Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][N:19]=[C:18]3[O:25][CH2:26][CH2:27][C:17]=23)[CH2:11][C@H:10]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl-].[NH4+].O>[Fe].CCO>[NH2:22][C:21]1[C:16]([N:12]2[CH2:13][C@H:14]([CH3:15])[C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])[C@H:10]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:11]2)=[C:17]2[CH2:27][CH2:26][O:25][C:18]2=[N:19][CH:20]=1
Reactant: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a mixture of tert-butyl [(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (73.4 mg, 0.144 mmol), iron powder (89.0 mg, 1.59 mmol), and ammonium chloride (151.4 mg, 2.830 mmol) was added EtOH (2.0 mL) followed by water (0.50 mL, 28 mmol). The mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was eluted with a 10% aqueous solution of K3PO4 (20 mL), and EtOAc (20 mL). The organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to give the crude sub-title compound (67.8 mg). The crude product was used directly in the next step without further purification. LCMS calc. for C24H43N4O4Si (M+H)+: m/z=479.3. found 479.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[NH:16][C:17](=[O:20])[CH:18]=[CH2:19])[C:5]([Cl:21])=[CH:4][N:3]=1.NC1C=CC(F)=CC=1NC(=O)C=C.ClC1N=C(Cl)C(Cl)=CN=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][C:59]=1[C:60]#[N:61])[C:54]([NH2:56])=[O:55].C1(P(N(C)C)C2C=CC=CC=2)C=CC=CC=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C>C(O)(CC)(C)C.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]>[C:17]([NH:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([Cl:21])=[CH:4][N:3]=[C:2]([NH:50][C:51]2[CH:52]=[C:53]([CH:57]=[CH:58][C:59]=2[C:60]#[N:61])[C:54]([NH2:56])=[O:55])[N:7]=1)(=[O:20])[CH:18]=[CH2:19]
Reactant: N#Cc1ccc(C(N)=O)cc1N
Reactant: C=CC(=O)Nc1cc(F)ccc1Nc1nc(Cl)ncc1Cl
Agent: [Pd]
Agent: C=CC(=O)Nc1cc(F)ccc1N
Agent: CN(C)P(c1ccccc1)c1ccccc1
Solvent: CCC(C)(C)O
Product: C=CC(=O)Nc1cc(F)ccc1Nc1nc(Nc2cc(C(N)=O)ccc2C#N)ncc1Cl
Temperature: 90 °C
Yield: 20.5 %

Procedure:
Compound I-207 was prepared according to the step described below. To a stirred solution of N-(2-((2,5-dichloropyrimidin-4-yl)amino)-5-fluorophenyl)acrylamide (200 mg, 0.613 mmol), which was prepared using N-(2-amino-5-fluorophenyl)acrylamide and 2,4,5-trichloropyrimidine in a method similar to step 1 of Example 162, in tert-amyl alcohol (5 mL) was added aqueous sodium carbonate (96 mg, 0.905 mmol), 3-amino-4-cyanobenzamide (100 mg, 0.324 mmol) and diphenylphosphino-N,N-dimethylamine (125 mg, 0.919 mmol). The mixture was degassed for 20 min. To this mixture, Pd2(dba)3 (625 mg, 0.733 mmol) and Davephos (96 mg, 0.244 mmol) were added and again degassed for 10 min. The reaction mixture was heated to 90° C. for 2 h. TLC showed completion of starting material. The crude mixture was purified by silica gel column chromatography followed by preparative HPLC to yield 30 mg of the title compound. MS m/z: 452.1 (ES+, M+H); 1HNMR (DMSO-d6) δ 5.77-5.80 (dd, 1H J=2.0 Hz and 10.2 Hz), 6.26-6.31 (dd, 1H J=1.9 Hz and 17 Hz), 6.46-6.52 (dd, 1H J=10.2, 17 Hz), 6.90-6.95 (dt, 3.0, 8.4 Hz), 7.38-7.41 (dd, 1H J=3.0, 10.4 Hz), 7.56-7.64 (m, 3H), 7.78 (d, 1H J=8.1 Hz), 7.96 (d, 1H J=1.2 Hz), 8.10-8.12 (m, 2H), 8.5 (s, 1H), 9.4 (s, 1H), 10.02 (s, 1H). MS m/z: 452.1 (ES+, M+H).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=2)=[CH:13][CH:14]=1)[C:5]([OH:7])=[O:6])[CH3:2].[CH3:23]O>S(=O)(=O)(O)O>[CH2:1]([O:3][C@@H:4]([CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH3:22])[CH:16]=2)=[CH:13][CH:14]=1)[C:5]([O:7][CH3:23])=[O:6])[CH3:2]
Reactant: CO
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(NC)c2)nc1)C(=O)O
Agent: O=S(=O)(O)O
Product: CCO[C@@H](Cc1ccc(-c2cccc(NC)c2)nc1)C(=O)OC
Temperature: 65 °C
Yield: 70 %

