Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](Cl)=[O:13])[C:10]3[N:15]=[CH:16][CH:17]=[CH:18][C:9]=3[NH:8][C:7](=[O:19])[C:6]=2[CH:20]=1.[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([NH:35][CH2:34][CH2:33][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]3[CH2:26][N:23]([CH2:21][CH3:22])[CH2:24][CH3:25])=[O:13])[C:10]3[N:15]=[CH:16][CH:17]=[CH:18][C:9]=3[NH:8][C:7](=[O:19])[C:6]=2[CH:20]=1
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccc(Cl)cc21
Solvent: ClCCCl
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccc(Cl)cc2C(=O)Nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.1 g (0.01 mol) of 8-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 2.6 g (0.0122 mol) of 2-[2-[(diethylamino)methy]-piperidin-1-yl]ethanamine and 310 ml of 1,2-dichloroethane was stirred for 21/2 hours at ambient temperature, then extracted exhaustively with dilute hydrochloric acid. The combined aqueous extracts were made alkaline with saturated aqueous potassium carbonate solution and extracted exhaustively with dichloromethane. The dichloromethane phases were combined, dried over sodium sulphate with the addition of 1 g of animal charcoal and evaporated down in vacuo. After being triturated with diisopropylether the oily residue became crystalline and was recrystallised from acetonitrile. 2.9 g (60% of theory) of colourless crystals were obtained, m.p. 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][C@H:18]([C:20]([O:22]C(C)(C)C)=[O:21])[CH3:19])=[O:16])=[C:5]2[OH:27].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])=[O:16])=[C:5]2[OH:27]
Reactant: C[C@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O)C(=O)O
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To 1,1-dimethylethyl N-((6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)-L-alaninate (320 mg, 812 μmol) was added TFA (2 mL) at ambient temperature. The mixture was stirred for 30 minutes and was then concentrated, precipitated with hexanes, filtered, washed, and dried in a vacuum oven to give the title compound (220 mg) as a white solid. MS (m/z)=338 (M+H)+. Calculated for C16H16ClNO5 337.07.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[CH:12]([OH:18])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].I[CH3:24]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:10]2[C:11]3[CH:12]([O:18][CH3:24])[CH2:13][CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)CC3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(OC)CC3
Yield: 112.3 %

Procedure:
To a stirred solution of the product from step (a) (45 mg, 0.16 mmol) in DMF (2 ml) at RT over an argon atmosphere was added NaH (16 mg, 0.41 mmol). The reaction mixture was stirred until gas evolution had ceased and then iodomethane (0.025 ml, 0.41 mmol) was added. The reaction mixture was stirred at RT for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate extracts were washed with brine, dried (Na2SO4), and solvent evaporated in vacuo to give the sub-titled compound as a colorless oil (52 mg). MS: ESI (positive): 290 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CCNCC
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
The compound from Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of diethylamine (469 mg, 6.41 mmol) in CH2Cl2. Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 50% EtOAc/hexane giving a yellow oil (1.1 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH3:22][CH:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH2:31])[CH:26]=1)[CH3:24]>>[CH:23]([C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:26]=1)([CH3:24])[CH3:22]
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Reactant: CC(C)c1cc(CN)no1
Product: CC(C)c1cc(CNC(=O)c2ccc(OCC3CC3)c(-c3ccc(Cl)cc3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 41 using 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAN 154016-49-6) as starting materials, LC-MS (peak area/EIC) 98.2%, 426.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH2:17])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19]O>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH2:17])[C:13]([O:15][CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 2(S)-benzyloxycarbonylamino-3-aminopropionoic acid (2.4 g) in methanol at 0° C. was saturated with HCl gas. After stirring for 2 h at 20° C. the solution was evaporated to obtain the title compound. 1H NMR (300 MHz, CD3OD ) δ 7.35 (5H, m), 5.13 (2H, s), 4.50 (1H, m), 3.77 (3H, s), 3.45 (1H, m), 3.22 (1H, m).
