Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.[Br:12]N1C(=O)CCC1=O.BrBr>O>[Br:12][CH:10]([C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([Cl:8])[C:5]=1[F:9])[CH3:11]
Reactant: CCc1nc(Cl)nc(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Solvent: O
Product: CC(Br)c1nc(Cl)nc(Cl)c1F
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of the compound of part (i) (400 g), N-bromosuccinimide (730 g), azoisobutyronitrile (33.7 g), bromine (65.5 g) and water (6.4 L) was heated at 80-85° C. for 5 hours. Further N-bromosuccinimide (183 g) was added, heating continued for 2 hours then further azoisobutyronitrile (33.7 g) added. After heating for 2 hours at 85° C. further azoisobutyronitrile (33.7 g) was added and heating continued for 3 hours. The reaction was cooled, diluted with water (4 L) and extracted with dichloromethane (2×3 L). The combined organic extracts were washed with a solution of sodium metabisulphate (600 g) in water (2.5 L), followed by water (3 L). The solvent was removed by evaporation under reduced pressure, toluene (1.0 L) added and the solution concentrated under reduced pressure to give the product as an oil (534 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([OH:12])[C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[C:15](OC(=O)C)(=[O:17])[CH3:16]>[OH-].[Na+]>[C:15]([O:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[NH:5][C:6](=[O:14])[C:7]1=[O:13])(=[O:17])[CH3:16]
Reactant: O=c1[nH]c2cc(Cl)ccc2n(O)c1=O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)On1c(=O)c(=O)[nH]c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of 0.4 g (1.9 mmol) 6-chloro-1-hydroxyquinoxaline-2,3(1H,4H)-dione in 15 ml 0.5N sodium hydroxide was added with stirring 1 ml acetic anhydride. Stirring was continued at 25° C. for 1 h to give a precipitate. Recrystallization (dimethylformamide-water) gave 0.2 g (42%) 1-acetoxy-6-chloroquinoxaline-2,3(1H,4H)-dione. M.p. 219° C. 1H-NMR (DMSO-d6): 12.5 (1H, broad s), 7.2 (3H, m), 2.50 (3H, s). MS (m/e). 254 (M+, 30%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[C:9](=[N:15]O)[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C.S(=O)(=O)(O)O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH2:15])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc2c(c1)CC(=NO)C2=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc2c(c1)CC(N)C2
Yield: 34.4 %

Procedure:
5-tert-Butyl-indan-1,2-dione 2-oxime (11.67 g) was hydrogenated over 10% palladium on carbon catalyst (2.95 g) using a mixture of 233 ml acetic acid and 15.6 ml concentrated sulfuric acid as solvent. The reaction was run at ambient temperature for 17 hours, under 60 psi hydrogen. After removal of catalyst by filtration, the filtrate was quenched by dropwise addition of 30 ml conc. ammonium hydroxide. The quenched mixture was then extracted with ethyl ether, the organic extracts dried with magnesium sulfate, and the solvent removed under vacuum to give 3.50 g of the product which was used without further purification. 1H NMR (300 MHz, CDCl3) 7.17 (m, 3H), 3.84 (m, 1H), 3.14 (m, 2H), 2.67 (m, 2H), 1.31 (s, 9H). MS (CSI) m/e 190 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:15]([C:16]([NH:18][CH3:19])=[O:17])=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[O:13][C:5]2=[N:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39]>CC(N(C)C)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:15]([C:16](=[O:17])[NH:18][CH3:19])=[C:14]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[O:13][C:5]2=[N:6][C:7]=1[N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Reactant: COC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCC(=O)OC)S(C)(=O)=O)c(I)cc12
Temperature: 150 °C
Yield: 46.1 %

