Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[F:11].C([Li])CCC.[CH2:17]([Sn:19](Br)([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18]>CCOCC>[F:11][C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[Sn:19]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:17][CH3:18]
Reactant: Fc1oc2ccccc2c1Br
Reactant: CC[Sn](Br)(CC)CC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC[Sn](CC)(CC)c1c(F)oc2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis-(tetrafluoroborate (“Selectfluor®”) (13.11 g, 37.01 mmol) was added to a mixture of benzofuran-2-carboxylic acid (5.0 g, 30.84 mmol) and sodium bicarbonate (6.22 g, 74.0 mmol) stirred in 70 mL of pentane/water (2:5 by volume) at room temperature. After 1 hour at the pentane layer containing 2-fluorobenzofuran was separated from the mixture, and the water layer was extracted with pentane. The combined organic extract was dried through MgSO4, and then the solvent was evaporated to give 2-fluorobenzofuran (1.70 g) as a yellow oil. The 2-fluorobenzofuran (850 mg, 6.24 mmol) and potassium acetate (1.29 g, 13.11 mL) were stirred in of chloroform (3.5 mL) at room temperature, and a solution of bromine (2.05 g, 12.80 mmol) in of chloroform (1 mL), and added slowly into the reaction mixture. After stirring for 1 h at room temperature, the mixture was washed with 5% NaHSO3 then brine, dried through MgSO4, and the solvent was evaporated to give trans-2-fluoro-3-hydro-2,3-dibromo-benzofuran as a light-brown oil (1.70 g). trans-2-Fluoro-3-hydro-2,3-dibromo-benzofuran (1.66 g, 5.62 mmol) was dissolved in anhydrous ethanol (11 mL), and sodium ethoxide (420 mg, 6.18 mmol) was added. The mixture was stirred at RT for 5 min then brine was added, and the solution was extracted with pentane. The pentane layer was washed with water and with brine, dried through MgSO4, and then the solvent was evaporated to give 3-bromo-2-fluorobenzofuran as a light-brown oil (950 mg). Under nitrogen, 3-bromo-2-fluorobenzofuran (465 mg, 2.16 mmol) was dissolved in anhydrous ether (5 mL), and stirred at −78° C. under nitrogen. n-Butyllithium (1.6M, 1.50 mL, 2.38 mmol) was added followed after 5 min by triethylstannyl bromide (680 mg, 2.38 mmol). The mixture was then allowed to warm to room temperature and stirring was continued for a further 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give the sub-title compound as a brown oil (370 mg), which was used directly without further purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH2:9]([O:8][C:7]1[C:2]2[N:3]([C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([CH3:25])[N:1]=2)[CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cccn12
Temperature: 100 °C

