Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[N:8]=[C:7]2[NH:25][C:26]1[N:27](C(C)(C)C)[N:28]=[C:29]([CH3:31])[CH:30]=1)([O-:3])=[O:2]>C(O)=O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:9]2[N:8]=[C:7]([NH:25][C:26]3[NH:27][N:28]=[C:29]([CH3:31])[CH:30]=3)[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:10]2=[O:14])=[CH:16][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc([N+](=O)[O-])cc23)n(C(C)(C)C)n1
Solvent: O=CO
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc([N+](=O)[O-])cc23)[nH]n1
Yield: 47.3 %

Procedure:
12 mg 6-Nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one (preparation see ZB-1) were deprotected by heating in formic acid as described for ZB-1. Evaporation of excess formic acid and chromatography of the residue on silica, eluting with dichloromethane and then with dichloromethane/methanol 20:1 gave 5 mg of the title product. 1H-NMR: (400 MHz, D6-DMSO) 11.9 (1H, br s), 9.78 (1H, s), 9.52 (1H, s), 8.65–8.56 (2H, m), 7.65 (2H, d), 7.53 (2H, d), 6.26 (1H, s), 2.20 (3H, s), 1.35 (9H, s); MS (ESI+)=418.32 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)CCN
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N,N-dimethyl-1,2-ethanediamine by following the procedures in Example 79c. LC-MS m/z 562 (M+H)+; 1H-NMR (MeOD) 2.15 (m, 6 H), 2.36 (m, 4 H), 2.65 (m, 1 H), 3.27 (m, 2 H), 6.38 (d, J=8.4 Hz, 1 H), 7.17 (m, 1 H), 7.25 (m, 2 H), 7.49 (m, 2 H), 7.59 (m, 2 H), 8.00 (s, 1 H), 8.11 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Yield: 109.4 %

Procedure:
A mixture of N4-(1-ethyl-propyl)-6-methyl-3-nitro-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine (40 mg, 0.112 mmol) and 8 mg of 10% palladium/carbon (Pd/C) in 20 ml of ethanol was hydrogenated at 50 psi overnight. The mixture was filtered through celite and the filtrate was concentrated to dryness to give a dark residue (40 mg). 1H NMR (CDCl3) δ 6.88 (s, 2H), 5.97 (s, 1H), 4.32 (d, 1H), 3.28 (m, 1H),2.27 (s, 3H), 2.26 (s, 3H), 2.18 (s, 6H), 1.45–1.75 (m, 4H), 0.93 (t, 6H) ppm. The corresponding di-HCl salt was prepared as a tan solid, mp 213–216° C., 1H NMR(DMSO-d6) δ 11.1 (s, 1H), 8.48 (s, 1H), 6.98 (s, 2H), 6.73 (brs, 2H), 6.38 (s, 1H), 3.36 (m, 1H), 2.28 (s, 3H), 2.19 (s, 3H), 2.08 (s, 6H), 1.54 (m, 4H), 0.88 (t, 6H) ppm.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[O:8][C:7](OC)([O:16]C)[CH2:6]1)(=[O:3])[CH3:2].O.Cl>CO>[O:16]=[C:7]1[CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]([CH3:15])[O:8]1
Reactant: COC(=O)C1=C(C)OC(OC)(OC)CC1NC(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)C1C(NC(C)=O)CC(=O)OC1C
Reaction time: 5 h
Yield: 34.8 %

Procedure:
To a solution of methyl 4-acetylamino-2,2-dimethoxy-6-methyl-3,4-dihydro-2H-pyran-5-carboxylate (13.7 g) (Example 23) in methanol (100 ml) at 20°-25° C. was added water (4.0 ml) and 1N HCl (0.4 ml). The mixture was stirred at 20°-25° C. for five hours, then the solvents were evaporated at reduced pressure and the residual gum (13 g) was redissolved in trifluoroacetic acid (100 ml), to which was added methylene chloride (25 ml) and triethylsilane (25 ml). The mixture was stirred at 20°-25° C. for 70 hours and then the solvents were evaporated at reduced pressure. The residue was purified by chromatography on K60 silica eluting with ethyl acetate to give methyl 2-oxo-4-acetylamino-6-methyl-3,4,5,6-tetrahydro-2H-pyran-5-carboxylate (4.0 g) m.p. 135°-6° C. (EtOAc/hexane) (4,5-trans: 5,6-trans isomer).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([OH:22])[CH2:11][P:12]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:14])[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[O:25]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[O:33]=[C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]([O:14][P:12]([CH2:11][C@H:10]([OH:22])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:13])[O:25]1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OC1OC(=O)c2ccccc21
Temperature: 120 °C
Yield: 21.5 %