Procedure:
5-iodo-N-methyl-6-(methylsulfonamido)-2-p-tolylfuro[2,3-b]pyridine-3-carboxamide (100 mg, 0.206 mmol) was dissolved in dimethylacetamide (10 mL) and K2CO3 (39.9 mg, 0.288 mmol) was added then followed by methyl 5-bromopentanoate (0.059 mL, 0.412 mmol). The mixture was heated at 150° C. in the microwave for 20 min. Conversion approx 75% by LCMS, after which addition of additional methyl 5-bromopentanoate (3 eqs) and K2CO3 (2 eqs) did not result in additional conversion. Filtration and purification by HPLC (TFA/CH3CN/H2O) afforded 57 mg (0.095 mmol, 46%) methyl 5-(N-(5-iodo-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)pentanoate MS-ES [M+H]+=599.8, LC RT=1.61 min, Method A.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][NH:13][C:14](=[O:34])[CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:20]=[C:19]1[CH2:31][CH2:32][CH3:33].[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:36][C:22]1[C:21]2[N:20]=[C:19]([CH2:31][CH2:32][CH3:33])[N:18]([CH2:17][CH2:16][CH2:15][C:14]([NH:13][CH3:12])=[O:34])[C:30]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)NC
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)NC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
mCPBA (3.3 g, 15 mmol) was added to a solution of N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide (1.83 g, 5.90 mmol) in chloroform (75 mL), and the reaction was stirred for 1.5 hours at ambient temperature. Concentrated ammonium hydroxide (75 mL of 29%) and p-toluenesulfonyl chloride (1.7 g, 8.9 mmol) were then sequentially added with stirring, and the reaction was stirred for 45 minutes. The aqueous layer was separated and extracted with chloroform (1×50 mL). The combined organic fractions were washed with 5% aqueous sodium hydroxide solution (2×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was recrystallized from a mixture of toluene (20 mL) and methanol (4 mL) and then recrystallized three times from 5:1 methanol:water (18 mL) and dried overnight in a vacuum oven at 80° C. During the recrystallization, the product was mixed with material from another run to provide 0.720 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-methylbutanamide as a tan solid, hp 177-179° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)(O)[O-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[CH2:36]([O:35][C:33]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH2:8][CH2:9][CH:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:11][CH2:12]2)[CH2:5][CH2:6]1)=[O:34])[CH3:37]
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2CCNCC2)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 8 h

Procedure:
Forty-one (41) mg of 1-[1-(piperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one.di-trifluoroacetate was dissolved in 5 ml of dichloromethane, and to which 25 mg of diisopropylethylamine and 11 mg of ethyl chloroformate were added, followed by stirring overnight. The reaction mixture was distributed between chloroform and saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1). Thus 22 mg of the title compound was obtained as a colorless, amorphous substance.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:4]([C:24](O)=[O:25])[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:38][O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[NH2:42].C(N(C(C)C)CC)(C)C.Cl>O.CN(C=O)C.C(Cl)CCl>[CH3:38][O:39][C:40](=[O:45])[C:41]([NH:42][C:24]([C:4]1[CH:3]=[C:2]([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:25])([CH3:44])[CH3:43]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1cc(F)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCCl
Product: COC(=O)C(C)(C)NC(=O)c1cc(F)c2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
To 0.2 g of 4-fluoro-1-[4-(trifluoromethyl)benzyloxy]naphthalene-2-carboxylic acid, 158 mg of EDC, 104 mg of 1-hydroxybenzotriazole and 102 mg of 2,2-dimethylglycine methyl ester hydrochloride was added 5.3 ml of DMF followed by 0.29 ml of diisopropylethylamine. The mixture was stirred for 16 h at room temperature. The mixture was poured into cold water, acidified to pH 2-3 with 1M HCl, extracted with ethyl acetate, washed with water, brine, dried (sodium sulphate) filtered and concentrated to an oil. The material was flash chromatographed on silica gel eluting with ethyl acetate/heptanes to provide 0.207 g of 2-{[4-fluoro-1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:39])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[NH:17][CH:16]2[C:36]([OH:38])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[CH2:43][O:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:45][C@H:44]([CH2:43][OH:42])[CH2:46][CH2:47][NH:48][C:36]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:39])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[NH:17]1)=[O:38]
Reactant: CC(C)(CO)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 31.5 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 105c (1 g, 1.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.73 g, 5 mmol), HATU (1.14 g, 3 mmol) and iPr2NEt (1.46 mL, 8.4 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-hydroxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 64%).
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]3[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([O:31]C)=[O:30])[CH:23]=4)[NH:18]3)[CH:13]=[CH:14][C:15]=2[F:16])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:17]3[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=[O:30])[CH:23]=4)[NH:18]3)[CH:13]=[CH:14][C:15]=2[F:16])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C3CCCCC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NC(=O)C2CCCCC2)c1
Yield: 74 %

