Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12BC(CCC1)CCC2.[CH:10]([CH:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][N:13]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[CH2:11].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:38]1[CH:39]=[CH:40][CH:41]=[C:36]([CH2:11][CH2:10][CH:12]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:15][CH2:14][N:13]2[C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH:37]=1
Reactant: Brc1cccnc1
Reactant: C=CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CCc2cccnc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
9-Borabicyclo[3.3.1]nonane (0.5M solution in THF, 54 mL, 27 mmol) was added to 1-benzyl 4-tert-butyl 2-vinylpiperazine-1,4-dicarboxylate (2.33 g, 6.73 mmol). After 3 h, 3-bromopyridine (0.99 mL, 10.1 mmol), triphenylphosphine (0.53 g, 2.0 mmol), and tetrakis(triphenylphosphine) palladium(0) (0.311 g, 0.27 mmol) were added. Sodium hydroxide (1N aqueous solution, 16.8 mL, 16.8 mmol) was added slowly. Once bubbling ceased, the reaction mixture was heated to reflux overnight. Upon cooling to rt, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chomatography (10 to 40% EtOAc in Hexane gradient) gave 1.79 g (63%) of the desired product as a thick oil. Rf=0.57 in 80% EtOAc/Hexane. LC-MS: RT=7.69 min., [M+H]+=426.2. The material was contaminated with ˜15% triphenylphosphine, and was used without further purification.
Reaction SMILES: FC(F)(F)C1C=CC=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[F:36][C:37]([F:50])([F:49])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([N:46]=[C:47]=[S:48])=[O:45]>C1(C)C=CC=CC=1.C(O)C>[F:49][C:37]([F:36])([F:50])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([N:46]=[C:47]=[S:48])=[O:45].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][N:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:47]([NH:46][C:44](=[O:45])[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[C:37]([F:36])([F:50])[F:49])=[S:48])=[CH:31][CH:30]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=C(N=C=S)c1ccccc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C(F)(F)F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
2-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([C:25]([F:28])([F:27])[F:26])[CH2:24][CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([C:25]([F:27])([F:28])[F:26])[CH2:24][CH2:23][CH2:22]3)[C:17]([NH:32][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:35][CH:34]=3)=[O:18])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2(C(F)(F)F)CCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2(C(F)(F)F)CCC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
90 mg (purity 69%, 0.14 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclobutyl]propanoic acid (racemate) and 29 mg (0.15 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 58 mg (67% of theory)
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=[N:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1OCCCN1CCCCC1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCCc1ccccc1)c1ccccc1OCCCN1CCCCC1
Yield: 91.8 %

Procedure:
2-[3-(1-Piperidinyl)propoxy]benzaldehyde (47.6 g) is reacted with 24 g of phenethylamine in 190 ml of toluene following the procedure described in Example 1A to yield 61.9 g of product as an oil, boiling point 214°-218° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: C([NH:5][S:6]([C:9]1[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[CH:11][N:10]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[CH:11]1[N:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=12
Reactant: CC(C)(C)NS(=O)(=O)c1ncc2ccccn12
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ncc2ccccn12
Temperature: 25 °C
Reaction time: 336 h
Yield: 77.1 %

Procedure:
N-(t-Butyl)imidazo[1,5-a]pyridine-3-sulfonamide (1.0 g) is dissolved in 20 ml of trifluoroacetic acid and stirred for 14 days at room temperature. The mixture is concentrated under reduced pressure, and ether is added to the residue to precipitate crystals. The crystals are collected by filtration and dried to give 0.60 g of the title compound. mp. 179°-180° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13]CC(=O)C[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.[F:15][C:16]([F:48])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]([CH3:36])[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)=[O:21].CN(C)CCCCl>>[F:48][C:16]([F:15])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:28]([CH3:36])[N:27]([CH2:3][CH2:2][CH2:1][N:8]([CH3:13])[CH3:9])[C:26]2=[O:37])[CH2:38][CH2:39]1)=[O:21]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Agent: CN(C)CCCCl
Product: CC1N(CCCN(C)C)C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1

Procedure:
The title compound, MS: m/e=571.1 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 1-benzyl-piperidin-4-one and 3-dimethylamino1-propyl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=1[O:26]CC1C=CC=CC=1)(=[O:16])=[O:15])[C:9]([NH:11][CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].C1COCC1>[Pd].CO>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[OH:26])(=[O:15])=[O:16])[C:9]([NH:11][CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1O
Yield: 109.4 %

