Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](Cl)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Reactant: COc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Product: COc1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3ccccc23)cc1

Procedure:
The product from Example 151A and 2-(3,5-difluorophenyl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.73 (s, 1H), 8.39-8.42 (m, 1H), 7.87-8.05 (m, 2H), 7.75-7.79 (m, 1H), 7.52-7.55 (m, 2H), 7.05-7.23 (m, 5H), 3.85 (s, 3H), 3.77 (s, 2H); MS (ESI+) M/Z 422 (M+H)+.
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[N:11]=[C:10]([C:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:13])[CH:9]=[C:8]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:7]=1>O.[Pd]>[CH:22]1([O:21][C:8]2[N:7]=[CH:6][N:11]=[C:10]([C:12]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[CH:9]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C(OC1CCCCC1)c1cc(OC2CCCCC2)nc(Cl)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: O=C(OC1CCCCC1)c1cc(OC2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(13.40 g; 212 mmol) in water (30 ml). A suspension of palladium on calcium carbonate (754 mg; 0.71 mmol) in IPrOH (144 ml) and was treated with 7.5 mL of ammonium formate solution and with cyclohexyl 2-chloro-6-(cyclohexyloxy)pyrimidine-4-carboxylate (4.80 g; 14.2 mmol). After 10 min, a second aliquot of 7.5 mL of ammonium formate solution was added and the mixture was stirred at room temperature for 24 h. The mixture was filtered through a pad of celite and rinsed with MeOH. Solvents were concentrated under vacuum. The crude was dissolved in DCM and washed with water and brine. Organic phase was dried over MgSO4, filtered off and concentrated under vacuum to afford the title compound as an orange solid without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([NH:19]C(CC[Si](C)(C)C)=O)[CH2:16][N:15]2[C:28](=[O:45])[C@@H:29]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=C)=[O:13])[CH2:8][C@H:7]1[CH:9]=C)=[O:5])[CH3:2]>C(Cl)Cl.CC(OC1C(C=[Ru](Cl)Cl)=CC=CC=1)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[CH2:1]([O:3][C:4]([C@@:6]12[CH2:8][C@H:7]1[CH:9]=[CH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]([NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C:28](=[O:45])[N:15]1[C@@H:14]([CH2:18][C@@H:17]([NH2:19])[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](NC(=O)CC[Si](C)(C)C)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Agent: CC(C)Oc1ccccc1C=[Ru](Cl)Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](N)C[C@H]1C(=O)N2
Temperature: 40 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
D A solution of 1-{[1-(2(S)-tert-butoxycarbonylamino-non-8-enoyl)-4(R)-(2-trimethylsilylethyl carbonylamino)-pyrrolidine-2(S)-carbonyl]-amino}-2(S)-vinyl-cyclopropane-1-(R)-carboxylic acid ethyl ester (1.27 g, 1.91 mmol) in methylene chloride (195 ml) was degassed for 1 h by bubbling N2 throughout the solution. Dichloro(o-isopropoxyphenyl-methyene)(tricyclohexylphosphine)ruthenium (II) (0.057 g, 0.096 mmol) was added and the reaction stirred at 40° C. for 16 h. The reaction was concentrated, placed onto silica gel and eluted with 50% ethyl acetate/hexanes. The resulting oil was treated with TBAF (1.0 M in THF, 2.87 ml) and heated to 50° C. for 4 h. The reaction was placed onto silica gel and eluted with 20% methanol/methyene chloride to give a tan solid (0.65 g, 69%). 1H NMR (CDCl3, 400 MHz): δ 1.06-1.66 (m, 17H), 1.85-1.95 (m, 2H), 2.0-2.1 (m, 1H), 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 2.65-2.75 (M, 1H), 3.40 (m, 1H), 3.73-3.83 (m, 2H), 4.08-4.19 (m, 2H), 4.56 (m, 1H), 4.78 (d, J=5.5 Hz, 1H), 5.20 (t, J=8.1 Hz, 1H), 5.34 (d, J=8.1 Hz, 1H), 5.47 (dt, J=4.5, 10.8 Hz, 1H), 7.08 (s, 1H). 493(H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])[C:5]([OH:7])=O.Cl.[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:19][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:12])[C:10]([OH:11])=[C:2]([Cl:1])[C:3]=1[OH:13]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc(Cl)c(O)c(Cl)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc(Cl)c(O)c(Cl)c1O
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of 3,5-dichloro-2,4-dihydroxybenzoic acid (17 g), L-phenylalanine methyl ester hydrochloride (19.8 g), WSC.HCl (17.6 g) and HOBT (12.4 g) in DMF (70 ml) was added dropwise triethylamine (12.8 ml) at room temperature, and the mixture was stirred for 16 hours. Then, the mixture was post-treated in the same manner as in the above Example 1, Step 5) to give the title compound (18.32 g, yield 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1ccnc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)c1

