Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:25]12([N:35]=[C:36]=[O:37])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:36]([NH:35][C:25]23[CH2:34][CH:29]4[CH2:28][CH:27]([CH2:33][CH:31]([CH2:30]4)[CH2:32]2)[CH2:26]3)=[O:37])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-chlorobenzhydryloxy]azetidine hydrochloride (98) (0.55 mmol) and 1-adamantyl isocyanate (0.55 mmol) using the procedure described for compound (10) (229 mg, 83%).
Reaction SMILES: N1(O[C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)C2C=CC=CC=2N=N1.[NH2:24][NH:25][C:26]([NH2:28])=[S:27].C(OC(C)C)(C)C>CN(C)C=O>[CH2:19]([O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:24][NH:25][C:26]([NH2:28])=[S:27])=[O:23])=[CH:17][CH:16]=1)[CH2:20][CH2:21][CH3:22]
Reactant: NNC(N)=S
Reactant: CCCCOc1ccc(C(=O)On2nnc3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: CCCCOc1ccc(C(=O)NNC(N)=S)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
To a solution of 4-n-butyloxybenzoic acid benzotriazol-1-yl ester (15 g) in N,N-dimethylformamide (100 ml) was added thiosemicarbazide (5.27 g) and the mixture was stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with diisopropyl ether. The precipitate was collected by filtration to give 1-(4-n-butyloxybenzoyl)thiosemicarbazide (11.51 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25])([O-:17])=[O:16]>ClCCl>[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH:6][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N+:15]([O-:17])=[O:16])(=[O:25])=[O:26]
Reactant: COC(=O)CN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Glycine methyl ester hydrochloride (15.0 g) was dissolved in dichloromethane, and to the solution triethylamine (26.48 g) was added at 0° C. A solution of 2-nitrobenzenesulfonyl chloride (23.57 g) in dichloromethane (50 mL) was then gradually added dropwise. After the mixture was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The resultant mixture was washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crystals were recrystallized from ethyl acetate-hexane to obtain the title compound.
Reaction SMILES: ClC1C2C3CN(C)CCC=3NC=2C=CC=1C.[Cl:17][C:18]1[C:19]([CH3:32])=[CH:20][C:21]2[C:22]3[CH2:30][N:29]([CH3:31])[CH2:28][CH2:27][C:23]=3[NH:24][C:25]=2[CH:26]=1.[H-].[Na+].[CH3:35][C:36]1([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH2:38][O:37]1>CN(C=O)C>[Cl:17][C:18]1[C:19]([CH3:32])=[CH:20][C:21]2[C:22]3[CH2:30][N:29]([CH3:31])[CH2:28][CH2:27][C:23]=3[N:24]([CH2:35][C:36]([C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)([OH:37])[CH3:38])[C:25]=2[CH:26]=1
Reactant: CC1(c2cccnc2)CO1
Reactant: Cc1cc2c3c([nH]c2cc1Cl)CCN(C)C3
Agent: Cc1ccc2[nH]c3c(c2c1Cl)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c3c(n(CC(C)(O)c4cccnc4)c2cc1Cl)CCN(C)C3
Reaction time: 0.25 h
Yield: 11.1 %

Procedure:
A mixture of 9-chloro-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 7-chloro-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.00 g, 8.5 mmol) was dissolved in DMF (15 mL). Sodium hydride (1.708 g, 42.71 mmol) was added at 0-10° C. and stirred at the same temperature for 15 min., 3-(2-methyloxiran-2-yl)pyridine (2.309 g, 17.08 mmol) was added dropwise into the reaction mixture and the mixture was stirred at RT for 16 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (100 mL) and extract with EtOAc (300 mL). The organic layer was washed with water (5×100 mL). The organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude. The crude product was purified by reverse phase column chromatography to obtain 350 mg of 1-(7-chloro-2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-ol. 1H NMR (CD3OD, HCl salt) δ (ppm): 8.68 (m, 3H), 7.95 (m, 1H), 7.29 (d, 1H), 6.9 (m, 1H), 4.68 (dd, 1H), 4.38 (m, 2H), 4.32 (dd, 1H), 3.9 (m, 1H), 3.52 (m, 2H), 3.25 (m, 1H), 3.12 (s, 3H), 2.35 (d, 3H), 1.83 (d, 3H). Separation by chiral HPLC provided enantiomers II-123a-b.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.[OH-].[K+].CS(C)=O.[Cl:26][CH:27]=[CH:28][CH:29](Cl)C>O>[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([O:17][CH2:29][CH:28]=[CH:27][Cl:26])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Reactant: CC(Cl)C=CCl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(Cl)c(OCC=CCl)cc1-n1nc2c(c1Cl)CCCC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
