Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:11]1[N:15]2[N:16]=[C:17]([CH3:25])[CH:18]=[C:19]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:14]2=[N:13][C:12]=1[CH3:26].[CH3:27][O-:28].[Na+]>[Cu]I.CO>[CH2:21]([CH:20]([C:19]1[C:14]2[N:15]([C:11]([C:3]3[S:4][C:5]4[C:6](=[N:7][CH:8]=[CH:9][CH:10]=4)[C:2]=3[O:28][CH3:27])=[C:12]([CH3:26])[N:13]=2)[N:16]=[C:17]([CH3:25])[CH:18]=1)[CH2:23][CH3:24])[CH3:22]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3Br)c(C)nc12
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CO
Product: CCC(CC)c1cc(C)nn2c(-c3sc4cccnc4c3OC)c(C)nc12
Temperature: 120 °C
Yield: 43.8 %

Procedure:
50 mg of 3-(3-Bromo-thieno[3,2-b]pyridin-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.12 mmol) and 13 mg of sodium methoxide (0.24 mmol) and 22 mg of copper (I) iodide (0.12 mmol) are placed into 4 ml reaction vial with 3.0 ml of dry MeOH. The reaction vial is capped with a Teflon cap and heated at 120° C. overnight. The reaction mixture is filtered, and water and CH2Cl2 are added. The separated CH2Cl2 is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (1st column; Hexane:AcOEt:2M NH3 in MeOH=20:4:1, 2nd column; CH2Cl2:Hexane:Acetnitrile=5:4:1) to give the title compound 20 mg (45%). mass spectrum (m/e): 381; 1H-NMR (CDCl3): 8.72 (m, 1H), 8.10 (m, 1H), 7.29 (dd, 1H, J=4.6 Hz, 8.3 Hz), 6.72 (s, 1H), 4.03 (s, 3H), 3.34 (m, 1H), 2.55 (s, 3H), 2.54 (s, 3H), 1.84 (m, 4H), 0.88 (t, 6H, J=7.6 Hz) ppm.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C:9]2([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=4[NH2:31])[CH2:20][CH:19]3[OH:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[C:35](Cl)(=[O:44])[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH:31][C:35](=[O:44])[CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:20][C:19]3=[O:32])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:33][CH:34]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccc(F)cc3)CCCCC2)C(O)C1
Product: O=C(CCc1ccccc1)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3ccc(F)cc3)CCCCC2)C(=O)C1

Procedure:
In accordance with the same procedure as in Example 87, except that 4-[N-[1-[N-(4-fluorobenzoyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-aminophenyl)piperidin-3-ol and hydrocinnamoyl chloride was used instead of methoxyacetyl chloride in Step 3 thereof, 671 mg of the titled compound was prepared.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17](=[S:19])[NH2:18])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:21][C:22](=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:19][CH:21]=[C:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:18]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(C(N)=S)c1-c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Yield: 97.7 %

Procedure:
A solution of the compound (2.90 g, 10.46 mmol) obtained in step 4 and ethyl 4-chloroacetoacetate (1.554 mL, 11.50 mmol) in ethanol (30 mL) was stirred at 80° C. for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate and hexane to give ethyl 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetate (3.96 g, 10.22 mmol, 98%) as a pale-yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11]C(=O)C)[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].Cl.N>>[NH2:11][C:6]1[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)Nc1ccc(O)c(C(C)=O)c1
Agent: Cl
Agent: N
Product: CC(=O)c1cc(N)ccc1O

Procedure:
A suspension of N-(3-acetyl-4-hydroxy-phenyl)-acetamide (1.029 g, 5.3 mmol) in 15% HCl (1.5 ml, 6.2 mmol, 1.2 equ) was heated to reflux for 40 minutes, then cooled and neutralised with 10% aqueous ammonia. The precipitated solid was collected by filtration as 1-(5-amino-2-hydroxy-phenyl)-ethanone (0.677 g, 84%) a green solid.
Reaction SMILES: [ClH:1].O1CCOCC1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([C@H:35]2[N:39](C(OC(C)(C)C)=O)[C:38]([CH3:48])([CH3:47])[CH2:37][CH2:36]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])=[C:11]([F:49])[CH:10]=1>C(Cl)Cl>[ClH:1].[ClH:1].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([C@H:35]2[CH2:36][CH2:37][C:38]([CH3:48])([CH3:47])[NH:39]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]4[C@H:32]([CH3:33])[CH2:31][C@@H:30]([OH:34])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:20][CH2:19]2)=[O:17])=[C:11]([F:49])[CH:10]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)cc4F)[C@H]4CCC(C)(C)N4)CC3)c21
Reaction time: 8 h
Yield: 62 %