Reaction SMILES: C(O[C@H:5]1[C@@H:10]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:9][C@H:8]2[C@H:17]3[C@H:27]([CH2:28][CH2:29][C@:6]12[CH3:7])[C@:25]1([CH3:26])[C@H](CCC(=O)[CH2:24]1)CC3)(=O)C.[OH2:31]>N1CCCCC1.C(O)=O>[N:11]1([C@H:10]2[CH2:24][C@@:25]3([CH3:26])[C@@H:6]([CH2:29][CH2:28][C@@H:17]4[C@@H:27]3[CH2:28][CH2:29][C@@:6]3([CH3:7])[C@H:8]4[CH2:9][C@H:10]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[C@@H:5]3[OH:31])[CH2:8][CH2:9]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O
Reactant: CC(=O)O[C@H]1[C@@H](N2CCCCC2)C[C@H]2[C@@H]3CC[C@H]4CCC(=O)C[C@]4(C)[C@H]3CC[C@@]21C
Solvent: C1CCNCC1
Solvent: O=CO
Product: C[C@]12C[C@H](N3CCCCC3)CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Temperature: 25 °C

Procedure:
A solution of 17β-acetyloxy-16β-(1-piperidinyl)-5α-androstan-2-one (8.24 g) in piperidine (36 ml) and formic acid (12 ml) was heated at reflux temperature under a nitrogen (oxygen-free) atmosphere for 4.5 h. When the solution had cooled to room temperature, water (50 ml) was added to precipitate the product, which was filtered off and washed well with water (300 ml). A solution of the crude product in diethyl ether (60 ml) was washed with water (2×100 ml), dried (MgSO4) and evaporated to dryness. Crytsllisation of the residue from acetone afforded 2β,16β-di-(1-piperidinyl)-5α-androstan-17β-ol (4.17 g), m.p. 176°-181° C.; [α]D +41.3° (c 0.59 in CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:19][CH2:18][C:17]4[S:20][C:21](=[O:23])[NH:22][C:16]=4[CH2:15][CH2:14]3)=[O:12])[CH:10]=2)[CH:7]=1.[CH3:24]I.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:19][CH2:18][C:17]4[S:20][C:21](=[O:23])[N:22]([CH3:24])[C:16]=4[CH2:15][CH2:14]3)=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CI
Reactant: O=C(c1cc2ncc(Br)cn2n1)N1CCc2[nH]c(=O)sc2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(sc1=O)CCN(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
30.0 mg (0.076 mmol) 6-(6-bromo-pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3,4,5,6,7,8-hexahydro-thiazolo[4,5-d]azepin-2-one, 6.3 μL (0.099 mmol) methyliodide, 3.7 mg (0.084 mmol) sodium hydride (50%) in 1.0 mL DMF were stirred at RT for 1 h. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 5 mg (16% of theory). ESI-MS: m/z=408 (M+H)+; Rt(HPLC): 0.95 min. (Method N).
Reaction SMILES: I[CH2:2][CH2:3][OH:4].C(=O)(O)[O-].[Na+].[C:10]([C@@H:13]1[CH2:17][C@H:16]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:15][NH:14]1)(=[O:12])[NH2:11]>CN(C)C=O>[C:10]([C@@H:13]1[CH2:17][C@H:16]([S:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:15][N:14]1[CH2:2][CH2:3][OH:4])(=[O:12])[NH2:11]
Reactant: OCCI
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(CCO)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
0.175 ml of 2-iodoethanol and 0.16 g of sodium bicarbonate were added, whilst ice-cooling, to a solution of 0.5 g of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in preparation 1-(5)] dissolved in 5 ml of dry dimethylformamide, and the mixture was stirred at the same temperature for 1 hour, at room temperature for 2.5 hours, and at 40° C. for 19 hours. The reaction mixture was then poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was subjected to column chromatography through silica gel (Wako Pure Chemicals, Ltd.; Wako gel C-100). 0.465 g of the title compound was obtained as crystals from the fractions eluted with a 95:5 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[C:13]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]3[N:7]=2)[CH2:5][CH2:4]1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH2:27]([O:1][CH2:2][C:3]1([C:6]2[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[C:13]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]3[N:7]=2)[CH2:5][CH2:4]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(CO)CC3)nc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(COCc4ccccc4)CC3)nc12
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere [1-(5-Iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropyl]-methanol (compound 150)(0.033 g, 0.06 mmol) was dissolved in DMF (0.5 mL). NaH (0.014 g, 0.36 mmol) was added and the suspension was heated at 65° C. for 1 h after which benzyl bromide (0.071 mL, 0.6 mmol) was added. The reaction mixture was stirred at 65° C. for 30 min after which is was cooled to rt. Aq. NaHCO3 and H2O was added. The aqueous phase was extracted with EtOAc (×2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica using DCM:MeOH 99:1 as eluent to afford the title compound as a solid.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[N:17]1([CH2:21][C@@H:22]([NH2:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:21][C@@H:22]([NH:30][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: N[C@H](CN1CCC1)c1ccc(Cl)cc1
