Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@@H:9]([CH3:29])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([CH3:28])[CH2:22][C:21]3[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=3[O:19]2)=[N:16][CH:17]=1>N1C=CC=CC=1.CO.[OH-].[Na+]>[OH:27][C:25]1[CH:24]=[CH:23][C:21]2[CH2:22][C:18]([C:15]3[N:16]=[CH:17][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:1](=[O:3])[CH3:2])[CH3:29])=[CH:13][CH:14]=3)([CH3:28])[O:19][C:20]=2[CH:26]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](N)COc1ccc(C2(C)Cc3ccc(O)cc3O2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](C)COc1ccc(C2(C)Cc3ccc(O)cc3O2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of acetic anhydride (0.126 mL) was added dropwise to a solution of diastereomer of 2-(5-{[(2S)-2-aminopropyl]oxy}pyridin-2-yl)-2-methyl-2,3-dihydro-1-benzofuran-6-ol (500 mg) in pyridine (15 mL) at ambient temperature. After being stirred at ambient temperature for 2 hr, the mixture was diluted with methanol (15 mL) and 4 M sodium hydroxide (10 mL). The mixture was stirred at ambient temperature for 15 hr. The organic solvent was removed under reduced pressure, and the aqueous solution was acidified with 4 M hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (350 mg).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14].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.[Br:48][C:49]1[CH:50]=[C:51]([S:55][C:56]2[C:61](O)=[CH:60][CH:59]=[CH:58][N:57]=2)[CH:52]=[CH:53][CH:54]=1>C1COCC1>[Br:48][C:49]1[CH:50]=[C:51]([S:55][C:56]2[C:61]([O:14][CH2:13][CH2:12][CH2:11][C:10]3[CH:9]=[CH:8][N:7]=[CH:6][C:5]=3[OH:4])=[CH:60][CH:59]=[CH:58][N:57]=2)[CH:52]=[CH:53][CH:54]=1
Reactant: COCOc1cnccc1CCCO
Reactant: Oc1cccnc1Sc1cccc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Oc1cnccc1CCCOc1cccnc1Sc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (1.59 g, 9.2 mmol) obtained in Example 2 and triphenylphosphine (2.78 g, 10.6 mmol) are dissolved in THF (40 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (1.85 g, 9.2 mmol) and 2-(3-bromophenylthio)-3-pyridinol (2.00 g, 7.1 mmol) obtained in Reference Example 1 under ice-cooling. The mixture is stirred at room temperature for 30 minutes, and the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (50 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (200 ml) and a 15% aqueous hydrochloric acid solution (10 ml), and the mixture is heated under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/ethyl acetate), and further recrystallized from diethyl ether to give the title compound (1.98 g) as colorless crystals, m.p. 169-171° C.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([NH:28][CH2:27][C:23]4[O:22][CH:26]=[CH:25][CH:24]=4)=[O:19])=[CH:20][CH:21]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NCc1ccco1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)NCc1ccco1
Yield: 91 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.3 g, 1.04 mmol) and furan-2-ylmethaneamine (0.101 g, 1.04 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(furan-2-ylmethyl)acetamide as a white solid (0.346 g, 90.8% yield).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[C:19]1([CH2:25][SH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC#N>[CH2:25]([S:26][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cc([N+](=O)[O-])ccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 133.2 %

Procedure:
To a solution of 2-chloro-5-nitrobenzonitrile (50 g, 0.15 mol) in MeCN (1000 mL) was added K2CO3 (45.5 g, 0.33 mol) and phenylmethanethiol (34 g, 0.27 mol). The mixture was stirred at room temperature overnight. The mixture was filtered through the celite pad and the filtrate was concentrated in vacuo to give 2-(benzylthio)-5-nitrobenzonitrile (54 g, 73%) as a yellow solid. 1H NMR CDCl3 400 MHz δ 8.43 (s, 1H), 8.27-8.25 (m, 1H), 7.44-7.31 (m, 6H), 4.35 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24]>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:24]
