Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32]([OH:34])=O.[C:35]1([C:41]2([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:46][CH2:45][CH2:44][NH:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:47]1([C:41]2([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:46][CH2:45][CH2:44][N:43]([C:32](=[O:34])[CH2:31][N:15]3[CH2:16][CH2:17][C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:14]3=[O:13])[CH2:42]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: c1ccc(C2(c3ccccc3)CNCCO2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCOC(c2ccccc2)(c2ccccc2)C1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.060 g, 0.313 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.059 g, 0.198 mmol) and 2,2-diphenylmorpholine (0.050 g, 0.209 mmol, CAS 77373-34-3) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.43 (s, 20H), 4.15 (s, 2H), 4.09 (s, 2H), 3.39-3.44 (m, 2H), 3.28-3.33 (m, 2H), 3.27 (t, J=6.4 Hz, 2H), 2.57 (t, J=6.6 Hz, 2H); MS (ESI+) m/z 517 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([NH:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[NH2:39])[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:30]1([CH2:29][CH2:28][CH2:27][CH:26]([NH:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[NH:39][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:25][CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N[C@@H](Cc2cccnc2)C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.66 g; 2.89 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 3-(3-Pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (85) (1.00 g; 2.41 mmol), N,N-diisopropylethylamine (0.68 g; 5.29 mmol) and PyBOP (1.50 g; 2.89 mmol) are added sequentially. The reaction is stirred for 5 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (80%→100% ethyl acetate in hexanes) affording the desired product (86) as a white solid. ESMS: MH+ 627.6
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[CH:17]=[N:16][NH:15][C:14]1=[S:18].[Cl:19][C:20]1[CH:47]=[CH:46][C:23]([C:24]([C:26]2[CH:27]=[C:28]3[C:33]4=[C:34]([O:36][CH2:37][N:32]4[C:31](=[O:38])[CH:30]=[C:29]3[C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[CH:35]=2)=[O:25])=[CH:22][CH:21]=1>C1COCC1>[Cl:45][C:41]1[CH:40]=[C:39]([C:29]2[C:28]3[C:33]4=[C:34]([O:36][CH2:37][N:32]4[C:31](=[O:38])[CH:30]=2)[CH:35]=[C:26]([C:24]([C:23]2[CH:46]=[CH:47][C:20]([Cl:19])=[CH:21][CH:22]=2)([OH:25])[C:17]2[N:13]([CH3:12])[C:14]([SH:18])=[N:15][N:16]=2)[CH:27]=3)[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc2c3c(c1)c(-c1cccc(Cl)c1)cc(=O)n3CO2
Reactant: Cn1cn[nH]c1=S
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(S)nnc1C(O)(c1ccc(Cl)cc1)c1cc2c3c(c1)c(-c1cccc(Cl)c1)cc(=O)n3CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.4 %

Procedure:
nBuLi 1.6M in hexane (0.0086 mol) was added at −78° C. to a solution of 2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (0.0043 mol) in THF (25 ml) under N2 flow. The mixture was stirred at 0° C. for 1 hour, then cooled to −78° C. 8-(4-chlorobenzoyl)-6-(3-chlorophenyl)-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one (0.0024 mol) described in International Publication WO98/40383, was added portionwise. The mixture was stirred at room temperature for 4 hours, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.38 g) was purified by column chromatography over silica gel (15-40 μm) (eluent: CH2Cl2/CH3OH/NH4OH97/3/0.1). The pure fractions were collected and the solvent was evaporated. A part of the residue (0.049 g) was purified by column chromatography over silica gel (10 μm) (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 0.018 g (1%) of 6-(3-chlorophenyl)-8-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one, melting point: 193° C. (intermediate 13).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH:27][CH3:28])[CH:25]=[CH2:26]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:27]([CH2:24][CH:25]=[CH2:26])[CH3:28])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCNC
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCBr)ccc21
Solvent: CN(C)C=O
Product: C=CCN(C)CCCCOc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C
Yield: 73.9 %