3-Chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (1 g) was suspended in a solution of potassium hydroxide (0.84 g) in water (8 ml). Dimethylsulfoxide (21 ml) was added to the suspension to make a uniform solution. To the resultant solution, 1,3-dichloro-1-butene (1.26 g) was added, and the mixture was stirred at 100° C. for 4 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gel thin chromatography using a mixture of ether and hexane (1:3) as an eluent to give 3-chloro-2-[4-chloro-2-fluoro-5-(3-chloro-2-propenyloxy)phenyl]-4,5,6,7-tetrahydro-2H-indazole (0.65 g) (Compound No. 2). M.P., 68.5°-70.5° C.
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][CH:10]([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[F:9][CH:10]([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:34]2[CH2:35][CH2:36][N:32]([C:24]3[S:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:22]([CH3:21])[N:23]=3)[C:33]2=[O:37])=[CH:14][CH:13]=1
Reactant: FC(F)Oc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(OC(F)F)cc3)C2=O)nc1C
Yield: 88 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-(difluoromethoxy)benzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 88% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.37 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 6.48 (t, JF-H=73.8 Hz, 1H), 4.46 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 4.07 (t, J=7.8 Hz, 2H), 3.45 (t, J=7.8 Hz, 2H), 2.56 (s, 3H), 1.30 (t, J=7.2 Hz, 3H); MS (ES+) m/z 412.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[Cl:19])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)/C=C/c3ccc(F)cc3Cl)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid. LC-MS-conditions 05: tR=0.83 min; [M+H]+=404.9.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=C[N:25]=[C:24]4C)=[CH:19][CH:18]=3)[CH:11]=2)[CH2:8][CH2:7][O:6][CH:5](C)[CH2:4]1)#[N:2].[NH:29]1C=C(C2C=CC(I)=CC=2)N=N1.C(C1(C2C=CC=C(S[Si](C(C)C)(C(C)C)C(C)C)C=2)CCOCC1)#N.C(C1(C2C=CC=C(S[Si](C(C)C)(C(C)C)C(C)C)C=2)CCOC(C)C1)#N>>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:24]=[N:25][N:29]=[CH:27]4)=[CH:19][CH:18]=3)[CH:11]=2)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1)#[N:2]
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(C#N)CCOC(C)C3)c2)cc1
Reactant: Ic1ccc(-c2c[nH]nn2)cc1
Agent: CC(C)[Si](Sc1cccc(C2(C#N)CCOCC2)c1)(C(C)C)C(C)C
Agent: CC1CC(C#N)(c2cccc(S[Si](C(C)C)(C(C)C)C(C)C)c2)CCO1
Product: N#CC1(c2cccc(Sc3ccc(-n4cnnc4)cc3)c2)CCOCC1

Procedure:
The titled compound was prepared according to the procedure described in example 29E for the preparation of (2SR,4RS)-4-cyano-2-methyl-4-[3-[4-(2-methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran using 4-(triazol-4-yl)phenyl iodide and 4-cyano-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran in place of 4-(2-methylimidazol-1-yl)phenyl iodide and (2SR,4RS)-4-cyano-2-methyl-4-(3-triisopropylsilylthiophenyl)-3,4,5,6-tetrahydro-2H-pyran, respectively. MS(EI): m/z 362(M+)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:33](=[O:40])[NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:17]2(=[O:32])=[O:31])[CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[S:17]2(=[O:31])=[O:32])[CH:11]=1)[C:33]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:40]
Reactant: CCCCCNC(=O)[C@H](Cc1cccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNC(=O)[C@@H](N)Cc1cccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1
Reaction time: 0.5 h

Procedure:
A solution of the title F compound, ((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamic acid t-butyl ester (156 mg, 0.265 mmol) in CH2Cl2 (1 mL) is treated with TFA (1 mL). After 30 min, the solvent is evaporated under stream of nitrogen. The residue is partitioned between EtOAc and saturated aqueous NaHCO3. The organic solution is washed with brine, dried over anhydrous MgSO4 and concentrated to yield (S)-2-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamide as a white solid: [M+1]+=489.