Procedure:
0.1 g (0.3 mmol) of 2(S)-ethoxy-3-[6-(3-methylaminophenyl)pyrid-3-yl]propanoic acid is placed in 5 ml of methanol and 2 drops of concentrated sulfuric acid are added. The reaction medium is heated at 65° C. for 18 hours. The methanol is evaporated off and the residue is taken up in an ethyl acetate/water mixture. The pH is brought to 7 by addition of 1N sodium hydroxide solution and the reaction medium is extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulfate, filtered and evaporated. 70 mg (70%) of methyl 2(S)-ethoxy-3-[6-(3-methylaminophenyl)pyrid-3-yl]propanoate are obtained.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([OH:16])[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:5]=2[O:4]1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>C(OCC)(=O)C>[CH3:15][O:14][C:10]1[C:9]([OH:16])=[C:8]([CH3:17])[C:6]2[CH2:7][C:3]([CH3:18])([CH2:2][N:28]3[CH2:29][CH2:30][CH:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[O:4][C:5]=2[C:11]=1[O:12][CH3:13]
Reactant: COc1c(O)c(C)c2c(c1OC)OC(C)(CBr)C2
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(O)c(C)c2c(c1OC)OC(C)(CN1CCC(c3ccccc3)CC1)C2
Temperature: 180 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydro-6,7-dimethoxy-2,4-dimethylbenzofuran-5-ol (1.2 g), 4-phenylpiperidine (1.2 g) and triethylamine (1.1 ml) was stirred at under an atmosphere of argon in a sealed tube at 180° C. for 16 hours. After the reaction mixture was cooled, water, triethylamine and ethyl acetate were added, and the mixture was shaken. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the title compound (0.6 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:9][CH:10]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To 6-chloro-nicotinoyl chloride (0.540 g, 3.07 mmoles) in dichloromethane (10 mL) was added of morpholine, (0.294 g, 1.1 equivalents) followed by triethylamine (940 uL, 2.2 equivalents). The reaction was stirred overnight at room temperature to give (6-chloro-pyridin-3-yl)-morpholin-4-yl-methanone. No starting material, 6-Chloro-nicotinoyl chloride, remained and mass spectrometry showed correct M+ion. An aqueous work-up was performed and the crude material was taken to the next step. The crude residue, (6-chloro-pyridin-3-yl)-morpholin-4-yl-methanone, weighed 0.610 g (88% yield) after aqueous work-up.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([CH:8]=[O:9])=[C:5]([C:10]#[N:11])[CH:4]=1)[CH3:2].[N+]([O-])(O)=[O:13]>O.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+]>[C:10]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[NH:7][C:6]=1[C:8]([OH:13])=[O:9])#[N:11]
Reactant: O=[N+]([O-])O
Reactant: CCc1cc(C#N)c(C=O)[nH]1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(C#N)c(C(=O)O)[nH]1
Temperature: 100 °C

Procedure:
Silver nitrate (1.41 g, 8.3 mmol) in water (100 ml) was added to a solution of 5-ethyl-2-formyl-1H-pyrrole-3-carbonitrile (Intermediate 58) (819 mg, 5.53 mmol) in 1 N sodium hydroxide (100 ml) in the dark. The mixture was heated at 100° C. in the dark for 1 h. The reaction mixture was cooled to room temperature and acidified with 65% aqueous nitric acid. The yellow/brown solution was extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo to give the title compound (600 mg).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:20]4([CH3:25])[O:24][CH2:23][CH2:22][O:21]4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6]1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO.ClCCl>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:20]4([CH3:25])[O:21][CH2:22][CH2:23][O:24]4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6]1
Reactant: CC1(C2(c3ccc(N4C[C@H](CN=[N+]=[N-])OC4=O)cc3)CC2)OCCO1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: ClCCl
Solvent: CO
Product: CC1(C2(c3ccc(N4C[C@H](CN)OC4=O)cc3)CC2)OCCO1
Reaction time: 2.5 h

