Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[CH:17]([O:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23])[CH3:18].[OH-:28].[Na+].O>C(O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[CH:17]([O:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]([NH2:23])=[O:28])[CH3:18]
Reactant: [OH-]
Reactant: CC(Oc1ncccc1C#N)c1nnc(-c2ccccc2C(F)(F)F)n1C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(Oc1ncccc1C(N)=O)c1nnc(-c2ccccc2C(F)(F)F)n1C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
2-(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)nicotinonitrile (270 mg) was dissolved in ethanol (10 ml), a 1M aqueous sodium hydroxide solution (3.7 ml) was added thereto, followed by stirring at 70° C. for 5 hours. The reaction solution was cooled to room temperature, and water was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting solid was washed with ethyl acetate, to obtain, as a colorless solid, 2-(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)nicotinamide (120 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:21]([N:24]1[C:28]([C:29]2[N:38]=[C:37]3[N:31]([CH2:32][CH2:33][O:34][C:35]4[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][C:36]=43)[CH:30]=2)=[N:27][CH:26]=[N:25]1)([CH3:23])[CH3:22]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:43]([C:40]2[CH:41]=[CH:42][C:35]3[O:34][CH2:33][CH2:32][N:31]4[C:37](=[N:38][C:29]([C:28]5[N:24]([CH:21]([CH3:22])[CH3:23])[N:25]=[CH:26][N:27]=5)=[CH:30]4)[C:36]=3[CH:39]=2)(=[O:45])=[O:44])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (216 mg, 1.16 mmol) and NEt3 (272 μL, 1.93 mmol) in DCM (30 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (270 mg, 0.39 mmol) in DCM (20 mL) and the resulting mixture warmed to RT after 10 min then stirred for 30 min. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-5% MeOH in DCM) affording 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl]piperazine-1-carboxylic acid tert-butyl ester (196 mg, 93%) as a white solid. LCMS: RT 4.72 min [M+H]+ 544.3. 1H NMR (DMSO, 400 MHz): δ 8.77 (1H, d, J=2.43 Hz), 8.01 (1H, s), 7.94 (1H, d, J=0.61 Hz), 7.63 (1H, dd, J=8.64, 2.44 Hz), 7.28 (1H, d, J=8.64 Hz), 5.75-5.71 (1H, m), 4.67-4.57 (4H, m), 3.44-3.38 (4H, m), 2.91 (4H, t, J=4.83 Hz), 1.50 (6H, d, J=6.62 Hz), 1.32 (9H, s)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([OH:18])=O)[CH:12]=[C:6]2[C:5]=1[NH:22][C@@H:23]([CH:25]1[CH2:27][CH2:26]1)[CH3:24])(=[O:3])[NH2:2].[CH3:28][NH:29][CH3:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:25]1([C@H:23]([NH:22][C:5]2[C:6]3[N:7]([CH:10]=[C:11]([C:13]4[CH:21]=[CH:20][CH:19]=[C:15]([C:16](=[O:18])[N:29]([CH3:30])[CH3:28])[CH:14]=4)[CH:12]=3)[N:8]=[CH:9][C:4]=2[C:1]([NH2:2])=[O:3])[CH3:24])[CH2:26][CH2:27]1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(C(=O)O)c3)cc12)C1CC1
Reactant: CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(C(=O)N(C)C)c3)cc12)C1CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
To a solution of (R)-3-(3-carbamoyl-4-(1-cyclopropylethylamino) pyrrolo[1,2-b]pyridazin-6-yl)benzoic acid (Example 85, 15 mg, 0.041 mmol), dimethylamine (0.021 mL, 0.041 mmol) and triethylamine (8.61 μl, 0.062 mmol) in DMF (0.5 mL) was added BOP (18.21 mg, 0.041 mmol) which was stirred at 23° C. for 30 minutes. The reaction mixture was purified by reverse-phase preparative HPLC (condition C) to yield the title compound (5.7 mg, 35%). HPLC (condition H): retention time=1.47 minutes. LC/MS (M+H)+=392.3. 1H NMR (500 MHz, MeOD) δ ppm 8.06 (1 H, s), 7.86 (1 H, d, J=1.9 Hz), 7.67-7.71 (1 H, m), 7.64 (1 H, t, J=1.4 Hz), 7.45 (1 H, t, J=7.6 Hz), 7.24-7.27 (1 H, m), 7.09 (1 H, d, J=1.7 Hz), 4.01-4.09 (1H, m), 3.13 (3 H, s), 3.04 (3 H, s), 1.44 (3 H, d, J=6.4 Hz), 1.09-1.18 (1 H, m), 0.57 (2H, dd, J=13.5, 8.7 Hz), 0.34-0.41 (2 H, m).