Procedure:
25 g (124.8 mmol) of 2-amino-3-benzyloxypyridine were dissolved in 781 ml of ethanol, 102.7 g (624.2 mmol) of ethyl 2-chloroacetoacetate and two tablespoons of 4 A molecular sieve were added, and the reaction mixture was then heated at reflux (bath temperature 100° C.) for 2 days. The mixture was concentrated, and excess ethyl 2-chloroacetoacetate was removed on a rotary evaporator with dry ice cooling. The residue was purified by silica gel chromatography (mobile phase cyclohexane:ethyl acetate gradient 9:1, 4:1). This gave 20.81 g of the target compound (54% of theory, purity 99%).
Reaction SMILES: O=O.CC1SC(C)=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=1C1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=C(C)SC=1C.[CH3:43][O:44]/[C:45](=[CH:49]\[C:50]1[C:55]2[S:56][CH:57]=[CH:58][C:54]=2[C:53]([O:59][CH2:60][CH2:61][C:62]2[N:63]=[C:64]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[O:65][C:66]=2[CH3:67])=[CH:52][CH:51]=1)/[C:46]([OH:48])=[O:47].C1([C@@H](N)C)C=CC=CC=1.[H][H]>C1COCC1.CO>[CH3:43][O:44][C@@H:45]([CH2:49][C:50]1[C:55]2[S:56][CH:57]=[CH:58][C:54]=2[C:53]([O:59][CH2:60][CH2:61][C:62]2[N:63]=[C:64]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[O:65][C:66]=2[CH3:67])=[CH:52][CH:51]=1)[C:46]([OH:48])=[O:47]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Agent: C[C@H](N)c1ccccc1
Agent: Cc1sc(C)c(P(c2ccccc2)c2ccccc2)c1-c1c(C)sc(C)c1P(c1ccccc1)c1ccccc1
Agent: O=O
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 0.62 mg of [Ru(OAc)2((S)-TMBTP)] (0.0008 mmol, S/C 3′000) (prepared according to EP 1,670,792 B1; TMBTP=2,2′,5,5′-Tetramethyl-4,4′-bis(diphenylphosphino)-3,3′-bithiophene) and 5 ml of methanol. The resulting orange solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 4 ml of methanol, 6 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.7% (99.9% conversion) and an enantiomeric purity of 89%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][B:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)[O:29][C@@H:28]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][B:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=4)[O:29][C@@H:28]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OB(c2cccc([N+](=O)[O-])c2)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OB(c2cccc([N+](=O)[O-])c2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2-(3-nitrophenyl)-1,3,2-dioxaborinan-4-yl)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH3:9].[Cl:10]N1C(=O)CCC1=O.O.[OH-].[NH4+]>CS(O)(=O)=O>[NH2:1][C:2]1[C:7]([Cl:10])=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(N)cccc1O
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1c(O)ccc(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a stirred solution of 3-amino-o-cresol (60 g) in anhydrous methanesulfonic acid (300 ml) was added N-chlorosuccinimide (68.3 g in five equal portions) over 2 h and 10 min, keeping the reaction temperature between 10 and 12° C. by use of a cooling bath. The dark mixture was allowed to stir overnight and warm to room temperature. It was then added to 1000 ml water with stirring (final temperature approx. 51° C.). Concentrated ammonium hydroxide (370 ml) was added with stirring, keeping the temperature between 50 and 60° C. by use of a cooling bath. The product crystallized out near the end of the addition at 50-53° C. The product slurry was cooled to ice bath temperature and held for 1 h. The product, isolated in 70.5% yield by filtration, washing with ice water, and drying in vacuo at 50° C., was 98.44% pure by area-normalized HPLC with correction for relative response factors. It contained only 0.8% of the 6-chloro isomer and 0.68% of the 4,6-dichloro impurity. Recrystallization from isopropanol-water with charcoal treatment gave, in 94% recovery, purified product that was 99.67% pure by HPLC (mp 143-144° C.).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>CN(C)C(=O)C>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([O:7][C:6]2[CH:5]=[C:4]([NH:3][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:10]=1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
To a solution of 5-(3-aminophenoxy)pyridine-2-amine dihydrochloride (3.5 g, 12.7 mmol) in N,N-dimethylacetamide (30 mL) was added 3-(trifluoromethyl)benzoylchloride (2.80 g, 13.4 mmol), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, 5% aqueous sodium hydrogen carbonate solution (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (30 mL)/hexane (20 mL) was added to the obtained residue, and the obtained precipitate was collected by filtration and air-dried to give the title compound (3.95 g, 83%) as a colorless powder.
Reaction SMILES: CN.CNC.C[NH:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:22])[CH:14]=[C:15]([O:20][CH3:21])[C:16]=2[O:18][CH3:19])[N:11]=[C:10]([Cl:23])[N:9]=1.CN(C)C1C2C(=C(Cl)C=C(OC)C=2OC)N=C(Cl)N=1>>[NH2:7][C:8]1[C:17]2[C:12](=[C:13]([Cl:22])[CH:14]=[C:15]([O:20][CH3:21])[C:16]=2[O:18][CH3:19])[N:11]=[C:10]([Cl:23])[N:9]=1
Reactant: CNc1nc(Cl)nc2c(Cl)cc(OC)c(OC)c12
Agent: CN
Agent: CNC
Agent: COc1cc(Cl)c2nc(Cl)nc(N(C)C)c2c1OC
Product: COc1cc(Cl)c2nc(Cl)nc(N)c2c1OC

