Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Boc-Val-OH (8.69 g, 40.0 mmol) and Gly-OBzl.HCl (8.07 g, 40.0 mmol) were dissolved in methylene chloride (100 ml), and the solution was maintained at 0° C. Triethylamine (6.13 ml, 44.0 mmol), HOBt (1-hydroxybenzotriazole, 6.74 g, 44.0 mmol), and WSC.HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 8.44 g, 44.0 mmol) were added to the solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (50 ml), 5% citric acid aqueous solution (50 ml×twice), saturated brine (50 ml), 5% sodium hydrogencarbonate aqueous solution (50 ml×twice), and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, then the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain white crystals of Boc-Val-Gly-OBzl (13.2 g, 36.2 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=3)[N:11]=2)[N:8]=1.[Cl:22]N1C(=O)CCC1=O>C(#N)C.O.C([O-])(O)=O.[Na+]>[Cl:22][C:9]1[N:7]2[N:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]2=[N:11][C:10]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)cn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Cl)n2n1
Temperature: 60 °C
Yield: 98.9 %

Procedure:
To a stirred solution of 6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.250 g, 0.879 mmol) in acetonitrile (20 mL) is added N-chlorosuccinimide (0.879 mmol) and the mixture is heated at 60° C. for 8 hours. The reaction mixture is diluted with water (50 mL), and sat. aqueous NaHCO3 (50 mL). The precipitate that forms is collected by filtration, washed with water (3×25 mL) and dried under vacuum to give the title compound (0.277 g, 98% yield) as a yellow solid: Rf 0.60 (1:1 EtOAc:hexanes); LCMS (m/z)=319.3, 321.2 [M+H]+, tR=3.02 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[C:25]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([F:49])[C:39]([C:42]4[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=4)=[C:40]([F:41])[C:35]=3[N:34]=[C:33]2[O:50][CH:51]2[CH2:56][CH2:55][CH:54]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:53][CH2:52]2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O.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:25]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:26]=[CH:27][C:28]([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([F:49])[C:39]([C:42]4[CH:43]=[CH:44][C:45]([C:13]5[CH:12]=[CH:11][C:10]([C:8]([N:5]6[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]6)=[O:9])=[CH:15][CH:14]=5)=[CH:46][CH:47]=4)=[C:40]([F:41])[C:35]=3[N:34]=[C:33]2[O:50][CH:51]2[CH2:52][CH2:53][CH:54]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:55][CH2:56]2)=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(O)CC3)cc2)OC1(C)C
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(Br)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccc(C(=O)N6CCC(O)CC6)cc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 120 °C

Procedure:
To a yellow solution of (4-hydroxypiperidin-1-yl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone (0.147 g, 0.443 mmol), ethyl 4-{[1-(biphenyl-4-ylmethyl)-5-(4-bromophenyl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclohexane-carboxylate (0.260 g, 0.403 mmol), and Pd(PPh3)4 (0.028 g, 0.024 mmol) was added 1 M K2CO3 (1.20 mL, 1.20 mmol) dropwise via syringe. The mixture was heated at 120° C. for 45 min, and then diluted with EtOAc and H2O. The aqueous layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (100% EtOAc) afforded the desired compound as a ˜2:1 mixture of trans/cis isomers. The cis/trans isomers were separated via reverse phase Gilson™ HPLC (60-100% MeCN/H2O) to afford a faster eluting isomer A and a slower eluting isomer B as white solids.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.[CH3:12][O:13][C:14]([NH:16][C:17](=NC(OC)=O)SC)=[O:15]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]=[C:17]([NH:16][C:14](=[O:15])[O:13][CH3:12])[NH:8][C:6]=2[CH:7]=1
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: Nc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cnc(Br)cc2[nH]1
Temperature: 75 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A solution of 2-bromo-5-nitropyridin-4-amine (1.5 g, 6.9 mmol) in acetic acid (20 mL) was added in portions into a 75° C. suspension of iron powder (1.5 g, 27 mmol) in acetic acid (20 mL). The reaction mixture was stirred at 75° C. for 2 h, cooled to room temperature, and filtered through celite. To the filtrate was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.4 g, 6.9 mmol), and the mixture was stirred at 65° C. for 60 h. The reaction mixture was cooled to room temperature and concentrated. The solid residue was triturated with dichloromethane and dried to give the title Compound (1.8 g, quantitative yield) as an orange solid. MS (EI) for C8H7BrN4O2: 271/273 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]2[C:14]([OH:30])=[CH:15][C:16]([CH:18]([CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH3:19])=[CH:17][C:4]=2[O:3]1.C(O)C>CCOCC.[Pd]>[CH3:31][C:2]1([CH3:1])[CH2:7][CH:6]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[C:5]2[C:14]([OH:30])=[CH:15][C:16]([CH:18]([CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH3:19])=[CH:17][C:4]=2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C=C2c1ccncc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)CC2c1ccncc1