Reactant: COC(=O)c1ccccc1N
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NC(=O)c1ccc(OC)c(OC)c1
Reaction time: 0.5 h

Procedure:
Methyl 2-aminobenzoate (compound A) (2.0 g) was dissolved in anhydrous methylene chloride (40.0 ml). Subsequently, pyridine (2.0 ml) and 3,4-dimethoxybenzoyl chloride (compound B) (3.14 g) were added to the solution at room temperature, and the mixture was stirred at that temperature for 30 min. After the completion of the reaction, distilled water was added thereto, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over sodium sulfate, and was then concentrated to give methyl 2-[(3,4-dimethoxybenzoyl)amino]benzoate as a useful intermediate (4.17 g, yield 100%).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[CH3:11][O:12][CH:13]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH3:14].[C:29](=[O:31])=[O:30]>CCOCC>[CH3:11][O:12][CH:13]([C:15]1[CH:20]=[C:19]([C:29]([OH:31])=[O:30])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH3:14]
Reactant: COC(C)c1cc(Br)ccc1-c1ccccc1C
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: COC(C)c1cc(C(=O)O)ccc1-c1ccccc1C
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
A solution of tert-butyllithium in pentane (1.5M, 8.05 mL, 12.1 mmol) was added into anhydrous Et2O (40 mL) cooled at −78° C. under nitrogen atmosphere. Then a solution of 1-(4-bromo-2′-methylbiphenyl-2-yl)ethyl methyl ether (1.84 g, 6.03 mmol) in anhydrous Et2O (10 mL) was added dropwise over 10 minutes. The resulting mixture was stirred at −78° C. for 25 minutes, and then a large excess of dry ice was added and the cooling bath was removed. The reaction mixture was stirred until the temperature came back at RT, then diluted with water (20 ml) and a 5N aqueous solution of NaOH (0.5 mL). The layers were separated and the aqueous layer was washed with Et2O (20 ml). The organic layers were extracted with a 0.1N aqueous solution of NaOH (20 mL). The combined aqueous layers were acidified with a 5N aqueous solution of HCl (until pH˜1) and extracted with MTBE (2×50 mL). The organic layers were washed with brine (30 mL), combined, dried (Na2SO4) and concentrated under vacuum to give a pale yellow solid. After crystallization from a mixture of Et2O and heptane, the title compound was obtained as a white powder. HPLC (Method A) Rt 4.2 min (Purity: 98.2%). LC/MS (Method B): 269.1 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.03 (s, 1H), 8.09 (d, J=1.8 Hz, 0.4H), 8.07 (d, J=1.8 Hz, 0.6H), 7.89 (dd, J=7.9, 1.8 Hz, 1H), 7.36-7.24 (m, 3H), 7.22 (d, J=7.9 Hz, 0.4H), 7.20 (d, J=7.9 Hz, 0.6H), 7.13 (d, J=6.9 Hz, 0.4H), 7.07 (d, J=6.9 Hz, 0.6H), 4.12 (q, J=6.4 Hz, 0.4H), 3.92 (q, J=6.4 Hz, 0.6H), 3.05 (s, 1.2H), 3.04 (s, 1.8H), 2.03 (s, 1.8H), 1.98 (s, 1.2H), 1.19 (d, J=6.4 Hz, 1.8H), 1.13 (d, J=6.4 Hz, 1.2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:3]=1.[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9](=[CH:20][O:21][CH2:22][CH3:23])[C:10]([CH:12]2[CH2:13][CH2:14]2)=[O:11])=[C:4]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CS(=O)(=O)c1cc(Cl)ccc1C(=O)CC(=O)C1CC1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(Cl)cc1S(C)(=O)=O)C(=O)C1CC1
Yield: 99.7 %

Procedure:
