Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:18]([O:33][CH3:34])[CH2:17]1)=[O:15].Cl>CO.C(OCC)(=O)C>[C:3]([CH:2]([CH2:13][C:14]([N:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])[C@H:18]([O:33][CH3:34])[CH2:17]1)=[O:15])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: CO[C@@H]1CN(C(=O)CCl)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC)C1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl acetoacetate (510 mg, 4.4 mmol) was dissolved in methanol (15 ml). Sodium methoxide (210 mg, 3.9 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Further, benzyl cis(±)-[1-(chloroacetyl)-3-methoxypiperidin-4-yl]carbamate obtained in Example (188a) was dissolved in methanol (10 ml). The solution was added to the reaction solution, and the mixture was stirred at 70° C. overnight. The reaction solution was diluted with ethyl acetate, neutralized with 1 N hydrochloric acid, washed with brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the title compound was obtained. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [C:1]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:2].N1CCCCC1.[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45]([NH:47][CH2:48][C:49]3[CH:57]=[CH:56][C:52](C(O)=O)=[CH:51][CH:50]=3)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C.C(N(CC)C(C)C)C>[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45]([NH:47][CH2:48][C:49]3[CH:50]=[CH:51][C:52]([C:1]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:2])=[CH:56][CH:57]=3)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCC1c2ccccc2-c2ccccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CCN(CC)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(O)CCNC(=O)c1ccc(CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To the above resin bound Fmoc β-alanine was added 500 μL of a 20% solution of piperidine in DMF. Upon shaking for 30 min, the resin was drained and washed with 1 mL DMF containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2×1 mL). Then 200 μmol 4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]benzoic acid (74.2 mg) dissolved in a mixture of 430 μL DMF and 70 μL diethylisopropylamine was added followed by 200 μmol bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93 mg) dissolved in 500 μL DMF. The mixture was shaken for 4 hours at 25° C. followed by filtration and washing of the resin with 3×1 mL DMF.
Reaction SMILES: Cl[Pd:2]Cl.[OH-].[Na+].[C:6]1(=[O:13])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[Pd:2].[C:6]1(=[O:13])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cl[Pd]Cl
Agent: O=C1CCCCCN1
Agent: [Na+]
Agent: [OH-]
Product: [Pd]
Temperature: 100 °C
Reaction time: 2 h

Procedure:
5.0 g PdCl2 and 100 g molten caprolactam having a purity not less than 80% and a moisture not more than 20% are added to a reactor, and then stirred for 30 min at the temperature of 100° C., so that PdCl2 is fully dissolved in a molten caprolactam solvent. 1 g NaOH is rapidly added under stirring for the purpose of reaction for 2 h at the temperature of 100° C., and then, 2 g KBH4 is added for continuous reaction for 2 h to obtain nano Pd/caprolactam mixture.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.B(OC(C)C)(OC(C)C)OC(C)C.C(=O)([O-])[O-].[Na+].[Na+].Br[C:32]1[CH2:33][C:34]2[C:39]([CH:40]=1)=[C:38]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[C:37]([CH3:49])=[CH:36][CH:35]=2>COCCOC.CCCCCC.C1(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)C=CC=CC=1.O>[CH3:1][C:2]1[O:3][C:4]([C:32]2[CH2:33][C:34]3[C:39]([CH:40]=2)=[C:38]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:37]([CH3:49])=[CH:36][CH:35]=3)=[CH:5][CH:6]=1
Reactant: COc1ccc(-c2c(C)ccc3c2C=C(Br)C3)cc1
Reactant: Cc1ccco1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCCCCC
Product: COc1ccc(-c2c(C)ccc3c2C=C(c2ccc(C)o2)C3)cc1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
