Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4](C2C=CC(F)=CC=2C)[CH:3]=1.[Cl:34][C:35]1[C:36](I)=[CH:37][C:38]([F:41])=[N:39][CH:40]=1>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=2)=[C:4]([C:36]2[C:35]([Cl:34])=[CH:40][N:39]=[C:38]([F:41])[CH:37]=2)[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Fc1cc(I)c(Cl)cn1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1cc(F)ncc1Cl

Procedure:
The title compound was prepared in analogy to example 73, from N-(6-chloro-4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 72, intermediate) and 5-chloro-2-fluoro-4-iodopyridine (CAS RN 659731-48-3) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic separation. Colorless oil (89%). MS (ESI): m/z=511.009 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH3:29])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([O:27][NH2:28])(=[O:26])=[O:25].O.CCOCC>ClCCl>[CH3:23][C:18]1[CH:19]=[C:20]([CH3:22])[CH:21]=[C:16]([CH3:29])[C:17]=1[S:24]([O-:27])(=[O:26])=[O:25].[NH2:28][N+:11]1[CH:12]=[C:13]([Cl:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Clc1cncc(OCc2ccccc2)c1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1cc(Cl)cc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-(benzyloxy)-5-chloropyridine (4.00 g, 18.2 mmol) in dichloromethane (30.0 mL) was cooled to 0° C. under argon. O-(mesitylsulfonyl)hydroxylamine (5.23 g, 10% water, 21.9 mmol, prepared using a procedure similar to that reported in Org. Proc. Res. Dev. 2009, 13, 263-267) was added slowly and the mixture stirred at 0° C. for 1 h. 100 mL of ether was added, stirred for 5 minutes and filtered. The solids were washed with cold ether and dried on the frit to afford 1-amino-3-(benzyloxy)-5-chloropyridin-1-ium 2,4,6-trimethylbenzenesulfonate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]5[O:34][CH:33]=[N:32][CH:31]=5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.C1C=CC2N(O)N=NC=2C=1.[S:50]1[CH:54]=[CH:53][C:52]([CH2:55][C:56](O)=[O:57])=[CH:51]1>CC(N(C)C)=O>[O:34]1[C:30]([C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:56](=[O:57])[CH2:55][C:52]6[CH:53]=[CH:54][S:50][CH:51]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:31][N:32]=[CH:33]1
Reactant: O=C(O)Cc1ccsc1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[3-(1,3-oxazol-5-yl)phenyl]-2-pyrimidinamine (50 mg, 0.112 mmol) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and 3-thienylacetic acid (48 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by mass-guided prep LC (C18, 15% H20 (with 0.1% formic acid)/CH3OH to 100% CH3OH gradient) to afford the title compound (30 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ 3.65 (s, 2H), 6.51 (d, 1H, J=5.37 Hz), 7.07-7.12 (m, 2H), 7.23-7.48 (m, 7H), 7.55 (s, 1H), 7.68-7.76 (m, 2H), 7.89 (s, 1H), 8.20 (s, 1H), 8.27 (d, 1H, J=5.37 Hz), 8.38 (s, 1H), 8.50-8.51 (m, 1H), 8.81 (d, 1H, J=6.84 Hz), 9.73 (s, 1H), 10.28 (s, 1H). ES-LC/MS m/z=570 [M+H]+.
Reaction SMILES: C([BH3-])#N.[Na+].[CH:5]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH3:7])[CH3:6].O.[OH-].[Na+]>C(O)(=O)C>[CH:5]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)c1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C1Cc2ccccc2N1
Temperature: 15 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
4.65 g of sodium cyanoborohydride are gradually added to a solution of 5.0 g of 2-isopropylindole in 50 ml of acetic acid under argon cooled to a temperature of about 15° C. The reaction mixture is stirred at a temperature of about 15° C. for 2 hours and is then treated with 25 ml of water. It is then cooled to a temperature of about 5° C. and alkalinized by gradual addition of powdered sodium hydroxide. The reaction mixture is allowed to warm up to ambient temperature and is then stirred for 16 hours. The precipitate is filtered off through sintered glass and washed with 50 ml of water and then 50 ml of ethyl acetate. The filtrate is diluted with 50 ml of water and 70 ml of ethyl acetate and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 2×100 ml of ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 90 g cartridge of 15-40 μm silica, elution being carried out with a 95/5 v/v cyclohexane/ethyl acetate mixture, at a flow rate of 50 ml/min. 4.0 g of (±)-2-isopropylindoline are thus obtained in the form of a colorless oil which crystallizes into a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]([CH3:15])=[C:6]([CH:8](O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:16][CH3:17])=[CH:4][C:5]=1[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(O)c1cc(Cl)c(OC)cc1C
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(Cl)c1cc(Cl)c(OC)cc1C
Yield: 99.3 %