A mixture of 1-(4-chloro-2-methylsulphonylphenyl)-3-cyclopropylpropan-1,3-dione (7.1 g) and triethyl orthoformate (6.9 g) in acetic anhydride was stirred and heated at reflux for 2 hours. The mixture was evaporated to dryness, toluene was added and the solution was re-evaporated to give 1-(4-chloro-2-methylsulphonylphenyl)-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (8.4 g) as a red gum which was not purified further.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:8]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[C:7](=[O:25])[C:6]=1[OH:26])=[O:4].[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>O>[CH3:1][CH:2]([CH3:27])[C:3]([C:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:8]([C:18]2[CH:23]=[CH:22][C:21]([C:30]3[CH:31]=[CH:32][S:28][CH:29]=3)=[CH:20][CH:19]=2)[C:7](=[O:25])[C:6]=1[OH:26])=[O:4]
Reactant: COc1ccccc1C1C(C(=O)C(C)C)=C(O)C(=O)N1c1ccc(Br)cc1
Reactant: OB(O)c1ccsc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1C1C(C(=O)C(C)C)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Yield: 29.1 %

Procedure:
After a mixture of (−)-4-(2-methylpropionyl)-3-hydroxy-1-(4-bromophenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (0.10 g, 0.23 mmol), 3-thiophene-boronic acid (0.045 g, 0.35 mmol), tripotassium phosphate (0.148 g, 0.7 mmol), 1,2-dimethoxyethane (3 mL) and water (3 mL) was placed in a flask under nitrogen, 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.019 g, 0.023 mmol) was added to the mixture, and the resulting mixture was stirred at reflux for 3 hours. To the reaction mixture was added water (50 mL), and the resulting mixture was extracted with dichloromethane (50 mL). The extract was washed with brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (methanol/chloroform). The resulting compound was triturated with ethyl acetate/n-hexane to give (−)-4-(2-methylpropionyl)-3-hydroxy-1-(4-thiophene-3-ylphenyl)-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (0.029 g, yield: 29%) as pale brown powder.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[C:8]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:7]=1[N+:22]([O-:24])=[O:23])(=O)C.Cl.O>CO>[CH2:18]([CH:17]([NH:16][C:8]1[C:7]([N+:22]([O-:24])=[O:23])=[C:6]([C:11]([CH3:12])=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14])[CH2:5][OH:4])[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(COC(C)=O)c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(CO)c1[N+](=O)[O-]

Procedure:
A sample of 3-[(1-ethylpropyl)amino]-6-methyl-2,4-dinitrobenzyl acetate (23.1 g; 0.068 mol) is added to a mixture of concentrated hydrochloric acid (30 ml), water (40 ml) and methanol (320 ml). The reaction mixture is refluxed for 4 hours, cooled down and concentrated in vacuo. It is then diluted with water, extracted with ether, and the ether layer dried. The ether is removed in vacuo to leave a red oil, which readily solidifies to a yellow-orange solid (19.9 g; 98.5%). A similarly prepared and purified sample has a melting point of 51°-54° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.Cl.[NH2:13][OH:14]>CO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[N:13][OH:14]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: NO
Agent: Cl
Solvent: CO
Product: ON=C1CCc2c(Br)cccc21
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (3.00 g, 14.21 mmol) in MeOH (40 mL) was added hydroxylamine hydrochloride (3.95 g, 56.9 mmol). The resulting mixture was refluxed for 1 h and concentrated in vacuo. The resulting residue was partitioned between DCM and 50% saturated NaHCO3, and stirred vigorously for 20 min. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (3.18 g, 99% yield) as a pale yellow solid. LCMS, [M+H]+=226.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[N:3][CH:2]=1.Cl.[OH:21][C:22]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:22]=4[OH:21])[CH2:27]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[N:3][CH:2]=1
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccncn2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccncn3)nc3ccccc13)C2
Yield: 13 %

Procedure:
