Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].[OH:28][C:29]1[CH:44]=[CH:43][C:32]([CH2:33][NH:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[OH:28][C:29]1[CH:44]=[CH:43][C:32]([CH2:33][N:34]([CH2:35][C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:27])[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[C:23]([F:26])([F:25])[F:24])=[CH:11][C:3]=2[O:2][CH3:1])=[CH:31][CH:30]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)c(OC)c2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)c(OC)c2)c(C(F)(F)F)c1
Yield: 99 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-23 (404 mg, 1.05 mmol), tert-butyl 2-((4-hydroxybenzyl)amino)acetate INT-22 (250 mg, 1.05 mmol) and TEA (367 μL, 2.63 mmol) in DMF (5 mL) was added HATU (421 mg, 1.11 mmol). After 2 h the reaction mixture was diluted with EA (100 mL) and washed with brine (2×150 mL). The organics were pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford 633 mg (99%) of tert-butyl 2-(N-(4-hydroxybenzyl)-2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-24 as a waxy solid. LCMS-ESI (m/z) calculated for C31H33F3N2O7: 602 found 601 [M−H]−, tR=2.29 min (Method 10). 1H NMR (400 MHz, DMSO 100° C.) δ 10.25 (s, 1H), 9.28 (s, 1H), 7.52-7.41 (m, 2H), 7.27-7.04 (m, 5H), 6.95 (d, J=8.0 Hz, 1H), 6.72 (dd, J=20.5, 7.9 Hz, 2H), 4.52 (br s, 1H), 4.22 (s, 1H), 3.81 (m, 9H), 3.62 (s, 1H), 1.40 (d, J=2.1 Hz, 4.5H), 1.30 (d, J=2.1 Hz, 4.5H).
Reaction SMILES: [Cl:1][C:2]([Cl:18])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)[OH:20]>>[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]([Cl:18])([Cl:1])[C:3]([OH:5])=[O:4])(=[O:20])[NH2:17]
Reactant: O=S(=O)(O)O
Reactant: N#CCCCCCCCCCCC(Cl)(Cl)C(=O)O
Product: NC(=O)CCCCCCCCCCC(Cl)(Cl)C(=O)O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
200 mg (0.70 mmol) 8 was fed into 10 ml 80% sulfuric acid and kept at room temperature for 6 h. The solution that was obtained was poured into 150 ml ice water, the beige-coloured precipitate was suction filtered and washed with petroleum ether. 180 mg (85%) 35, melting point 93-94° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:10][C:5]2=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:32](=[O:33])[CH2:31][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:35][C:36]4[CH:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:37]=4)[CH2:12]3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: COCCCn1c(C2CCCNC2)nc2ccc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(Cl)nc21
Yield: 61.5 %

Procedure:
Compound 35C (0.288 mmol, 0.122 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.455 mmol, 0.150 g) and N-methylmorpholine (1.15 mmol, 0.127 mL) were then added and the solution was allowed to stir at it for 5 min. HATU (0.317 mmol, 0.120 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (40-95% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording (R)-tert-Butyl 4-(3-(5-chloro-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (35D) as a clear oil (0.177 mmol, 0.110 g, 62% yield). ESI-MS: m/z 620.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:13])=[CH:5][C:6]=1[CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.Cl[C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:30])[C:20]([C:27]([OH:29])=[O:28])=[CH:21][N:22]2[CH2:25][CH3:26])=[CH:17][C:16]=1[F:31]>N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:13])=[CH:5][C:6]=1[CH:7]1[NH:8][CH2:9][CH2:10][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([C:19](=[O:30])[C:20]([C:27]([OH:29])=[O:28])=[CH:21][N:22]3[CH2:25][CH3:26])=[CH:17][C:16]=2[F:31])[CH2:12]1
Reactant: Cc1cc(C2CNCCN2)c(C)s1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc(C)sc4C)C3)cc21

Procedure:
