Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: Ic1ccccc1
Product: COc1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indol-6-yl methyl ether and iodobenzene: ESMS m/e: 224.0 (M+H)+.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:18])=[CH:9][CH:8]=1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Reactant: COC(=O)c1ccc(OCc2ccccn2)cc1
Product: O=C(c1ccc(OCc2ccccn2)cc1)N1CCC[C@@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 4-(Pyridin-2-ylmethoxy)-benzoic acid methyl ester and 1-[(2R)-2-pyrrolidinylmethyl]pyrrolidine [CAS 60419-23-0]. MS (ES+) 366.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[OH-].[Na+].[CH3:19]O>>[CH3:19][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[I:11]
Reactant: CO
Reactant: O=C(O)c1cc(F)ccc1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(F)ccc1I
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 5-fluoro-2-iodo-benzoic acid (10.05 g, 39.47 mmol) and conc. H2SO4 (10 mL) in MeOH (100 ml) was reflux for 6 hours. After cooling to room temperature, NaOH (2N) was added dropwise to adjust the pH˜8. After most of organic solvent was removed under reduced pressure, the mixture was extracted with dichloromethane three times. The combined organic layers were washed with water, dried and concentrated to give the titled compound (10.80 g, yield 98%)
Reaction SMILES: C([O:5][C@H:6]([CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=O)CC.[OH-].[Na+].O>C(O)C>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:6]([OH:5])[CH3:17])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: CCC(=O)O[C@H](C)Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@@H](O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of (1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate (step 1 of Example 248, 1.91 g, 8.05 mmol) in ethanol (20 ml) was added 2N aqueous NaOH (5 ml) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, extracted with diethyl ether (2×50 ml). The organic layer was washed with brine, dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/diethyl ether (1:1) afforded 1.16 g (80%) of title compound as a colorless solid (79% e.e.). Recrystallization from hexane/diethyl ether afforded 717 mg of a colorless needle (99% e.e.).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[CH:22]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:22][C:21]3[CH:24]=[C:25]([CH3:28])[C:26]([OH:27])=[C:19]([CH3:18])[CH:20]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C=Nc2[nH]nc(Nc3cccc(Cl)c3)c2C(N)=O)cc(C)c1O

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was suspended in EtOH and 3,5-dimethyl-4-hydroxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2cc(N)ccc21

Procedure:
Palladium on carbon (10%, 1.110 g) is added to a mixture of N-acetyl-5-nitro indoline (II, EXAMPLE 1, 5.00 g) in ethyl acetate (freshly opened bottle, about 500 ml). The mixture is stirred under 1 atm of hydrogen (ballon) for 39 hr then filtered and the palladium on carbon is washed with methanol/ethyl acetate (20/80). The filtrate is concentrated under reduced pressure to give the title compound, mp 183°-185°; NMR (CDCl3, 300 MHz) 8.01, 6.53, 6.50, 3.98, 3.56, 3.04 and 2.17 δ; CMR (CDCl3 ; 75.47 MHz) 23.86, 28.05, 48.71, 111.55, 113.73, 117.66, 132.8, 135.6, 149.1 and 168.1 δ; IR (CHCl3, 3000, 1640, 1600, 1490, 1410, 1330 and 1300 cm-1.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:32]=[CH:31][C:18]([CH2:19][N:20]4[CH2:23][CH:22]([C:24]([O:26]C(C)(C)C)=[O:25])[CH2:21]4)=[CH:17][CH:16]=3)[N:11]=2)[C:6]=1[CH2:33][CH2:34][CH3:35])[CH:2]([CH3:4])[CH3:3].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:19][N:20]4[CH2:21][CH:22]([C:24]([OH:26])=[O:25])[CH2:23]4)=[CH:31][CH:32]=3)[N:11]=2)[C:6]=1[CH2:33][CH2:34][CH3:35])[CH:2]([CH3:4])[CH3:3].[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: CCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1CC(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3)no2)noc1CC(C)C
Reaction time: 2.5 h

