Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@@H:4]([C:15]([OH:17])=[O:16])[N:3]1[C:18]([S:20][CH3:21])=[S:19].[N+](=[CH2:24])=[N-]>CCOCC>[CH3:1][C@H:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][C@@H:4]([C:15]([O:17][CH3:24])=[O:16])[N:3]1[C:18]([S:20][CH3:21])=[S:19]
Reactant: CSC(=S)N1[C@H](C(=O)O)Cc2c([nH]c3ccccc23)[C@@H]1C
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](C)N1C(=S)SC
Yield: 81.6 %

Procedure:
A mixture of (1S,3S)-1-methyl-2-[(methylthio)thiocarbonyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.28 g), diazomethane [prepared from N-nitrosomethylurea (3.0 g) and 40% NaOH (9 ml)] and ether (100 ml) is allowed to stand under ice-cooling overnight. The resulting precipitates are collected by filtration and dried to give the title compound (1.09 g, 82%), m.p. 229°-230° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].O.NN>[Ni].CO>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cccc(C(=O)O)c1N
Temperature: 65 °C

Procedure:
3 g of the above mentioned 2-amino-3-nitrobenzoic acid is added into 30 ml of methanol, 20% sodium hydroxide aqueous solution with the same molar as 2-amino-3-nitrobenzoic acid is dropped into the above methanol solution till dissolve completely. 0.2 g of Raney nickel at the moment is added in to the methanol solution, and to heat it to 65° C. and reflux it at the temperature; and then drop 80 g/g % hydrazine hydrate (about 1.5 equivalent weight×1.1) till the yellow disappears completely. Hot Raney nickel is filtered; and then heat and concentrate the mother liquid and acidize it with the concentrated chlorhydric acid to produce 2.3 g of red 2,3-diaminobenzoic acid; afterwards isolate and purify the crude product of red 2,3-diaminobenzoic acid by column chromatography.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:18][C:17]=1[C:27]([F:30])([F:29])[F:28]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:26])/[CH:24]=[CH:25]/[C:2]2[CH:14]=[CH:13][C:5]([CH2:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[CH:18][C:17]=1[C:27]([F:28])([F:29])[F:30]
Reactant: C=CC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Ic1ccc(Cc2ccncc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(Cc2ccncc2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 95 °C
Yield: 87.8 %

Procedure:
A mixture of 4-(4-iodobenzyl)pyridine (129 mg, 0.44 mmol), TEA (67 μL, 0.48 mmol), Pd(PPh3)4 (254 mg, 0.222 mmol) and N-[4-chloro-3-(trifluoromethyl)-phenyl]acrylamide (0.120 g, 0.44 mmol) in DMF (4.4 mL) was heated at 95° C. for 3 h. The reaction mixture was cooled to rt, diluted with water, extracted with EtOAc, washed with brine, dried over NaSO4, filtered and concentrated. The residue was purified by column chromatography to give the title compound (161 mg, 40%). LCMS: (FA) ES+ 417.2 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][C:15]1[CH:16]=[C:17]([CH2:23][CH:24]([O:28][CH:29]([CH3:31])[CH3:30])[C:25]([O-:27])=[O:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][CH2:14][C:15]2[CH:16]=[C:17]([CH2:23][CH:24]([O:28][CH:29]([CH3:31])[CH3:30])[C:25]([OH:27])=[O:26])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CO)nc1
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CBr
Product: CCCCc1ccc(COCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)nc1

Procedure:
Using (5-butyl-2-pyridyl)methanol and 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(5-butyl-2-pyridyl)methoxy]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 247).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH3:13])[CH2:11][C:10]([NH:14][CH:15]=[O:16])=[N:9]2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([CH3:13])[CH2:11][C:10]([NH:14][C:15](=[O:16])[CH3:17])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(NC=O)=NN1c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Product: CC(=O)NC1=NN(c2ccc(Cl)cc2)C(C)C1
Reaction time: 48 h

