Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=O.[NH2:5][C:6]([NH:8][N:9]([CH2:18][C:19]([O:21]C)=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1)=[O:7].C[O-].[Na+].C[O-]>CO>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH2:18][C:19](=[O:21])[NH:5][C:6](=[O:7])[NH:8]2)=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCc1ccc(N(CC(=O)OC)NC(N)=O)cc1
Agent: C[O-]
Agent: NC(N)=O
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(N2CC(=O)NC(=O)N2)cc1
Reaction time: 2 h
Yield: 29.9 %

Procedure:
The urea (Intermediate 62 2.2 g, 8.6 mmol) and sodium methoxide (567 mg, 10.5 mmol) were stirred in methanol (10 ml) for 3 h. After this time, a second amount of methoxide (100 mg, 1.9 mmol) was added and the reaction was left to stir for 2 h. The reaction mixture was then quenched with 2N HCl to pH7. The solid formed was filtered, and then recrystallised (methanol/dioxan) to give the title compound (563 mg, 29%)
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:13]([O-])=[CH:14][C:15](=O)[C:16]([O:18]CC)=[O:17])[CH:6]=[C:7]([O:9][CH:10]([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][NH2:53])[CH:47]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:13]2[N:52]([C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)[N:53]=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=2)[CH:6]=[C:7]([O:9][CH:10]([F:11])[F:12])[CH:8]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)F)c2)n(-c2cccnc2)n1

Procedure:
247 mg (0.67 mmol) of the compound of Example 9A is reacted analogously to the synthesis of the compound of Example 20A with 145 mg (1.00 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 51 mg (19% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21](O)=[O:22].C(OC([NH:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21]([N:34]1[CH2:35][CH2:36][CH:32]([NH2:31])[CH2:33]1)=[O:22]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Product: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)N2CCC(N)C2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid (Example 36) and 3-(tert-butoxycarbonylamino)pyrrolidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](B1OC(C)(C)C(C)(C)O1)([CH3:30])=[CH2:29].C([O-])([O-])=O.[Cs+].[Cs+]>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]([CH3:30])=[CH2:29])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: C[C@@H]1CN(CC(=O)N2CCc3ccc(Br)cc32)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Temperature: 85 °C
Yield: 80.5 %

Procedure:
Pd(PPh3)4 (32 mg, 0.03 mmol), (R)-4-[2-(6-bromo-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (246 mg, 0.56 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (113 mg, 0.67 mmol) were dissolved in DMF (1.87 mL). Cs2CO3 (549 mg, 1.7 mmol) dissolved in water (0.37 mL) was added to the DMF solution. The reaction was degassed and heated to 85° C. for 18 h then was filtered and concentrated. Column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), gave (R)-4-[2-(6-isopropenyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g) as a yellow oil. 10% Pd/C (48 mg, 0.05 mmol) and (R)-4-[2-(6-isopropenyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g) were mixed with MeOH (4.5 mL). The reaction was hydrogenated at 1 bar for 30 min at ambient temperature then filtered under vacuum and concentrated, to give the title compound (157 mg, 86%) as a colourless oil. 1H NMR (Me-d3-OD): 8.08 (1H, s), 7.15 (1H, d), 6.95 (1H, d), 4.35-4.18 (3H, m), 3.83 (1H, d), 3.30 (2H, s), 3.25-3.12 (3H, m), 2.97-2.76 (3H, m), 2.33 (1H, dd), 2.20-2.08 (1H, m), 1.48 (9H, s), 1.31 (3H, d), 1.25 (6H, d).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[Cl:22][C:23]1[S:27][C:26]([CH2:28][NH2:29])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CC(N(C)C)=O>[Cl:22][C:23]1[S:27][C:26]([CH2:28][NH:29][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([CH3:20])=[C:15]([CH:17]5[CH2:19][CH2:18]5)[N:16]=4)[CH:13]=3)[C:4](=[O:21])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccc(Cl)s1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(NCc4ccc(Cl)s4)cc3=O)cn12
Temperature: 120 °C
Yield: 24 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (30 mg), 1-(5-chloro-2-thienyl)methanamine (20 mg), tris(dibenzylideneacetone)dipalladium(0) (2.0 mg), cesium carbonate (57 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3 mg) and DMA (0.4 ml) was heated at 120° C. for 1 h under microwave irradiation. To this mixture was added water, and the precipitate was collected by filtration. The resulting solid was recrystallized from EtOAc-hexane-EtOH to give the title compound (8.6 mg) as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1.[OH:21]O>C(O)(=O)C>[NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11](=[O:21])[C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1
Reactant: OO
Reactant: c1ccc2c(c1)CCc1ccc(-c3nnn[nH]3)cc1S2
Solvent: CC(=O)O
Product: O=S1c2ccccc2CCc2ccc(-c3nnn[nH]3)cc21

