Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C>CO>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([C:1](=[O:3])[CH3:2])=[CH:5][NH:6]2)=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)c1c[nH]c2cc(CC(=O)O)ccc12
Solvent: CO
Product: COC(=O)Cc1ccc2c(C(C)=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (3-acetyl-1H-indol-6-yl)-acetic acid [39689-58-2] (500 mg, 2.85 mmol) in MeOH (14 mL), cooled to at 0° C., was added (trimethylsilyl)diazomethane (2M solution in Et2O; 6.00 mL, 12.0 mmol). After stirring at RT for 30 min, the reaction mixture was concentrated in vacuo to afford the title compound as a yellow wax. MS: 190 [M+H]+; tR (HPLC conditions k): 3.20 min. The material thus obtained was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].C=O.CN.[CH3:23][N:24]1[CH2:29]COC[CH2:25]1>CO.CCO.O>[CH2:1]([N:3]1[CH2:25][N:24]([CH3:29])[CH2:23][N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[C:4]1=[O:5])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CCNC(=O)Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: C=O
Agent: CN
Solvent: CO
Solvent: CCO
Solvent: O
Product: CCN1CN(C)CN(c2nc3ccc([N+](=O)[O-])cc3s2)C1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
N-Ethyl-N′-(6-nitro-1,3-benzothiazol-2-yl)urea (2.8 g) was suspended in about 100 mL 1:1 EtOH/H2O at room temperature. About 8 mL of a 37% aqueous solution of formaldehyde is added followed by addition of about 15 mL of a 2M solution of MeNH2 in MeOH, then about 2.2 mL of N-methylmorpholine. The solution was warmed to about 80° C. then allowed to stir for about 16 hours. The slurry was then cooled to room temperature, filtered and washed well with water. After drying in vacuo, about 3.2 grams was isolated. 1H NMR 1.13 (t, 3H, J=7.1 Hz), 2.55 (s, 3H), 3.38 (q, 2H, J=7.1 Hz), 4.39 (s, 2H), 5.16 (s, 2H), 7.81 (d, 1H, J=8.9 Hz), 8.22 (dd, 1H, J=2.4 Hz, J=8.9 Hz), 8.95 (d, 1H, J=2.4 Hz) LC/MS=3.33 min, 322 (MH+), 320(M−H−).
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][C:21](Cl)=[N:20]3)=[O:16])[C:9]=1[F:28])OC(C)(C)C.[CH3:30][N:31](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:28][C:9]1[C:8]([OH:7])=[CH:13][CH:12]=[C:11]([F:14])[C:10]=1[C:15]([C:17]1[CH:18]=[C:19]2[C:24]([N:23]=[CH:22][C:21]([C:30]#[N:31])=[N:20]2)=[CH:25][CH:26]=1)=[O:16]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cnc2ccc(C(=O)c3c(F)ccc(O)c3F)cc2n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
To a solution of tert-butyl (3-(3-chloroquinoxaline-6-carbonyl)-2,4-difluorophenyl) carbonate (80 mg, 0.2 mmol, 1 eq.) in DMF (5 mL) were added Zn(CN)2 (20 mg, 0.12 mmol, 0.6 eq.), DPPF (4 mg, 0.0064 mmol, 0.032 eq.) and Pd2(dba)3 under N2 protection. The resulting mixture was stirred at 120° C. overnight, then cooled and concentrated. The residue was purified via prep-HPLC to afford 7-(2,6-difluoro-3-hydroxybenzoyl)quinoxaline-2-carbonitrile as yellow oil (1.8 mg, 3%). LRMS (M−H+) m/z calculated 310.1, found 309.9. 1H NMR (CDCl3, 400 MHz) δ 9.18 (s, 1 H), 8.52-8.56 (m, 2H), 8.33-8.35 (d, 1 H), 7.18-7.24 (m, 1 H), 6.96-7.01 (m, 1 H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22](B(O)O)=[CH:23][C:18]=2[O:17][CH2:16]1>>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:2]3[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: Nc1nnc(-c2ccc3c(c2)OCO3)c(-c2ccccc2)n1
Yield: 61.8 %

