Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:25]([O:28][C:29]1([CH2:53][CH2:54][CH2:55][OH:56])[CH2:34][C:33]2[CH:35]=[CH:36][C:37]([O:39][CH:40]([CH2:42][CH2:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH3:41])=[CH:38][C:32]=2[O:31][C:30]1([CH3:52])[CH3:51])(=[O:27])[CH3:26].[CH3:57][S:58](Cl)(=[O:60])=[O:59]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[C:25]([O:28][C:29]1([CH2:53][CH2:54][CH2:55][O:56][S:58]([CH3:57])(=[O:60])=[O:59])[CH2:34][C:33]2[CH:35]=[CH:36][C:37]([O:39][CH:40]([CH2:42][CH2:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH3:41])=[CH:38][C:32]=2[O:31][C:30]1([CH3:51])[CH3:52])(=[O:27])[CH3:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC1(CCCO)Cc2ccc(OC(C)CCCc3ccccc3)cc2OC1(C)C
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Solvent: c1ccncc1
Product: CC(=O)OC1(CCCOS(C)(=O)=O)Cc2ccc(OC(C)CCCc3ccccc3)cc2OC1(C)C
Temperature: 5 °C

Procedure:
To 1.823 g (4.15 mmole) dl-5-acetoxy-3-(3-hydroxypropyl)-2,2-dimethyl-7-(5-phenyl-2-pentyloxy)-3,4-dihydro-2H-benzopyran was added 20 ml of pyridine, the mixture stirred under nitrogen to affect solution and cooled to 5° C. Methanesulfonyl chloride, 520 mg (4.56 mmole), was added, the resulting mixture stirred at 5°-10° C. for 20 minutes, then allowed to warm to room temperature and stirred for an additional 50 minutes. The mixture was concentrated in vacuo and the residual oil taken up in ethyl acetate, washed twice with water, once with brine and the organic layer dried over anhydrous magnesium sulfate. After evaporation of solvent in vacuo the desired product was obtained as an oil, 1.999 g.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@H]2CCCN2)O)C=CC=CC=1.B(OC)(OC)OC.B.C(N(CC)C1C=CC=CC=1)C.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46](=[O:61])[CH2:47][CH2:48][C:49]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([N+:58]([O-:60])=[O:59])[CH:52]=2)=[O:50])=[CH:42][C:41]=1[N+:62]([O-:64])=[O:63]>C1COCC1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C@@H:46]([OH:61])[CH2:47][CH2:48][C@@H:49]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([N+:58]([O-:60])=[O:59])[CH:52]=2)[OH:50])=[CH:42][C:41]=1[N+:62]([O-:64])=[O:63]
Reactant: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: B
Agent: COB(OC)OC
Agent: OC(c1ccccc1)(c1ccccc1)[C@H]1CCCN1
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc([C@@H](O)CC[C@H](O)c2ccc(Cl)c([N+](=O)[O-])c2)ccc1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
(R)-(+)-α,α-Diphenyl-2-pyrrolidinemethanol (1.08 g, 4.28 mmol) was dissolved in 70 mL of THF at ambient temperature in a dry flask under nitrogen and trimethyl borate (650 uL, 5.54 mmol) was added dropwise. The resulting solution was stirred for 1 hour. The solution was cooled in a cold bath to ˜10° C. and the N,N-diethylaniline borane (9.18 mL, 51.6 mmol) was added dropwise with some bubbling. After 15 minutes, this solution was transferred to an addition funnel and added dropwise to 1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione (Intermediate 5B) (10.0 g, 25.2 mmol) suspended in 200 mL of THF and cooled to ˜10° C. Bubbling was observed. After the addition, the mixture was stirred at ambient temperature for 4 hours. The mixture was cooled in an ice bath and 30 mL or methanol was added dropwise until bubbling stopped, then the mixture was allowed to stir at ambient temperature for 30 minutes. The mixture was filtered to get rid of a trace of insoluble unreacted starting material. The filtrate was concentrated, poured into 1 M HCl and extracted into ethyl acetate, dried over sodium sulfate, and concentrated to give the title compound (9.9 g, 99%) as a yellow waxy solid. Chiral HPLC e.e. >99.9% (RR diol was undetectable). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (d, J=1.9 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.60 (dd, J=8.4, 1.9 Hz, 2H), 4.65 (m, 2H), 1.62 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[F:32])(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccccc4F)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2-fluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=579.6)=80%.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][N:30]1[CH2:31][CH2:32][CH:27]([C:23]2[CH:22]=[C:21]([NH:20][C:18](=[O:19])[CH:17]([CH3:33])[CH3:16])[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)Cc3ccccc3-4)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 9H-fluorene-2-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[C:14]([CH3:27])[N:15]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([Br:9])[C:5]([F:8])([F:7])[F:6].O.[OH-].[Li+]>C1COCC1.O>[CH2:20]([N:15]1[C:16]2[C:12](=[C:11]([O:10][C:4]([Br:9])([C:5]([F:6])([F:7])[F:8])[C:3]([OH:28])=[O:2])[CH:19]=[CH:18][CH:17]=2)[CH:13]=[C:14]1[CH3:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C(Br)(Oc1cccc2c1cc(C)n2Cc1ccccc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(OC(Br)(C(=O)O)C(F)(F)F)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1-benzyl-2-methyl-1H-indol-4-yloxy)-2-bromo-3,3,3-trifluoro-propionic acid methyl ester (4) (0.07 g, 0.177 mmole) in THF:H2O (4:1, 10 mL), lithium hydroxide mono hydrate (0.01 g, 0.238 mmole) was added. The mixture was stirred at room temperature for 30 minutes. THF was evaporated and the mixture was acidified with 2M HCl to pH 3. The aqueous layer was extracted with ethyl acetate (3×10 mL). The organic layer was separated, dried over magnesium sulphate and concentrated to afford intermediate (5) as a pink solid. Yield: (0.066 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][NH:28][CH2:27][CH2:26]2.C(N(CC)CC)C>CC(N(C)C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH:7]=[N:8]2)=[C:4]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:29]2)[N:3]=1
Reactant: CC(c1ccccc1)n1cnc2nc(Cl)nc(Cl)c21
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1OC)CN(c1nc(Cl)nc3ncn(C(C)c4ccccc4)c13)CC2
Yield: 38.4 %

Procedure:
Employing the procedure of Preparation B, 730 mg of 2,6-dichloro-7-(1-phenylethyl)purine, 573 mg of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride and 505 mg of triethylamine in 25 ml of dimethylacetamide gave 430 mg of the desired intermediate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.Cl.[C:13](=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:13][O:9][C:8](=[O:10])[C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:11])=[N:4][CH:5]=1
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
The solution of 2.0 g (11.5 mmol) 3-chloro-2-hydroxypyridine-5-carboxylic acid in 28 mL (35 mmol) hydrochloric acid (1.25M in methanol) was stirred for 5 h under reflux. The reaction was allowed to cool to room temperature, poured on 100 mL 10% aqueous sodium bicarbonate solution and 100 mL ethyl acetate, extracted and washed with 100 mL brine. The aqueous layer was extracted a second time with 100 mL ethyl acetate and the combined organic layers dried with magnesium sulfate, filtered and concentrated under vacuum. The light yellow residue was suspended in 30 mL tert-butyl methyl ether, stirred for 1 h at room temperature and filtered to give the desired compound as a white solid (55%) which was pure enough for the next step. MS (Turbo Spray): m/z=188.1 [M+H].