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][C:43]=1[O:44][CH3:45])[C:32]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=O.C(OP([CH2:54][C:55]#[N:56])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:54][C:55]#[N:56])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: COc1ccc(C(=O)c2ccc(F)cc2)cc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc(F)cc2)cc1OC

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(4′-fluorophenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3,4-dimethoxy-4′-fluorobenzophenone (1.3 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (5.5 mL, 5.5 mmol, 1M) with a reaction time of 22 hours at room temperature. The crude product was purified by chromatography (silica gel, 1% ethyl acetate/methylene chloride) to afford 2.38 g (55%) of a mixture of the E and Z isomers as a white solid: mp 100-102° C.; 1H NMR (CDCl3) δ7.54-6.74 (m, 14 H), 5.67 (s, 1 H), 5.57 (s, 1H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.83 (s, 3 H); 13C NMR (CDCl3) δ166.0, 165.6, 162.0, 161.6, 151.3, 150.7, 148.9, 148.7, 135.4, 135.4, 133.2, 133.1, 131.7, 131.6, 131.3, 130.7, 130.5, 129.2, 123.1, 122.1, 118.1, 118.0, 115.8, 115.8, 115.5, 115.4, 112.6, 111.0, 110.8, 93.4, 93.2, 56.0, 56.0, 55.9; Anal. Calcd for C17H14FNO2. Theoretical: C, 72.07; H, 4.98; N, 4.94. Found: C, 71.91; H, 4.98; N, 4.79.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>O>[Br:13][C:14]1[CH:15]=[CH:16][C:17](/[C:20](=[CH:6]\[C:5]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])/[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C(O)/C(=C/c1ccc(Cl)cc1[N+](=O)[O-])c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A 2 L flask equipped with a mechanical stirrer was charged with 183 g of 2-nitro-4-chlorobenzaldehyde, 212 g of 4-bromophenylacetic acid and 233 mL of acetic anhydride. To this solution was added 82 g of potassium carbonate and the reaction was stirred overnight at 100° C. The resulting dark mixture was cooled down to room temperature and 1.6 L of water was added followed by 800 mL of 10% HCl. The solution was decanted and taken up in water/ethyl acetate. Layers were separated, organic phase was washed with brine, dried over magnesium sulphate and volatiles were removed under reduced pressure. The residue was triturated in EtOH and the mother liquor was triturated 4 more times with EtOH to afford 219 g of the desired (2E)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH:4]=C[CH:2]=1.COC1C=NC2C(C=1)=CC=C1C=CC=CC=21.C([Li])CCC.CCO[C:39]([CH3:41])=[O:40]>C1COCC1>[CH3:2][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH:4]=[CH:41][CH:39]1[OH:40]
Reactant: CCOC(C)=O
Reactant: c1ccc2c(c1)ccc1cccnc12
Agent: COc1cnc2c(ccc3ccccc32)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1c2c(ccc3ccccc23)C=CC1O
Reaction time: 1 h

Procedure:
Compound 13 was alkylated with Mel according to a general amino group alkylation procedure as follows. The 3-methoxybenzoquinoline derivative (100 mg) 13 was suspended in 5 mL of dry THF and cooled to -5° C. (ice/NaCl). 1.1 equivalents of n-butyl lithium (1 M) was added dropwise, and the reaction was stirred for 1 hour. 3 equivalents of the Mel alkylating agent was added slowly and the reaction was allowed to stir at room temperature for 2 hours. Aqueous work-up using NH4C1 and EtOAc gave a crude alkylated 3-methoxybenzoquinoline intermediate 14. Intermediate 14 was then purified by normal phase flash chromatography employing EtOAc: hexane (1:19) as the mobile phase (1HNMR: CD3Cl d 8.1 (broad d, 1 H, J=8.1 Hz), 7.68(dd, 1 H, J=8.1, 1.8 Hz), 7.34 (m, 2 H), 6.8 (s, 1 H), 3.92 (s, 3 H), 3.21 (m, 2 H), 2.94 (s, 3 H), 2.77 (t, 2H, J=6.6 Hz), 1.92 (m, 2 H)). Subsequent methoxy group deprotection by the general boron tribromide procedure described above in Example 1 resulted in the N-methyl-hydroxybenzoquinoline derivative 15.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C@@H:12]3[N:6]3[CH2:7][CH2:8][NH:9][C:10]([CH:11]=1)=[C:5]23.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17][C@@H:12]3[N:6]3[CH2:7][CH2:8][NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCN3
