Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Br[CH2:14][C@@H:15]([CH3:25])[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCCC.CCOC(C)=O>[Si:18]([O:17][CH2:16][C@@H:15]([CH3:25])[CH2:14][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20]
Reactant: C[C@H](CBr)CO[Si](C)(C)C(C)(C)C
Reactant: O=C1COc2cc(F)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2cc(F)ccc21
Yield: 71 %

Procedure:
7-Fluoro-4H-benzo[1,4]oxazin-3-one (111MF12) (2.52 g, 15.1 mmol), (S)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03 g, 15.1 mmol) and Cs2CO3 (12.3 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) gave the title compound (111MF14) (3.79 g, 71%). 1H NMR (CDCl3) δ 7.12 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.67-6.34 (m, 2H), 4.60 (q, J=14.8 Hz, J=25.4 Hz, 2H), 4.03 (dd, J=8.4 Hz, J=14.0 Hz, 1H), 3.82 (dd, J=5.6 Hz, J=14.0 Hz, 1H), 3.57 (dd, J=4.8 Hz, J=10.0 Hz, 1H), 3.45 (dd, J=7.0 Hz, J=9.8 Hz, 1H), 2.15-2.05 (m, 1H), 0.93-0.89 (m, 12H), 0.06 (s, 6H); 13C NMR (CDCl3) δ 164.1, 158.9 (d, J=243.7 Hz), 146.4 (d, J=11.6 Hz), 125.3 (d, J=3.0 Hz), 116.4 (d, J=9.6 Hz), 109.1 (d, J=22.7 Hz), 105.1 (d, J=25.8 Hz), 67.8, 66.0, 44.1, 34.5, 26.0, 18.4, 14.9, −5.3, −5.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:34]([N:36]=[C:37](SC)[S:38][CH3:39])#[N:35]>C(#N)C>[C:34]([N:36]=[C:37]([S:38][CH3:39])[NH:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)#[N:35]
Reactant: CSC(=NC#N)SC
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Solvent: CC#N
Product: CSC(=NC#N)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Yield: 100.5 %

Procedure:
A mixture of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro phenyl)-1,3-oxazinan-2-one (40 mg, 0.09 mmol) and dimethyl cyanocarbonimidodithioate (40 mg, 0.27 mmol) in acetonitrile (4 mL) was heated to reflux overnight. The solvent was removed to give methyl N′-cyano-N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)carbamimidothioate (50 mg, crude), which was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)=[O:13])[NH:11][C:6]2=[CH:5][CH:4]=1.[C:25](=[O:37])([O:34][CH2:35][CH3:36])[O:26][CH2:27][CH2:28][N:29]([C:31](Cl)=[O:32])[CH3:30].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:25](=[O:37])([O:26][CH2:27][CH2:28][N:29]([C:31]([N:9]1[C:7]2=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[N:11]=[C:10]1[S:12]([CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=1)=[O:13])=[O:32])[CH3:30])[O:34][CH2:35][CH3:36]
Reactant: CCOC(=O)OCCN(C)C(=O)Cl
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2ccc(OC)nc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine synthesized according to the method described in JP-A-63-146882 was subjected to preparative HPLC for optical resolution to give a (+) enantiomeric form (0.10 g) thereof. To a solution (5 mL) of this form in tetrahydrofuran were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.081 g) obtained in Reference Example 34, triethylamine (0.080 mL) and 4-dimethylaminopyridine (0.007 g) and the mixture was stirred at 50° C. for 18 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=2:1) to give a 2:1 mixture (0.115 g) of the title compound and (+)-ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridin-1-yl]carbonyl](methyl)amino]ethyl carbonate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:16]([O-])=O.[H][H]>[Ni].O1CCCC1>[NH2:16][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:2]=1[NH2:1])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: [H][H]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2ccccc2)cc1N
Yield: 100 %

Procedure:
Fifty grams of 4-amino-3-nitrobenzophenone were hydrogenated at room temperature in 945 ml. of tetrahydrofuran with 15 g. of Raney nickel at 2.74×106 dynes/cm.2. After 4 hours three equivalents of hydrogen were absorbed. The catalyst was filtered and the filtrate was evaporated in vacuo to a solid residue. The residue was chromatographed over silica gel using ethyl acetate as eluant. Fractions 5-9 were combined to yield 43.6 g. (100 percent yield) of 3,4-diaminobenzophenone.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[O:5][N:4]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:17][CH:2]([F:1])[C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[S:13][C:12]([C:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])=[CH:11][CH:10]=2)[O:5][N:4]=1
Reactant: Cc1c(C(F)F)noc1-c1ccc(C(=O)O)s1
Reactant: C1CCNCC1
Product: Cc1c(C(F)F)noc1-c1ccc(C(=O)N2CCCCC2)s1
Yield: 72 %