Procedure:
When, in the above procedure, methylamine or dimethylamine is employed in place of ammonia the corresponding 4-methylamino-2,8-dichloro-5,6-dimethoxyquinazoline and 4-dimethylamino-2,8-dichloro-5,6-dimethoxyquinazoline are obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:21]=[C:6]2[N:7]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[O:13])[CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1[CH3:22]>CO>[Cl:2][C:3]1[N:21]=[C:6]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[OH:13])[CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1[CH3:22]
Reactant: Cc1c2cccn(CC(=O)c3ccc(F)cc3)c-2nc1Cl
Agent: Cl
Solvent: CO
Product: Cc1c2cccn(CC(O)c3ccc(F)cc3)c-2nc1Cl
Yield: 99.6 %

Procedure:
A solution of 1,0 g (2,8 mmol) of 2-chloro-3-methyl-7-(p-fluorophenacyl)pyrrolo [2,3-b]pyridine hydrochloride in 50 ml methanol was treated with NaBH in the same manner as ex. 18 to give 0,85 g (99%) of the title compound as white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7].C(Cl)(=O)C([Cl:22])=O>ClCCCl>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([Cl:22])=[O:18])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1ccc(N(CCCl)CCCl)cc1
Solvent: ClCCCl
Product: O=C(Cl)CCc1ccc(N(CCCl)CCCl)cc1
Reaction time: 3 h

Procedure:
3-[4-[N,N-Bis(2-chloroethyl)amino]phenyl]propionic acid (0.24 g; 0.83 mmol) was dissolved in 5 ml of 1,2-dichloroethane, followed by the dropwise addition of 0.22 ml (2.58 mmol; 3.1 equivalents) of oxalyl chloride (with ice-cooling from an intermediary time point due to violent exotherm). After completion of the dropwise addition, the temperature of the resultant mixture was allowed to rise again to room temperature, at which the mixture was stirred for 3 hours and then allowed to stand overnight. The mixture was thereafter concentrated under reduced pressure, whereby the title compound was obtained in a crude form. The crude compound was provided for use in the next reaction without purification.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[Cl:23]N1C(=O)CCC1=O>ClCCl.O1CCOCC1>[Cl:23][C:10]1[C:11](=[O:14])[CH2:12][CH2:13][C:9]=1[NH:8][C@@H:7]1[C:6]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:5]=2[O:4][C:3]([CH3:22])([CH3:21])[C@H:2]1[OH:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=CC(=O)CC2)[C@@H]1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC2=C(Cl)C(=O)CC2)[C@@H]1O

