Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33]>ClCCl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:18][CH2:17]3)=[CH:22][CH:23]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: c1cc(-n2cnnn2)ccc1OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-((1R,2S)-2-(2-(4-(1H-Tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine (Step A, Example 1; 100 mg, 0.319 mmol) and triethylamine (97 mg, 0.96 mmol) were dissolved in dichloromethane (5 mL). Isobutyl chloroformate (52 mg, 0.38 mmol) was added. The mixture was stirred at RT for 30 min and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (12 g RediSep, eluted with dichloromethane/methanol, 199:1, 500 mL). The product containing fractions were combined and concentrated under reduced pressure. The compound was further purified by prep-HPLC (SunFire C18 OBD, 10 μm, 50×150 mm, 118 mL/min, acetonitrile/water 10:90 to 90:10 at 25 min, total run 30 min) provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 4.20-4.10 (m, 4H), 3.86 (d, J=6.6 Hz, 2H), 2.85-2.60 (m, 2H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.70 (m, 2H), 1.60-1.45 (m, 1H), 1.40-1.25 (m, 2H), 1.10-0.90 (m, 2H), 0.94 (d, J=6.7 Hz, 6H), 0.80-0.65 (m, 2H), −0.09 (q, J=5.2 Hz, 1H). MS (ESI) m/z 414 [M+H]+. GPR119 Human EC50:1.6 nM
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[CH2:23]([NH2:25])[CH3:24]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:17][CH2:18]2)[C@H:10]([C:12]([NH:25][CH2:23][CH3:24])=[O:14])[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:20])[F:21])#[N:2]
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CCN
Product: CCNC(=O)[C@H](C)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)alanine and ethylamine: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.84 (dd, J=8.8, 2.7 Hz, 1H), 6.33 (bs, 1H), 4.27 (q, J=7.2 Hz, 1H), 3.40-3.20 (m, 4H), 1.51 (d, J=7.1 Hz, 3H), 1.05 (t, J=7.3 Hz, 3H), 1.04 (m, 1H), 0.68 (m, 2H), 0.34 (m, 2H).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:31][CH2:30][C:29]4[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=4)=[O:3])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)NCc3ccc(C(F)(F)F)cc3)(CC1)CC2
Yield: 29.6 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-(trifluoromethyl)benzylamine (60.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-(4-[N-(4-trifluoromethylphenylmethyl)amino]carbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (22.0 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]([NH2:23])=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1>CS(C)=O>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:31][C:5]2[CH:4]=[C:3]([C:9]3[N:14]=[C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:12]([NH2:23])=[N:11][CH:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:25][CH2:26]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Nc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Solvent: CS(C)=O
Product: Nc1ncc(-c2cc(N[C@H]3CC[C@H](N)CC3)ncc2Cl)nc1NCC1CCOCC1
Temperature: 100 °C

Procedure:
To a scintillation vial containing 6-(5-chloro-2-fluoropyridin-4-yl)-N2-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2,3-diamine (17 mg, 0.050 mmol) was added DMSO (1.3 ml) and trans-cyclohexane-1,4-diamine R2 (57.5 mg, 0.503 mmol). The homogenous reaction mixture was capped and heated to 100° C. in a oil bath for 16 hr. The reaction mixture was purified by reverse phase preparative HPLC to yield 6-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)-N2-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2,3-diamine (13.7 mg, 0.025 mmol, 49.9% yield), LCMS (m/z): 432.1 (MH+), retention time=0.41 min as a TFA salt after lypholyzing. 1H NMR (400 MHz, METHANOL-d4) d ppm 1.30-1.50 (m, 4H) 1.51-1.65 (m, 2H) 1.69-1.78 (m, 2H) 1.93-2.06 (m, 1H) 2.07-2.24 (m, 4H) 3.10-3.19 (m, 1H) 3.36-3.45 (m, 2H) 3.48 (d, J=6.65 Hz, 2H) 3.64-3.75 (m, 1H) 3.96 (dd, J=11.35, 3.13 Hz, 2H) 7.04-7.10 (m, 1H) 7.64 (s, 1H) 8.01 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2cc(CCO)ccc2C2CCCC12
Solvent: c1ccncc1
Product: CC(=O)OCCc1ccc2c(c1)NC(=O)C1CCCC21

Procedure:
A solution of 560 mg (2.4 mmol) of 7-hydroxyethyl-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 10 ml of pyridine is stirred with 5 ml of acetic anhydride for 24 hours at room temperature. The batch is concentrated by evaporation in a vacuum and purified by column chromatography on silica gel with hexane-ethyl acetate: 500 mg of product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert-butyl ester {CAS-No. [335255-26-0]} (231 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (322 mg, 81%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCOC(=O)c1ccc(OC(C)=O)cc1