Procedure:
6-(1,3-Benzodioxol-5-yl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 62%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and benzo[d][1,3]dioxol-5-ylboronic acid (57.0 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: ClC1C(C2C=CC=CC=2)=NN=C2N(CCI)N=C(C3C=CC=CC=3)C=12.[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:30]=[C:29]2[N:39]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][N:53]([CH3:56])[CH2:52][CH2:51]3)[N:40]=[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:28]=12.Cl.N1CCNCC1=[O:64].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:30]=[C:29]2[N:39]([CH2:48][CH2:49][N:50]3[CH2:51][CH2:52][N:53]([CH3:56])[C:54](=[O:64])[CH2:55]3)[N:40]=[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:28]=12
Reactant: O=C1CNCCN1
Reactant: CN1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Agent: Cl
Agent: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(CCn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1=O
Reaction time: 48 h

Procedure:
A solution of 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (example 74 step 1 (Compound 81)) (100 mg, 0.21 mmol) in CH2Cl2 (1 ml) was added to piperazinone hydrochloride (160 mg, 1.05 mmol) and diisopropylethylamine (DIPEA) (220 μl, 12.6 mmol) in CH2Cl2 (0.5 ml) and the reaction stirred at ambient for 2 days. Further piperazinone hydrochloride (160 mg, 1.05 mmol) and diisopropylethylamine (DIPEA) (220 μl, 12.6 mmol) were added and the reaction stirred for a further 24 h. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane, then 0 to 100% ethyl acetate/acetone) followed by preparative HPLC to give Compound 84 as a yellow glass solid (17 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:23])=[C:17]([CH:22]=1)[CH:18]=[N+:19]([CH3:21])[CH3:20].BrC1C=CC(F)=C(C=1)C=O.CNC>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:23])=[C:17]([CH:18]([N:19]([CH3:20])[CH3:21])[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[CH:22]=1
Reactant: C[N+](C)=Cc1cc(Br)ccc1F
Reactant: Cn1ccc2ccccc21
Agent: CNC
Agent: O=Cc1cc(Br)ccc1F
Agent: [Cl-]
Product: CN(C)C(c1cc(Br)ccc1F)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (5-bromo-2-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 5-bromo-2-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([NH2:9])=[N:7][N:8]=2)[CH2:3][CH2:2]1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:31](=O)[CH2:32][CH2:33][CH3:34])[C:26](OCC)=[O:27])=[CH:20][CH:19]=1)#[N:11]>ClC1C=CC(Cl)=CC=1Cl>[CH:1]1([C:4]2[N:5]=[C:6]3[NH:9][C:26](=[O:27])[C:25]([CH2:24][C:21]4[CH:22]=[CH:23][C:18]([C:13]5[C:12]([C:10]#[N:11])=[CH:17][CH:16]=[CH:15][CH:14]=5)=[CH:19][CH:20]=4)=[C:31]([CH2:32][CH2:33][CH3:34])[N:7]3[N:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1nnc(C2CC2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C3CC3)nn12
Yield: 21.3 %

Procedure:
A solution of 5-cyclopropyl-4H-1,2,4-triazol-3-amine (1 g) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (2.8 g) in 1,2,4-trichlorobenzene (20 mL) was stirred at 180° C. for 6 hr. After evaporation of the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.7 g, 21%).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][N:5]=[C:6]([C:12]([CH3:14])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[CH3:3][O:4][N:5]=[C:6]([C:12]([CH2:14][Br:1])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=NOC)C(=O)CBr

Procedure:
Bromine (100 g.) was dropwise added over 40 minutes under reflux to a solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (100 g.) in a mixture of carbon tetrachloride (300 ml.) and acetic acid (300 ml.). The mixture was stirred at 70° to 80° C. until the evolution of hydrogen bromide ceased. The reaction mixture was washed twice with water (300 ml.), a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solution was treated with activated charcoal (2 g.) and concentrated under reduced pressure to give ethyl 2-methoxyimino-4-bromoacetoacetate (a mixture of syn and anti isomers) (120.8 g.).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: COc1cccc(B(O)O)c1
Agent: O=Cc1cccc(B(O)O)c1
Product: COc1cccc(C2=NCC(=O)N(C)c3ccc(-c4ccccc4)cc32)c1
Yield: 10 %