Procedure:
Prepared from 5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-thiophene-2-carboxylic acid (Preparative Example 27) and piperidine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, then chromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluant to afford product as a colorless solid (110 mg, 72%). 1H NMR (CDCl3) 1.66-1.72 (6, 3 H), 2.35 (s, 3 H), 3.67-3.71 (m, 4 H), 6.79 (t, J=53.2, 1 H), 7.31 (d, J=4.0, 1 H), 7.45 (d, J=4.0, 1 H). 13C NMR 7.7, 24.7, 26.3, ˜46 (br), 39.8 (br), 108.7, 110.3 (t, J=236), 126.8, 128.8, 130.6, 140.6, 158.6 (q, J=30), 162.1, 162.5. 19F NMR −117.4 (J=53.5). LC/MS 6.36 min, [M+1]+ 327.
Reaction SMILES: [C:1](=[NH:9])([O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[C:18]([N:9]=[C:1]([O:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH3:5])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCCCC(=N)OCC
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=NC(=O)OCC)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
A solution of 6.5 g (50.3 mmol) of ethyl valerimidate (free base) in 90 mL of dry CH2Cl2 was treated with 7.71 mL (5.60 g, 55.3 mmol) of triethylamine. The resulting solution was stirred under N2 at -10° C. in an ice-salt bath as a solution of 4.81 mL (5.46 g, 50.3 mmol) of ethyl chloroformate in 10 mL of CH2Cl2 was added dropwise over 25 minutes. Upon completion of the addition, the cooling bath was removed, and the mixture was stirred at room temperature for 2 hours. Next, the solvent was removed by evaporation in vacuo. The residue was taken up in hexane and filtered to remove triethylamine hydrochloride. Concentration of the filtrate yielded 7.08 g (70%) of the product as a yellow oil, suitable for use in the next step without further purification. NMR indicated a mixture of syn and anti isomers. TLC (98:2 CH2Cl2 --MeOH) showed a close pair of spots, Rf 0.48, 0.52.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH3:13])[C:5]=1[OH:14].[CH2:15]([N:22]1[C:30]2[C:29](Cl)=[N:28][C:27]([Cl:32])=[N:26][C:25]=2[CH:24]=[CH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1C(=O)CCC1.O>[CH2:15]([N:22]1[C:30]2[C:29]([O:14][C:5]3[C:4]([CH3:3])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:6]=3[CH3:13])=[N:28][C:27]([Cl:32])=[N:26][C:25]=2[CH:24]=[CH:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Reactant: Clc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1nc(Cl)nc2ccn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of NaH (61.9 mg, 2.6 mmol) in dry NMP (4.7 mL) was added 2,6-dimethyl-4-nitrophenol (258.9 mg, 1.55 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (431 mg, 1.55 mmol) in dry NMP (4 mL) and heated at 90° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed twice with water, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (3:1-1:1), to give the product as a white solid (598 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[N:9]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCNCC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7.5 parts of 3,6-dichloropyridazine in 75 parts of N,N-dimethylformamide was added dropwise a solution of 8 parts of ethyl 1-piperazinecarboxylate and 5.6 parts of N,N-diethylethanamine in 25 parts of N,N-dimethylformamide. Upon completion, the whole was stirred overnight at a temperature of about 50° C. After cooling, the reaction mixture was poured onto water and the product was extracted with trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol, yielding 3.6 parts of ethyl 4-(6-chloro-3-pyridazinyl)-1-piperazinecarboxylate; mp. 123.8° C. (compound 208).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:28])[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1>CCCCCC.C1(C)C=CC=CC=1>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)([OH:28])[CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: Cc1ccc(C(=O)CCN2CCCC2)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(C(O)(CCN2CCCC2)c2ccccn2)cc1
Temperature: -40 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
400 ml of toluene is charged into a round-bottom flask, which is cooled to −40° C. and then solution of n-butyllithium (76.6 g) in hexane is added and the temperature of the reaction mixture is maintained at −40° to −50° C. 2-Bromopyridine (189.2 g) is then added to the reaction mixture and the temperature is maintained at −65° to −55° C. for 35 to 45 minutes. 200 g of 4′-methyl-3-pyrrolidinopropiophenone in 200 ml of toluene is added to the reaction mixture in the R.B. flask. The reaction mass is stirred at −65° to −55° C. for 2 hours and it is further stirred for 1 hour at −40° to −50° C. The reaction mass is quenched in ice water and HCl is added slowly at 10° to 20° C. to get a clear solution. The aqueous layer is separated and it is added slowly to NaOH in the R.B. flask at 15° C.-20° C. The reaction mass is stirred for half an hour and the precipitated solid is filtered off. The solid is transferred into a round-bottom flask and then 500 ml of methanol is added. The reaction mass is refluxed at 60° C. for half an hour and the mass is cooled to 10°-20° C. The solid mass is filtered and dried under suction for one hour. On drying the solid compound at 70°-80° C. for 4 hours, 1-(4-methylphenyl)-1-(2-pyridyl)-3-pyrrolidinopropan-1-ol (220 g, 80.5% yield) with 99.3% HPLC purity is obtained whose melting point is in the range of 115°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([OH:30])(=O)=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.C[N:32](C)C=O>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([NH2:32])(=[O:30])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2nc3ccc(S(N)(=O)=O)cc3nc2-c2ccc(OC)cc2)cc1
Reaction time: 0.05 h