Reaction of 2-(4-pyrimidinyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 70 (13% yield) as a light brown solid. 1H NMR (300 MHz, DMSO-d6) δ 2.61 and 2.90 (2t, 2H), 3.49 and 4.04 (2t, 2H), 3.73 and 3.80 (2s, 3H), 4.38 and 4.92 (2s, 2H), 6.30 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.90-8.31 (m, 4H), 8.48-8.54 (m, 1H), 8.68-8.74 (2s, 1H), 9.06-9.43 (m, 1H), 9.44 (s, 1H); MS (ESI) m/z 414 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](N)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+].NC(N)=O>O>[Cl:1][C:2]1[CH:9]=[C:8]([OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(O)cc1Cl
Yield: 32.8 %

Procedure:
The 2-chloro-4-aminobenzonitrile (57 g, 0.37 m) was added to a cold stirred solution of concentrated sulfuric acid (115 g) in water (1,000 ml). Then a cold solution of sodium nitrite (26.5 g, 0.38 m) in water (250 ml) was added to the suspension solution at a temperature between 0° and 6° C. Upon addition of the sodium nitrite, stirring continued for approximately three hours at which time urea (3 g) was added to the reaction mixture. The reaction mixture reacted at a temperature between 69° and 76° C. for approximately three hours. The reaction product was filtered and crystallized from water to yield the fifth step product 2-chloro-4-hydroxybenzonitrile (18.8 g, 33%, mp 157°-158° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][C:14]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[C:16]([CH3:22])[N:15]=1.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[F:12])[N:1]=2)[CH:17]=[C:16]([CH3:22])[N:15]=1
Reactant: NC(=O)c1c(N)cc(F)cc1F
Reactant: Cc1cc(C=O)cc(C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-amino-4,6-difluoro-benzamide (1.03 g, 6.00 mmol) and 2,6-dimethyl-pyridine-4-carbaldehyde (0.81 g, 6.00 mmol) in N,N-dimethyl acetamide (15 mL), sodium hydrogen sulfite (58.5 wt %, 1.31 g, 7.20 mmol) and p-toluenesulfonic acid monohydrate (0.11 g, 0.60 mmol) were added and the reaction mixture was stirred at 115° C. for 16 hours. The solvent was evaporated in vacuo, water was added, and the precipitated solid was filtered to give 2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one as a yellow solid, which was used in the next step without further purification. Yield: 0.72 g (42%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].BrC1C=CC(S([O:17][C@@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)(=O)=O)=CC=1.[Br:34][C:35]1[C:44](O)=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][CH3:47])[CH:41]=2)[N:36]=1>CN1C(=O)CCC1.CCOC(C)=O>[Br:34][C:35]1[C:44]([O:17][C@H:18]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C@H:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19]2)=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][CH3:47])[CH:41]=2)[N:36]=1
Reactant: COc1ccc2nc(Br)c(O)cc2c1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2cc3cc(OC)ccc3nc2Br)CN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Cs2CO3 (10.7 g, 32.9 mmol) was added to a stirred mixture of 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (8.78 g, 18.9 mmol) and 2-bromo-6-methoxyquinolin-3-ol (4.18 g, 16.45 mmol) in NMP (46 mL). The resulting mixture was stirred at 50° C. for 3 h, then cooled and diluted with EtOAc. The organics were washed with saturated aqueous NaHCO3, water and brine then dried over Na2SO4. Filtration and removal of the volatiles gave a residue, which was purified by column chromatography on silica gel (gradient elution: 1 to 100% EtOAc in petroleum ether) to give the title compound (5.56 g, 70.2%). LCMS (ES+) m/z 481, 483 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[C@H:4]([O:12][CH3:13])[CH2:3]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:13][O:12][C@@H:4]1[CH2:3][C@@H:2]([O:1][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:7][CH2:6][C@H:5]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)[C@@H]1CC[C@H](O)C[C@H]1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H](OS(C)(=O)=O)C[C@H]1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A