Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.O>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:9]1[NH:8][CH:12]=[CH:11][CH:10]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reaction time: 1 h

Procedure:
45 g (247 mmol) of trichloroacetyl chloride and 100 ml of ethyl ether were introduced into a three-necked flask. A solution of 15.4 g (230 mmol) of pyrrole in 100 ml of ethyl ether was added dropwise and stirring was carried out at room temperature for one hour. A solution of 20 g of potassium carbonate in 60 ml of water was then slowly added. The organic phase was separated by settling, dried over magnesium sulfate and evaporated and the residue was triturated in hexane and filtered. 42.7 g (87%) of the expected compound, with a melting point of 78°-79° C., were recovered.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[C:13]#[N:14].[C:15]([O-:18])([O-])=[O:16].[K+].[K+].[CH3:21][C:22]#[N:23]>>[C:13]([C:6]1[CH:7]=[C:8]([C:9]#[N:10])[CH:11]=[CH:12][C:5]=1[O:4][CH2:3][CH2:2][N:23]1[CH:8]2[CH2:11][CH2:12][CH:22]1[CH2:21][N:10]([C:15]([O:18][C:6]([CH3:13])([CH3:7])[CH3:5])=[O:16])[CH2:9]2)#[N:14]
Reactant: CC#N
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(OCCBr)c(C#N)c1
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2CCOc1ccc(C#N)cc1C#N
Temperature: 70 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
The free base (0.9 g, 4.1 mmol) was dissolved in CH3CN (50 mL) and 4-(2-bromoethoxy)isophthalonitrile (1.17 g, 4.7 mmol; from step (a) above) and K2CO3 (0.93 g, 6.75 mmol) were added. The mixture was stirred at 70° C. for 6 h, the solids were filtered off and the residue was evaporated and purified by column chromatography (CHCl3:MeOH, 95:5) to give the sub-title compound in 84% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(O)(c2ccc(F)c(F)c2)C1

Procedure:
Preparation according to Example 24: Enantiomer E2 of 3-(3,4-difluorophenyl)-pyrrolidin-3-ol (0.27 g, 1.35 mmol), acetonitrile (3 mL), potassium carbonate (0.279 g, 2.02 mmol) and iodoethane (0.21 g, 1.35 mmol). Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 35:65 to 50:50). Yield 0.14 g. [α]D=−18.8° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 136-137° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 11), 141, (20), 113 (17), 72 (43), 71 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[C:4]([F:30])[CH:3]=1.[H-].[Na+].I[CH3:34].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]4=[N:15][CH:16]=3)=[N:7][N:8]2[CH3:34])=[C:4]([F:30])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(Cl)cc(F)c34)cnc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2c(F)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
2-(6-Chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.5 g, 1.12 mmol) was dissolved in DMF (5.6 ml) and cooled in an ice bath. Sodium hydride (60% dispersion, 67 mg, 1.68 mmol) was carefully added. The mixture was stirred for 10 min then iodomethane (84 ul, 1.35 mmol) was added and the reaction was warmed to room temperature and stirred for 18 h. Water and ethyl acetate were added to the reaction. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed water and sodium chloride solution and dried over sodium sulfate. After evaporation the remaining residue was purified by silica gel chromatography (ethyl acetate/dichloromethane) to give 257 mg (50%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde. (M+H)+=460.
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH2:4][CH2:3][O:2]1.[CH2:14](Cl)[CH3:15].[CH3:17][NH2:18]>CO>[CH3:17][NH:18][CH2:14][CH2:15][CH:1]1[C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH2:4][CH2:3][O:2]1
Reactant: c1ccc2c3c(sc2c1)COCC3
Reactant: CCCl
Reactant: CN
Solvent: CO
Product: CNCCC1OCCc2c1sc1ccccc21
Reaction time: 48 h