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[OH:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25]([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[OH:23])[CH2:10][CH2:9]1)=[O:26])[CH3:29]
Reactant: Oc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3ccccc3c(O)c2CC1
Yield: 20 %

Procedure:
11-Hydroxy-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared analogous to Example 101 from 3-benzyl-11-hydroxy-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline and ethyl chloroformate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH2:20][CH2:21][CH3:22])[CH3:2].[CH2:23]([Mg]Br)[CH3:24].[Cl-].[NH4+]>O1CCCC1.C(OCC)C.O>[CH2:1]([C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH2:23][CH3:24])([OH:19])[CH2:17][CH3:18])=[CH:12][C:11]=2[CH2:20][CH2:21][CH3:22])=[CH:5][C:6]([OH:9])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(O)ccc1CC
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1cc(C(O)(CC)CC)ccc1-c1cc(O)ccc1CC
Temperature: -10 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
370 g (1.248 mol) of 1-(2′-ethyl-5′-hydroxy-2-propylbiphenyl-4-yl)propan-1-one in solution in 3.7 liters of tetrahydrofuran are placed in a reactor. 915 ml of a 3M solution of ethylmagnesium bromide in ethyl ether are slowly run into this solution cooled to −10° C. At the end of the addition, the reaction mixture is kept stirred for 1 hour and then transferred onto 5 liters of a 2.5 molar solution of ammonium chloride in water. The organic phase is separated by settling and washed twice with 800 ml of water. After evaporating under reduced vacuum, the residue is dissolved with 2.75 liters of methylene chloride at reflux. The medium is allowed to return to ambient temperature with stirring and is then cooled to 5° C. The crystals are filtered off and then dried under vacuum. 260 g (64%) of 6-ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-ol are obtained. Melting point: 130° C. 1H NMR (d6-DMSO) (ppm): 0.67-0.74, m, 9H; 0.9, t, 3H; 1.38, m, 2H; 1.71-1.77, m, 4H; 2.13-2.35, m, 4H; 4.48, s, 1H; 6.45, d, 1H; 6.70, dd, 1H; 6.94, d, 1H; 7.07, d, 1H; 7.18, dd, 1H; 7.26, s, 1H; 9.16, s, 1H
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12]CC)=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:15][CH2:16][C@H:17]([N:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[C:30]([F:32])[C:27]([C:28]#[N:29])=[C:26]([Cl:33])[CH:25]=2)=[N:20]1)[CH3:18]>>[Cl:33][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][N:19]([C@H:17]([CH3:18])[CH2:16][NH:15][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[N:20]=2)[CH:31]=[C:30]([F:32])[C:27]=1[C:28]#[N:29]
Reactant: C[C@H](CN)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CCOC(=O)c1coc(C(C)(C)O)n1
Product: C[C@H](CNC(=O)c1coc(C(C)(C)O)n1)n1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared using the procedure described in Example 52(g) starting from ethyl 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylate (0.5 mmol, 139 mg) and (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (0.5 mmol, 100 mg). Yield 27 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.45 (d, 3H), 1.49 (s, 6H), 3.55-3.61 (m, 1H), 3.66-3.73 (m, 1H), 4.67-4.76 (m, 1H), 5.65 (s, 1H), 7.03 (d, 1H), 7.88 (d, 1H), 7.91 (d, 1H), 8.0 (s, 1H), 8.19 (t, 1H), 8.51 (s, 1H). LC-MS: [M+1]=432.02.