Procedure:
A solution of 150 mg of the title compound of example 5 in 5 ml of dichloromethan and 5 ml of dioxan is mixed with 77 mg of N-chloro-succinimide. After 50 minutes at room temperature the solution is poured on water and the organic components are extracted with dichloromethane/ethanol. Recristallisation of the raw product obtained after concentration yields white crystalls of the title compound having a m.p. of 288°-89° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(O)C.O>[F:20][C:15]1[CH:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc(Br)cc1F
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: N#Cc1ccc(-c2ccc(O)c(F)c2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
4-Cyanophenylboronic acid (0.92 g, 6.26 mmol), 4-bromo-2-fluorophenol (1.0 g, 5.2 mmol), potassium phosphate tribasic monohydrate (3.0 g, 15.6 mmol) and Pd (Ph3P)2Cl2 (73.0 mg, 0.1 mmol) were combined in a mixture of IPA/H2O (40 mL, 3:1) and heated at 70° C. After 2 hours, the mixture was allowed to cool to room temperature and was filtered over celite. The filtrate was diluted with 150 ml of CH2Cl2 and washed with water twice. The organic phase was dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed over silica gel using CH2Cl2 to provide the title compound as a white powder (0.61 g, 55% yield). 1HNMR (300 MHz, CDCl3) δ5.20 (bs, 1H), 7.15-7.78 (m, 7H); MS (DCI) m/z 214 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.Br[C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][N:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:35]1([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:28]=2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH2:26])[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16]3)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][N:36]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Cc1cccc(C2=NCCc3ccccc32)c1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C2=NCCc3ccccc32)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A mixture of 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.18 g, 0.50 mmol), 1-(2-bromo-3-methylphenyl)-3,4-dihydroisoquinoline (0.10 g, 0.33 mmol), potassium phosphate (0.354 g, 1.67 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.032 g, 0.067 mmol) and Pd2 dba3 (0.015 g, 0.017 mmol) were treated with dioxane (2.22 mL) and Water (1.11 mL) in a medium-sized Smith synthesizer vial. The mixture was heated to 140° C. for 12 min in a microwave reactor. The reaction mixture was filtered then partitioned between EtOAc and water. The organic layers were washed with water and brine and then concentrated in vacuo. The crude product was purified by silica flash chromatography (1-10% MeOH:DCM) and then by HPLC (10-75% acetonitril/H2O; TFA modifier). A single fraction was treated with NH4OH, concentrated, filtered and air-dried to afford 6-(2-(3,4-dihydroisoquinolin-1-yl)-6-methylphenyl)-3-morpholinoquinolin-2-amine MS (ESI, pos. ion) m/z: 449 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]([N+:28]([O-])=O)=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:14][C@H:13]1[O:31][CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C.C1COCC1>[NH2:28][C:21]1[CH:20]=[CH:19][C:18]([N:15]2[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[C@H:13]([O:31][CH3:32])[CH2:14]2)=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Methyl cis(±)-5-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-2-nitrobenzoate obtained in Example (185a) was dissolved in ethanol (20 ml) and THF (20 ml). Tin (II) chloride dihydrate (4.4 g, 19.6 mmol) was added, and the mixture was stirred at 75° C. overnight. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with aqueous sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, 900 mg of the title compound was obtained as an oily substance.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:4]1[CH:21]=[C:20]([CH2:22][Br:23])[CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)C(Oc1ccc(C)cc1C(C)=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1C(C)=O)c1ccccc1

Procedure:
To a solution of 1.25 g (4.19 mmol) of the product of Step A dissolved in 15 mL of CCl4 was added 0.821 g (4.61 mmol) of N-bromosuccinimide and 20 mg (catalytic amount) of AIBN. The mixture was stirred at reflux for 3.5 hours, then cooled, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.431 g (27%) yield of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH3:31])[C:26]([O:32][CH2:33][CH3:34])=[CH:25][C:24]=2[N:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH3:36])[C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([N:44](C(C)C)CC)(C)C.Cl.NO>C(O)C.CO.C(O)(=O)C.[Ni]>[C:17]1([S:14]([NH:13][C:11](=[O:12])[CH:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]([NH2:44])=[NH:2])=[CH:4][CH:5]=2)[C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH3:31])[C:26]([O:32][CH2:33][CH3:34])=[CH:25][C:24]=2[N:35]([S:37]([CH3:40])(=[O:38])=[O:39])[CH3:36])(=[O:16])=[O:15])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1cc(C(Nc2ccc(C#N)cc2)C(=O)NS(=O)(=O)c2ccccc2)c(N(C)S(C)(=O)=O)cc1OCC
Agent: [Ni]
Agent: Cl
Agent: NO
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)C(=O)NS(=O)(=O)c2ccccc2)c(N(C)S(C)(=O)=O)cc1OCC
Temperature: 60 °C
Reaction time: 6 h

