Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([O:13][C:14]1[C:15]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=3)=[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[O:20][C:16]=2[N:17]=[CH:18][N:19]=1)[CH3:12])(C)(C)C>Cl.O1CCOCC1>[CH2:29]([C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:15]3[C:14]([O:13][CH:11]([CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:38])=[O:5])=[N:19][CH:18]=[N:17][C:16]=3[O:20][C:21]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:24][CH:25]=1)[CH3:30]
Reactant: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(OC(C)CCCCC(=O)OC(C)(C)C)c23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(OC(C)CCCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 80 mg (0.15 mmol) 6-{[5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}heptanoic acid tert.-butyl ester in 2 ml 4 N hydrogen chloride in dioxan and stir for 16 h at RT. After concentrating the reaction solution by evaporation under vacuum, purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 12 mg (16% of theor.) of the desired product is obtained as racemate.
Reaction SMILES: [Cu][C:2]#[N:3].N1C=CC=CC=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([N:22]3[C:26]([CH3:28])([CH3:27])[CH2:25][O:24][C:23]3=[O:29])[S:20][CH:21]=2)=[C:13]([F:30])[CH:12]=1>CC(N(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>[CH3:27][C:26]1([CH3:28])[CH2:25][O:24][C:23](=[O:29])[N:22]1[C:19]1[S:20][CH:21]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:2]#[N:3])=[CH:12][C:13]=2[F:30])[N:18]=1
Reactant: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2F)cs1
Reactant: N#C[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2F)cs1
Yield: 116.6 %

Procedure:
Copper (I) cyanide (0.09 g, 1.0 mmol) and pyridine (0.17 mL, 1.6 mmol) were added under a nitrogen atmosphere to a solution of 3-[4-(4-bromo-2-fluorophenyl)-1,3-thiazol-2-yl]-4,4-dimethyl-1,3-oxazolidin-2-one (0.4 g, 1.0 mmol), prepared in step 7 of Example 78, and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.1 mmol) in dimethylacetamide. The reaction solution was sealed and placed in a microwave reactor (200° C./1 h). LC/MS indicated the reaction was complete. The reaction was concentrated under reduced pressure. The residue was purified on silica gel using a stepwise gradient of 1-3% methanol:methylene chloride to give the title compound (370 mg, 55%) as a yellow solid, mp 237° C. (dec.).
Reaction SMILES: [CH2:1]([Si:4]1(Cl)[N:8]([CH3:9])[C@@H:7]([CH3:10])[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:5]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:25][CH:26]([OH:28])[CH3:27]>C(Cl)Cl>[CH2:1]([Si:4]1([O:28][CH:26]([CH3:27])[CH3:25])[N:8]([CH3:9])[C@@H:7]([CH3:10])[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)O
Reactant: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[Si]1(OC(C)C)O[C@@H](c2ccccc2)[C@H](C)N1C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
To a solution of (4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (2.08 g, 7.8 mmol) in methylene chloride (25 mL) was added triethylamine (1.2 mL, 8.6 mmol). 2-Propanol (0.6 mL, 7.8 mmol) was added slowly by syringe and the mixture was allowed to stir for 12 hours. The methylene chloride was removed by distillation and pentane (20 ml) was added to the residue. The mixture was stirred for 3 hours. The mixture was then filtered through a pad of celite. The filtrate was concentrated to afford an oil which was distilled under reduced pressure (b.p. ˜72° C., ˜0.2 mm Hg) to yield 1.08 g (48%) of (4S,5S)-2-Allyl-2-isopropoxy-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine as a ˜2:1 mixture of diastereomers.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[CH3:1][N:2]([CH2:10][C:11]1[CH:12]=[N+:13]([O-:25])[CH:14]=[CH:15][CH:16]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(Cc1cccnc1)C(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(Cc1ccc[n+]([O-])c1)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a stirred solution of tert-butyl methyl(pyridin-3-ylmethyl)carbamate of Step A (0.50 g, 2.25 mmol) in dichloromethane (15 mL) was added 90% m-chloroperbenzoic acid (1.3 g, 6.8 mmol). After stirring overnight, the reaction was quenched with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.38 g of product as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11](N3CCC4C=CNC=4C3C)=[O:12])[CH:10]=2)[CH:7]=1.[CH3:23][CH:24]1[C:29]2[N:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[O:32][C:28]=2[CH2:27][CH2:26][NH:25]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:26][CH2:27][C:28]4[O:32][C:31]([C:33]([F:36])([F:34])[F:35])=[N:30][C:29]=4[CH:24]3[CH3:23])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2oc(C(F)(F)F)nc21
