Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=C)=[CH:23][CH:22]=5)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:20][N:19]=[C:18]4[C:21]5[C:26]([CH2:27][CH2:28][C:17]=34)=[CH:25][C:24]([CH:29]=[O:35])=[CH:23][CH:22]=5)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a clear solution of 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 89A, 0.15 g, 0.368 mmol) in THF (1.5 mL) were added NMO (50% in water, 0.092 mL, 0.442 mmol) and osmium tetroxide (4% in water, 0.068 mL, 0.011 mmol) at room temperature. The solution was vigorously stirred at room temperature overnight. Sodium periodate (0.102 g, 0.479 mmol) in water (0.5 mL) was added. The mixture was stirred vigorously at room temperature under nitrogen for 30 min. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×2 mL). The combined ethyl acetate extracts were dried (sodium sulfate), filtered through a pad of silica gel which was then rinsed with ethyl acetate and concentrated to give 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.15 g, 0.366 mmol, 100% yield) as a green solid. The compound had an HPLC retention time=3.64 min. (condition C); LC/MS M+1=409.9.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[S:8])[NH2:7].Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C(O)C.O>[C:13]1([C:11]2[N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[S:8][CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=S)c1cccs1
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2csc(-c3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
To a stirred solution of 2-thiophenethiocarboxamide (1.56 g, 0.0109 mole) in ethanol (50 mL) was added 2-bromoacetophenone (2.19 g, 0.0110 mole). After complete addition the mixture was heated at reflux for two hours, then was allowed to cool to room temperature and stir for approximately 18 hours. The solvent was removed from the reaction mixture by evaporation under reduced pressure, leaving an oil which solidified. This solid was suspended in water and extracted twice with methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 2.48 g of 4-phenyl-2-(thien-2-yl)thiazole as a solid, mp 51°-53° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 5.6 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (1.70 g, 3.426 mmol) and methylamine (2 ml, 4 mmol, 2.0M in THF) were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (92 mg, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.28 (brs, 1H), 8.67 (brs, 1H), 8.61 (s, 1H), 7.89 (d, J=9 Hz, 1H), 7.82 (brs, 1H), 7.68 (s, 1H), 7.17 (d, J=12 Hz, 1H), 6.00 (s, 1H), 3.58 (s, 3H), 2.90 (d, J=5 Hz, 3H), 2.08 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 480.2(M+H+).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:29](=[O:30])[CH2:28][N:27]([CH3:31])[C:26]1=[O:32])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:29](=[O:30])[CH2:28][N:27]([CH3:31])[C:26]1=[O:32])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C)C1=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.3 %

Procedure:
A solution of 0.133 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-N-(3-methyl-2,5-dioxo-1-imidazolidinyl)valeramide in 5 ml of methanol was treated with 0.014 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2.5 hours at room temperature and then evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with diethyl ether and hexane to give 0.049 g of (E)-2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methyl-N-(3-methyl-2,5-dioxo-1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:17]3[CH2:25][OH:26])=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27]O>C(#N)C.Cl>[CH3:27][O:26][CH2:25][C:17]1[N:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: CO
Reactant: OCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Agent: Cl
Solvent: CC#N
Product: COCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Reaction time: 2 h