Procedure:
A mixture of 3,4-dihydro-1H-[1]benzothieno[2,3-c]pyran-1-ethyl chloride (6.0 g), described in Example 35, and a saturated solution of methylamine in dry methanol (75 ml) is heated in a pressure bottle at 60° C. for 2 hr. The mixture is kept at room temperature for 2 days and then evaporated to dryness. The residue is dissolved in dilute hydrochloric acid and washed with ether. The free base is then liberated from the aqueous phase by the addition of 5% sodium hydroxide solution and extracted with ether. The extract is dried and concentrated to give the title compound, λmaxEtOH 231 nm (29,600), 261 nm (7580), 290 nm (2960), 298 nm (3140); nmr (CDCl3) δ 2.25, 2.86, 5.00.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17].[CH3:24][N:25]([CH3:28])C=O>N1C=CC=CC=1>[NH2:13][C:14]1[C:15]([C:16](=[O:17])[NH2:18])=[CH:19][CH:20]=[CH:21][C:22]=1[NH:23][C:16](=[O:17])[C:15]1[CH:14]=[CH:22][C:24]([C:11]2[O:2][CH:1]=[N:8][CH:12]=2)=[N:25][CH:28]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)C=O
Reactant: NC(=O)c1cccc(N)c1N
Solvent: c1ccncc1
Product: NC(=O)c1cccc(NC(=O)c2ccc(-c3cnco3)nc2)c1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of EXAMPLE 50A (60.0 mg, 0.316 mmol) in a mixture of pyridine (1.5 mL) and N,N-dimethylformamide (1.5 mL) was treated with 1,1′-carbonyldiimidazole (56.3 mg, 0.347 mmol) at 45° C. for 2 hours. After cooling, 2,3-diaminobenzamide (HCl salt) (70.7 mg, 0.316 mmol) was added and the mixture stirred at room temperature for 5 hours. After concentration, the residue was treated with 20% brine and ethyl acetate. The solid was filtered, washed with ethyl acetate and water, and dried under vacuum to provide the title compound. This material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15]Br.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>CCOC(C)=O.CCOCC>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=[C:2]1[NH:27][C:26]1[CH:28]=[CH:29][C:23]([C:22]([F:21])([F:30])[F:31])=[CH:24][CH:25]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Fc1ccc(CBr)cc1F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Fc1ccc(Cn2c(Nc3ccc(C(F)(F)F)cc3)nc3ccccc32)cc1F

Procedure:
The title compound was prepared by Procedure B in two steps from 2-chloro-benzimidazole, 3,4-difluorobenzyl bromide and 4-trifluoromethylaniline. The product was isolated by preparative LCMS and recrystallization (EtOAc/Et2O) to give the title compound as the free base (off-white solid, mp 167-170° C.). MS(ES+) m/z 404 ([M+1]+, 100). 1NMR (DMSO-d6) δ 5.55 (s, 2H), 6.90-6.97 (m, 1H), 7.02-7.13 (m, 2H), 7.25-7.50 (m, 4H), 7.65-7.71 (m, 2H), 8.04-8.12 (m, 2H), 9.55 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([Cl:20])=O)[CH:13]=1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[ClH:20].[OH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][O:8][C:5]2[CH:6]=[CH:7][C:2]3[O:1][C:18]([C:14]4[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=4)=[CH:10][C:9](=[O:11])[C:3]=3[CH:4]=2)[CH2:24][CH2:23]1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(=O)c1cc(O)ccc1O
Product: Cl
Product: O=c1cc(-c2cccnc2)oc2ccc(OCCCCCCN3CCC(O)CC3)cc12

Procedure:
The compound was prepared by the method of Example 11 from 2',5'-dihydroxyacetophenone, 3-pyridylcarbonyl chloride, and 4-hydroxypiperidine:
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]1([NH2:32])[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:22]1([NH:32][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]3[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=3)=[CH:15][CH:16]=2)[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCc1noc(-c2ccc(CNc3cccc4c3CCCC4)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 5,6,7,8-tetrahydronaphthalen-1-ylamine gave the title compound as an oil. M+(LC/MS(ESI)): 418.4. HPLC (Condition A), Rt: 5.83 min (HPLC purity: 82.3%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[N:9]=[CH:8]2)#[C:2][CH2:3][CH3:4].I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[Br:27][C:28]1[CH:33]=[CH:32][C:31](/[C:1](/[C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:9]=[CH:8]3)=[C:2](\[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[CH2:3][CH3:4])=[CH:30][CH:29]=1
Reactant: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Ic1ccccc1
Product: CC/C(=C(/c1ccc(Br)cc1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1

