A suspension of 11.6 g (0.060 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 40 ml of dimethyl-formamide was treated with 8.0 ml (0.060 mol) of 5,6,7,8-tetra-hydro-isoquinoline, dissolved at 120° and stirred at 800 for 16 hours. The mixture was cooled, suction filtered, washed with a small amount of dimethylformamide, then with ethyl acetate and dried in a vacuum. 16.5 g (84%) of 2-(4-amino-2-methyl-pyrimidin-5-ylmethyl)-5,6,7,8-tetrahydro-isoquinolinium chloride hydrochloride were obtained as yellowish crystals; m.p. 242°-244°.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH-].[Na+].[N:9]#[C:10][NH2:11].[CH3:12]OS(OC)(=O)=O>O>[CH2:5]([O:4][C:2]([N:9]([CH3:12])[C:10]#[N:11])=[O:3])[CH3:6]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)Cl
Reactant: N#CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N(C)C#N
Reaction time: 3 h
Yield: 81 %

Procedure:
657 Parts of ethyl chloroformate and 945 parts of a 50% aqueous sodium hydroxide solution were added simultaneously to a solution of 504 parts of a 50% aqueous cyanamide solution in 825 parts of water at 25° during a period of 90 minutes and at a pH of 6.9 to 7.1. As the addition of the reactants progressed, the temperature of the reaction mass was allowed to rise to 53°-55° and was maintained within that range by cooling. When the addition was comlete, the reaction mass was cooled to 40°. Dimethylsulfate (1,134 parts) was then added during one hour with stirring while maintaining the pH at 7 to 7.1 by the addition of 50% aqueous sodium hydroxide solution. After holding 3 hours at 40° the resulting two-phase solution was transferred to a separatory funnel. The upper phase of N-ethoxycarbonyl-N-methylcyanamide was separated and the lower aqueous phase was sent to secondary recovery, either distillation or extraction. The upper phase of 669 parts was 93% N-ethoxycarbonyl-N-methylcyanamide (81% yield). This upper phase is usually pure enough for subsequent steps. However, vacuum distillation was used to provide pure N-ethoxycarbonyl-N-methylcyanamide, b.p. 67° at 2.2 mm.Hg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)=[N:2]1.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][NH:29][CH3:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH2:23][N:29]([CH3:30])[CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])=[CH:19]2)=[N:2]1
Reactant: CNCCN(C)C
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CCN(C)Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Compound 167 (0.06 g, 0.19 mmol) was dissolved in dichloroethane (2.0 mL) and the solution was added with N,N,N′-trimethylethylenediamine (62 μL, 0.57 mmol), acetic acid (63 μL, 0.57 mmol) and sodium triacetoxyborohydride (0.12 g, 0.57 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water, extracted with ethyl acetate and the organic layer was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=9/1) to obtain Compound 188 (41 mg, 54%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=O>>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH:26]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1cc2ccccc2[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[N:17]=3)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[NH:33]1[CH2:36][CH:35]([C:37]([OH:39])=[O:38])[CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCCl>[C:1]1([N:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH2:25][N:33]5[CH2:36][CH:35]([C:37]([OH:39])=[O:38])[CH2:34]5)=[CH:27][CH:28]=4)[N:17]=3)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4cnn(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 56 %

Procedure:
To a solution of 4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (700 mg, 1.821 mmol) in MeOH (12 mL) and 1,2-dichloroethane (3 mL) was added 0.1 mL of acetic acid and azetidine-3-carboxylic acid (203 mg, 2.0 mmol). The mixture was allowed to stir at room temperature for 40 min. and then sodium triacetoxyborohydride (618 mg, 2.91 mmol) was added. The mixture was allowed to stir at room temperature for 5 hours, then was filtered to afford a white solid that was washed with water (1 mL) and MeOH (3×1 mL). The solid was dried under vacuum to give 1-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (480 mg, 1.02 mmol). The compound had an HPLC retention time=6.91 min. −Column: Low pH Col-1: Sunfire C18 3.5 um, 4.6×150 mm; Start % B=10; 12 Min. 100%; 15 Min. 100%; Flow Rate=2 mL/min; Wavelength1=220; Wavelength2=254; Solvent Pair=TFA-MeCN/H2O; Solvent A=0.05% TFA in H2O:MeCN (95:5); Solvent B=0.05% TFA in H2O:MeCN (5:95); Column 1=LOW pH-Parallel HPLC; At 220 nm LC/MS M+1=470.1 1H NMR (500 MHz, MeOD) δ ppm 3.41 (dt, J=8.8 Hz, 7.7 Hz, 1H), 4.12-4.18 (m, 4H), 4.38 (s, 2H), 7.57-7.66 (m, 7H), 8.23 (d, J=8.3 Hz, 2H), 8.50 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(=C)[C:14]#[N:15].O1CC[CH2:19][CH2:18]1.CC(C)([O-])C.[K+]>C(OCC)C>[CH2:1]([N:8]1[CH2:19][CH2:18][O:11][CH:10]([C:14]#[N:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: OCCNCc1ccccc1
Reactant: C=C(Cl)C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: N#CC1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-benzylethanolamine (intermediate 23, 44.8 ml, 314 mmol) and 2-chloroacrylonitrile (intermediate 24, 25 ml, 314 mmol) was stirred at room temperature for 24 hours. After the mixture was cooled to 0° C., tetrahydrofuran (300 ml) and then potassium tert-butoxide was added to the mixture, and the mixture was stirred at 0° C. for one hour. The mixture was diluted by ethyl ether, and then washed with water and brine and dried over magnesium sulfate. Solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; 5% ethyl acetate in hexane) to afford 4-benzylmorpholine-2-carbonitrile (intermediate 25) as colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:21]([O:28][C:29](=[O:37])[CH2:30][C@@H:31]([NH2:36])[CH2:32][N:33]([CH3:35])[CH3:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:37])[CH2:30][C@@H:31]([NH:36][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:32][N:33]([CH3:34])[CH3:35])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)CCCCCCCCCc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=377.3 ([M+H]+), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 10-phenyldecanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(10-phenyl-decanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH3:17]N(CCN(C)C)C.[Li]C(C)(C)C.CCCCC.CI>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH2:15][CH3:17])([CH3:14])[CH3:16])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCC
Product: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)CC
Temperature: -78 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of the compound of example 45 (1.28 g, 5 mmol) and TMEDA (0.91 mL, 6.0 mmol, 1.2 eq) in THF at -78° C. was added a 1.7 M solution of t-BuLi in pentane (7.1 mL, 12 mmol, 2.4 eq) such that the temperature was less than -70° C. The reaction was stirred at -78° C. for 2 h and methyl iodide (0.44 mL, 7.0 mmol, 1.4 eq) was added. The reaction was stirred for 15 min at -78° C. and worked up in the usual manner. The crude product was recrystallized from aq methanol and then from hexanes to afford the title compound as white crystals (0.62 g, 46%). m.p. 94-95° C.