Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([F:39])=[C:14]([C@:16]([NH:31]S(C(C)(C)C)(=O)=O)([CH3:30])[C:17]([F:29])([F:28])[C:18]([CH3:27])([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:19])[CH:15]=1.CCOC(C)=O>ClCCl.CCCCCCC>[NH2:31][C@@:16]([C:14]1[CH:15]=[C:10]([Br:9])[CH:11]=[CH:12][C:13]=1[F:39])([CH3:30])[C:17]([F:28])([F:29])[C:18]([CH3:27])([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:19]
Reactant: CCOC(=O)COC(C)(C)C(F)(F)[C@](C)(NS(=O)(=O)C(C)(C)C)c1cc(Br)ccc1F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)COC(C)(C)C(F)(F)[C@](C)(N)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
Dropwise addition of TRIFLUOROMETHANESULFONIC ACID in CH2Cl2 0.25 M (225 ml, 56.3 mmol, Eq: 3) to a solution of (R)-ethyl 2-(4-(5-bromo-2-fluorophenyl)-4-(1,1-dimethylethylsulfonamido)-3,3-difluoro-2-methylpentan-2-yloxy)acetate (RO5545483-000-005) (10 g, 18.8 mmol, Eq: 1.00) in Dichloromethane (188 ml) at 0° C. this reaction mixture was stirred at room temperature for 30 minutes Extracted with sat NaHCO3, CH2Cl2, dried over Na2SO4, filtered off, evaporated, dried in HV to give a brown oil (8.8 g; 114%) The residue was chromatographed, 50 g SiO2 (Flashmaster) with EtOAc 0%-50% in heptane to give (R)-ethyl 2-(4-amino-4-(5-bromo-2-fluorophenyl)-3,3-difluoro-2-methylpentan-2-yloxy)acetate (6.85 g, 16.6 mmol, 88.5% yield) as a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4]([CH2:12][CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[S:17][CH:18]=2)([CH:9]([CH3:11])[CH3:10])[O:5][C:6](=[O:8])[CH:7]=1.[C:23]([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:23]([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36][C:7]1[C:6](=[O:8])[O:5][C:4]([CH2:12][CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[S:17][CH:18]=2)([CH:9]([CH3:11])[CH3:10])[CH2:3][C:2]=1[OH:1])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)Nc1nc(CCC2(C(C)C)CC(O)=CC(=O)O2)cs1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCC2(C(C)C)CC(O)=C(Sc3cc(C)c(CO)cc3C(C)(C)C)C(=O)O2)cs1

Procedure:
The title compound was prepared according to General Method 16a using N-{4-[2-(4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-thiazol-2-yl}-acetamide (Example E-13; 0.49 g, 1.5 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.66 g, 1.8 mmol), potassium carbonate (0.83 g, 6.0 mmol), and DMF (5 mL). The product was chromatographed on silica gel, eluting with 5% MeOH in CH2Cl2, to give the title compound, mp 128-130° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:6]=[C:5]([C:24]([O:26]CC)=O)[C:4]=2[NH:3]1.ClC1N=C(C(OCC)=O)C2NC(=O)CN(C3C=CC=CC=3)C=2[N:31]=1.C([Sn](CCCC)(CCCC)C1C=CN=CC=1)CCC>CN(C=O)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:1]=[C:2]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[N:8]=[C:7]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[N:6]=[C:5]([C:24]([NH2:31])=[O:26])[C:4]=2[NH:3]1
Reactant: CCOC(=O)c1nc(Cl)nc2c1NC(=O)CN2c1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccncc2)nc2c1NC(=O)CN2c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1nc(-c2ccncc2)nc2c1NC(=O)CN2c1ccccc1
Temperature: 120 °C
Yield: 50 %

