Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C@:20]([OH:30])([C@H:27]([SH:29])[CH3:28])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1>CN(C)C=O.C1C=CC=CC=1>[C:3]([CH2:2][S:29][C@H:27]([CH3:28])[C@:20]([C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[F:12])([OH:30])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)(=[O:4])[NH2:5]
Reactant: NC(=O)CBr
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C[C@@H](SCC(N)=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
58 mg (0.42 mmole) of 2-bromoacetamide and 48 mg (0.35 mmole) of potassium carbonate were added to a solution of 100 mg (0.35 mmole) of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol in 3 ml of anhydrous dimethylformamide, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was diluted with benzene and washed with a saturated aqueous solution of sodium chloride, after which the solvent was removed by distillation under reduced pressure. The virtually pure product thus obtained was recrystallized from a mixture of acetone and hexane to afford 90 mg of the title compound, melting at 144°-145° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[N+:36]=[N-:37])[CH:30]=1)=[O:28])C.N(C1C=C(C=CC=1)C(Cl)=O)=[N+]=[N-]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:20][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]=[N+:36]=[N-:37])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(N=[N+]=[N-])c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Agent: [N-]=[N+]=Nc1cccc(C(=O)Cl)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1cccc(N=[N+]=[N-])c1

Procedure:
Prepared (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (569 mg, 2 mmol) and 3-(3-azido-phenyl)-3-oxo-propionic acid ethyl ester (700 mg, 3 mmol; prepared from 3-azido-benzoyl chloride (Bioorg. Chem 1986, 134) using the procedure described in Synthesis, 1993, 290, method A; MS (EI) 233 (M+)) according to the general procedure K. Obtained as an orange solid (367 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][C@:5]1([CH3:30])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25]O)[C:19]=3[S:18](=[O:28])(=[O:27])[N:17]=2)[C:6]1=[O:29].N12CCCN=C1CCCCC2.C1(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)C=CC=CC=1>ClCCl>[N:58]([CH2:25][C:24]1[C:19]2[S:18](=[O:28])(=[O:27])[N:17]=[C:16]([C:7]3[C:6](=[O:29])[C@@:5]([CH2:4][CH2:3][C:2]([CH3:32])([CH3:31])[CH3:1])([CH3:30])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:21][C:20]=2[S:22][CH:23]=1)=[N+:59]=[N-:60]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)c2ccccc21
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN=[N+]=[N-])csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A solution of Example 185 (1 g, 2.11 mmol) in 25 mL of dichloromethane was cooled to to 0° C., treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.7 mL, 11.2 mmol) and diphenylphosphoryl azide (2.3 mL, 10.9 mmol), allowed to warm to room temp, stirred for 16 h, and concentrated onto silica gel. The crude material was chromatographed on silica gel with hexane, hexane/dichloromethane (1:1), followed by dichloromethane, and methanol/dichloromethane (1:99) to afford the title compound (610 mg, 59% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (td, J=12.7, 3.3 Hz, 1 H), 0.72 (s, 9 H), 0.81 (td, J=13.1, 4.6 Hz, 1 H), 1.57 (s, 3 H), 2.05 (m, 1 H), 2.22 (td, J=12.6, 4.6 Hz, 1 H), 4.56 (s, 2 H), 7.29 (m, J=8.6, 8.6 Hz, 1 H), 7.54 (s, 1 H), 7.74 (m, J=4.0 Hz, 2 H), 8.13 (d, J=7.7 Hz, 1 H), 14.09 (s, 1 H); MS (APCI+) m/z 498 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:18][C:19]1[C:23]([CH:24]=[CH2:25])=[CH:22][S:21][CH:20]=1>CN1C(=O)CCC1.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][CH2:24][C:23]3[C:19]([CH3:18])=[CH:20][S:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cscc1C
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cscc2C)CCN(C)C1
Reaction time: 0.08 h
Yield: 0.3 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (250 mg, 1.255 mmol) in NMP (1 mL), was added powdered KOH (490 mg, 8.75 mmol). After stirring for 5 min, 3-methyl-4-vinyl-thiophene (310 mg, 2.50 mmol) was added into the reaction mixture, which was stirred at 85° C. for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The organic layer was washed with water (6×30 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography using silica (100:200) and 2% MeOH-DCM, followed by reverse phase HPLC to yield 1.10 mg of 2,8-dimethyl-5-[2-(4-methyl-thiophen-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.3 (d, 1H), 7.24 (s, 1H), 7.07 (d, 1H), 6.92 (s, 1H), 6.78 (s, 1H), 4.6 (d, 1H), 4.3 (m, 3H), 3.62 (m, 1H), 3.3 (m, 3H), 3.0 (m, 4H), 2.8 (m, 1H), 2.4 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=O)(C)(C)C.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH2:27])=[CH:25][C:20]=2[O:19][CH2:18]1>>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C:10]([C@@H:9]3[CH2:13][C:14](=[O:16])[CH2:15][NH:8]3)=[O:12])=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: NCc1ccc2c(c1)OCO2
Product: O=C1CN[C@H](C(=O)NCc2ccc3c(c2)OCO3)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-oxoproline, and 1,3-benzodioxol-5-ylmethylamine the title compound was obtai-ned in 71% purity by LC/MS. MS(ESI+): m/z=263.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[CH3:22]>CC(C)=O>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH:27][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])[CH3:22]
Reactant: CCOC(=O)CCN
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNS(=O)(=O)c1cccc(OC)c1
Reaction time: 0.5 h