Procedure:
A mixture of 1.0 g (1.91 mmol) 3-(2-benzyloxy-4-nitro-benzenesulfonylamino)-N-methyl-succinamic acid tert-butyl ester from Route D, 0.2 g 20% Pd/C, and 75 mL of a 1:1 mixture of THF:MeOH was shaken under 50 psi H2 gas for 4.5 h. TLC analysis showed reaction complete. The reaction was filtered to remove catalyst and the solvent evaporated under reduced pressure to give 3-(4-amino-2-hydroxy-benzenesulfonylamino)-N-methyl-succinamic acid tert-butyl ester 0.78 g (100%) as a light yellow foam. MS (APCI) m/z 402 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])#[N:13]>CN(C1C=CN=CC=1)C>[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])=[O:21])#[N:13]
Reactant: Nc1cccc2cccnc12
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Product: N#Cc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 46.9 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), 2-cyanobenzenesulfonyl chloride (140 mg, 0.69 mmol) and DMAP (cat.) gave the title compound (100 mg, 50%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C(OC(=O)[N:7]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[C:19]([CH3:28])=[CH:18][C:17]2=[O:29])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:35]1[C:34]2[CH:39]=[CH:40][C:31]([CH2:30][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=5)[C:19]([CH3:28])=[CH:18][C:17]4=[O:29])[CH2:10][CH2:9]3)=[CH:32][C:33]=2[O:38][CH2:37][CH2:36]1
Reactant: COc1ccc2c(C)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To 2 mL of a dichloromethane solution containing 95 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred for 3 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=9:1] to give 60 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH:10]C(OC(C)(C)C)=O.[Cl:18][C:19]1[C:24]([C:25]([N:27]=[C:28]=[O:29])=O)=[C:23]([F:30])[C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([F:30])[C:24]=1[C:25]1[NH:27][C:28](=[O:29])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)cc1F
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(F)cc3F)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(2,4-difluorophenyl)hydrazinecarboxylate (Intermediate-54, 0.060 g, 0.21 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.101 g, 0.32 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.018 g of pure product. 1H NMR (300 MHz, CDCl3): δ 1.16 (s, 9H), 4.38 (d, J=5.4 Hz, 2H), 6.25 (m, 1H), 6.79-6.82 (m, 1H), 6.90-6.96 (m, 2H), 7.20-7.32 (m, 2H), 7.50-7.53 (m, 1H); MS (m/z): 437.26 (M−H−).
Reaction SMILES: [C@H:1]12[CH2:13][C@H:4]([N:5](C(OC(C)C)=O)[CH2:6]1)[CH2:3][N:2]2[C:14]([O:16][C:17](C)([CH3:19])[CH3:18])=[O:15].[ClH:21]>CO>[ClH:21].[C@H:1]12[CH2:13][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CC(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
(1S,4S)-2-tert-Butyl 5-isopropyl 2,5-diazabicyclo[2.2.1]heptane-2,5-dicarboxylate (1.3 g, 4.6 mmol) was dissolved in methanol (200 mL). Concentrated hydrochloric acid (6 mL, 72 mmol) was added and the solution stirred at 50° C. for 2 h, then evaporated to dryness to provide (1S,4S)-isopropyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate hydrochloride as 0.9 g of white solid. LRMS (ESI) m/z 185.1 [(M+H)]+, calc'd for C9H16N202: 184.24.
Reaction SMILES: [Mg].[CH3:2][Ge:3](Cl)([CH3:5])[CH3:4].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1>O1CCCC1>[CH3:2][Ge:3]([CH3:5])([CH3:4])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)=[CH:10][CH:9]=1
Reactant: C[Ge](C)(C)Cl
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(c2ccc([Ge](C)(C)C)cc2)OCCO1
Yield: 46.6 %