Procedure:
Ethyl 6-oxo-8-phenyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydropteridine-4-carboxylate. To a solution of ethyl 2-chloro-6-oxo-8-phenyl-5,6,7,8-tetrahydropteridine-4-carboxylate (0.160 g, 0.48 mmol) in anhydrous DMF (6.7 mL) was added 4-(tributylstannyl)pyridine (0.884 g, 2.40 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.170 g, 0.24 mmol). The solution was purged with nitrogen then heated in a Biotage Emrys Optimizer microwave reactor for 30 min at 120° C. The volatiles were evaporated and the resulting residue was purified by chromatography on a normal phase silica gel column (1-10% methanol in dichloromethane). Fractions containing product were combined and the solvent evaporated. The material was re-purified using reverse-phase preparatory HPLC (10-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing the desired material were combined and concentrated under reduced pressure to afford a residue. The residue was dissolved in methylene chloride (100 mL) which was washed with aqueous potassium carbonate solution (saturated, 10 mL) and dried over sodium sulfate. The organic phase was concentrated and the resulting solid was dried under high vacuum at 60° C. to afford the title compound (0.090 g, 0.24 mmol, 50% yield). MS (ESI) m/z 376.4 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[NH2:16][C:17]1(N)[CH2:22][CH:21]=[CH:20][CH:19]=[C:18]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: NC1(N)CC=CC=C1c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Nc1cccc(Cl)c1C(=O)Nc1ccccc1-c1ccccc1
Yield: 57.2 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.0 g, 11.7 mmol) and SOCl2 (2.1 mL, 29.3 mmol) in benzene (60 mL), followed by 2-aminobiphenylamine (4.15 g, 24.5 mmol) and CHCl3 (60 mL). The product was chromatographed in CH2Cl2 to provide 2.16 g of a foamy dark-amber residue (57%). 1H NMR (CDCl3) δ: 8.48 (d, J=8.2 Hz, 1H); 7.79 (br s, 1H); 7.34-7.46 (m, 6H); 7.20-7.30 (m, 2H); 7.00 (t, J=8.1 Hz, 1H); 6.63 (dd, J=0.6, 7.9 Hz, 1H); 6.54 (d, J=8.3 Hz, 1H); 4.58 (br s, 2H). MS (ES): m/z 323.1 (M+).
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:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH: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:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1nc(Nc2ccccc2)c2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-(phenylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, aniline, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:16]=1[O:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:19][CH2:18][O:17][C:16]2[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:15]=2[CH3:14])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(C)c1OCCBr
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1OCCSc1cnn(C(C)(C)C)c(=O)c1Cl
Temperature: 25 °C
Yield: 95 %

Procedure:
In 30 mm of N,N-dimethylformamide was dissolved 2.2 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 2.3 g of 2-(2',6'-dimethylphenoxy)ethyl bromide, and thereto were added 1.1 g of anhydrous sodium carbonate. The resulting solution was stirred at room temperature for fifteen hours. This solution was poured into water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and freed of solvent under reduced pressure to give crystals. The crystals thus obtained were washed with n-hexane to give 3.5 g of the intended compound. m.p. 104.3°~105.2° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:22]3[CH2:23][C:9]4([CH2:13][N:12]([CH2:14][CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[CH2:11][CH:10]4[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=43)[C:8]=2[CH:28]=1)(=O)[CH3:2].Cl.[NH2:30][OH:31].[OH-].[Na+].C(Cl)Cl>C(O)C.O>[C:1](=[N:30][OH:31])([C:4]1[CH:5]=[CH:6][C:7]2[CH:22]3[CH2:23][C:9]4([CH2:13][N:12]([CH2:14][CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[CH2:11][CH:10]4[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=43)[C:8]=2[CH:28]=1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(=NO)c1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Yield: 24.7 %

Procedure:
To a stirred mixture of 5.0 g (13.6 mmoles) of 5-acetyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole, (Example 66), and 1.5 g (21.3 mmoles) of hydroxylamine hydrochloride in 25 ml of ethanol and 5.0 ml of water was added portionwise 2.8 g (70 mmoles) of powdered sodium hydroxide. The reaction mixture was then heated at reflux for 5 minutes, cooled, and distributed between water and methylene chloride. The organic layer was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel CC No. 7 with 5% methanol in chloroform to give 1.3 g of 5-acetyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole oxime as an oil; nmr spectrum: δ 1.0-4.0 (m, 19); 2.2 (s, 2); 6.8-7.4 (m, 7); 7.5 (s, 1).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH2:10][NH:11][N:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[CH3:14])[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:10]1[N:11]=[N:12][CH:13]=[C:8]2[CH:7]=[C:6]([CH3:14])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:9]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2c(n1CC(C)C)CNN=C2
Product: Cc1cc2cnnc(Cl)c2n1CC(C)C
Yield: 75 %

Procedure:
3.8 g (12 mmol) of 1-isobutyl-2-methyl-6,7-dihydropyrrolo[2,3-d]pyridazine are reacted at 100° C. for 2 h in 30 ml of phosphorus oxychloride. Purification: chromatography on silica gel (eluent: toluene/dioxane=2:1). Yield: 75%. M.p.: 96°-99° C.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([NH2:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:19][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCN=C=S
Reactant: CCCCCCCCN
Solvent: c1ccccc1
Product: CCCCCCCCNC(=S)NCCCCCCC
Yield: 105.2 %

