Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C:4](=[CH2:7])[C:3]1=[O:8].C=C1CCCNC1=[O:16]>>[CH2:7]=[C:4]([CH2:5][CH2:6][NH:2][CH3:1])[C:3]([OH:8])=[O:16]
Reactant: C=C1CCN(C)C1=O
Reactant: C=C1CCCNC1=O
Product: C=C(CCNC)C(=O)O

Procedure:
By substituting 1-methyl-3-methylene-2-pyrrolidinone [J. Org. Chem., 39, 893 (1974)] for the 3-methylene-2-piperidone in the procedure of Example 9, 2-methylene-4-methylaminobutanoic acid hydrochloric is obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:36])([F:35])[C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:28][C:24]([C:23]([F:36])([F:22])[F:35])=[CH:25][N:26]=3)[CH2:30][CH2:31]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1)C(F)(F)F
Yield: 57 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A16) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as an off-white crystalline solid (yield 57%). MS (m/e): 532.0 (M+H+, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:28])[CH:22]=1)=[O:17]>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH:19]4[CH2:20][CH:18]4[C:16]([OH:17])=[O:15])=[CH:22][C:23]=3[F:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCC1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccnc2SC2CCC2)c(F)c1
Yield: 84 %

Procedure:
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.032 g, 0.15 mmol) obtained in Step C of Preparation Example 23 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.037 g, 84%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C1(P(C(C)C(P(C2C=CC=CC=2)C2C=CC=CC=2)C)C2C=CC=CC=2)C=CC=CC=1.[C:39](=[O:42])([O-])[O-:40].[K+].[K+].[C]=O>[Pd](Cl)Cl.O>[CH3:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:39]([OH:40])=[O:42]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: CC(C(C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: O
Product: Cc1cccc(C(=O)O)c1
Temperature: 210 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
In an autoclave made of metal were placed 2.53 g of meta-chlorotoluene, 35.5 mg of palladium chloride, 426 mg of bisdiphenylphosphinobutane and 3.04 g of potassium carbonate. The air in the autoclave was replaced with carbon monoxide introduced thereinto in several times, after which carbon monoxide was further introduced to adjust its pressure therein to 50 kg/cm2. The reaction was carried out with stirring for 3 hours on a salt bath at a bath temperature of 210° C. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added. The aqueous layer was separated, after which acid was added thereto and the deposited crystals were collected by filtration and dried. Thus, 1.10 g of the desired compound meta-methylbenzoic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([N:8]=[N:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([CH2:18][OH:19])[C:11]=2[OH:20])[CH:7]=1.[OH-].[Na+].C(S(O)=O)(N)=N.Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:21][N:9]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([CH2:18][OH:19])[C:11]=3[OH:20])[N:8]=[C:6]2[CH:7]=1
Reactant: COc1cc(CO)c(O)c(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c1
Agent: Cl
Agent: N=C(N)S(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(CO)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
In a 500 ml round bottom flask equipped with a magnetic stirrer, addition funnel, powder addition funnel, and nitrogen inlet was added 27.4 g (81.0 mmol) 2-((5-chloro-2-nitrophenyl)diazenyl)-6-(hydroxymethyl)-4-methoxyphenol and 200 ml ethanol. NaOH (19.7 g, 493 mmol) was dissolved in 100 ml deionized water and approximately one-fourth was added dropwise to the reaction mixture. The mixture was heated to 80° C. and 26.5 g (245 mmol) formamidine sulfinic acid and the remaining sodium hydroxide solution were concurrently added dropwise to the reaction mixture. The mixture was stirred at 80° C. for 2 hours and then poured into 3 L deionized water. The mixture was acidified to pH 3 using 1N HCl and the solid was collected by filtration, rinsed with ample amounts of water, and then worked up as in Example 5 to afford 7.4 g (30%) solid which was used in the next esterification step.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([CH3:12])=[N:6][C:5]=2[S:4][C:3]=1[CH3:13].C(OCC)(=O)C.[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[CH:8]=[C:7]([CH3:12])[N:6]=[C:5]2[S:4][C:3]([CH3:13])=[C:2]([C:20]#[N:21])[C:10]=12
Reactant: Cc1cc(N)c2c(Br)c(C)sc2n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(N)c2c(C#N)c(C)sc2n1
Temperature: 140 °C