Procedure:
A solution of ethyl 2-(5-chloro-4-methoxy-2-methylphenyl)-2-hydroxyacetate (Intermediate 3-6; 1.1 g, 4.25 mmol) in thionyl chloride (3.42 mL, 46.89 mmol) under nitrogen was stirred at 80° C. for 30 minutes. The reaction mixture was allowed to cool concentrated and diluted with water (20 mL), extracted with EtOAc (2×20 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford ethyl 2-chloro-2-(5-chloro-4-methoxy-2-methylphenyl)acetate (1.170 g, 99%) as a yellow gum.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[B:5]([OH:7])[OH:6].O[C:9]([C:12](O)([CH3:14])[CH3:13])([CH3:11])[CH3:10].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Cl:1][CH2:2]/[CH:3]=[CH:4]/[B:5]1[O:7][C:12]([CH3:14])([CH3:13])[C:9]([CH3:11])([CH3:10])[O:6]1
Reactant: OB(O)/C=C/CCl
Reactant: CC(C)(O)C(C)(C)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC1(C)OB(/C=C/CCl)OC1(C)C
Yield: 57.8 %

Procedure:
A solution of (E)-3-chloroprop-1-enylboronic acid (5 g, 41 mmol), pinacol (4.9 g, 41 mmol), and magnesium sulfate (15 g, 120 mmol) in methylene chloride (100 mL) was stirred at room temperature for 18 h. The reaction mixture was filtered through silica gel and the filter cake was washed with methylene chloride. The filtrate was concentrated to afford the desired product (4.8 g, 60%) as a colorless oil: ESI MS m/z 203 [C9H16BClO2+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Fc1ccc2cccc(CBr)c2c1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure B, 5-chloro-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 5-chloro-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 352.2 ([M−H]−).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:40])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]2[NH:24][C:25](=[O:40])[CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH:38]=[N:37][CH:36]=[N:35]4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:18])[CH3:19]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2
Yield: 88.1 %

Procedure:
Prepared from {5-(isobutyl-methyl-amino)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M122) (0.50 g, 0.87 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (350 mg, 88%).
Reaction SMILES: [C:1]([O:5][C:6](N1C[C@@H](C)N2[C@H](CC3C2=NC(Br)=CC=3)C1)=O)(C)(C)[CH3:2].[C:23]([O:27][C:28]([N:30]1[CH2:42][C@@H:41]([CH3:43])[N:40]2[C@H:32]([CH2:33][C:34]3[C:39]2=[N:38][C:37]([OH:44])=[CH:36][CH:35]=3)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[H-].[Na+].COCCBr>>[C:23]([O:27][C:28]([N:30]1[CH2:42][C@@H:41]([CH3:43])[N:40]2[C@H:32]([CH2:33][C:34]3[C:39]2=[N:38][C:37]([O:44][CH2:2][CH2:1][O:5][CH3:6])=[CH:36][CH:35]=3)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: COCCBr
Agent: [H-]
Agent: [Na+]
Product: COCCOc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 22 intermediate b), from (4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, sodium hydride and 2-bromoethyl methyl ether.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:36]=[O:37])=[C:5]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:36][OH:37])=[C:5]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]([CH3:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(CO)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Yield: 98.3 %

Procedure:
To a solution of 2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (1.5 g) in ethanol (15 ml) was added sodium borohydride (112 mg) under stirring and ice-cooling, and this mixture was further stirred for 20 minutes at the same temperature. The reaction mixture was adjusted with 0.1 N hydrochloric acid to pH 6 to 7 under ice-cooling, and concentrated under reduced pressure. To the residue was added ethyl acetate and water, and the aqueous layer was further washed with ethyl acetate twice. The extract obtained above and the washings were put together, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give an oil (1.48 g) of 2-(N-methyl-N-benzylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][N:10]=2.[Se](=O)=[O:13]>O1CCOCC1>[N:10]1[CH:9]=[CH:8][N:7]=[C:6]2[N:11]=[C:2]([CH:1]=[O:13])[CH:3]=[CH:4][C:5]=12
Reactant: Cc1ccc2nccnc2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ccc2nccnc2n1
Temperature: 110 °C
Yield: 50.1 %