Procedure:
To a solution of 3.14 grams (0.02 mole) n-heptylisothiocyanate dissolved in 15 milliliters of benzene is added 2.58 grams (0.02 mole) n-octylamine. The temperature rose to 41° C. The mixture was then refluxed on a steam-bath for about 20 minutes, until the mixture reached a neutral pH. The solution was then evaporated under vacuum. A yield of 6.03 grams of 1-n-heptyl-3-n-octylthiourea was obtained.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:7]1[N:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[S:10][CH:11]=1)[CH2:5][NH2:6].Cl[CH2:17][C:18](OCC)=[O:19].Cl>C1(C)C=CC=CC=1.O.C(O)C>[F:13][C:12]([F:15])([F:14])[C:9]1[S:10][CH:11]=[C:7]([CH:4]2[O:3][CH2:17][C:18](=[O:19])[NH:6][CH2:5]2)[N:8]=1
Reactant: CCOC(=O)CCl
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1COC(c2csc(C(F)(F)F)n2)CN1

Procedure:
0.3 g (0.0064 mol) of a dispersion of sodium hydride (50-55% in oil) is added in small portions to a stirred solution of 1 g (0.0047 mol) of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in 15 ml of toluene at 30° C. After 1 hour a solution of 0.55 g (0.0045 mol) of ethyl chloroacetate in 2 ml of toluene is added dropwise. After 2 hours first 1 ml of ethanol and then 4 ml of water are added dropwise. The mixture is then acidified with hydrochloric acid and extracted several times with methylene chloride, and the extract is dried over sodium sulphate. The resulting product is purified on a silica gel column using ethyl acetate/methanol =1/1 as eluant and, after evaporation to dryness, digested with a little ether.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH:13]1([CH2:12][N:10]2[C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[I:1])[CH:8]=[N:9]2)[CH2:15][CH2:14]1.[CH:13]1([CH2:12][N:9]2[CH:8]=[C:4]3[N:5]=[CH:6][CH:7]=[C:2]([I:1])[C:3]3=[N:10]2)[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: Ic1ccnc2cn[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccnc2cn(CC3CC3)nc12
Product: Ic1ccnc2cnn(CC3CC3)c12
Temperature: 80 °C

Procedure:
7-Iodo-1H-pyrazolo[4,3-b]pyridine (50 mg, 0.204 mmol), bromomethylcyclopropane (27.5 mg, 0.204 mmol) and cesium carbonate (133 mg, 0.408 mmol) in DMF (1.0 mL) were heated in a microwave at 80° C. for 15 minutes. Additional bromomethylcyclopropane (27.5 mg, 0.204 mmol) was then added and the reaction was further heated in a microwave at 80° C. for 30 minutes. The reaction was cooled and poured into water (10 mL) and extracted with ethyl acetate (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(cyclopropylmethyl)-7-iodo-1H-pyrazolo[4,3-b]pyridine and 2-(cyclopropylmethyl)-7-iodo-2H-pyrazolo[4,3-b]pyridine as a mixture (60/40); MS [M+H] found 300.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[NH:14][C:13]([CH3:22])=[C:12]2[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=O.[C:32]1([CH2:38][CH2:39][CH2:40]Br)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[C:12]([C:23]([O:25][CH3:26])=[O:24])=[C:13]([CH3:22])[N:14]([CH2:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:15]([CH3:21])=[C:16]2[C:17]([O:19][CH3:20])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc(OC)c(OC)c1
Reactant: BrCCCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C1=C(C)N(CCCc2ccccc2)C(C)=C(C(=O)OC)C1c1ccc(OC)c(OC)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
60% Sodium hydride (0.26 g) was washed with several milliliters of anhydrous n-hexane in an argon gas atmosphere, and 10 ml dimethylformamide was added. To the resulting mixture, was added dropwise 20 ml of a dimethylformamide solution containing 2 g (5.5 mmol) dimethyl 1,4-dihydro-4-(3,4-dimethoxyphenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate with stirring. The mixture was heated at 90° C. for one hour, 20 ml of a dimethylformamide solution of 3-phenylpropyl bromide was then added, and heating at 90° C. was continued for one hour. After cooling the mixture to room temperature, 20 ml diethyl ether was added, the resulting mixture was washed with water, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by column chromatography (SiO2 /n-hexane-ethyl acetate 2:1), affording 0.8 g (30%) of the pure product. M.P.: 97°-98° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:9]([N+:21]([O-])=O)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S1C=CC=C1.[H][H]>CO.[Pt]>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:21])[C:10]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1NCc1cccnc1
Agent: [Pt]
Solvent: c1ccsc1
Solvent: CO
Product: Nc1cc(Cn2ccnc2)ccc1NCc1cccnc1
Yield: 100 %