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:12])=[O:2].S(Cl)(Cl)=O.[CH3:17]O>>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:17])=[O:8])=[CH:5][C:4]=1[OH:12])=[O:2]
Reactant: CO
Reactant: O=Cc1ccc(C(=O)O)cc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C=O)c(O)c1
Yield: 85 %

Procedure:
4-Formyl-3-hydroxybenzoic acid (5 g, 30 mmol) was suspended in methanol (70 mL), and treated with thionyl chloride (3.29 mL 45 mmol) dropwise. The mixture was heated to reflux overnight. Concentrated to dryness, and 50 mL of toluene was added, and concentrated again. The residue was recrystallized from ethyl acetate-hexane. A total of 4.8 g (85%) of methyl 4-formyl-3-hydroxybenzoate was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1.N1C=CC=CC=1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)Cl>[CH3:35][O:36][CH2:37][C:38]([O:16][CH2:15][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([N:18]3[CH2:22][CH:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:17])=[O:39]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)OCC(=O)N1CCN(c2ccc(N3CC(CNC(C)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
The (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (263 mg, 0.67 mmol) was slurried in dry CH2Cl2 (10 mL) and cooled to 0° C. in an ice bath. The soluton became homogeneous after the addition of the pyridine (0.216 mL, 2.67 mmol). Next, the methoxyacetyl chloride (0.064 mL, 0.69 mmol) was added drop wise. The reaction was stirred at 0° C. for 30 minutes and then the ice bath was removed. After one hour, the reaction was found to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction mixture was diluted with CH2Cl2 (100 mL) and then washed with 1N HCl/brine (50 mL each), saturated NaHCO3 /brine (50 mL each), and brine (100 mL). Each aqueous portion was back-extracted with more CH2Cl2 (2×25 mL). The organic layers were combined, dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to give an orange solid. This solid was chromatographed on silica gel (35 g,) eluting with a gradient of 1-5% MeOH in 10% CH3CN/CHCl3 to give an orange solid. The latter solid was recrystallized by dissolving it in a minimal amount of CH2Cl2 /MeOH and then triturating with ether to yield 158 mg (51%) of the title compound as an off-white solid with a melting point of 147°-148° C. Aqueous solubility (pH 7, phosphate buffer) was 6.4 mg/ml.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:12]([CH3:13])=[CH:11][S:10][C:9]=1[C:14]1[N:15]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:16](=[O:19])[NH:17][N:18]=1.Cl[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(#N)C>[Cl:7][C:8]1[C:12]([CH3:13])=[CH:11][S:10][C:9]=1[C:14]1[N:15]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:16](=[O:19])[N:17]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:18]=1
Reactant: CCOC(=O)CCl
Reactant: Cc1csc(-c2n[nH]c(=O)n2CC(C)C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(-c2scc(C)c2Cl)n(CC(C)C)c1=O

Procedure:
570 mg (4.12 mmol) of potassium carbonate are added to a suspension of 560 mg (2.06 mmol) of 5-(3-chloro-4-methyl-2-thienyl)-4-isobutyl-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 247A and 253 mg (2.06 mmol) of ethyl chloroacetate in 10 ml acetonitrile and heated for 4 hrs under reflux. For the workup, this is concentrated, and the residue taken up in water and extracted three times with ethyl acetate. The combined organic phases are concentrated, and the crude product remaining as the residue is purified by preparative HPLC [Method 12]. 705 mg (96% of theory) of the target compound are thus obtained.
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH:7]=[O:8])([O-:3])=[O:2].[CH2:10](O)[CH2:11][OH:12].O>C1C=CC=CC=1>[N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH:7]1[O:12][CH2:11][CH2:10][O:8]1)([O-:3])=[O:2]
Reactant: OCCO
Reactant: CC(=CC=O)C[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: O
Product: CC(=CC1OCCO1)C[N+](=O)[O-]

Procedure:
0.1 Mol of 4-nitro-3-methyl-2-butenal and 0.1 Mol of ethyleneglycol is benzene were refluxed for 1 hour, collecting 0.1 Mol of water in a Dean Stark trap. After cooling the reaction mixture it was quenched in a solution of sat. Sodiumbicarbonate and extracted several times with benzene. The reaction product was purified by Kugelrohr distillation followed by chromotography over silica gel. The product was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([N:28]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[S:53](=[O:56])(=[O:55])[NH2:54])=[CH:43][CH:42]=1)[C:29]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)=[O:30])[CH2:24][CH2:25][CH2:26][CH3:27].N12CCCN=C1CCCCC2>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:54][S:53]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:29]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32]2)=[O:30])=[CH:46][CH:45]=1)(=[O:56])=[O:55])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCCN(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(=O)N1CCc2ccccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1)C(=O)N1CCc2ccccc21
Temperature: 55 °C
Reaction time: 29 h
Yield: 67.8 %

Procedure:
A solution of 21 mg (0.13 mmole) of 2-chlorobenzoic acid and 22 mg (0.13 mmole) of 1,1'-carbonyldiimidazole (CDI) in 0.8 mL of THF was stirred under N2 at 65° C. for 2.5 hours. Subsequently, a solution of 32 mg (0.067 mmole) of 1-[N-pentyl-N-[(2'-sulfamoylbiphenyl-4-yl)methyl]carbamoyl]indoline (from Step B) and 20 μL (0.13 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 0.8 mL of THF was added. After stirring for 29 hours at 55° C., the mixture was partitioned between EtOAc and 5% citric acid (aqueous). The organic layer was washed with water and brine, then dried over sodium sulfate. After filtration and removal of volatiles, the crude product was flash chromatographed over silica gel (gradient elution with 0.5-1.0% MeOH in CH2Cl2) to give 28 mg (68%) of the title compound as an off-white solid, mp 83°-85° C.; homogeneous by TLC (95:5 MeOH--CH2Cl2); FAB-MS m/e 616 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=1[CH3:28].[CH3:29][C:30]1([CH3:45])[C:34]2=[N:35][CH:36]=[C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:38]=[C:33]2[NH:32][CH2:31]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:29][C:30]1([CH3:45])[C:34]2=[N:35][CH:36]=[C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH:38]=[C:33]2[N:32]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=2[CH3:28])[CH2:31]1
Reactant: Cc1c(N(C(=O)OC(C)(C)C)c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(N(C(=O)OC(C)(C)C)c2ccccn2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring tert-butyl 4-chloro-5,7-difluoro-3-methylquinolin-2-yl(pyridin-2-yl)carbamate (100 mg, 0.246 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (57.5 mg, 0.246 mmol), Pd2dba3 (22.6 mg, 0.025 mmol), XPhos (23.5 mg, 0.049 mmol), sodium tert-butoxide (71.0 mg, 0.739 mmol), and toluene (2.5 mL) at 100° C. for 30 min. Purification by column chromatography on silica gel (0-60% EtOAc in hexanes) gave tert-butyl 4-(3,3-dimethyl-6-morpholino-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-5,7-difluoro-3-methylquinolin-2-yl(pyridin-2-yl)carbamate. Mass Spectrum (ESI) m/e=603.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:21][CH2:22][C:23](O)=[O:24])=[CH:14][C:15]=2[C:17]([F:20])([F:19])[F:18])[N:10]([CH3:26])[N:9]=1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:46][C@H:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:21][CH2:22][C:23]([NH:54][C@H:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH3:46])=[O:24])=[CH:14][C:15]=2[C:17]([F:20])([F:18])[F:19])[N:10]([CH3:26])[N:9]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Cn1nc(-c2ccccc2F)c2c(C(F)(F)F)cc(OCC(=O)O)nc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)COc1cc(C(F)(F)F)c2c(-c3ccccc3F)nn(C)c2n1)c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
A solution of 2-(3-(2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetic acid (70 mg, 0.189 mmol), DIC (31.1 mg, 0.246 mmol) and HOBt (38.4 mg, 0.285 mmol) in DMF (3 ml) was stirred at rt for 15 min. (S)-(−)-α-methyl benzyl amine (25.3 mg, 0.208 mmol) was added dropwise to the reaction mixture at rt and then the mixture was heated at 100° C. for 1 h. After completion of the reaction, ice-cold water was added and the reaction mixture was stirred for 10 min. The resulting precipitate was collected by filtration. The crude product was re-crystallized from diethyl ether to yield 46 mg (51%) of the title compound. [1H-NMR (CDCl3, 300 MHz) δ 7.55-7.05 (m, 9H), 7.01 (s, 1H), 6.55 (d, 1H), 5.23 (m, 1H), 5.01 (s, 2H), 4.03 (s, 3H), 1.60 (d, 3H); HPLC RtA=5.384 min (98%); LCMS RtD=3.055; [M+H]+=473.1].