Solution of 2-methylfuran (1.9 g, 23 mmol) in absolute DME was cooled at −70° C., and solution of n-butyllithium in n-hexane (1.66 M, 14 mL) was dropped. Reaction solution was stirred for 3 hours at low temperature of about −30° C. as it was, subsequently, triisopropyl borate (5.9 mL, 25.5 mmol) was added, and reaction solution was stirred at room temperature day and night. After stirring, distilled water (5 mL) was added to hydrolyze, and aqueous solution (20 mL) of sodium carbonate (4.8 g, 45 mmol), crude product of 2-bromo-4-(4-methoxyphenyl)-5-methylindene synthesized in the above, further, tetrakis(triphenylphosphino)palladium (0.6 g) were added, and heated for 2.5 hours under reflux. Water was added to the reaction solution to separate organic layer, organic layer was filtered through Celite, and washed with saturated solution of sodium chloride, and dried over magnesium sulfate, and solvent was distilled off under reduced pressure.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([NH2:17])[N:14]([C@H:18]([CH3:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=3[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([NH:17][C:32](=[O:34])[CH3:33])[N:14]([C@H:18]([CH3:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[C:13]=3[CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](n1c(N)nc2ccc(C#Cc3ccccc3)cc21)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc2ccc(C#Cc3ccccc3)cc2n1[C@H](C)C(C)(C)C
Reaction time: 18 h

Procedure:
Add 6-phenylethynyl-1-(1-(R)-methyl-2,2-dimethylpropyl)-1H-benzimidazol-2-ylamine (5.81 g, 0.018 mol), triethylamine (12 mL), dichloromethane (100 mL), N,N-dimethylaminopyridine (0.11 g, 0.9 mmol), and acetic anhydride (7.5 mL) and stir for about 18 hours. Evaporate and redissolve in ethyl acetate and wash with water, 1N HCl (3×), saturated sodium bicarbonate, and saturated sodium chloride. Add 2M ammonia in methanol to organic layer and stir 10 minutes and evaporate. Redissolve in dichloromethane and wash with saturated sodium bicarbonate, saturated sodium chloride, dry magnesium sulfate, and concentrate to give the desired compound as an orange foam (6.92 g, quant).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18](I)=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S-:25].[Na+].CC(C)([O-])C.[Na+].C1(P(C(C)(C)C)F)CCCCC1>COCCOC.CCCCCCC.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([S:25][CH3:24])=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(I)n[nH]c3c2)CC1
Reactant: C[S-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(F)C1CCCCC1
Solvent: COCCOC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CSc1n[nH]c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc12
Temperature: 100 °C

Procedure:
To a mixture of 4-(3-iodo-1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (213 mg, 0.50 mmol), sodium methanethiolate (39 mg, 0.55 mmol) and sodium tert-butoxide (67 mg, 0.7 mmol) in a pre-dried flask sealed under N2 was added 1 mL of a catalyst solution, which was prepared by mixing Pd(OAc)2 (12.4 mg, 0.055 mml) and JOSIPHOS CyPF-t-Bu (30.6 mg, 0.055 mmol) in DME (1.1 mL) under N2. The resulting mixture was heated in 100° C. oil bath for 5 h, then cooled and loaded onto a silica-gel column and chromatography (gradient eluant 20% to 50% EtOAc in heptane) to yield 4-(3-Methylsulfanyl-1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as white crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([OH:20])=O.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][N:23]=1)[C:18]([NH:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:20]
Reactant: Cc1onc(-c2ccccc2)c1C#Cc1cc(C(=O)O)ccn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1C#Cc1cc(C(=O)NC2CCOCC2)ccn1
Yield: 73 %

Procedure:
