Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:5]=[C:4]([C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][C:28]=2[O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[N:3]=1.C(N(CC)CC)C.Cl[C:47](Cl)([O:49]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH:36]1([CH2:35][O:34][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:27]=2[C:4]2[CH:5]=[C:6]([CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[C:7]3[CH2:8][N:9]([S:10]([CH3:13])(=[O:11])=[O:12])[C:47](=[O:49])[NH:1][C:2]=3[N:3]=2)[CH2:37][CH2:38]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CNS(C)(=O)=O)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc3c2CN(S(C)(=O)=O)C(=O)N3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-{[(methylsulfonyl)amino]methyl}-4-pyridinyl)-1-piperidinecarboxylate (0.050 g, 0.091 mmol) and triethylamine (0.077 mL, 0.549 mmol) in tetrahydrofuran (15 mL) was added to a solution of triphosgene (0.027 g, 0.091 mmol) in tetrahydrofuran (5 mL) under an argon atmosphere. The mixture was allowed to warm to room temperature, and the stirring was continued for 3 hrs under an argon atmosphere. After quenched by water, the mixture was extracted with ethy acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting yellow solid was triturated with diisopropyl ether and collected by filtration to give tert-butyl 3-[7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-(methylsulfonyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]-1-piperidinecarboxylate as a yellow solid (0.028 g, yield; 55%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CCC(=O)N1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:24][CH2:25][CH2:26]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:26][CH2:25][O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCOCc1ccccc1
Reactant: COc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(OCCOCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
A mixture of 1-bromo-2-hydroxy-4-methoxy benzene (68.3 g, 0.336 moles), anhydrous potassium carbonate (51.2 g 0.37 moles) and 0.5 L of N,N-dimethylforrnamide was heated to 65° C. Benzyloxyethylbromide (76.0 g, 0.353 moles) was added dropwise over 0.5 hr. After stirring for 1.5 hr. at 65° C., the reaction mixture was cooled and filtered. The filtrate was diluted with 1 L of deionized water, and extracted with 3×0.5 L ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. Distillation gave 93 g (83%) of product as a yellow liquid (b.p. 170-175° C., 0.5 mm).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.[Li+].[B-](CC)(CC)CC>C1COCC1>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C@H:5]1[CH2:3][OH:2])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To (2S,3R)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (51A) (8.05 g, 22.39 mmol) in THF (90 mL) at −78° C. was added a 1 M solution of Super-Hydride® in THF (112 mL, 112 mmol) in five portions over 15 min The cold bath was removed and the reaction was allowed to warm to rt. After 3 h, the reaction was poured into a 1-L Erlenmeyer flask and was carefully quenched with ice while stirring and then diluted with EtOAc. The layers were separated and the organic layer washed with 1 M H3PO4, NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residue was diluted with CH2Cl2, stirred with silica gel overnight, then concentrated and purified via flash chromatography eluting with 30% EtOAc/hexane to obtain the title compound (6.70 g) as a clear oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2].C1(C)C([S:36]([OH:39])(=[O:38])=[O:37])=CC=CC=1.C(O)C>O>[S:36]([C:6]1[CH:5]=[CH:4][C:3]([CH3:1])=[CH:12][CH:7]=1)([OH:39])(=[O:38])=[O:37].[C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2]
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
250 mg (0.63 mmol) of 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are dissolved in 2 ml of water, and one equivalent of toluenesulfonic acid is added. The solution is stirred at room temperature for 30 minutes and then poured onto 20 ml of ethanol. The resulting precipitate is filtered off with suction and then dried.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][C:26]=1[S:35]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103 %

Procedure:
To a solution of 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (1.18 g, 4.98 mmol) in dichloromethane (40 ml) was added DIPEA (2.70 ml, 15.45 mmol) and then 2-bromo-5-(trifluoromethyl)benzenesulfonyl chloride (1.613 g, 4.98 mmol). The reaction mixture was stirred for 1 h 20 min at room temperature, and then washed with water (50 ml), dried on a phase separation cartridge and concentrated under vacuum to give the crude title compound (2.5 g) used directly in the next step.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]3[CH:12]=[N:11][N:10](CC4C=CC(OC)=CC=4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1cnn2Cc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Temperature: 25 °C