Procedure:
3.0 g. (0.0072 mole) of the compound of Example 3 was hydrogenated in 100 ml. of ethanol at 3 atmospheres employing 0.7 g. of 5% Pd/C. After the reaction was completed the ethanol was stripped off, the obtained white glass dissolved in ether and a white solid isolated which, after recrystallization from acetonitrile, gave a m.p. of 162°-164° C. The structure was confirmed by NMR.
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:26]([Zn+])[CH:27]([CH3:29])[CH3:28]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([C:20]#[N:21])[CH:15]=1)[N:12]([CH3:22])[C@H:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@@H:10]21)[CH:27]([CH3:29])[CH3:28]
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Reactant: CC(C)C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CC(C)Cc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
Following the general procedure for Example 127–146, the title compound was prepared (13 mg, 48%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), iso-butylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 270 (base, M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([OH:16])[C:9]([C:13]([OH:15])=[O:14])=[CH:10]2)=[CH:5][CH:4]=1)=O.C(O)(=O)C.[CH3:21][CH:22]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH3:23].C([BH3-])#N.[Na+].Cl>CO>[OH:16][C:8]1[C:9]([C:13]([OH:15])=[O:14])=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([CH2:1][NH:28][C:27]1[CH:29]=[CH:30][C:24]([CH:22]([CH3:23])[CH3:21])=[CH:25][CH:26]=1)[CH:12]=2
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=Cc1ccc2cc(O)c(C(=O)O)cc2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1ccc(NCc2ccc3cc(O)c(C(=O)O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
7-Formyl-3-hydroxynaphthalene-2-carboxylic acid (40 mg, 0.19 mmol) (example 342) was suspended in methanol (300 μL). Acetic acid (16 μL, 17 mg, 0.28 mmol) and 4-(2-propyl)aniline (40 μL, 40 mg, 0.30 mmol) were added consecutively, and the resulting mixture was stirred vigorously at room temperature for 2 hours. Sodium cyanoborohydride (1.0 M in tetrahydrofuran, 300 μL, 0.3 mmol) was added, and the stirring was continued for another 17 hours. The reaction mixture was poured into 6 N hydrochloric acid (aq.) (6 mL), and the precipitate was filtered off and rinsed with water (3×2 mL) to yield the title compound (40 mg) as its hydrochloride salt. No further purification was necessary.
Reaction SMILES: [C-:1]#[N:2].[K+].FC(F)(F)S(O[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([CH3:19])[C:11]=1[CH3:20])(=O)=O.S([O-])(O)(=O)=O.[K+].O>O1CCCC1>[CH3:20][C:11]1[C:12]([CH3:19])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[C:1]#[N:2]
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)ccc([N+](=O)[O-])c1C
Reactant: [C-]#N
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C#N)ccc([N+](=O)[O-])c1C
Reaction time: 10 h
Yield: 91 %

Procedure:
Potassium cyanide (2.26 g, 34.7 mmol) was added to a solution of 2,3-dimethyl-4-nitrophenyl trifluoromethane-sulfonate (5.20 g, 17.4 mmol) in tetrahydrofuran (21 ml) at room temperature, followed by deaeration. After tetrakistriphenylphosphine (1.00 g, 0.865 mmol) was added thereto, deaeration was conducted again and then the reaction was carried out under reflux conditions for 10 hours. A 0.5M-aqueous potassium hydrogensulfate solution and then water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and distilled to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: n-hexane/chloroform) to obtain 2,3-dimethyl-4-nitrobenzonitrile (2.79 g, 90.9%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([CH3:11])[CH3:10].C(N(CC)CC)C>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:15]2[CH2:16][CH2:17][N:12]([CH:9]([CH3:11])[CH3:10])[CH2:13][CH2:14]2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2,6-dichloropyrazine (250.0 mg, 1.678 mmol) in 1,4-dioxane (2 mL) was added 1-isopropylpiperazine (0.29 mL, 2.014 mmol) and triethylamine (0.70 mL, 5.034 mmol). The reaction mixture was stirred at room temperature for 1 day, filtered through Celite (1,4-dioxane eluent) then concentrated. Purification by flash column chromatography on silica gel using 100:5:1 EtOAc/MeOH/NH4OH (0 to 100%) in EtOAc provided the product. LCMS-ESI+ calc'd for C11H18ClN4 (M+H+): 241.1; Found: 241.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]3)[N:11]3[C:24](=[O:27])[NH:25][N:26]=[C:10]3[C:9]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1.ClC1C=CC(C2N=C(N3CC(NCC)(C(N)=O)C3)N3C(=O)N(CC)N=C3C=2C2C=CC(Cl)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]3)[N:11]3[C:24](=[O:27])[N:25]([CH2:41][C:40]4[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:45])[F:46])=[CH:44][CH:43]=4)[N:26]=[C:10]3[C:9]=2[C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[CH:6][CH:7]=1
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3n[nH]c(=O)n23)C1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Product: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(Cc4ccc(C(F)(F)F)cc4)c(=O)n23)C1

