Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:22]#[N:23])[C:10]([NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([Cl:20])=[CH:14][C:13]=3[Cl:21])=[C:5]2[S:4][CH:3]=1.[CH:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>COCCOC.C(=O)(O)[O-].[Na+]>[Cl:21][C:13]1[CH:14]=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12]=1[NH:11][C:10]1[C:9]([C:22]#[N:23])=[CH:8][N:7]=[C:6]2[C:2]([C:29]3[CH:30]=[CH:31][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=3)=[CH:3][S:4][C:5]=12
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COc1cc(Nc2c(C#N)cnc3c(Br)csc23)c(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3c(-c4ccc(C=O)cc4)csc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A mixture of 3-bromo-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile (1.67 g, 3.89 mmol), 4-formylphenyl boronic acid (1.17 g, 7.78 mmol), and tetrakis(triphenylphosphine)pallidium (225 mg, 0.20 mmol) in 50 mL of ethylene glycol dimethyl ether and 42 mL of saturated aqueous sodium bicarbonate is heated at reflux for 2 hours and then cooled to room temperature. The precipitate is collected by filtration washing with ethyl acetate and diethyl ether to provide 1.09 g of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-3-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile as a tan solid, mp 268° C. dec; 1H NMR (DMSO-d6) δ 3.87 (s, 3H), 7.44 (s, 1H), 7.79 (s, 1H), 8.01 (d, J=8 Hz, 2H), 8.23 (d, J=8 Hz, 2H), 8.55 (s, 1H), 8.73 (s, 1H), 9.86 (s, 1H), 10.05 (s, 1H); MS 454.0, 456.0 (M+H)+; HRMS found: 454.01716 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].C(N(CC)CC)C.[C:40]([CH2:42][C:43](OCC)=[O:44])#[N:41]>O>[C:40]([CH2:42][C:43]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[N:14]=[C:13]([CH3:28])[N:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)=[O:10])[CH:16]=3)[CH2:21]2)[CH2:27][CH2:26]1)=[O:44])#[N:41]
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)CC#N)CC4)C3)nc(C)n2)ccc1F
Temperature: 150 °C

Procedure:
A 100 mL sealed tube was charged with N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.15 g, 0.32 mmol, Preparation #K.1), triethyl amine (0.163 g, 1.6 mmol, Sd Fine Chem), and ethyl cyanoacetate (0.54 mL, 4.8 mmol). The reaction mixture was heated at about 150° C. for about 12 h, cooled to RT and water (15 mL) was added. The product was extracted with EtOAc (2×15 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified by preparative HPLC (Table 2, Method d) to afford 6-(5-(1-(2-cyanoacetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide as an off white solid 0.065 g (40.8%). LC/MS (Table 1, Method c) Rt=1.38 min; MS m/z: 495.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]1([C:7]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1c[nH]nc1-c1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c[nH]nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a solution of 3-phenyl-1H-pyrazole-4-carboxylic acid (1.0 g, 5.31 mmol) in dichloromethane (14.2 mL) and methanol (3.5 mL) was added trimethylsilyldiazomethane (2.66 mL, 5.31 mmol). The mixture was stirred at ambient temperature. After 30 min, additional trimethylsilyldiazomethane (0.80 mL, 1.59 mmol) was added. After 10 min, the mixture was concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (0.9 g). MS 203.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[C:6]2[N:10]=[CH:9][NH:8][C:7]=12.[Br-].[CH2:28]([Zn+])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=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>[CH2:28]([C:2]1[N:3]=[N:4][C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[C:6]2[N:10]=[CH:9][NH:8][C:7]=12)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: FC(F)(F)c1ccc(N2CCN(c3nnc(Cl)c4[nH]cnc34)CC2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: FC(F)(F)c1ccc(N2CCN(c3nnc(Cc4ccccc4)c4[nH]cnc34)CC2)nc1
Temperature: 80 °C
Yield: 7.1 %