As described for example 7b, 2-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-isonicotinic acid (50 mg; 0.16 mmol) instead of 3-(5-methyl-3-phenyl-isoxazol-4-ylethynyl)-benzoic acid was converted (using 4-amino-tetrahydropyrane instead of aminomethylcyclopropane) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 46 mg, 73%) which was obtained as a yellow solid. MS: m/e=388.2 [M+H]+.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>ClCCl>[F:33][C:31]([F:34])([F:32])[C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[C:21]2[O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]1[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[O:8][CH:9]=1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3ccc(C(F)(F)F)cc23)co1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=c1cc(CN2CCOCC2)occ1OCCCCCOc1ccnc2ccc(C(F)(F)F)cc12
Temperature: 45 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(7-trifluoromethyl-quinolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 16 (100 mg, 0.20 mmol) was dissolved in dichloromethane (5 mL). Morpholine (44 μL, 0.50 mmol) was added via syringe. The mixture was stirred at 45° C. for 18 h. After cooling to room temperature CH2Cl2 (75 ml) was added and the mixture was washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=9:1. 5-(5-(6-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(morpholinomethyl)-4H-pyran-4-one EHT 1426 was obtained (37 mg, 35% yield) as an orange oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][N:4]([CH2:11][C:12]1[S:16][C:15]([Cl:17])=[N:14][C:13]=1[Cl:18])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:20]([OH:29])(=[O:28])[C@@H:21]([C@H:23]([C:25]([OH:27])=[O:26])[OH:24])[OH:22].C1COCC1>O>[OH2:22].[C:25]([CH:23]([CH:21]([C:20]([OH:29])=[O:28])[OH:22])[OH:24])([OH:27])=[O:26].[CH3:1][CH:2]([CH3:19])[CH2:3][N:4]([CH2:11][C:12]1[S:16][C:15]([Cl:17])=[N:14][C:13]=1[Cl:18])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:1][CH:2]([CH3:19])[CH2:3][N:4]([CH2:11][C:12]1[S:16][C:15]([Cl:17])=[N:14][C:13]=1[Cl:18])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[C:25]([CH:23]([CH:21]([C:20]([OH:29])=[O:28])[OH:22])[OH:24])([OH:27])=[O:26]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CC(C)CN(Cc1sc(Cl)nc1Cl)C1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-(2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine (193.6 g, 0.6 mol) in 2 L THF at 65° C. are added seed crystals and L-tartaric acid (90.15 g, 0.6 mol, 1 equiv.) solution in 100 ml water dropwise over 5 min (after 15 min the solution becomes turbid and the product begins to crystallize). After 3 h at 64° C., the mixture is cooled down to room temperature, and then stirred for an additional 20 h. The reaction mixture is then cooled down to 10° C. and filtered; the solid is washed with cold THF/water 95/5 and dried under vacuum to afford 245.8 g of N-(2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine tartrate hemihydrate (87% yield). 1H NMR (250 MHz, DMSO d6): δ=3.97 (2H, s), 3.69 (2H, s), 3.24 (2H, brd), 2.77 (3H, m), 2.20 (2H, d), 1.63 (5H, m), 0.80 (6H, d); 13C NMR (62 MHz, DMSO d6): δ=175.09, 149.48, 138.32, 131.24, 72.39, 58.12, 55.08, 47.04, 43.29, 26.72, 24.60, 20.81.
Reaction SMILES: C[O-].[Na+].CO.[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.[N:15]1([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[N:16]1>C(OC(C)(C)C)C>[F:14][C:7]([F:6])([F:13])[C:8](=[O:10])[CH2:27][C:26]([C:23]1[CH:22]=[CH:21][C:20]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[CH:25][CH:24]=1)=[O:28]
Reactant: CC(=O)c1ccc(-n2cccn2)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)(C)C
Solvent: CO
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-n2cccn2)cc1
Temperature: 20 °C
Reaction time: 22 h
Yield: 63.4 %

Procedure:
A 5.4 N solution of sodium methoxide in methanol (3.0 mL, 16.2 mmol) was added drop wise over 10 min to a solution of ethyl trifluoro-acetate (1.81 mL, 15.2 mmol) in 2-ethoxy-2-methyl-propane (20 mL) at 20° C. followed by the addition of a suspension of 1-(4-pyrazol-1-yl-phenyl)-ethanone (2.57 g, 13.8 mmol) in 2-ethoxy-2-methyl-propane (10 mL). The reaction mixture was stirred for 22 h at 20° C. and then poured onto ice-water (50 mL). The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The remaining solid was recrystallized from ethyl acetate/heptane to give the title compound (2.47 g, 63%) as off-white solid. Mp 96° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:22][S:23]([CH3:25])=[O:24])=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)=[O:11])[N:3]=1.[OH:26]O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:22][S:23]([CH3:25])(=[O:26])=[O:24])=[C:14]([S:18]([NH2:21])(=[O:19])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[O:11])[N:3]=1