Procedure:
To a solution of ((R)-3-tert-butoxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid (0.5 g, 1.49 mmol) in 30 mL toluene was added 3-bromo-3H-isobenzofuran-1-one (952 mg, 4.47 mmol) and silver carbonate (1.23 g, 4.47 mmol). The reaction mixture was heated to 120° C. for 2 h. After filtering hot and concentrating in vacuo the crude product was purified by gradient flash chromatography (methanol/methylene chloride) on a 35 g RediSep disposable column to give ((R)-3-tert-butoxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid 3-oxo-1,3-dihydro-isobenzofuran-1-yl ester (150 mg, 0.32 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.92 (m, 1H), 7.73 (m, 2H), 7.12 (m, 1H), 5.1 (m, 1H), 4.40 (m, 1H), 4.2 (m, 1H), 3.4-3.22 (m, 1H), 3.20-3.04 (m, 1H), 2.01-1.58 (m, 10H), 1.48 (s, 9H), 1.40-0.95 (m, 6H). LC/MS m/z: [M+H]+=468.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([Cl:23])[N:17]=1.[OH-].[Na+]>CN(C=O)C>[Cl:23][C:18]1[N:17]=[C:16]([NH:15][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:21]=[C:20]([Cl:22])[N:19]=1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Reactant: Nc1cc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc(Nc2ncnc3[se]c4c(c23)CCCC4)nc(Cl)n1
Yield: 68.5 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (500 mg, 1.83 mmol, from step b of example 1) in DMF (10 mL) was added sequentially 4-amino-2,6-dichloropyrimidine (450 mg, 2.75 mmol) and powdered NaOH (220 mg, 5.50 mmol) at rt. Work-up of the mixture as described in example 2, gave the product as an off-white color solid (500 mg, 68%), mp 268-270° C. 1H NMR (400 MHz, CDCl3): δ 8.67 (1H, s), 8.64 (1H, s), 8.23 (1H, s, exchangeable with D2O), 3.11 (2H, t, J=6.1 Hz), 2.97 (2H, t, J=6.1 Hz), 2.01-2.06 (2H, m), 1.92-1.98 (2H, m); 13C NMR (100 MHz, CDCl3): δ 172.9, 162.7, 160.0, 159.2, 152.4, 151.0, 142.7, 126.3, 121.3, 107.8, 28.3, 28.2, 22.7, 22.4; LC-MS (negative ion mode): m/z 396, 398, 400, 402 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[O:20][C:19]3[CH:18]=[C:17]([OH:21])[CH:16]=[C:15]([OH:22])[C:14]=3[C:12](=[O:13])[CH:11]=2)=[CH:7][C:8]=1[OH:9].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C)C=O.CN(P(N(C)C)(N(C)C)=O)C>[CH2:25]([C:16]1[C:17]([O:21][CH2:12][CH:11]=[CH2:10])=[CH:18][C:19]2[O:20][C:10]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH2:4][CH:3]=[CH2:8])[CH:7]=3)=[CH:11][C:12](=[O:13])[C:14]=2[C:15]=1[O:22][CH2:7][CH:6]=[CH2:5])[CH:26]=[CH2:27]
Reactant: C=CCBr
Reactant: COc1ccc(-c2cc(=O)c3c(O)cc(O)cc3o2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOc1cc(-c2cc(=O)c3c(OCC=C)c(CC=C)c(OCC=C)cc3o2)ccc1OC
Temperature: 40 °C