Procedure:
A mixture of 8.0 g. of 3-amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline (prepared as described in Example 20), 400 mg. of 4-dimethylaminopyridine and 20.0 ml. of acetic anhydride is allowed to stand at room temperature for 48 hours. The solid formed is collected by filtration, washed with cold acetic anhydride, then with hexane and is dried to give a white solid. The solid is recrystallized from dichloromethane-hexane to give 6.6 g. of the product of the Example as a white solid, m.p. 167°-169° C.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].O.[C:16]([O:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>C(O)C.O>[C:16]([O:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][S:1][C:2]3[N:3]([CH3:12])[C:4](=[O:11])[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:32][CH:33]=2)=[O:25])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]
Reactant: Cn1c(S)nc2ccsc2c1=O
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Oc1ccc(C(=O)c2ccc(CSc3nc4ccsc4c(=O)n3C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.98 g) and 1N-sodium hydroxide/water (10 ml) in ethanol (30 ml) was added 4-(4-acetoxybenzoyl)benzyl bromide (3.95 g) and the mixture was stirred at 60° C. for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate to provide the title compound as colorless solid (3.87 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:27])([CH3:26])[C:23]#[C:24][CH3:25])[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[C@@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)(C)(C)C.[ClH:36].CO>CCOC(C)=O>[ClH:36].[ClH:36].[CH3:27][C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:28][CH3:29])=[C:16]([CH:21]=1)[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:26])[C:23]#[C:24][CH3:25]
Reactant: CC#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of Compound 56 (73 mg, 0.15 mmol) in AcOEt (6 ml) was added an excess amount of 10% HCl-MeOH (3 ml), and stirred for 18 h. After the solvent was evaporated in vacuo, the residual solid was recrystallized from MeOH-ether to give Compound 57 (48 mg, 78%) as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:33][CH:34]=[C:35](Cl)[N:36]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11]([C:32]4[S:33][CH:34]=[CH:35][N:36]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Clc1csc(Br)n1
Reactant: C[C@@H](Oc1cc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2nccs2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 6.1 %