Agent: Cl
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(Cl)cc3)ncnc12

Procedure:
Compound 36 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(4-chloro-phenyl)-ethylamine dihydrochloride to give the title compound as an off-white solid. LC/MS [383 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.27-8.84 (m, 2H), 8.53 (s, 1H), 8.37 (d, J=4.4 Hz, 1H), 8.17 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 5.37-4.98 (m, 2H), 3.16-2.94 (m, 3H), 2.78 (dd, J=11.9, 5.3 Hz, 1H), 2.07-1.65 (m, 2H).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=NNC=1)=O.[F:33][C:34]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([F:53])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37]>>[F:33][C:34]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([F:53])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][C:14]=3[N:13]=2)=[N:41][NH:42][CH:43]=1)=[O:37]
Reactant: COc1cc(F)c(C(=O)Nc2c[nH]nc2C(=O)O)c(F)c1
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: COc1cc(F)c(C(=O)Nc2c[nH]nc2-c2nc3cc(CN4CCOCC4)ccc3[nH]2)c(F)c1

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-(2,6-difluoro-4-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid to give 2,6-difluoro-4-methoxy-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (32 mg) as a pink solid. (LC/MS: Rt 1.99, [M+H]+ 469.21).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[CH:7]=1)=[O:5])C.[OH-].[K+].Cl>CCO.O>[CH3:21][O:20][C:15]1[CH:14]=[C:13]([CH:12]=[CH:11][C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:10][N:9]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: CCOC(=O)c1cc(C=Cc2ccc(O)c(OC)c2)n[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C=Cc2cc(C(=O)O)[nH]n2)ccc1O
Temperature: 25 °C
Yield: 67.8 %

Procedure:
Ethyl-3-[β-(3-methoxy-4-hydroxyphenyl)ethenyl]-1H-pyrazole-5-carboxylate (0.49 g, 1.7 mmoles) is added to a solution of KOH (0.38 g, 6.8 mmoles) in 0 ml EtOH. The reaction is warmed to reflux overnight. After cooling to room temperature, the reaction is diluted to 200 ml with H2O, and acidified to pH=4 with HCl. A white precipitate forms, and it is collected by filtration. Drying in vacuum in the presence of P2O5 gives 0.3 g (68%) of the desired product, mp=270°-271° C. (dec).
Reaction SMILES: C([O:8][C:9](=[O:50])[CH2:10][CH:11]([NH:21][C:22]([CH:24]1[N:29]2[C:30](=[O:49])[CH:31]([NH:36][C:37]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=3)=[O:38])[CH2:32][CH:33]=[CH:34][CH2:35][CH:28]2[CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])C1C=CC=CC=1.O>CO.[OH-].[Na+]>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][CH2:12][CH:11]([NH:21][C:22]([CH:24]1[N:29]2[C:30](=[O:49])[CH:31]([NH:36][C:37]([C:39]3[CH:48]=[CH:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=3)=[O:38])[CH2:32][CH:33]=[CH:34][CH2:35][CH:28]2[CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:10][C:9]([OH:50])=[O:8])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC(CC(=O)OCc1ccccc1)NC(=O)C1CCCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC(CC(=O)O)NC(=O)C1CCCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Reaction time: 5 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-3-({7-[(naphthalene-2-carbonyl)-amino]-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carbonyl}-amino)-butyric acid benzyl ester, 114, (0.52 gm) is dissolved in 10 mL methanol, to which 1.73 mL of 1N aqueous sodium hydroxide is added at RT. The reaction is stirred for 5 h and a second aliquot (0.7 mL) of 1N sodium hydroxide solution is added. The reaction is allowed to proceed for 18 h at RT. Water is added and the mixture is extracted three times with diethyl ether. The aqueous layer is then acidified to pH ˜3 with 10% aqueous citric acid, and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate powder, and concentrated in vauo to afford the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([Cl:26])=[CH:18][C:17]=2[C:27](=[O:38])[NH:28][C:29]([C:33]([O:35]CC)=[O:34])([CH3:32])[CH2:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([Cl:26])=[CH:18][C:17]=2[C:27](=[O:38])[NH:28][C:29]([C:33]([OH:35])=[O:34])([CH3:32])[CH2:30][CH3:31])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)(NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