Procedure:
A mixture of methyl 2-(3-(cyclohexanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.26 mmol, 1.0 eq.) and 4.5 mL sodium hydroxide (1 mol/L) in 3 mL methanol was stirred at reflux for 1-2 h. LC-MS indicated that the starting material was consumed completely. The methanol was removed by reduced pressure. The residue was acidified pH to 5-6 with 1 M hydrochloric acid. A lot of precipitates were formed and collected by filtration to afford 2-(3-(cyclohexanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid; Yield: 74%; MS (ESI+APCI) M−1=423.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:30]([C:31]2[NH:35][N:34]=[CH:33][C:32]=2[F:36])=[CH:29][C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:13][N:12]=1.[NH:37]1[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]1>CC(O)C.CCOC(C)=O>[F:36][C:32]1[CH:33]=[N:34][NH:35][C:31]=1[C:30]1[C:11]([N:37]2[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]2)=[N:12][CH:13]=[C:14]([CH:29]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)=[O:16]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2[nH]ncc2F)c1
Temperature: 140 °C

Procedure:
DIPEA (71.9 μL, 0.412 mmol) was added to a solution of 6-chloro-5-(4-fluoro-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 5.1, 75 mg, 0.187 mmol) and (R)-pyrrolidin-3-ol (19.97 mg, 0.225 mmol) in iPrOH (187 μL) in a vial which was sealed and heated at 140° C. for 1 h. After cooling at RT, the RM was dissolved in EtOAc and washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 10% MeOH) to afford the title compound as a white foam. HPLC (Condition 4) tR=4.73 min, UPLC-MS (Condition 3) tR=0.93 min, m/z=452.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.95 (m, 2H) 3.00 (d, J=11.34 Hz, 1H) 3.18-3.51 (m, 3H) 4.22 (br. s, 1H) 4.86 (br. s, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.77-8.11 (m, 4H) 8.76 (br. s, 1H) 10.17 (s, 1H) 12.90 (br. s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1[N:18]=CC(COP(O)(O)=O)=C(C=O)C=1O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[C:1]1([CH2:7][CH2:8][CH:9]([NH2:18])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Reactant: CC(=O)CCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(N)CCc1ccccc1

Procedure:
In the same manner as in Example 12, a cell-dispersion solution was prepared. Into a flask in which substrates, that is, 504.6 mg of 1-phenyl-3-butanone and 618.8 mg of (S)-α-phenethylamine were added in advance, 3 ml of the cell-dispersion solution, 3.7 mg of pyridoxal phosphate, and 3 mL of a 1M potassium phosphate buffer (pH 6.8) were introduced. The whole volume was adjusted to 30 mL by adding deionized water therein. This was reacted at 30° C. for 16 hours with stirring. After the reaction is completed, 1-phenyl-3-butylamine thus produced in the reaction mixture was analyzed in the manner described below. This showed that 1-phenyl-3-butylamine was produced with a conversion rate of 68%, and it had a (S) configuration and optical purity of 95.8% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH4+].[OH-]>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCCc1ccc(Cl)c(Cl)c1
Yield: 92 %

Procedure:
A solution of 3,4-dichlorophenylacetonitrile (3.001 g, 16.13 mmol) in ethanol (33 mL) and 29% NH4OH (6.7 ml, 611.2 mg, 17.44 mmol) in the presence of Raney Ni (333 mg, 3.887 mmol) was stirred vigorously under H2 (1 atm) for 6 h. The reaction mixture was filtered through Celite then the filtrate was concentrated under reduced pressure to give 2-(3,4-dichlorophenyl)ethylamine (2.82 g, 92%) as a pale yellow oil. LC/MS ((10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=190.3; tr=0.80 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([N:32]([CH2:36][CH2:37]O)[CH:33]([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N2CCN(C(C)C)C(=O)C=12)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:37][CH2:36][N:32]([CH:33]([CH3:35])[CH3:34])[C:30](=[O:31])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4ccc(Cl)c(Cl)c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O