Procedure:
A mixture of 600 mg. of 10,11-dihydro-3-(5-tetrazolyl)dibenzo[b,f]thiepin, 25 cc. acetic acid and 5 cc. 30% hydrogen peroxide is stirred for 6 hours. The suspended solid is filtered, washed with acetic acid, then water and dried to yield 575 mg. of pure material, m.p. 287° C. dec.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH:14]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15][CH2:16][N:17]2[C@H:22]3[CH2:23][CH2:24][C@@H:18]2[CH2:19][CH:20]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[CH2:21]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].C([O-])([O-])=[O:44].[K+].[K+]>C(O)(C)(C)C>[CH3:34][C:26]1[N:25]([CH:20]2[CH2:21][C@H:22]3[N:17]([CH2:16][CH2:15][CH:14]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:13][NH:12][S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:44])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[C@H:18]([CH2:24][CH2:23]3)[CH2:19]2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(CNS(=O)(=O)c1ccc(C#N)cc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(CNS(=O)(=O)c1ccc(C(N)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a suspension of the title compound from example 4 (63 mg, 0.11 mmol) in t-butanol (1 mL) was added 1M NaOH (0.28 mL) and the reaction stirred at room temperature for 2 h, followed by heating to 80° C. for 2 h. The reaction was cooled to room temperature and partitioned between ethyl acetate and pH 8 buffer solution. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse-phase HPLC eluting with 10-90% water/acetonitrile/0.1% TFA. The title compound (40 mg, 63% yield) was obtained as a white solid (free-based with K2CO3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COc1ccc(-c2ccc(C#N)c(F)c2)cc1
Agent: BrB(Br)Br
Product: N#Cc1ccc(-c2ccc(O)cc2)cc1F
Yield: 95 %

Procedure:
The product from Example 166A and 1.0M BBr3 were processed as described in Example 164B to provide the title compound (95% yield). 1HNMR (300 MHz, CDCl3) δ4.95 (s, 3H), 6.80-7-55 (m, 7H); MS (DCI) m/z 214 (M+H)+.
Reaction SMILES: [Na].[C:2]1([CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1)[OH:3].Cl[CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].[Cl-].[NH4+]>O.CN(C)C=O>[CH3:15][O:14][CH:13]([O:16][CH3:17])[CH2:12][CH2:11][O:3][C:2]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: COC(CCCl)OC
Reactant: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCOc1ccc(O)cc1)OC
Temperature: 90 °C

Procedure:
The monosodium salt of hydroquinone (0.05 mole) and dimethylformamide (75 ml) are charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture is stirred until dissolved, and 1-chloro-3,3-dimethoxypropane (0.05 mole) is added dropwise over a period of about 20 minutes. After the addition is completed, the reaction mixture is heated at about 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) is added, and the reaction mixture is carefully neutralized with ammonium chloride. The reaction mixture is then extracted with chloroform, and the organic phase is separated from the aqueous phase. The organic phase is then stripped of solvent, leaving an oil. This oil is distilled under reduced pressure to yield the desired product 4-(3,3-dimethoxypropoxy)phenol.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)[CH3:2].[CH2:18]([SH:21])[CH2:19][SH:20].B(F)(F)F.CCOCC.CC(O)=O>ClCCl>[OH:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([C:1]2([CH3:2])[S:21][CH2:18][CH2:19][S:20]2)[CH:9]=1
Reactant: SCCS
Reactant: CCOC(=O)CCc1ccc(O)cc1C(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(O)cc1C1(C)SCCS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed ethyl 3-(2-acetyl-4-hydroxyphenyl)propanoate (200 mg, 0.85 mmol, 1.00 equiv), dichloromethane (10 mL), ethane-1,2-dithiol (398 mg, 4.23 mmol, 5.00 equiv), BF3/Et2O (597 mg, 4.23 mmol, 5.00 equiv), AcOH (542 mg, 9.03 mmol, 8.00 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:2). This resulted in 150 mg (57%) of ethyl 3-[4-hydroxy-2-(2-methyl-1,3-dithiolan-2-yl)phenyl]propanoate as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.I[CH2:19][CH2:20][CH3:21].[BH4-].[Na+]>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH:17]=1
Reactant: CCCI
Reactant: CS(=O)(=O)c1cccc(-c2ccncc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Product: CCCN1CC=C(c2cccc(S(C)(=O)=O)c2Cl)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To neat 4-[2-chloro-3-(methylsulfonyl)phenyl]-pyridine (1.0 g, 3.8 mmol) was added 1-iodopropane (5 ml) and the resulting mixture was heated at 100° C. for 2 h. Excess 1-iodopropane was evaporated under reduced pressure and ethanol (60 ml) was added. The mixture was cooled to −20° C. and sodium borohydride (1.3 g, 38 mmol) was added in portions. The resulting mixture was stirred for 1 h, after which aqueous sodium carbonate (10%, 50 ml) was added. The aqueous phase was extracted with ethylacetate (3×100 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.5 g). MS m/z (rel. intensity, 70 eV) 313 (M+, 18), 286 (39), 285 (17), 284 (bp), 128 (12).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:26]#[N:27])(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:11][CH:12]=2)[C:26]#[N:27])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1Cl
Product: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1Cl