Procedure:
To a 20 mL microwave vial were combined ethyl 6-cyclopropyl-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (2.05 g, 5.83 mmol), trifluoroacetic acid (6.74 ml, 88 mmol) and anisole (1.912 ml, 17.50 mmol). The reaction vessel was sealed and irradiated (microwave) at 100° C. for 5 minutes. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with water (20 mL) and then saturated NaHCO3 until basic. The contents were extracted with DCM (4×20 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography (eluent: 0 to 20% EtOAc:Hex). The final product was obtained as 1.06 g (79%). LCMS E-S (M+H)=232.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.21 (m, 4H) 1.41 (t, J=7.07 Hz, 3H) 2.33-2.46 (m, 1H) 4.44 (q, J=7.07 Hz, 2H) 7.67 (s, 1H) 8.26 (d, J=1.26 Hz, 1H) 13.75 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(O)(C)C.[NH3:16]>>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([NH2:16])[N:3]=[N:4][CH:5]=1
Reactant: N
Reactant: FC(F)(F)c1cnnc(Cl)c1
Solvent: CC(C)O
Product: Nc1cc(C(F)(F)F)cnn1
Temperature: 80 °C

Procedure:
3-Chloro-5-(trifluoromethyl)pyridazine (28.0 g, 153 mmol) was dissolved in ammonia in isopropanol (200 mL, 400 mmol, 2.0 M) and heated at 80° C. in a pressure vessel for 3 days. The reaction was cooled to room temperature and concentrated under reduced pressure to take the isopropanol off. The residue was purified by flash chromatography to afford the title compound as an off white solid, 1H NMR (500 MHz, CDCl3) δ 8.83 (s, 1H); 6.91 (s, 1H); 5.00 (s, 2H, br). LRMS (APCI) calc'd for (CsH4F3N3) [M+H]+, 164.1. found 164.1.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([CH:15]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH2:4]1)=O.[N:32]1[O:36][N:35]=[C:34]2[C:37]([CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:38][CH:39]=[CH:40][C:33]=12>>[N:32]1[O:36][N:35]=[C:34]2[C:37]([CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][N:47]([CH2:1][C@@H:3]4[C@@H:7]([C:8]5[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=5)[CH2:6][N:5]([C@H:15]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:16]([OH:18])=[O:17])[CH2:4]4)[CH2:46][CH2:45]3)=[CH:38][CH:39]=[CH:40][C:33]=12
Reactant: c1cc(CCCC2CCNCC2)c2nonc2c1
Reactant: O=C[C@H]1CN(C(C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1cccc(F)c1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3cccc4nonc34)CC2)[C@@H](c2cccc(F)c2)C1

Procedure:
The title compound was prepared from 30 mg (0.071 mmol) 2-(R)-((3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 102, Step A) and 4-(3-(benzofurazan-4-yl)propyl)piperidine. HCl (from EXAMPLE 117, Step B) using procedures analogous to those described in EXAMPLE 1, Steps J and K. For the title compound: HPLC (Zorbax SB-C8 4.6 mm×7.5 cm column, gradient elution using 10:90 v/v CH3CN/H2O+0.1% TFA to 100% CH3CN over 7.5 min, hold for 45 sec, 2.25 mL/min, 220 nm): Retention Time: 4.31 min; ESI-MS 563.0 (M+H).
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[K+].[K+].[K+].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=1[C:12]#[N:13]>>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=1[C:12]([NH2:13])=[O:2]
Reactant: O=P([O-])([O-])[O-]
Reactant: N#Cc1c(F)cccc1F
Agent: [K+]
Product: NC(=O)c1c(F)cccc1F

