Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12])=[O:5])[CH3:2].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9][NH:8][C:7]1=[O:12])=[O:5])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1NCCNC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)NCCN1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
To a cold (-20° C.) solution of above 2-oxopiperazine-3-carboxylic acid ethyl ester (0.34 g) in tetrahydrofuran are dropwise added benzyl chloroformate (340 mg) and triethylamine (202 mg). After standing for 30 minutes the reaction mixture is concentrated in vacuum, diluted with ethyl acetate, and chromatographed to give oily 2-oxo-4-benzyloxycarbonylpiperazine-3-carboxylic acid ethyl ester (320 mg) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][CH2:15]O)[CH:3]=1.P(Br)(Br)[Br:18].O>C1(C)C=CC=CC=1>[Br:18][CH2:15][CH2:14][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCc1cc(Cl)ccc1-c1ccccc1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2ccccc2)c(CCBr)c1
Reaction time: 20 h
Yield: 119.4 %

Procedure:
To a solution, maintained at 5° C., of 710 mg (3.05 mmol) of 2-(4-chlorobiphenyl-2-yl)ethanol, prepared in Example 51, in 10 ml of toluene are added 97 μl (1.02 mmol) of PBr3, and the reaction medium is allowed to return to room temperature. After stirring for 20 hours, the reaction medium is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4 and then concentrated under vacuum to give a yellow liquid, which is purified by flash chromatography on a column of silica, in dichloromethane. 360 mg of a pale yellow oil are obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:4][C:5]2[C:6]([N:17]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15][OH:16])[O:8]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[NH:4][C:5]2[C:6]([N:17]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15][O:16][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[O:8]1
Reactant: OCC1CCc2ccc3[nH]c(C(F)(F)F)nc3c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Yield: 86.9 %

Procedure:
A solution of (2-trifluoromethyl-3,6,7,8-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl)-methanol (400 mg, 1.47 mmol) and p-toluenesulfonyl chloride (344 mg, 1.76 mmol) in anhydrous pyridine (50 mL) was stirred for 12 hours and then the solvent was removed in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 mL) and washed with water (3×30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent removed in vacuo to a residue. The residue was purified by chromatography (20% CH2Cl2-hexanes) to give 545 mg (87%) of the title compound as a solid: mp 160° C.; 1H NMR (400 MHz, CDCl3): [tautamer a]:δ1.95 (m, 1H), 2.05 (m, 1H), 2.44 (s, 3H), 2.90 (m, 2H), 4.30 (m, 2H), 4.40 (m, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.3 Hz, 2H), 10.35 (bs, 1H). [tautamer b]: δ1.95 (m, 1H), 2.05 (m, 1H), 2.44 (s, 3H), 2.90 (m, 2H), 4.25 (m, 2H), 4.40 (m, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 9.95 (bs, 1H); IR: 3400, 3080, 2970, 1600, 1550, 1500, 1080 cm−1; MS 427 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])C.[OH-].[Na+].Cl>C(O)C.O>[Cl:23][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[C:10]=2[CH:21]=[CH:22][C:7]=1[O:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccc(Cl)cc3)noc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1ccc2c(-c3ccc(Cl)cc3)noc2c1Cl
Reaction time: 0.5 h

Procedure:
A mixture of 25 g of ethyl{[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, Example 14, and 20 ml of 50% sodium hydroxide in 400 ml of ethyl alcohol is refluxed for 1 hour The hot mixture is diluted with 300 ml of water and then acidified with concentrated hydrochloric acid. The acidified mixture is stirred for 30 minutes and then filtered and the filter cake is recrystallized from a dimethylformamide-ethylacetate mixture to yield the product {[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having a melting point of 254° to 257° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[C:4]([CH3:16])[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>C(OCC)(=O)C.O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[C:4]([CH3:16])[N:3]=2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cc1nc(Cl)c2ccccc2c1CC(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(Oc2ccc(Cl)cc2)c2ccccc2c1CC(=O)O

Procedure:
A mixture of 1-chloro-3-methyl-4-isoquinoline acetic acid (237 mg., 1.01 mmol) prepared as in Example 8, 4-chlorophenol (260 mg., 2.02 mmol), and potassium tert-butoxide (226 mg., 2.02 mmol) were heated at 100° for 3 hr. After cooling the mixture was diluted with ethyl acetate and water and acidified to pH 1-2. The separated aqueous phase was extracted with 20 ml. ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and vacuum evaporated to a brown oil. Chromatography of this on silica gel eluted with ethyl acetate gave a pale yellow solid; 80 mg., 24%, mp 192°-195° d.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:11]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-n2ccc3ccccc32)cc1
Yield: 20.2 %

