Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:17][C:18]1[C:19]([NH2:25])=[N:20][CH:21]=[C:22]([Br:24])[CH:23]=1)[CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)C.[H-].[Na+]>CS(C)=O.O>[Br:24][C:22]1[CH:21]=[N:20][C:19]2[NH:25][C:4](=[O:3])[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH2:17][C:18]=2[CH:23]=1
Reactant: CCOC(=O)CN(CCCN1CCN(C)CC1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(CCCN2CC(=O)Nc3ncc(Br)cc3C2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.4 %

Procedure:
A solution of {(2-amino-5-bromo-pyridin-3-ylmethyl)-[3-(4-methyl-piperazin-1-yl)propyl]amino}acetic acid ethyl ester (0.50 g, 1.17 mmol) in DMSO (10 mL) was treated with NaH (60% dispersion in mineral oil, 47 mg, 1.17 mmol). After stirring at room temperature for 3 d, the mixture was diluted with H2O (30 mL) and then extracted with EtOAc (4×50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2, MeOH, 92:8 to 87:13) gave the title compound (0.23 g, 51%) as a white solid: MS (ESI) m/e 382 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])=[N:5][C:4]=1C(O)=O)#[N:2].O>C(O)COCCO>[C:1]([C:3]1[NH:7][C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]=2[Cl:19])=[N:5][CH:4]=1)#[N:2]
Reactant: N#Cc1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(=O)O
Solvent: O
Solvent: OCCOCCO
Product: N#Cc1cnc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Temperature: 170 °C
Yield: 35.1 %

Procedure:
A solution of 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole-4-carboxylic acid (7.09 g, 0.02 mol) in diethyleneglycol (70 ml) was stirred and heated at 170° C. in an atmosphere of nitrogen for 36 hours. The reaction mixture was cooled to room temperature and water (150 ml) was added. The reaction mixture was extracted with ethyl acetate (2×100 ml), washed with water (50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The solid residue was purified by chromatography on silica gel eluting with a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.)(1:1) and recrystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) to give 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole (2.15 g) as a white solid m.p. 210°-212° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C@@H:21]([S:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][C@H:19]1[CH2:43]I)=[O:17])[CH:13]=[CH2:14].S([O-])(O)(=O)=O.[K+]>CN(C)C=O.O>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][C@@H:21]([S:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][C@@H:19]1[CH2:43][CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6])=[O:17])[CH:13]=[CH2:14]
Reactant: COC(=O)CC(=O)OC
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CI
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CC(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 90.3 %

Procedure:
To an ice-cooled suspension of sodium hydride (60%, in oil suspension, 300 mg, 7.5 mmol) in N,N-dimethylformamide (15 ml) was added dropwise dimethyl malonate (0.92 ml, 8.05 mmol) under a nitrogen atmosphere, and the mixture was stirred for 3.0 min at the same temperature. To the mixture was added a solution of (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-triphenylmethylthiopyrrolidine (2.85 g, 5 mmol) in N,N-dimethylformamide (10 ml), and the mixture was stirred for 30 min under ice-cooling, for 1 h at room temperature, and then for 6 h at 60° C. The reaction mixture was poured into a mixture of water (30 ml) and 1N aqueous potassium hydrogensulfate (30 ml), and extracted with ethyl acetate (1×100 ml, 2×50 ml). The combined organic layer was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to give (2S,4S)-N-allyloxycarbonyl-2-[2,2-bis(methoxycarbonyl)ethyl]-4-triphenylmethylthiopyrrolidine (2.59 g, yield: 90%).
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].C1(C)C=CC(S(O[CH2:43][CH:44]([F:51])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])(=O)=O)=CC=1>C(O)CCC>[CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:43][CH:44]([F:51])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:26][CH:25]=4)=[CH:20][N:19]=3)[CH:15]=2)[CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(O)cc4)cn3)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCCCC1Cc2ccc(-c3ncc(-c4ccc(OCC(F)CCCCCC)cc4)cn3)cc2C1
Temperature: 0 °C
Yield: 63.4 %

