Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:28])([C:7]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:29].O>C(OCC)(=O)C.CO.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:28])([C:7]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:29]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(NC(=O)c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CN1C(=O)CC[C@]2(C)c3ccc(NC(=O)c4cccc(N)c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 200 mg portion of the product of Example 268 was dissolved in ethyl acetate and methanol. Twenty ml of 20% aqueous titanium trichloride was added, the flask was evacuated and the mixture was stirred at ambient temperature for 16 h. The mixture was then made basic with ammonium hydroxide, resulting in an exotherm and the formation of a dark solid. Water was added to break up the solid, and the mixture was extracted with dichloromethane. The remaining reaction mixture was filtered, and the solid filter cake was washed with dichloromethane. The organic layers were collected, dried and concentrated under vacuum. The residue was recrystallized from dichloromethane/hexane to obtain 190 mg of the desired product. It was purified by chromatography over silica gel, eluting with ethyl acetate going to 10% methanol/ethyl acetate, and recrystallized again from dichloromethane/hexane to obtain 80.5 mg of purified product, m.p. 154°-156°. FDMS: m/e=363.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([NH2:20])=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([CH:22]=[CH2:23])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)ccc2N)CC1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(N)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 3-amino-6-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.49 g, prepared from 3-amino-2-bromo-pyridine following procedures described in Example 6, Step A to Step C), tributylvinyl tin (0.36 g), tetrakis(triphenylphosphine)palladium (0.035 g) in toluene (20 ml) was heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1) to afford 3-amino-6-vinyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.32 g) as a yellow solid. MS (ES+) 443/445 (MH+); 1H NMR (400 MHz, CDCl3) 1.40 (s, 9H), 1.70 (m, 2H), 1.90 (m, 2H), 2.75 (m, 2H), 2.80 (m, 1H), 4.15 (m, 2H), 5.4 (d, 1H), 6.2 (d, 1H), 6.7 (dd, 1H), 7.15 (d, 1H), 7.6 (d, 1H), 7.7 (s, 1H), 7.8 (m, 1H), 7.9 (s, 1H), 8.5 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:15]2[NH:14][S:13](=[O:17])(=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[CH3:1][C:2]1[C:15]2[N:14]([S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[S:13](=[O:17])(=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C)c2c1NS(=O)(=O)c1ccccc1-2
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N2c3c(C)ccc(C)c3-c3ccccc3S2(=O)=O)cc1
Temperature: 60 °C

Procedure:
1,4-Dimethyl-10H-9-thia-10-aza-phenanthrene 9,9-dioxide (2.6 g, 10 mmol) is dissolved in pyridine (10 mL) and treated with p-toluenesulfonyl chloride (2.8 g, 15 mmol). The reaction mixture stirred at 60° C. until TLC shows disappearance of the starting material. The reaction mixture is allowed to cool and then poured into 100 mL of 3N HCl. The mixture is extracted 2×100 mL EtOAc and the combined organic layers are washed with sat. brine, dried over MgSO4, filtered, and concentrated to a solid, which is recrystallized from hot EtOAc/hexanes to give 1,4-dimethyl-10-(toluene-4-sulfonyl)-10H-9-thia-10-aza-phenanthrene 9,9-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([OH:22])=O)=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH:29]1[CH2:34][CH2:33][CH:32]([N:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37][C:36]2=[O:44])[CH2:31][CH2:30]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH2:37][C:36]4=[O:44])[CH2:31][CH2:30]3)=[O:22])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccccc2N1C1CCNCC1
Reactant: O=C(O)c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12)N1CCC(N2C(=O)Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a suspension of 0.10 g (0.31 mmol) 6-chloro-1-(3,5-difluoro-benzyl)-1H-indole-3-carboxylic acid and one drop of DMF in 2 ml dichloromethane were added dropwise at 0° C. 0.032 ml (0.37 mmol) oxalyl chloride. The mixture was allowed to warm to room temperature, stirred for 1 h and subsequently added dropwise to a solution of 74 mg (0.34 mmol) 1-piperidin-4-yl-1,3-dihydro-indol-2-one and 63 mg (0.62 mmol) triethylamine in 1 ml dichloromethane at room temperature. After stirring over night the reaction mixture was concentrated and the residue was purified by flash chromatography to give 78 mg (48%) of the title compound as a light yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[N:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[N:34][CH:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M65) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (269 mg).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[CH3:13].[I-].[Na+].[C-:16]#[N:17].[Na+]>CN(C)C=O>[CH3:13][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH2:12][CH:3]1[CH2:2][C:16]#[N:17]
Reactant: CC1c2ccccc2CCC1CO
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1c2ccccc2CCC1CC#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 25.5 g of the p-toluenesulfonate ester of 2-hydroxymethyl-1-methyl-1,2,3,4-tetrahydronaphthalene, 2.25 g of sodium iodide and 7.5 g of sodium cyanide in 150 ml of dimethylformamide was stirred for about 20 hours at room temperature. The reaction mixture was poured into ice and extracted with ether. The extracts were dried over anhydrous magnesium sulfate and concentrated to a brown oil (15.2 g). The latter was treated with pentane to afford 12.5 g of 1,2,3,4-tetrahydro-1-methyl-2-naphthaleneacetonitrile as a colorless solid which melted at room temperature.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([CH:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:8][CH:7]=1)C.[OH-].[Na+].O>CO>[CH:16]1([C:14](=[O:15])[CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([C:5](=[O:24])[C:4]([OH:25])=[O:3])=[CH:7][CH:8]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)C2CCCCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCC(=O)C2CCCCCCC2)cc1
Yield: 60.9 %