Procedure:
7-Chloro-4-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-imidazo[4,5-d]pyridazine (149 mg, 0.389 mmol), benzyl zinc bromide (9.34 mL, 0.5M in THF, 4.67 mmol), and tetrakis (triphenylphosphine) palladium0 (23 mg, 0.020). The reaction mixture is heated to 80° C. for 32 h. Add H2O and extract product with EtOAc. Wash combined organics with brine and concentrate in vacuo. The residue is purified by flash chromatography on silica gel (60-100% EtOAc/Heptane flushed with 10% MeOH/EtOAc) to afford the title compound (12.1 mg, 7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:32][CH2:31][CH2:30][C@@:10]3([C:14](=[O:15])[N:13]([C@H:16]4[CH2:21][CH2:20][C@@H:19]([O:22][Si](C(C)(C)C)(C)C)[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[CH2:9]2)=[C:4]([Cl:33])[CH:3]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH2:43]([NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51](B2OC(C)(C)C(C)(C)O2)=[CH:50][N:49]=1)=[O:47])[CH3:44]>CN(C)C=O.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>[Cl:33][C:4]1[CH:3]=[C:2]([C:51]2[CH:52]=[CH:53][C:48]([C:46]([NH:45][CH2:43][CH3:44])=[O:47])=[N:49][CH:50]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:32][CH2:31][CH2:30][C@@:10]2([C:14](=[O:15])[N:13]([C@H:16]3[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH2:9]1
Reactant: CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCN(c4ccc(Br)cc4Cl)C3)C2=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-c2ccc(N3CCC[C@]4(CCN([C@H]5CC[C@@H](O)CC5)C4=O)C3)c(Cl)c2)cn1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (5S)-7-(4-bromo-2-chlorophenyl)-2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00004 mol), [1,1 ′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.0 mg), tetrakis(triphenylphosphine)palladium (1.0 mg) and potassium carbonate (14.9 mg, 0.000108 mol) in anhydrous N,N-dimethylformamide (1 mL) was added N-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (14.5 mg, 0.054 mmol). The resulting reaction mixture was heated at 150° C. and stirred overnight, followed by the removal of TBS protecting group by the addition of 1.7 M of fluorosilicic acid in water (0.10 mL) and the mixture was stirred at r.t. overnight. The reaction mixture was then directly purified by RP-HPLC to afford the desired product. LC/MS m/e 511.2 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8.92 (1H, d, J=2.3 Hz), 8.84 (1H, t, J=5.9 Hz), 8.26 (1H, dd, J=8.2, 2.3 Hz), 8.06 (1H, d, J=8.2 Hz), 7.89 (1H, d, J=2.2 Hz), 7.74 (1H, dd, J=8.5, 2.2 Hz), 7.30 (1H, t, J=8.5 Hz), 4.39 (1 H, d, J=3.1 Hz), 3.80 (1H, m), 3.72 (1H, m), 3.24-3.44 (5H, m), 3.01 (1H, d, J=11.4 Hz), 2.63-2.74 (2H, m), 2.40-2.53 (1H, m), 1.64-1.91 (8H, m), 1.41-1.53 (3H, m), 1.20-1.32 (2H, m), 1.13 (3H, t, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[H-].[Na+]>C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][N:5]1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1=[O:14]
Reactant: O=C(Cl)CCCCCl
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(CN1CCCCC1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a stirred mixture of aminoacetaldehyde dimethylacetal (0.74 g, 7 mmole) in ethyl acetate (20 mL) and 2M sodium carbonate (20 mL) was added 5-chlorovaleryl chloride (1.55 g, 10 mmole). The reaction mixture was stirred at ambient temperature for 1 hour. The aqueous layer was separated and extracted with ethyl acetate. The combined organic phase was washed with 1% hydrochloric acid and water, dried (magnesium sulfate), and concentrated. The oily residue was dissolved in tetrahydrofuran, and sodium hydride (60% in oil) (0.3 g, 7.5 mmole) was added. The reaction mixture was heated under reflux for 1.5 hours and filtered. The filtrate was concentrated to give 1-(2,2-dimethoxyethyl)-piperidin-2-one (1.06 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: O=S(=O)(CCCCCCCl)NCCO
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCCO
Yield: 92.3 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and N-(2-hydroxyethyl)-6-chlorohexanesulfonamide (487.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-6-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (915.2 mg) as a pale yellow oil (92.3%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>CN(C)C=O.O>[CH2:20]([O:19][CH2:18][CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: BrCCOCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2c1ccn2CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.75 g of Methyl 1H-indol-4-carboxylate was dissolved in 10 ml of N,N-dimethylformamide, and 0.7 g of 60% sodium hydride was added under ice-cooling. The reaction solution was stirred at room temperature for 30 minutes, treated with 2.5 ml of benzyl 2-bromoethyl ether, and stirred at room temperature for a further 2 hours. The reaction solution was cooled with ice, treated with water and ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (8% ethyl acetate-hexane), to give 3.6 g of the title compound.
Reaction SMILES: [CH2:1]([N:4]([C:12]1[C:13](Br)=[N:14][CH:15]=[CH:16][CH:17]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=C.C(NC1C(Br)=NC=CC=1)C=C.CC([O:34]C(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[O:34]=[C:2]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH2:1]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=CCN(C(=O)OC(C)(C)C)c1cccnc1Br
Agent: C=CCNc1cccnc1Br
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)c2ncccc21
Temperature: 25 °C