Procedure:
To a solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (137.2 mg, 0.33 mmol, 1.00 equiv) in thionyl chloride (12 mL) was added N,N-dimethylformamide (2 mL) dropwise with stifling. The mixture was stirred at reflux for 3 hr in an oil bath. The resulting mixture was concentrated in vacuo. The residue was dissolved in acetonitrile (10 mL) and added to a solution of ammonia (2 g) in acetonitrile (10 mL) dropwise at 0° C. The resulting mixture was stirred overnight at room temperature, then concentrated in vacuo. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (UV-Directed)): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and CH3CN (10% CH3CN up to 65% in 2.8 min, hold 65% in 2.5 min, up to 100% in 0.1 min, hold 100% in 0.6 min, down to 10% in 0.1 min); Detector, UV 254 nm. This resulted in 16 mg (12%) of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonamide as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[C@:7]([C:25](=O)[CH3:26])([CH3:24])[CH2:6]1)=[O:4].C(O)(=O)C.[CH3:32][NH:33][NH2:34]>CO>[CH3:1][O:2][C:3]([N:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[C@@:7]([CH3:24])([C:25](=[N:34][NH:33][CH3:32])[CH3:26])[CH2:6]1)=[O:4]
Reactant: CNN
Reactant: COC(=O)N1CC(c2ccc(OC)c(OC3CCCC3)c2)[C@@](C)(C(C)=O)C1
Solvent: CO
Solvent: CC(=O)O
Product: CNN=C(C)[C@@]1(C)CN(C(=O)OC)CC1c1ccc(OC)c(OC2CCCC2)c1

Procedure:
To a stirred solution of (R)-3-acetyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-pyrrolidine-1-carboxylic acid methyl ester (see Example 12 of Feldman et al. U.S. Pat. No. 5,665,654, incorporated herein by reference) (or (R)-3-acetyl-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-pyrrolidine-1-carboxylic acid methyl ester) (0.133 mmol, 50 mg) in methanol (2 mL) with catalytic amount of acetic acid (20 μL) was added methyl hydrazine (0.147 mmol, 7.8 μL). The reaction was heated gently for 36 hours, and three more portions of methl hydrazine were added. The resulting hydrazone was purified by HPLC. The named product was confirmed by HNMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.C(=O)(O)[O-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[CH:16][CH:15]=3)([CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Temperature: 0 °C
Yield: 91.2 %

Procedure:
To a solution of 1-(4-amino-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.5 g, 5.5 mmol), in 1:1 acetone:water (12 mL) was added sodium bicarbonate (1.2 g, 13.7 mmol). The resulting solution was cooled to 0° C. and benzyl chloroformate (2.8 mL, 8.2 mmol, 50% solution in toluene) was added dropwise. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 5:5 EtOAc:Pet. ether) to provide the title compound (2.05 g, 92%) as off white solid.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([CH2:15][CH:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[CH:23][CH:22]=3)[C:17]([O:19]C)=[O:18])[NH:12]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].O.C(#N)C>Cl>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[C:11]([CH2:15][CH:16]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[CH:25][CH:26]=3)[C:17]([OH:19])=[O:18])[NH:12]2)=[CH:8][CH:7]=1)(=[NH:4])[NH2:5]
Reactant: COC(=O)C(Cc1cc2ccc(C(=N)N)cc2[nH]1)c1ccc(O[C@H]2CCNC2)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: N=C(N)c1ccc2cc(CC(C(=O)O)c3ccc(O[C@H]4CCNC4)cc3)[nH]c2c1
Temperature: 5 °C
Reaction time: 168 h
Yield: 148.8 %