A solution of 41 mg of 4-[4-chloro-2-(1-ethoxycarbonyl-1-methyl-propylcarbamoyl)-naphthalen-1-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (see example 160, step a)) in 4 mL THF and 1 mL MeOH was treated with 4 mL of 2 M aqueous sodium hydroxide. The reaction mixture was stirred at room temperature overnight. The organic solvent was removed in vacuo. The residue was taken up in 6 ml of water and washed with ethyl acetate. It was treated with 2 M hydrochloric acid to adjust the pH to 5-6 and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated to give 12 mg of 4-[2-(1-carboxy-1-methyl-propylcarbamoyl)-4-chloro-naphthalen-1-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([O:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1OC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1OC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution of tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yloxy}piperidine-1-carboxylate (0.020 g, 0.041 mmol) in methylene chloride (3.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (3.0 mL), and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was azeotroped twice with toluene under reduced pressure. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(piperidin-4-yloxy)benzofuran-3(2H)-one (0.016 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:19][C:17](=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C[OH:21].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH:14]([OH:19])[CH2:15][CH2:16][C:17]([OH:18])=[O:21])=[CH:12][CH:13]=1
Reactant: O=C1CCC(c2ccc(-c3ccccc3Cl)cc2)O1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 5.44 gm (0.02 mol) of γ-(2'-chloro-4-biphenylyl)-γ-butyrolactone (b.p. 212°-213° C. at 0.03 mm Hg), 50 ml of methanol, 1 gm of sodium hydroxide and 2 ml of water was boiled for 2 hours. The reaction mixture was then evaporated, the residue was distributed between dilute hydrochloric acid and ethyl acetate, and the cyclohexylamine salt was precipitated from the washed and dried ethyl acetate solution. Yield: 5.8 gm m.p. of the cyclohexylamine salt: 158°-159° C. (from water).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[S:7][CH3:8].ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[S:7]([CH3:8])=[O:17]
Reactant: CSc1ccsc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of compound 25 (3.64 g, 17.4 mmol) in CH2Cl2 (100 mL) at −40° C., was added 3-chloroperbenzoic acid (3 g, 17.4 mmol) in CH2Cl2 (50 mL) dropwise and the resulting solution was allowed to stir at room temperature overnight. The reaction mixture was washed with aqueous Na2CO3, dried with anhydrous sodium sulfate and evaporated in vacuum. Column chromatography (silica gel, hexane/EtOAc (1/2) yields the pure compound 26 (2.74 g, 70%). 1H NMR (CDCl3): δ 2.82 (3H, s), 7.35 (1H, d), 7.43 (1H, d). MS (EI): calcd, 225.1. found M+, 210.1=product-16).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[O:25]([C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Oc2ccccc2)nc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 88.6 %

Procedure:
To a solution of ethyl 2-chloropyrimidine-5-carboxylate (0.5 g, 2.7 mmol) in N,N-dimethylformamide (6.0 mL) was added cesium carbonate (676 mg, 2.1 mmol) and phenol (205 mg, 2.18 mmol). The mixture was stirred at 100° C. for 24 hours. The mixture was concentrated in vacuo. To the residue, was added water (50 mL) and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulphate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20/1) to give the product ethyl 2-phenoxypyrimidine-5-carboxylate (472 mg, 81%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 8.55 (s, 2H), 7.43-7.06 (m, 5H), 4.29 (q, J=8.9 Hz, 2H), 1.31 (t, J=8.9 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH2:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20](Cl)[N:19]=[CH:18][N:17]=1.C(N(CC)C(C)C)(C)C.C(O)C>>[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:12][CH:10]([C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Br:1])[C:3]=2[O:13][CH3:14])[CH3:11])[N:19]=[CH:18][N:17]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COc1c(C(C)N)cc(Cl)c(F)c1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1c(C(C)Nc2ncnc(N)c2C#N)cc(Cl)c(F)c1Br
Temperature: 100 °C
Yield: 54 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanamine (40 mg, 0.14 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (J & W PharmLab, #70-0156 33 mg, 0.21 mmol) and N,N-diisopropylethylamine (74 μL, 0.43 mmol) in ethanol (1.6 mL, 27 mmol) was heated at 100° C. overnight. Purification by preparative LC/MS (pH10) gave the desired compound (54% yield). LCMS calculated for C14H13BrClFN5O (M+H)+: m/z=400.0, 402.0. found: 400.0, 402.0. 1H NMR (300 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.77 (m, 1H), 7.28 (br s, 2H), 5.56 (m, 1H), 3.92 (s, 1H), 1.40 (m, 3H).