Procedure:
A solution of tert-butyl 1-(4-(5-(5-isobutyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (23 mg, 0.048 mmol) in TFA (0.5 mL) was allowed to stand at rt for 2.5 hr. The volatiles were removed in vacuo and the residue was triturated with Et2O and dried to afford 1-(4-(5-(5-isobutyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid, TFA (24 mg, 0.044 mmol, 92% yield) as a light yellow glassy solid. HPLC retention time=3.21 minutes (YMC Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=425.20. 1H NMR (400 MHz, MeOD) δ ppm 1.01 (m, 9H) 1.60-1.71 (m, 2H) 2.14 (m, 1H) 2.77 (m, 4H) 3.62-3.73 (m, 1H) 4.30-4.40 (m, 4H) 4.51 (s, 2H) 7.68 (d, J=7.8 Hz, 2H) 8.24 (d, J=7.8 Hz, 2H).
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)(C)C.O>[OH:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([C:5]2[C:6]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:1]([CH3:3])[CH3:2])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(S(=O)(=O)c3c(-c4ccccc4)noc3C(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)c1onc(-c2ccccc2)c1S(=O)(=O)c1ccc(O)cc1
Yield: 81.5 %

Procedure:
A mixture of 2.5 g (0.005 mol) of 5-isopropyl-3-phenyl-4-(4-tosyloxy-benzenesulphonyl)-isoxazole and 0.8 g (0.02 mol) of sodium hydroxide in 20 ml of isopropanol and 10 ml of water was heated under reflux for 2.5 hours. After reacting, the mixture was allowed to cool, diluted with 50 ml of water and acidified with concentrated hydrochloric acid. The product so obtained was suction-filtered and washed with water to obtain 1.4 g of the desired compound which was purified by elution chromatography on silica using chloroform as eluent.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:18]([C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[N:24][C:23]=3[CH3:37])[CH:19]([CH3:21])[CH3:20])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[OH-].[Na+]>>[CH3:20][CH:19]([CH3:21])[CH:18]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=2)=[N:24][C:23]=1[CH3:37])[O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:38])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1)C(C)C
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(Oc1ccc2ccn(CC(=O)O)c2c1)C(C)C

Procedure:
In analogy to the procedure described in example 2 c], [rac]-(6-{2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with NaOH to obtain [rac]-(6-{2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid as yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12].C([Li])CCC>C(OCC)C.C1COCC1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([CH:9]([OH:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:7][N:6]=1
Reactant: CC(C)CC=O
Reactant: Clc1ncc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(O)c1cnc(Cl)nc1
Temperature: -78 °C
Yield: 38.2 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (5.0 g, 25.8 mmol) in diethyl ether (129 mL) and THF (129 mL) was added isovaleraldehyde (4.45 g, 51.7 mmol). The reaction mixture was cooled to −78° C., and n-butyllithium (15.4 mL of a 1.6 M solution in hexanes, 24.6 mmol) was added. The mixture was stirred for 30 m at −78° C. The reaction mixture was quenched by addition of saturated aqueous NH4Cl, and extracted with ethyl acetate (300 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 1-(2-chloropyrimidin-5-yl)-3-methylbutan-1-ol (1.98 g) as yellow oil. 1HNMR (400 MHz, CDCl3) δ 8.54 (s, 2H), 4.76-4.80 (m, 1H), 1.75-1.66 (m, 2H), 1.45-1.37 (m, 1H), 0.89 (d, J=6.35 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1([F:40])[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:30][C:31]1([F:40])[CH2:36][CH2:35][CH:34]([C:37]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:38])[CH2:33][CH2:32]1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(O)C1CCC(F)(F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCC(F)(F)CC1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a stirred mixture of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.205 g, 0.74 mmol), DIEA (0.14 mL, 0.81 mmol), and 4,4-difluoro-cyclohexanecarboxylic acid (0.13 g, 0.81 mmol) in DMF (4 mL) was added HATU (0.31 g, 0.81 mmol). The reaction mixture was continued to stir for 2 h, quenched with H2O, and extracted with DCM (3×). The organic extracts were dried over Na2SO4, concentrated and purified by ISCO (20% EtOAc/hexanes) to give the white solid. MS (ESI, positive ion) m/z: 424 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH2:30]O)[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(O)[C:56]#[N:57].N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH2:30][C:56]#[N:57])[CH:21]=1)=[N:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(O)C#N
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CO)c(OC)c(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CC#N)c(OC)c(OC)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
After dissolving 194 mg of [2-(3-hydroxymethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (22b)), 315 mg of triphenylphosphine and 0.11 ml of acetone cyanohydrin in 4 ml of THF under a nitrogen atmosphere, the solution was cooled to −78° C. Next, 0.23 ml of diisopropyl azodicarboxylate (hereinafter, “DIAD”) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (197 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](O)=[O:22])[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4].[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[C:7](=[O:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:22])[NH:41][CH2:40][CH2:39][N:38]([CH3:42])[CH3:37])[CH:16]=1)=[CH:12][C:11]([Cl:24])=[CH:10][CH:9]=2)=[O:4]
Reactant: CN(C)CCN
Reactant: COC(=O)c1c(-c2cccc(C(=O)O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: O
Product: COC(=O)c1c(-c2cccc(C(=O)NCCN(C)C)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To a solution (2 ml) of 4-(3-carboxyphenyl)-6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and N,N-dimethylethylenediamine (23 μl) in acetonitrile were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg) and 4-hydroxybenzotriazole monohydrate (38 mg) at room temperature with stirring, and the mixture was stirred at room temperature for 12 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was dried and concentrated to dryness. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to give the title compound (56 mg) as colorless crystals.
Reaction SMILES: CC([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][C:18]2[CH:23]=[C:22]([CH:24]([F:26])[F:25])[CH:21]=[C:20]([C:27]#[N:28])[CH:19]=2)[C:11]=1[F:29])C(=O)[O-])(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[NH2:5][CH2:9][C:10]1[C:11]([F:29])=[C:12]([O:17][C:18]2[CH:19]=[C:20]([CH:21]=[C:22]([CH:24]([F:26])[F:25])[CH:23]=2)[C:27]#[N:28])[C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: CC(C)(C)N(Cc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)F)c2)c1F)C(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 1,1-dimethylethyl[(4-chloro-3-{[3-cyano-5-(difluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]carbamate (210 mg, 0.492 mmol) in DCM (10 ml) was added TFA (3.0 mL, 38.9 mmol) and the reaction mixture was stirred at RT for 30 minutes. The solvent was removed and the crude material 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(difluoromethyl)benzonitrile trifluoroacetate (183 mg, 0.415 mmol, 84% yield) was used directly in the next step without purification. 1H NMR
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].B(O)(O)[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[N:8]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc1