Procedure:
m-Methoxybenzenesulfonyl chloride (3.53 g, 0.017 mol) and Et3N (4.76 mL, 0.034 mol) were dissolved in acetone (35 mL) at 0° C. β-Alanine ethyl ester hydrochloride (2.0 g, 0.017 mol) was added and stirring was continued at room temperature under N2 for 0.5 h. The reaction mixture was concentrated, partitioned between 0.1N HCl solution and EtOAc. The aqueous layer was washed with EtOAc, the organics combined, washed with H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][CH:29]([C:31]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42]O)[CH2:38][CH2:37]2)[O:33][N:32]=1)[CH3:30].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:30][CH:29]([C:31]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][CH:39]([CH2:42][O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])(=[O:15])=[O:16])=[CH:12][CH:13]=4)=[CH:4][CH:3]=3)[CH2:40][CH2:41]2)[O:33][N:32]=1)[CH3:28]
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCNC(=O)OC(C)(C)C)cc4)cc3)CC2)n1
Yield: 44.7 %

Procedure:
The title compound (169 mg, 45%) was prepared as a white solid from 1,1-dimethylethyl (2-{[(4′-hydroxy-4-biphenylyl)sulfonyl]amino}ethyl)carbamate (246 mg, 0.63 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Step 3, 214 mg, 0.95 mmol) and Ph3P (249 mg, 0.95 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.187 mL, 0.95 mmol) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, DMSO-d6) δ 7.84-7.72 (m, 4H), 7.70-7.60 (m, 3H), 7.03 (d, 2H, J=8.8 Hz), 6.76 (t, 1H, J=5.4 Hz), 4.03-3.91 (m, 2H), 3.90 (d, 2H, J=6.4 Hz), 3.15-3.05 (m, 2H), 2.98-2.88 (m, 2H), 2.83-2.67 (m, 3H), 2.06-1.94 (m, 1H), 1.89-1.79 (m, 2H), 1.38-1.24 (m, 11H), 1.14 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 600 (M+H).
Reaction SMILES: [CH:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])([CH3:3])[CH3:2].[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH:1]([CH3:3])[CH3:2])=[O:5])=[N:7]1)=[O:16])[CH2:12][CH3:13]
Reactant: CC(C)S(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)n1cnc(S(=O)C(C)C)n1

Procedure:
A mixture of 6.4 g. 3-isopropylsulphinyl-1,2,4-triazole, 8.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give 1-dipropylcarbamoyl-3-isopropylsulphinyl-1,2,4-triazole as an oily residue which subsequently solidified, m.p. 15° - 20° C. Elemental analysis satisfactory.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][OH:14]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[OH:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.8 %

Procedure:
A solution of methane sulfonyl chloride (10.2 ml, 0.13 mol) in chloroform (100 mL) was added dropwise to a solution of (2-aminophenyl)methanol (15.0 g, 0.12 mol) in pyridine (100 mL) and chloroform (150 mL) under nitrogen over 1 h at 0° C. The reaction mixture was stirred for 12 h at ambient temperature and then washed with hydrochloric acid (2N, 200 ml×2). The organic phase was dried over anhydrous MgSO4 and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:3) to afford N-[2-(hydroxymethyl)phenyl]methanesulfonamide (13.0 g, 53% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:13])[C:3]=1[OH:14].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[N:23]=[C:24]=S>CO>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24]1[O:14][C:3]2[C:4]([F:13])=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Cc1cccc(Cl)c1N=C=S
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3c(C)cccc3Cl)oc2c1F
Reaction time: 120 h
Yield: 90.8 %