Procedure:
0.25 g (0.62 mM) of 2-octyl-5-[5-(4-hydroxyphenyl)pyrimidine-2-yl]indan, 0.05 g (0.76 mM) of 85%-potassium hydroxide, 0.23 g (0.76 mM) of 2-fluorooctyl p-toluenesulfonate and 5 ml of n-butanol were placed in a 20 ml-round bottomed flask, followed by heat-refluxing for 7 hours under stirring. After the reaction, the reaction mixture was poured into ice water. The resultant insoluble matter was recovered by filtration and washed with methanol, followed by purification by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene/methanol) to obtain 0.21 g of 2-octyl-5-[5-{4-(2-fluorooctyloxy)phenyl)pyrimidine-2-yl]indan (Yield: 63.4%). ##STR141##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:11][N:12](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[N:10]1[C:5]2[C:6](=[N:7][C:2]([C:11]#[N:12])=[CH:3][CH:4]=2)[S:8][CH:9]=1
Reactant: Clc1ccc2ncsc2n1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ccc2ncsc2n1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To an 8 mL screw cap vial equipped with a magnetic stirring bar were added 5-chlorothiazolo[5,4-b]pyridine (Q-4) (460 mg, 2.7 mmol), Zn(CN)2(316 mg, 2.7 mmol), Pd2(dba)3 (123 mg, 0.13 mmol), DPPF (150 mg, 0.27 mmol) and DMF (5 mL, wet, containing 1% of H2O). The vial was flushed with nitrogen, then sealed with the screw cap. The mixture was stirred at 120° C. for overnight, and then concentrated in vacuo. The resulting residue was purified by chromatography on silica gel to give the title compound (151 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:16][CH2:17][CH2:18][CH2:19][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c[nH]c(C(=O)OCC)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(C(=O)OCC)n(CCCBr)c1

Procedure:
To a stirred solution of diethyl 1H-pyrrole-2,4-dicarboxylate (2 g, 9.47 mmol) and 1,3-dibromopropane (10 mL, 98 mmol) in acetonitrile was added potassium carbonate (1.7 g, 12.3 mmol). The mixture was refluxed overnight, then filtered and concentrated to give crude diethyl 1-(3-bromopropyl)-1H-pyrrole-2,4-dicarboxylate. 1H NMR (CDCl3, 300 MHz) δ7.47 (s, 1H), 7.36 (s, 1 H), 4.47 (t, J=6.6 Hz, 2 H), 4.27 (m, 4 H), 3.32 (t, J=6.2 Hz, 2 H), 2.32 (m, 2 H), 1.34 (m, 6 H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 71 but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cyclopropylamine (1.0 mL) as a white powder (30 mg, 59%). HPLC, Rt: 2.98 min. (purity 99.6%). LC/MS, M+(ESI): 363.3, M−(ESI): 361.3.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])[N:8]=[N:9][C:10]=1[CH:11]([CH3:13])[CH3:12])=O)C.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[N:7]1[C:6]([CH2:4][OH:3])=[C:10]([CH:11]([CH3:13])[CH3:12])[N:9]=[N:8]1
Reactant: CCOC(=O)c1c(C(C)C)nnn1-c1c(Cl)cccc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Temperature: 25 °C
Yield: 90 %

Procedure:
To a 0° C. solution of 3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazole-4-carboxylic acid ethyl ester (2.88 g) in THF (25 mL) is added 1 M DIBAL in toluene (38 mL). The reaction is allowed to warm to room temperature. Upon completion, the reaction mixture is quenched slowly with water and is acidified with 1 N HCl. The resulting solution is extracted two times with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.26 g). ES/MS (m/e) 284 (M+0), 286 (M+2); mp: 154-155° C.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]2)[OH:20])=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH:3]([CH3:5])[CH3:4].[CH2:30](O)[CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:30]1[CH2:31][O:32][CH:6]([CH2:7][C@H:8]([C@@H:10]2[C@:28]3([CH3:29])[C@H:13]([C@H:14]4[C@H:25]([CH2:26][CH2:27]3)[C@:23]3([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]3)[OH:20])=[CH:16][CH2:15]4)[CH2:12][CH2:11]2)[CH3:9])[CH:2]([CH:3]([CH3:5])[CH3:4])[O:1]1
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C1OCCOC1C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 105 °C

