Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:6]=2[CH:17]=1.[Cl-].[NH4+].[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[NH2:16][C:12]1[N:11]=[C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:20]#[N:21])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH:15]=[CH:14][N:13]=1
Reactant: CN(C)C=O
Reactant: Nc1nccc(-n2cnc3ccc(Br)cc32)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Product: N#Cc1ccc2ncn(-c3ccnc(N)n3)c2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask equipped with a condenser and nitrogen bubbler attached to a bleach scrubber bath was added 4-(6-bromo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (90% purity, 83 mg, 0.26 mmol) and zinc cyanide (30.23 mg, 0.26 mmol) in de-gassed DMF (2 mL). Tetrakis(triphenylphosphine)palladium (29.75 mg, 0.03 mmol) was then added and the reaction heated stirred at 100° C. under nitrogen for 30 min. The reaction mixture was allowed to cool to RT and poured into saturated aqueous ammonium chloride (6 mL) and extracted into DCM (×2). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was combined with the precipitate formed during the aqueous work up process and was purified by flash chromatography (Isolute column, 10% MeOH in DCM) to afford the title compound as a pale beige solid; 1H NMR (500 MHz, DMSO) δ 6.90-7.42 (3H, m), 7.76 (1H, dd, J=8.35, 1.58 Hz), 7.94 (1H, d, J=8.04 Hz), 8.40 (1H, d, J=5.52 Hz), 9.20 (1H, d, J=0.95 Hz), 9.33 (1H, s); LC-MS: m/z=+236.95 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[C:6]([C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].ClC1C=CC=CC=1C[NH2:20].Cl>C1(C)C=CC=CC=1>[NH2:20][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:11]([Cl:13])=[C:10]([Cl:14])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1c(Cl)c(Cl)cc([N+](=O)[O-])c1Cl
Reactant: NCc1ccccc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: Nc1c([N+](=O)[O-])cc(Cl)c(Cl)c1C(=O)O

Procedure:
To a stirred solution of 3-nitro-2,5,6-trichlorobenzoic acid (37.1 mmol, 10.0 g) in 150 mL of toluene, was added 2-chlorobenzylamine (81.6 mmol, 11.56 g). The reaction mixture was refluxed overnight, poured into dilute hydrochloric acid and vigorously stirred. The resulting solid was filtered. The product was dissolved in toluene and then precipitated with diethyl ether. Recrystallization of the product from methanol gave 3.4 g of 2-[2-chlorophenyl)methyl]amino-5,6-dichloro-3-nitrobenzoic acid; mp 168.5°-171° C.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:20](=O)([O:60]C1C=CC([N+]([O-])=O)=CC=1)[O:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C@H:30]2[C@@H:42]3[CH2:43][O:44][C:45](=[O:46])[C@H:41]3[C@@H:40]([O:47][C:48]([NH:50][C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)=[O:49])[C:39]3[C:31]2=[CH:32][C:33]2[O:37][CH2:36][O:35][C:34]=2[CH:38]=3)=[CH:24][C:23]=1[O:58][CH3:59].O>ClCCl>[N:8]1([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:21][C:22]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([C@H:30]4[C@@H:42]5[CH2:43][O:44][C:45](=[O:46])[C@H:41]5[C@@H:40]([O:47][C:48]([NH:50][C:51]5[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=5)=[O:49])[C:39]5[C:31]4=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=5)=[CH:24][C:23]=3[O:58][CH3:59])=[O:60])[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](OC(=O)Nc3ccc(F)cc3)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1OC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc([C@@H]2c3cc4c(cc3[C@H](OC(=O)Nc3ccc(F)cc3)[C@@H]3C(=O)OC[C@@H]23)OCO4)cc(OC)c1OC(=O)N1CCC(N2CCCCC2)CC1
Reaction time: 2 h