Procedure:
4.0M HCl/Dioxane (0.121 mL, 0.483 mmol) was added to a solution of (S)-tert-butyl 5-((S)-1-(4-bromo-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.104 g, 0.161 mmol) in DCM (1 mL). The solution stirred overnight, and the solvent was removed to yield (S)-2-(4-bromo-2-fluorophenyl)-2-((R)-5,5-dimethylpyrrolidin-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.0618 g, 0.0998 mmol, 62.0% yield). HPLC, 254 nm=1.988 minutes, 99.66% purity, LCMS (APCI+) 547.7 m/z [M+H]+; Retention time=2.45 minutes. 1H NMR (400 MHz, D2O) 8.58 (s, 1H), 7.54 (dd, J1=1.952 Hz, J2=9.761 Hz, 1H), 7.46 (dd, J1=1.562 Hz, J2=8.199 Hz, 1H), 7.35 (t, J=7.809 Hz, 1H), 5.32 (t, J=8.199 Hz, 1H), 4.79 (d, J=9.761 Hz, 1H), 4.40-4.31 (m, 1H), 4.0-3.9 (m, 2H), 3.82-3.62 (m, 3H), 2.30-2.28 (m, 1H), 2.27-2.15 (m, 1H), 2.02-1.84 (m, 4H), 1.58 (s, 3H), 1.44 (s, 3H), 1.29 (d, J=6.637 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[CH:19]2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][OH:30])[C:10]=2[CH2:9]1>O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:19]=2[C:18]2[C:17]3[CH:16]=[C:15]([O:26][CH3:27])[CH:14]=[CH:13][C:12]=3[N:11]([CH2:28][CH2:29][OH:30])[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)c1c(n2CCO)CC(c2ccccc2Cl)C2C(=O)NC(=O)C12
Agent: O=[Mn]=O
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCO)C(=O)NC3=O
Reaction time: 18 h
Yield: 72 %

Procedure:
4-(2-Chlorophenyl)-6-(2-hydroxyethyl)-9-methoxy-4,5,6,10c-tetrahydropyrrolo[3,4-c]carbazole-1,3(2H, 3aH)-dione (IV; Ar=2-chlorophenyl, R10═CH2CH2OH) (45) prepared according to example 42 was reacted with MnO2 using the procedure described in example 79 except that the reaction time was 18 h gave 4-(2-Chlorophenyl)-6-(2-hydroxyethyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10═CH2CH2OH) (46) in a 72% yield as a yellow powder, mp 255–257° C. 1H NMR δ [(CD3)2SO] 11.10 (br s, 1H), 8.52 (d, J=2.6 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.59–7.56 (m, 1H), 7.52–7.43 (m, 4H), 7.29 (dd, J=9.0, 2.2.6 Hz, 1H), 4.84 (t, J=5.0 Hz, 1H), 4.53 (t, J=5.2 Hz, 2H), 3.90 (s, 3H), 3.77 (m, 2H). Found: C, 65.50; H, 4.07; N, 6.59. C23H17ClN2O4 requires C, 65.64; H, 4.07; N, 6.66.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH2:13][C:14]#[N:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:17]1[CH:22]=[C:21]([S:23][CH3:24])[N:20]=[CH:19][N:18]=1.[Cl-].[NH4+]>O1CCCC1>[C:14]([CH:13]([C:17]1[CH:22]=[C:21]([S:23][CH3:24])[N:20]=[CH:19][N:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:15]
Reactant: CSc1cc(Cl)ncn1
Reactant: N#CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1cc(C(C#N)c2ccccc2)ncn1
Temperature: 0 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
In 30 ml of tetrahydrofuran was suspended 5.24 g of potassium t-butoxide, to which 2.63 g of phenylacetonitrile and 3.0 g of 4-chloro-6-methylthiopyrimidine, followed by stirring at 0° C. for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 3.67 g of 4-(α-cyanobenzyl)-6-methylthiopyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([F:20])[CH:14]=2)[N:9]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:21])=[C:13]([F:20])[CH:14]=2)[N:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cc(F)c(F)cc2nc1-c1ccccc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc2cc1F