Reactant: OO
Reactant: Cc1cc(C)nc(NC(=O)c2cccc(S(N)(=O)=O)c2CS(C)=O)n1
Solvent: CC(=O)O
Product: Cc1cc(C)nc(NC(=O)c2cccc(S(N)(=O)=O)c2CS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 0.1 g (0.2 mmol) of [N-(4,6-dimethylpyrimidinyl)aminocarbonyl]-o-methylsulfinylmethylbenzenesulfonamide and 0.3 ml of 30% hydrogen peroxide in 5 ml of acetic acid was stirred at room temperature for 3 days. The resulting white solid precipitate was filtered to afford 30 mg of the desired product: m.p. 222°-225° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:40]([CH2:43][CH3:44])=[C:41]=[O:42].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][CH2:43][CH3:44])=[O:42])=[CH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH3:39])=[O:38])[C:30]=2[CH:31]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(N)cc2)cc1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a solution of N-[1-(4′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (68 mg, 0.12 mmol) in dichloromethane (2 mL) was added isocyanatoethane (36.5 mg, 0.51 mmol). Triethylamine (36 mg, 0.36 mmol) was added, and the resultant mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure, and the residue was purified by Gilson preparative HPLC (Xterra Prep RP, 30×100 mm, 45 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 20 to 50% over 15 min, UV detection at 214 nm) to give 53.5 mg (70%) of the title compound as an off white solid. MS (ES) m/e 640.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O.S(Cl)(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[CH3:14][CH:10]1[CH2:9][C:8]2[C:15](=[CH:16][CH:17]=[CH:18][C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:11]1=[O:13]
Reactant: CC(Cc1ccccc1-c1ccccn1)C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC1Cc2c(cccc2-c2ccccn2)C1=O
Temperature: 80 °C

Procedure:
A solution of 193 g (0.80 mol) of 2-(2-(2-(pyridyl)benzyl)propionic acid in 81 cm3 (1.2 mol) of thionyl chloride was stirred at room temperature for 18 hours. Excess thionyl chloride was removed at 10 mbar and the acid chloride was taken up in 400 cm3 of toluene. The solution was added dropwise at 10° C. to a suspension of 113 g (0.85 mol) of AlCl3 in 1500 cm3 of toluene and heated at 80° C. for 1 hour. The reaction mixture was poured onto 2000 g of ice and acidified with concentrated aqueous HCl to a pH of 1. The organic phase was separated off and the aqueous phase was further extracted 3 times with 200 cm3 each time of Et2O. The combined organic phases were washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution and subsequently dried (MgSO4). This gave 132 g (74%) of 2-methyl-4-(2-pyridyl)-1-indanone which was further reacted without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([O:15]CC)=[O:14])[CH:9]=2)[N:4]([CH3:18])[CH:3]=1.[H-].[Na+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.[OH-].[Li+].Cl>CN(C)C=O.O.CO>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:1][C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:13]([OH:15])=[O:14])[CH:9]=3)[N:4]([CH3:18])[CH:3]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(=O)c(O)cn2C
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(COc2cn(C)c3ccc(C(=O)O)cc3c2=O)cc1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