Procedure:
To a mixture of 108 mg (4.44 mmol) of magnesium and 766 mg (5.00 mmol) of trimethylgermyl chloride was added a solution of 972 mg (4.00 mmol) of 2-(4-bromophenyl)-2-methyl-1,3-dioxolane in 12 ml of dry tetrahydrofuran (THF) at 40° C. with stirring. The mixture was refluxed for 1.5 hours and stirred at room temperature overnight. An insoluble substance was filtered off and washed with ether. The filtrate and washings were mixed and evaporated. The residue was purified by column chromatography on silica gel [eluent: petroleum ether-methylene chloride (2:1-1:2)] and recrystallized from petroleum ether to give 524 mg of white prisms, m.p. 63.5°-65° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1>[F:10][C:11]1[C:12]([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:9])=[CH:13][C:14]([CH:17]=[O:18])=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(F)c(B(O)O)c1
Reactant: Cc1cccc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cccc(C)c1-c1cc(C=O)ccc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In an atmosphere of nitrogen, tetrakistriphenylphosphine palladium was added to a mixture of 2-bromo-1,3-dimethylbenzene, 2-fluoro-5-formylphenyl boronic acid, a 1 M sodium carbonate aqueous solution, ethanol and toluene, followed by stirring at 80° C. for 8 hours to obtain 6-fluoro-2′,6′-dimethylbiphenyl-3-carbaldehyde. Under cooling on an ice-methanol bath, sodium borohydride was added in small portions to an ethanol solution of the resulting 6-fluoro-2′,6′-dimethylbiphenyl-3-carbaldehyde, and the reaction mixture was stirred at the same temperature for 1 hour to obtain (6-fluoro-2′,6′-dimethylbiphenyl-3-yl)methanol.
Reaction SMILES: ICl.[OH:3][CH2:4]C(CO)OCN1C=C(C=C)C(=O)NC1=O.[OH:20][CH2:21][CH2:22][O:23][CH2:24][N:25]1[CH:32]=[C:31]([CH:33]([N:36]=[N+:37]=[N-:38])[CH2:34][I:35])[C:29](=[O:30])[NH:28][C:26]1=[O:27]>C(Cl)(Cl)Cl.CO>[OH:20][CH2:21][CH:22]([CH2:4][OH:3])[O:23][CH2:24][N:25]1[CH:32]=[C:31]([CH:33]([N:36]=[N+:37]=[N-:38])[CH2:34][I:35])[C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: [N-]=[N+]=NC(CI)c1cn(COCCO)c(=O)[nH]c1=O
Reactant: C=Cc1cn(COC(CO)CO)c(=O)[nH]c1=O
Agent: ClI
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NC(CI)c1cn(COC(CO)CO)c(=O)[nH]c1=O
Yield: 29.6 %

Procedure:
Reaction of iodine monochloride (72.0 mg, 0.44 mmol) with 9a (95 mg, 0.39 mmol), using the procedure described for the preparation of 2c, and purification of the product by silica gel column chromatography using chloroform-methanol (90:10, v/v) as eluent afforded 10c as a syrup (48 mg, 29.6%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][NH:9][CH2:10][CH2:11][CH2:12][OH:13]>>[CH3:8][N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccncc1
Reactant: CNCCCO
Product: CN(CCCO)c1ccncc1
Yield: 2560.8 %

Procedure:
Using a procedure analogous to that described for the starting material in Example 46, 4-chloropyridine (885 mg, 59 mmol) and 3-(methylamino)propanol (2.1 g, 0.23 mmol), (Tetrahedron Lett. 1994, 35, 1545-1548), were heated for 8 hours to give 3-(N-methyl-N-(4-pyridyl)amino)propanol (979 mg, 61%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:42][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[CH:18][C:17]([CH2:22][NH:23][C@H:24]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:25][CH2:26][NH:27][C:28]1([C:33]([O-:35])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:16]3.[K+].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:35]=[C:33]1[C:28]2([CH2:29][CH2:30][CH2:31][CH2:32]2)[NH:27][CH2:26][CH2:25][C@@H:24]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:23]1[CH2:22][C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[CH:14][C:13]1[CH2:42][C@:3]3([CH2:11][C:12]=1[CH:21]=2)[C:4]1[C:5](=[N:6][CH:7]=[CH:8][CH:9]=1)[NH:10][C:2]3=[O:1]
Reactant: O=C([O-])C1(NCC[C@H](NCc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)c2ccccc2)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)[C@H](c2ccccc2)CCNC12CCCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of potassium 1-{[(3S)-3-({[(7S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclo-penta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-3-yl]methyl}amino)-3-phenylpropyl]amino}cyclopentanecarboxylate from step B (˜50 mg, ˜0.87 mmol) in DMF (4.5 mL) was added HOAt (18 mg, 0.13 mmol) and EDCI (150 mg, 0.80 mmol, in 4 portions). After 5 hours at ambient temperature, the reaction mixture was placed into a 60° C. bath for 16 hours. After the reaction was allowed to cool back to ambient temperature, the bulk of the DMF was removed in vacuo, before being diluted with chloroform (20 mL) and half-saturated sodium bicarbonate (5 mL). The aqueous layer was separated and extracted once with chloroform. The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue. This residue was applied to a silica gel column for purification, eluting with a gradient of CH2Cl2:MeOH—99:1 to 92:8. Product-containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=544 (M+1). HRMS: m/z=544.2762; calculated m/z=544.2707 for C34H34N5O2.
Reaction SMILES: C([NH:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:7]2[C:8]([O:10][C:11](=[O:12])[C:6]=12)=O)(=O)C.[F:19][C:20]1[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][C:21]=1[OH:27].CS(O)(=O)=O>O>[NH2:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:7]2[C:6]=1[C:11](=[O:12])[O:10][C:8]12[C:25]2[CH:26]=[C:20]([F:19])[C:21]([OH:27])=[CH:22][C:23]=2[O:24][C:23]2[C:25]1=[CH:26][C:20]([F:19])=[C:21]([OH:27])[CH:22]=2
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc2c1C(=O)OC2=O
Reactant: Oc1ccc(F)c(O)c1
Agent: CS(=O)(=O)O
Solvent: O
Product: Nc1c([N+](=O)[O-])ccc2c1C(=O)OC21c2cc(F)c(O)cc2Oc2cc(O)c(F)cc21
Temperature: 80 °C
Reaction time: 60 h
Yield: 60.7 %

