Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]2[O:34][CH2:35][CH2:36][O:37]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:17][CH:16]=1.O[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59]>>[C:58]([NH:57][CH2:56][CH2:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[O:37][CH2:36][CH2:35][O:34][CH:22]1[CH:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[CH:16][CH:17]=2)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:23]1)(=[O:60])[CH3:59]
Reactant: CC(=O)NCCc1ccccc1O
Reactant: COc1ccccc1CCOCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1CCOCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.50 g of tert-butyl 4-(4-{2-[2-(2-Methoxyphenyl)ethoxy]ethoxy}phenyl)-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate and 0.27 g of N-[2-(2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a colourless oil. Rf=0.45 (EtOAc); Rt=5.52.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2.S(OCC)(O[CH2:19][CH3:20])(=O)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.C(Cl)Cl>[CH2:19]([N:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:3])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14])[CH3:20]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1ccc2c(c1)CCC(=O)N2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCN1C(=O)CCc2cc(C)ccc21
Reaction time: 20 h
Yield: 83.4 %

Procedure:
1.4 g of benzyltriethyl ammoniumchloride (TEBA) and a solution of 12 g of sodium hydroxide in 12 ml of water are added with stirring to a solution of 9.6 g of 6-methyl-1,2,3,4-tetrahydroquinolin-2-one in 150 ml of methylene chloride. After 20 minutes 23.2 g of diethyl sulphate are added slowly dropwise; stirring is effected for 20 hours, the last 4 hours under reflux. Excess diethyl sulphate is decomposed by addition of 100 ml of 4 N sodium hydroxide solution. One acidifies and extracts for several times with methylene chloride. The organic phase is dried and concentrated and the residue is purified by chromatography over silica gel (eluent: methylene chloride). 9.4 g (83% of theory) of 1-ethyl-6-methyl-1,2,3,4-tetrahydroquinolin-2-one are obtained as oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]([O:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:8][N:7]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[N:7]=[CH:8][C:9]2[O:20][CH2:21][CH2:22][N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:10]=2[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(OS(=O)(=O)C(F)(F)F)c(OCCNC(=O)OC(C)(C)C)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cc2c(cn1)OCCN2C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 80.1 %

Procedure:
A mixture of (5-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]oxy}-4-{[(trifluoromethyl)sulfonyl]oxy}-2-pyridinyl)methyl acetate (1.58 g, 3.4 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BI NAP) (110 mg, 0.2 mmol), palladium(II) acetate (25 mg, 0.1 mmol) and cesium carbonate (1.57 g, 4.8 mmol) in toluene (20 ml) was heated to 100° C. under argon for 16 hours then filtered and evaporated. (See S. L. Buchwald, Org Letts, 1999, 1, 35-37; for the procedure). The residue was chromatographed on silica gel, eluting with 0-100% ethyl acetate in petrol, to afford a white solid (0.84 g, 79%)
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[C:23]([CH3:33])[CH:22]=4)[CH:19]=3)[N:14]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:13]=2)[CH:9]=[N:8]1.[CH3:47][C@H:48]1[CH2:50][O:49]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:31][CH2:32]5)=[C:23]([CH3:33])[CH:22]=4)[CH:19]=3)[N:14]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:35])=[O:36])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)c(C)c4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)c(C)c4)cnc32)cc1
Yield: 97.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-methyl-4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (172 mg. 0.277 mmol) was alkylated using (S)-2-methyloxirane (24 mg, 0.416 mmol), DIPEA (54 mg, 0.416 mmol) and ethanol (4 mL) to get 183 mg (97.3% yield) of the titled compound. MS: m/z=679.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([Cl:11])[C:3]=1[NH2:4].[C:12](Cl)(Cl)=[S:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([Cl:11])[C:3]=1[N:4]=[C:12]=[S:13]
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(Cl)c(N)c1Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)c(N=C=S)c1Cl