Procedure:
tert-butyl allyl(2-bromopyridin-3-yl)carbamate. To a solution of N-allyl-2-bromopyridin-3-amine (1 eq.) and DCM (0.2 M) is added (Boc)2O (1.5 eq.). The solution is stirred at room temperature until judged complete by TLC. The solution is concentrated in vacuo and purified by column chromatography to give the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8])=O.[NH2:14]/[C:15](/[CH3:21])=[CH:16]\[C:17]([O:19][CH3:20])=[O:18]>CO>[CH3:20][O:19][C:17]([C:16]1[CH:1]([C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[O:5][CH2:6][C:7]([OH:9])=[O:8])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[NH:14][C:15]=1[CH3:21])=[O:18]
Reactant: O=Cc1ccccc1OCC(=O)O
Reactant: COC(=O)/C=C(/C)N
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1OCC(=O)O

Procedure:
A solution of 5 g of 2-formylphenoxyacetic acid and 6.4 g of methyl 3-aminocrotonate in methanol was refluxed for 24 hours and evaporated. The residue was dissolved in a solution of sodium carbonate in water. This solution was washed twice with ethyl acetate and acidified to pH 2 with dilute hydrochloric acid, after which the solution was again extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was crystallized from ethyl acetate/petroleum ether 60-80.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:3]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:27][N:36]=[C:31]([CH2:32][CH2:33][O:34][CH3:35])[N:30]=3)[CH2:10]2)=[O:8])[CH2:3]1
Reactant: COCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)C2)C1
Product: COCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(O)C3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 112A and 88 mg (0.75 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 67 mg (27% of theory).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:21].C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:23][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:21]
Reactant: BrC(Br)(Br)Br
Reactant: O=C1N(CCO)CCC1(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1N(CCBr)CCC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 64A (0.3, 1.1 mmol) in methylene chloride was added carbon tetrabromide (0.7 g, 2.13 mmol) and triphenylphosphine (0.56 g, 2.13 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the obtained residue was chromatographed on silica gel eluting with 10-30% ethyl acetate/hexane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.31 (m, 10H), 3.78 (t, J=6.44 Hz, 2H), 3.54 (t, J=5.59 Hz, 2H), 3.49 (t, J=5.76 Hz, 2H), 2.80 (t, J=6.44 Hz, 2H); MS (ESI+) m/z 345 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:30])=[C:20]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[CH3:29])[N:21]=2)=[CH:13][CH:12]=1>>[CH3:30][C:19]1[O:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:12][CH:13]=2)=[N:21][C:20]=1[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH3:29]
Reactant: OB(O)c1cccnc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3cccnc3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 3-pyridyl boronic acid (176 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 49 mg (49%). MS (m/e) 348.3 (M+1)
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][CH:9]([F:40])[N:10]1[C:14]2[C:15]([O:31][C@@H:32]([C@H:34]3[CH2:38][NH:37][C:36](=[O:39])[CH2:35]3)[CH3:33])=[N:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[CH:18][C:13]=2[N:12]=[CH:11]1.CCN(C(C)C)C(C)C.[O:50]1[CH2:53][C:52](=O)[CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[F:40][CH:9]([F:8])[N:10]1[C:14]2[C:15]([O:31][C@@H:32]([C@H:34]3[CH2:38][NH:37][C:36](=[O:39])[CH2:35]3)[CH3:33])=[N:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:52]5[CH2:53][O:50][CH2:51]5)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[CH:18][C:13]=2[N:12]=[CH:11]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C4COC4)CC3)cc2)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Temperature: 52.5 °C
Reaction time: 3 h