Procedure:
Prepared from 5-Chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3-methoxyphenyl boronic acid. The title compound (11 mg) was obtained as a yellow solid, (yield=10%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1)[S:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([O-:22])=O)=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Na+].C(Cl)(=O)C(Cl)=O.Cl.[CH3:45][O:46][NH2:47].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:45][O:46][NH:47][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([S:13]([N:12]([C:3]2[N:4]=[CH:5][C:6]3[C:11]([C:2]=2[CH3:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=2)(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: CON
Reactant: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)[O-])cc2)ncc2ccccc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CONC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a suspension of sodium 4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate (107.7 mg, 0.200 mmol) prepared in Example 2 in chloroform (1 mL) was added oxalyl dichloride (21 μL, 0.240 mmol), and the mixture was stirred at room temperature for 2 hours. Then, thereto was added additional oxalyl dichloride (21 μL, 0.24 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Then, the resulting residue was suspended in chloroform (1 mL), and added dropwise to a suspension of O-methylhydroxylamine hydrochloride (50.1 mg, 0.600 mmol) and triethylamine (139 μL, 1.00 mmol) in chloroform (1 mL), and the mixture was stirred at room temperature for 1 hour. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→0:10) to give N-methoxy-4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)-benzamide (88.1 mg, 81%) as a white powder.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C@H:9]2OC(=O)N[C@@H:10]2C2C=CC=C(C#CC3C=CC=CC=3)C=2)[CH:6]=[CH:7][CH:8]=1.Br[C:30]1[CH:31]=[C:32]([C@@H:37]2[C@@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=3)[O:40][C:39](=[O:49])[NH:38]2)[C:33]([F:36])=[N:34][CH:35]=1.C1(C#C)C=CC=CC=1>>[F:36][C:33]1[C:32]([C@@H:37]2[C@@H:41]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=3)[O:40][C:39](=[O:49])[NH:38]2)=[CH:31][C:30]([C:10]#[C:9][C:5]2[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=2)=[CH:35][N:34]=1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Reactant: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2cccc(F)c2)O1
Solvent: C#Cc1ccccc1
Product: O=C1N[C@H](c2cc(C#Cc3ccccc3)cnc2F)[C@@H](c2cccc(F)c2)O1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(3-fluorophenyl)oxazolidin-2-one and phenylacetylene. 1H NMR (CDCl3) δ: 8.39 (d, J=0.9 Hz, 1H), 8.11 (dd, J=9.0, 2.0 Hz, 1H), 7.56 (dd, J=7.8, 1.7 Hz, 2H), 7.35-7.46 (m, 4H), 7.07-7.22 (m, 3H), 6.77 (s, 1H), 5.37 (d, J=5.2 Hz, 1H), 5.04 (d, J=5.2 Hz, 1H). 19F NMR (CDCl3) δ: −70.65 (d, J=13.0 Hz, 1F), −111.45 (br. s., 1F). 13C NMR (CDCl3) δ: 163.2, 158.8, 159.6, 150.5, 140.8, 139.8, 131.8, 131.0, 129.3, 128.7, 122.0, 121.2, 121.2, 119.8, 116.6, 112.7, 93.8, 84.0, 83.6, 58.0. Mass spec.: 377.2 (MH)+.
Reaction SMILES: [CH3:1][C@@H:2](CCCC1C=CC=CC=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7].Br[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][C@@H:2]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3](=[O:11])[CH2:4][P:5](=[O:10])([O:6][CH3:7])[O:8][CH3:9]
Reactant: BrCCc1ccccc1
Reactant: COP(=O)(CC(=O)[C@@H](C)CCCc1ccccc1)OC
Product: COP(=O)(CC(=O)[C@@H](C)CCc1ccccc1)OC