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCN3
Yield: 61.8 %

Procedure:
Tert-butyl (6bR,10aS)-5-(2,4-dichlorophenyl)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (37 mg, 60%) was prepared via coupling of tert-butyl (6bR,10aS)-5-bromo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (50 mg, 0.13 mmol) with 2,4-dichlorophenyl boronic acid (74 mg, 0.39 mmol) as illustrated above using the general procedure for Suzuki coupling. 1H NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.82–1.96 (m, 2H), 2.74–2.82 (m, 1H), 2.99–3.05 (m, 1H), 3.16–3.22 (m, 2H), 3.33–3.39 (m, 1H), 3.43–3.50 (m, 1H), 3.52–3.57 (m, 1H), 3.62–3.69 (m, 1H), 3.43–3.50 (m, 1H), 3.52–3.57 (m, 1H), 3.62–3.69 (m, 1H), 3.71–3.79 (m, 1H), 3.80–3.85 (m, 1H), 3.89–4.14 (m, 1H), 6.44 (s, 1H), 6.59 (s, 1H), 7.22 (s, 2H), 7.42 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:23]=[C:22]([OH:24])[CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]([C:10]1[S:11][C:12]([S:26][CH3:27])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[Cl:29])[CH:21]=[C:22]([OH:24])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(O)cc(Br)c1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(O)cc(-c2ccccc2Cl)c1
Yield: 23.5 %

Procedure:
Following the procedure outlined in Example 1: step c, {[4-(3-bromo-5-hydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (80 mg, 0.158 mmol) was reacted with 2-chlorophenylboronic acid (98.6 mg, 0.631 mmol), Na2CO3 (134 mg, 1.26 mmol), and Pd(PPh3)4 (45.5 mg, 0.039 mmol). Aqueous workup followed by SiO2 flash chromatography yielded the title compound (20 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([C:8]3=O)[CH2:6]1)[CH2:12]2)=[O:4].[NH3:16].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH2:16])[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: N
Reactant: COC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C12CC3CC(C1)C(N)C(C3)C2
Reaction time: 18 h

Procedure:
5 g of 4-oxoadamantane-1-carboxylic acid methyl ester are placed in 26 ml of methanol under nitrogen. 86 ml of a 7N solution of ammonia in methanol are added. The reaction medium is stirred for 18 h, 4 g of sodium borohydride are then added at 0° C. and the reaction medium is stirred for a further 3 h. After concentrating to dryness under reduced pressure and adding water and ethyl acetate, the aqueous phase is extracted three times in ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated to dryness. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of heptane/acetone/methanol/NH4OH solvent from 1/0/0 to 4/5/1/0.1. 1.5 g of 4-aminoadamantane-1-carboxylic acid methyl ester are obtained in the form of a mixture of cis/trans (1/3) isomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20]Br.Cl.[CH3:24][NH:25][CH3:26].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20][N:25]([CH3:26])[CH3:24]
Reactant: CNC