Procedure:
To a microwave tube equipped with a stifling bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (300 mg, 0.729 mmol), 2-bromo-4-chlorothiazole (144.8 mg, 0.729 mmol), 1,2-dimethoxyethane (3 mL), 1 N Na2CO3 aqueous solution (2.41 mL, 2.41 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (84.3 mg, 0.073 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2.5 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give yellow solids, 16.4 mg (yield 6.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.88 (d, J=3.3 Hz, 1H), 7.73 (d, J=3.3 Hz, 1H), 7.62-7.57 (m, 2H), 7.45-7.42 (m, 1H), 4.82 (p, J=5.9 Hz, 1H), 3.72 (m, 1H), 3.45-3.36 (m, 1H), 3.27-3.15 (m, 1H), 2.90-2.74 (m, 1H), 2.37-2.20 (m, 2H), 1.34 (d, J=6.0 Hz, 3H), 1.16-1.09 (m, 2H), 1.09-0.98 (m, 2H) ppm; MS (ESI+) m/z 369 (M+H).
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)[C:7]#[CH:8].C([OH:20])(C)C.O>CC(C)=O.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH2:6]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:20])=[O:16])[CH2:11][CH2:10]1)[C:7]#[CH:8]
Reactant: CC(C)O
Reactant: C#CCC1CCC(CO)CC1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: C#CCC1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of chromium trioxide (600 mg, 6.0 mmol) in 1.5 M H2SO4 (2.6 mL, 150 mmol) was cooled to 5° C. and added to a solution of 86 (280 mg, 1.84 mmol) in acetone (15 mL). The mixture was allowed to warm to room temperature and allowed to stir overnight. Isopropanol (4 mL) was added to the green/black solution, which turned light blue after 1 hr. After adding water (15 mL), the solution was extracted with CHCl3 (6×25 mL). The organic layers were pooled and concentrated in vacuo to yield a white solid. The solid was dissolved in ether (50 mL) and extracted with 1 M NaOH (2×30 mL). The basic extracts were pooled, acidified w/10% HCl, and re-extracted with ether (3×30 mL). The ether layers were combined, dried with sodium sulfate and concentrated in vacuo to yield a white solid. The product was recrystallized from acetone/water to yield 88 (222 mg, 73%) as white needles: mp 84-85° C.; 1H NMR (CDCl3) δ 2.30-2.23 (m, 1H), 2.17-2.11 (m, 2H), 2.07-2.03 (m, 2H), 1.97-1.91 (m, 3H), 1.51-1.39 (m, 3H), 1.13-1.01 (m, 2H); 13C NMR (CDCl3) δ 182.5, 83.8, 69.6, 40.7, 37.7, 32.3, 29.6, 26.5; APCI m/z (rel intensity) 165 (M−, 100).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH2:13]>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]([CH:12]=[O:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O
Reactant: Cc1nc2ccccc2cc1O
Solvent: Cc1ccccc1C
Product: O=Cc1nc2ccccc2cc1O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
3-Hydroxy-2-methyl-quinoline (0.46 g) was suspended in xylene (30 ml), zelene dioxide (2.55 g) was added to the suspension, and the mixture was stirred at 130° C. for 30 min. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 3-hydroxyquinoline-2-carbaldehyde (124 mg, yield 25%).
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](O)=[O:5].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[F:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][C:36]=1[O:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]2[CH:44]=[C:45]([I:47])[S:46][C:39]=12)[NH2:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:29][C:30]1[CH:31]=[C:32]([NH:33][C:4](=[O:5])[CH2:3][C:2]([NH:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:1])[CH:34]=[CH:35][C:36]=1[O:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]2[CH:44]=[C:45]([I:47])[S:46][C:39]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1)Nc1ccccc1
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A solution of the acid 1 (465 mg, 2.59 mmol) and BOPCl (666 mg, 2.59 mmol) was mixed in DCM (5 mL) at 0° C. and stirred at the same temperature for 15 min. The reaction mixture was then treated with a solution of 410 (500 mg, 1.29 mmol) and iPr2NEt (1.3 mL, 1 g, 7.79 mmol) in DCM (5 mL) at 0° C. and allowed to stir at room temperature for overnight. The mixture was diluted in DCM (30 mL), washed with saturated NaHCO3 solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using the gradient 75-100% EtOAc in hexanes as an eluent, to provide 411 (382 mg, 54% yield). 1H NMR 6 (400 MHz, CD3OD): 8.33 (d, 5.7 Hz), 7.79 (dd, 1H, J=2.4 Hz, J=12.3 Hz), 7.54 (m, 5H), 7.2-7.4 (m, 4H), 7.09 (t, 1H, J=7.2 Hz), 6.50 (d, 1H, J=5.5 Hz), 3.51 (s, 2H), 7.75 (s, 1H). MS (m/z): (M+1) 547.9 (100%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([S:17]([CH2:20][C@@H:21]([N:25]1[C@H:30]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([F:38])[CH:32]=2)[C@@H:29]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[CH2:28][C@@:27]([CH2:47][C:48](O)=[O:49])([CH3:46])[C:26]1=[O:51])[CH:22]1[CH2:24][CH2:23]1)(=[O:19])=[O:18])([CH3:16])([CH3:15])[CH3:14].[NH2:52][C:53]1[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[C:55]([O:63][CH3:64])[CH:54]=1.Cl>N1C=CC=CC=1.CCOCC>[C:13]([S:17]([CH2:20][C@@H:21]([N:25]1[C@H:30]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([F:38])[CH:32]=2)[C@@H:29]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=2)[CH2:28][C@@:27]([CH2:47][C:48]([NH:52][C:53]2[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[C:55]([O:63][CH3:64])[CH:54]=2)=[O:49])([CH3:46])[C:26]1=[O:51])[CH:22]1[CH2:23][CH2:24]1)(=[O:19])=[O:18])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CC(C)(C)S(=O)(=O)C[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)c(F)c3)N([C@H](CS(=O)(=O)C(C)(C)C)C3CC3)C2=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 76 g, 398 mmol) was added to a mixture of 2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (79.4 g, 133 mmol, Example 4, Step J) and methyl 4-amino-2-methoxybenzoate (26.4 g, 146 mmol) in pyridine (332 mL) at 3° C. The mixture was allowed to warm to room temperature and was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0° C. and added to an ice-cold solution of 1 M hydrochloric acid (1 L). Ether (1 L) was added and the layers were agitated and then separated. The organic layer was washed with 1 M hydrochloric acid (6×500 mL), saturated aqueous sodium bicarbonate (500 mL), brine (500 mL), dried over magnesium sulfate, filtered and concentrated under a vacuum to provide an off-white foam.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].C(N(CC)CC)C.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O.C(O)C>[NH:13]=[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]1[CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CCl
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: N=c1ccccn1CC(=O)O
Temperature: 90 °C