Procedure:
0.87 mmol of triethylamine and 0.87 mmol of 4-piperidino-piperidine are added, under an argon atmosphere, to a solution of 0.56 mmol of the compound of Example 23 in 20 ml of anhydrous dichloromethane. After 2 hours, 20 ml of water are added to the reaction mixture. After extraction with dichloromethane, washing, drying, filtration, and concentration of the organic phases under reduced pressure, chromatography on silica gel (dichloromethane, methanol: 95/5) enables the expected product to be isolated.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([CH:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:23](O)=[O:24])[CH2:17]3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:2][CH2:3][CH2:4][NH:5][C:23](=[O:24])[CH:22]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([NH:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[NH:6][N:7]=[CH:8]3)[CH2:17]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Reactant: NCCF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCCF)C(c1ccccc1)N1CCCC(Nc2ccc3[nH]ncc3c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.3 %

Procedure:
2-Fluoroethylamine hydrochloride (50 mg) and the compound prepared in Example 222 (88 mg) were dissolved in dimethylformamide (1 ml), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-chloride (86 mg), 1-hydroxybenzotriazole (77 mg), and dimethylaminopyridine (5 mg) were added to the solution. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give 39 mg of the title compound as two diastereomers (ratio=ca. 50:50).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([NH:29][C@H:30]([C:35](O)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])(OCC1C=CC=CC=1)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]([C:35](=[O:36])[C@H:30]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH2:29])[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Product: CC(C)C[C@H](N)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Yield: 34.3 %

Procedure:
By reacting 7 g of N-(indan-2-yl)glycine tert-butyl ester with 8.5 g of N-(carbobenzoxy)-L-leucine and treating the reaction mixture as in Reference Example 5, there is obtained 3.5 g of L-leucyl-N-(indan-2-yl)glycine tert-butyl ester as colorless amorphous powder.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23]Cl>CN(C)C(=O)C>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23][N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][CH:12]=[N:13][C:5]=2[NH:4][CH2:1][CH2:2][CH3:3]
Reactant: Fc1cccc(Cl)c1CCl
Reactant: CCCNc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCNc1ncnc2c1ncn2Cc1c(F)cccc1Cl
Yield: 59.2 %

Procedure:
In a procedure analogous to that of Example 9, by using 1.77 g of 6-n-propylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.89 g of 9-(2-chloro-6-fluorobenzyl)-6-n-propylaminopurine as colorless needles (yield: 59%), m.p. 166°-167° C.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:18])[C:6]2=[O:17].[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O.COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:13]([C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][CH:5]([CH3:18])[C:6]2=[O:17])=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=2)[C:10]=1[O:11][CH3:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COc1c(C(C)(C)C)cc2c(c1Br)CC(C)C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)CC(C)C2=O
Yield: 79.8 %

Procedure:
A mixture of 31.1 g (100 mmol) of 4-bromo-6-tertbutyl-5-methoxy-2-methylindanone, 25.0 g (140 mmol) of 4-tert-butylphenylboronic acid, 29.4 g (280 mmol) of Na2CO3, 1.35 g (6.00 mmol, 6 mol. %) of Pd(OAc)2, and 3.15 g (12.0 mmol, 12 mol. %) of PPh3 in 130 ml of water and 380 ml of DME was refluxed for 6 h in argon atmosphere. The formed mixture was evaporated to dryness. To the residue 500 ml of dichloromethane and 500 ml of water were added. The organic layer was separated, the aqueous layer was additionally extracted with 100 ml of dichloromethane. The combined organic extract was dried over Na2SO4, evaporated to dryness, and the crude product was isolated using flash chromatography on silica gel 60 (40-63 um; eluent: hexanes-dichloromethane=2:1, vol.). This crude product was recrystallized from n-hexane to give 29.1 g (81%) of a white solid.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1.BrCC1C=CC=CC=1[F:44].C(OC(=O)C(C)(C)CSC1SC(N)=NC=1)C>>[F:44][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Product: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl-2-fluoro-benzene and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@:24]([OH:28])([CH3:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[OH:28][C@:24]1([CH3:27])[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: C[C@@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: C[C@@]1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1