Procedure:
Methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.02 mmol) was dissolved in methanol (30 ml). To the resulting solution was added 2-chloro-6-methylphenyl isothiocyanate (841 mg, 4.58 mmol) at room temperature. After the resulting mixture was stirred for 5 days, mercuric oxide (yellow) (1.14 g, 4.36 mmol) was added thereto. The mixture was stirred at 70° C. for 23 hours. After cooling, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (30/1) eluate fractions, methyl (2-(2-chloro-6-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.45 g, 95%) was obtained as a red amorphous substance.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:15]([C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1)=[CH:8]2)=[O:17])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(C(=O)NC(C)C)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and isopropylamine to give 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid isopropylamide. LC-MS: m/e 368 (MH+).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:10]([Cl:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I-:21].[Na+]>CC(C)=O>[I:21][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:10]([Cl:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [I-]
Reactant: CCOC(=O)C(Br)c1ccc(C2CCCCC2)c(Cl)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C(I)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 40.5 g. (0.1 moles) of ethyl α-bromo-3-chloro-4-cyclohexylphenylacetate and 150 g. of sodium iodide in 1 liter of anhydrous acetone is refluxed for 4 hours. The reaction mixture is then evaporated to dryness and extracted with ether. The ether is then washed with water, dried and evaporated to dryness to obtain ethyl α-iodo-3-chloro-4-cyclohexylphenylacetate.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][C@@H:12]1[CH2:14][O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][CH:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1>CC#N>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:17]([NH:16][CH2:14][C@H:12]([OH:13])[CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:15])[CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=C(NC[C@@H]1CO1)OCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(NC[C@H](O)CNC(=O)OCc2ccccc2)C1
Yield: 68 %

Procedure:
The title compound was prepared in analogy to Example 17, step 17.1, starting from [(2R)-oxiranylmethyl]-carbamic acid benzyl ester (8.23 g; prepared according to WO 2004/002973) and rac-3-amino-1-Boc-pyrrolidine (7.40 g; commercial) in MeCN (300 mL), affording a colourless oil (10.7 g; 68% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[NH:15][CH3:16].[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH:15][CH3:16]
Reactant: CNc1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CNc1c(N)cc(C(F)(F)F)cc1Cl
Yield: 90.4 %

Procedure:
To a mixture of (2-chloro-6-nitro-4-trifluoromethylphenyl)-methylamine (3.70 g) and ethanol (60 ml), Raney® nickel (slurry in water, 0.5 ml) was added, and stirred under about 1 atm of hydrogen at room temperature for 1.5 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 2.95 g of 3-chloro-N2-methyl-5-trifluoromethylbenzene-1,2-diamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](N2CCOCC2)=[O:9])=[C:4]([F:16])[CH:3]=1.[CH3:17][Mg]Br.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[CH3:17])=[C:4]([F:16])[CH:3]=1
Reactant: O=C(c1ccc(Br)cc1F)N1CCOCC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.8 %

Procedure:
4-[(4-Bromo-2-fluorophenyl)carbonyl]morpholine (5.06 g, 17.6 mmol, 1.00 equiv) was dissolved in 150 mL of THF and the resultant solution was cooled to 0° C. Methyl magnesium bromide (17.6 mL, 3.0 M in Et2O, 52.7 mmol, 3.00 equiv) was added over 5 minutes via syringe. The reaction mixture was maintained for 30 minutes, an additional portion of methyl magnesium bromide was added (10 mL, 29.9 mmol, 1.70 equiv) and the reaction mixture was allowed to warm to room temperature. After an additional 1.5 h, the reaction mixture was poured into saturated NH4Cl. The mixture was diluted with EtOAc and the phases were separated. The organic phase was washed with 1N HCl, saturated NaHCO3, and saturated NaCl, then dried over Na2SO4, filtered and concentrated en vacuo. The resulting residue was purified by column chromatography (40 g SiO2, 0→10% EtOAc/Hexanes) to afford 2.59 g (68%) of a colorless oil. 1H NMR (CDCl3) δ 7.79 (t, J=8.2 Hz, 1H), 7.42-7.36 (m, 2H), 2.66 (d, J=5.0 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:26])C=1.C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[O:26]1[CH2:3][CH:2]1[CH2:1][C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CO2)CC1
Yield: 32.6 %