Procedure:
12 g of diosmetin in 100 ml of dimethylformamide and 15 ml of HMPA are added very slowly to a suspension of 4.8 g of sodium hydride in 30 ml of dimethylformamide. The mixture is then stirred at 40° C. until the evolution of gas has ceased. 17.25 g of allyl bromide are then added dropwise and the whole is heated at 60° C. for 16 hours, after which the solvents are removed by distillation under reduced pressure. The residue is taken up in dichloromethane and then chromatographed on silica using a 98% dichloromethane/2% methanol mixture as eluant. In that manner a fraction of 7.6 g of compound very fluorescent under 366 nm is recovered. An analytical sample of the title compound is prepared by recrystallisation from isopropanol, m.p.: 107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:12][C:13]([CH:21]([CH3:23])[CH3:22])([CH2:18][CH2:19][CH3:20])[C:14](OC)=[O:15]>O1CCCC1>[CH2:18]([C:13]1([CH:21]([CH3:23])[CH3:22])[NH:12][C:10](=[S:11])[N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:14]1=[O:15])[CH2:19][CH3:20]
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CCCC(N)(C(=O)OC)C(C)C
Solvent: C1CCOC1
Product: CCCC1(C(C)C)NC(=S)N(c2cc(Cl)cc(Cl)c2)C1=O
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of 2.0 g of 3,5-dichlorophenyl isothiocyanate in 10 ml of absolute tetrahydrofuran was added dropwise at 20° C. to a solution of 1.7 g of methyl 2-amino-2-(1-methylethyl)-pentanoate in 10 ml of absolute tetrahydrofuran and the mixture was stirred at 20° C. for a further 4 hours. Then the solvent was removed and the residue was recyrstallized from diisopropyl ether to obtain 1.6 g (46% of theory) of title compound melting at 160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22][OH:23])=[C:18]([CH3:26])[CH:17]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([O:23][CH2:22][CH2:21][O:20][C:19]1[CH:24]=[CH:25][C:16]([C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)=[CH:17][C:18]=1[CH3:26])(=[O:30])=[O:29]
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO
Reactant: CS(=O)(=O)Cl
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O

Procedure:
Prepared analogously to Example 4.1a from 310 mg (0.93 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethanol and 88 μL (1.12 mmol) methanesulphonic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:14][C:15]1[N:16]=[C:17]([NH2:26])[S:18][C:19]=1[CH2:20][CH2:21][O:22][N+:23]([O-:25])=[O:24]>>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:26][C:17]1[S:18][C:19]([CH2:20][CH2:21][O:22][N+:23]([O-:25])=[O:24])=[C:15]([CH3:14])[N:16]=1)=[O:8]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Product: Cc1nc(NC(=O)COc2ccc(Cl)cc2Cl)sc1CCO[N+](=O)[O-]
Yield: 77 %

Procedure:
Pet-163 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using (2,4-dichloro-phenoxy)-acetic acid and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 77%.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]2[S:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].I[CH3:19]>C1COCC1.CO>[CH3:19][NH:3][C:4]1[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][C:7]2[CH:12]=[CH:11][S:10][C:8]=2[N:9]=1
Reactant: CI
Reactant: CCOC(=O)c1nc2ccsc2nc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1nc2ccsc2nc1NC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a stirred suspension of neat NaH (0.82 g, 3.40 mmol) in 10 ml THF at -78° C. was canulated a cold (-78° C.) 20 ml THF solution of ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate (0.690 g, 3.09 mmol). The reaction mixture was allowed to warm to rt, stir for 2 h and was then treated with iodomethane (0.460 g, 3.24 mmol). After stirring for 12 h at rt, the mixture was diluted with 5 ml MeOH and concentrated. Purification by column chromatography on silica gel eluting first with 10:1 then 5:1 hexanes:ethyl acetate gave the title compound (0.610 g, 84%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ1.40 (t, 3H), 3.60 (d, 3H), 4.36 (q, 2H), 7.48 (br s, 2H), 8.54 (d, 1H), 8.57 (d, 1H). MS (DCI/NH3) m/e 238 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13](OS(C)(=O)=O)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:26]1([N:29]2[C:33]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[N:32][NH:31][C:30]2=[S:40])[CH2:28][CH2:27]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([S:40][C:30]3[N:29]([CH:26]4[CH2:28][CH2:27]4)[C:33]([C:34]4[CH:35]=[CH:36][N:37]=[CH:38][CH:39]=4)=[N:32][N:31]=3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(OS(C)(=O)=O)c1nnn(-c2cccc(Cl)c2)n1
Reactant: S=c1[nH]nc(-c2ccncc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Sc1nnc(-c2ccncc2)n1C1CC1)c1nnn(-c2cccc(Cl)c2)n1
Yield: 68.2 %