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3-chloro-4-methoxybenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 64%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[CH2:12]([O:19][C:20]([C:22]1[C@H:23]2[CH2:31][CH:30]=[C:29]([CH3:32])[C@@H:24]2[C@@H:25]([OH:28])[O:26][CH:27]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[CH2:12]([O:19][C:20]([C:22]1[C@H:23]2[CH2:31][CH:30]=[C:29]([CH3:32])[C@@H:24]2[C@H:25]([O:28][C:10](=[O:11])[NH:9][CH3:8])[O:26][CH:27]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN=C=O
Reactant: CC1=CC[C@@H]2C(C(=O)OCc3ccccc3)=CO[C@H](O)[C@@H]12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OCc2ccccc2)[C@H]2CC=C(C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
9.2 ml of triethylamine and 2.4 ml of methylisocyanate were added to an acetonitrile solution containing 4.98 g of (1S,4aS,7aR)-1-hydroxy-7-methyl-1,4a,5,7a-tetrahydrocyclopenta [c]-pyrane-4-carboxylic acid benzyl ester followed by stirring for 1 hour at room temperature. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ethyl acetate eluate in the form of (1S,4aS,7aR)-7-methyl-1-(methylcarbamoyloxy)-1,4a,5,7a-tetrahydrocyclopenta [c]-pyrane-4-carboxylic acid benzyl ester of 5.10 g (yield: 86%). The physicochemical properties of this compound are shown below.
Reaction SMILES: [NH:1]([CH2:5][CH2:6]O)[CH2:2][CH2:3][OH:4]>O>[OH:4][CH2:3][CH2:2][N:1]1[CH2:6][CH2:5][N:1]([CH2:2][CH2:3][OH:4])[CH2:6][CH2:5]1
Reactant: OCCNCCO
Solvent: O
Product: OCCN1CCN(CCO)CC1

Procedure:
170.8 g of diethanolamine (1.63 mol) is added, and after 6 hours of reaction, 30 g of water that contains 2.3 g of diethanolamine is recovered. The residual acid index is equal to 1.4 mg of KOH/g of product, and the content of N,N′-bis (2-hydroxyethyl) piperazine that is obtained by chromatographic analysis is 2.8%. 448 g of product that can be used directly as is or after dilution that is aimed at appreciably reducing viscosity so that it can be handled easily is recovered in fine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([F:20])=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.CN(C)CCCN=C=NCC.[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([F:20])=[C:17]([Cl:19])[CH:18]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.8 %