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (99) and 3-fluorobenzyl bromide according to General Procedure B. Yield 297 mg (38%), MP 211° C.; 1H-NMR (DMSO-d6): δ 3.72 (m, 4H), 3.95 (m, 4H), 5.52 (s, 2H), 6.67 (dd, J=1.6, 3.6, Hz, 1H), 7.06-7.10 (m, 4H), 7.33 (m, 1H), 7.89 (d, J=1.6 Hz, 1H), 8.18 (dd, J=2.8, 9.2 Hz, 1H), 8.78 (d, J=2.8 Hz, 1H); EIMS: 476 (M+1). Anal. (C25H19F2N5O3) C, H, N.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24]Cl)[CH3:21].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>CN(C)C=O.C1(C)C=CC=CC=1.C(#N)C.O>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][CH2:24][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[N:11]1
Reactant: CN(C)CCCCl
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN(C)CCCn1nc(C2CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a stirred suspension of 1.15 g of sodium hydride (50% oil dispersion) in 30 ml of dimethylformamide, under nitrogen, was added dropwise 4.3 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 30 ml of hot dimethylformamide. After stirring at ambient temperature for 1 hr, a solution of 3.3 g of dimethylaminopropylchloride in 30 ml of toluene was added dropwise. The reaction was then heated at 60° for 1 hr and then stirred at ambient temperature for 16 hrs. The reaction mixture was poured into water and the aqueous suspension was extracted with ethyl acetate (3×150 ml). The organic extracts were combined, washed with water, brine, dried over anhydrous magnesium sulfate, and the solvent evaporated in vacuo to yield an oil. The oil was dissolved in 25 ml of acetonitrile and 4.6 g of fumaric acid was added. The mixture was warmed on the steam bath (ca. 15 min), and then left at ambient temperature for 15 hrs. The resultant solid was filtered and recrystallized from dimethylformamide (thrice) with cooling (ca. 5°) to yield 1.4 g (18.7%) of product, mp 161°-163° C.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C@H:3]([NH:8][C:9](=[O:32])[C@H:10]([CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:11]([N:13]([CH:21]=[O:22])[O:14]C1CCCCO1)[CH3:12])[C:4](=[O:7])[NH:5][CH3:6]>C(O)(=O)C.O>[CH3:33][C:2]([CH3:1])([CH3:34])[C@H:3]([NH:8][C:9](=[O:32])[C@H:10]([CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:11]([N:13]([CH:21]=[O:22])[OH:14])[CH3:12])[C:4](=[O:7])[NH:5][CH3:6]
Reactant: CNC(=O)[C@@H](NC(=O)[C@H](CCCc1ccccc1)[C@H](C)N(C=O)OC1CCCCO1)C(C)(C)C
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)[C@@H](NC(=O)[C@H](CCCc1ccccc1)[C@H](C)N(O)C=O)C(C)(C)C
Yield: 93 %

Procedure:
A solution of (2R,3S)-3-(Formyl-2-tetrahydropyranyloxyamino)-2-(3-phenyl-1-propyl)butanoic acid [(1S)-2,2-dimethyl-1-(methylcarbamoyl)-1-propyl]amide (3.0 g, 6.32 mmol) in acetic acid-water (4:1, 10 mL) is heated to 50° C. for 16 h. The reaction mixture is concentrated, then dissolved in toluene and concentrated in vacuo. The procedure is repeated once again to afford the crude product which is triturated from hot dichloromethane-diethyl ether to provide (2R,3S)-3-(Formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid [(1S)-2,2-dimethyl-1-(methylcarbamoyl)-1-propyl]amide as a white solid (2.3 g, 93% yield).