Procedure:
6-Methyl-pyrido[2,3-b]pyrazine (100 mg, 0.69 mmol) was dissolved in dioxane. Selenium dioxide (269 mg, 2.4 mmol) was added, and the suspension was refluxed at 110° C. for 3 minutes. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate was washed with brine, dried using magnesium sulfate, and concentrated to yield the title product (55 mg, 50%) as a pink solid. 1H NMR (DMSO-d6): δ=8 s, 1H), 9.31 (d, 1H,J=1.6 Hz), 9.21 (d, 1H, J=1.6 Hz), 8.81 (d, 1H, J=8.5 Hz), 8.42 (d, 1H, J=8.5 Hz). Calculated mass=159, [M+H]+=160.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1Cl)([O-:3])=[O:2].C1(CC2C=CC=CC=2)C=CC=CC=1.[CH2:31]([O:33][P:34]([CH2:39][NH2:40])(=[O:38])[O:35][CH2:36][CH3:37])[CH3:32]>C(Cl)Cl>[CH2:31]([O:33][P:34]([CH2:39][NH:40][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:38])[O:35][CH2:36][CH3:37])[CH3:32]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2ccccc2c1Cl
Reactant: CCOP(=O)(CN)OCC
Solvent: ClCCl
Solvent: c1ccc(Cc2ccccc2)cc1
Product: CCOP(=O)(CNc1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12)OCC
Yield: 68 %

Procedure:
4 g of 2,4 dinitro-1-chloronaphthalene (15.84 mmol) is dissolved in 6.5 g of aminomethanephosphonic acid diethyl ester and 4 g of diphenylmethane and stirred for 72 hours at room temperature. The batch is diluted with methylene chloride, washed with 1N NaOH and washed twice with brine, dried and spun in. The crude product is chromatographed on silica gel with 3.5 liters of cyclohexane and ethyl acetate 1:1 as mobile solvent. 68% of product is obtained in several fractions as viscous oil. NMR (DMSO, delta in ppm): 1.15(6H,tr), 4(4H dq)4.25 (2H m), 7.8, 7.98, 8.9, 9.05 each 1H, 8.6 (2H,d)
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:9]1([B-](F)(F)F)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[K+].Cl[C:21]1[C:26]2[O:27][CH:28]([CH3:32])[C:29](=[O:31])[NH:30][C:25]=2[CH:24]=[C:23]([CH:33]=[O:34])[CH:22]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O>[CH3:32][CH:28]1[O:27][C:26]2[C:21]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:22][C:23]([CH:33]=[O:34])=[CH:24][C:25]=2[NH:30][C:29]1=[O:31]
Reactant: F[B-](F)(F)c1ccccc1
Reactant: CC1Oc2c(Cl)cc(C=O)cc2NC1=O
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1Oc2c(cc(C=O)cc2-c2ccccc2)NC1=O
Temperature: 115 °C
Reaction time: 42 h
Yield: 19.4 %