Procedure:
The title compound (25.2 mg, 68%, white solid) was prepared from methanesulfonic acid 1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (26.4 mg, 0.087 mmol) using potassium carbonate (13.3 mg, 0.096 mmol) and 4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione (19.0 mg, 0.087 mmol) in acetonitrile (3 mL) at room temperature overnight. The reaction mixture was purified by chromatography using a silica SPE tube (2% methanol in dichloromethane). 1H NMR (CDCl3) δ (ppm): 8.78 (d, 2H), 8.16 (s, 1H), 8.04 (m, 1H), 7.75 (d, 2H), 7.49 (m, 2H), 5.67 (q, 1H), 3.24 (m, 1H), 2.08 (d, 3H), 1.16 (m, 2H), 0.82 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH2:13]([O:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCO)OCc1ccccc1
Reaction time: 1 h
Yield: 85.8 %

Procedure:
In 300 ml of methylene chloride was dissolved 50 g of 3-aminopropanol, and thereto were successively added dropwise 33 g of triethylamine and 57 g of benzyloxycarbonyl chloride at -10° C. to -5° C. At the same temperature, the resulting mixture was stirred for 1 hour and then further stirred at room temperature for 1 hour. Subsequently, the reaction mixture was washed successively with 100 ml of diluted hydrochloric acid and 100 ml of water, and thereafter dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 60 g (yield 86%) of 3-(benzyloxycarbonylamino)propanol having a melting point of 55°-56° C.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([OH:17])[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([O:24][C:25](=[O:34])[NH:26][CH:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25](=[O:34])[NH:26][CH:27]1[CH2:28][CH2:29][CH:30]([NH:33][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([OH:17])[CH:16]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:19][CH:18]=3)[CH:9]=2)[CH2:31][CH2:32]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: N#Cc1ccc(Oc2cc(O)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 37.8 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano phenoxy)-5-hydroxy benzoic acid 0.9 g (3.52 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.75 g, 3.52 mmol) were used to afford 0.6 g of the required product. 1H NMR (DMSO-d6): 1.35 (4H, m), 1.4 (9H, s), 1.8 (4H, m), 3.15 (1H, m), 3.7 (1H, m), 6.62 (1H, s), 6.76 (1H, d), 7.04 (1H, s), 7.16 (3H, m), 7.86 (2H, m), 8.2 (1H, d), 10.0 (1H, s).
Reaction SMILES: C(C1C=CC2NN=NC=2C=1)(O)=[O:2].[CH:13]1([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C=O>[C:20]([NH:19][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:2]
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 1 h

Procedure:
In 50 ml of dimethylformamide were dissolved 8.1 g of 5-carboxybenzotriazole and 15.3 g of the amino compound obtained in above step 4-(2) and while stirring the solution at 0° C. in a nitrogen gas atmosphere, 5 ml of dimethylformamide solution containing 10.3 g of dicyclohexylcarbodiimide were added dropwise to the solution over a period of 15 minutes. After stirring the mixture for one hour, the mixture-was further stirred for 2 hours at 25° C. Then, dicyclohexylurea formed was removed by filtration and the filtrate thus obtained was added to 1.5 liters of ice water. Crude crystals thus deposited were collected by filtration and dispersed in 100 ml of isopropanol for 15 minutes under heating. The reaction mixture was cooled to room temperature and filtered to provide 12.1 g of desired Compound 201 having a melting point of from 196° C. to 199° C. (decompd.) with the yield of 54%.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.C(O)C>[C:10]1([C:2]2[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: O=C(O)c1csc(-c2ccccc2)c1