Procedure:
{1-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]-1H-indol-2-yl}methanol (15 mg) was dissolved in a mixture of methanol, acetonitrile, and 1 N HCl. After standing at room temperature for 2 hours, the solution was purified by semi-prep LC-MS to give 1.1 mg of the desired product. LC-MS (C23H28N2O2 calc'd 364) m/z 365 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.66-7.61 (m, 1H), 7.33 (d, J=9 Hz, 2H), 7.20-6.75 (m, 5H), 6.66 (s, 1H), 4.40 (s, 2H), 4.10 (t, J=6.3 Hz, 2H), 3.28 (s, 3H), 2.82-2.71 (m, 6H), 2.17-2.08 (m, 2H), 1.87 (m, 4H).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].[Cl:9][C:10]1[CH:11]=[C:12]([N:17]=[C:18]=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([N:2]=[C:3]2[CH2:7][CH2:6][CH2:5][N:4]2[CH3:8])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CN1CCCC1=N
Agent: Cl
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
A 6.73 g. (0.05 mole) sample of 2-imino-1-methylpyrrolidine HCl is converted to free base in the usual way. To the K2CO3 -dried, benzene extracts are added a pre-filtered solution of 3,4-dichlorophenylisocyanate (9.4 g.; 0.05 mole). Almost immediately there is a separation of product. After stirring for a short time, the product is collected and recrystallized from acetone-methanol-water and finally from acetone-water to give the pure product, 1-(3,4-dichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. m.p. = 160°-161° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].Cl[S:29]([C:32]1[CH:33]=[CH:34][C:35]([O:53][CH3:54])=[C:36]([CH:52]=1)[C:37]([O:39][CH2:40][CH2:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1)(=[O:44])=[O:43])=[O:38])(=[O:31])=[O:30].O>C(Cl)Cl>[C:48]1([CH3:51])[CH:49]=[CH:50][C:45]([S:42]([CH2:41][CH2:40][O:39][C:37](=[O:38])[C:36]2[CH:52]=[C:32]([S:29]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:31])=[O:30])[CH:33]=[CH:34][C:35]=2[O:53][CH3:54])(=[O:44])=[O:43])=[CH:46][CH:47]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
To a clear solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (740 mg, 2.0 mmol) and NaH (60 mg, 2.5 mmol) in 10 mL of CH2Cl2 was added 2-(p-toluenesulfonyl)ethyl 5-chlorosulfonyl-2-methoxybenzoate (Intermediate 7, 1.0 g, 2.3 mmol). The resulting mixture was stirred at room temperature for 1.5 h. Thereafter water was added and the mixture was extracted with CH2Cl2. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a thick oil. The oil was purified by column chromatography (silica gel, CH2Cl2 to 2% MeOH in CH2Cl2) to give 1.0 g (65%) of 2-methoxy-5-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 8).
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:12]=[CH:11][CH:10]=[CH:9]1.[F:20][C:21]([F:34])([F:33])[C:22]([N:24]1[C@H:29]2[CH2:30][CH2:31][C@@H:25]1[CH2:26][C:27](=O)[CH2:28]2)=[O:23]>ClC(Cl)C>[F:34][C:21]([F:20])([F:33])[C:22]([N:24]1[CH:29]2[CH2:30][CH2:31][CH:25]1[CH2:26][C:27]1([O:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:8]3[CH:9]=[CH:10][CH:11]=[C:12]13)[CH2:28]2)=[O:23]
Reactant: O=C1C[C@H]2CC[C@@H](C1)N2C(=O)C(F)(F)F
Reactant: Oc1ccccc1-n1cccc1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1C2CCC1CC1(C2)Oc2ccccc2-n2cccc21)C(F)(F)F
Temperature: 70 °C
Yield: 51.4 %

Procedure:
A solution of TFA (387 μL, 5.02 mmol) in dichloroethane (18 mL) was added to 2-pyrrol-1-ylphenol (401 mg, 2.52 mmol) and (1R,5S)-8-(2,2,2-trifluoroacetyl)-8-azabicyclo[3.2.1]octan-3-one (620 mg, 2.80 mmol). The solution was heated at 70° C. overnight. The solvent was evaporated and the crude residue was purified by column chromatography (silica gel: 0-10% EtOAc in hexanes) to afford 2,2,2-trifluoro-1-(8′-azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]-8′-yl)ethanone as a clear oil (469 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J=7.5 Hz, 1H), 7.07-6.94 (m, 4H), 6.23 (t, J=3.2 Hz, 1H), 5.87 (d, J=3.4 Hz, 1H), 4.74 (d, J=7.4 Hz, 1H), 4.42 (s, 1H), 2.50-2.34 (m, 2H), 2.34-2.16 (m, 3H), 2.16-1.89 (m, 3H). ESI-MS m/z calc. 362.4. found 363.3 (M+1)+; Retention time: 2.07 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26](Br)[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)#[N:40].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:30][N:21]4[N:22]=[C:23]5[C:28]([CH:27]=[C:26]([C:45]6[CH:44]=[CH:43][CH:42]=[C:41]([C:39]#[N:40])[CH:46]=6)[CH:25]=[CH:24]5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(Br)ccc5nn4cc3-c3ccccc3)cc2)CCC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(-c6cccc(C#N)c6)ccc5nn4cc3-c3ccccc3)cc2)CCC1