Procedure:
27 g of 24-oxocholesterol was dissolved in 717 ml of anhydrous benzene. To the solution were added 179 ml of ethylene glycol and 358 mg of p-toluen sulfonic acid. The mixture was stirred and heated at a bath temperature of 105° C. for 20 hours in a flask equipped with receiver capable of mesuring water in which was added a molecular sieve. Water was added to separate the reaction mixture into layers. The aqueous layer was extracted with benzene.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[C:23]1[N:27]2[CH:28]=[C:29](F)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1>CN(C=O)C>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[C:23]1[N:27]2[CH:28]=[C:29]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:30]=[CH:31][C:26]2=[N:25][N:24]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 323 mg, 8.06 mmol) in DMF (10.0 mL) was added (1R,4S)-4-amino-1,2,3,4-tetrahydro-naphthalen-1-ol (329 mg, 2.02 mmol) and the reaction stirred for 20 min. Intermediate 96b (500 mg, 2.02 mmol) was added in DMF (2.00 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH. The residue was purified by FCC, using 0-10% (2M NH3 in MeOH) in DCM, to give the title compound (453 mg, 57%). LCMS (Method 4): Rt 2.13, m/z 392 [MH+].
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[CH:33][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N:21]([CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:22][CH2:23][CH3:24])[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:43]>O1CCCC1.CO>[ClH:43].[ClH:43].[CH:1]1([C:7]2[C:8]3[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N:21]([CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:22][CH2:23][CH3:24])[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCN(CCN1CCCCC1)c1cccc2c1OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCN1CCCCC1)c1cccc2c1OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of methyl 12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (3.25 g, 5.98 mmol) in tetrahydrofuran (16 ml) and methanol (8 ml) was added 4N aqueous sodium hydroxide solution (4.5 ml), and the mixture was stirred at 65° C. for 2 hr. The reaction mixture was adjusted to pH 6.5 with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. 4N HCl-ethyl acetate solution (10 ml) was added to a solution of the residue in chloroform, and the solvent was evaporated under reduced pressure. A mixed solvent (hexane:ethyl acetate=4:1) was added to the residue and the precipitated solid was collected by filtration to give 12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride (3.41 g, yield 95%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:31]=[C:32]([C:34](=[O:43])[NH:35][C:36]4[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH:33]=3)[O:17][CH:18]([CH2:24][CH2:25]OS(C)(=O)=O)[C:19](OCC)=[O:20])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[Na+].[I-].[CH:46]1([NH2:49])[CH2:48][CH2:47]1>C(#N)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:33]=[C:32]([CH:31]=[C:16]([O:17][C@@H:18]4[CH2:24][CH2:25][N:49]([CH:46]5[CH2:48][CH2:47]5)[C:19]4=[O:20])[CH:15]=3)[C:34]([NH:35][C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:43])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CCOS(C)(=O)=O)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Reactant: NC1CC1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H]3CCN(C4CC4)C3=O)c2)cn1
Temperature: 120 °C
Yield: 42 %

Procedure:
To a solution of ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate (Intermediate 27) (250 mg, 0.41 mmol) in acetonitrile (5 mL), was added NaI (62 mg, 0.41 mmol) and cyclopropylamine (56 μL, 0.81 mmol). The resulting mixture was heated in a microwave at 120° C. for 60 minutes. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography eluting with 0-40% methanol in DCM to afford the racemic product (91 mg, 42%). 3-[6-(Azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3R)-1-cyclopropyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide was separated from its enantiomer by chiral HPLC using a Merck 50 mm 20 μm Chiralcel OJ column eluting with methanol at a flow rate of 60 mL/min. 91 mg of racemic material was separated in 1 injection of 5 mL at 18 mg/ml in methanol to afford the product which eluted before its enantiomer (27 mg, 12%). 1H NMR δ (300 MHz, CDCl3) 0.66-0.91 (m, 4H), 2.14 (sextet, 1H), 2.35 (quintet, 2H), 2.48-2.62 (m, 4H), 2.66-2.78 (m, 1H), 3.27-3.49 (m, 2H), 4.25 (t, 2H), 4.70 (t, 2H), 4.92 (t, 1H), 6.96 (s, 1H), 7.22 (s, 1H), 7.38 (d, 1H), 7.45 (s, 1H), 8.11 (d, 1H), 8.13 (s, 1H), 8.33 (s, 1H), 8.57 (s, 1H), 9.51 (s, 1H); m/z 529 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC=CC=1>O>[CH:9](=[N:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: NC1C=CCCCC1
Solvent: O
Solvent: c1ccccc1
Product: C1=CC(N=Cc2ccccc2)CCCC1
Yield: 83.8 %

Procedure:
A mixture of 2-cycloheptenylamine (11.1 g, 0.1 mole), benzaldehyde (10.6 g, 0.1 mole) and benzene (50 ml) was heated under reflux, and resulting water was removed by azeotropic distillation. The mixture was concentrated to obtain 16.7 g of N-benzylidene-2-cycloheptenylamine [Compound (280)].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[CH:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([C:23]([F:26])([F:25])[F:24])[CH:15]=3)[N:10]=[C:9]([C:27]#[N:28])[C:8]=2[N:7]=[CH:6]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C.CO>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[N:10]=[C:9]([C:27]#[N:28])[C:8]3[N:7]=[CH:6][N:5]([CH2:4][CH2:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]=3[CH:12]=2)=[CH:15][C:16]=1[C:23]([F:26])([F:25])[F:24])[CH3:22]
Reactant: CCOc1ccc(-c2cc3c(ncn3CCCBr)c(C#N)n2)cc1C(F)(F)F
Reactant: C1COCCN1
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cc3c(ncn3CCCN3CCOCC3)c(C#N)n2)cc1C(F)(F)F
Temperature: 120 °C