Procedure:
The N-{(4-cyano-phenylamino)-[4,5-diethoxy-2-(methanesulfonyl-methyl-amino)-phenyl]-acetyl}benzenesulfonamide obtained above (126 mg, 0.21 mmole) was dissolved in ethanol (1.8 ml) and heated to 60° C. Diisopropylethylamine (DIPEA—260 ul, 1.5 mmole) was added followed by hydroxylamine-hydrochloride (74 mg, 1.04 mmole). The reaction was stirred at 60° C. under a nitrogen atmosphere for 6 hours. The reaction was then allowed to cool to room temperature. The solution was diluted with methanol (5 ml) and acetic acid (2 ml) and Raney Nickel 2800 (ca. 50 mg) added as a suspension- The reaction was then stirred vigorously under a hydrogen atmosphere for 1 hour. The catalyst was filtered off and the solvent removed. The crude product was purified by preparative reverse-phase HPLC using a water-acetonitrile (0.1% TFA) gradient to yield 40 mg of desired 4-{2-benzenesulfonylamino-1-[4,5-diethoxy-2-(methanesulfonyl-methyl-amino)-phenyl]-2-oxo-ethylamino}benzamidine as its trifluoroacetic acid salt. MS: (M+H)=604.
Reaction SMILES: [CH:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:21])=[N:18][CH:19]=1)=O.[Cl:30][C:31]1[CH:36]=[C:35]([NH2:37])[CH:34]=[CH:33][C:32]=1[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1.CC(O)=O.[BH3-]C#N.[Na+].[NH4+].[Cl-]>CCO>[Cl:30][C:31]1[CH:36]=[C:35]([NH:37][CH2:1][C:3]2[C:8]([CH3:9])=[CH:7][C:6]([C:10]([F:12])([F:13])[F:11])=[CH:5][C:4]=2[C:14]2[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:21])=[N:18][CH:19]=2)[CH:34]=[CH:33][C:32]=1[C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C)c2C=O)cn1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C)c2CNc2ccc(-c3ccc(C(F)(F)F)cc3)c(Cl)c2)cn1
Temperature: 80 °C

Procedure:
Ethyl 3-(5-(2-formyl-3-methyl-5-(trifluoromethyl)phenyl)picolinamido)propanoate (37 mg, 0.09 mmol), 2-chloro-4′-(trifluoromethyl)-[1,1-biphenyl]-4-amine (39 mg, 0.14 mmol) and HOAc (5 μL, 0.09 mmol) were dissolved in EtOH (2 mL) and the resulting mixture was heated to 80° C. After 5 h the resulting mixture was cooled to room temperature, solid NaCNBH3 (28 mg, 0.45 mmol) was added and the resulting mixture was stirred at room temperature. After 2 h saturated aqueous NH4Cl was added and the aqueous phase was extracted with EtOAc. The combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:10]([O:21]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Reaction time: 8 h
Yield: 55.6 %

Procedure:
2,5-Dihydro-pyrrole-1-carboxylic acid tert-butyl ester (46 g, 65% purity) was dissolved in CH2Cl2 (500 mL). The solution was cooled to 0° C. mCPBA (122 g, 2 eq, 77% purity) was slowly added to the solution at 0° C. The reaction mixture was stirred at 0° C. to RT for overnight. The mixture was concentrated to 200 ml, and filtered. The organic phase was washed with 1 N NaOH solution (4×100 mL), dried over Na2SO4 The resulting oil was purified by column chromatography (hexane:ethyl acetate 3:1) to give 28 g of desired product as a colorless oil (87% yield). 1H-NMR (300 MHz, CDCl3): δ 1.41 (s, 9H), 3.26 (dd, 2 H), 3.25-3.80 (m, 4 H)