Procedure:
The suspension of the bacterial cells (corresponding to 5.92 mg of the dry cells) obtained in Example 8 was added to 4 ml of the reaction solution containing 10 mM of a potassium phosphate buffer (pH 8.0) and 0.5 M of 2,6-difluorobenzonitrile, and the reaction was conducted at 25° C. with adding 0.5 M of 2,6-difluorobenzonitrile to the reaction solution after 2,4,6 and 8 hours from the initiation of the reaction, respectively. After 22 hours from the initiation of the reaction, 2.5 M (393 g/lit.) of 2,6-difluorobenzamide was produced with a 100% conversion.
Reaction SMILES: [CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].[Li]CCCC.[C:19]([Si:23]([O:26][C@@H:27]1[CH2:31][C@@H:30]([CH2:32]I)[CH2:29][C@H:28]1[F:34])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[Si:23]([O:26][C@H:27]1[C@H:28]([F:34])[CH2:29][C@H:30]([CH2:32][C@H:7]2[C:6]([O:12][CH3:13])=[N:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[C:9]([O:10][CH3:11])=[N:8]2)[CH2:31]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)C[C@H]1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@H]1C[C@@H](F)[C@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.2 g, 1.5 equiv.) in dry THF (30 mL) was cooled to −78° C. n-BuLi (1.6 M in Hexane, 4.08 mL, 1.5 equiv.) was added dropwise. After stirring 1 h at −78° C., a solution of (±)-tert-butyl((1r,2R,4R)-2-fluoro-4-(iodomethyl)cyclopentyloxy)dimethylsilane (1.56 g, 4.36 mmol) in dry THF (8 mL) was added dropwise. The mixture was stirred another 2 h at −78° C. The mixture was warmed up to rt slowly, quenched by sat. NH4Cl solution (30 mL), extracted by diethyl ether (2×150 mL). The combined organic layers were washed by brine (30 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (40 g column, 0˜25% EtOAc in Hexanes) to afford (2S,5R)-2-(((1r*,3R*,4R*)-3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentyl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.81 g, quant. yield) as a clear oil. MS ESI +ve m/z 415 (M+1).
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(OCC)C>O>[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([O:22][CH2:21][CH:20]([CH2:23][O:24][C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: CCCCCCCCCCCCCCCCCCOC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Yield: 83.1 %

Procedure:
A solution of 2-O-Octadecyl-3-O-trityl-glycerol (10 g, 17.04 mmol) in 52 ml water-free pyridine is added dropwise during 30 min. to a solution of p-toluenesulfonyl chloride (5.1 g, 26.75 mmol) in 39 ml water-free pyridine under stirring. After 2 days at room temperature 162 ml diethyl ether are added and the precipitate formed is removed by filtration. The organic phase is washed successively with water (6×50 ml), 0.5N HCl (2×29 ml), 0.5N sodium carbonate (2×29 ml), and water (4×50 ml). Evaporation of the solvent under vacuum gives an oily product which becomes solid after drying in vacuo. The product, 1-p-toluenesulfonyl-2-O-Octadecyl-3-O-trityl-glycerol (10.5 g, 85% yield), is used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:32][C:33]1[C:41]([NH2:42])=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH2:37])=[O:36].N>N1C=CC=CC=1.CN(C=O)C>[NH2:32][C:33]1[C:34]([C:35]([NH2:37])=[O:36])=[CH:38][CH:39]=[CH:40][C:41]=1[NH:42][C:13](=[O:15])[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1cccc(C(N)=O)c1N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2-{[(Benzyloxy)carbonyl]amino}-2-methylpropanoic acid (5.18 g, 21.83 mmol) in a mixture of pyridine (25 mL) and DMF (25 mL) was treated with 1,1′-carbonyldiimidazole (3.72 g, 22.92 mmol) and heated at 40° C. for 2 hours. 2,3-Diaminobenzamide dihydrochloride (4.89 g, 21.83 mmol), prepared as described in WO0026192, was added and the mixture was stirred at room temperature overnight. The solvents were removed under vacuum and the residue was partitioned between ethyl acetate and diluted sodium bicarbonate aqueous solution. The formed slightly yellow solid material was collected by filtration, washed with water and ethyl acetate, and dried to give Example 1A. MS (DCI/NH3) m/z 371 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH2:24](I)[CH3:25]>>[C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:24][CH3:25])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2)c1N=Cc1ccccc1
Reactant: CCI
Product: CCn1c(C)c(C(C)=O)c(N=Cc2ccccc2)c1-c1ccccc1