A mixture of 2.35 g of 2-(2,5-dimethyl-3-thienyl)piperazine and 1.076 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of pyridine was heated for 48 hours, then cooled and filtered. The filtrate was evaporated under reduced pressure and the residue triturated with chloroform:methanol (9:1),. giving mg of the desired product, mp 248°-250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:17][CH:16]=[C:15]([C:18]([OH:20])=O)[C:11]=3[N:12]=[CH:13][N:14]=2)=[C:5]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:4]=1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@@H:36]([NH:39][C:18]([C:15]2[C:11]3[N:12]=[CH:13][N:14]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:21][CH2:22][CH2:23][O:24][CH3:25])[C:10]=3[NH:17][CH:16]=2)=[O:20])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)O)c[nH]c12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@@H](NC(=O)OC(C)(C)C)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A74) and commercially available cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:13]N1C(=O)CCC1=O.[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH3:32])[C:27](=[O:33])[CH:26]=[C:25]2[CH3:34]>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:34][C:25]1[C:24]2[C:29](=[CH:30][CH:31]=[C:22]([F:21])[CH:23]=2)[N:28]([CH3:32])[C:27](=[O:33])[CH:26]=1
Reactant: Cc1cc(=O)n(C)c2ccc(F)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(=O)cc(CBr)c2cc(F)ccc21
Temperature: 70 °C
Yield: 38.9 %

Procedure:
2,2′-Azobis(2-methylpropionitrile) (AIBN, 17.2 mg, 0.105 mmol) and N-bromosuccinimide (NBS, 97.7 mg, 0.549 mmol) were added to a suspension of 6-fluoro-1,4-dimethylquinolin-2(1H)-one (100 mg, 0.523 mmol) in CCl4 (10 mL) at 70° C. After 1 h an additional 2 eq. of NBS and 0.4 eq. of AIBN were added and the mixture heated at 70° C. for 1 h. The mixture was concentrated and the residue purified by preparative TLC to give desired the title compound (55 mg, 31%) as white solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[C:22](=S)=[S:23].CCN=C=NCCCN(C)C.CCN(CC)CC>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:5]2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([N:1]=[C:22]=[S:23])[N:8]=[C:7]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:15]=1
Reactant: CN1C(=O)C(N)N=C(c2cccnc2)c2cc(Cl)ccc21
Reactant: S=C=S
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(=O)C(N=C=S)N=C(c2cccnc2)c2cc(Cl)ccc21
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
As illustrated in the scheme above, a solution of 3-amino-7-chloro-1,3-dihydro-1-methyl-5-(3-pyridinyl)-2H-1,4benzodiazepin-2-one (1.36 g, 4.52 mmol) in dry THF (55 mL) was cooled to −15° C. Carbon disulfide (2.7 mL, 45 mmol) was added, followed by EDCI (1.73 g, 9.03 mmol). The mixture was stirred for 10 min., and then Et3N (1.26 mL, 9.04 mmol) was added. The reaction was stirred for 16 h while it was allowed to slowly warm to room temperature. The precipitated solid was removed by filtration and was washed well with CH2Cl2 and then discarded. The filtrate was concentrated in vacuo, and the residue was dissolved in CH2Cl2. The organic phase was washed with water, saturated NaHCO3, and brine, and was then dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (3:1 CH2Cl2:EtOAc) provided the title compound as a solid (0.652 g, 42%). 1H-NMR (CDCl3): δ 8.75 (s, 2H), 8.12 (dt, J=2.0 Hz, J=8.0 Hz, 1H), 7.63 (dd, J=2.0 Hz, J=8.8 Hz, 1H), 7.43 (dd, J=4.8 Hz, J=8.0 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 5.22 (s, 1H), 3.50 (s, 3H). MS (ESI) (M+H)+=343.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:29]=[C:30]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH:31]=[CH:32][CH:33]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:40].N.[Cl-].[Ca+2:43].[Cl-]>CC(C)=O.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:29]=[C:30]([CH2:34][CH2:35][CH2:36][C:37]([O-:39])=[O:38])[CH:31]=[CH:32][CH:33]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:40].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:29]=[C:30]([CH2:34][CH2:35][CH2:36][C:37]([O-:39])=[O:38])[CH:31]=[CH:32][CH:33]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[C:24]([F:25])([F:27])[F:26])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:40].[Ca+2:43]
Reactant: Cc1cc2c(-c3cccc(CCCC(=O)O)c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Agent: N