Procedure:
Prepared according to Procedure H using (2-(2-chlorophenyl)-6,7-difluoro-quinolin-3-yl)methanamine (0.080 g, 0.279 mmol), 6-chloropurine (0.065 g, 0.42 mmol, 1.5 eq) and DIEA (0.56 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-chlorophenyl)-6,7-difluoroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=551 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.46 (s, 1 H), 8.13 (s, 1 H), 8.09 (s, 1 H), 7.83-7.94 (m, 3 H), 7.49-7.55 (m, 2 H), 7.41-7.48 (m, 1 H), 7.35-7.41 (m, 1 H), 4.89-4.85 (m, 2H), Mass Spectrum (ESI) m/e=423 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:4]1.[Cl:20][C:21]1[C:22]([N:32]([CH3:34])[CH3:33])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[Cl:20][C:21]1[C:22]([N:32]([CH3:33])[CH3:34])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([NH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:4]1)=[O:27]
Reactant: COc1cc(N(C)C)c(Cl)cc1C(=O)O
Reactant: NCC1CN(CCCOc2ccc(Cl)cc2)CCO1
Product: COc1cc(N(C)C)c(Cl)cc1C(=O)NCC1CN(CCCOc2ccc(Cl)cc2)CCO1

Procedure:
The hemihydrate of the title compound is prepared in substantially the same manner as in Example 6(1), using 2-aminomethyl-4-[3-(4-chlorophenoxy)propyl]morpholine and 5-chloro-4-dimethylamino-2-methoxybenzoic acid, respectively, in place of 2-aminomethyl-4-(4-cyanobenzyl)morpholine and 4-amino-5-chloro-2-methoxybenzoic acid in Example 6(1), mp 128°-130° C. (recrystallized from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=1)[C:28](O)=[O:29]>C1COCC1>[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=1)[C:28]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[C:5]([CH3:21])=[CH:4][CH:3]=1)=[O:29]
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1cncc(Br)c1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cncc(Br)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 885.3 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (26.4 mg, 0.009 mmol) and 5-bromonicotinic acid (38 mg, 0.18 mmol) were mixed in THF (2 ml) and the mixture shaken in a varian tube for 5 min at room temperature. Carbodiimde resin (250 mg, 0.27 mmol) was added and shaking continued for 72 h. The solution was filtered off and concentrated under vacuum. The residue was chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:2 then 1:1) and the solvent evaporated under vacuum to give 5-bromo-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl1,1′-biphenyl-3-yl)nicotinamide (37 mg, 85%). NMR; δH [2H6]—DMSO 10.50,(1H, s), 9.05,(1H, m), 8.90,(1H, m), 8.62,(1H, t), 8.54,(1H, t), 7.93,(2H, d), 7.70,(1H, dd), 7.66,(1H, d), 7.44,(2H, d), 7.31,(1H, d), 3.16,(2H, t), 2.21,(3H, s), 1.04,(1H, m), 0.43,(2H, m). LCMS: retention time 3.44 min, MH+464/466.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH:14]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH:14]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)N1CCC(c2cc3ccccc3o2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1CCC(c2cc3ccccc3o2)CC1

Procedure:
Analogously to Example 10, 8.0 g of 1-acetyl-4-(2-benzofuranyl)-piperidine in 100 ml of tetrahydrofuran is reduced with 12.0 g of lithium aluminium hydride in 150 ml of tetrahydrofuran, whereby the reaction mixture is refluxed for 15 hours. The crude 1-ethyl-4-(2-benzofuranyl)-piperidine obtained is converted into the hydrochloride which, after recrystallisation from ethyl acetate, melts at 198°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])O.[Na+].[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([CH3:19])[CH3:18])#[N:16]>O1CCCC1>[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8])=[O:24])([CH3:19])[CH3:18])#[N:16]
Reactant: Cc1ccc(O)cc1N
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(O)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a two-layer solution of 3-amino-4-methylphenol (3.25 g, 26.4 mmol) in tetrahydrofuran (20 mL)/1N aqueous sodium hydrogen carbonate solution (39 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 3 hr. The aqueous layer was separated, and extracted with ethyl acetate (100 mL). The combined organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate (45 mL)/hexane (45 mL) to give the title compound (5.95 g, 77%) as a colorless powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:13]2[CH:22]=[CH:21][N:20](S(C3C=CC(C)=CC=3)(=O)=O)[C:14]=2[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[OH:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[O:41][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:13]2[CH:22]=[CH:21][NH:20][C:14]=2[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1
Reactant: Oc1ccc(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(S(C)(=O)=O)ccc4F)cn(C)c(=O)c32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Yield: 80 %