Procedure:
(S)-Dimethyl (3-methyl-2-oxo-5-phenylpentyl)phosphonate was prepared in the same manner as the second alternative preparation of (S)-(+)-dimethyl (3-methyl-2-oxo-6-phenylhexyl)phosphonate (15mb(i)) using the same sequence of reactions except that (2-bromoethyl)benzene was used instead of (3-bromopropyl)benzene. The crude product was purified by silica gel chromatography. Elution with ethyl acetate-heptane (50:50 v/v) afforded the title compound (460 mg) as a colorless oil; TLC Rf 0.14 (solvent system: 50:50 v/v ethyl acetate:heptanes); MS (ESI+) m/z 285.1 (M+H)+; 1H-NMR (CDCl3) δ 7.30-7.24 (m, 2H), 7.21-7.14 (m, 3H), 3.76 (d, J=14.65 Hz, 3H), 3.76 (d, J=8.06 Hz, 3H), 3.16-3.03 (m, 2H), 2.77 (q, J=6.84 Hz, 1H), 2.64-2.56 (m, 2H), 2.03 (ddt, 1H), 1.16 (d, J=6.96 Hz, 3H); [α]Tλ=α/cl, [α]21.9D=0.052/(0.01998 g/1.5 mL)(0.5)=+7.81° (c=1.33, CHCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1.C1(P(C2CCCCC2)C2(N(C)C)CC=CC=C2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][C:19]1[N:18]=[C:17]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Cc1cccc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)C1(P(C2CCCCC2)C2CCCCC2)CC=CC=C1c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)n1

Procedure:
From 1-(4-nitro-phenyl)-piperazine and 2-chloro-6-methylpyridine, by heating in the presence of palladium (II) acetate, 2-dicyclohexylphospino-2-(N,N′-dimethyl amino)biphenyl and caesium carbonate in a mixture of toluene and THF to give 1-(6-methyl-pyridin-2-yl)-4-(4-nitro-phenyl)-piperazine then catalytic hydrogenation over Raney nickel in methanol.
Reaction SMILES: Cl[C:2]1[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([Cl:28])[C:22]([F:29])=[CH:21][C:3]=1[C:4]([C:6](=[CH:12][NH:13][C@@H:14]([CH3:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[C:17]([O:16][CH2:15][C@@H:14]([N:13]1[C:2]2[C:3](=[CH:21][C:22]([F:29])=[C:23]([Cl:28])[C:24]=2[N+:25]([O-:27])=[O:26])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]1)[CH3:20])(=[O:19])[CH3:18]
Reactant: CCOC(=O)C(=CN[C@@H](C)COC(C)=O)C(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn([C@@H](C)COC(C)=O)c2c([N+](=O)[O-])c(Cl)c(F)cc2c1=O
Reaction time: 1.5 h
Yield: 95 %

Procedure:
45.69 g of (+) ethyl 2-(2,4-dichloro-3-nitro-5-fluorobenzoyl)-3-[(1-acetoxyprop-2(S)-yl)amino]acrylate was dissolved in 270 ml of acetonitrile under heating to 78˜82° C. 32.25 g (1.5 eq.) of K3PO4 was added in portions to the reaction mixture, which was then stirred at the same temperature for 1.5 hours. The reaction mixture was filtered under a reduced pressure and washed with 500 ml of dichloromethane. The filtrate was concentrated under a reduced pressure. The resulting residue was dissolved in 300 ml of dichloromethane and then washed with water. The organic layer was concentrated under a reduced pressure to give 46.0 g of (−) ethyl N-(acetoxy-prop-2(S)-yl)-6-fluoro-7-chloro-8-nitro-4-quinolone-3-carboxylate (Yield: 95.0%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:47][C:48](=[O:51])[CH2:49]Br)[CH3:46]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:49][C:48]([O:47][CH2:45][CH3:46])=[O:51])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1ccccc1
Temperature: 100 °C

Procedure:
To a solution of 60 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 20 ml of DMF, 73 mg of cesium carbonate and 38 mg of Bromo-acetic acid ethyl ester was added and heated to 100° C. for 4 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the subsequent reaction.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCN(CC)CC>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:35](=[O:36])[CH2:34][NH:33][C:31]([O:30][CH2:29][CH:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:28]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:32])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.6 %