Procedure:
The title compound was prepared from Intermediate 3, iodobenzene, and (4-bromophenyl)boronic acid following General Procedure C. LCMS: 403 [(M-THP+H)+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH:39]=[CH:38][C:37]=1[NH2:52].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:52][C:37]3[CH:38]=[CH:39][C:40]([CH:42]4[CH2:43][CH2:44][N:45]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH2:46][CH2:47]4)=[CH:41][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(C2CCN(CC(C)C)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(C2CCN(CC(C)C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 55.3 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(methyloxy)-4-[1-(2-methylpropyl)-4-piperidinyl]aniline (Example 160, step C) (51 mg, 0.19 mmol), and p-toluenesulfonic acid (98 mg, 0.52 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (72 mg, 0.105 mmol, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.41 (d, J=6.23 Hz, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.13 Hz, 1H), 8.04 (d, J=7.87 Hz, 1H), 7.80 (d, J=7.69 Hz, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.57-7.65 (m, 2H), 7.43-7.49 (m, 1H), 7.35-7.43 (m, 1H), 7.16-7.22 (m, 2H), 6.99 (t, J=6.87 Hz, 1H), 6.95 (d, J=1.28 Hz, 1H), 6.78 (dd, J=8.24, 1.28 Hz, 1H), 6.48-6.54 (m, 1H), 3.82 (s, 3H), 2.90 (d, J=10.62 Hz, 2H), 2.40-2.46 (m, 1H), 1.97-2.05 (m, 2H), 1.91 (t, J=10.62 Hz, 2H), 1.65-1.76 (m, 5H), 0.84 (d, J=6.59 Hz, 6H). MS (ESI): 688 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:16])=[C:4]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C[O-].[Na+].Cl[CH2:21][S:22][C:23]#[N:24]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([S:16][CH2:21][S:22][C:23]#[N:24])=[C:4]([S:10]([N:13]([CH3:14])[CH3:15])(=[O:11])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CN(C)S(=O)(=O)c1cc(Cl)c(Cl)c(Cl)c1S
Reactant: N#CSCCl
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)S(=O)(=O)c1cc(Cl)c(Cl)c(Cl)c1SCSC#N
Temperature: 62 °C
Reaction time: 0.25 h

Procedure:
To a stirring mixture a 1.5 grams (0.0047 mole) of 3,4,5-trichloro-N,N-dimethyl-2-(mercapto)benzenesulfonamide in 80 milliliters of methanol at 25° C, was added 0.39 grams of sodium methoxide. The mixture was stirred for 15 minutes and thereafter 1.0 gram (0.009 mole) of chloromethylthiocyanate was added thereto and the mixture stirred at room temperature for 3 hours. At the end of this time period, the reaction mixture was filtered to remove the solids which had precipitated. The filtrate further heated at 62° C for 2 hours and after cooling, the solvent was reduced in volume by evaporation under reduced pressure. The solids were thereafter removed by filtration. Additional filtrations gave additional solids. The recovered solids were combined and dissolved in chloroform and filtered. The solvent was removed by evaporation under reduced pressure and the solid product which remained was air dried. The 3,4,5-trichloro-N,N-dimethyl-2-((thiocyanomethyl)thio)benzenesulfonamide product was recovered in a yield of 0.7 grams (40 percent of theoretical) and melted at 155°-156° C.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:18])[CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C1COCC1.O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:9](=[O:18])[C@@H:10]([OH:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:20]
Reactant: O=C(ON1C(=O)CCC1=O)C(O)c1ccccc1
Reactant: CCNCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)[C@@H](O)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of the hydroxy-phenyl-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (0.70 g, 2.8 mmol) in THF/H2O (10 mL, 1:1) was added diethylamine (25% in H2O, 0.58 mL, 5.6 mmol). After stirring for 16 h, the reaction solvent was evaporated under reduced pressure. The resulting residue was diluted with H2O and extracted with EtOAc (3×50 mL). The organic extracts were combined, dried (Na2SO4), and the solvent was evaporated under reduced pressure to yield the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][NH2:29])=[CH:23][C:22]=3[F:30])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][NH:29][C:41]([NH:40][CH2:38][CH3:39])=[O:42])=[CH:23][C:22]=3[F:30])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CCN=C=O
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CN)cc3F)CC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)NCc1cc(F)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 16a (23 mg) and triethylamine (0.1 mL) in 1 mL of DCM was added a drop of ethyl isocyanate (excess) and the reaction mixture was stirred for 30 minutes at room temperature. The mixture was then quenched with water and extracted with DCM to give 33 mg of crude product which was purified on preparative HPLC to give 16-1: LC-MS 496.2 (MH+).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:32][C:33](O)=[O:34]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:33](=[O:34])[CH2:32][C@@H:27]5[CH2:28][CH2:29][CH2:30][CH2:31][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C[C@@H]1CCCCO1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(C[C@@H]1CCCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, off-white solid (21.5 mg, 67.3%), MS (ISP) m/z=457.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and (S)-2-(tetrahydro-2H-pyran-2-yl)acetic acid
Reaction SMILES: [Se](=O)=[O:2].[Cl:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[C:16]3[CH3:21])=[CH:7][CH:6]=1>O1CCOCC1.O>[Cl:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[C:16]3[CH:21]=[O:2])=[CH:7][CH:6]=1
Reactant: Cc1ccnc2c(OCc3ccc(Cl)cc3)cccc12
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccnc2c(OCc3ccc(Cl)cc3)cccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
Selenium dioxide (620 mg, 5.6 mmol) was suspended in dioxane (5 mL); a few drops of water was added until a clear solution was obtained. The mixture was heated to 100° C. and 8-(4-chlorobenzyloxy)-4-methyl quinoline (1.6 g, 5.6 mmol) in dioxane (20 mL) was added dropwise during a period of 2 hours. The mixture kept at 100° C. for 4 hours, filtered hot and concentrated. The residue was treated with 1N HCl (200 ml), and filtered. The filtrate was neutralized with 3N NaOH, and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (Na2SO4), and concentrated. Recrystallization from toluene provided 1.02 g (62%) yellow needles.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1.[CH:23]([N:26]([CH2:30][CH3:31])[CH:27](C)C)(C)C.BrCC=[CH:35][C:36](Cl)=[O:37].CNC.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:22][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:36](=[O:37])[CH:35]=[CH:31][CH2:30][N:26]([CH3:23])[CH3:27])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: O=C(Cl)C=CCBr
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CC=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
Dissolved 1.50 g (4.80 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile in 50 ml THF, added 836 μl (4.80 mmol) N,N-diisopropylethylamine, and chilled to 0° C. under N2. Added 500 μl (4.80 mmol) 4-bromo-but-2-enoyl chloride and after 1 hour dropwise added the mixture to 10 ml of a 2M solution (19 mmol) of dimethylamine in THF cooled to −78° C. At 2 hours, added 5 ml (9.5 mmol) more of dimethyl amine solution and warmed to 25° C. After 1 hour, poured onto a cold solution of sodium bicarbonate. Extracted with ethyl acetate, dried organics with brine and sodium sulfate, reduced to small volume and loaded onto a column of silica gel. Eluted with 70% methanol/ethyl acetate, stripped solvent of desired fractions and dried in vacuo, giving 427 mg of yellow solid: mass spectrum (electrospray m/e): M+H=424.0, 426.0.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](O)=[O:15])[N:10]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:9]=[CH:8]2.[O:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:36][CH:33]1[CH2:34][CH2:35][O:30][CH2:31][CH2:32]1)=[O:15])[N:10]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:9]=[CH:8]2
Reactant: O=C(O)c1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1CCOCC1)c1cc2c(cnn2C2CCCCO2)cc1Oc1ccc([N+](=O)[O-])cc1F
Yield: 80.9 %