Procedure:
60.7 g of 2,6-dichloro-3-methoxy-aniline are dissolved in 65 ml of toluene and treated with 25 ml of thiophosgene in 50 ml of toluene. The solution obtained is heated to boiling under reflux overnight and subsequently evaporated in vacuo. There is obtained 2,6-dichloro-3-methoxyphenylisothiocyanate of boiling point 99° (0.13 Torr).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:14]3[CH2:21][CH2:22][CH2:23][N:13]3[CH2:12]2)=[CH:7][CH:6]=1.N1C2C(=CC=CC=2)C=CC=1.CO.CCN(CC)CC>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(Cl)Cl>[OH:1][CH2:2]/[CH:3]=[CH:4]\[C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C@H:14]3[CH2:21][CH2:22][CH2:23][N:13]3[CH2:12]2)=[CH:9][CH:10]=1
Reactant: OCC=Cc1ccc([C@@H]2CN3CCC[C@@H]3c3ccccc32)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: OC/C=C\c1ccc([C@@H]2CN3CCC[C@@H]3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.3 %

Procedure:
To a stirred solution of trans-1,2,3,5,6,10b-Hexahydro-6-[4'-(3-hydroxy-1-propynyl)phenyl]pyrrolo[2,1-a]isoquinoline (17) (154 mg, 0.507 mmol) in 10 mL of absolute ethanol was added the Lindlar catalyst (15 mg) at room temperature followed by addition of 7 mg of quinoline. The reaction mixture was stirred under hydrogen at room temperature for 12 h, filtered through a sintered glass funnel with celite, rinsed with methylene chloride (2×10 mL). The filtrate was concentrated to afford a crude product. Flash chromatography with 3.75% MeOH, 0.075% Et3N in methylene chloride gave 98 mg of thick red oil (63% yield). 1H NMR (CDCl3) δ 1.73-2.05 (m, 3H, C2H2 & C1H), 2.30-2.2.44 (m, 1H, C1H), 2.579 (dt, 1H, J=9.0, 8.7 Hz, C3H), 2.869 (dd, 1H, J=5.1, 11.1 Hz, C5H), 2.90-3.03 (m, 2H, C3H & C5H), 3.480 (dd, 1H, J=7.2, 9.0 Hz, C10bH), 4.125 (t, 1H, J=4.8 Hz, C6H), 6.865 (d, 1H, J=7.5 Hz, aryl), 6.995 (d, 2H, J=8.1 Hz, C6 phenyl aryl), 7.04-7.20 (m, 3H, aryl), 7.575 (d, 2H, J=8.1 Hz, C6 phenyl aryl); 13C NMR (CDCl3) δ 22.17 (C2), 30.31 (C1), 45.48 (C3), 54.13 (C10b), 55.95 (C6), 63.67 (C5), 91.60 (4'C), 125.73 (aromatic), 126.30, 129.30, 130.97, 137.23.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)=[CH:4][C:3]=1[CH2:17][OH:18].[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)=[CH:4][C:3]=1[CH2:17][O:18][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1
Reactant: C1=COCCC1
Reactant: O=Cc1ccc(Oc2ccc(Br)c(CO)c2)nc1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: O=Cc1ccc(Oc2ccc(Br)c(COC3CCCCO3)c2)nc1
Yield: 100 %

Procedure:
THP protection of 6-(4-bromo-3-(hydroxymethyl)phenoxy)nicotinaldehyde (2.4 g, 7.78 mmol) with 3,4-dihydro-2H-pyran (2.2 mL) catalyzed with (1S)-(+)-10-camphorsulfonic acid in CH2Cl2 (80 mL) at r.t. for 1 h provided the desired 6-(4-bromo-3-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)nicotinaldehyde as colorless oil (3.07 g, 7.8 mmol, yield 100%) after silica gel column purification (hexane:EtOAc=3:1, v/v).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[NH:7]/[C:6]/1=[N:15]\[NH2:16])[CH2:2][CH2:3][CH3:4].[CH:17]([O-])([O-])OCC>>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[CH:17]=[N:16][N:15]=[C:6]12)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC([O-])[O-]
Reactant: CCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Product: CCCCn1c2nc[nH]c2c(=O)n2cnnc12
Temperature: 100 °C
Yield: 71.8 %