Procedure:
The crude TFA salt of (R)-4-((R)-1-((3-(difluoromethyl)-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (3.63) (0.06 mmol) was dissolved in THF (1.05 mL) and iPr2NEt (11 μL, 0.063 mmol) was added followed by oxetan-3-one (15 μL, 0.26 mmol) and sodium triacetoxyborohydride (57 mg, 0.27 mmol). The reaction mixture was stirred at 50-55° C. for 3 h and was diluted with water, 5% (w/v) aqueous Na2CO3, and EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (0-25% MeOH in DCM) to yield (R)-4-((R)-1-((3-(difluoromethyl)-6-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (3.66).
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH3:5][C:6](C)([C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9])C.Br>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]([CH3:9])([CH3:10])[CH2:6][CH2:5][P:1]([OH:3])(=[O:2])[OH:4])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(C)(C)c1ccc(O)cc1
Reactant: O=[PH](O)O
Agent: Br
Product: CC(C)(CCP(=O)(O)O)c1ccc(O)cc1
Reaction time: 1 h

Procedure:
3.0 Parts of dimethyl-3-(4-hydroxyphenyl)-3-methyl-butane phosphonate from Example 23a and 30 parts of 48% hydrobromic acid were heated on a steam--bath for 1 hour and the volatiles then removed at 80° C. under reduced pressure. Crystallisation of the residual solid from water gave 3-(4-hydroxyphenyl)-3-methyl-butane phosphonic acid m.p. 192°-5° C. with the following percentage composition by weight.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=4)[CH:12]=[C:11]([C:25]([O:27][CH3:28])=[O:26])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[F:29][C:30]([F:45])([F:44])[S:31](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:22][C:21]([F:24])([F:23])[C:17]1[CH:16]=[C:15]([C:13]2[CH:12]=[C:11]([C:25]([O:27][CH3:28])=[O:26])[C:7]3[NH:8][C:9]4[CH:10]=[C:2]([O:1][S:31]([C:30]([F:45])([F:44])[F:29])(=[O:33])=[O:32])[CH:3]=[CH:4][C:5]=4[C:6]=3[N:14]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
A suspension of methyl 7-hydroxy-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (800 mg, 2.07 mmol), 4-nitrophenyl trifluoromethanesulfonate (842 mg, 3.11 mmol), and potassium carbonate (859 mg, 6.21 mmol) in DMF (12 ml) was stirred at RT for 3 hr. The reaction was partitioned between water and EtOAc. The organic phase was separated and washed with water (5×) and brine. It was dried with sodium sulfate and the solvent was removed. Column chromatography (step gradient elution with hexane containing 20 to 80% DCM) afforded methyl 2-(3-(trifluoromethyl)phenyl)-7-(trifluoromethylsulfonyloxy)-5H-pyrido[3,2-b]indole-4-carboxylate (548 mg, 1.06 mmol, 51% yield) as a light yellow solid. MS (ESI) m/z 587.09 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 9.76 (1H, s), 8.51 (1H, d, J=8.55 Hz), 8.44 (1H, s), 8.31-8.38 (2H, m), 7.60-7.72 (2H, m), 7.51 (1H, d, J=2.14 Hz), 7.29 (1H, dd, J=8.55, 2.14 Hz), 4.13 (3H, s).
Reaction SMILES: [CH2:1]([CH:3]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[C:6]([Cl:20])[C:7]([Cl:19])=[C:8]([OH:18])[CH:9]=2)[C:4]1=[O:21])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32]CC)=[O:31]>CN(C)C=O>[O:21]=[C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:18][CH2:29][C:30]([OH:32])=[O:31])=[C:7]([Cl:19])[C:6]=2[Cl:20])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]1[CH2:1][CH3:2]
Reactant: CCC1C(=O)c2c(cc(O)c(Cl)c2Cl)C1c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1c1ccccc1

Procedure:
(1-Oxo-2-ethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid is prepared following substantially the same procedure described in Example 4, Step F, using the following substances: 2-ethyl-3-phenyl-5-hydroxy-6,7-dichloro-1-indanone (16.6 g., 0.0518 mole); potassium carbonate (14.4 g., 0.104 mole); ethyl bromoacetate (17.3 g., 0.104 mole); and dimethylformamide (80 ml.); and hydrolyzing the resultant ester in accordance with Example 4, Step F, there is obtained 14.4. g. (74%) of (1-oxo-2-ethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid which after recrystallization from acetic acid melts at 203°-206° C.