Procedure:
The title compound, MS: m/e=308.2 (M+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-fluoro-4-methylpyridine.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.NC(N)=O>C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O>[C:14]1([NH:20][C:21]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: NC(N)=O
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 82 %

Procedure:
0,5 mole of diphenylamine was taken together with 0.53 mole of phenyl isocyanate and 0.6 g of di-n-butl phosphate in 150 ml of toluene. The mixture was heated at 100° C. for 24 hours, with stirring, and then cooled to room temperature. At about 30° C., the urea started to crystallize out. After filtering off, washing with 150 ml of cold toluene and drying, 0.41 mole of N-phenyl-N',N'-diphenylurea was obtained. Melting point: 131° C./yield: 82% of theory.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:17]3[C:13]([C:14]([CH3:21])([CH3:20])[CH:15]([OH:19])[N+:16]=3[O-])=[CH:12][C:11](=[O:22])[C:10]=2[CH:23]=1)[CH2:2][CH2:3][CH3:4].Cl.C1(=O)C=CC(=[O:31])C=C1>CCO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:17]3[C:13]([C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[N:16]=3)=[C:12]([OH:31])[C:11](=[O:22])[C:10]=2[CH:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCCCOc1ccc2c(c1)C(=O)C=C1C2=[N+]([O-])C(O)C1(C)C
Agent: Cl
Solvent: CCO
Product: CCCCOc1ccc2c(c1)C(=O)C(O)=C1C2=NC(=O)C1(C)C

Procedure:
A solution of 7-Butoxy-2-hydroxy-3,3-dimethyl-2,3-dihydro-5H-benzo[g]indol-5-one 1-oxide (compound 6 prepared in step (ii) above)(13 mg, 0.036 mmol) in EtOH (2 mL) with conc. HCl in EtOH (0.5 mL) was heated at 60° for 1 h. The yellow solution turned red. When no starting material remained, benzoquinone (39 mg, 0.36 mmol) was added and the mixture was heated 1 h. The solvent was evaporated and the crude product was purified on RP-HPLC. Yield. 12 mg. (24%). 1H NMR (400 MHz, CDCl3) δ 1.00 (tr., 3H), 1.51 (m, 2 H), 1.55 (s, 6 H), 1.82 (m, 2 H), 4.10 (tr., 2H), 7.20 (dd, 1 H), 7.46 (d, 1 H), 7.70 (d, 1 H), 9.62 (br.s, 1 H). MS (EI) m/z 313 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]([OH:9])[CH3:8])[O:4][N:3]=1.C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]>O.CCOC(C)=O>[F:32][C:30]1[CH:29]=[CH:28][C:27]([N+:33]([O-:35])=[O:34])=[C:26]([CH:31]=1)[O:9][CH:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[CH3:8]
Reactant: Cc1cc(C(C)O)on1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(C)Oc2cc(F)ccc2[N+](=O)[O-])on1

Procedure:
To a solution of 4.15 g (32.64 mmol) 1-(3-Methylisoxazol-5-yl)ethanol in THF 32.64 mL (1 M in THF; 32.64 mmol) LiHMDS is added drop wise. After 30 minutes of stirring 5.19 g (32.64 mmol) 2,4-difluoro-1-nitro-benzene is added. The mixture is stirred over night. The mixture is diluted with water and EtOAc. The organic layer is separated, washed with water, dried and evaporated. The residue is purified by FC giving rise to 5-[1-(5-fluoro-2-nitro-phenoxy)ethyl]-3-methyl-isoxazole.
Reaction SMILES: [C:1]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][N:22]=C(OCC)C)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.Cl>C(O)C>[NH2:22][O:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1
Reactant: CCOC(C)=NOCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: Cl
Solvent: CCO
Product: NOCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Yield: 61.1 %