Procedure:
5-Bromo-thiophene-3-carboxylic acid (2.07 g, 10 mmol) was dissolved in dimethoxyethane (15 mL) and ethanol (15 mL). Phenyl boronic acid (14 mmol), [1,1′-bis(diphenylphosphino)ferrocine]dichloropalladium (II) (0.5 mmol) and caesium carbonate (14 mmol) were added and the reaction mixture refluxed under nitrogen overnight. The solvent was evaporated under vacuum, and the residue dissolved in ethyl acetate. The organic solution was washed with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and the solvent evaporated. The residue was dissolved in hot ethyl acetate, filtered and the solvent evaporated to give the title compound as a pale brown solid. LCMS m/z 203.20 [M−H]− R.T.=3.23 min (Analytical Method 5).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17](N[C@H](C2C=CC=CC=2)CO)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32]S(O)(=O)=O.[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17]([OH:18])=[O:32])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 15 h

Procedure:
(2S)-3-[4-(benzyloxy)phenyl]-2-ethoxy-N-[(1R)-2-hydroxy-1-phenylethyl ]propanamide (4.3 kg, 10.2 mol) were dissolved in dioxane (30 L) and diluted with deionized water (35 L). To this opaque reaction mixture, H2SO4 (19.2 kg, 192 mol) was added. The reaction temperature was raised to 80° C. and kept at 80° C. for 15 hours. The reaction mixture was extracted twice with TBME (64 L, 70 L) at room temperature. The combined organic phases were extracted twice with 1 M NaOH (2×20 L, 2×20 mol). The aqueous phases were acidified with H2SO4 (24 L, 24 mol), extracted with TBME (40 L) and the organic phases dried with saturated NaCl solution. The solution was concentrated to yield 64 L concentrate which contained 2.9 kg, 100% (GLC 68% area (2S)-3-[4-(benzyloxy) phenyl]-2-ethoxypropanoic acid and 28% area (2S)-2-ethoxy-(4-hydroxyphenyl) propanoic acid).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]3[CH2:23][CH2:22][OH:21])=[N:12][C:11]1=2)[CH3:14]
Reactant: OCCC1CCCCN1
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCCCC3CCO)nc21

Procedure:
The title compound, m.p. 234°-237° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 2-(hydroxyethyl)piperidine using procedures analogous to those described above, except that the mixture was heated at reflux for 1.25 hrs, and the product was crystallized from ethyl acetate/ethanol.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH2:42])([CH3:41])[CH3:40]>>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([NH:42][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([CH3:40])[CH3:41]
Reactant: COc1ccccc1C(C)(C)N
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: COc1ccccc1C(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 96 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(2-methoxyphenyl)-1-methylethylamine (prepared as described in Preparation 10c) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 96%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=3)=[CH:23][N:24]=[N:25]2)=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.O>[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH:1][CH:2]4[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]4)(=[O:36])=[O:37])=[CH:33][CH:34]=3)=[CH:23][N:24]=[N:25]2)=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Reactant: CCN1CCCC(N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN1CCCC(NS(=O)(=O)c2ccc(Nc3cnnc4cc(Cl)ccc34)cc2)C1
Temperature: 3 °C
Reaction time: 0.75 h

Procedure:
3-Amino-1-ethylpiperidine (0.4 ml) in chloroform (15 ml) was treated with anhydrous sodium carbonate (2.94 g) in water (15 ml) and cooled to 3° C. The mixture was vigorously stirred and treated with 4-(7-chloro-4-cinnolinylamino)benzenesulphonylchloride hydrochloride (1.0 g). The dark orange mixture was stirred at 3° C. for 15 minutes, then at room temperature for 45 minutes. During this period the colour lightened considerably. The chloroform layer was separated and dried over magnesium sulphate. The residue on evaporation solidified when triturated with methanol, to give the title compound (0.5 g), m.p. 213°-15° C. (with decomposition).