Procedure:
3.5 Grams of 4-acetoxybenzoic acid was added to 25 ml of thionyl chloride, and the mixture was allowed to react under reflux for 10 hours. Then, excessive thionyl chloride was distilled off, 10 ml of pyridine and 50 ml of toluene were then added, and 1.5 g of n-heptanol was dropwise added. After the addition, the mixture was refluxed under heat for 4 hours, and then the reaction mixture was allowed to cool and diluted with 500 ml of dichloromethane. An organic layer was consecutively washed with diluted hydrochloric acid, with a 1N sodium hydroxide aqueous solution and with water, and dried over magnesium sulfate. Further, the solvent was distilled off to give 1.7 g of the crude intended product.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C([Li])(C)(C)C.CN(OC)[C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>O1CCCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][CH:8]=[C:7]3[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:35])=[CH:29][CH:30]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(C(=O)c4ccc(Cl)cc4)cc23)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.21 gm (1.05 mMol) potassium hydride in 5.0 mL tetrahydrofuran at 0° C. were added a solution of 0.3 gm (1.0 mMol) 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole in 5.0 mL tetrahydrofuran and the solution stirred for about 30 minutes. The resulting mixture was cooled to about -78° C. and to it were added 1.47 mL (2.3 mMol) t-butyllithium, which had been precooled to -78° C., via cannula. After about 15 minutes, a solution of 1.0 gm (5.0 mMol) N-methyl-N-methoxy-4-chlorobenzamide (Preparation VII) in 3.0 mL tetrahydrofuran were added. The reaction mixture was allowed to gradually warm to ambient and was then quenched with 2N sodium hydroxide. The mixture extracted well with diethyl ether and the ether extracts were then washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by radial chromatography (2 mm silica), eluting with 95:5 ethyl acetate:methanol, to give the title compound as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH:6]([CH3:17])[C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH:6]([CH3:17])/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC1C(=O)c2cc(Br)ccc2OC12CCCOC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1/C(=N\C#N)c2cc(Br)ccc2OC12CCCOC2
Temperature: 65 °C
Yield: 137.7 %

Procedure:
A solution of 6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (200 mg, 0.65 mmol) and TiCl4 (864 mg, 4.55 mmol) in anhydrous DCM (8 mL) was heated at 50 under microwave for 5 mins. Then bis-trimethylsilylcarbodiimide (360 mg, 1.95 mmol) was added and the mixture was heated at 65° C. for another 1 hr. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give (E)-N-(6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (300 mg, crude), which was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[Si:63]([O:70][CH2:71][CH2:72][N:73]1[CH:77]=[CH:76][C:75]([NH2:78])=[N:74]1)([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64]>>[C:66]([Si:63]([CH3:65])([CH3:64])[O:70][CH2:71][CH2:72][N:73]1[CH:77]=[CH:76][C:75]([NH:78][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:11](=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[N:74]1)([CH3:69])([CH3:68])[CH3:67]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)n2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with 1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-3-amine (WO2009127544) (0.16 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide as a off white foam (Yield 0.1 g, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[CH3:25])[C:16]=1[CH3:39])=[O:14].CO.[ClH:42]>>[ClH:42].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)[CH3:25])[C:16]=1[CH3:39])=[O:14]
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc12
Agent: Cl
Solvent: CO
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
A 250 mL round bottom flask was charged with a magnetic stir bar, (R or S)-tert-butyl 4-(1-(3-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methylcarbamoyl)-2-methyl-1H-indol-1-yl)ethyl)piperidine-1-carboxylate (Compound 327) (1.850 g, 3.45 mmol), MeOH (13.79 ml, 3.45 mmol), and HCl (2.59 ml, 10.34 mmol) (4 N in dioxane). The reaction was allowed to stir at rt for 6 h before being conc., in vacuo to afford the title compound (1.65 g, 3.14 mmol, 91% yield). LCMS 437 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([N+:13]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Sn](Cl)Cl>Cl>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1cc(F)c(F)c2cccnc12
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1cc(F)c(F)c2cccnc12
Yield: 72 %

Procedure:
In a similar fashion using route 1 general procedure 4,5,6-difluoro-8-nitroquinoline (Intermediate 37) (200 mg, 0.95 mmol), tin (II) chloride (540 mg, 2.85 mmol) and 6N HCl (2 drops) gave the title compound (120 mg, 72%) which was used in the next step without purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:51])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][C@H:16]([N:20]([CH2:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)[C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)[C:15]3[CH:42]=[C:43]([CH3:50])[C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:14]2=3)=[CH:8][CH:7]=1.Cl>CO>[F:36][C:34]([F:35])([F:37])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:31]=1)[CH2:27][N:20]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:16]1[CH2:17][CH2:18][CH2:19][N:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:51])=[O:4])=[CH:7][CH:8]=2)[C:14]2[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[C:43]([CH3:50])=[CH:42][C:15]1=2
Reactant: COC(=O)c1ccc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccc(C(=O)O)cc1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C
Yield: 90.3 %