Procedure:
A mixture of 3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-amine (Description 8) (200 mg, 0.778 mmol), zinc cyanide (183 mg, 1.556 mmol) and tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.078 mmol) in DMF (5 mL) was heated in a microwave at 140° C. for 1 h. Another batch of 3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-amine (200 mg, 0.778 mmol) was subjected to the same conditions. The mixtures were then combined and ethyl acetate (50 mL) added. The resulting mixture was washed with saturated NaHCO3 (20 mL) followed by brine (20 mL×2) and the organic layer dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-40% ethyl acetate in cyclohexane, to give the title compound (237.7 mg). LCMS (A) m/z: 204 [M+1]+, Rt 0.61 min (acidic).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[N:11]=[C:10]2[N:12]([CH3:15])[N:13]=[CH:14][C:9]2=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:7]=1)(=[O:4])=[O:3].O.O.Cl[Sn]Cl>CCO.C1COCC1>[CH3:1][S:2]([CH2:5][C:6]1[N:11]=[C:10]2[N:12]([CH3:15])[N:13]=[CH:14][C:9]2=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH:7]=1)(=[O:4])=[O:3]
Reactant: Cn1ncc2c(-c3ccc([N+](=O)[O-])cc3)cc(CS(C)(=O)=O)nc21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ncc2c(-c3ccc(N)cc3)cc(CS(C)(=O)=O)nc21

Procedure:
In analogy to GP3, reaction of 1000 mg 6-methanesulfonylmethyl-1-methyl-4-(4-nitro-phenyl)-1H-pyrazolo[3,4-b]pyridine (Intermediate 18.1; 2.89 mmol, 1 eq.) with 3.26 g SnCl2.2H2O (14.46 mmol, 5 eq.) in 56 mL 2.5:1 EtOH/THF at reflux for 3 h yielded after standard work-up the crude aniline which was used without further purification.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4](OC)[CH:3]=1.[F:40]C1C=CC=CC=1B(O)O>C(Cl)Cl.CO>[F:40][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35]
Reactant: OB(O)c1ccccc1F
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)CCNc1cnccc1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methanesulfonyl-ethyl)-amine (example 158, intermediate b) and 2-fluorophenylboronic acid (CAS RN 1193-03-9) and using a gradient of CH2Cl2:methanol (100:0 to 70:30) for the chromatographic purification. Light brown solid (85%). MS (ESI): m/z=295.09 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH:25]3[O:27][CH2:26]3)[CH:18]=2)[CH:14]=1)=[O:7].[CH3:34][N:35]([CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:41])[CH3:34])[CH3:40])[CH:18]=2)[CH:14]=1)=[O:7]
Reactant: CNCCCN(C)C
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN(C)CCCN(C)C)c1
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 31, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)benzamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 45% yield; NMR Spectrum: (DMSOd6) 1.8 (m, 2H), 2.18 (s, 3H), 2.33 (s, 3H), 2.58 (s, 6H), 2.6 (m, 2H), 2.92 (t, 2H), 2.96 (s, 6H), 4.03 (m, 5H), 6.9 (m, 1H), 7.15 (m, 1H), 7.2 (m, 3H), 7.28 (t, 1H), 7.48 (t, 1H), 7.56 (m, 2H), 7.8 (d, 1H), 9.95 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M+H+ 562.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[N:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:17]
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Nitrobenzamide (2.5 g, 15 mmol) was dissolved in dimethylformamide-dimethylacetal (10 mL) and heated to 100° C. for 1 hour. Upon cooling, the reaction mixture was placed in a freezer at −23° C. overnight. The white precipitate was collected by filtration and rinsed with hexane to provide N-[(dimethylamino)methylene]-2-nitrobenzamide (3.06 g), which was used without further purification.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]1[CH2:19][CH2:18][CH2:17][N:16]2[N:20]=[C:21]([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[CH:22]=[C:15]2[CH2:14]1)(=O)=O)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C>[O:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[O:26][NH:25][C:23]([C:21]1[CH:22]=[C:15]2[CH2:14][NH:13][CH2:19][CH2:18][CH2:17][N:16]2[N:20]=1)=[O:24]
Reactant: O=C(NOC1CCCCO1)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Product: O=C(NOC1CCCCO1)c1cc2n(n1)CCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a mixture of 5-[(2-nitrophenyl)sulfonyl]-N-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (0.15 g, 0.32 mmol) and cesium carbonate (0.2 g, 0.62 mmol) in acetonitrile (10 mL) was added a solution of benzenethiol (0.063 mL, 0.62 mmol) in acetonitrile (0.60 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue applied directly to silica purification (5% MeOH/DCM) to afford the title compound as a white solid (0.082 g, 91%). LC-MS: (FA) ES+281; 1H NMR (400 MHz, CDCl3) δ 6.59 (s, 1H), 5.30 (s, 1H), 5.08 (s, 1H), 4.39-4.32 (m, 2H), 4.08-4.00 (m, 1H), 3.92 (q, J=15.7 Hz, 2H), 3.71-3.61 (m, 1H), 3.26-3.15 (m, 2H), 2.29 (s, 1H), 1.92-1.79 (m, 5H), 1.70-1.54 (m, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]([CH2:11][N+:12]([O-:14])=[O:13])[O:8][B:7]([OH:15])[C:6]=2[C:5]([O:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.[CH3:19][Sn](C)(C)C>CN(C=O)C.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>[CH2:17]([O:16][C:5]1[C:6]2[B:7]([OH:15])[O:8][CH:9]([CH2:11][N+:12]([O-:14])=[O:13])[C:10]=2[C:2]([CH3:19])=[CH:3][CH:4]=1)[CH3:18]
Reactant: CCOc1ccc(Br)c2c1B(O)OC2C[N+](=O)[O-]
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOc1ccc(C)c2c1B(O)OC2C[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
A mixture of 4-bromo-7-ethoxy-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (200 mg, 0.63 mmol), tetramethylstannane (341.7 mg, 1.90 mmol) and Pd(PPh3)4 (Cat. 20 mg) in DMF (35 mL) was stirred overnight at 90° C. under N2 protection. The reaction was quenched by adding ice-water and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-TLC to give the product (72 mg, yield 45.3%). 1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.23-7.21 (d, 1H), 6.83-6.81 (d, 1H), 5.77-5.75 (m, 1H), 5.27-5.24 (m, 1H), 4.50-4.44 (m, 1H), 4.08-4.03 (m, 2H), 2.25 (s, 3H), 1.33-1.29 (t, 3H).
Reaction SMILES: [K].[CH2:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH2:3][CH2:4][CH3:5].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>C(O)C>[CH2:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:3][CH2:4][CH3:5]
Reactant: BrCCCCCCCCBr
Reactant: CCCCc1ccccc1O
Agent: [K]
Solvent: CCO
Product: CCCCc1ccccc1OCCCCCCCCOc1ccccc1CCCC