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: CC1c2nc(C(F)(F)F)oc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 4-methyl-2-trifluoromethyl-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:37])[C:9]2[N:10]=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=3)[S:12][C:13]=2[C:14]2[N:15](COCC[Si](C)(C)C)[CH:16]=[CH:17][N:18]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:37])[C:9]2[N:10]=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=3)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[CH:16][N:15]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1cc(-c2nc(C(O)c3ccc(Cl)cc3)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(C(O)c3ccc(Cl)cc3)c(-c3ncc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
N-{4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.120 g, 0.216 mmol) was dissolved in DCM (5 mL) and trifluoroacetic acid (5.0 mL, 65 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated, azeotroped with toluene and purified using column chromatography on silica gel (0 to 10% MeOH in DCM) to give the title compound (0.050 g, 50%). LCMS: (FA) ES+, 426, 428. 1H NMR (400 MHz, d4-methanol) δ: 8.68 (s, 1H), 8.38 (d, J=5.24 Hz, 1H), 7.64 (dd, J=5.25, 1.60 Hz, 1H), 7.45-7.37 (m, 2H), 7.30-7.23 (m, 2H), 7.25-7.09 (m, 2H), 6.37 (s, 1H), 2.20 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:32]1([CH3:41])[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[C:18]1([N:13]2[C:12]([C:35]3[CH:36]=[CH:37][C:32]([CH3:41])=[CH:33][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: Cc1ccccc1B(O)O
Solvent: COCCOC
Product: Cc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1

Procedure:
The title compound (17.5 mg) was prepared from 188.9 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 93.3 mg of p tolylboronic acid as in Example 199, using DME as the solvent. MS (ESI): exact mass calculated for C20H21N3, 303.17; found, m/z 304.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.26-7.23 (m, 2H), 7.21-7.16 (m, 3H), 7.15-7.12 (m, 2H), 7.04-7.01 (m, 2H), 3.11-3.07 (m, 2H), 3.04-3.00 (m, 2H), 2.98-2.96 (m, 2H), 2.68-2.65 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:16][CH:15]3[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CO>[Pd].C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:16][CH:15]3[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C2

Procedure:
The product from Example 10A (200 mg) was treated with 10% Pd/C (20 mg) in a 1:1 mixture of methanol:ethanol (5 mL) under a hydrogen atmosphere (1 atm). After filtration to remove the catalyst, the filtrate was concentrated and the residue triturated with diethyl ether to afford the title compound as a violet solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([F:14])([F:13])[F:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15](=[O:22])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[NH2:16].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[F:12][C:11]([F:14])([F:13])[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:16][C:15](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)C1(c2ccc(Br)cc2)CC1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(C2(C(F)(F)F)CC2)cc1
Temperature: 115 °C
Reaction time: 7 h

Procedure:
1-Bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene (1.00 g, 3.77 mmol) was mixed with tert-butyl carbamate (1.77 g, 15.1 mmol), Pd2(dba)3 (350 mg, 0.38 mmol), XantPhos (650 mg, 1.13 mmol), fine-powder cesium carbonate (7.40 g, 22.6 mmol) in 80 mL dioxane. The mixture was degassed using nitrogen stream for 5 min, and stirred in 115° C. bath under nitrogen atmosphere for 7 hours. It was cooled to RT, diluted with 200 mL EtOAc, well stirred, filtered using ChemGlass OP-6602-12 disposable funnel, concentrated in vacuo, and subjected to silica flash column using 0 to 1% MeOH in DCM to isolate tert-butyl 4-(1-(trifluoromethyl)cyclopropyl)phenylcarbamate. It was treated with 1:1 DCM/TFA (10 mL/10 mL) at RT for 10 min, concentrated in vacuo, taken into chloroform, washed with 1N NaOH (aq) and water, dried, concentrated and subjected to silica flash column to isolate 4-(1-(trifluoromethyl)cyclopropyl)aniline (330) (300 mg, 40%).