Procedure:
1-(3-Bromo-propyl)-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile was dissolved in DMF (0.5 ml) and morpholine (19 mg, 0.22 mmol) was added. The mixture was heated to 120° C. in a Smith Creator microwave. Mixture was diluted with methanol and passed through an SCX cartridge, then eluted with 2M methanolic ammonia. Mixture was then prep HPLC purified and acetonitrile was removed under reduced pressure. Resulting aqueous solution was made basic with sodium bicarbonate, extracted into DCM (5 ml), then organics were dried and evaporated to afford 6-(4-ethoxy-3-trifluoromethyl-phenyl)-1-(3-morpholin-4-yl-propyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a white solid (8 mg). 1H NMR (CDCl3) δ 8.25 (d, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.89 (s, 1H), 7.11 (d, 1H), 4.42 (t, 2H), 4.21 (q, 2H), 3.71 (m, 4H), 2.37 (m, 4H), 2.26 (t, 2H), 2.08 (m, 2H), 1.49 (t, 3H). MS m/z 460.6 (M+1).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[S:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:9][S:10][CH:11]=1)(=O)=O.O[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:21]([CH3:32])[C:20]=1[CH3:33]>>[Cl:17][C:14]1[S:13][C:12]([C:8]2[C:7]([CH2:6][O:5][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:21]([CH3:32])[C:20]=3[CH3:33])=[CH:11][S:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Cl)s1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2csnc2-c2ccc(Cl)s2)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(5-chlorothiophen-2-yl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.19 (s, 1H), 7.03 (d, J=5.5 Hz, 1H), 6.89 (s, 1H), 6.76 (d, J=5.5 Hz, 1H), 5.15 (s, 2H), 2.96 (t, J=5.0 Hz, 2H), 2.62 (t, J=5.1 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>C1COCC1.CCOCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]#[N:33])=[N:14][CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: N#Cc1ccccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccccc2C#N)nc1
Yield: 68.6 %

Procedure:
A mixture of [5-(tert-Butyldimethylsilyloxymethyl)pyridin-2-yl]tri-n-butylstannane (11.5 g, 0.022 mol), 2-iodobenzonitrile (5.1 g, 0.022 mol), CuI (0.43 g, 0.002 mol), and bis(triphenylphosphine)palladium(II) chloride (0.80 g, 0.001 mol) in THF (40 mL) was heated under reflux for 48 h. The mixture was diluted with ether and washed with saturated aqueous NH4Cl, aqueous NH4OH, water, and brine, dried (MgSO4), and concentrated to give 4.9 g (67%) of product as a brown oil.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)=O)C>C(O)C.C(O)(=O)C.[Fe]>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([N:7]2[C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:14][C:4](=[O:3])[CH2:6]2)=[O:27])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CC(=O)Nc3ccccc32)cc1
Temperature: 80 °C
Yield: 16.2 %

Procedure:
A mixture of N-ethoxycarbonylmethyl-N-(4-nitrobenzoyl)-2-nitroaniline (500 mg) and iron powder (374 mg) in a mixture of ethanol (10 ml) and acetic acid (1 ml) was heated at 80° C. for 3 hours and the solution was cooled to ambient temperature. The mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform (20 ml) and the solution was neutralized with aqueous sodium hydrogen carbonate. The solution was filtered through celite and the organic filtrate was washed with brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give a crude oil. The oil was purified by silica gel column (10 g, 2% methanol in chloroform) to give 4-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoxalin-2-one (58 mg) as a pale yellow powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:15]O.N1C=CC=CC=1>CCOCC>[Cl:3][CH2:15][C:8]1[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=1[O:6][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CO)c(OC)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1ccc(CCl)c(OC)c1
Temperature: 0 °C

Procedure:
Thionyl chloride (116 mL, 1586 mmol) was added dropwise over 1 hour to a turbid solution of (2,4-dimethoxyphenyl)methanol (97.00 g, 577 mmol) and pyridine (93 mL, 1153 mmol) in anhydrous Et2O (1153 mL) at 0° C. under nitrogen with mechanical stirring. After 1 hour the reaction mixture was poured into 2 L of ice water and the layers were separated. The aqueous layer was extracted with Et2O (2×1 L) and the organics were pooled, washed with ice water (1.2 L), cold 5:1 sat. aq. NaCl solution/sat. aq. NaHCO3 (1.2 L), dried (MgSO4), filtered and most of the ether was removed in vacuo at 12° C. Benzene (300 mL) was added and the mixture was concentrated at 12° C. until 100 mL of benzene remained to provide a solution of 1-(chloromethyl)-2,4-dimethoxybenzene.