Procedure:
The title compound was prepared as described in the final step of Example 1 from 1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea (0.022 g, 0.050 mmol), and p-tolylboronic acid (0.014 g, 0.1 mmol), using copper (II) acetate (0.014 g, 0.075 mmol), pyridine (0.01 mL, 0.1 mmol), molecular sieves (4 Å activated, 0.030 g) and methylene chloride (2 mL). The title compound was obtained as a yellow-white solid (0.013 g, 50%), mp 144-146° C.; 1H NMR (DMSO) δ 1.26(s, 9H), 2.36(s, 3H), 2.53(t, 4H) 2.82(t, 2H), 3.52(t, 4H), 4.23(t, 2H), 6.32(s, 1H), 6.94(d, 1H), 7.33(d, 1H), 7.42(d, 1H), 7.54(m, 3H), 7.90(d, 1H), 8.15(d, 1H), 8.18(d, 1H), 8.82(s, 1H), 8.96(s, 1H); MS (CI) 528(M++H).
Reaction SMILES: C([O:3][CH:4](OCC)/[CH:5]=[CH:6]/[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:8]=1[F:16])C.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(=O)(O)O>>[Br:20][C:10]1[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:7](/[CH:6]=[CH:5]/[CH:4]=[O:3])=[C:8]([F:16])[CH:9]=1
Reactant: CCOC(/C=C/c1c(F)cccc1[N+](=O)[O-])OCC
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Product: O=C/C=C/c1c(F)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A mixture of (E)-2-(3,3-diethoxyprop-1-enyl)-1-fluoro-3-nitrobenzene (63.5 mg, 0.22 mmol), 1,3-dibromo-5,5-dimethylhydantoin (63.5 mg, 0.222 mmol, Aldrich) and sulfuric acid, 95% (0.5 mL, 7.14 mmol) was stirred at room temperature for 4 h. Ice (5 g) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with saturated NaCl (6 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude product was purified by silica gel chromatography eluting with 20% EtOAc/hexanes to give (E)-3-(4-bromo-2-fluoro-6-nitrophenyl)acrylaldehyde (46 mg, 0.168 mmol, 39.3% yield). 1H NMR (300 MHz, CDCl3) δ 7.47-7.58 (m, 1H) 7.58-7.71 (m, 1H) 8.10 (d, J=8.33 Hz, 1H) 8.15 (s, 1H) 9.50 (s, 1H). m/z (ESI, +ve ion) 273 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:19]([CH2:28][CH3:29])=[N:18][C:12]=3[C:13]([NH2:17])=[N:14][C:15]=2[CH:16]=1.C(N(CC)CC)C.[CH:37]([N:40]=[C:41]=[O:42])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:17][C:13]1[C:12]2[N:18]=[C:19]([CH2:28][CH3:29])[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][NH:3][C:41]([NH:40][CH:37]([CH3:39])[CH3:38])=[O:42])=[CH:16][C:15]=2[N:14]=1
Reactant: CC(C)N=C=O
Reactant: CCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(OCCNC(=O)NC(C)C)ccc3c2n1CC1CCOCC1
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (0.480 g, 1.03 mmol; prepared as in Example 552), dichloromethane (10 mL), and triethylamine (0.702 mL, 5.03 mmol) were combined and stirred for 10 minutes. Isopropyl isocyanate (0.101 mL, 1.03 mmol) was added dropwise and the reaction was stirred for 16 hours. Saturated aqueous sodium carbonate (˜5 mL) was added and the reaction was stirred for 10 minutes. The layers were separated. The organic fraction was washed with water and then concentrated under reduced pressure. The resulting crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution of 2-20% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.390 g of N-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N′-isopropylurea as a white solid, mp 223-225° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH:14]([F:16])[F:15])=[C:9]([F:12])[CH:10]=2)[N:5]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:4]=1[C:21]1[N:26]=[CH:25][C:24]([S:27]([NH:30][C@@H:31]([CH3:36])[C:32]([F:35])([F:34])[F:33])(=[O:29])=[O:28])=[CH:23][CH:22]=1)#[N:2].[Br:37]Br.OS([O-])=O.[Na+]>[Fe].ClCCCl>[Br:37][C:10]1[C:9]([F:12])=[C:8]([O:13][CH:14]([F:15])[F:16])[CH:7]=[C:6]2[C:11]=1[C:3]([C:1]#[N:2])=[C:4]([C:21]1[N:26]=[CH:25][C:24]([S:27]([NH:30][C@@H:31]([CH3:36])[C:32]([F:34])([F:35])[F:33])(=[O:28])=[O:29])=[CH:23][CH:22]=1)[N:5]2[CH:17]1[CH2:18][CH2:19][CH2:20]1
Reactant: BrBr
Reactant: C[C@H](NS(=O)(=O)c1ccc(-c2c(C#N)c3cc(F)c(OC(F)F)cc3n2C2CCC2)nc1)C(F)(F)F
Agent: [Fe]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H](NS(=O)(=O)c1ccc(-c2c(C#N)c3c(Br)c(F)c(OC(F)F)cc3n2C2CCC2)nc1)C(F)(F)F
Temperature: 50 °C
Yield: 46.3 %