Procedure:
(R)-5-Bromo-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 66.1, 60 mg, 0.130 mmol), pyrimidin-5-ylboronic acid (32.3 mg, 0.261 mmol), Pd(PPh3)2Cl2 (9.15 mg, 0.013 mmol) and Na2CO3 (41.5 mg, 0.391 mmol) were added to a MW vial and treated with a mixture of DME (553 μL), water (158 μL) and EtOH (79 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 120° C. for 10 min. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 45.3 mg, 0.065 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column Silica, from 23% to 28% in 6 min) to yield the title compound as a white solid. UPLC-MS (Condition 3) tR=0.94 min, m/z=460.4 [M+H]+, m/z=458.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 3H) 1.67-1.83 (m, 2H) 2.96 (d, J=10.54 Hz, 1H) 3.03 (d, J=10.54 Hz, 1H) 3.18-3.26 (m, 1H) 3.38-3.47 (m, 1H) 4.75 (s, 1H) 7.36 (d, J=8.28 Hz, 2H) 7.82-7.90 (m, 2H) 8.10 (d, J=2.38 Hz, 1H) 8.79 (d, J=2.38 Hz, 1H) 8.89 (s, 2H) 9.20 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: Cl.[CH:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:24])[CH:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:14])=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[C:25]([Cl:30])(=[O:29])[CH2:26][CH2:27][CH3:28]>C(#N)C>[ClH:30].[C:25]([O:24][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([S:5][CH:2]([CH3:4])[CH3:3])=[CH:7][CH:8]=1)[CH:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:14])(=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC(=O)Cl
Reactant: CCCCCCCCNC(C)C(O)c1ccc(SC(C)C)cc1
Agent: Cl
Solvent: CC#N
Product: CCCCCCCCNC(C)C(OC(=O)CCC)c1ccc(SC(C)C)cc1

Procedure:
A mixture made of 10 gr (27 mmol) of 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol hydrochloride and 11.4 gr (107 mmol) of butyryl chloride is heated at reflux temperature until a limpid solution is obtained. 10 ml of acetonitrile are added and reflux is maintained for about 2 hours. The solution so obtained is diluted with 40 ml of acetonitrile before being cooled. The white solid if filtered off. After recrystallisation from acetonitrile, the product weights 6.4 gr (14 mmol, 52%) and has a melting point of 104.1° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[N:36]=[CH:35][C:34]3[C:29](=[C:30]([F:41])[CH:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:33]=3)[C:28]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:37]([C:32]1[CH:33]=[C:34]2[C:29](=[C:30]([F:41])[CH:31]=1)[C:28](=[O:42])[N:27]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=4)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:36]=[CH:35]2)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C)[nH]n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)n[nH]1
Temperature: 30 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A mixture of 121a (86 mg, 0.15 mmol) and lithium hydroxide (36 mg, 1.5 mmol) in THF/i-propanol (5:3, 8 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (5 mL). It was then extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 121 (24 mg, 30%) as a white solid. MS-ESI: [M+H]+ 530.3. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=5.0 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.58-7.53 (m, 4H), 7.44 (s, 1H), 5.78 (s, 1H), 4.51-4.49 (m, 2H), 3.73 (s, 3H), 2.03 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7](=[O:31])[CH2:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]#[N:29])[CH:22]=2)(=[O:20])=[O:19])[C:10]=1[CH3:30].O>C(Cl)Cl>[C:28]([C:23]1[CH:22]=[C:21]([S:18]([N:11]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:17]3[C:9]([CH2:8][C:7]([OH:31])=[O:6])=[C:10]2[CH3:30])(=[O:19])=[O:20])[CH:26]=[CH:25][C:24]=1[F:27])#[N:29]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(C#N)c2)c2ncccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(F)c(C#N)c1
Reaction time: 0.33 h