Procedure:
A mixture of 17.57 g (0.15 mole) of indole, 23.55 g (0.15 mole) of bromobenzene, 21 g of anhydrous potassium carbonate, 0.75 g of CuO, and 30 mL of DMF was stirred and heated under reflux for 43 hours. The cooled mixture was diluted with 200 mL of H2O and extracted with 150 mL of ether. The extract was washed with H2O (2×50 mL) and 50 mL of brine and dried over MgSO4. The oil was chromatographed on the solvent left 35.7 g of brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 15-22 were combined giving 5.86 g (20%) of 1-phenylindole as a yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]([O-:8])=O.[Na+].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]>O>[OH:8][N:6]=[C:12]([C:10]#[N:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C#N)=NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
62.5% sulfuric acid (603.7 g) were added dropwise to sodium nitrite (507.2 g) and ethyl cyanoacetate (791.0 g) in water (2,540 ml) at 30° to 40° C. over 2.2 hrs. under cooling. After completion of the addition, the mixture was stirred at a room temperature for 2 hrs, and the nitrogen oxide (NO2) was removed under reduced pressure, and the residue was cooled to 15° C. to separate crystals, which were filtered off and washed twice with water (150 ml) and twice with toluene (200 ml), and dried at 50° C. to give ethyl 2-hydroxyiminocyanoacetate (932.9 g, yield: 93.9%).
Reaction SMILES: Cl[C:2]([Cl:12])=[CH:3][C:4]([CH2:10][CH3:11])([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8].[C:13]1([O-:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>CN(C)C=O.C(Cl)Cl>[Cl:12][CH:2]=[C:3]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([CH2:10][CH3:11])([CH3:9])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(C)(C=C(Cl)Cl)CC
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCC(C)(CC)C(=CCl)Oc1ccccc1
Yield: 65.3 %

Procedure:
626 g (3 moles) of 1,1-dichloro-3-ethyl-3-methyl-1-heptene and 676 g (6 moles) of sodium phenolate are heated under relfux in 3 l of dimethylformamide for 16 hours. The mixture is diluted with methylene chloride and extracted by shaking several times with 2N aqueous sodium hydroxide solution. After drying and evaporating on a rotary evaporator, 666 g of crude product remain. Distillation at boiling point0.1 100°-110° C. gives 523 g (65% of theory) of 1-chloro-3-ethyl-3-methyl-2-phenoxy-hept-1-ene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:35])[C@@H:9]([CH3:34])[C:10]([NH:12][C@@H:13]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:60][C:61]1[CH:67]=[CH:66][CH:65]=[C:64]([CH3:68])[C:62]=1[NH2:63].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[F:60][C:61]1[CH:67]=[CH:66][CH:65]=[C:64]([CH3:68])[C:62]=1[NH:63][C:25]([C@H:17]1[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:35])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18]1)=[O:27]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)O)C1CCOCC1)N(C)C(=O)OC(C)(C)C
Reactant: Cc1cccc(F)c1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(F)c1NC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1CCOCC1
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a solution of (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (60 mg, 122 pilot, Eq: 1.00) and diisopropylethylamine (64 μL, 367 μmol, Eq: 3) in DCM (1.8 mL) was added diphenylphosphinic chloride (63.7 mg, 51 μL, 269 μmol, Eq: 2.2). After stirring for 5 min, 2-fluoro-6-methylaniline (18.4 mg, 147 μmol, Eq: 1.2) was added and the resulting solution stirred at rt for 2 d. The reaction mixture was poured into aqueous 0.1 M KHSO4 (20 mL) and the resulting mixture was extracted with EtOAc. The combined organic layers were concentrated in vacuo and the crude material was purified by flash chromatography (silica gel, 4 g, 10% to 50% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-2-((S)-2-(2-fluoro-6-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylamino)-1-oxopropan-2-yl(methyl)carbamate (30 mg), m/z=598 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH2:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([NH:25][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:11])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1
Reactant: COC(=O)C(N)Cc1ccc(Br)cc1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1O