Procedure:
(b-1) A mixture of 6.2 parts of N-[4-(1H-imidazol-1-ylmethyl)-2-nitrophenyl]-3-pyridinemethanamine, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 5.6 parts (100%) of 4-(1H-imidazol-1-ylmethyl)-N1 -(3-pyridinylmethyl)-1,2-benzenediamine as a residue (int. 80).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])=[CH:8][N:7]=[CH:6][C:5]=1[O:19][C:20]1[CH:21]=[C:22]([NH:26]C(=O)OC(C)(C)C)[CH:23]=[CH:24][CH:25]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[O:19][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cncc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(Nc2ccc(I)cc2F)cncc1Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
840 mg of tert-butyl [3-({4-carbamoyl-5-[(2-fluoro-4-iodophenyl)amino]pyridin-3-yl}oxy)phenyl]carbamate (1.488 mmol, 1 eq.) were dissolved in 8 mL dichloromethane under a nitrogen atmosphere. Then 1.6 ml of TFA were added and the brownish solution was stirred at room temperature for 18 hours. Then 4 ml of saturated aqueouse NaHCO3 solution was added and the mixture was stirred for 4 hours while a suspension was forming, that was filtered off. Drying of the precipitate in vacuo yielded 615 mg of the analytically pure target compound (1.488 mmol, 87% yield) as a yellowish solid.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]([S:14][C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)[CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][CH:4]=1>O>[OH-:8].[C:11]([CH2:10][CH:9]1[S:14][C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N+:19]=2[C:7]1([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:22][CH:21]=1)[OH:8])([OH:13])=[O:12]
Reactant: Cn1ccnc1SC(CC(=O)O)C(=O)c1ccc(Cl)cc1
Agent: Br
Solvent: O
Product: Cn1cc[n+]2c1SC(CC(=O)O)C2(O)c1ccc(Cl)cc1
Product: [OH-]

Procedure:
Finely ground 3-(p-chlorobenzoyl)-3-(1-methylimidazol-2-ylthio)propionic acid, hydrobromide, (6.0 g.) is added to 250 ml. of water and the mixture stirred for 20 min. The solid is collected and dried at room temperature. The crude material which weighs 4.6 g. and melts at 160°-2° is recrystallized from acetone. The recrystallized material melts at 161°-3°.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH3:29][C:30](=[O:33])[C:31]#[CH:32]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:32]=[C:31]([C:30](=[O:33])[CH3:29])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CC(C)=O
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: CC(=O)c1cn(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.125 mmol) and but-3-yn-2-one (0.125 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 50:50 as the eluent to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:19]([CH:16]1[CH2:18][CH2:17]1)=[O:20]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and cyclopropanecarbonyl chloride.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[OH:10]N1C(=O)N(O)C(=O)N(O)[C:12]1=[O:21].[O:22]=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:12]([OH:21])=[O:22])=[CH:2][CH:3]=1)#[N:8].[C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH:9]=[O:10])=[CH:2][CH:3]=1)#[N:8]
Reactant: Cc1ccc(C#N)cc1
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Reactant: O=O
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)O)cc1
Product: N#Cc1ccc(C=O)cc1

Procedure:
A mixture of 0.351 g of p-tolunitrile, 0.005 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (1% by mole relative to p-tolunitrile), 5 g of acetic acid and 0.004 g of cobalt(II) acetate.4H2O was stirred at 100° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 14 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield 4-cyanobenzoic acid and 4-cyanobenzaldehyde in 74% and 1% yields, respectively, at 81% conversion of p-tolunitrile.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]2)=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COCC1(CBr)COC1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(-c3ccc4c(c3)COC4=O)ccc(OC)c2OC(F)F)COC1
Temperature: 70 °C
Yield: 18.6 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (144 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 18%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19](Cl)[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:24][S:25]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1)(=[O:27])=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[N:30][CH:31]=2)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(NS(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (103 mg, 0.32 mmol) and 6-(methylsulfonamido)nicotinic acid, intermediate 15, (84 mg, 0.39 mmol) in CH2Cl2 (2 mL) and DMF (2 mL) is added TEA (0.18 mL, 1.29 mmol) and HATU (159 mg, 0.42 mmol) at room temperature. The crude is stirred at room temperature for 2 hrs. The crude is quenched with saturated NaHCO3, diluted in EtOAc. The organic layer is washed with six times with water, brine, dried over MgSO4, filtered, and concentrated. The crude is purified via RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (R)-ethyl 4-(biphenyl-4-yl)-3-(6-(methylsulfonamido)nicotinamido)butanoate as a white solid (4.1 mg). HPLC retention time=1.61 minutes (condition A); MS (m+1)=482.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22 (t, J=7.2 Hz, 3H), 2.56 (t, J=4.8 Hz, 2H), 2.84-2.92 (m, 1H), 3.05 (dd, J=13.6, 6.1 Hz, 1H), 3.16 (s, 3H), 4.08-4.18 (m, 2H), 4.57-4.71 (m, 1H), 7.03 (d, J=8.3 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.22 (d, J=8.3 Hz, 2H), 7.26-7.31 (m, 1H), 7.33-7.40 (m, 2H), 7.44-7.54 (m, 5H), 7.98 (dd, J=8.8, 2.3 Hz, 1H), 8.52 (s, 1H).