Procedure:
The solution of 5-(2-fluoro-4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-carboxylic acid (0.5 g, 1.25 mmol), tetrahydropyran-4-ylamine (0.13 g, 1.25 mmol), EDCI (0.24 g, 1.25 mmol), HOBT (0.17 g, 1.25 mmol), N-methylmorpholine (0.5 mL) in DMF (5 mL) is stirred at RT overnight. Then the reaction mixture is partitioned with saturated aqueous NH4Cl (20 mL) and EtOAc (50 mL). The organic phase is separated, dried over MgSO4, and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (1:1) to provide the product (0.49 g, 81.2% yield). MS (m/z): 485.1 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=O)[CH2:7]C)=[CH:2]1.[C:10](=[O:13])([O-])[O-].[K+].[K+].[CH2:16](Cl)Cl>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:13][CH2:10][CH3:16])=[CH2:7])=[CH:2]1
Reactant: ClCCl
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)c1ccoc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: O
Product: C=C(OCC)c1ccoc1
Yield: 29 %

Procedure:
To a stirring mixture of 1-(3-furyl)-1-propanone (6.75 g, 0.0612 mol) in 150 mL of methylene chloride was added TEOF (13.2 mL, 0.079 mol) with stirring followed by 100 mg of p-toluenesulfonic acid monohydrate and the resulting mixture was stirred for 126 h. Potassium carbonate (2 g) was added to the above reaction mixture, stirred for 10 min, filtered, and concentrated in vacuo. The residue was distilled (35 mm, 82°-85° C.) to afford 2.5 g (29%) of 1-(3-furyl)-1-ethoxy-ethylene (Formula III: R3 =R4 =H; R5 =CH3CH2O;R6 =3-furanyl), as a clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19](O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O.O>C(OCC)(=O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH:19]([Cl:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
In a mixture of 200 ml of ethyl acetate and 12 g of pyridine is dissolved 11.5 g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxybutyrate, and 5 ml of thionyl chloride is added to the solution, followed by refluxing with stirring for 1 hour. After cooling, 500 ml of water and 100 ml are added to the reaction solution, followed by extraction. The extract is washed with 0.1N hydrochloric acid and water successively, dried over anhydrous magnesium sulfate and treated with activated carbon. The ethyl acetate is evaporated off to give 10.5 g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorobutyrate pale yellow oil.