Procedure:
To a solution of potassium phosphate, tribasic (0.564 g, 2.66 mmol), potassium phenyltrifluoroborate (0.245 g, 1.330 mmol), and 8-chloro-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 15 (0.2 g, 0.886 mmol) in toluene (Ratio: 4.00, 16 mL) and water (Ratio: 1.000, 4.0 mL) was added PdOAc2 (0.015 g, 0.066 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (0.062 g, 0.133 mmol) at 23° C. The reaction was stirred at 115° C. for 42 hr. The reaction mixture was poured into water (2 mL) and extracted with Et2O (3×5 mL). The organic layer was dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The resulting crude material was purified via medium pressure chromatography using a gradient eluant of CH2Cl2/MeOH. The appropriate fractions were combined and concentrated via rotary evaporation. The impure material was reconstituted in DMSO (1.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 45-70% ACN:0.05% TFA (aq). The early fractions were combined and the solvent was removed via rotary evaporation. The purified product was dried in vacuo to provide the title compound as an off-white solid (0.0459 g, 0.172 mmol, 19.37% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.82 Hz, 3H) 4.85-4.92 (m, 1H) 7.38-7.43 (m, 2H) 7.46-7.51 (m, 2H) 7.57-7.62 (m, 2H) 7.64 (d, J=2.02 Hz, 1H) 9.91 (s, 1H) 11.04 (s, 1H). ESI-MS: m/z 268.1 (M+H)+.
Reaction SMILES: C(=O)([O-])O.[Na+].I[C:7]1[C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]([CH3:28])[N:8]=1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O)(=[O:31])[CH3:30].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:13][C:12]1[C:7]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:29](=[O:31])[CH3:30])=[N:8][C:9]([CH3:28])=[CH:10][CH:11]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: CC(=O)c1ccccc1B(O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3C(C)=O)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 2-acetylphenylboronic acid (97 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, a 1 N aqueous sodium hydroxide solution was then added, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (10 mg, yield 20%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=O)[N:12]=2)=[CH:4][CH:3]=1.Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:22][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH3:21]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCN1CCC[C@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Example 56) (0.35 g, 1.2 mmol), 2-bromomethylpyridine hydrobromide (0.40 g, 1.6 mmol), and Cs2CO3 (1.4 g, 4.3 mmol) in DMF (5 mL) is stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc (2×), and the combined organic phase is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by flash chromatography [40 g SiO2, elute 20% (10% 2 M NH3 in MeOH/90% CH2Cl2): 80% CH2Cl2 to 70% (10% 2 M NH3 in MeOH/90% CH2Cl2): 30% CH2Cl2] to yield the title compound. MS (m/e): 378.3 (M+1)
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:26][O:27]CC)[N:18]([CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([NH2:23])=[O:22])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.[OH-].[K+]>ClCCl.ClCCCl.CO>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:26][OH:27])[N:18]([CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([NH2:23])=[O:22])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)C(N)=O
Agent: BrB(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(Cn1c(CO)nc2c(N)nc3ccccc3c21)C(N)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Boron tribromide (15 mL of a 1 N solution in dichloromethane) was added to a solution of 3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanamide (1.1 g, 3.2 mmol, Example 28) in 1,2-dichloroethane (35 mL). The reaction was heated at reflux for 35 minutes, cooled to approximately 0° C., and adjusted to pH 8 with the addition of a solution of potassium hydroxide (90 mL of a 0.5 N solution in methanol). The volatiles were removed under reduced pressure, and the residue was mixed with methanol (50 mL) and isolated by filtration. The filtrate was concentrated under reduced pressure, and the residue was stirred overnight with saturated aqueous sodium bicarbonate (35 mL). The resulting solid was isolated by filtration, combined with material from another run, and purified by column chromatography on silica gel (eluting with 20% methanol in dichloromethane containing 1% ammonium hydroxide) and dried in a vacuum oven for three hours at 60° C. to provide 3-[4-amino-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanamide as white crystals, mp 201-203° C.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:31])[C:12]([N:18]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])=[CH:3][CH:2]=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C:9]2[CH:10]=[C:11]([CH3:31])[C:12]([N:18]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N(C)c2c(C)cc(C#Cc3ccc(-c4ccccc4)cc3)cc2C(=O)O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N(C)c2c(C)cc(CCc3ccc(-c4ccccc4)cc3)cc2C(=O)O)cc1
Yield: 85.8 %

Procedure:
To a solution of 0.20 g (0.391 mmol) of the product of Example 352 in 25 mL of methanol and 10 mL of ethyl acetate was added 0.050 g of 10% palladium on carbon. The mixture was hydrogenated in a Parr apparatus at 30 psi of hydrogen for 5 h, then filtered through Celite. The Celite pad was washed with 100 mL of methanol and 100 mL of ethyl acetate and the filtrate was concentrated in vacuo. The residue was trituratedwith ether to give 0.173 g (86%) of the carboxylic acid as a pale yellow solid. Electrospray Mass Spec: 514.2 (M-H)-.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:14][CH:15]=[CH:16][C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[CH:7]=1>O=[Pt]=O.CO>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CN(CC=Cc2cc(Cl)cc(Cl)c2)S(=O)(=O)c2ccccc2)c1
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)CCc1cccc(CN(CCCc2cc(Cl)cc(Cl)c2)S(=O)(=O)c2ccccc2)c1
Reaction time: 2 h
Yield: 100.9 %

Procedure:
A mixture of 3-[3-{benzenesulfonyl-[3-(3,5-dichlorophenyl)-allyl]-amino}-methyl)-phenyl]-propionic acid methyl ester of Step A (237 mg), PtO2 (30 mg), and MeOH was hydrogenated on a Parr shaker at 50 psi for 2 h. The catalyst was removed by filtration through Celite and the volatiles were removed in vacuo to provide the title compound (240 mg). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 2H), 7.76-7.50 (m, 3H), 7.23 (m, 1H), 7.07 (m, 4H), 6.74 (s, 2H), 4.26 (s, 2H), 3.64 (s, 3H), 3.09 (t, 2H), 2.90 (t, 2H), 2.56 (t, 2H), 2.37 (t, 2H), 1.56 (m, 2H).