Procedure:
The mixture of (2E)-3-butyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (200 mg, 0.0009 mol) in Ethyl orthoformate (5 mL, 0.03 mol) was heated at 100° C. overnight. After cooling to room temperature, the reaction mixture was filtrated and dried to give the desired product (150 mg, 71.8%). LCMS calculated for C10H13N6O (M+H): 233.1. Found: 233.1.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[O:13][C:14]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=2[CH:16]=1)=O)C>CCOCC.O1CCOCC1.O=[Mn]=O>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:15]2[CH:16]=[C:12]([CH:10]=[O:9])[O:13][C:14]=2[CH:20]=1
Reactant: CCOC(=O)c1cc2ccc(OC)cc2o1
Agent: O=[Mn]=O
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2cc(C=O)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a stirred slurry LiAlH4 (0.114 g, 3 mmol) in anhydrous Et2O (5 ml) was added drop wise the solution of ethyl-6-methoxybenzofuran-2-carboxylate (0.380 g, 1.73 mmol) and stirring was continued for 0.5 h at room temperature. The reaction mixture was quenched with EtOAc:H2O:MeOH mixture (7:3:1), diluted to 20 ml with EtOAc and filtered through Celite. The filtrate was evaporated and the residue was dried in vacuo to give the creamy paste (0.324 g) which was used as such for next step. This (0.310 g) was dissolved in anhydrous dioxane (10 ml) and MnO2 (1 g, excess) was added to it. The suspension was stirred at reflux for 3 h, cooled to room temperature and filtered through Celite pad. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane: EtOAc; 70:30), to give the title compound (0.182 g; 76%), as light pink crystalline solid. 1H-NMR (CDCl3) 3.87 (s, 3H); 6.96 (dd, 1H, J=2.22, 8.73 Hz); 7.03 (d, 1H, J=1.83 Hz); 7.48 (5, 1H); 7.59 (d, 1H, J=8.7 Hz); 9.74 (s, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[NH:6][CH2:5]1)[CH2:2][CH3:3].[Br:14][CH2:15][CH2:16][CH2:17]Br>>[CH2:1]([CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]([CH2:17][CH2:16][CH2:15][Br:14])[CH2:5]1)[CH2:2][CH3:3]
Reactant: BrCCCBr
Reactant: CCCC1CNc2ccccc2O1
Product: CCCC1CN(CCCBr)c2ccccc2O1
Yield: 33 %

Procedure:
From 2-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.65 g, 1 eq, 9.3 mmol) obtained in step (iii) above, and 1,3-dibromo propane (9.4 ml, 10 eq, 93 mmol) and following the procedure of step (iv), preparation 17 title compound (915 mg, yield 33%) was obtained as viscous oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14]C)=O)=[CH:6][C:5]=1[F:18])(=[O:3])[NH2:2].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:28]=[C:27]([N:29]=[C:30]=[S:31])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CS(C)=O.O>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([N:29]2[C:12](=[O:14])[C:11]([CH3:17])([CH3:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([F:18])[CH:6]=3)[C:30]2=[S:31])=[CH:28][C:21]=1[C:20]([F:19])([F:32])[F:33])#[N:24]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: COC(=O)C(C)(C)Nc1ccc(C(N)=O)c(F)c1
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(N)=O)c(F)c1
Reaction time: 0.03 h

Procedure:
A solution of methyl 2-(4-carbamoyl-3-fluorophenylamino)-2-methylpropanoate and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (1.5 equivalents) in dry DMSO (5 mL per mmol) was heated to 80-82° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 40% Acetone-Hexanes. MS (m/z): 451 (M+1). HPLC: Column, YMC ODS A, 4.6×150 mm, 5 μm, Mobile Phase A:10 mM Ammonium acetate, Mobile Phase B: Acetonitrile, Gradient, 10% B up to 2 min, 10% to 90% B in 3 min, hold for 3 min, 90% to 10% B in 5 min, Retention time, 2.782 min, HPLC Purity, 99.4%, Flow Rate, 1 mL/min. 1H NMR (CDCl3, Freebase): δ (ppm) 8.3 (t, 1H), 8.0 (d, 1H) 7.98 (s, 1H), 7.8 (d, 1H), 7.27 (d, 1H), 7.2 (d, 1H), 6.65 (d, 1H), 6.0 (s, 1H), 1.62 (s,6H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21]CC3C=CC=CC=3)[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([CH:29]([CH3:31])[CH3:30])[N:7]=2>C1COCC1.CO.[Pd]>[ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([CH:29]([CH3:31])[CH3:30])[N:7]=2
Reactant: COc1ccc(Cn2cnc(N)c3nc(C(C)C)nc2-3)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2cnc(N)c3nc(C(C)C)nc2-3)cc1O
Yield: 78.6 %

