Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[CH3:30])=[O:12])[C:7]=1[C:8](O)=[O:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(OC)(C)(C)C>[I:1][C:2]1[C:7]2[C:8](=[O:9])[O:12][C:11](=[N:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:29])([C:25]([F:26])([F:27])[F:28])[C:21]([F:23])([F:24])[F:22])=[CH:16][C:15]=3[CH3:30])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1cccc(I)c1C(=O)O
Solvent: COC(C)(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N=C1OC(=O)c2c(I)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
In methyl t-butyl ether (60 ml) was suspended 5.47 g (10 mmol) of 6-iodo-N-{2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl}phthalamic acid, and a solution of 3.15 g (15 mmol) of trifluoroacetic anhydride in methyl t-butyl ether was slowly dropped thereinto. The resulting mixture was stirred at room temperature for 3 hours and then poured into ice water, followed by three runs of extraction with ethyl acetate. The extract solution was washed twice with saturated aqueous sodium hydrogencarbonate solution and then once with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and the crude crystals thus obtained were washed twice with a solvent (hexane:ethyl acetate=4:1) to obtain 5.0 g (yield 94%) of 1,3-dihydro-7-iodo-3-{2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoro-methyl)ethyl]phenylimino}-2-benzofuran-1-one.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:21]([C:25](O)=[O:26])[CH:22]([CH3:24])[CH3:23].CC(C)N=C=NC(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:1]1([C:7]2([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:25]([CH:21]([NH:20][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH:22]([CH3:24])[CH3:23])=[O:26])=[CH:17][CH:18]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Reaction time: 19 h

Procedure:
To a stirred solution at room temperature of 4-(1-phenylcyclohexyl)phenol (311 mg, 1.23 mmol) in dry THF (2 mL) was added BocValOH (295 mg, 1.36 mmol) dissolved in THF (2 mL). A solution of DIC (231 μL; 1.48 mmol) in THF (2 mL) was added drop wise, which caused precipitation after a few minutes. After 5 min DMAP (166 mg; 1.36 mmol) was added and stirring was continued for 19 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography (eluent: EtOAc (0-10%) in heptane) affording 517 mg (1.14 mmol; 93%) of colourless oil. LC-MS purity (UV/MS): 100/100%, Rt 6.77 min, M+18: 469.53.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]3[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1>C(OCC)(=O)C.CO>[ClH:1].[N:2]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C@@H:17]3[O:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(OCCCN3CCCC3)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: c1cc([C@H]2CNCCO2)ccc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Hydrogen chloride in ethyl acetate solution (4N) was added to a solution of tert-butyl (2S)-2-(4-(3-(pyrrolidin-1-yl)propyloxy)phenyl)morpholine-4-carboxylate (1.13 g, 2.89 mmol) in methanol. The mixture was stirred for one hour at room temperature and the solvent was evaporated under reduced pressure to give a white solid, which was recrystallized from ethanol to afford (2S)-2-(4-(3-(pyrrolidin-1-yl)propyloxy)phenyl)morpholine hydrochloride (0.9 g, 86%) as white crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[C:6]2[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=12.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C(OCC)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:6]3[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cn(C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Solvent: CCOCC
Product: Cc1cn(C)c2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCOCC3)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 1-(7-chloro-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-morpholin-4-yl-methanone (100 mg) and using 3-chloroaniline (72 ul) instead of 3-bromoaniline. Isolated by MDAP rather than trituration with diethyl ether to give 1-[7-(3-chloro-phenylamino)-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-morpholin-4-yl-methanone (69 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:41](=[O:42])[C:40]3[CH:44]=[CH:45][C:37]([Cl:36])=[CH:38][CH:39]=3)=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
{4′-Amino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (0.08 g, 0.2 mmol), 4-chlorobenzoyl chloride (0.04 mL, 0.3 mmol), and triethylamine were reacted in CH2Cl2 to give the title compound.
Reaction SMILES: [CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:24]([O:26]CC)=[O:25])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O.O.[OH-].[Li+].Cl>O1CCCC1>[CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:24]([OH:26])=[O:25])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCCC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1
Yield: 55.3 %