Procedure:
100 mg (0.18 mmol) {1-[4-(9-Bromo-3-phenylpyrimido[1,2-b]indazole-2-yl)phenyl]-cyclobutyl}carbamic acid tert-butyl ester (intermediate example Int-2-0), 51.6 mg (0.35 mmol) (3-cyanophenyl)boronic acid, 14.3 mg (0.02 mmol) bis(diphenylphosphino)ferrocenedichloropalladium(II) and 55 mg (0.53 mmol) sodium carbonate in 1.8 mL dioxane and 0.3 mL water were heated in a microwave vial which had been sealed with a microwave cap for 18 hours at 105° C. (heating block). After the usual work up, the crude mixture (131.2 mg) was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23](O)[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>O1CCCC1>[C:35]([C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[CH:19]([CH2:18][CH2:17][C@@H:16]3[C@@H:15]2[CH2:14][CH2:13][C@@:12]2([CH3:27])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
To tetrahydrofuran was added 0.1 mole of lithocholic acid and 0.1 mole of triethylamine, and the resulting solution was maintained at a temperature below 4° C. in an ice bath. 0.12 mole of acetyl chloride was slowly added thereto, and the resulting solution was reacted for 8 hours. Thereafter, residual solvent was removed by using a vacuum distillator. A compound was extracted by using ethyl acetate, and washed with water a few times, to obtain 3α-acetylcholanic acid. To tetrahydrofuran was added 0.2 mole of 3α-acetylcholanic acid thus obtained and 0.3 mole of acetic anhydride. 0.21 mole of tert-butanol was added to the resulting solution. Then, the resulting solution was reacted for 12 hours, to obtain 3α-acetyl tert-butyl lithocholate of formula 2 (yield: 68%).
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na]>CO.O1CCCC1>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 75.0 g (0.226 mol) of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of 807 mL of methanol and 807 mL of tetrahydrofuran at -2° C., was added 13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borehydride over one hundred minutes. The solvents were removed under reduced pressure at 40° C. and the residue dissolved in ethyl acetate (approx. 1L). The solution was washed sequentially with 1M potassium hydrogen sulfate, saturated sodium bicarbonate and then saturated sodium chloride solutions. After drying over anhydrous magnesium sulfate and filtering, the solution was removed under reduced pressure. To the resulting oil was added hexane (approx. 1L) and the mixture warmed to 60° C. with swirling. After cooling to room temperature, the solids were collected and washed with 2L of hexane. The resulting solid was recrystallized from hot ethyl acetate and hexane to afford 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150°-151° C. and M+Li+ =340.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[N:10]=2)[CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.C1(C)C=CC=CC=1>[C:13]1([C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1)c1cn2cc(Br)ccc2n1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1cn2cc(-c3ccccc3)ccc2n1
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
0.391 g of (6-bromoimidazo[1,2-a]pyridin-2-yl)(phenyl)methanone, 0.237 g of phenylboronic acid, 45 mg of tetrakis(triphenylphosphine)palladium, 4 mL of aqueous 2M sodium carbonate solution, 6 mL of acetonitrile and 6 mL of toluene are introduced into a 20 mL microwave tube. The mixture is stirred for 20 minutes in a microwave machine set at 150° C. After cooling, the organic phase is separated out, dried and evaporated. The residue is taken up in a mixture of dichloromethane and pentane. The solid is filtered off and then purified by trituration in methanol to give 0.16 g of phenyl(6-phenylimidazo[1,2-a]pyridin-2-yl)methanone in the form of an off-white solid.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:21])[CH3:20])=[CH:15][C:14]=1[CH3:22]>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][C:14]=1[CH3:22]
Reactant: Cc1cc(C(C)O)ccc1Br
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Pyridinium chlorochromate (48 g, 223 mmol) was added to a solution of 1-(4-bromo-3-methylphenyl)ethanol (31.9 g, 148 mmol) in dichloromethane (800 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=25:1) to give 1-(4-bromo-3-methylphenyl)ethanone (27.3 g, 87%).
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.Cl[CH2:41][C:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=O>>[CH2:45]([N:44]([CH2:47][CH3:48])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)[CH3:46]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 89.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N,N-diethylacetamide (8.1 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.2 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]2)[CH:12]=[CH:11][CH:10]=1.[CH3:29][C:30]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:31]=1[CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:29][C:30]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:31]=1[CH2:32][O:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]2)[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3O)n2)c1C(F)(F)F
Reactant: Cc1ccc(CO)c(C)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3OCc3ccc(C)cc3C)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the title compound from Example 15 Step A (200 mg, 0.397 mmol), 2,4-dimethylbenzyl alcohol (81.0 mg, 0.596 mmol), and triphenylphosphine (156 mg, 0.596 mmol) in DCM (2 mL) was added diisopropyl azodicarboxylate (0.114 mL, 0.596 mmol), and the resulting mixture was stirred at ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 20% EtOAc in hexanes, then 20 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 594.8 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.85-7.81 (m, 2H), 7.60 (d, J=7.5 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.95-6.92 (m, 2H), 4.69 (s, 2H), 4.41 (q, J=7.0 Hz, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 1.43 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: CCOC(=O)CC(NC(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1

Procedure:
Corresponding to Example 3a, 5.0 g of (1b) were acetylated by addition of benzoyl chloride. A white solid was obtained (yield: 3.3 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:33]([CH3:34])=[CH:32][N:31]([CH3:35])[C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:33]([CH3:34])=[CH:32][N:31]([CH3:35])[C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)c(C)cn5C)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4cnc5c(c4)c(C)cn5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate: (28 mg, 0.044 mmol) in THF/CH3OH (1.0 mL/1.0 mL) was added 2N NaOH (0.22 mL, 0.44 mmol). The reaction mixture was heated at 50° C. for 2 h and the crude was purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C34H31ClN4O3S: 611.2 (M+H+); Found: 611.2 (M+H+); 1H NMR (400 MHz, CD3OD) δ 9.11 (s, 1H), 8.79 (d, J=5.6 Hz, 1H), 8.18-7.64 (m, 8H), 7.32 (s, 1H), 5.29 (s, 1H), 3.96 (s, 3H), 2.66 (s, 3H), 2.34 (s, 3H), 0.99 (s, 9H).