Procedure:
5-Chloro-4-(5-chloro-6-fluoropyridin-3-yloxy)-2-fluorobenzoic acid (Preparation 162, 6.100 g, 19.60 mmol), 4-dimethylaminopyridine (2.330 g, 19.06 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (5.480 g, 28.59 mmol) and methanesulfonamide (2.720 g, 28.59 mmol) were suspended in DCM (20 mL). The reaction mixture was stirred at room temperature for 18 hours, quenched with aqueous 1M HCl and extracted with EtOAc. Combined organics were concentrated in vacuo. The resulting residue was purified by reverse phase chromatography to afford the title compound as a white solid (4.50 g):
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:55][C@@H:56]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]3C=CC=CC=3)=[C:60]([NH:72][S:73]([CH2:76]CC3C=CC=CC=3)(=[O:75])=[O:74])[CH:59]=2)[OH:57])[CH2:26][C@H:27]([OH:54])[C:28]2[CH:33]=[CH:32][C:31]([O:34]CC3C=CC=CC=3)=[C:30]([NH:42][S:43]([CH2:46]CC3C=CC=CC=3)(=[O:45])=[O:44])[CH:29]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1.C[OH:86]>C(O)(=O)C.[OH-].[OH-].[Pd+2].ClCCl>[C:65]([OH:86])(=[O:64])[CH3:66].[C:65]([OH:86])(=[O:64])[CH3:66].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:55][C@H:56]([OH:57])[C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[C:60]([NH:72][S:73]([CH3:76])(=[O:74])=[O:75])[CH:59]=2)[CH2:26][C@@H:27]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=2)[OH:54])=[CH:19][CH:20]=1
Reactant: CO
Reactant: O=C(NCCCCc1ccc(CCCCN(C[C@H](O)c2ccc(OCc3ccccc3)c(NS(=O)(=O)CCc3ccccc3)c2)C[C@H](O)c2ccc(OCc3ccccc3)c(NS(=O)(=O)CCc3ccccc3)c2)cc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN(CCCCc2ccc(CCCCN)cc2)C[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of (4-{4-[4-(bis-{2-[3-(benzylmethanesulfonylamino)-4-benzyloxyphenyl]-2-(R)-hydroxyethyl}amino)butyl]phenyl}butyl)carbamic acid benzyl ester (38) (0.45 g, 0.383 mmol), palladium dihydroxide (0.12 g, 10% Pd(OH)2 on carbon, 50% wet), ten drops of acetic acid, methanol (12 mL), and dichloromethane (6 mL) was stirred at rt for 18 h under atmospheric hydrogen pressure. The catalyst was removed by vacuum filtration through a Celite pad and the filtrate was concentrated by rotary evaporation and further dried under high vacuum to give the desired amine diacetic acid salt 41 as a white solid (0.30 g, 98%): m/z (ESI) 679 [C32H42N4O6+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>>[F:23][C:3]1[C:2]([C:33]#[C:32][C:30]([OH:34])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH3:31])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1ccccn1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(O)c3ccccn3)cc1-2
Yield: 10 %

Procedure:
10-bromo-9-fluoro-N3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with 2-(pyridin-2-yl)but-3-yn-2-ol via General Procedure E to yield 8.4 mg (10%) of (±)-9-fluoro-10-[3-hydroxy-3-(2-pyridyl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20]C(C)C)=[O:19])[C:12]2=[CH:11][CH:10]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([OH:20])=[O:19])[C:12]2=[CH:11][CH:10]=1)=[O:8]
Reactant: CC(C)OC(=O)C1CCCn2c(C(=O)c3cccn3C)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cn1cccc1C(=O)c1ccc2n1CCCC2C(=O)O

Procedure:
A mixture of 0.314 g. of isopropyl 3-(N-methyl-2-pyrroyl)-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate, 0.28 g. of potassium carbonate and 10 ml. of a (1:1) methanol-water mixture is refluxed under nitrogen atmosphere for 3 hours, cooled, and evaporated to dryness. The residue is taken up in 50 ml. of water and extracted with ethyl acetate (3×10 ml.). The aqueous solution is acidified with 10% hydrochloric acid and extracted with ethyl acetate (10×15 ml.). The combined extracts are washed with saturated sodium chloride solution dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure, to afford 3-(N-methyl-2-pyrroyl)-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid, (XIVa, R=H, Q=CH3, n=2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=1.[CH2:16]([N:18]([CH2:39][CH3:40])[C:19](=[O:38])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCCl.O>[CH2:39]([N:18]([CH2:16][CH3:17])[C:19](=[O:38])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([F:15])[CH:3]=3)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:40]
Reactant: CCN(CC)C(=O)COc1cc(C)c(-c2cccc(C=O)c2)c(C)c1
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(OCC(=O)N(CC)CC)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a solution of ethyl 3-(4-amino-2-fluorophenyl)propanoate (0.496 g, 2.35 mmol) and N,N-diethyl-2-[(3′-formyl-2,6-dimethylbiphenyl-4-yl)oxy]acetamide (0.725 g, 2.14 mmol) in 1,2-dichloroethane (10 mL) was added acetic acid (0.245 mL, 4.28 mmol), and the mixture was stirred at room temperature for 3 hr. Sodium triacetoxyborohydride (0.907 q, 4.28 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. Water and 10% aqueous citric acid solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-70% ethyl acetate/hexane) to give the title compound (0.978 g, yield 86%) as a yellow oil.