To a suspension of ethyl 3-hydroxy-1-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (6.7 g, 27.1 mmol) in N,N-dimethylformamide (18.0 ml) at 0° C. was added sodium hydride (2.168 g, 54.2 mmol), and the mixture was stirred for 20 min. At this time, 1-(chloromethyl)-4-methoxybenzene (3.7 ml, 27.3 mmol) was added and the reaction was heated to 75° C. and allowed to stir for 2 h. After cooling, the reaction was poured into ice, and the resulting precipitate was filtered, washed with water and diethyl ether, collected, and dried. Methanol (24.00 ml), water (8.00 ml) and lithium hydroxide (0.86 g, 35.9 mmol) were added, and the reaction was stirred at 60° C. for 2 h. The reaction was cooled and the pH was adjusted to 3-4 by addition of 2N hydrochloric acid (18.00 ml, 36 mmol). The resulting precipitate was filtered, washed with water and diethyl ether, and dried to give 3-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (6.1937 g, 18.25 mmol, 67.4% yield. LCMS: (M+H)+: 340.1.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][C:6]1[C:11]2[O:12][C@:13]3([CH3:53])[O:16][CH:17]=[CH:18][C@H:19]([O:51][CH3:52])[C@@H:20]([CH3:50])[C@@H:21]([O:46][C:47]([CH3:49])=[O:48])[C@H:22]([CH3:45])[C@H:23]([OH:44])[C@H:24]([CH3:43])[C@@H:25]([OH:42])[C@@H:26]([CH3:41])[CH:27]=[CH:28][CH:29]=[C:30]([CH3:40])[C:31]([NH:33][C:34]4[C:38](=[O:39])[C:8](=[C:9]([C:36](=[O:37])[CH:35]=4)[C:10]=2[C:14]3=[O:15])[C:7]=1[OH:54])=[O:32]>CNC=O.C(Cl)Cl>[CH3:41][C@@H:26]1[C@H:25]([OH:42])[C@@H:24]([CH3:43])[C@@H:23]([OH:44])[C@@H:22]([CH3:45])[C@H:21]([O:46][C:47]([CH3:49])=[O:48])[C@H:20]([CH3:50])[C@@H:19]([O:51][CH3:52])[CH:18]=[CH:17][O:16][C@:13]2([CH3:53])[C:14](=[O:15])[C:10]3[C:11]([O:12]2)=[C:6]([CH3:5])[C:7]([OH:54])=[C:8]2[C:38](=[O:39])[C:34](=[C:35]([NH2:1])[C:36]([C:9]=32)=[O:37])[NH:33][C:31](=[O:32])[C:30]([CH3:40])=[CH:29][CH:28]=[CH:27]1
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Reactant: [N-]=[N+]=[N-]
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: [Na+]
Solvent: CNC=O
Solvent: ClCCl
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C(N)=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O

Procedure:
3-amino-4-deoxo-4-imino-rifamycin S, (a) above, is described in U.S. Pat. No. 4,017,481, where it is made by reacting 3-amino-rifamycin S with gaseous ammonia. The reaction is carried out in a solution of tetrahydrofuran at room temperature for 15 hours with further addition of ammonia. The starting material, 3-amino-rifamycin S may obtained as described in U.S. Pat. No. 4,007,169, where it is obtained by reacting sodium azide with rifamycin S. The reaction is carried out in methylformamide at 35° C. for 60 minutes. The reaction mixture is diluted with methylene chloride and washed with water. The aqueous phase contains rifamycin SV which may be oxidized by, for example, nitrous acid to the starting material rifamycin S. The organic phase is washed with water, dried with sodium sulphate and evaporated to yield 3-amino rifamycin S which is recrystallized from 2-methoxy ethanol.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:6]=1[CH2:7][NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.Cl[S:21]([C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])(=[O:23])=[O:22].O>C1COCC1>[CH3:3][O:4][C:5]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:6]=1[CH2:7][N:8]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)[S:21]([C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])(=[O:23])=[O:22]
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2nccs2)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Sodium hydride (60% in mineral oil, 239 mg, 5.99 mmol, 1.5 eq) was added portionwise to a solution of N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 1 g, 3.995 mmol, 1 eq) in THF (10 ml) at 0° C. The mixture was stirred for 40 minutes before the addition of methyl 3-(chlorosulfonyl)benzoate (937, 3.995 mmol, 1 eq) and the reaction mixture stirred for a further 1 hour at 0° C. and 5 hours at room temperature. Water (2 ml) was added and the THF evaporated in vacuo. The residue was extracted from water (10 ml) into ethyl acetate (3×5 ml), washed with brine, dried over magnesium sulphate, filtered and evaporated in vacuo to yield methyl 3-{[(2,4-dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}benzoate.