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9])[CH3:2].[I-].I[CH:25]([CH3:27])[CH3:26].[Na+].[I-]>>[CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[CH2:5][CH2:6][C:7]([CH:25]([CH3:27])[CH3:26])([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9])[CH3:2]
Reactant: CCOC(CCC(C#N)c1ccc(OC)c(OC)c1)OCC
Reactant: CC(C)I
Agent: [I-]
Agent: [Na+]
Product: CCOC(CCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C)OCC
Temperature: 0 °C

Procedure:
The resulting acetal derivative of formula 5 is then alkylated with about 1 eq of an alkylhalide using a strong metallic base and a catalytic amount of an iodide source, e.g., 2-iodopropane or NaI, in a polar aprotic solvent at about 10°-40° C. for 2-18 hours, followed by treatment with sufficient ice water to decompose excess base, to yield a dialkylated derivative of formula 6. For example, 2-(3,3-diethoxypropyl)-2-(3,4-dimethoxyphenyl)acetonitrile (5) in DMF is treated with a slight molar excess of 2-chloropropane (and 0.1-5 mol% 2-iodopropane) at 20° C., stirred for 10 minutes, then treated with 1 eq NaH in mineral oil and slowly heated to 40° C. After adding 200 ml ice water and purifying the product, 2-(3,3-diethoxypropyl)-2-(prop-2-yl)-2-(3,4-dimethoxyphenyl)acetonitrile (6) is obtained.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.O[CH2:17][C@@H:18]1[O:22][CH2:21][C@@H:20]([S:23][C:24](=[O:26])[CH3:25])[CH2:19]1>C(Cl)Cl.N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][CH2:17][C@@H:18]1[O:22][CH2:21][C@@H:20]([S:23][C:24](=[O:26])[CH3:25])[CH2:19]1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)S[C@@H]1CO[C@@H](CO)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CO[C@@H](COS(=O)(=O)C(F)(F)F)C1
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of 0.535 ml of trifluoromethanesulfonic anhydride in 3.75 ml of methylene chloride is added, via a syringe, a 0° C. solution of 0.529 g of product from Example 6 in 0.75 ml of methylene chloride and 0.243 ml of pyridine. The reaction is stirred in an ice bath for 45 minutes; during which time the progress of reaction is checked by thin layer chromatography. The mixture is concentrated in vacuo, slurried with ethyl acetate and filtered. The filtrate is purified by chromatography (Silica Gel: 50% ethyl acetate/hexane) to give 0.799 g of the desired product.
Reaction SMILES: CN(C)C=O.[I:6]N1C(=O)CCC1=O.[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[C:22]([F:26])[CH:21]=[C:20]([CH3:27])[C:16]=1[C:17]([OH:19])=[O:18]>O>[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[C:22]([F:26])[C:21]([I:6])=[C:20]([CH3:27])[C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1c(F)cc(C)c(C(=O)O)c1N
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(N)c(C(=O)O)c(C)c(I)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
An N,N-dimethylformamide (14 ml) solution of N-iodosuccinimide (1.89 g, 8.4 mmol) was dropwise added to an N,N-dimethylformamide (14 ml) solution of 2-amino-4-fluoro-3-methoxy-6-methylbenzoic acid (I-29) (1.4 g), followed by stirring at room temperature for 2 hours and a half. Water was added to the reaction liquid, followed by extraction three times with ethyl acetate, the organic layer was washed with aqueous saturated sodium thiosulfate solution and saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (2:1) was concentrated under reduced pressure to obtain the entitled compound (1.77 g, 78%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:12](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (25 g, 0.159 mmol) in acetonitrile (500 mL) and methanol (500 mL) was treated with diisopropyl ethylamine (28 mL). The reaction mixture was cooled in an ice-bath and after 30 minutes, trimethylsilyldiazomethane was added dropwise. The mixture was stirred at room temperature for 18 hours then evaporated under vacuum to afford the product as an oil (29.4 g, 100%). MS (+ve ion electrospray) m/z 172 (MH+).