solution of methyl (1R,2R,4S)-4-hydroxy-2-methoxycyclohexanecarboxylate (racemic) (1.50 g, 7.97 mmol) in dichloromethane (40 mL) was treated with methanesulfonyl chloride (1.23 mL, 15.9 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h and partitioned between ethyl acetate and water. The organic phase was concentrated and purified on silica gel (eluting with 50% ethyl acetate in hexanes) to give the desired product (2.12 g, 91%). 1H NMR (400 MHz, CDCl3) δ 4.62 (1H, m), 3.71 (3H, s), 3.48 (1H, m), 3.33 (3H, s), 3.02 (3H, s), 2.64 (1H, m), 2.32 (1H, m), 2.19 (1H, m), 2.00 (1H, m), 1.60-1.42 (3H, m) ppm.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([CH2:20][C@H:21]([NH2:25])[C:22](O)=[O:23])[CH:14]=1>CCOC(C)=O>[NH2:25][CH:21]([CH2:20][C:15]1[CH:14]=[CH:13][CH:18]=[C:17]([OH:19])[CH:16]=1)[C:22]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: OCc1ccccc1
Reactant: N[C@@H](Cc1cccc(O)c1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To 10 mL of benzyl alcohol at −5° C. was added, with stirring, 0.2 mL of SOCl2 slowly. The clear colorless solution was cooled to −5° C. and 490 mg of meta-Tyrosine was added. After 5 min, the resulting solution was heated to 120° C. overnight. 100 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na3SO4, filtered and concentrated to afford 170 as a white solid (430 mg, 59%). 1H NMR (DMSO): δ 1.90 (s, 3H), 2.87 (dd, 1H, J=13.1, 6.5 Hz), 2.94 (dd, 1H, J=13.1, 6.5 Hz), 3.73 (t, 1H, J=6.5 Hz), 5.19 (s, 2H), 6.70 (d, 1H, J=7.7 Hz), 6.75 (s, 1H), 7.17 (t, 1H, J=7.7 Hz), 7.41 (d, 1H, J=7.0 Hz), 7.48 (m, 5H), 9.37 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([S:9][C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.CC(C)=[O:21].ClC1C=C(C=CC=1)C(OO)=O>C(OCC)(=O)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([S:9]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(Sc2cccc(C(F)(F)F)c2)nc1
Reactant: CC(C)=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)c2cccc(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(3-(Trifluoromethyl)phenylthio)-3-aminopyridine (4.0 grams) was dissolved in 50 ml. of acetone and m-chloroperoxybenzoic acid (4.0 grams) added. The solution was allowed to stir at room temperature for 2 hours, and an additional 1.0 gram of m-chloroperoxybenzoic acid was added. The reaction mixture was passed over a column of silica gel with ethyl acetate, and the fraction corresponding to the product collected and crystallized from ethyl acetate-hexanes, yield, 4.0 grams m.p. 74°-76° C.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([O:18]C)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][O:21][CH3:22])=[CH:8]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][O:21][CH3:22])=[CH:8]2)=[CH:23][CH:24]=1
Reactant: COCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12
Temperature: 40 °C
Yield: 72 %

Procedure:
To a solution of methyl 1-(4-fluorobenzyl)-3-(methoxymethyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. (960 mg 1.2.924 mmol) in methanol (10 mL) was added lithium hydroxide monohydrate (246 mg 5.847 mmol, 2 eq.) and water (5 mL), and the clear solution was warmed to 40° C. for 15 hours. Methanol was removed under vacuum and 1 M HCl added (5.8 mL 5.847 mmol, 2 eq.). The crude product precipitated and was filtered under vacuum, washed with ether (40 ml) and dried in vacuo at 75° C. to give the title product as a white powder 664 mg (72%). LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—3 minutes, ESI, +mode): RT-0.828 min, m/e=315.2 (M+H+, base). 1H-NMR (300 MHz, DMSO): δ=3.28 (s, 3H), 4.64 (s, 2H), 5.62 (s, 2H), 7.20 (t, 2H), 7.38 (m, 2H), 7.94 (s, 1H), 8.36 (s, 1H), 8.97 (s, 1H).