Procedure:
As in example 19, a stirred solution of 4-(2-cyclooctyl-2-oxoethoxy)-alpha-oxobenzeneacetic acid ethyl ester (0.318 g) in warm methanol (5 mL) was treated with 1N sodium hydroxide (2 mL). Within 5 minutes water (20 mL) was added, then after the methanol was removed in vacuo, the mixture was acidified with 1N hydrochloric acid (2.5 mL) and extracted with dichloromethane (1×40 mL, 1×10 mL). The dried (MgSO4) extracts were evaporated and the resulting solid (0.255 g) was crystallized from diethyl ether-hexane to give 0.178 g of 4-[2-(cyclooctyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 109°-110° C.
Reaction SMILES: NCCN[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[NH2:22][C@@H:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)[C@H](N)CO
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: CC(C)[C@@H](CO)NC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using (2S)-2-amino-3-methylbutan-1-ol instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 345 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (1H, br. s.) 10.02 (1H, s) 7.99 (1H, d, J=5.47 Hz) 7.79 (1H, d, J=5.27 Hz) 7.57 (1H, d, J=8.98 Hz) 7.41 (1H, d, J=5.47 Hz) 7.29 (1H, dd, J=3.32, 2.34 Hz) 6.69 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.51, 1.56 Hz) 4.58 (1H, t, J=5.56 Hz) 3.80 (1H, dd, J=8.88, 6.74 Hz) 3.46 (2H, t, J=5.95 Hz) 1.85 (1H, dq, J=13.64, 6.78 Hz) 0.85 (3H, d, J=6.64 Hz) 0.78 (3H, d, J=6.83 Hz)
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[C:7]([CH:9](Br)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=O)[CH:6]=[CH:5][N:4]=1.[C:20]([NH2:24])(=[S:23])[CH2:21][CH3:22]>CN(C)C=O>[CH2:21]([C:20]1[S:23][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH2:2])[CH:8]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:24]=1)[CH3:22]
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(N)c2)c1
Reactant: CCC(N)=S
Agent: Br
Solvent: CN(C)C=O
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Yield: 81.9 %