Reaction SMILES: COC(=O)C(C1C=CC(SCC2C=CC(C3C=CC(C(F)(F)F)=CN=3)=CC=2)=C(OC)C=1)(C)C.[CH3:34][O:35][C:36](=[O:49])[CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][C:45]([SH:47])=[CH:46][C:41]=2[O:40][C:39]1=[O:48].[F:50][C:51]([F:69])([F:68])[C:52]1[CH:67]=[CH:66][C:55]([CH2:56][O:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64]Cl)[CH:59]=2)=[CH:54][CH:53]=1>>[CH3:34][O:35][C:36](=[O:49])[CH2:37][N:38]1[C:42]2[CH:43]=[CH:44][C:45]([S:47][CH2:64][C:60]3[CH:61]=[CH:62][CH:63]=[C:58]([O:57][CH2:56][C:55]4[CH:66]=[CH:67][C:52]([C:51]([F:50])([F:68])[F:69])=[CH:53][CH:54]=4)[CH:59]=3)=[CH:46][C:41]=2[O:40][C:39]1=[O:48]
Reactant: FC(F)(F)c1ccc(COc2cccc(CCl)c2)cc1
Reactant: COC(=O)Cn1c(=O)oc2cc(S)ccc21
Agent: COC(=O)C(C)(C)c1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cn3)cc2)c(OC)c1
Product: COC(=O)Cn1c(=O)oc2cc(SCc3cccc(OCc4ccc(C(F)(F)F)cc4)c3)ccc21
Yield: 25 %

Procedure:
Compound 76D was prepared analogously to compound 21D using the product prepared from compound 76C and 6B. Yield was 25% after flash column purification. MS m/z 504 (M+1). 400 MHz 1H NMR (DMSO-d6) δ 7.61-6.71 (m, 11H), 5.05 (s, 2H), 4.50 (s, 2H), 3.99 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:16][OH:17])[CH:12]=[C:13]([CH3:15])[CH:14]=2)[C:5]([CH:18]([CH3:20])[CH3:19])=[C:4]([Cl:21])[N:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH:16]=[O:17])[C:5]([CH:18]([CH3:19])[CH3:20])=[C:4]([Cl:21])[N:3]=1
Reactant: Cc1cc(CO)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: Cc1cc(C=O)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A mixture of (68) (2.36 g, 7.22 mmol), pyridinium chlorochromate (1.56 g, 7.22 mmol), and dried celite (2 g) was stirred in dichloromethane (20 ml) for 2 hr. at room temperature. The mixture was then filtered through a short silica gel pad and washed with EA. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:15)) to afford 1.71 g (73%) of a pale yellow syrup. 1H NMR (200 MHz, CDCl3) δ 1.42 (6H, d, J=7.2 Hz), 2.49 (3H, s), 3.61 (1H, m), 7.20 (1H, s), 7.44 (1H, s), 7.62 (1H, s), 10.01 (1H, s).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:12]([Cl:16])(=O)(=[O:14])[OH:13]>>[N:7]1([C:1]2[CH:6]=[C:5]([S:12]([Cl:16])(=[O:14])=[O:13])[CH:4]=[CH:3][CH:2]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(N2CCCC2)cc1
Product: O=S(=O)(Cl)c1cccc(N2CCCC2)c1
Temperature: 60 °C
Yield: 7 %

Procedure:
1-phenylpyrrolidine (4.3 g, 29.25 mmol) was added dropwise to sulfurochloridic acid (20 mL) at 0° C. and the resulting solution was then maintained at 60° C. overnight. The reaction mixture was then quenched by adding 200 mL of ice/salt. The resulting solution was extracted with ethyl acetate (3×100 mL), and the organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography using a 1:500 ethyl acetate/petroleum ether solvent system. The collected fractions were combined and concentrated to give 0.5 g (7%) of 3-(pyrrolidin-1-yl)benzene-1-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.36 (m, 1H), 7.24 (d, 1H), 7.07 (s, 1H), 6.82 (d, 1H), 3.34 (t, 4H), 2.05 (t, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[C:10]1([C:16]2[S:20][C:19]([CH:21]=O)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[C:3]([F:9])=[C:4]([CH2:21][C:19]2[S:20][C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:17][CH:18]=2)[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=Cc1ccc(-c2ccccc2)s1
Product: Cc1ccc(Br)c(F)c1Cc1ccc(-c2ccccc2)s1

Procedure:
4-Bromo-3-fluorotoluene and 5-phenyl-2-thiophenecarboxaldehyde were treated in a manner similar to Reference Example 116 to give the target compound as pale blue powders. APCI-Mass m/Z 361/363 (M+H).