Procedure:
6-Amino-3-(3-benzyloxy-4-methoxy-benzyl)-8-isopropyl-3H-purine hydrochloride (4.04 g, 9.2 mmole), in THF:methanol (1:1) (600 ml) was hydrogenated for 10 hours over 10% Pd-C (0.8 g) at room temperature and pressure. The catalyst was filtered off, the solvents removed in vacuo and the residue crystallized from acetone to give 6-amino-3-(3-hydroxy-4-methoxy-benzyl)-8-isopropyl-3H-purine hydrochloride (2.53 g, 78.8%), mp 125-130/185-195° C.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:35])[NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH:27]=4)[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:25]1[CH2:26][CH:27]=[C:22]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[NH:11][C:10]([NH:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:36])([F:37])[F:1])[N:8]=2)=[O:35])[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3nccc(NC(=O)Nc4cccc(C(F)(F)F)n4)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(C3=CCNCC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
0.2 g of tert-butyl 4-{4-[3-(6-trifluoromethyl-pyridin-2-yl)-ureido]-quinolin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylate (0.389 mmol) were dissolved in 0.6 ml DCM (yellow solution). 0.300 ml of TFA (3.89 mmol) were added and the reaction mixture was stirred for 2 h at RT. After evaporation of the solvent and excess TFA in vacuum, water was added to the residue, the acidic mixture extracted with ethyl acetate, the water phase adjusted to pH 9 with 1M NaOH and subsequently extracted three times with DCM. The combined DCM solutions were washed with a small amount of brine, dried over sodium sulphate and the solvent was removed in vacuum. 130 mg of the desired product were obtained as light yellow powder (yield: 81%).
Reaction SMILES: [Na].[CH3:2][CH2:3][C@@H:4]([C:23]([C@H:25]([C@@H:27]([OH:43])[C@@H:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[C:33]=1[C:40]([OH:42])=[O:41])[CH3:29])[CH3:26])=[O:24])[C@H:5]1[O:9][C@@:8]([C@@H:12]2[O:17][C@@H:16]([CH3:18])[C@@:15]([OH:21])([CH2:19][CH3:20])[CH2:14][CH2:13]2)([CH2:10][CH3:11])[CH2:7][C@@H:6]1[CH3:22].C(Cl)(Cl)[Cl:45].ClCl>C(Cl)(Cl)(Cl)Cl>[Cl:45][C:37]1[C:32]([CH2:31][CH2:30][CH:28]([CH3:29])[CH:27]([OH:43])[CH:25]([CH3:26])[C:23](=[O:24])[CH:4]([CH2:3][CH3:2])[CH:5]2[CH:6]([CH3:22])[CH2:7][C:8]([CH2:10][CH3:11])([CH:12]3[CH2:13][CH2:14][C:15]([CH2:19][CH3:20])([OH:21])[CH:16]([CH3:18])[O:17]3)[O:9]2)=[C:33]([C:40]([OH:42])=[O:41])[C:34]([OH:39])=[C:35]([CH3:38])[CH:36]=1
Reactant: ClC(Cl)Cl
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: ClCl
Agent: [Na]
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(Cl)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reaction time: 0.5 h