Procedure:
To a solution of ethyl N-[(4-biotinamidobutyl)oxy]acetimidate (4) (0.4 g, 1.0 mmol) in 25 mL of absolute ethanol in a 50 mL round bottom flask fitted with a reflux condenser was added 0.2 mL of concentrated aqueous hydrochloric acid and the solution was stirred and refluxed for 1 hour. The solvents were removed on a rotary evaporator and the residue was azeotroped with four successive 20 mL volumes of absolute ethanol. Deionized water (20 mL) was added to the crude product and the solution was filtered and the solid discarded. A solution of 0.1N aqueous sodium carbonate was added to the filtrate to bring the pH to 8.0 and the solution was reduced to dryness on a rotary evaporator. The white solid, which contained some sodium carbonate, was treated with 5 mL of absolute ethanol, which dissolved the organic material and filtered to remove sodium carbonate. This procedure was repeated twice more to yield 202 mg (60%) of N-(4-aminooxybutyl)-biotinamide (V). Single spot on TLC (85:15 chloroform:methanol) Rf =0.14. m.p. 168° C.-170° C. 1H NMR (DMSO-d6): δ7.8 (m, 1H), 6.4 (s, 1H), 6.3 (s, 1H), 5.7 (s, 2H), 4.3 (m, 1H), 4.1 (m, 1H), 3.4(t, 2H), 2.9-3.2 (m, 4H), 2.7 (dd, 2H), 2.5 (d, 2H), 2.0 (t, 2H), 1.2-1.7 (m, 8H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12](O)=[O:13])[C:3]1=[O:15].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([Cl:19])=[O:13])[C:3]1=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(=O)c(C(=O)O)cc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C(=O)Cl)cc2cccnc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.0 g (4.9 mmol) of 1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 1.0 mL (12 mmol) of oxalyl chloride was added thereto. Three droplets of N,N-dimethylformamide were added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in acetonitrile (30 mL), and this solution was added to an acetonitrile (50 mL) solution of 0.60 g (5.4 mmol) of 1,3-cyclohexanedione and 0.82 mL (5.9 mmol) of triethylamine under ice cooling. The resulting mixture was stirred for one hour at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, an aqueous solution of sodium hydrogen carbonate, and water in this order, and then was dried and concentrated. The residue was washed with diisopropyl ether, and thus 0.83 g of the title compound was obtained as a light yellow solid (yield: 57%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].[OH-].[Na+]>C(O)C>[N+:8]([CH:11]=[CH:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccsc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccsc1
Temperature: 0 °C
Reaction time: 1.3 h
Yield: 72.2 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, step 1, thiophene-3-carbaldehyde (3 g, 26.78 mmol) in ethanol (50 mL) was reacted with nitro methane (1.45 mL, 26.78 mmol) and 10N NaOH (3.5 mL, 28.11 mmol). The resulting mixture was stirred at 0° C. for 1.30 hours to afford 3 g of the product (72.28% yield).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:1]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCCCCCc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of benzaldehyde (10 mL) in toluene (200 mL) were added, under ice-cooling, 4-octylaniline (22.5 mL) and molecular sieves 4A (20 g), and the mixture was stirred overnight at room temperature. The molecular sieves 4A was filtered off from the reaction mixture and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (200 mL) and sodium borohydride (2.3 g) was added under ice-cooling. The mixture was stirred at room temperature for 5 hr. Methanol was evaporated and water was added to the residue. The mixture was extracted with chloroform and the organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give benzyl(4-octylphenyl)amine (29 g).
Reaction SMILES: [OH:1][C:2]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>CCCCCC>[CH3:10][C:2]([O:1][Si:22]([CH3:25])([CH3:24])[CH3:23])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(C)(O)CCCC
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(C)(CCCC)O[Si](C)(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of 75.4 g (0.537 moles) of 4-hydroxy-4-methyl-1-octyne (Example 122), 104.9 g (1.54 moles) of imidazole, and 325 ml of dimethylformamide is added 65.2 g (0.60 moles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 800 ml of hexane. The mixture is washed thoroughly with water followed by sodium bicarbonate solution and brine. The solution is dried over magnesium sulfate, filtered, and evaporated to give a liquid, p.m.r. spectrum, δ 1.26 (singlet, 3, CH3), 1.92 (triplet, 1, HC), 2.30 (doublet, 2, CH2).
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.ClC1[N:72]=[CH:71][N:70]=[C:69]([NH:73][CH2:74][CH3:75])[CH:68]=1>>[Cl:37][C:35]1[CH:34]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]3[CH:68]=[C:69]([NH:73][CH2:74][CH3:75])[N:70]=[CH:71][N:72]=3)[CH2:44]2)=[O:41])[CH:32]=[C:31]([Cl:30])[CH:36]=1
Reactant: CCNc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: CCNc1cc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)ncn1