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1CN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.102 g (0.273 mmol) of the above (example 45A]) prepared 2-bromomethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester was dissolved in 1.5 ml of acetonitrile and treated with 0.027 g (0.331 mmol) of dimethylamine hydrochloride and 0.080 ml (2 eq.) of triethylamine. After stirring for 2 h at ambient temperature, the reaction mixture was poured onto crashed ice/KHSO4-solution and extracted twice with AcOEt. Washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, AcOEt/MeOH/NEt3=9/1/0.05), produced 0.047 g of pure title compound as off-white crystals.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].[CH2:8]([OH:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:4][CH2:5][CH2:6][Cl:7])[O:10][CH2:8][CH3:9]
Reactant: O=C(Cl)OCCCl
Reactant: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)OCCCl
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a solution of chloroethyl chloroformate (23.16 g, 0.162 mol) and ethanol (7.45 g, 0.162 mol) in methylene chloride (200 ml), pyridine (12.82 g, 0.162 mol) was added at 0° C. After 10 min at 0° C. and 21 hours at 25° C. the reaction mixture was washed with aqueous hydrochloric acid (100 ml), aqueous saturated sodium hydrogen carbonate (100 ml) and water (100 ml). The solvent was removed under reduced pressure after drying (MgSO4), giving 18.5 g (74%) of the intermediate ethyl chloroethyl carbonate as a crude product.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[N:5]=1)=[C:2]=[S:3].[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[N:20]([CH:24]([CH3:29])[C:25]([NH:27][NH2:28])=[O:26])[N:19]=1>C(Cl)Cl>[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[N:20]([CH:24]([CH3:29])[C:25]([NH:27][NH:28][C:2](=[S:3])[NH:1][C:4]2[CH:8]=[CH:7][N:6]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:5]=2)=[O:26])[N:19]=1
Reactant: Cc1cccc(Cn2ccc(N=C=S)n2)n1
Reactant: Cc1cc(C)n(C(C)C(=O)NN)n1
Solvent: ClCCl
Product: Cc1cccc(Cn2ccc(NC(=S)NNC(=O)C(C)n3nc(C)cc3C)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Intermediate 74 2[(3-isothiocyanato-1H-pyrazol-1-yl)methyl]-6-methylpyridine (101 mg, 0.439 mmol) was dissolved in 4 mL of DCM, and then Intermediate 102 2-(3,5-dimethyl-1H-pyrazol-1-yl)propanohydrazide (80 mg, 0.439 mmol) was added. The mixture was stirred at room temperature for 2 h. Solvent was evaporated under vacuum to give 2-[2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl]-N-{1-[(6-methyl-2-pyridinyl)methyl]-1H-pyrazol-3-yl}hydrazinecarbothioamide (181 mg, 0.439 mmol, 100% yield) as yellow solid. [ES+MS] m/z 413 (MH+)]. Solid was dissolved in 5 mL of POCl3 and the mixture was stirred at 100° C., until no starting material was detected (1 h 30 minutes). Crude of reaction was partitioned between DCM and distilled water. Organic layer was dried over MgSO4 (anh), filtered and concentrated to give a light yellow solid. This solid was purified by HPLC preparative using X-Terra chromatography column (30 mm×150 mm), gradient 0% to 40% ACN/H2O, in neutral conditions to yield the title compound as a white solid (22 mg, 12.7%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.87 (br s, 1H), 7.77 (d, 1H), 7.59-7.65 (m, 1H), 7.15-7.17 (m, 1H), 6.77-6.80 (m, 1H), 6.01 (d, 1H), 5.83 (br s, 1H), 5.77 (q, 1H), 5.26 (s, 2H), 2.45 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H), 1.78 (d, 3H). [ES+MS] m/z 395 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:22])=[CH:15][CH:14]=1
Reactant: C1CCNCC1
Reactant: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Product: CC1=C(C)C(=O)C(Cc2ccc(CCC(=O)N3CCCCC3)cc2)=C(C)C1=O
Yield: 175 %

Procedure:
3-[4-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (25 mg, 0.08 mmol) and piperidine (0.012 ml, 0.12 mmol) were used, and a method similar to that described in Production Example 46 was employed to obtain the title compound (53 mg, 0.14 mmol, yield 59%).