Procedure:
Mix 3-[(phenacyl)ethylamino]-2-carbethoxy-4,6-dichloroindole (600 mg, 1.48 mmol), water (10 mL) and tetrahydrofuran (10 mL). Add lithium hydroxide monohydrate (0.22 g, 5.18 mmol) and stir at room temperature for 24 hours.Heat to reflux for 5 hours then pour into 1N hydrochloric acid (100 mL). Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo to give the crude product (0.72 g) as a white solid. Recrystallize (ethyl acetate/hexane) to give the title compound (0.32 g, 57%); mp 254°-6° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:22]([CH:23]=O)=[CH:21][C:11]3[C:12]([C:15]4[N:19]([CH3:20])[N:18]=[CH:17][N:16]=4)=[N:13][O:14][C:10]=3[C:9]=2[F:25])[CH2:5][C@@H:4]([CH3:26])[O:3]1.[NH:27]1[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]1=[O:35]>CO>[F:25][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][N:16]=3)[C:11]=2[CH:21]=[C:22]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:26])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:31]1([C:30](=[O:34])[NH:29][C:28](=[O:35])[NH:27][C:32]1=[O:33])[CH2:23]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-c4ncnn4C)noc3c2F)C[C@@H](C)O1
Solvent: CO
Product: C[C@@H]1CN2c3c(cc4c(-c5ncnn5C)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 150 °C

Procedure:
A mixture of 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 537, 124 mg, 0.35 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (44.2 mg, 0.35 mmol) in methanol (3 ml) was heated at 150° C. for 1 hour in a microwave reactor. Solvent was removed and the residue was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% TFA). The solid was taken up in 9:1 CH2Cl2— MeOH and washed with NaHCO3 and brine. The aqueous layers were repeatedly extracted with additional 9:1 CH2Cl2-MeOH with each extract being washed with brine. The combined organic layers were dried (MgSO4) and concentrated and the residue was dissolved in THF. After removal of solvent, the solid residue was dried in vacuo at 50° C. overnight to afford desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[O:28][CH3:29])[CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)NCCO[C@@H](c1cc(Cl)ccc1C)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
(R)-tert-Butyl 3-((R)-(5-chloro-2-methylphenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (1.0 g, 2.27 mmol) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (20 mL). The reaction mixture was stirred at room temperature for 2 h, TLC showed the starting material disappeared, a solution of saturated sodium bicarbonate was added dropwise to adjust pH=7-8. The resulting mixture was extracted with CH2Cl2 (3×30 mL), washed with brine, dried over Na2SO4, concentrated in vacuo to afford methyl 2-((R)-(5-chloro-2-methylphenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate (780 mg, 100%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[OH:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1>>[OH:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:22]1
Reactant: OC1CCCNC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Product: Cc1c(-c2ccc(C(=O)N3CCCC(O)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (±)-3-hydroxypiperidine hydrochloride by the method described in Example 41. Colorless solid (101 mg, 85%). 1H NMR (CD3OD) 1.51-1.71 (m, 2H), 1.84-2.05 (m, 2H), 2.39 (q, JH-F=1.5, 3H), 3.34-3.65 (m, 2H), 3.68-3.85 (m, 2H), 3.86-4.14 (m, 1H), 7.49 (d, br, J=3.9, 1H), 7.60 (d, br, J=3.9, 1H). 13C NMR 8.0, 23.6 (br), 33.5, 45.1 (br), 55.1 (br), 67.0, 116.7 (q, J=2), 120.3 (q, J=270), 129.8, 130.9, 132.4, 141.1, 155.8 (q, J=40), 159.4, 165.0. 19F NMR −64.8. LC/MS 6.00 min, [M+1]+ 361.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:15]([C:19]1[N:20]=[C:21]([SH:24])[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[N:20]=[C:21]([S:24][CH2:2][C:3]([N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][CH2:6]2)=[O:4])[S:22][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1csc(S)n1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: CC(C)(C)c1csc(SCC(=O)N2CCCc3ccccc32)n1
Yield: 37 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 4-tert-butylthiazole-2-thiol as the nucleophile to yield 34 (37%): MS: m/z+ 347.2 [M+H]+. Anal. Calcd (found) for C18H22N2OS2: C, 62.39 (62.60); H, 6.40 (6.43); N, 8.08 (8.06); S, 18.50 (18.39).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:26]2)[CH:10]=[C:11]([O:17]CC2C=CC=CC=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]>C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=3)[O:26]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO

Procedure:
A solution of trans-2-[3-(2-hydroxyethylsulfonyl)-4-n-propoxy-5-benzyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (440 mg) in ethyl acetate (6 mL) was hydrogenated over 10% palladium-on-charcoal (120 mg) at 45 psi for 1 h. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were evaporated to give the title compound: Rf 0.1 (hexane-ethyl acetate; 1:1, v/v); NMR (CDCl3) δ 1.07 (t, CH2CH2CH3), 3.60 (q, SO2CH2), 3.95 (q, SO2CH2CH2), 3.84 (s, OCH3), 3.88 (s, 2 OCH3), 4.11 (t, CH2CH2CH3), 5.13-5.25 (m, H-2 and H-5), 6.61 (s, 2 H, C5ArH), 7.32 and 7.49 (2 d, J=2.0 Hz, C2ArH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.1 %

Procedure:
To a solution of 3-fluorophenylacetic acid (5.0 g, 32 mmol) in MeOH (25 mL) and CH2Cl2 (25 mL) at 0° C. was added trimethylsilyldiazomethane (2 M in hexane, 30 mL, 60 mmol). After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude methyl 3-fluorophenylacetate (5.6 g), which was used without further purification. Thus, the crude methyl 3-fluorophenylacetate obtained above (2.5 g, 15 mmol) was converted to the title compound (purified on silica gel) by reacting with 4-chlorobenzyl bromide (4.6 g, 22 mmol) and sodium hexamethyldisilazide (1 M in THF, 15 mL, 15 mmol) following the procedure described in Reference Example 2, Step A. 1H NMR (400 MHz, CD3OD): δ 7.35-6.88 (m, 8H), 3.92 (t, 1H), 3.60 (s, 3H), 3.34 (dd, 1H), 3.00 (dd, 1H). LC-MS: m/e 305 (M+Na)+ (3.9 min).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:20]1)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:9]([N:19]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:20]1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: CCCCOC(=O)C1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Benzylchloroformate (2.86 ml) was added to a stirred suspension of N-benzyl-3-n-butoxy carbonyl pyrrolidine (1.75 g) and sodium bicarbonate (2.52 g) in dichloromethane (30 ml). The reaction was stirred for 0.5 hours, filtered and the filtrate evaporated to give an oil. The residual oil was purified by chromatography on silica gel; elution with ethyl acetate/hexane (1/9 v/v) gave, as a pale yellow oil, N-Cbz-3-n-butoxycarbonyl pyrrolidine (1.40 g);
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3ccc([N+](=O)[O-])cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc([N+](=O)[O-])cc12
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a mixture of methyl 4-{[cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)methyl]amino}benzoate (2.66 g) synthesized above, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (20.0 mL) was added at 0° C. The resulting precipitate was collected by filtration and the obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (2.22 g, 86%) as a pale-brown solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:21]2[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccnn1Cc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(Cn2nccc2NC2CCC3(CC2)OCCO3)cc1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of 1-benzyl-1H-pyrazol-5-amine (43.3 g) in acetic acid (500 mL) was added 1,4-dioxaspiro[4.5]decan-8-one (47 g) at room temperature, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (64 g) was added by small portions at room temperature, and the mixture was stirred for 18 hr. Acetic acid was evaporated, and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a small amount of ethyl acetate, and the mixture was crystallized using diisopropyl ether. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the title compound as a pale-yellow solid (61 g, 78%).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].C(=O)([O-])O.[Na+].[CH2:15]([OH:17])[CH3:16]>>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:17][CH2:15][CH3:16])[N:1]=1
Reactant: CCO
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1nc(Cl)nc(Cl)n1
Temperature: 0 °C