Procedure:
The title compound of Example 143 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 6-chloro-N-ethylpyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 8.08 (s, 1H), 6.63 (t, J=1.70 Hz, 1H), 6.48 (d, J=1.89 Hz, 2H), 5.70 (s, 1H), 3.89-4.03 (m, 2H), 3.74 (s, 2H), 3.55 (d, J=7.55 Hz, 2H), 1.91-2.03 (m, 1H), 1.76-1.87 (m, 2H), 1.65 (dt, J=4.20, 8.59 Hz, 1H), 1.26 (t, J=7.18 Hz, 3H). EIMS (m/z): calcd. for C19H24Cl2N6O (M+1H) 423. found 423.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][P:9](=[O:14])([CH2:12][CH3:13])[CH2:10][CH3:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][P:9](=[O:14])([CH2:10][CH3:11])[CH2:12][CH3:13])=[CH:6][CH:5]=1
Reactant: CCP(=O)(CC)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCP(=O)(CC)Cc1ccc(N)cc1
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A mixture of 4-nitrobenzyldiethylphosphine oxide (0.4 g) and 10% Pd-C (0.06 g) in ethanol (10 ml) was vigorously stirred under hydrogen atmosphere for 16 hours, and the Pd-C was filtered off. The filtrate was concentrated under reduced pressure to give 4-aminobenzyldiethylphosphine oxide (349 mg) as brown oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCN(CC)CC>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.[Cu]I.CCOC(C)=O>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=2)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH:8]=[CH:7][CH:6]=1)=[O:18]
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(NC(=O)c2ccccc2C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
In a 4 mL vial, N-(3-ethynylphenyl)-2-methylbenzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) were added and dissolved into EtOAc (2 mL) The mixture was then degassed for ˜20 min after which NEt3 (0.141 mL, 1.035 mmol) was added followed by Pd(PPh3)2Cl2 (21.0 mg, 0.030 mmol) and CuI (2.9 mg, 0.016 mmol). The reaction mixture was allowed to stir at 50° C. for 4 hours after which the reaction mixture was partitioned between EtOAc (4 mL) and water (4 mL). The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated. The residue as purified by chromatography (silica gel, gradient elution 25% EtOAc/Hexanes EtOAc). The product containing fractions were concentrated to give the title compound as a solid (121 mg, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:37])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:36]=[CH:35][C:25]([CH2:26][NH:27]C(=O)OC(C)(C)C)=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[S:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=2[OH:37])(=[O:11])=[O:10])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of tert-butyl 4-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)benzylcarbamate (569 mg, 1.00 mmol) in methylene chloride (9 mL) was added TFA (3 mL). The reaction mixture was stirred at rt for 2 h, and then concentrated. The residue was dissolved in with methylene chloride (100 mL) and washed with saturated aq sodium bicarbonate solution, brine, dried over MgSO4, and concentrated to give the title compound (446 mg, 95%) as a tan solid. MS (ESI): m/z 468.9 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:36])=[C:27]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=[O:32])[CH:28]=2)[NH:23][C:22](=[O:37])[C:21]=1[C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)=O)C1C=CC=CC=1.Br>C(O)(=O)C>[Cl:36][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([O:19][CH2:18][CH2:17][CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][NH:11]3)=[C:21]([C:38]3[CH:39]=[C:40]([CH3:45])[CH:41]=[C:42]([CH3:44])[CH:43]=3)[C:22](=[O:37])[NH:23]2)=[CH:28][C:27]=1[NH:30][C:31]([NH:33][CH2:34][CH3:35])=[O:32]
Reactant: CCNC(=O)Nc1cc2c(OCCC3CCCCN3C(=O)OCc3ccccc3)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl
Agent: Br
Solvent: CC(=O)O
Product: CCNC(=O)Nc1cc2c(OCCC3CCCCN3)c(-c3cc(C)cc(C)c3)c(=O)[nH]c2cc1Cl

Procedure:
A solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-ethylureido)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid benzyl ester (50 mg in 5 mL of a 30% solution of hydrobromic acid in acetic acid) was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was treated with saturated sodium bicarbonate and then extracted with methylene chloride. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:3:1) gave the title compound (18 mg). MASS: 497 (M+H)