Procedure:
5.0 g (13.0 mmol) 6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester were treated with 3.66 g (51.5 mmol) N-allyl-methylamine in 100 ml DMF at 50° C. for 30 min. The mixture was concentrated in vacuo, dissolved in Et2O and water. The inorganic layer was extracted with Et2O, and the combined organic phases were washed with water and dried over Na2SO4. Purification by column chromatography on silica gel with CH2Cl2/MeOH 10:1 yielded 3.6 g (74%) 6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as light yellow oil, MS: 375 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:35]([O:39][C:40](=[O:70])[CH2:41][N:42]([CH2:56][C:57]1[N:58]([CH2:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[CH:59]=[CH:60][N:61]=1)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](O)=[O:54])([CH3:38])([CH3:37])[CH3:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:66]([O:65][C:63](=[O:64])[CH2:62][N:58]1[CH:59]=[CH:60][N:61]=[C:57]1[CH2:56][N:42]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](=[O:54])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:41][C:40]([O:39][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:70])([CH3:69])([CH3:67])[CH3:68]
Reactant: CC(C)(C)OC(=O)CN(CCCCCCCCCCC(=O)O)Cc1nccn1CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCCCCCN(CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 64.8 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (85 mg, 0.175 mmol), 11-((2-tert-butoxy-2-oxoethyl)((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)undecanoic acid (89 mg, 0.175 mmol), EDCI (38 mg, 0.20 mmol), HOBt (26 mg, 0.20) and DIPEA (0.30 mL) in DCM (5.0 mL) was stirred at rt for 3 days. The reaction mixture was purified by biotage eluting with 1% to 10% MeOH in DCM to afford (19S,23S)-tetra-tert-butyl 2-((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-1,19,23,25-tetracarboxylate (111 mg, 65%) as a yellow oil. MS (ESI), 490.5 (M/2-H)+.
Reaction SMILES: [SH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([CH3:13])=[N:4][N:3]=1.[CH3:14][O-].[Na+].CI>CO>[CH3:13][C:5]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([S:1][CH3:14])=[N:3][N:4]=1
Reactant: Cc1nnc(S)n1-c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSc1nnc(C)n1-c1ccccc1
Reaction time: 0.17 h

Procedure:
3-Mercapto-5-methyl-4-phenyl-1,2,4-triazole (19.1 g) was suspended in 200 ml of methanol, and 20 g of 28% sodium methylate was added thereto. After 10 minutes, 15 g of methyl iodide was added dropwise. They were reacted for 2 hours and then the methanol was distilled away. Upon extraction of the residue with ethyl acetate, 5-methyl-3-methylthio-4-phenyl-1,2,4-triazole was obtained.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=O)=[CH:8][CH:7]=1>CO>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:2][NH2:3])=[O:15])=[CH:8][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=O)NN)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrazine hydrate (4.7 cm3) was added dropwise to ethyl (4-methoxyphenyl)acetate (3.73 g) and then methanol (20 cm3) was added to form a homogeneous reaction mixture. This mixture was stirred for 18 hours at ambient temperature during which time a white precipitate formed. The precipitate was isolated by filtration and washed with methanol and water, then air-dried to give (4-methoxyphenyl)acetic acid hydrazide (2 g). M+ =180; 1H NMR: δ 3.50(2H,s); 3.80(3H,s); 3.85(2H,br s); 6.70(1H,br s); 6.90(2H,d); 7.20(2H,d); (solid).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].N1C=CC=CC=1.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>C1COCC1>[CH3:2][O:3][N:4]([CH3:5])[C:12](=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: CNOC
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=C(C)C(=O)N(C)OC
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
O,N-dimethylhydroxylamine hydrochloride (74.6 g, 765 mmol) was dissolved in THF (1 L) and pyridine (123 ml, 1531 mmol) was added and stirred for 30 min. Methacryloyl chloride (37.4 ml, 383 mmol) was added slowly and stirred overnight. The solids were filtered and concentrated. The residue was partitioned between water and CH2Cl2, washed with water, dried over sodium sulfate, filtered and concentrated to afford N-methoxy-N-methylmethacrylamide (56.5 g, 335 mmol, 87.5% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:9][CH:8]=2)[N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:28]=[CH:27]2>>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([N:20]1[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:4]4[N:3]=[C:2]([CH3:1])[O:6][N:5]=4)=[CH:8][CH:9]=3)[CH2:22][CH2:21]1)(=[O:36])=[O:35])[CH:28]=[CH:27]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: Cc1nc(-c2ccc(CCC(=O)N3CCNCC3)cc2)no1
Product: Cc1nc(-c2ccc(CCC(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)no1

