Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:11][C:12]#[CH:13]>[Cu]I.N1CCCC1>[N:14]1([CH2:10][CH2:11][C:12]#[C:13][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCN1CCCCC1
Agent: [Cu]I
Solvent: C1CCNC1
Product: O=Cc1cccc(C#CCCN2CCCCC2)c1
Temperature: 50 °C
Reaction time: 40 h
Yield: 85.3 %

Procedure:
To the mixture of Pd(PPh3)Cl2 (24 mg, 0.034 mmol, 0.02 equiv.), CuI (13 mg, 0.068 mmol, 0.04 equiv.) and 3-bromobenzaldehyde (0.316 g, 1.7 mmol, 1 equiv.), pyrrolidine (10 mL) were added under N2. The use of pyrrolidine is preferred in the context of this synthesis. A stream of N2 was bubbled into to the solution for 5 min, and then 1-but-3-ynyl-piperidine (0.46 g, 3.3 mmol, 2 equiv.) was added. The reaction mixture was stirred at 50° C. for 40 h. This temperature is preferred in the context of this synthesis. On TLC and HPLC, the reaction was complete. The white precipitate (Et3N.HBr) was filtered and washed with EtOAc. The solvent was evaporated and the residue was re-dissolved in EtOAc. The organic layer was washed with aqueous NaOH (1N) twice, and dried over MgSO4. After filtration, the EtOAc solution was poured directly onto a short pad of silica gel (neutralized with 5% Et3N in hexanes) and washed with EtOAc. The solvent was evaporated to afford the product as a brown oil (0.35 g, 1.45 mmol, 86%); purity >95% on HPLC; MS M+H+242. This product does not need further purification in its use for subsequent steps in the context of this invention. A yield of 86% is in marked contrast with conventional methodologies, which produce the title compound with typical yields that do not exceed 30%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([OH:17])[C:11]=2[NH:18][C:19]([C:21]2[S:22][CH:23]=[C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:25]=2[Cl:26])=[O:20])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:42]([O:44][CH2:45][CH2:46]Br)[CH3:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH2:43][CH2:42][O:44][CH2:45][CH3:46])[C:11]=2[NH:18][C:19]([C:21]2[S:22][CH:23]=[C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:25]=2[Cl:26])=[O:20])=[N:6][CH:7]=1
Reactant: CCOCCBr
Reactant: CN1CCN(Cc2csc(C(=O)Nc3c(O)cc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)c2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOCCOc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN2CCN(C)CC2)c1Cl
Temperature: 60 °C

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide (2.0 g, 3.6 mmol) in DMF (20 mL) were added cesium carbonate (8.0 g, 25 mmol) and 2-bromoethyl ethyl ether (0.71 g, 4.6 mmol). The suspension was heated at 60° C. for 16 hours. The mixture was cooled to ambient temperature and filtered, and the filtrate was acidified with trifluoroacetic acid. Purification by HPLC on a C18 Dynamax column acetonitrile in water gradient with 0.1% trifluoroacetic acid afforded N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-ethoxyethoxy)-5-chlorobenzamide, trifuoroacetic acid salt as a white solid; NMR (DMSO-d6/TFA) 11.9 (s, 1), 9.4 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.4 (s, 1), 7.3 (s, 1), 4.4 (s, 2), 4.2 (t, 2), 3.7 (t, 2), 3.5 (q, 2), 3.5 (br, 8), 2.9 (s, 3), 1.0 (t, 3) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][C@@H:33]([CH2:37][OH:38])[C@H:34]([CH3:36])[OH:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:38][CH2:37][C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29])[C@@H:34]([OH:35])[CH3:36]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@H](O)[C@@H](N)CO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)N[C@@H](CO)[C@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 84.2 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.75 g, 3.91 mmol) synthesized in Example (106c) was dissolved in methanol (30 mL), and D-threoninol (1.00 g, 9.51 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (2.85 g, 10.30 mmol) were added, followed by stirring at room temperature for 5 days under nitrogen atmosphere. After the solvent was distilled off under reduced pressure, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (80 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%) to afford the desired compound (1.76 g, yield 84%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([Cl:18])=[N:15][C:16]([Cl:17])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=O)(C)(C)C>C(Cl)Cl.CO>[Cl:17][C:16]1[N:15]=[C:14]([Cl:18])[N:11]2[CH2:12][CH2:13][NH:8][CH:9]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)nc(Cl)c2C1CCc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CO
Product: FC(F)(F)c1ccc(CCC2NCCn3c(Cl)nc(Cl)c32)cc1