Procedure:
In addition, 92.21 g (0.500 mole) of cyanuric chloride and 50.41 g (0.600 mole) of sodium hydrogen carbonate were added in this order to 800 ml (13.73 moles) of ethanol kept at 5° C. with mechanical stirring and the mixture was reacted at this temperature for 8 hours with stirring. The resulting solution was poured into 650 g of ice-water and the precipitated white substance was immediately collected by filtration with suction. The substance was washed with 200 ml of water (0° C.) two to three times and dried in a vacuum dryer. It was recrystallized from petroleum ether to give b 2,4-dichloro-6-ethoxy-s-triazine as a colorless solid substance.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:19]([C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[CH:18]=1)#[N:20]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C#N)cc2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)CCNCC2
Yield: 43.8 %

Procedure:
A mixture of 3-(tert-butoxycarbonyl)-7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (765 mg, 2.81 mmol) and trifluoroacetic acid (2 ml), in dichloromethane (20 ml) was stirred at 40° C. for 1 h. The reaction mixture was evaporated to dryness in vacuo and partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was basified using potassium carbonate and re-extracted with ethyl acetate (2×30 ml). The combined basic organic extracts were dried over sodium sulfate and evaporated in vacuo to give the title compound as a colourless oil (212 mg, 44%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f22) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.O.C(O)(=O)C.[Br:17]Br>>[Br:17][C:5]1[S:1][C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:3]=2[CH:4]=1
Reactant: BrBr
Reactant: O=C1CCCCc2sccc21
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCCc2sc(Br)cc21
Temperature: -5 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-one (4.96 g, 29.8 mmol) in water (23.0 mL, 1200 mmol) and acetic acid (23.0 mL, 4000 mmol) at −5° C. was added a solution of bromine (1.6 mL, 31 mmol) in acetic acid (3.2 mL, 56 mmol) dropwise and the reaction mixture was stirred at −5° C. for 1 hr. The reaction mixture was quenched into aqueous sodium acetate, ethyl acetate (30 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated and dried under high vacuum to afford 7.3 g product as a brownish solid (99.0% yield). LCMS: (FA) ES+ , 246. 1H NMR (300 MHz, CDCl3) δ: 7.35-7.36 (br s, 1H), 2.98-3.0 (m, 2H), 2.68-2.73 (m, 2H), 1.85-2.0 (m, 4H).
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([C:11]1[CH:19]=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1)[CH3:10].[I-:20].[Na+]>C(OCC)(=O)C.O>[CH2:9]([C:11]1[C:19]([I:20])=[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1)[CH3:10]
Reactant: [I-]
Reactant: CCc1cc2ccccn2n1
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nn2ccccc2c1I
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
N-Chlorosuccinimide (411 g, 3.08 mol) was gradually added to a mixture of 2-ethylpyrazolo[1,5-a]pyridine (360 g, 2.46 mol), ethyl acetate (3600 mL), water (1800 mL) and sodium iodide (480 g, 3.20 mol, 1.3 equivalents) over a period of 30 minutes while cooling with ice, and then the reaction mixture was stirred for 2 hours and 20 minutes at room temperature. After the reaction, water and ethyl acetate were added to the reaction mixture and extraction was performed with ethyl acetate. The organic extract was washed twice with 10% aqueous sodium thiosulfate, and then concentrated. Hexane was added to the residue, the mixture was heated to dissolution and the resulting solution was filtered to remove insoluble residue. After then washing the hexane solution with water, the hexane layer was concentrated, the residue was dissolved in ethyl acetate and the solvent was evaporated to afford 663 g of the title compound (98.9% yield).