Procedure:
A solution of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromide (125 g, 0.323 mol) and thiopropionamide (28 g, 0.314 mol) in N,N-dimethylformamide (1200 mL) was stirred at room temperature for 14 hrs. The solvent was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate solution was poured into the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried and concentrated. Crude crystals were washed with hexane-ethyl acetate=1:1 to give the title compound (76.0 g, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 8.8 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (574.6 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.64 ml) and 1-methyl-2-chloropyridinium iodide (907.5 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (113 mg).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[Br:53][C:54]1[CH:55]=[C:56]([CH2:61][NH2:62])[CH:57]=[CH:58][C:59]=1[F:60]>C(Cl)(Cl)Cl>[Br:53][C:54]1[CH:55]=[C:56]([CH2:61][NH:62][C:18]([C:17]2[CH:16]=[C:15]([CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:57]=[CH:58][C:59]=1[F:60]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
Reactant: NCc1ccc(F)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(Br)c3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To solution of the commercially available 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (200 mg, 0.63 mmol) in CHCl3 (5 mL) was added HOBt (90 mg, 0.67 mmol), EDCI (180 mg, 0.94 mmol), and triethylamine (0.2 ml, 1.4 mmol), followed by [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (151 mg, 0.62 mmol). The resulting mixture was allowed to stir at room temperature for 2 hours then quenched with saturated aq. NaHCO3 (1 mL) was added. The organic layer was separated, dried over Na2SO4 and evaporated to give a residue which was purified by Combiflash® chromatography eluting with hexane/ethyl acetate (95/5 to 70/30 over 15 min.) to give the title compound as white solid (265 mg, 80%). LC/MS: m/z, 505 (M+H), 2.81 min.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].C(O)(=O)C>CO>[CH2:15]([NH:19][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CN
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CNCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Under a nitrogen atmosphere add sodium cyanoborohydride (5.77 g, 91.6 mmol) to 4-cyanobenzaldehyde (3 g, 22.9 mmol), iso-butylamine (3.34 g, 45.8 mmol) and acetic acid (1.37 g, 22.9 mmol) in methanol (30 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Add water (40 mL), saturated aqueous K2CO3 (30 mL) and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel (500 g) eluting with 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the desired intermediate (3.63 g, 84%). MS (APCI+) m/z: 189 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].[CH3:19][NH:20][CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[CH3:19][N:20]([CH3:21])[C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:14]=[CH:15][C:3]([NH:2][CH3:1])=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=1)=[O:13]
Reactant: CNC
Reactant: CNc1ccc(C(=O)NCC(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)NCC(=O)N(C)C)cc1[N+](=O)[O-]

Procedure:
N-Dimethylcarbamoylmethyl-4-methylamino-3-nitro-benzamide (800 mg) was prepared by following General Procedure F starting from (4-methylamino-3-nitro-benzoylamino)-acetic acid (800 mg), 2 M dimethylamine in THF (3 mL), HBTU (1.5 g), and DIEA (1.3 mL) in DMF (2 mL).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)(=[O:19])=[O:18])[C:13]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:12]([O:36][CH3:37])[N:11]=2)[CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[CH2:45]([N:47]=[C:48]=[O:49])[CH3:46].Cl>C1(C)C=CC=CC=1.C(Cl)Cl.CO>[CH2:45]([NH:47][C:48](=[O:49])[NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=3)(=[O:19])=[O:18])[C:13]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:12]([O:36][CH3:37])[N:11]=2)[CH:7]=[CH:6][N:5]=1)[CH3:46]
Reactant: CCN=C=O
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CN)c2)nc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCNC(=O)NCc1cc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1

Procedure:
A solution of 70 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-aminomethyl-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide hydrochloride, product of example 30 b), in toluene (5 ml), was treated at RT with 26 mg of triethyamine then with 10 mg of ethylisocyanate and refluxed for 1 h until the reaction was complete according to TLC analysis (CH2Cl2/MeOH: 95/5). The mixture was poured into cold diluted HCl and the product extracted into CH2Cl2. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The solid residue was crystallised from CH2Cl2/Et2O to afford 5-methyl-pyridine-2-sulfonic acid [2-{2-[(3-ethyl-ureido)-methyl]-pyridin-4-yl}-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as off-white crystals. ISP mass spectrum, m/e 580.1 (M+1 calculated for C27H29N7O6S: 580).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([C:23]#[C:24][CH2:25][OH:26])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1>CO.[Pd]>[F:1][C:2]1[CH:22]=[C:21]([CH2:23][CH2:24][CH2:25][OH:26])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:15][CH2:16][CH2:17][OH:18])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)NCCO)c(Nc2ccc(C#CCO)cc2F)cc1=O
Agent: [Pd]
Solvent: CO
Product: Cn1cc(C(=O)NCCO)c(Nc2ccc(CCCO)cc2F)cc1=O
Yield: 92 %