Procedure:
According to the general procedure (GP13), Boc-deprotection of 1,3-dichloro-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (185.7 mg; 0.400 mmol) and purification by FC (DCM/MeOH/25% aq. NH4OH=150/10/1) gave the expected product 1,3-dichloro-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine as a yellow oil (121 mg; 0.332 mmol; 83%). LC-MS: tR=0.79 min.; [M+H]+=364.11 g/mol.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:22]([CH3:21])[CH:23]=[CH:24]3)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cn1ccc2cc(C=O)ccc21
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2c(ccn2C)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 1-methyl-1H-indole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 378.93 g/mol.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([NH:18][CH2:19][C:20]([OH:22])=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[CH2:31]([NH:33][CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[CH3:32]>O1CCCC1>[CH2:31]([N:33]([C:20](=[O:22])[CH2:19][NH:18][C:16]([O:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:17])[CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[CH3:32]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCNCCc1c[nH]c2ccccc12
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CCc1c[nH]c2ccccc12)C(=O)CNC(=O)OCc1ccccc1
Temperature: -15 °C
Yield: 101.6 %

Procedure:
30 ml of anhydrous tetrahydrofuran and 1.05 g of triethylamine are added to 2.17 g of N-benzyloxycarbonyl-glycine, and 1.43 g of isobutyl chloroformate are added dropwise thereto at -15° C. under stirring. A solution of 1.96 g of N-ethyl-tryptamin (i.e., 3-(2-ethylamino)ethylindole) in 40 ml of anhydrous tetrahydrofuran is added dropwise to the mixture at the same temperature, and said mixture is stirred at 0° C. for one hour and further stirred at room temperature for 16 hours. After the reaction, the reaction mixture is evaporated to remove solvent. The residue (oil) is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform (1:1). 4.0 g of N-ethyl-N-(N-benzyloxycarbonylglycyl)-tryptamine are thereby obtained as a colorless oil. Yield: 100%.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][O:5][C:4]([C:14]#[N:15])=[CH:3]1.[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[C:8]1([C:7]2[C:2](=[O:1])[CH:3]=[C:4]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)[O:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(=O)c(-c2ccccc2)co1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2nnn[nH]2)occ1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-oxo-5-phenyl-4H-pyran-2-carbonitrile (2.0 g), sodium azide (1.0 g) and ammonium chloride (0.8 g) in dimethylformamide (20 ml) was stirred at room temperature for an hour. Ice (20 g) was added and the clear solution was acidified with 2 N hydrochloric acid (20 ml) giving a pale solid which was recrystallised from ethanol to give the title product (mp 237°-238° C. with decomposition).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([CH3:13])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4]>CCO.[Pd]>[NH2:1][C@@H:2]([CH:5]([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4]
Reactant: CC(=Cc1ccccc1)[C@H](N)CO
Agent: [Pd]
Solvent: CCO
Product: CC(Cc1ccccc1)[C@H](N)CO
Yield: 49 %

Procedure:
A solution of (S)-2-amino-3-methyl-4-phenyl-but-3-en-1-ol (115 mg) in EtOH (5 ml) was hydrogenated at normal pressure (balloon) overnight in the presence of 10% Pd/C (10 mg). The reaction mixture was filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give (S)-2-amino-3-methyl-4-phenyl-butan-1-ol (57 mg, 49%) as light yellow oil. MS (ISP): 180.3 ([M+H]+))
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=5[C:32]([OH:34])=O)[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[CH:40]1([NH2:43])[CH2:42][CH2:41]1.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[F:39][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=5[C:32]([NH:43][CH:40]5[CH2:42][CH2:41]5)=[O:34])[O:27][N:26]=4)[N:24]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: NC1CC1
Reactant: O=C(O)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CC1)c1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzoic acid (105 mg) in dichloromethane (10 ml) are added, at room temperature, cyclopropanamine (11 mg), 4-dimethylaminopyridine (2 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (37 mg). The mixture is stirred at room temperature for 3 hours and then admixed with water. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}-N-cyclopropylbenzamide (78 mg).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:13]([O:17][C:18]([NH:20][C:21](=[N:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])SC)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Ag+]>[C:28]([O:27][C:25]([NH:24][C:21]([NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])=[N:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: NCCCc1ccc(O)cc1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Ag+]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(=NCCCc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Silver acetate (1.3 g) was added to a solution of 3-(4-hydroxyphenyl)propylamine hydrochloride (1.2 g) and N,N'-Bis(tert-butoxycarbonyl)-S-methylisothiourea (1.86 g) in DMF (10 mL) containing triethylamine (3.0 g). The mixture was stirred for 3 hr, and an additional 1.0 g silver acetate was added. After one hour, the mixture was diluted with ethyl acetate, filtered through Celite, washed with water, dried over magnesium sulfate, and the solution evaporated. Chromatography on silica gel with 20% ethyl acetate in hexane provided the title compound as a white solid, mp 142°-144° C. (dec) after recrystallization from hexane-ethyl acetate (2.1 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([F:10])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>>[N:15]([CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([F:10])[CH:6]=1)=[N+:16]=[N-:17]
Reactant: OCc1cc(F)cnc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1cc(F)cnc1Cl