Procedure:
3-Acetamido-4-nitrophthalic anhydride (1.3 g, 5.0 mmol) and 4-fluororesorcinol (1.3 g, 10 mmol) were added to methanesulfonic acid (10 ml), and the mixture was stirred at 80° C. under an argon atmosphere for 60 hours. The reaction mixture was added with water (120 ml) and refluxed for 2 hours. The reaction mixture was adjusted to pH 2, and precipitates were collected by filtration. The obtained product was dried and purified by silica gel chromatography (3% methanol/97% dichloromethane, v/v) to obtain the title compound (1.3 g, 61%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[C:25]([F:28])([F:27])[F:26])=[CH:11][N:10]=1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][CH2:8][C:9]1[N:10]=[CH:11][C:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[C:25]([F:28])([F:26])[F:27])=[CH:13][C:14]=1[F:15]
Reactant: COc1ccc(Nc2cnc(CNC(=O)OC(C)(C)C)c(F)c2)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(Nc2cnc(CN)c(F)c2)c(C(F)(F)F)c1

Procedure:
Tert-butyl[3-fluoro-5-(4-methoxy-2-trifluoromethyl-phenylamino)-pyridin-2-ylmethyl]-carbamate (0.13 mmol) was stirred for two hours at 60° C. in a mixture of 2 mL semi-concentrated hydrochloric acid and 3 mL dioxane. The mixture was then evaporated to dryness, then the residue was stirred with 3 mL toluene and evaporated down again. The crude product thus obtained (89% of theory) was used further without purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([Br:18])[CH:15]=[CH:16][CH:17]=1>O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([Br:18])[C:15]([N+:1]([O-:4])=[O:2])=[CH:16][CH:17]=1
Reactant: COc1cccc(Br)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(Br)c1
Temperature: 50 °C
Yield: 30 %

Procedure:
Nitric acid (70%, 5 mL) was placed in a 25 mL round-bottomed flask. Concentrated sulphuric acid (4 mL) was then added dropwise with stirring. The mixture was kept cool during the addition by immersing the flask in an ice bath. 3-Methoxybromobenzene (4 g, 21.5 mmol) was then introduced dropwise. The reaction mixture was then heated to 50° C. and stirred for 5 h. After cooling, the mixture was poured into 100 mL of cold water and extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with water (50 mL×4) and brine. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 95:5 hexanes:ethyl acetate. The first compound that eluted from the column was 3-methoxy-4-nitrobromobenzene (1.2 g) in 24% yield; 1H NMR (CDCl3) δ3.96(3H, s), 7.17 (1H, dd, J1=8.6, J2=1.9), 7.24 (1H, d, J=1.9), 7.75 (1H, d, J=8.6); 13C NMR δ57.34 117.58, 124.00, 127.41, 129.05, 142.26, 154.02. The second compound eluting from the column was 24 (1.5 g, 30% yield); 43-45° C.; 1H NMR (CDCl3) δ3.89 (3H, s), 6.91 (1H, dd, J1=9.1, J2=2.7), 7.21 (1H, d, J=2.7), 7.98 (1H, d, J=9.1); 13C NMR δ56.68, 114.02, 117.29, 120.61, 128.46, 163.23.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25]Cl)=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:30].[Na+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][I:30])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)OCCl)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)OCI)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of chloromethyl 3-(N-benzyloxycarbonyl-L-valyloxy)-benzoate (2.0 g, 4.76 mmole) in dry acetone (30 ml) was added sodium iodide (3.15 g, 21 mmole) and the mixture was stirred overnight at room temperature. The mixture was evaporated under reduced pressure and extracted with ethyl actate/water. The organic phase was washed with a 5% sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. Yield: 2.3g=94%.