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc2c(-c3cccc(CCCC(=O)[O-])c3)c(CC(=O)Nc3ccc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-{3-[7-chloro-3-(2-{[4-fluoro-2-(trifluoromethyl)phenyl]amino}-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl}butanoic acid obtained in Reference Example 9 (26.7 g, 0.0463 mol) in acetone (534 ml) was added 25% aqueous ammonia (4 ml) at 50° C., and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of acetonitrile (534 ml) and water (107 ml). The reaction mixture was heated to 70° C., and a solution of calcium chloride (3.14 g, 0.0255 mol) in water (107 ml) was slowly added dropwise thereto. The reaction mixture was stirred at 70° C. for 3.5 hours, water (214 ml) was added thereto and the mixture was further stirred at 70° C. for 1 hour and at room temperature for 12 hours. Crystals obtained were collected by filtration, washed with water (100 ml) and dried at 50° C. under reduced pressure to obtain the title compound (26.67 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([NH2:17])[CH:8]=1)([CH3:6])[CH3:5].[F:19][C:20]1[CH:21]=[C:22]([C:26]2[N:31]=[C:30]([CH3:32])[C:29]([C:33](O)=[O:34])=[CH:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([NH:17][C:33]([C:29]2[C:30]([CH3:32])=[N:31][C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[N:27][CH:28]=2)=[O:34])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1cn(N)c2ccc(F)cc12
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1cn(NC(=O)c2cnc(-c3cccc(F)c3)nc2C)c2ccc(F)cc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (0.85 mmol) and 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (217 mg, 0.935 mmol) in DMF (8.5 mL) is stirred at 40° C. for 0.5 h. The mixture is treated with DMTMM (246 mg, 0.89 mmol) and stirred at 60° C. for 1 h. The mixture is concentrated in vacuo, diluted with saturated aqueous Na2CO3 (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-(5-fluoro-1-{[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-1H-indol-3-yl)-2-methyl-propionic acid methyl ester, which is used in the next step without further purification.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:4]([CH3:3])[C:5](=[O:13])[N:6]=2)[CH:11]=1
Reactant: CC1C(=O)Nc2ccccc21
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1=c2cc(Br)ccc2=NC1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.7 %

Procedure:
Under an atmosphere of nitrogen, bromine (0.96 g, 6.0 mmol) in acetic acid (5 cm3) was added drop wise to a solution of 3-methyl-2-indolinone (0.8749 g, 6.0 mmol) (Kende, et al, Synth. Commun., 12, 1, 1982) and sodium acetate (0.50 g, 6.0 mmol) in acetic acid (10 cm3). The reaction was stirred at room temperature for 3.5 h. Saturated sodium carbonate was added to quench the reaction. The water layer was extracted EtOAc (×3), dried (MgSO4), filtered, and evaporated to give the title compound (1.26 g, 93%), Mp=119-120° C.; 1H NMR (DMSO) δ 1.32 (d, 3H, J=7.66 Hz), 3.45 (q, 1H, J=7.62 Hz), 6.77 (d, 1H, J=8.23 Hz), 7.46 (s, 1H), 7.36-7.33 (m, 1H), 10.4 (s, 1H); IR (KBr) 3200, 1725 cm−1; MS (EI) m/z 224/226 (M−H)−; CHN calculated for C9H8BrNO: C, 47.82; H, 3.57; N, 6.20; Found: C, 47.44; H, 3.42; N, 6.04.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[CH:17]=[N:18][NH:19][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[I:20]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[C:17]([I:20])=[N:18][NH:19][C:13]=3[CH:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2cc3[nH]ncc3cn2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(-c2cc3[nH]nc(I)c3cn2)c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of 6-(3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridine (0.80 g, 3.1 mmol) and N-iodosuccinimide (0.78 g, 3.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at r.t. over weekend. Water was added to the mixture with stirring. The light brown solid precipitated and was collected by filtration to afford the desired product (0.83 g) which was directly used in next step reaction without further purification. LCMS (M+H)+=382.0.