Procedure:
Two molar equivalents of the potassium salt of butylphenol and one molar equivalent of 1,8-dibromooctane are reacted in ethanol according to the procedure described in Example 1, to afford 1,8-bis (butylphenoxy) octane. Sulfonation with sulfur trioxide or chlorosulfonic acid, followed by neutralization of the disulfonic acid with methanolic potassium hydroxide, affords the potassium sulfonate.
Reaction SMILES: [CH2:1]([N:5]([CH2:27][CH3:28])[C:6]1[C:7]2[C:15]([CH3:16])=[CH:14][N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH2:24]O)=[CH:19][C:18]=3[CH3:26])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4].CN(S(F)(F)[F:33])C>C(Cl)Cl>[CH2:1]([N:5]([CH2:27][CH3:28])[C:6]1[C:7]2[C:15]([CH3:16])=[CH:14][N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH2:24][F:33])=[CH:19][C:18]=3[CH3:26])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC)c1nc(C)nc2c1c(C)cn2-c1c(C)cc(CO)cc1C
Reactant: CN(C)S(F)(F)F
Solvent: ClCCl
Product: CCCCN(CC)c1nc(C)nc2c1c(C)cn2-c1c(C)cc(CF)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {4-[4-(butyl-ethyl-amino)-2,5-dimethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-3,5-dimethylphenyl}-methanol (0.071 g, 0.186 mmol) in 2 ml anhydrous methylene chloride was cooled to −78° C. and treated with dimethylaminosulfur trifluoride (0.063g, 0.390 mmol) and stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with chloroform. The organic layer was washed with brine, dried, and concentrated to give an oil which was purified through silica gel using 2% methanol/chloroform as eluent to give the title compound as an off-white solid, mp 163-165° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10](O)=[O:11])=[CH:8][C:7]2[CH2:13][C:14]([CH3:17])([CH3:16])[CH2:15][C:6]1=2.[O-]CC.[Na+]>C(O)C>[CH3:16][C:14]1([CH3:17])[CH2:13][C:7]2[CH:8]=[C:9]3[N:5]([CH2:4][CH2:3][NH:2][C:10]3=[O:11])[C:6]=2[CH2:15]1
Reactant: CC1(C)Cc2cc(C(=O)O)n(CCN)c2C1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Temperature: 55 °C
Yield: 23.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with crude 1-(2-aminoethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride 107d (˜18 mmol), sodium ethoxide (6.2 g, 92 mmol) and ethanol (120 mL). The mixture was stirred at 55° C. over night. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The solution was filtered. The solid was washed with ethyl acetate (15 mL) to give 850 mg of desired product 107e. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to near dryness. The solution was filtered and the solid (1.44 g) was washed with ethyl acetate (15 mL). The combined solids were dried under vacuum a afford 61% yield (2.3 g) of 107e.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:13](=[O:24])[NH:14][C@H:15]1[CH2:21][CH2:20][C@@H:19]([CH3:22])[NH:18][CH2:17][CH:16]1[OH:23])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28](=[O:37])[C@@H:29]([N:34]=[C:35]=[O:36])[CH2:30][CH:31]([CH3:33])[CH3:32]>C1COCC1>[CH3:26][O:27][C:28](=[O:37])[C@@H:29]([NH:34][C:35]([N:18]1[CH2:17][CH:16]([OH:23])[C@@H:15]([NH:14][C:13](=[O:24])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:25])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:21][CH2:20][C@H:19]1[CH3:22])=[O:36])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NCC1O
Reactant: COC(=O)[C@H](CC(C)C)N=C=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)N1CC(O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)CC[C@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
[(S)-3-Methyl-1-((4S,7R)-7-methyl-3-hydroxy-azepan-4-ylcarbamoyl)-butyl]-carbamic acid tert-butyl ester (Example 12a-i, 500 mg, 1.4 mmol) was dissolved in THF (7 ml), then (S)-(−)-2-isocyanato-4-methylvaleric acid methyl ester (180 mg, 1.05 mmol) was added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 1% to 2% MeOH/CH2Cl2) to yield the title compound as a white solid (91%, 506 mg): LC/Electrospray mass spec: M+H+=529.4.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([C:29]([O:31][CH3:32])=[O:30])=[N:12][C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:15]=1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]I>C1COCC1.C([O-])([O-])=O.[Cs+].[Cs+]>[C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:33])[C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:12][C:11]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)c1nc(C2CCCN2C(=O)OC(C)(C)C)nc(O)c1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1nc(C2CCCN2C(=O)OC(C)(C)C)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 40 °C