Procedure:
In a 100 mL round bottom flask, 2-chloroacetic acid (10 g, 106 mmol) in water (16.3 mL) was treated with triethylamine (16.67 mL, 120 mmol) dropwise over about 6 minutes. After stirring the reaction at ambient temperature for 10 minutes, 2-aminopyridine (11.76 g, 125 mmol) was added and the mixture was heated at 90° C. for 5 hours. The reaction mixture was cooled to ambient temperature and diluted with ethanol (11 mL). The resulting suspension was stirred in an ice bath for 1 hour and filtered. The solid collected was washed with about 30 mL cold ethanol and dried under vacuum to a constant weight to provide the title compound. MS (DCI+) m/e 152.9 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2cccnc2)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A mixture of 1,3-dibenzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (34 mg, 0.071 mmol), glycine (2.85 g, 38 mmol) and NaOMe solution (57 mL, 29 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 3, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was further purified by silica gel chromatography (0-80% EtOAc/hexanes+2% AcOH) to give 20 mg of the title compound MS: (+) m/z 521.17 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:17][C:18]1[CH:25]=[C:24](F)[C:21]([C:22]#[N:23])=[CH:20][N:19]=1>CN1C(=O)CCC1>[NH2:17][C:18]1[CH:25]=[C:24]([O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])[C:21]([C:22]#[N:23])=[CH:20][N:19]=1
Reactant: COCC(C)O
Reactant: N#Cc1cnc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COCC(C)Oc1cc(N)ncc1C#N
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
1-methoxypropan-2-ol (329 mg, 3.65 mmol) was treated at room temperature with KHMDS (1M in THF, 1.82 ml, 1.82 mmol). The reaction mixture was stirred for 10 min. Then, the mixture was added to a solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 50 mg, 0.365 mmol) in NMP (0.5 ml). The solution was then heated at 50° C. for 1 h. The reaction mixture was quenched with water and diluted in EtOAc. The layers were separated and the aq. layer was extracted 3× with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated; the obtained oil was dissolved in water and lyophilized to give the title compound as a white solid. (UPLC-MS 3) tR 0.57 min; ESI-MS 208.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:14][CH2:15]Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: N#CCc1ccc(Br)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: N#CC1(c2ccc(Br)cc2)CC1
Temperature: 60 °C

Procedure:
To a room temperature solution of 4-bromophenylacetonitrile (18.0 g) in a solution of 22 mL of sodium hydroxide (50% in water W/W) were added 1-bromo-2-chloroethane and (2.0 mL) and benzyltriethylammonium chloride (627 mg). The mixture was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and diethyl ether was added (300 mL) and partitioned. The ether layer was washed with water (100 mL), hydrogen chloride (100 mL, 10% HCl in water) and brine. Then dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by swish using diethyl ether and hexanes to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:11][OH:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CCCCCC.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[Cl:1][C:2]1[S:3][C:4]([CH2:11][O:12][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=1
Reactant: OCc1sc(Cl)nc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)COCc1sc(Cl)nc1C(F)(F)F
Yield: 16.6 %

Procedure:
A mixture of 4.32 G (0.02 Mol) of the compound of Example 4, 0.1 g of Aliquat 336, 3.9 g of t-butyl bromoacetate, 50 ml of hexane, 10 g of sodium hydroxide and 24 ml of water was held at reflux for 1 hour. The reaction mixture was filtered. The hexane layer was separated, dried over MgSO4 and concentrated under reduced pressure. The residue (1.6 g) was chromatographed on silica gel using ether-petroleum ether (2:98 v/v) as eluant. The first fraction gave 1.1 g (16.5%) of t-butyl {[2-chloro-4-(trifluoromethyl)-5-thiazolyl]methoxy}acetate, as an oil, nD25 1.4607.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][C@H:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:34]=3[CH:44]=2)[C@@H:25]([C:45]2[CH:50]=[CH:49][C:48]([CH2:51][O:52][CH2:53][C@@H:54]([CH3:58])[CH2:55][O:56][CH3:57])=[CH:47][CH:46]=2)[C@H:24]([CH2:59][OH:60])[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.COC(C)(C)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:23][C@@H:24]([CH2:59][O:60][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C@H:25]([C:45]2[CH:50]=[CH:49][C:48]([CH2:51][O:52][CH2:53][C@@H:54]([CH3:58])[CH2:55][O:56][CH3:57])=[CH:47][CH:46]=2)[C@@H:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]3[O:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:34]=3[CH:44]=2)[CH2:27]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](CO)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)C[C@@H](COS(=O)(=O)c4ccc(C)cc4)[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.077 mmol of 4-methyl-benzenesulfonyl chloride are added to a solution of 6.583 mmol of (3S,4R,5R)-3-hydroxymethyl-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl) -phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (Example 1a), 9.875 mmol of triethylamine and 0.329 mmol of dimethyl-pyridin-4-yl-amine in 65 ml of dichloromethane under argon at 0° C. After overnight stirring at room temperature, the reaction mixture is diluted with tert-butyl methyl ether, washed successively with saturated aqueous sodium bicarbonate solution, water and brine, dried with sodium sulfate and evaporated. The crude title compound is obtained as a yellow oil. Rf=0.44 (EtOAc-heptane 2:1); Rt=5.94 (gradient I).