Procedure:
Similarly to Example 1, reaction of 3-[4-(5-methyl[1,2,4]oxadiazol-3-yl)phenyl]-1-piperazin-1-ylpropan-1-one [obtainable from 3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-1-(4-tert-butyloxycarbonyl)piperazin-1-yl-propan-1-one by treatment with TFA/CH2Cl2] and 6-chloronaphthalene-2-sulphonyl chloride gives the compound 1-[4-(6-chloronaphthalene-2-sulphonyl)piperazin-1-yl]-3-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]propan-1-one and, after hydrogenation, 4-{3-oxo-3-[4-(6-chloronaphthalene-2-sulphonyl)piperazin-1-yl]propyl}benzamidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([C:23](O)=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:23]([CH:19]3[O:20][CH2:21][CH2:22][N:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:18]3)=[N:9][C:4]=2[CH:3]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: Nc1ccc(Cl)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A mixture of 4-chlorobenzene-1,2-diamine (2.0 g, 14.03 mmol) and 4-benzylmorpholine-2-carboxylic acid (4.66 g, 21.04 mmol) in polyphosphoric acid (20 mL) was stirred at 140° C. overnight. The reaction mixture was cooled to room temperature and treated with 100 mL of water. The aqueous phase was adjusted to weakly basic with 2 N aqueous sodium hydroxide and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to give the crude product as a off-white solid. The residue was triturated with hex/EtOAc (1×25 mL). The resulting solid was filtered, rinsed with n-hexane, and collected. The solvent was evaporated in vacuo to afford the title compound (2.1 g). LC-MS (ES) m/z=328 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:14])(=[O:13])[NH:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=O)=[C:23]([O:31][CH3:32])[CH:22]=2)[N:16]=1.[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:13])(=[O:14])[NH:9][CH:10]2[CH2:11][CH2:12]2)=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([C:34]([F:33])([F:42])[F:43])[CH:36]=3)=[O:27])=[C:23]([O:31][CH3:32])[CH:22]=2)[N:16]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3cc(S(=O)(=O)NC4CC4)ccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3cc(S(=O)(=O)NC4CC4)ccc3Cl)[nH]c2=O)ccc1C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2-chloro-5-(N-cyclopropylsulfamoyl)phenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-40, 0.040 g, 0.08 mmol), 3-(trifluoromethyl)aniline (0.020 g, 0.12 mmol), trimethyl aluminium (2M solution in toluene) (1 ml) and dry toluene (5.0 mL) to afford 0.015 g of crude product, which was purified by washing with methanol:DCM:DEE to afford 0.015 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 0.42 (s, 2H), 0.54 (d, J=5.4 Hz, 2H), 2.20 (m, 1H), 3.96 (s, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.61 (t, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.80-7.84 (m, 2H), 7.96 (s, 3H), 8.18 (m, 2H), 8.26 (s, 1H), 10.40 (s, 1H), 12.88 (br s, 1H); MS (m/z): 606.13 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[C-:12]#[N:13].[Na+].C(Cl)Cl.C([O-])(O)=O.[Na+]>O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:12]#[N:13])[CH:5]=[N:4][C:3]=1[O:10][CH3:11]
Reactant: COc1ncc(CBr)cc1Br
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ncc(CC#N)cc1Br
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 3-bromo-5-bromomethyl-2-methoxy-pyridine (Step AM2) (3.9 g, 14.0 mmol) in H2O was added NaCN (750 mg, 15.3 mmol) and the mixture was stirred at 50° C. for 1.5 h. CH2Cl2 and a saturated aqueous solution of NaHCO3 were added and the phases were separated. The organic layer was washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (heptane/EtOAc, 80:20→0:100). tR: 0.88 min (LC-MS 1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][N:10]=[CH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>C(Cl)Cl>[OH:9][N:10]=[C:11]([Br:1])[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(C=NO)cc1
Solvent: ClCCl
Product: N#Cc1ccc(C(Br)=NO)cc1
Temperature: 25 °C

Procedure:
The compound was prepared according to Tanaka et al. Bull. Chem. Soc. Jpn. 1984, 57, 2184. A 0.05M solution of N-bromosuccinimide (724 mg, 4.07 mmol, 1.20 eq) in CH2Cl2 was added dropwise to a 0° C. solution of 4-(hydroxyiminomethyl)-benzonitrile (496 mg, 3.39 mmol, 1.00 eq) in CH2Cl2 (50 mL). The solution was warmed to room temperature before being volumetrically partitioned between two different reaction vials. Each vial was then concentrated and the crude residues were used without further purification.
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([CH:9]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:4](=[O:29])[O:3]1>N1C=CC=CC=1.C(O)C.[Cu]>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([CH:9]([C:10]2[C:18]3[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:29])=[CH:23][CH:24]=1
Reactant: CSCc1cccc2c(C(c3ccc(C)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)CC(c1ccc(C)cc1)c1c[nH]c2c(CSC)cccc12
Yield: 67.7 %