Reaction SMILES: [NH2:1][C:2]1[C:16]2[C:15](=[O:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][N:7]3[C@@H:8]([CH2:11][F:12])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:22].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][CH2:31][NH2:32].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:16]2[C:15](=[O:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][N:7]3[C@@H:8]([CH2:11][F:12])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:32][CH2:31][CH2:30][NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[C:3]=1[F:22]
Reactant: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](CF)CO2
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCNc2ccccn2)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](CF)CO2
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 67.1 %

Procedure:
A mixture of (3R)-8-amino-9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (200 mg, 0.636 mmol), 2-(2-pyridylamino)ethylamine (131 mg, 0.955 mmol), and triethylamine (0.13 mL, 0.933 mmol) in DMSO (2.0 mL) was stirred at 120° C. for 2.5 h. After dilution of the reaction mixture with 10% MeOH in CHCl3, the whole mixture washed with water and the washing was extracted with 10% MeOH in CHCl3 three times. The combined the organic layer and the extracts washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography of the residue (10% MeOH in CHCl3) gave (3R)-8-amino-9-fluoro-3-fluoromethyl-2,3-dihydro-7-oxo-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (184 mg, 67%) as a yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:23][OH:24].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:23][OH:24])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(C(CCC(=O)O)=NO)cc2)cc1
Reaction time: 60 h
Yield: 49.6 %

Procedure:
A stirred suspension of 4-(4′-cyano-biphenyl-4-yl)-4-oxo-butyric acid (0.7908 g, 0.002831 mol), hydroxylamine hydrochloride (0.2038 g, 0.00293 mol), sodium carbonate (0.3158 g, 0.00298 mol) in absolute ethanol (17 mL) was refluxed under nitrogen for 12 hours and allowed to cool. The mixture was allowed to stand for 2.5 days for convenience. Volatiles were rotary evaporated, and the residue was partitioned between dichloromethane-tetrahydrofuran (50/50 v/v) and 0.05 M aqueous hydrochloric acid (60 mL). The aqueous layer was extracted with additional organics. The extracts were combined, dried (Na2SO4) and rotary evaporated. The residue was dissolved/suspended in dichloromethane and chromatographed on silica gel (165 g, 230-400 mesh), eluting with dichloromethane-methanol (25:1, 30×125 mL; 15:1, 5×125 mL) to give 0.413 g of 4-(4′-cyano-biphenyl-4-yl)-4-hydroxyimino-butyric acid as an off-white solid; mp 157-159° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:23]#[N:24].[K+].Cl>O1CCCC1.O>[OH:22][CH:21]([CH:9]1[CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13][N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:23]#[N:24]
Reactant: O=CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
To a solution of 5.2 g of crude 1,4-dibenzyl-2-formylpiperazine in a mixture of 30 ml of tetrahydrofuran and 10 ml of water are added 2.2 g (33.8 mmoles) of potassium cyanide and 3.4 ml of concentrated hydrochloric acid under ice-cooling, and the mixture is stirred for 30 minutes, mixed with water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 5.70 g of crude oily 2-hydroxy-2-(1,4-dibenzylpiperazin-2-yl)acetonitrile.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH3:9]>>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: N
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
The cultures of H-9183 strain as obtained in Example 1 were suitably diluted, to which was added fumaric acid to the concentration of 100 g/liter. Then, ammonia was added thereto to adjust the pH at 8.7. The reaction was carried out at 30° C. with gently stirring.