Procedure:
A mixture of (S)-6-(3-cyano-1-cyclobutyl-6-(difluoromethoxy)-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (500 mg, 0.94 mmol), Fe powder (700 mg, 13 mmol), Br2 (300 μL, 5.9 mmol), and 1,2-dichloroethane (3 mL) was heated at 50° C. for 3 hours. The reaction mixture was then poured into aq. NaHSO3 solution. This was extracted into CH2Cl2. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (ethyl acetate in hexanes, 20% to 30%) yielded (S)-6-(4-bromo-3-cyano-1-cyclobutyl-6 (difluoromethoxy)-5-fluoro-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (266 mg, 46%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(NC(=O)C(C)(C)C)cn3)cc2)CC1
Reaction time: 15 h

Procedure:
To a mixture of {4-[4-(5-amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (100 mg, 0.3 mmol) in methylene chloride (10 ml) was added triethylamine (43 ul, 0.3 mmol) and trimethylacetyl chloride (40 ul, 0.3 mmol). After 15 hours at room temperature, the reaction was diluted with hexanes to afford a precipitate which was collected by filtration: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (dd, J=12.69, 1.71 Hz, 2H) 1.26 (s, 10H) 1.42-1.56 (m, 1H) 1.50 (d, J=9.85 Hz, 1H) 1.82 (d, J=11.37 Hz, 5H) 2.26 (d, J=6.69 Hz, 2H) 3.61 (s, 3H) 7.32 (d, J=8.34 Hz, 2H) 7.87 (d, J=8.72 Hz, 1H) 7.95 (d, J=8.34 Hz, 2H) 8.15 (dd, J=8.72, 2.53 Hz, 1H) 8.88 (d, J=2.53 Hz, 1H) 9.53 (s, 1H); (M+H)+409.2.