Procedure:
A suspension of 5(R)-azidomethyl-3-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]oxazolidin-2-one (1.46 g) and Lindlar catalyst (500 mg) in methanol (20 mL) and dichloromethane (4 mL) was hydrogenated at 1 atm for 2.5 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give 5(S)-aminomethyl-3-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]oxazolidin-2-one. To a solution of crude 5(S)-aminomethyl-3-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]oxazolidin-2-one thus obtained in dichloromethane (20 mL) was added triethylamine (1.2 mL) and acetic anhydride (0.8 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour, and then concentrated in vacuo. The residue was added acetic acid (30 mL) and water (3 mL), the resulting mixture was stirred at room temperature for 8 hours, and allowed to stand for overnight. After dilution with ethyl acetate, the mixture was washed with saturated sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate:methanol=20:1) of the residue gave N-[5(S)-3-[4-(1-acetylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide (800 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(=O)(O)[O-].[Na+].[CH2:14]([C:16]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:15]>O.CCOCC>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:24]([C:16]1([CH2:14][CH3:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:25])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CCC1(C(=O)Cl)CCCCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CNC(=O)C1(CC)CCCCCCC1

Procedure:
Glycine ethyl ester hydrochloride (0.04 mole) and sodium bicarbonate (0.08 mole) were dissolved in water (50 ml.). 1-Ethylcyclooctanecarbonyl chloride (1 g. 0.04 mole) in ether (20 ml.) was then added with stirring. The other layer was separated, dried (MgSO4) and concentrated. The residue was recrystallised from 40°-60° petroleum ether to give N-(1-ethylcyclooctanecarbonyl) glycine ethyl ester mp. 65°-7°
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC#N>C1COCC1>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)Oc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Amino-5-methyl-pyrazine (2.00 g, 21.25 mmol) was dissolved in THF (80 mL), cooled to 0° C., and treated with pyridine (1.77 g, 22.3 mmol) followed by the dropwise addition of phenylchloroformate (3.49 g, 22.3 mmol) in THF (30 mL). After stirring for 3 h, 100 mL of MeCN was added and the reaction mixture was reduced to a volume of 100 mL in vacuo. The title compound as white crystals was collected by filtration (2.5 g, 55%) and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][CH:14](OC)OC)[N:6]([CH3:19])[CH:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.N>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:14]=[CH:13][N:12]=[C:7]1[N:6]([CH3:19])[CH:5]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(CNC1=Nc2ccc(Cl)cc2C(c2ccccc2)N1C)OC
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CN1c2nccn2-c2ccc(Cl)cc2C1c1ccccc1
Yield: 38.2 %

Procedure:
A mixture of 3.5 g of 6-chloro-3,4-dihydro-2-(2,2-dimethoxyethylamino)-3-methyl-4-phenylquinazoline and 20 ml of concentrated sulfuric acid was heated at 50°-60° C. for 2 hours. The reaction mixture was poured onto ice, and the resulting mixture was neutralized with concentrated ammonia water and then extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was chromatographed on silica gel using chloroform as an eluent to give 1.1 g of 7-chloro-4,5-dihydro-4-methyl-5-phenylimidazo[1,2-a]quinazoline as viscid oil.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[C:6](=[CH:11][CH:12]=1)[CH2:7][C:8]([OH:10])=O)[CH3:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[O:1]([C:3]1[CH:4]=[C:5]2[C:13](=[O:14])[O:15][C:8](=[O:10])[CH2:7][C:6]2=[CH:11][CH:12]=1)[CH3:2]
Reactant: COc1ccc(CC(=O)O)c(C(=O)O)c1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)OC(=O)C2
Temperature: 25 °C
Yield: 110.1 %

Procedure:
1.1 g (5.2 mmol) of 4-methoxylhomophthalic acid (IIb) was dissolved in 20 ml toluene, and 0.7 ml (7.9 mmol) of acetic anhydride was added. The mixture was heated to the reflux temperature and reacted for 0.5 h. Then, the reaction mixture was cooled to the room temperature and concentrated to dry in a reduced pressure to obtain 1.1 g of a pale yellow solid with the yield of 100%. m.p. 142-143° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:16](=[O:32])[NH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOCC.O1CCOCC1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:17]2[C:16](=[O:32])[NH:15][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:18]=2[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2[nH]c(=O)c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=c1[nH]n(C2CCNCC2)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Reaction time: 2.25 h