Procedure:
The title compound was prepared by coupling 1-(7,8-bis(4-chlorophenyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide with 4-trifluoromethylbenzyl bromide in a manner analogous to that in which 1-(7,8-bis(4-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide was prepared. HPLC/MS: retention time=3.866 min, [M+H]30 =656.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O)(C)C>CC(N(C)C)=O>[CH3:10][C@@H:7]1[N:6]2[C:5]3[C:14]([C:13]([C:12]([C:17]([OH:19])=[O:18])=[CH:11]2)=[O:16])=[CH:15][C:2]([F:1])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:4]=3[O:9][CH2:8]1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)N(C)C
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 110 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
10 g (35.6 mmole) of (S)-(−)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4]benzoxazine-6-carboxylic acid was put in suspension in 5 mL of DMA (dimethyl acetamide) and 8.3 mL (75 mmole) of N-methyl piperazine. The reaction mixture was heated to 110° C. until the complete conversion of the starting material, about 1.5 h. The reaction mixture was then cooled to 80° C. and 60 ml of isopropyl alcohol was added. The reaction mixture was then slurried for 3 hours at ambient temperature filtered under vacuum, washed with 40 ml IPA and dried in vacuum oven overnight to obtain 11.48 g (89.3%) of levofloxacin.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].Cl[C:14]([O:17]C(Cl)=O)(Cl)Cl>O1CCOCC1>[N:1]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])=[C:14]=[O:17]
Reactant: COC(=O)c1ccc(N)c(C)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N=C=O)c(C)c1

Procedure:
1.50 g (9.08 mmol) methyl 4-amino-3-methyl-benzoate are dissolved in 250 ml dioxane combined with 1.3 ml (10.7 mmol) trichloromethyl-chloroformate and refluxed for 5.5 hours with stirring. Then the mixture is evaporated down i. vac. and the residue is further reacted without any more purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[S-:12][C:13]#[N:14].[K+]>CC(O)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([S:12][C:13]#[N:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 70.9 %

Procedure:
2,4-Dichloro-5-nitropyrimidine (12 g) was dissolved in AcOH (70 mL) and cooled to 0° C. Potassium thiocyanate (6.31 g) was added portion-wise to the solution over 2 h. The reaction was diluted with water and filtered. The filter cake was washed with cold ether to afford the desired 2-chloro-5-nitro-4-thiocyanatopyrimidine (9.5 g, 71%).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[CH2:11][CH2:12][N:13]([CH3:51])[C@@H:14]1[CH2:21][N:20]2[C:22]3[CH:23]=[C:24]([C:35]([NH:37][S:38]([N:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)(=[O:40])=[O:39])=[O:36])[CH:25]=[CH:26][C:27]=3[C:28]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[C:19]2[C:18]2[CH:47]=[CH:48][CH:49]=[CH:50][C:17]=2[O:16][CH2:15]1>CC#N>[CH:29]1([C:28]2[C:27]3[CH:26]=[CH:25][C:24]4=[CH:23][C:22]=3[N:20]3[CH2:21][C@H:14]([CH2:15][O:16][C:17]5[C:18]([C:19]=23)=[CH:47][CH:48]=[CH:49][CH:50]=5)[N:13]([CH3:51])[CH2:12][CH2:11][N:44]2[CH2:43][CH2:42][N:41]([CH2:46][CH2:45]2)[S:38](=[O:40])(=[O:39])[NH:37][C:35]4=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CN(CCCl)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)N4CCNCC4)cc3n2C1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN2CCN(CC2)S(=O)(=O)NC(=O)c2ccc3c(C4CCCCC4)c4n(c3c2)C[C@@H]1COc1ccccc1-4
Yield: 26 %