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][C:20]2[C:25]3[C@@H:26]4[C@H:31]([CH2:32][CH2:33][C:24]=3[CH:23]=[CH:22][CH:21]=2)[NH:30][CH2:29][CH2:28][CH2:27]4)=[CH:17][CH:16]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:30]3[C@@H:31]4[C@@H:26]([C:25]5[C:20]([CH2:19][C:18]6[CH:34]=[CH:35][C:15]([O:14][CH3:13])=[CH:16][CH:17]=6)=[CH:21][CH:22]=[CH:23][C:24]=5[CH2:33][CH2:32]4)[CH2:27][CH2:28][CH2:29]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(Cc2cccc3c2[C@H]2CCCN[C@H]2CC3)cc1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1ccc(Cc2cccc3c2[C@H]2CCCN(C(=O)c4ccc5[nH]cnc5c4)[C@H]2CC3)cc1
Yield: 17 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-10-(4-methoxy-benzyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 17% of theory; LC (method 1): tR=3.21 min; Mass spectrum (ESI+): m/z=452 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[NH2:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]2)[N:3]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: O[C@H]1CC[C@H](Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1

Procedure:
trans-2-chloro-6-[(4-hydroxy)cyclohexylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, trans-4-(amino)cyclohexanol, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [ClH:1].C([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)C.[OH-].[Li+]>O1CCCC1.O>[ClH:1].[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][C@H:6]([O:24][CH2:25][CH3:26])[C:5]([OH:27])=[O:4])=[CH:9][CH:10]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Yield: 41.7 %

Procedure:
Water (200 ml) was added to a solution of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (described in Example 41b) (15 g; 42 mmole) in tetrahydrofuran (100 ml). Lithium hydroxide (3.4 g; 84 mmole) dissolved in a small amount of water was added while stirring and then the reaction mixture was stirred at room temperature over night. Tetrahydrofuran was evaporated and the remaining residue was extracted twice with ethyl acetate. The water phase was acidified with hydrochloric acid (2 M) and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate. Evaporation gave 6.4 g of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride. The acidic water phase, from above, was neutralized with sodium hydroxide to pH5 and extracted with dichloromethane. The organic phase was dried with magnesium sulfate and evaporated. This procedure gave 1.4 g more of the desired product. The total yield of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride was 7.8 g (50.8%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.O=S(Cl)[Cl:15]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCc1cc(Br)ccc1C(=O)Cl
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of 4-bromo-2-ethyl-benzoic acid (1.72 g, 7.51 mmol) in SOCl2 (50 mL) was heated to 90° C. and stirred for 2 hours. The volatiles were removed in vacuo to yield a brown solid (1.80 g, 96%). 1H NMR (300 MHz, CDCl3): δ 1.22 (t, J=7.4 Hz, 3 H), 2.89 (q, J=7.5 Hz, 2 H), 7.49 (m, 2 H), 8.03 (d, J=9.0 Hz, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH2:15])[C:7]=2[CH:16]=1)#[N:2].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>C(O)C.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:22]3[CH:23]=[C:18]([Cl:17])[N:19]=[CH:20][N:21]=3)[C:7]=2[CH:16]=1)#[N:2]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Nc2cc(Cl)ncn2)[C@@H]1O

Procedure:
A solution of trans-6-cyano-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (prepared as described in U.S. Pat. No. 4,446,113) (2.0 g) and 4,6-dichloropyrimidine (1.5 g) in ethanol (25 mL) and triethylamine (1.3 mL) was heated under reflux for 72 h. The solution was allowed to cool and the precipitate filtered off, and dissolved in ethyl acetate. The ethyl acetate solution was washed with water, 0.5N hydrochloric acid, sodium bicarbonate solution, brine, and then dried (Na2SO4). Removal of drying agent and solvent gave the title compound as a solid (1.08 g). A sample recrystallised from acetonitrile had m.pt. 204°-8° C.