Procedure:
1.8 g of methyl (+)-3-(6-amidino-2-indolyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride was dissolved in 60 ml of concentrated hydrochloric acid, and the solution was stirred at 5° C. for 7 days. After concentrating the resulting reaction solution to dryness under a reduced pressure at a temperature of 50° C. or below, the thus obtained residue was subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel and using a water/acetonitrile mixture as an elution solvent. Thereafter, thus eluted fractions of interest were pooled, mixed with dilute hydrochloric acid, and then concentrated to dryness. In this way, 1.3 g of the title compound was obtained in a solid form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](OC1C=CC=CC=1)=[N:8][CH:7]=[CH:6]2.C([O-])(=O)C.[NH4+:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9]([NH2:25])=[N:8][CH:7]=[CH:6]2
Reactant: [NH4+]
Reactant: COc1cc2ccnc(Oc3ccccc3)c2cc1C
Agent: CC(=O)[O-]
Product: COc1cc2ccnc(N)c2cc1C
Temperature: 170 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
A mixture of the crude 6-methoxy-7-methyl-1-phenoxyisoquinoline (9 g, 33.96 mmol) and ammonium acetate (26 g) was melted with stirring at 170° C. for 5 h. The mixture was partitioned between aqueous sodium hydroxide (2 M) and ethyl acetate. The phases were separated and the organic phase extracted with dilute aqueous hydrochloric acid. The acidic aqueous phase was neutralized to pH 12 using sodium hydroxide (2M), extracted with ethyl acetate, dried (MgSO4) then dried in vacuo to give 6-methoxy-7-methylisoquinolin-1-ylamine (5.11 g, 27.18 mmol).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:31]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>O1CCCC1>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[CH:7][CH:8]=2)=[O:40])=[CH:42][CH:43]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O
Yield: 88.9 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.2 g; 0.547 mmole) was dissolved in tetrahydrofurane (5 ml). Sodium hydrogencarbonate (0.053 g; 0.631 mmole) was added and the mixture was stirred for a little while. 4-tert-Butylbenzoyl chloride (0.118 g; 0.6 mmole) was added. The reaction mixture was stirred overnight and then evaporated to dryness. Dichloromethane and water were added to the residue and the phases were separated. The organic phase was dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane:heptane (1:1), dichloromethane and finally methanol:dichloromethane (1:99) as eluants gave 0.238 g (89% yield) of 3-{4-[2-{4-(4-[tert-butyl]benzoyl)aminophenyl}ethoxy]phenyl}-2-(S)-ethoxypropanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:11][C:7]=1[CH:6]=[CH:5]2.C1C(=O)N([I:34])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[N:11][C:7]=1[CH:6]=[C:5]2[I:34]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(I)c3cc(Br)ccc3c2[nH]1
Temperature: 70 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
(S)-tert-butyl 2-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.990 g, 2.38 mmol) was suspended in DMF (8 mL) and treated with NIS (1.03 g, 4.59 mmol). The reaction mixture was stirred at 70° C. for 2 d, then cooled to RT. The mixture was then diluted with EtOAc and the organic solution was washed with 3× with brine then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (30% to 55% EtOAc/Hex) to afford (S)-tert-butyl 2-(7-bromo-5-iodo-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (753 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:17]3[CH:16]=[CH:15][C:14]([CH:19]([CH3:22])[C:20]#[N:21])=[CH:13][C:12]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC(C#N)c1ccc2oc(Nc3ccc(Cl)cc3)nc2c1

Procedure:
4-chlorophenylisocyanate (3.1 g.) was slowly added to a stirred solution of 2-(3-amino-4-hydroxyphenyl propionitrile (3.3 g.) in xylene (35 ml.) at room temperature. When the addition was complete p-toluenesulphonic acid (250 mg.) was added, and the solution was heated under reflux using a Dean and Stark apparatus. On cooling, the solution was washed with aqueous sodium bicarbonate solution and evaporated to dryness. The residue was recrystallised to give 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionitrile as a creme solid which was characterised by n.m.r. spectroscopy.