Procedure:
To a stirred solution of the product of Step 2 (1.0 eq.) in THF, Cs2CO3 was added (1.2 eq.) followed by the addition of CH3I (2.0 eq.). The reaction was stirred at 40° C. until the starting material was consumed as determined by MS analysis. The reaction was concentrated and the residue taken up with EtOAc, washed with 1 N HCl, saturated solution of NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. Reaction crude showed 3.4:1 ratio N (desired product) versus O methylation. The title product was purified by flash column chromatography (EtOAc: Petroleum Ether=1:1) and obtained as a 1: 1 mixture of rotamers by NMR.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[N:28][O:29][CH2:30][CH2:31][OH:32])[CH3:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:8][S:9]([O:32][CH2:31][CH2:30][O:29][N:28]=[C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1)[CH3:27])(=[O:11])=[O:10]
Reactant: CC(=NOCCO)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=NOCCOS(C)(=O)=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.83 ml) was added dropwise at 0° C. to a solution of methanesulfonyl chloride (1.15 ml) and 2-[[1-(4′-fluoro-4-biphenylyl)ethylidene]aminoxy]ethanol (3.70 g) obtained from Reference example 26(a) in dichloromethane (40 ml), and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were filtered off and washed with hexane and isopropyl ether to afford the target compound (4.70 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[N:22]12[CH2:32][CH2:31][CH2:30]N=C1CCCCC2.C1(N)CC1>C(O)C>[CH:32]1([NH:22][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]3)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=2)[CH2:30][CH2:31]1
Reactant: CCOC(=O)N1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: C1CCC2=NCCCN2CC1
Agent: NC1CC1
Solvent: CCO
Product: CCOC(=O)N1CCN(c2nc(NC3CC3)ccc2[N+](=O)[O-])CC1
Yield: 47.7 %

Procedure:
A solution of 126.0 g (0.4 mole) of 4-(6-chloro-3-nitro-2-pyridinyl)-1-piperazinecarboxylic acid, ethyl ester (prepared as described in European Patent Publication No. 9425), 76.1 g (0.5 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 28.6 g (0.5 mole) of cyclopropylamine and 500 ml of absolute ethanol was stirred at room temperature for 48 hours. The solution was then heated at reflux for four hours and concentrated in vacuo. The residue was partitioned between chloroform and water. The chloroform layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether to give 64.0 g of the title compound, mp 100-103° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:31](=[O:32])[CH2:30][CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: O=C(O)CC1CCOCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)CC3CCOCC3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and 2-(tetrahydro-2H-pyran-4-yl)acetic acid as a yellow solid (37%). 1H NMR (400 MHz, DMSO-d6) δ 1.05-1.08 (m, 2H), 1.30-1.38 (m, 11H), 1.79 (m, 1H), 1.97 (d, J=4.0 Hz, 2H), 2.56 (s, 3H), 3.07 (t, J=8.0 Hz, 2H), 3.61 (d, J=8.0 Hz. 2H), 4.28-4.34 (m, 4H), 6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.73 (s, 1H), 8.21 (s, 2H). MS 444 (MH+).