Procedure:
5-Chloro-2-hydroxy-benzoic acid (2.5 g, 28.97 mmol) was coupled with 2-amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride (4.26 g, 28.96 mmol) with HBTU (6.59 g, 34.76 mmol) and diisopropylethylamine (8 ml, 86.9 mmol) as per general procedure A to yield the corresponding 3-(4-bromo-phenyl)-(2S)-(5-chloro-2-hydroxy-benzoylamino)-propionic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24]
Reactant: CC(C)=CCBr
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCSc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.30 g (102.0 mmol) of 2-bromothiophenol, 160 ml of DMF and 15.50 g (112.0 mmol) of potassium carbonate are introduced into a three-necked flask. 13 ml (112.0 mmol) of 1-bromo-3-methyl-2-butene are added dropwise and the reaction mixture is stirred at room temperature for two hours. It is poured into water and extracted with ethyl acetate and the organic phase is separated by settling, washed with water, dried over magnesium sulphate and evaporated. 26.00 g (99%) of the expected compound are collected in the form of an orangey oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][N+:6]#[C-:7])[CH3:2].[CH2:9]([C:16](=[CH2:19])[CH:17]=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([O:3][C:4]([CH:5]1[CH:17]([C:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH2:19])[O:18][CH:7]=[N:6]1)=[O:8])[CH3:2]
Reactant: C=C(C=O)Cc1ccccc1
Reactant: [C-]#[N+]CC(=O)OCC
Product: C=C(Cc1ccccc1)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: By reaction of isocyanoacetic acid ethyl ester with 2-benzyl-propenal in a manner analogous to that described in Example 1 and after purification by column chromatography (silica gel; dichloromethane/ethyl acetate 98:2), 5-(3-phenyl-propen-2-yl)-2-oxazoline-4carboxylic acid ethyl ester is obtained in the form of a colourless oil, 1H-NMR (CDCl3): 3.33 (s, 2H, CH2); 4.37 (dd, 1H, C(4)-H); 4.87 (s, 1H); 5.07 (dd, H, C(5)-H); 5.16 (s, 1H).
Reaction SMILES: [CH2:1]([CH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([O:30]C)=[O:29])[CH:26]=2)[NH:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+].C>C(O)C.O>[CH2:1]([CH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=2)[NH:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCC1CNc2ccc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCC1CNc2ccc(C(=O)O)cc21
Reaction time: 24 h
Yield: 69.2 %

Procedure:
(RS)-Methyl 3-(n-octadecyl)indoline-5-carboxylate (13.6 g) in ethanol (380 ml), containing potassium hydroxide (2.7 g) and water (50 ml), was refluxed with stirring for 24 hours. The solvent was removed in vacuo to give an off-white solid. The solid was dissolved in water, and the solution treated with charcoal and filtered through diatomaceous earth. Glacial acetic acid (50 ml) was slowly added to the stirred solution and an off-white solid was collected, which was recrystallised from ethyl acetate to give (RS)-3-(n-octadecyl)indoline-5-carboxylic acid (9.1 g), in the form of a white solid, m.p. 84°-87° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH:18]S(C(C)(C)C)=O)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.CCOCC>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CS(C)(=O)=O)NS(=O)C(C)(C)C)ccc1OC
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Reaction time: 12 h

Procedure:
Finally, a reaction flask was charged with Compound F in MeOH (10 vol) at 20-25° C. then treated with 2N HCl/Et2O (˜2 mL, 2.0 equiv) and stirred for 12 h. The reaction mixture was concentrated to dryness and the resulting solid was dissolved in water/EtOAc. The aqueous portion was neutralized then extracted with CH2Cl2. The combined organic layers were dried with MgSO4 then concentrated to provide (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (Compound B).
Reaction SMILES: [NH3:1].CO[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19](Cl)[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:22]=3)[N:12]=2)[CH:6]=1.[NH3:36].CC(O)C>>[NH2:1][C:19]1[C:14]2[N:15]([C:11]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([NH2:36])=[O:35])=[N:12][C:13]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:22]=2)[CH:16]=[CH:17][N:18]=1
Reactant: N
Reactant: COC(=O)c1cccc(-c2nc(-c3cccc(OCc4ccccc4)c3)c3c(Cl)nccn23)c1
Solvent: CC(C)O
Product: NC(=O)c1cccc(-c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)c1
Temperature: 110 °C

Procedure:
Gaseous NH3 was condensed into a cooled (−78° C.) solution of 3-[1-(3-benzyloxyphenyl)-8-chloroimidazo[1,5-a]pyrazin-3-yl]-benzoic acid methyl ester (102 mg, 0.216 mmol) in NH3/i-PrOH (2M, 3 mL) in a pressure tube until the volume had doubled. The tube was sealed and heated to 110° C. for 2 d. After excess NH3/i-PrOH was removed in vacuo, the crude material was taken up in CH2Cl2, adsorbed onto Hydromatrix, and purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH:CH2Cl2 1%→5%], yielding the title compound, as an off-white solid; 1H NMR (d-DMSO, 400 MHz) δ 5.18 (s, 2H), 6.30 (s, br, —NH2), 7.10-7.18 (m, 2H), 7.25-7.58 (m, 9H), 7.67 (t, J=7.6 Hz, 1H), 7.81 (d, J=4.4 Hz, 1H), 8.00 (d, J=7.6 Hz, 2H), 8.16 (s, 1H), 8.31 (s, 1H); MS (ES+): m/z 436.0 (100) [MH+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH2:13]N(C)C)[CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:13][C:4]1[CH:3]=[CH:2][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:12]
Reactant: CN(C)Cc1cc(Cl)c2ccccc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2ccccc2c1O
Yield: 95 %