Reaction SMILES: COC(=O)[C@@H](NC(OC(C)(C)C)=O)CC1C=CC2O[C@@H](C3C=CC(OC(=O)C)=CC=3)COC=2C=1.Cl.[CH3:36][O:37][C:38](=[O:62])[C@@H:39]([NH2:61])[CH2:40][C:41]1[CH:60]=[CH:59][C:44]2[O:45][C@@H:46]([C:49]3[CH:54]=[CH:53][C:52]([O:55][C:56](=[O:58])[CH3:57])=[CH:51][CH:50]=3)[CH2:47][O:48][C:43]=2[CH:42]=1.[N+:63]([C:66]1[CH:71]=[CH:70][C:69]([S:72](Cl)(=[O:74])=[O:73])=[CH:68][CH:67]=1)([O-:65])=[O:64]>>[CH3:36][O:37][C:38](=[O:62])[C@@H:39]([NH:61][S:72]([C:69]1[CH:68]=[CH:67][C:66]([N+:63]([O-:65])=[O:64])=[CH:71][CH:70]=1)(=[O:73])=[O:74])[CH2:40][C:41]1[CH:60]=[CH:59][C:44]2[O:45][C@@H:46]([C:49]3[CH:50]=[CH:51][C:52]([O:55][C:56](=[O:58])[CH3:57])=[CH:53][CH:54]=3)[CH2:47][O:48][C:43]=2[CH:42]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)NC(=O)OC(C)(C)C
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
(S)-3-[(S)-2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-tert-butoxycarbonylamino-propionic acid methyl ester (208 mg) was converted to the HCl salt of (S)-3-[(S)-2-(4-acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-amino-propionic acid methyl ester according to General Procedure C. This intermediate was further reacted with 4-nitrobenzenesulfonyl chloride as described in General Procedure F to furnish (S)-3-[(S)-2-(4-acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (230 mg). LCMS (m/z): 558.
Reaction SMILES: CON(C)[C:4](=[O:29])[CH2:5][C@H:6]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[Li].[Cl:32][C:33]1[CH:38]=[C:37](I)[CH:36]=[C:35]([Cl:40])[N:34]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([C:4](=[O:29])[CH2:5][C@H:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH:36]=[C:35]([Cl:40])[N:34]=1
Reactant: CON(C)C(=O)C[C@H](c1ccc(-c2ccc(C(=O)O)cc2)cc1)c1ccccc1C
Reactant: Clc1cc(I)cc(Cl)n1
Agent: [Li]
Product: Cc1ccccc1[C@H](CC(=O)c1cc(Cl)nc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 74, step 5, from (R)-4′-(3-(methoxy(methyl)amino)-3-oxo-1-tolylpropyl)biphenyl-4-carboxylic acid, lithium salt and 2,6-dichloro-4-iodopyridine was prepared the title compound as light brown foam, MS (ESI−): m/z=488.2 ([M−H]−, 1Cl).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N+:35]([O-])=O)=[O:27])[CH:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:38]([F:41])([F:40])[F:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[NH:28][C:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]2[C:17]3[C:12](=[C:13]([C:38]([F:41])([F:39])[F:40])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[CH:1]([OH:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=1)=[O:27]
Reactant: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1ccccc1NC(=O)Nc1cccc(-c2c(C(O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from N-{3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}-N′-(2-nitrophenyl)urea by hydrogenation (Pd/C, 5 psi of H2). MS (ES) m/z 526.9.