Procedure:
4-[2-Fluoro-4-(3-hydroxy-1-propynyl)anilino]-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was hydrogenated in MeOH in the presence of 5% Pd/C as for example 3. Purification of the crude oil was carried out by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxypropyl)anilino]-N-(2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (92%), m.p. (CH2Cl2/MeOH) 177-179° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.88 (s, 1H), 8.40 (br t, J=5.2 Hz, 1H), 8.26 (s, 1H), 7.33 (t, J=8.4 Hz, 1H), 7.17 (dd, J=11.8, 1.4 Hz, 1H), 7.06 (dd, J=8.2, 1.2 Hz, 1H), 5.42 (d, J=0.8 Hz, 1H), 4.78 (t, J=5.5 Hz, 1H), 4.49 (t, J=5.1 Hz, 1H), 3.50 (q, J=5.8 Hz, 2H), 3.41 (q, J=6.0 Hz, 2H), 3.35 (s, 3H), 3.31-3.25 (m, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.72 (pentet, J=6.5 Hz, 2H). Anal. Calcd for C18H22FN3O4: C, 59.5; H, 6.1; N, 11.6. Found: C, 59.3; H, 6.3; N, 11.5.
Reaction SMILES: C(Cl)CCl.C1C=C[C:8]2N(O)N=[N:11][C:9]=2C=1.[O:15]=[C:16]1[N:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:20]2[S:28][C:29]([C:37](O)=[O:38])=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:19]=2[CH:18]=[CH:17]1.Cl.C(N)C.CN1CCOCC1>C(Cl)Cl.O>[CH2:9]([NH:11][C:37]([C:29]1[S:28][C:20]2[N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16](=[O:15])[CH:17]=[CH:18][C:19]=2[C:30]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:38])[CH3:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Agent: CCN
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
EDC (66 mg, 0.35 mmol) and HOBT (43 mg, 0.32 mmol) were added to the compound of Example 59 (100 mg, 0.29 mmol) in DCM (2 mL). After 15 min ethylamine hydrochloride (26 mg, 0.32 mmol) and NMM (0.070 mL, 0.63 mmol) were added and the reaction mixture was stirred at r.t. overnight. Water (2 mL) and DCM (2 mL) were added, the suspension filtered through a hydrophobic frit and the organic phase concentrated in vacuo. The crude product was purified by column chromatography on silica (1% MeOH in DCM) to give the title compound as a white solid (95 mg, 88%). δH (DMSO-d6) 7.69–7.61 (3H, m), 7.59–7.49 (3H, m), 7.45 (1H, d, J 9.6 Hz), 7.44–7.42 (4H, m), 7.05 (1H, t, J 5.4 Hz), 6.54 (1H, d, J 9.6 Hz), 3.03 (2H, q, J 7.1 Hz), 0.84 (3H, t, J 7.1 Hz). LCMS (ES+) RT 3.33 minutes, 375.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1>CO.[Pd]>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2F)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.6 %

Procedure:
A suspension of 1-(2,4-difluorophenoxy)-4-nitrobenzene (209 g, 1.17 mol) and 10% palladium-on-carbon (20 g, 50% wet) in methanol (1.0 L) was shaken under an atmosphere of hydrogen (60 psi) at room temperature for 5 h. The mixture was filtered through a plug of Celite® (150 g), washing with methanol (2×300 mL) and the solvent was removed under reduced pressure to afford the crude product as a dark red oil. This residue was triturated with hexanes (500 mL) and filtered to provide the title compound as a gray solid (175 g, 95%).1H NMR(300 MHz, DMSO-d6): 6.55(2H,d,J=8.8), 6.73(2H,d,J=8.8), 7.02-6.95(2H,m), 7.40(1H,t,J=11.4).
Reaction SMILES: C([O:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([C:19]2[CH:28]=[C:27]3[C:22]([C:23]([CH3:32])([CH3:31])[CH2:24][C:25]([CH3:30])([CH3:29])[O:26]3)=[CH:21][CH:20]=2)=[O:18])=[CH:12][CH:11]=1)C1C=CC=CC=1>C(OC(=O)C)C.[Pd]>[CH3:29][C:25]1([CH3:30])[CH2:24][C:23]([CH3:31])([CH3:32])[C:22]2[C:27](=[CH:28][C:19]([C:17]([O:16][C:13]3[CH:12]=[CH:11][C:10]([C:9]([OH:33])=[O:8])=[CH:15][CH:14]=3)=[O:18])=[CH:20][CH:21]=2)[O:26]1
Reactant: CC1(C)CC(C)(C)c2ccc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)cc2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CC(C)(C)c2ccc(C(=O)Oc3ccc(C(=O)O)cc3)cc2O1
Reaction time: 3 h

Procedure:
To a degassed solution of 400 mg (0.9 mmol) of Benzyl 4-(2,2,4,4-tetramethyl-7-chromanoyloxy) benzoate (Compound 2) in 15 ml of Ethylacetate, under argon was added 130 mg of 10% Palladium on carbon. The mixture was placed under a hydrogen atmosphere at 5 PSI and hydrogenated for 3 hours. The mixture was then filtered through celite and the filtrate was concentrated in-vacuo to give the title compound as a white solid.