Procedure:
A mixture of 14.18 g (60 m mole) 4-chloro-2-(dimethylaminomethyl)-1-naphthol (13) and 1.43 g 10% Pd-C in 240 ml ethanol was hydrogenated at 50 psi hydrogen atmosphere for 17 hours at room temperature then filtered over a layer of Celite. The filtrate was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated, whereby 8.99 g (representing a yield of 95%) 2-methyl-1-naphthol (1) were obtained: 1H NMR (300 MHz, DMSO-d6) δ2.32 (s, 3H), 7.21-7.40 (m, 4H), 7.75 (d, 1H, J=8 Hz), 8.15 (d, 1H, J=8 Hz), 9.01 (s, 1H, exch. with D2O); m/z 158 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O-:15])=[O:14]
Reactant: O=CC=Cc1ccccc1
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2C=Cc1ccccc1
Yield: 85.5 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with cinnamaldehyde as described in Example 11 to give 1-nitro-5-styryl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 171°-173° C. Yield: 85.5%.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.[ClH:16]>>[Cl:16][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2
Reactant: Cl
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Product: CC(=O)c1cccc2nc(C)c(Cl)nc12
Yield: 99 %

Procedure:
1-(3-Fluoro-2-methylquinoxalin-5-yl)ethanone (126g, 2.00 g, 9.79 mmol) was treated with HCl (4.0 M solution in 1,4-dioxane; 24.49 ml, 98 mmol), and the homogeneous reaction was fitted with a drying tube. After 6 h the reaction was concentrated in vacuo, and the solid was taken up in DCM. Solid NaHCO3 was added cautiously with rapid stirring; and saturated aq. NaHCO3 was sequentially added cautiously with rapid stirring. The mixture was partitioned between saturated NaHCO3 and DCM. The aq. layer was extracted with DCM (2×), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 1-(3-chloro-2-methylquinoxalin-5-yl)ethanone (254a, 99% yield) as an orange-brown solid. MS (ESI, pos. ion) m/z: 221.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:43]=[CH:42][C:38]2[N:39]=[CH:40][S:41][C:37]=2[CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:35]2[CH:43]=[CH:42][C:38]3[N:39]=[CH:40][S:41][C:37]=3[CH:36]=2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: Brc1ccc2ncsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1cccc(-c2ccc3ncsc3c2)c1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 6-bromo-benzothiazole (34.9 mg, 0.16 mmol), and Pd[P(Ph)3]4 (12.1 mg, 6.4 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.6 mg. MS: 458.1 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 1.18-1.25 (m, 2H), 1.76-2.00 (m, 3H), 2.10-2.34 (m, 1H), 4.28-4.40 (m, 1H), 4.87-5.10 (m, 2H), 7.00-7.56 (m, 7H), 7.68-7.66 (m, 1H), 7.97-8.15 (m, 2H), 8.33-8.39 (m, 1H), 9.35-9.39 (s, 1H), 10.09-10.16 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:33][C:34]2[CH:41]=[CH:40][CH:39]=[C:36]([CH3:37])[CH:35]=2)[CH:8]=1)=[O:6]
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccc(F)cc3c2=O)cc1C
Reactant: Cc1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(C)c(C)c3)c(=O)c3cc(F)ccc32)c1
Temperature: 60 °C
Yield: 77.3 %

Procedure:
Compound 4uu was prepared following the procedure outlined in Step 3 of Example 1. Briefly described here, 0.050 g (0.169 mmol) of 3-(3,4-dimethyl-benzoyl)-6-fluoro-1H-quinolin-4-one 3j, 0.4 mL of potassium hexamethyldisilazide (0.5 M in toluene, 0.203 mmol) and 37.6 mg (0.203 mmol) of 3-methylbenzyl bromide were combined in 1.5 mL of tetrahydrofuran and heated at 60° C. for 3 h. Purification of the crude product using flash chromatography (30-50% ethyl acetate in hexane) yielded 52.2 mg of 3-(3,4-dimethyl-benzoyl)-6-fluoro-1-(3-methyl-benzyl)-1H-quinolin-4-one as a white solid 4uu: LC-MSD, m/z for C26H22FNO2, [M+H]=400.5; Reverse phase HPLC gradient, 20-95% acetonitrile with 0.1% TFA in 4 minutes, retention time=2.9 min; 1H NMR (400 MHz, CDCl3): δ 8.26 (1H, s), 8.11 (1H, m), 7.64 (1H, s), 7.56 (1H, m), 7.38 (1H, m), 7.32-7.23 (2H, m), 7.18 (1H, m), 7.15 (1H, m), 6.97 (2H, m), 5.37 (2H, s), 2.33 (3H, s), 2.32 (3H, s), 2.31 (3H, s).