Procedure:
To a solution of 4-[4-(4-Chloro-phenyl)-3-oxo-5-pyridin-4-yl-2,3-dihydro-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester 200 mg in flask was added HCl in ether and dioxane. After 2.25 hours, the solvent was evaporated under reduced pressure to afford the title compound as yellow oil. MS (ES+): 355 (M+H)+; (ES−): 353 (M−H).
Reaction SMILES: Cl.[N:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]3)[C:6]=12.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[N:25]2)=[CH:20][CH:19]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:29]([C:26]4[CH:27]=[CH:28][N:24]([C:21]5[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=5)[N:25]=4)=[O:30])[CH2:12]3)[C:6]=12
Reactant: O=C(O)c1ccn(-c2ccc(F)cc2)n1
Reactant: N[C@H]1CCN(c2nccn3cnnc23)C1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3cnnc23)C1)c1ccn(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a suspension of (S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-amine hydrochloride salt (94 mg, 0.34 mmol), 1-(4-fluorophenyl)-1H-pyrazole-3-carboxylic acid (63 mg, 0.3 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (120 mg, 0.31 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 50 mg of the title compound (42% yield) as a white solid.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].C([O:10][C:11]([C:13]1[C:17](N)=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[N:15]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:14]=1)=O)C.C(OC(C1C(N)=C(C2C=CC(Cl)=CC=2)N(C2C=CC=CC=2Cl)N=1)=O)C>C(O)C>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:15]1[C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=2)=[C:17]2[N:6]=[CH:5][N:7]=[C:11]([OH:10])[C:13]2=[N:14]1
Reactant: N=CN
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(C(F)(F)F)cc2)c1N
Agent: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Solvent: CCO
Solvent: CC(=O)O
Product: Oc1ncnc2c(-c3ccc(C(F)(F)F)cc3)n(-c3ccccc3Cl)nc12

Procedure:
A mixture of formamidine acetate (12.5 g, 0.12 mol) and 4-amino-1-(2-chlorophenyl)-5-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (4.77 g, 11.6 mmol; prepared using procedures and reagents analogous to those described above in the synthesis of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (I-2A-1a)) in ethanol (400 ml) was heated at reflux for 20 hours. The reaction was then cooled and concentrated in vacuo. The residue was extracted from water, adjusted to pH 3.5 using citric acid, with ethyl acetate, and the combined organic layers were washed with half saturated brine, dried (MgSO4), and concentrated in vacuo. Purification of the residue by silica gel chromatography using 10-50% ethyl acetate in hexanes as eluant afforded compound I-2A-2a (1.03 g, 23%) as a solid: APcl MS (M+1) 389.1; 1H NMR (CD3OD) δ 7.92 (s, 1H), 7.71-7.53 (m, 8H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:25]=[CH:24][C:17]([O:18][CH:19]2[CH2:23][CH2:22][NH:21][CH2:20]2)=[CH:16][CH:15]=1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:21]2[CH2:22][CH2:23][CH:19]([O:18][C:17]3[CH:24]=[CH:25][C:14]([F:13])=[CH:15][CH:16]=3)[CH2:20]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1ccc(OC2CCNC2)cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Product: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2ccc(F)cc2)C1
Yield: 57.3 %

Procedure:
The title compound (D93) (235 mg) was prepared according to the experimental procedure described in Description 62 starting from methyl 2,5-dichloronicotinate (241.37 mg, 1.17 mmol) and 3-(4-fluorophenoxy)pyrrolidine (D59) (253 mg, 1.39 mmol).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)[C:9]([S:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[C:10]([CH:12]([CH3:14])[CH3:13])[N:11]=1)(=[O:3])[NH2:2].[H][H]>C(OCC)(=O)C.[Pt]>[NH2:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:8]2[C:9]([S:15][C:16]3[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=3)=[C:10]([CH:12]([CH3:13])[CH3:14])[N:11]=[C:7]2[CH2:6][CH2:5][O:4][C:1](=[O:3])[NH2:2])=[CH:30][CH:29]=1
Reactant: [H][H]
Reactant: CC(C)c1nc(CCOC(N)=O)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CCOC(N)=O)n(Cc2ccc(N)cc2)c1Sc1cc(Cl)cc(Cl)c1