Procedure:
DIPEA (20 eq) was added to a solution of (7R)-7-[(2-chloroethyl)(methyl)amino]-14-cyclohexyl-N-(piperazin-1-ylsulfonyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxamide (0.001 M) in MeCN and the mixture irradiated in a microwave (SmithCreator) at 150° C. for 5 mins. The volatiles were removed in vacuo and the residue purified by RP-HPLC, eluting with MeCN/TFA buffered with 0.1% TFA gradient. Fractions containing the product were combined and freeze dried to afford the product as a white powder (26% overall for steps 2 through to 6). 1H NMR (600 MHz, DMSO-d6+TFA, 330 K) δ 1.12-1.20 (m, 1H), 1.29-1.37 (m, 2H), 1.47-1.49 (m, 1H), 1.68-1.72 (m, 2H), 1.82-1.99 (m, 4H), 2.43 (s, 3H), 2.69-2.74 (m, 1H), 2.96-2.99 (m, 1H), 3.12-3.19 (m, 1H), 3.31-3.61 (m, 8H), 3.71-3.89 (m, 2H), 4.03-4.07 (m, 1H), 4.11-4.18 (m, 2H), 4.52-4.58 (m, 1H), 4.62-4.68 (m, 1H), 7.32-7.35 (m, 2H), 7.40-7.42 (m, 1H), 7.48 (d, J 8.4, 1H), 7.55-7.58 (m, 1H), 7.91 (d, J 8.4, 1H), 7.95 (s, 1H); (ES+) m/z 592 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].[C:7]([C:9]1[C:10](F)=[CH:11][C:12]([NH:15][C:16]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[N:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:17])=[N:13][CH:14]=1)#[N:8]>CC(N(C)C)=O.CCOC(C)=O>[C:7]([C:9]1[C:10]([O:4][CH:2]([CH3:3])[CH3:1])=[CH:11][C:12]([NH:15][C:16]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[N:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:17])=[N:13][CH:14]=1)#[N:8]
Reactant: CC(C)O
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(F)c(C#N)cn1)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(OC(C)C)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Propanol (16.2 mg, 0.269 mmol) was diluted in DMA (1 ml) under argon and treated with NaH (60% dispersion in mineral oil, 10.77 mg, 0.269 mmol). The reaction mixture was stirred for 30 min at room temperature. This mixture was added to a solution of N-(5-cyano-4-fluoropyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 33, 25 mg, 0.054 mmol) in DMA (1 ml). The reaction mixture was then stirred at room temperature for 1 h and the at 110° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with sat. aq. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated to give the title compound as a white solid. (UPLC-MS 3) tR 1.27 min; ESI-MS 412.2 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][SH:25])=[CH:20][CH:19]=1>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25][C:4]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1
Reactant: COc1ccc(CS)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Reaction time: 0.08 h
Yield: 62.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.6 g, 0.088 mol) was added to a cold solution of 2-chloro-5-nitrobenzoic acid (16.1 g, 0.08 mol) in dimethylformamide (200 mL) and the mixture was stirred for 5 min. The cold mixture was treated dropwise with a solution of 4-methoxy-α-toluenethiol (13.2 g, 0.08 mol) in dimethylformamide (80 mL) and stirred at room temperature for 16 h. The mixture was concentrated in vacuo, and the residue was diluted with water and acidified with dilute hydrochloric acid to pH 1. The resulting precipitate was filtered, washed with water and azeotroped to dryness from a mixture of methylene chloride-toluene. The residue was suspended in ethyl ether, filtered and washed with ethyl ether to give the title compound as a yellow solid (16 g, 63%), which was used without further purification. Mp 200-204° C.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1.[CH3:18]O>>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc2ccccc12
Temperature: -2.5 °C
Yield: 42 %

Procedure:
Thionyl chloride (4.5 ml) was added dropwise, under argon to a cooled, stirring slurry of 4-quinolinecarboxylic acid (5.32 g) in methanol (120 ml) maintaining an internal temperature of 0 to −5° C. Once addition was complete the reaction mixture was heated at reflux for 16 h. After cooling to ambient temperature the volatiles were removed at reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate and diethyl ether. The organic phase was washed with brine, dried (Na2SO4) and the solvent removed at reduced pressure to give the title compound as a pale yellow oil (4.82 g).