Procedure:
6.5 mg (102 μmol) of copper powder were added to a solution of 4.34 g of the compound from Example 94A in 75 ml of pyridine and 20 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) to result in 2.55 g of the title compound.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=1)[CH3:10]>C(Cl)Cl>[Br:8][C:16]1[C:11]([CH2:9][CH3:10])=[CH:12][C:13]([NH2:17])=[N:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccnc(N)c1
Solvent: ClCCl
Product: CCc1cc(N)ncc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NBS (231 mg, 1.30 mmol) was added to a solution of 4-ethylpyridin-2-amine (144 mg, 1.18 mmol) in DCM (5 ml) at room temperature. After stirring for 5 minutes at room temperature the reaction mixture was partitioned between aqueous Na2S2O3 and DCM, extracted with DCM (2×), the combined organic layers were dried over Na2SO4 and evaporated to give the title compound as a beige solid. (UPLC-MS 6) tR 0.61; ESI-MS 200.9 and 202.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 19 mg, 50 μmol) and methoxyacetyl chloride (16 mg, 150 μmol). Yield 23 mg (99%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9](N)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[OH-:18].[K+].Cl>OCCOCCO.C(OCC)C>[CH2:1]([C:3]1[C:8]([C:9]([OH:18])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCc1c(C(N)=O)cccc1-c1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: OCCOCCO
Product: CCc1c(C(=O)O)cccc1-c1ccccc1
Temperature: 0 °C
Yield: 104.5 %

Procedure:
A stirred solution of 2-ethyl-[1,1'-biphenyl]-3-carboxamide (2.1 g, 0.0093 mole) and potassium hydroxide (26.3 g, 0.4 mole) in 175 ml of 2-hydroxyethyl ether was heated at 163° for approximately 18 hours. The reaction mixture was cooled and diluted with 150 ml of ice water. The solution was acidified with concentrated hydrochloric acid to form a precipitate. The precipitate was isolated by filtration and dissolved in diethyl ether; the ethereal solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carboxylic acid (2.2 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH2:18][C:19]#[CH:20])[CH:12]=[CH:13][CH:14]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([N:15]([CH3:22])[C:16](=[O:21])[CH2:17][CH2:18][C:19]#[C:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: C#CCCC(=O)N(C)c1cccc(Cl)c1
Reactant: Brc1ccccn1
Product: CN(C(=O)CCC#Cc1ccccn1)c1cccc(Cl)c1
Yield: 33.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (80 mg, 0.51 mmol) and pent-4-ynoic acid (3-chloro-phenyl)-methyl-amide (113 mg, 0.51 mmol). The crude residue was purified by C18 flash chromatography to yield 51 mg (0.17 mmol, 33%) of N-(3-chlorophenyl)-N-methyl-5-(pyridin-2-yl)pent-4-ynamide as a brown liquid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([CH2:30][C:31]1[N:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:15]([C:17]1[CH:27]=[C:26]([O:28][CH3:29])[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.ClCCl.[C:54]1(=O)[CH2:57]C[CH2:55]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[C:31]([CH2:30][N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH:6]2[CH2:57][CH2:54][CH2:55]2)[C:15]([C:17]2[CH:27]=[C:26]([O:28][CH3:29])[C:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])[N:32]=1
Reactant: COc1cc(C(=O)N(Cc2cc3ccccc3nn2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc2c1OC(C)(C)O2
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N(Cc2cc3ccccc3nn2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2

Procedure:
Experimental conditions analogous to Example 1, from 172 mg (0.31 mmol) of (S)-2-{[cinnolin-3-ylmethyl-(7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester and 3 mL 10% trifluoroacetic acid/dichloromethane. The crude deprotected material was submitted to reductive amination reaction in 5 mL dichloromethane using 108 mg (1.55 mmol) of cyclobutanone and 329 mg (1.55 mmol) sodium triacetoxyborohydride. The reaction mixture was purified using flash chromatography elution with 0-10% methanol in dichloromethane, gave 47 mg of pale yellow solid as the free base. LC-MSD, m/z for C29H34N4O4 [M+H]+: 503.7. 1H NMR (400 MHz, CDCl3): δ 1.6-2.5 (m, 16 H), 2.8-2.9 (m, 1 H), 3.5-3.8 (m, 3 H), 3.8 (s, 3 H), 3.9-4.0 (m, 2 H), 5.1-5.3 (m, 2 H), 6.8 (bs, 1 H), 7.2 (bs, 1 H), 7.7-7.9 (m, 4 H), 8.4-8.5 (m, 1 H).