Procedure:
To a solution of 4.115 g of 4-allyl-1-(tert-butoxycarbonyl)piperidin-4-ol in dichloromethane (100 ml) were added 7.07 g of 3-chloroperbenzoic acid and 2.87 g of sodium hydrogencarbonate and the resulting mixture was heated under reflux for 24 hours. To the reaction mixture were added ethyl acetate and an aqueous solution of sodium metabisulfite and the resulting mixture was stirred for 1 hour. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichloromethane/ethyl acetate) to thereby give 1.43 g of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[O:23][CH3:24].[CH:25]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH:25]1([CH2:30][C:31]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[CH:6]=[C:5]3[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[O:23][CH3:24])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Reactant: O=C(O)CC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)CC4CCCC4)cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
A mixture of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.57 g.), cyclopentylacetic acid (0.23 g.), 4-(dimethylamino)pyridine (0.22 g.), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (0. 343 g.), was dissolved in dichloromethane (25 ml.), under an atmosphere of nitrogen, and stirred at room temperature for 18 hours. The mixture was poured into 1M hydrochloric acid (25 ml.), the separated aqueous layer extracted with dichloromethane (3×25 ml.), the combined organic extracts washed with water, brine, dried (MgSO4) and evaporated. The residual oil was crystallized from ethyl acetate to give the title compound (0.555 g. 73%) as a white powder; m.p. 180°-181° C.; partial NMR (250 MHz, DMSO-d6): 1.17(m,2H); 1.4-1.8 (m,6H); 2.25(m,3H); 3.70(s,3H, NMe); 3.82(s,3H, OMe); 3.92(s,3H, OMe); 3.97(s,2H, ArCH2); 9.62(br s,1 H, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=C(C#N)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:19]([OH:22])(=[O:21])[CH3:20].Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:20]([C:19]([OH:22])=[O:21])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a round bottom flask containing 3-(4-fluorophenyl)-1H-indazole-5-carbonitrile (8.05 g, 0.034 mol) was added acetic acid (250 mL) and concentrated HCl (250 mL). The reaction was heated to reflux temperature for 7.5 hours and then 105° C. for two and one half-hours. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and a solid crashed out of solution. The solid was collected by filtration and dried in a low temperature oven to yield the title compound (7.5 g, 86% yield). 1H NMR (DMSO-d6) δ 13.6 (br s, 1H), 13.0 (br s, 1H), 8.64 (s, 1H), 8.0–7.9 (m, 3H), 7.68 (d, 1H), 7.42 (t, 2H); ES-MS (m/z) 301 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N+:13]([O-:28])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOP(=O)(Cc1ccnc2ccccc12)OCC
Solvent: ClCCl
Product: CCOP(=O)(Cc1cc[n+]([O-])c2ccccc12)OCC
Reaction time: 0.75 h

Procedure:
To a solution of 5.7 g of 4-(diethylphosphonomethyl)quinoline in 100 ml of methylene chloride at room temperature is added 3.2 g of m-chloroperbenzoic acid. After reacting for 45 minutes, an additional 1.5 g portion of m-chloroperbenzoic acid is added, and the reaction mixture is stirred for one hour. The reaction mixture is washed with saturated potassium carbonate solution, dried over sodium sulfate and evaporated to dryness to give 4-(diethylphosphonomethyl)-quinoline-N-oxide.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:17]1([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of 4-bromo-2-nitroaniline 17 (1.0 g, 4.67 mmol), tributylphenyl tin (2.2 g, 6.07 mmol), bis(triphenylphosphine)palladium (II) chloride (164 mg, 0.234 mmol), and triphenylphosphine (613 mg, 2.34 mmol) in DMF (15 ml) was heated under N2 at 120° C. overnight. After the solution was cooled to room temperature, the reaction mixture was directly chromatographed on silica gel eluting with 2-5% EtOAc/Hexane to give 752 mg (75%) of 5 as a yellow solid: mp 169°-171° C.; IR (CHCl3) 3517, 3398, 3022, 1635, 1525, 1250; 1H NMR δ8.38 (1H, d, J=2.2), 7.66 (1H, dd, J=8.7, 2.2), 7.59-7.54 (2H, m), 7.49-7.34 (3H, m), 6.90 (1H, d, J=8.8), 6.13 (NH, brs); 13C NMR δ144.2, 139.3, 135.0, 130.9, 129.5, 127.8, 126.8, 124.4, 119.8, 112.8; Anal. Calcd for C12H10N2O2 : C, 67.28; H, 4.70; N, 13.08. Found: C, 67.38, H, 4.76; N, 13.01.