Procedure:
(2-chloro-5-fluoro-pyridin-3-yl)-methanol, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 187 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1C[CH2:37][CH2:36][CH2:35]1>O>[CH:20]1([NH:19][N:16]2[C:17](=[O:18])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:21][CH2:22][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.051 g, 0.115 mmol) in tetrahydrofuran (5 mL) and methanol (0.01 mL, 0.23 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.090 mL, 0.175 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 97:3 dichloromethane/methanolto give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.16 (m, 5 H) 1.59 (m, 5 H) 3.01 (m, 1 H) 5.75 (d, J=3.31 Hz, 1 H) 7.15 (d, J=5.52 Hz, 1 H) 7.19 (d, J=7.72 Hz, 1 H) 7.26 (t, J=7.54 Hz, 1 H) 7.54 (m, 1 H) 7.65 (d, J=7.72 Hz, 1 H) 7.72 (d, J=5.52 Hz, 1 H) 15.93 (s, 1 H). MS (ESI−) m/z 443 (M−H)−.
Reaction SMILES: Cl.C(=[N:15][N:16]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[CH2:18][C:17]1=[O:29])(C1C=CC=CC=1)C1C=CC=CC=1>O>[NH2:15][N:16]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[CH2:18][C:17]1=[O:29]
Reactant: COc1cccc(C2CC(=O)N(N=C(c3ccccc3)c3ccccc3)C2)c1
Agent: Cl
Solvent: O
Product: COc1cccc(C2CC(=O)N(N)C2)c1

Procedure:
Concentrated hydrochloric acid (0.35 mL) is added to a suspension of 1-(benzhydrylidene-amino)-4-(3-methoxy-phenyl)-pyrrolidin-2-one, (0.8 g, 2.16 mmol) in water (17 mL) and refluxed for one hour. The mixture is concentrated in vacuo and water azeotroped away using ethanol and toluene. The residue is dissolved in methanol (5 mL) and loaded on SCX resin (5 g). The resin is washed with methanol and 2 M solution of ammonia in methanol. Appropriate fractions are concentrated to yield the title compound, 402 mg (92%), as a white crystalline solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:54])[C:28]([CH3:53])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45][CH2:46][C:47]3[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=3)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[CH:1]1([NH:7][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:54])[C:28]=3[CH3:53])[CH:37]=[CH:38][C:39]=2[O:45][CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)NC3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 12.7 %