Procedure:
In 10 ml of ethyl acetate was dissolved 220 mg (0.43 mmol) of 2-(2-carbamoyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(p-nitrobenzyl)-1H-imidazole (128a), and 120 mg of platinum sulfided carbon was added at room temperature. Hydrogen gas was introduced for 7 hours under stirring, and the mixture was worked up. The reaction mixture was filtered through Celite under reduced pressure, and the filtrate was distilled off. The residual oil was treated with ether for crystallization to give Compound I-140 (yield 95%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.O.[BH4-].[Na+].C[NH2:16]>CO>[NH2:16][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NCc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of aldehyde product from Step B (2.0 g, 14 mmol) in methanol (100 mL), 40% methylamine in water (2.27 mL, 27.6 mmol) was added at room temperature over a period of 10 min. The mixture was stirred at room temperature under nitrogen overnight and then was cooled down to 0° C. Sodium borohydride (1.05 g, 27.6 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 h. Most of methanol was removed in vacuo, and the residue was diluted with water and extracted (3×) with ether. The combined organic layers were extracted with 2 N HCl (100 mL). The HCl layer was made basic (pH ˜11) with 2 N NaOH and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude 4-(aminomethyl)-indole as a white powder (1.95 g, 88%): 1H NMR (300 MHz, CDCl3) δ8.29 (s, br, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.22 (t, J=2.7 Hz, 1H), 7.16 (t, J=8.0, 7.3 Hz, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.64 (t, J=2.0 Hz, 1H), 4.06 (s, 2H), 2.51 (s, 3H); CI MS m/z=160 [C10H12N2+H]+.
Reaction SMILES: O=[O+][O-].[CH2:4]([C:7]1[CH:16]=[CH:15][CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=1[OH:17])[CH:5]=C>>[O:17]1[C:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=[CH:16][C:7]=2[CH:4]=[CH:5]1
Reactant: C=CCc1cccc(C(=O)OC)c1O
Agent: O=[O+][O-]
Product: COC(=O)c1cccc2ccoc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.7 %

Procedure:
Ozone was bubbled through a solution of methyl 3-allyl-salicylate (30 g, 156 mmol) at -78° C. for 2 hr until no starting material was present on TLC. The reaction was quenched with dimethyl sulfide and stirred at room temperature for 18 hr. The mixture was concentrated in vacuo, and the residue was dissolved in ether. The ether solution was washed with brine three times, and then concentrated in vacuo to a green oil. This oil was dissolved in toluene and heated to reflux with sulfuric acid (0.5 ml) for 4 hr. Sodium carbonate (5 g) was added, and the mixture was cooled and then filtered. The filtrated was concentrated in vacuo to a dark oil that was purified by chromatography on silica gel using methylene chloride as the eluent to give the product as a green oil (12 g, 44%).
Reaction SMILES: [Cl-].[C:2]([CH2:5][N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])(O)=O.[C:13](#[N:16])[CH:14]=C.CCN(CC)CC>C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:12][C:7]1[N:6]2[C:11]([CH:10]=[CH:9][CH:8]=1)=[C:14]([C:13]#[N:16])[CH:2]=[CH:5]2
Reactant: Cc1cccc[n+]1CC(=O)O
Reactant: C=CC#N
Agent: O=[Mn]=O
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cccc2c(C#N)ccn12
Reaction time: 12 h

Procedure:
To a solution of crude 1-Carboxymethyl-2-methyl-pyridinium chloride (7 g, 0.037 mol) in toluene (50 mL) were added acrylonitrile (7.4 mL, 0.11 mol), MnO2 (6.5 g, 0.075 mol) and Et3N (2 mL) at room temperature under nitrogen atmosphere. The solution was heated to 90 C and was stirred at the same temperature for 12 hours. The solution was cooled down and was filtered to remove the excess MnO2. The filtrate was concentrated and the residue was purified by CombiFlash with 10% EtOAc in Hexane to afford the desirable product 5-Methyl-indolizine-1-carbonitrile, CAS: 5-Methyl-indolizine-1-carbonitrile (3 g, 52%) as a white solid.