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[Cl:16][C:17]1[C:22]([C:23](O)=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19][CH:18]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:16][C:17]1[C:22]([C:23]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][CH:1]([CH3:3])[CH3:2])=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:19][CH:18]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC(C)Nc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 12.3 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-isopropylquinazoline-4,8-diamine (Intermediate-57, 140 mg, 0.69 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 223 mg, 0.78 mmol), oxalyl chloride (147 mg, 1.17 mmol), DMF (1 drop) and DIPEA (267 mg, 2.07 mmol) in CH2Cl2 (5 mL) to afford 40 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.38 (s, 1H), 8.69 (d, J=7.0 Hz, 1H), 8.48 (s, 1H), 8.16-8.14 (t, J=5.8 Hz, 1H), 8.10-8.07 (m, 2H), 7.55-7.51 (t, J=8.0 Hz, 1H), 7.42-7.40 (d, J=8.4 Hz, 1H), 7.36-7.33 (t, J=8.0 Hz, 1H), 4.56-4.51 (m, 1H), 4.31 (d, J=5.8 Hz, 2H), 1.28 (s, 3H), 1.25 (s, 3H), 1.14 (s, 9H); MS (m/z): 472.40 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: BrCc1ccccc1
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reaction time: 8 h

Procedure:
Treat a mixture of 2,6-dichloro-4-hydroxy-benzaldehyde (250 g, 1.3 mol) and potassium carbonate (361.8 g, 2.62 mol) in 2 L dimethylformamide with benzyl bromide (268.64 g, 1.57 mol). Stir the reaction at room temperature for 1 hour. Filter off solids and pour into 12 L of water. Filter off solid, wash several times with water, air dry and dissolve in ethyl acetate. Dry over magnesium sulfate, filter and concentrate under vacuum to ˜1.5 L. Allow to sit overnight then filter. Wash solid with minimal amount of hexane and vacuum dry. Concentrate the filtrate under vacuum and triturate with hexane to yield a second crop of product which when combined with the first crop equals 245 g white crystals. Repeat to obtain a 3rd crop of 80 g as a light-tan powder (88% overall yield): 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.43 (m, 5H), 7.28 (s, 2H), 5.25 (s, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][N:11]3[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]4[C:13](=[CH:14][C:15]([N+:23]([O-])=O)=[CH:16][CH:17]=4)[CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(O)C.[Zn]>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][N:11]3[CH2:20][C:19]([CH3:22])([CH3:21])[C:18]4[C:13](=[CH:14][C:15]([NH2:23])=[CH:16][CH:17]=4)[CH2:12]3)=[CH:26][CH:27]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1(C)CN(Cc2ccc(-n3ccnc3)cc2)Cc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CN(Cc2ccc(-n3ccnc3)cc2)Cc2cc(N)ccc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of Example 163A (1.45 g, 4.00 mmol) in 95% ethanol (20 mL) were added zinc (2 g, 30.6 mmol) and acetic acid (4 mL, 69.9 mmol). The reaction mixture was stirred for 4 hours at 50° C. Aqueous saturated NaHCO3 solution (200 mL) and CH2Cl2 (200 mL) were added to the reaction mixture and the suspension was filtered. The aqueous layer was extracted with CH2Cl2 (200 mL). The combined organic layers were washed with saturated NaCl (1×300 mL), dried over Na2SO4, filtered, and concentrated. The crude material was purified using the Chemflash system using a 120 g C18 column eluting with 40-80% methanol in water (0.8 g (NH4)2CO3 in 1 L of water) to provide the title compound. LC-MS: m/e=333 (M+H)+. 1H NMR (400 MHz, DMSO-d6), δ 8.25 (s, 1H), 7.73 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.11 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.41 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.16 (d, J=2.0 Hz, 1H), 4.76 (s, 2H), 3.62 (s, 2H), 3.43 (s, 2H), 2.31 (s, 2H), 1.15 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.Cl.[CH3:14][NH:15][O:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([NH:8][C:9]([N:15]([CH3:14])[O:16][CH2:17][C:18]([OH:20])=[O:19])=[S:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1N=C=S