Procedure:
Cyclohexylamine (0.149 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.215 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.032 g, 0.0634 mmol, 13%).
Reaction SMILES: FS([C:5]([F:14])([F:13])[C:6](O[Si](C)(C)C)=O)(=O)=O.[Br:15][C:16]1[C:17]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:18][C:19]2[O:23][C:22]([CH:24]=C)=[C:21]([C:26]([NH:28][CH3:29])=[O:27])[C:20]=2[CH:30]=1.[F-].[Na+]>C1(C)C=CC=CC=1.COCCOCCOC>[Br:15][C:16]1[C:17]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:33])=[O:34])=[CH:18][C:19]2[O:23][C:22]([CH:24]3[CH2:6][C:5]3([F:13])[F:14])=[C:21]([C:26]([NH:28][CH3:29])=[O:27])[C:20]=2[CH:30]=1
Reactant: C=Cc1oc2cc(N(C)S(C)(=O)=O)c(Br)cc2c1C(=O)NC
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Agent: [F-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(C2CC2(F)F)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
A solution of trimethylsilyl 2-fluorosulfonyl-2,2-difluoroacetate (31 mg, 0.12 mmol) in toluene (0.5 mL) was added dropwise to a solution of 5-bromo-N-methyl-6-(N-methylmethylsulfonamido)-2-vinylbenzofuran-3-carboxamide (30 mg, 0.07 mmol) and NaF (1 mg, 0.02 mmol) in diglyme (1 mL) at 120° C. over 15 min. The mixture was then stirred at 120° C. for 2 h. The mixture was concentrated in vacuum and the residue was purified by prep-TLC (PE:EA=1:1) to give the product of 5-bromo-2-(2,2-difluorocyclopropyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (7 mg, yield: 22%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.13 (s, 1H), 8.02 (s, 1H), 3.74˜3.66 (m, 1H), 3.19 (s, 3H), 3.18 (s, 3H), 2.84 (s, 3H), 2.38˜2.39 (m, 1H), 2.21˜2.17 (m, 1H). MS (M+H)+: 437/439.
Reaction SMILES: NC1SC(C2C(F)=CC=CC=2F)=NC=1C(NC1C=NN(C)C=1N1CCC[C@H](NCC2COC2)CC1)=O.[O:37]1[CH2:40][CH:39]([CH2:41][N:42]([CH2:80][CH:81]2[CH2:84][O:83][CH2:82]2)[C@@H:43]2[CH2:49][CH2:48][CH2:47][N:46]([C:50]3[N:54]([CH3:55])[N:53]=[CH:52][C:51]=3[NH:56][C:57]([C:59]3[N:60]=[C:61]([C:72]4[C:77]([F:78])=[CH:76][CH:75]=[CH:74][C:73]=4[F:79])[S:62][C:63]=3[NH:64]C(=O)OC(C)(C)C)=[O:58])[CH2:45][CH2:44]2)[CH2:38]1>>[NH2:64][C:63]1[S:62][C:61]([C:72]2[C:73]([F:79])=[CH:74][CH:75]=[CH:76][C:77]=2[F:78])=[N:60][C:59]=1[C:57]([NH:56][C:51]1[CH:52]=[N:53][N:54]([CH3:55])[C:50]=1[N:46]1[CH2:47][CH2:48][CH2:49][C@H:43]([N:42]([CH2:80][CH:81]2[CH2:84][O:83][CH2:82]2)[CH2:41][CH:39]2[CH2:38][O:37][CH2:40]2)[CH2:44][CH2:45]1)=[O:58]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](N(CC2COC2)CC2COC2)CC1
Agent: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC[C@H](NCC2COC2)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC[C@H](N(CC2COC2)CC2COC2)CC1

Procedure:
In the preparation of 342, tert-butyl N-[4-[[5-[(4R)-4-[bis(oxetan-3-ylmethyl)amino]azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(2,6-difluorophenyl)thiazol-5-yl]carbamate was deprotected following the procedure in Example 334 to give 343. LCMS (ES+) m/z 588 (M+1)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[H][H]>[Pt].O>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: Nc1cccnc1-c1ccccc1
Agent: [Pt]
Agent: Cl
Solvent: O
Product: NC1CCCNC1c1ccccc1

Procedure:
A 500 ml Parr bottle was charged with 5 grams of 5% platinum/carbon (50% water wet), 5 grams (0.0293 mol.) 3-amino-2-phenylpyridine (1 equivalent), 75 ml of water (15 vol.) and 25 ml of concentrated hydrochloric acid (5 vol.). The reaction was hydrogenated (maintaining the hydrogen pressure between 36 psi and 50 psi) until high pressure liquid chromatography (HPLC) indicated complete reaction. The catalyst was removed by filtration and the pH of the filtrate was adjusted from 0 to a stable 11.2 using 25% sodium hydroxide (NaOH). The aqueous layer was extracted twice with 50 ml of methylene chloride (CH2Cl2). The organic extracts were combined, dried with magnesium sulfate (MgSO4) and the filtrate was atmospherically distilled to an oil, 4.34 grams (84.1%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]([N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH3:17])(C)C>ClCCl>[CH3:12][N:15]1[C:18]2[C:20](=[CH:3][CH:4]=[CH:5][CH:19]=2)[C:17]([C:8]2[C:9](=[O:10])[O:10][C:9](=[O:11])[C:8]=2[C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:16]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)Cc1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cn1cc(C2=C(c3ccncc3)C(=O)OC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 65 h
Yield: 21.5 %

Procedure:
5 g of 4-pyridyl-acetic acid hydrochloride and 3.72 g of diisopropylethylamine in 50 ml of dichloromethane were treated at 0° C. firstly with 6.37 g of 1-methylindole-3-glyoxylyl chloride in 50 ml of dichloromethane and then with 7.5 g of diisopropylethylamine. The mixture was allowed to warm to room temperature and was then stirred for 65 hours. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane and chromatographed on silica gel with ethyl acetate. The product-containing fractions were concentrated. Crystallization from ethyl acetate/hexane yielded 940 mg of 3-(1-methyl-3-indolyl)-4-(4-pyridyl)furan-2,5-dione, m.p. 217°-219° C.