Procedure:
9-(Benzyloxy)-6-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-2-isopropyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (491) was synthesized as a white solid from 5-(benzyloxy)-2-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropylpyrimidine-4-carboxamide (490) following the procedure described for 9-benzyloxy-6-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (247).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]([O:15]C)=[O:14])[CH:8]=[C:9](Cl)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]([OH:15])=[O:14])[CH:8]=[C:9]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc(Cl)cc2c(N)ncnc12
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ncnc2c(C(=O)O)cc(-c3cccc(F)c3)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
To a 20 mL screw-cap vial was added methyl 4-amino-6-chloro-quinazoline-8-carboxylate (640 mg; 1.8 mmol), (3-fluorophenyl)boronic acid (2 equiv., 3.6 mmol, 0.49753 g), dioxane (10 mL), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.05 equiv. 0.09 mmol, 0.062945 g), and potassium phosphate tribasic (2M in water, 4 equiv., 7.2 mmol, 3.6 mL). The reaction was capped and shaken at 100° C. for 4 h. LCMS showed complete Suzuki coupling, as well as saponified ester. The Reaction was cooled to room temperature, and partitioned with water and ethyl acetate. The organic was extracted 2 additional times with water. The combined aqueous was acidified to pH 2 with conc. HCl. The resulting precipitate was collected via filtration, yielding 350 mg of 4-amino-6-(3-fluorophenyl)quinazoline-8-carboxylic acid, ˜85% pure. Product was carried directly on to the amide formation. LCMS M/Z (M+H)=284.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=1)=O.[Br:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.CC(O)=O>CCOC(C)=O.ClCCCl>[Br:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][CH2:15][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:32])=[N:29][CH:30]=2)=[CH:44][CH:43]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(OC)ccc2C=O)cn1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(OC)ccc2CNc2ccc(Br)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (1.3 g, 6.0 mmol) was added to a DCE solution (5 mL) of ethyl 3-(5-(2-formyl-5-methoxyphenyl)picolinamido)propanoate (1.4 g, 4.0 mmol), 4-bromoaniline (1.0 g, 6.0 mmol), and AcOH (0.23 mL, 4.0 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1]1([C:7]([CH2:18][CH2:19][O:20][C:21](=[O:23])C)(C(OCC)=O)C(OCC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([CH:7]2[CH2:18][CH2:19][O:20][C:21]2=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(CCOC(C)=O)(C(=O)OCC)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1OCCC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
The product of Example 2 (837 g, 2.6M) methanol (1.5 l) and 40% aq. NaOH (1 l, 10M) were heated to reflux for 2 hours. The reaction was then cooled to room temperature and acidified with conc. HCl (1l). The reaction was left as room temperature overnight and then extracted with methyl tert.butyl ether (1 l,500 ml). The extracts were washed with aq. Na2CO3, dried and evaporated to give the title compound(376 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH3:43][N:44]([CH3:50])[C:45](=[O:49])[CH2:46][NH:47][CH3:48].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:47]([CH2:46][C:45]([N:44]([CH3:50])[CH3:43])=[O:49])[CH3:48])=[O:24]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CNCC(=O)N(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)CN(C)C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and methylamino-acetic acid dimethylamide with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:12]1([CH2:18][C:19]#[N:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[C:19]([CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9])#[N:20]
Reactant: CCOC(=O)c1cccnc1
Reactant: N#CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: N#CC(C(=O)c1cccnc1)c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of ethyl nicotinate (10 g) and phenylacetonitrile (5.1 g) in tert-butyl alcohol (30 mL), was added potassium tert-butoxide (6.4 g), and the mixture was stirred at 100° C. for 3 h. After cooling, the resulting mixture was dissolved in water and washed with isopropyl ether. The aqueous phase was adjusted to pH 7.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with water, dried, and the solvent was evaporated. The crystalline residue was recrystallized from ethyl acetate-isopropyl ether to obtain the title compound (6.0 g, yield 62%).