Procedure:
To a cold solution (~3°) of 6.12 g. of the sodium salt of antibiotic X-537A in 50 ml. of chloroform/3 ml. of carbon tetrachloride was slowly added 34 ml. of carbon tetrachloride saturated with 10 millimoles of chlorine gas. The reaction was continued for 1/2 hour after which the solution was filtered and the filtrate treated with a saturated aqueous solution of Na2CO3. The solvent layer was dried over Na2SO4 and concentrated to a small volume from which after addition of hexane the crystalline product was recovered. The crystalline material which had a tendency to incorporate the solvent of crystallization was twice recrystallized from methylene chloride/ether and acetone/hexane, m.p. 183°-185°, [α]D25 -44.31° (C, 0.99%, CHCl3).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:41])(=[O:40])[NH2:39])=[CH:28][C:27]=2[F:42])[C:7](=[O:24])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:11]=2[Cl:23])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>CCOCC>[CH2:1]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:40])(=[O:41])[NH:39][C:46](=[O:47])[C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[Cl:43])=[CH:28][C:27]=2[F:42])[C:7](=[O:24])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:22])[NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:11]=2[Cl:23])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(N)(=O)=O)cc3F)c2=O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCNC(=O)c1ccc(Cl)c(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3F)c2=O)c1
Yield: 42 %

Procedure:
By the procedure of Example 51, 5-n-butyl-2-[5-(N-n-butylcarbamoyl)-2-chlorophenyl]-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step G) was reacted with 2-chlorobenzoic acid (2 equivalents), CDI (2 equiv), and DBU (2 equiv). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) followed by trituration with ether afforded a 42% yield of the title compound as a white solid, mp 218°-220° C.; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 753 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])=[CH:17][C:16]([C:27]([NH2:29])=O)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:12](=[O:30])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])=[CH:17][C:16]([C:27]#[N:29])=[CH:15][CH:14]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(C(N)=O)ccc2c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2F)c2cc(C#N)ccc2c1=O
Yield: 84.5 %

Procedure:
A solution of 3-[[(tert-butoxycarbonyl)amino]methyl]-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxamide (Example 10 (4)) (0.23 g, 0.5 mmol) and cyanuric chloride (0.28 g, 1.5 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give tert-butyl[6-cyano-4-(2-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.19 g, 86.4%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=2)[O:36]1>>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)C(O)CC(c1c(F)cccc1F)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2c(F)cccc2F)O3)nc1

Procedure:
2-(2,6-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 1.9 g of 2-(2,6-difluorophenyl)chroman-4,6-diol. 1H NMR (300 MHz, d6-DMSO) δ: 9.03 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.52 (m, 1H), 7.26-7.16 (m, 4H), 7.01 (dd, 1H, J 8.8, 2.9 Hz), 6.83 (d, 1H, 8.8 Hz), 5.69-5.64 (m, 2H), 4.98 (m, 1H), 2.37 (m, 1H), 2.29 (m, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([O:27][CH3:28])[CH:13]=1)[CH2:6][CH:7]1[CH2:9][CH2:8]1.[CH2:30]([NH2:32])[CH3:31].C[Al](C)C.CO>C1(C)C=CC=CC=1.O1CCCC1.CCCCCCC>[F:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:5]([CH2:6][CH:7]2[CH2:8][CH2:9]2)[CH2:4][C:3]([NH:32][CH2:30][CH3:31])=[O:2])=[CH:13][C:14]=1[O:27][CH3:28]
Reactant: CCN
Reactant: COC(=O)CN(CCc1ccc(OCc2cccc(F)c2)c(OC)c1)CC1CC1
Agent: C[Al](C)C
Solvent: CO
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CCNC(=O)CN(CCc1ccc(OCc2cccc(F)c2)c(OC)c1)CC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
105 mg (0.26 mmol) of 2-[[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-(cyclopropylmethyl)amino]-acetic acid methyl ester were dissolved in 5 ml of dry toluene. 0.5 ml of a 2 M (1 mmol) solution of ethylamine in tetrahydrofuran were added at 0° C., followed by 0.4 ml (0.8 mmol) of a 2 M solution of trimethyl aluminium in heptane. The reaction was stirred for 4 hours at room temperature. The solution was cooled to 0° C. and poured into methanol. The solvent was removed and the crude product was purified by flash chromatography (ethyl acetate/hexane 0:100→85:15 gradient v:v) to obtain 52 mg (48% yield) of the title compound as a hygroscopic solid.