Procedure:
A solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (5.72 g) in CH2Cl2 (150 mL) was treated with Et3N (3.51 g), N-(9-fluorenylmethyloxycarbonyl)glycine (7.93 g, 26.7 mmol), EDCI (3.80 g) and HOBt (4.33 g). After the reaction mixture was stirred at room temperature for 5 h, the mixture was washed with water (100 mL×3) and brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization from CH3CN/CH3OH (150 mL/1 mL) at 0° C. afforded 1-(tert-Butoxycarbonyl)-4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (5.75 g, 44%) as pale yellow crystals.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[O:8][C:7](=[O:9])[CH2:6][CH:5]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[Ca+2].[Cl-].Cl>C(O)C.O1CCCC1.C(OCC)(=O)C>[C:10]1([CH:5]([CH:4]([OH:8])[CH3:3])[CH2:6][CH2:7][OH:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1OC(=O)CC1c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)C(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 3.33 h
Yield: 85.5 %

Procedure:
0.64 g of sodium tetrahydroborate was added to a solution of 1.2 g of 5-methyl-4-phenyloxolane-2-one in 2 mL of ethanol and 20 mL of tetrahydrofuran in a nitrogen atmosphere at a temperature of 5° C. to 10° C., and thereafter, a solution of 2.0 g of calcium chloride in 8 mL of ethanol was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 200 minutes. Thereafter, 30 mL of ethyl acetate was added to the reaction mixture, and thereafter, 20 mL of 3 mol/L hydrochloric acid was added dropwise to the mixture. The organic layer was fractionated, and it was washed with a saturated sodium hydrogen carbonate aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.05 g of 3-phenylpentane-1,4-diol in the form of a colorless oily product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][C:3]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[CH:16][CH:17]=1.[ClH:30].[NH2:31][OH:32].N1C=CC=CC=1.CO>C(O)(=O)C>[ClH:30].[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[N:31][OH:32])=[CH:4][C:3]=1[C:12]1[N:13]=[N:14][C:15]([N:18]([CH3:29])[CH:19]2[CH2:20][C:21]([CH3:28])([CH3:27])[NH:22][C:23]([CH3:25])([CH3:26])[CH2:24]2)=[CH:16][CH:17]=1
Reactant: CN(c1ccc(-c2cc3c(cc2O)C(=O)CC3)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CN(c1ccc(-c2cc3c(cc2O)C(=NO)CC3)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a microwave vial was added 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-1-one (Example 35-1,150 mg, 0.38 mmol), hydroxylamine hydrochloride (264 mg, 3.80 mmol), pyridine (0.25 mL, 3.04 mmol) and MeOH (1.0 mL). The resulting suspension was stirred at RT for 1.5 hours. The reaction mixture was acidified with excess acetic acid and loaded onto an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford the title compound. MS [M+H+]=410.2, LCMS Rt=0.48 min [Method Q]; 1H NMR (400 MHz, DMSO-d6) ppm 10.94-11.13 (m, 1H), 8.91-9.21 (m, 1H), 8.29 (d, J=10.04 Hz, 1H), 8.09-8.21 (m, 1H), 7.83 (s, 1H), 7.52-7.73 (m, 1H), 7.08 (s, 1H), 4.83-5.31 (m, 1H), 2.91-3.04 (m, 5H), 2.74-2.85 (m, 2H), 1.91-2.09 (m, 2H), 1.79 (d, J=10.79 Hz, 2H), 1.53 (s, 6H), 1.47 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1.C(O)=O>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: CN(C)CCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Product: CN(C)CCCOc1ccc(N)cc1
Temperature: 60 °C

Procedure:
Palladium(II) hydroxide (20% on carbon; 0.4 g) was added to a solution of dimethyl-[3-(4-nitrophenoxy)propyl]amine (3.75 g) in ethanol (75 ml) under argon. Then formic acid (4 ml) was added dropwise, during which the reaction mixture heated to 60° C. while evolving much gas. After a reaction time of 90 minutes, the catalyst was filtered off and the filtrate was concentrated. The residue was partitioned between methyl tert-butyl ether and sodium hydroxide solution (2N). The organic phase was dried and concentrated. The product with the molecular weight of 194.28 (C11H18N2O); MS (ESI):195 ([M+H]+), was obtained in this way.