Procedure:
By procedure (a) of Example 49 and starting from the compound of Example 46 and ethyl iodide, the 4-acetyl-3-benzylideneamino-1-ethyl-5-methyl-2-phenylpyrrole is obtained, m.p. 139°-141° C. (from isopropanol/water). This compound is hydrolyzed as in procedure (b) of Example 49. Overall yield of the title compound: 54%, m.p. 107°-108° C. (from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[NH2:26][CH2:27][C@@H:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:26][CH2:27][CH:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from methyl 4-methyl-2-[(2S)-4-(4-oxo-piperidin-1-yl)-benzylamino]-pentanoic acid methyl ester (which was obtained in Example 166) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp>90° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.86 (d, J=6.4 Hz, 3 H), 0.92 (d, J=6.4 Hz, 3 H), 1.20–1.40 (m, 2 H), 1.50–1.95 (m, 5 H), 2.55–2.92 (m, 5 H), 2.91 (s, 3 H), 3.62 (s, 3 H), 3.70–3.85 (m, 2 H), 4.40–4.55 (m, 2 H), 6.82 (d, J=8.2 Hz, 1 H), 6.93 (d, J=8.9 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 2 H), 7.18 (d, J=2.0 Hz, 1 H), 7.75 (d, J=8.9 Hz, 2 H), 8.34 (d, J=7.7 Hz, 1 H); MS (ES) m/z: 577.3 (MH+); HRMS Calcd. for C28H41N4O7S (MH+): 577.2690. Found: 577.2682.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>>[Cl:14][C:15]1[CH:16]=[C:17]([C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2Cl)CC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
Tert-Butyl piperazine-1-carboxylate (0.931 g, 5 mmol) and 3-chloro-4-fluorobenzonitrile (0.785 g, 5.00 mmol) were combined, K2CO3 (0.898 g, 6.50 mmol) was added and the reaction mixture was stirred at 90° C. for 1 d. The mixture was triturated with ethyl acetate (3×5 mL) and the combined organic extracts were filtered. This was concentrated down to about 5-10 mL and subjected to flash column chromatograhy on silica gel (120 g SiO2, hexanes:ethyl acetate 1:0 to 4:1) to afford tert-butyl 4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate (1.264 g, 3.93 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.42 (s, 9 H) 3.00-3.09 (m, 4 H) 3.42-3.53 (m, 4 H) 7.25 (d, J=8.59 Hz, 1 H) 7.77 (dd, J=8.34, 2.02 Hz, 1 H) 7.97 (d, J=2.02 Hz, 1 H); [M+H] calc'd for C16H20ClN3O2, 322; found, 322.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:2]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH+:11]([O-:36])[C:12](=[O:27])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[N:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1cc2ccccc2cn1)c1ccccc1NCc1ccncc1
Solvent: ClCCl
Product: O=C(c1ccccc1NCc1ccncc1)[NH+]([O-])c1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.6 %

Procedure:
212 mg (0.6 mmol) of N-(isoquinolin-3-yl)-2-(4-pyridylmethyl)aminobenzoic acid amide is mixed in 10 ml of dichloromethane with 103 mg (0.6 mmol) of m-chloroperbenzoic acid, and it is stirred for 6 hours at room temperature in a moisture-free environment and under argon. The batch is then washed with 15 ml of saturated sodium bicarbonate solution and with saturated common salt solution, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol=10:1 as an eluant. 68 mg (30% of theory) of N-(isoquinolin-3-yl)-2-(4-pyridylmethyl)aminobenzoic acid amide-N-oxide with a melting point of 212.2° C. is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:22]1([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][N:16]2[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:15])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCCC2c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1CCCNC1)N1CCCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100 %

Procedure:
To a solution of 1 g 3-(2-phenyl-piperidine-1-carbonyl)-piperidine-1-carboxlic acid tert.-butyl ester in DCM (15 mL) was added 40% trifluoroacetic acid in DCM (6 mL). The mixture was stirred at room temperature for 4-5 h. After completion of the reaction all volatiles were evaporated, water (20 mL) was added and the mixture extracted with (2×25 mL) diethyl ether. The aqueous layer was adjusted with 10% aq. NaOH to pH=12, and extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure to yield 0.731 g (95%) of the title compound. (MH+) 273.36.