Reaction SMILES: [CH:1](=[C:8]1[NH:13][C:12](=[O:14])[CH:11]([CH2:15][C:16]#[N:17])[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CN(C)C=O.[C].[Pd]>[CH2:1]([CH:8]1[NH:13][C:12](=[O:14])[CH:11]([CH2:15][C:16]#[N:17])[NH:10][C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC1NC(=O)C(=Cc2ccccc2)NC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: N#CCC1NC(=O)C(Cc2ccccc2)NC1=O
Yield: 91 %

Procedure:
2.91 g (0.0121 mol) of 3-benzylidene-6-cyanomethyl-2,5-dioxopiperazine was dissolved in 80 ml of dimethylformamide and catalytically reduced with hydrogen at room temperature by adding 1.4 g of 10% palladium carbon. After reaction for 4 hours, the catalyst was removed by filtration, and the resulting filtrate was concentrated to obtained 2.68 g of 3-benzyl-6-cyanomethyl-2,5-dioxopiperazine. Yield: 91.5%. 1H NMR (d6 -DMSO) δ2.13 (dd, 1H), δ2.21 (dd, 1H), δ3.00 (dd, 1H), δ3.14 (dd, 1H), δ4.12 (m, 1H), δ4.29 (m, 1H, δ7.29 (m, 5H), δ8.32 (bs, 1H), δ8.41 (bs, 1H) MS (FAB):244 (MH+) mp:255°-256° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[Cl:30])=[O:19])[CH3:16].[O:31]([C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)(=O)C>ClC(Cl)C>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[C:38]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:39]=2)=[CH:25][C:24]=1[Cl:30])=[O:19])[CH3:16]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Sodium triacetoxyborohydride (0.424 g, 2.00 mmol) was added to a solution of the enantiomerically enriched-(trans)-ethyl-2-(4-amino-2-chlorophenyl)cyclopropanecarboxylate (III-1d) (0.191 g, 0.80 mmol) and 3-phenoxybenzaldehyde (0.160 g, 0.80 mmol) in 8 mL of dichloroethane. The mixture was stirred at room temperature for one hour. The reaction mixture was partitioned between chloroform and water. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by chromatography on silica gel with hexane:ethyl acetate to give 0.269 g (80% yield) of the title compound as a colorless oil. NMR (400 MHz, CDCl3) δ 7.32 (t, J=7.51 Hz, 2H), 7.28 (t, J=8.42 Hz, 1H), 7.10 (t, J=8.24 Hz, 1H), 7.06 (d, J=8.24 Hz, 1H), 6.99 (d, J=7.69 Hz, 2H), 6.98 (m, 1H), 6.90 (dd, J=8.06 Hz, 2.38 Hz, 1H) 6.79 (d, J=8.42 Hz, 1H), 6.61 (d, J=2.38 Hz, 1H), 6.40 (dd, J=8.42 Hz, 2.38 Hz, 1H), 4.25 (d, J=5.49 Hz, 2H), 4.19 (q, J=7.14 Hz, 2H), 4.12 (br s, 1H), 2.60 (m, 1H), 1.69 (m, 1H), 1.53 (m, 1H), 1.28 (t, J=7.14 Hz, 3H), 1.25 (m, 1H). ES-MS m/z 422 (MH)+.