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)cc1NC(=S)N(C)OCC(=O)O
Yield: 97.8 %

Procedure:
A mixture of 5-chloro-2-methoxyphenyl-isothiocyanate (11.45 g), N-methyl aminooxy acetic acid hydrochloride (8.15 g), triethylamine (20 g) and chloroform (250 mL) was heated at reflux for three hours, then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with 2N HCl (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give (17.1 g) of [[[[(5-chloro-2-metoxyphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil that solidifies upon standing. The acid (15.2 g) was dissolved in benzene (200 mL). Phosphorus pentachloride (10.4 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (40-60% methylene chloride in hexane). The title compound (5.1 g) was obtained as a solid, m.p. 189-191° C. Mass spectrum (El, M.+) m/z 286/288. 1H-NMR (DMSO-d6; 400 MHz) δ7.44 (d, 1H), 7.31 (s, 1H), 7.14 (d, 1H), 5.06 (s, 2H), 3.73 (s, 3H), and 3.63 ppm (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]([C:13]([N:15]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]2[C:21]([O-])=[O:22])=[O:14])=[C:11]([N+:28]([O-:30])=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-].CCOC(C)=O>C1COCC1>[CH2:1]([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]([C:13]([N:15]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]2[CH2:21][OH:22])=[O:14])=[C:11]([N+:28]([O-:30])=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)N2C[C@H](O)C[C@H]2C(=O)[O-])c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2C[C@H](O)C[C@H]2CO)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A solution of the ester 19 (3.8 g, 8.83 mmol, 1.0 equiv.) in THF (100 mL) was cooled to 0° C. and treated with LiBH4 (0.29 g, 13.25 mmol, 1.5 equiv.) in portions. After stirring for 30 min at 0° C., the reaction mixture was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 4 h at which time TLC (SiO2, EtOAc) revealed complete consumption of ester 19. The mixture was cooled to 0° C. again and water (100 mL) was carefully added followed by 1N HCl (250 mL) which provoked vigorous effervescence. After evaporation of the THF in vacuo, the mixture was neutralised to pH 7 with 1N NaOH. The aqueous solution was then extracted with EtOAc (4×70 mL), the combined organic layers washed with brine (50 mL), dried (MgSO4), filtered and evaporated in vacuo to furnished the pure diol 20 (3.2 g, 7.96 mmol, 90%), which was used in the subsequent reaction without further purification. [α]29D=−96° (c=0.15, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.85-1.99 (m, 1H, 1-H), 2.09-2.28 (m, 1H, 1-H), 3.11-3.20 (m, 1H, 11-H), 3.25-3.39 (m, 1H, 11-H), 3.70-3.82 (m, 1H, 3-H), 3.85-4.04 (m, 5H, 3-H, 7-OMe, OH), 4.30-4.38 (m, 1H, 11a-H), 4.46-4.61 (m, 2H, 2-H), 5.20 (m, 2H, OCH2Ph), 6.86 (s, 1H, 6-H), 7.29-7.50 (m, 5H, Ph), 7.74 (s, 1H, 9-H); 13C NMR (CDCl3, 100 MHz): δ 37.1, 56.8, 56.9, 59.9, 65.0, 69.4, 71.4, 109.1, 109.3, 127.6, 127.7, 128.5, 128.8, 135.2, 137.2, 148.2, 155; IR (neat): 3357, 2938, 1614, 1576, 1520, 1454, 1434, 1333, 1276, 1220, 1069, 1048, 1006, 730, 698, 647 cm−1; MS (ES+) m/z (relative intensity) 426 ([M+Na]+., 5), 403 ([M+H]+., 100), 404 ([M+2H]+., 40).