Procedure:
1M BBr3 in CH2Cl2 (7.66 mL, 7.66 mmol) is added to a solution of [1-(3-cyano-4-fluoro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.495 g, 1.27 mmol) in CH2Cl2 (2 mL). The reaction mixture is exposed to microwave irradiation at 60° C. for 45 minutes. Water is added to the reaction mixture which is stirred for further 20 minutes. The organic layer is isolated using the Isolute™ phase separator cartridge and evaporated. The residue is loaded on a pre-packed Isolute™ silica column and eluted using a gradient eluent from 100% CH2Cl2 to 5% methanol in CH2Cl2 to afford the title compound; MH+=374.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:17][C:18]1[CH:29]=[CH:28][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:24]2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: Fc1ccc(CC2CCNC2)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccc(F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(4-fluorobenzyl)pyrrolidine hydrochloride (12.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (6.3 mg). Calcd for C22H21FN2O2: 364.1587, found 364.1604.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-])=O)[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:5]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:3][CH2:2]1>CC(O)=O.[Fe]>[NH2:18][C:9]1[C:10]([F:17])=[C:11]([F:16])[C:12]([O:14][CH3:15])=[C:13]2[C:8]=1[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:5]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[N:4]2[CH:1]1[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(-c2ccccc2)n(C2CC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2)n(C2CC2)c2c(OC)c(F)c(F)c(N)c2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 102.3 %

Procedure:
A suspension of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxo-2-phenylquinoline-3-carboxylate (1.05 g, 2.36 mmol) and iron powder (793 mg, 14.2 mmol) in AcOH (25 mL) was stirred at 90° C. for 3 h. After the reaction mixture was concentrated in vacuo, water was added and the crude product was extracted with EtOAc, washed with saturated aq. NaHCO3 and brine, dried over MgSO4. The solvent was removed in vacuo and the residue was dried to yield ethyl 5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-2-phenyl-1,4-dihydroquinoline-3-carboxylate (1.00 g, quant.) as a yellow amorphous solid.
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1>[Cu]I.CS(C)=O>[CH3:40][O:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:18][CH:19]=1
Reactant: COc1cccc(I)c1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: COc1cccc(Oc2ccc(-c3cccnc3N)cc2)c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 1-iodo-3-methoxybenzene (754 mg) and DMSO (8 mL). The mixture was stirred at 120° C. under nitrogen for 6 hr. The insoluble material was removed by silica-filtration with EtOAc, and the filtrate was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (349 mg) as a yellow solid.
Reaction SMILES: C([O:5][C:6](=[O:32])[C@H:7]([CH2:27][CH2:28][C:29](=[O:31])[NH2:30])[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C.CO.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C1(C)C=CC=CC=1>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:26][C:16]1[C:15]2[C:20](=[CH:21][C:12]([S:9]([NH:8][C@H:7]([C:6]([OH:32])=[O:5])[CH2:27][CH2:28][C:29](=[O:31])[NH2:30])(=[O:11])=[O:10])=[CH:13][CH:14]=2)[C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCC(N)=O)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@@H](CCC(N)=O)C(=O)O)cc12

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-glutamine tert-butyl ester (15 mg, 0.03 mmol) was dissolved in trifluoroacetic acid (1 ml) and the resultant solution stirred at room temperature for 1 h, diluted with toluene and concentrated to a residue. Trituration with Et2O gave a powder to which was added MeOH and the suspension filtered. The filtrate was concentrated and then triturated with EtOAc to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-glutamine trifluoroacetate (9 mg, 0.02 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([NH2:11])=[C:5]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[CH:4]=1.Cl.Cl[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]Cl>ClC1C=CC=CC=1Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N:11]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:5]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)[CH:4]=1
Reactant: ClCCNCCCl
Reactant: COc1cc(N)c(C2CC(C)(C)CC(C)(C)C2)cc1OC
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: COc1cc(C2CC(C)(C)CC(C)(C)C2)c(N2CCNCC2)cc1OC
Temperature: 220 °C
Reaction time: 2 h

Procedure:
A mixture of the crude product of 4,5-dimethoxy-2-(3,3,5,5-tetramethylcyclohexyl)phenylamine produced in Example (87c), bis(2-chloroethyl)amine hydrochloride (700 mg, 3.91 mmol) and 1,2-dichlorobenzene (10 ml) was stirred for 2 hours at an external temperature of 220° C. During the reaction, nitrogen gas was blown in several times to remove the excess hydrogen chloride gas from the reactor. The reaction mixture was cooled to room temperature, saturated aqueous solution of sodium hydrogencarbonate was added and extraction was performed with chloroform. The aqueous layer was again extracted with chloroform, and the organic layers were combined, washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 490 mg of the title compound as a brown oil.