Procedure:
Add 5 N sodium hydroxide solution (0.5 mL) to a solution of (S)-4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-benzoic acid methyl ester (70 mg, 0.100 mmol) in methanol (1 mL) and heat at 60° C. for 4 h. After the reaction cools to room temperature, acidify to pH 4 with 2 N hydrochloric acid solution and extract the aqueous mixture with ethyl acetate (3×10 mL). Wash the organic layer with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to provide the title compound as a white solid (62 mg, 90%). mp 95-98° C.; 1H NMR (CDCl3, 300 MHz) δ 1.63-1.71 (m, 2H), 1.99-2.05 (m, 2H), 2.29 (s, 3H), 2.75-2.84 (m, 1H), 2.98-3.10 (m, 1H), 4.15 (s, 3H), 4.31-4.50 (m, 2H), 4.82-5.12 (m, 2H), 5.51-5.60 (m, 1H), 6.95 (s, 1H), 7.31-7.37 (m, 1H), 7.51-7.60 (m, 2H), 7.65-7.70 (m, 2H), 7.78-7.82 (m, 1H), 8.10-8.17 (m, 2H); ESI MS m/z 687 [C31H27F9N6O2+H]+; HPLC 98.1%, tR 17.0 min.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O.ClCCl>[CH2:19]([O:6][C:5]1[C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[O:8][C:2](=[O:1])[C:3]=1[OH:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1O[C@H]([C@@H](O)CO)C(OCc2ccccc2)=C1O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
Ascorbic acid (10 g, 56.8 mmol) was dissolved in 60 ml of dimethylsulfoxide, followed by addition of cesium carbonate (9.25 g, 28.4 mmol). After 20 minutes, benzyl bromide (6.75 ml, 56.8 mmol) was added to the reaction mixture and heated to 50° C. for 18 hours. The reaction mixture was cooled down to the room temperature and diluted with 150 ml of dichloromethane to produce a solid. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel to give 7.2 g of the 3-O-benzyl ascorbic acid (yield 48%).
Reaction SMILES: ClN1C(=O)C[CH2:4][C:3]1=O.Cl[C:10]1[C:14]([Cl:15])=[C:13]([CH3:16])[NH:12][C:11]=1[C:17]([OH:19])=[O:18].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:15][C:14]1[CH:10]=[C:11]([C:17]([O:19][CH2:3][CH3:4])=[O:18])[NH:12][C:13]=1[CH3:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Cl)c(C)[nH]1
Temperature: 40 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
N-Chlorosuccinimide (0.67 g, 5.08 mmol) was added to a solution of ethyl 5 -methyl-1H-pyrrole-2-carboxylate (Intermediate 3; 0.65 g, 4.23 mmol) in chloroform (20 ml). The reaction was warmed to 40° C. and stirred for 4 h, then poured to a beaker containing 2 N NaOH (20 ml) at 0° C. The layers were separated and the aqueous layer was extracted with chloroform (×3). The combined organic extracts were dried over magnesium sulfate and concentrated. The resultant off-white solid was purified by flash chromatography (hexanes/EtOAc, 16:1) to give the title product as a white solid (0.3 g, 38%). MS (ES): 188 (M+1) for C8H10ClNO2; NMR (CDCl3): 1.34 (t, 3H), 2.27 (s, 3H), 4.30 (q, 2H), 6.76 (s, 1H), 9.07 (brs, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](N)=[CH:15][CH:14]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[N+:20](C1C=CC(O)=CC=1)([O-])=O>>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:20])[CH:14]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(COc2ccc(N)cc2)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CNC(=O)c1cc(COc2cccc(N)c2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxymethyl)pyridine-2-carboxylic acid methylamide, substituting 3-nitrophenol for 4-nitrophenol. 1H-NMR (CD3OD) δ 8.40 (d, J=4.5 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.13 (t, J=6.3 Hz, 1H), 7.00 (dd, J=4.2, 1.8 Hz, 1H), 6.62 to 6.59 (m, 1H), 6.43 (t, J=1.8 Hz, 1H), 6.37 to 6.34 (m, 1H), 4.89 (s, 2H), 2.93 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18]([O:23][CH3:24])(=[O:22])[CH:19]([CH3:21])[OH:20]>O1CCCC1>[CH2:3]([O:10][C:11]1[C:12]([O:20][CH:19]([C:18]([O:23][CH3:24])=[O:22])[CH3:21])=[N:13][CH:14]=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ncncc1OCc1ccccc1
Reactant: COC(=O)C(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)Oc1ncncc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride is added to a mixture of 5-benzyloxy-4-chloropyrimidine, methyl lactate and tetrahydrofuran at 0° C. The mixture is stirred at room temperature for 1 hour, then, stirred for 30 minutes at 90° C. The reaction solution is cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer is washed with dilute hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-benzyloxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=O)[CH2:12][CH2:13][N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:9]=2[CH:8]=[CH:7]1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=[N:21][OH:22])[CH2:12][CH2:13][N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:9]=2[CH:8]=[CH:7]1
Reactant: CN1CCC(=O)c2c(ccn2CCCCCl)S1(=O)=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(=NO)c2c(ccn2CCCCCl)S1(=O)=O
Yield: 72.5 %

Procedure:
A suspension of 152 mg (0.5 mmol) of Compound 18, 174 mg (2.5 mmol) of hydroxylamine hydrochloride and 205 mg (2.5 mmol) of sodium acetate in 20 ml of ethanol was refluxed for 20 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of water to the residue. The resulting mixture was extracted with chloroform (3 times). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: methanol/chloroform=3/97), whereby 116 mg of the title compound were obtained (yield: 73%).