Procedure:
A mixture of Example 138a (0.05 g, 0.105 mmol), 2,4-difluorophenol (0.016 g, 0.126 mmol), and cesium carbonate (0.069 g, 0.211 mmol) in DMSO (1 mL) was heated at 120° C. for 16 hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by reverse phase Preparative HPLC (10-80% acetonitrile in 0.1% TFA/water) to give the title compound (0.036 g, 0.084 mmol, 79% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 7.99 (d, J=2.44 Hz, 1H), 7.86 (dd, J=8.54, 2.44 Hz, 1H), 7.40-7.56 (m, 3H), 7.31 (t, J=2.9 Hz, 1H), 7.14-7.20 (m, 1H), 6.98 (d, J=8.54 Hz, 1H), 6.28-6.30 (m, 1H), 3.59 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 431.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17](Cl)=[O:18].[CH3:20][NH2:21]>O1CCCC1.O>[CH3:20][NH:21][C:17]([N:3]1[CH2:4][C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C@@H:2]1[CH3:1])=[O:18]
Reactant: CN
Reactant: CC1C(Oc2cccc(C(F)(F)F)c2)CN1C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1C[C@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 6 h
Yield: 90.3 %

Procedure:
A solution of 4.02 g (0.01 mole) of crude (73%) 2-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride cis isomer in 20 ml of tetrahydrofuran was treated while stirring with 1.6 g (0.02 mole) of 40% aqueous monomethylamine. After stirring for 6 hr, the reaction mixture was diluted with 100 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo (4.2 g). The oil solidified on standing and was recrystallized from isooctane with a trace of benzene to give 2.6 g (90.3%) of white crystalline product, m.p. 89°-91° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[OH-].[NH4+:24].O>C(Cl)Cl>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH2:24])=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:17][CH:18]=1
Reactant: [NH4+]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (200 mg, 0.63 mmol) in methylene chloride (20 mL) was added saturated ammonium hydroxide (NH4OH). The solution was stirred overnight at room temperature when it was added to water (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuo to an oil. The resulting oil was chromatographed on silica gel, eluting with 10% methanol in methylene chloride to give the title compound (115 mg, 72%). 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 8.60 (s, 1H), 8.09 (m, 2H), 7.94 (d, 1H), 7.61 (d, 1H), 7.38 (t, 2H); ES-MS (m/z) 256 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14])[CH:7]=[CH:6][C:5]=1[NH:16]C(=O)C.O1CCOCC1>Cl>[NH2:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][OH:14])=[CH:9][C:4]=1[C:3]([OH:20])=[O:2]
Reactant: COC(=O)c1cc(OC[C@@H](C)CO)ccc1NC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](CO)COc1ccc(N)c(C(=O)O)c1
Yield: 100 %

Procedure:
2-Acetylamino-5-[(S)-(+)-3-hydroxy-2-methylpropoxy]benzoic acid methyl ester (1.00 g, 3.6 mmol) prepared as in Procedure VII (Step a) was dissolved in 6 N HCl (aq.) (10 mL) and dioxane (5 mL) and heated at reflux temperature for 8 h. The mixture was then cooled and concentrated in vacuo giving 2-amino-5-[(S)-(+)-3-hydroxy-2-methylpropoxy]benzoic acid (936 mg, 3.6 mmol, 100%) as the hydrochloride salt.
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]=1.[C:21](=O)([O-:23])[O-:22].[Ca+2].CN(C)C=O.O>C(OCC)C>[CH3:15][O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]=[C:4]([CH:3]([CH3:2])[C:21]([OH:23])=[O:22])[CH:13]=[CH:12]2
Reactant: COc1ccc2cc(C(OC)(OC)C(C)Br)ccc2c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 95 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(6-methoxy-2-naphthyl)-propane (3.39 g; 10 mmol), calcium carbonate (1 g; 10 mmol), N,N-dimethylformamide (12 g) and of water (8 g) is heated at reflux under stirring for 7 h. The mixture is cooled to 25° C., added with diethyl ether (100 ml) and the insoluble is filtered. The resulting solution is washed with water and the solvent is removed in vacuo. The residue is added with 30% sodium hydroxide aqueous solution (10 ml) and with methanol (30 ml). The reaction mixture is refluxed for 2 h and then cooled to room temperature, the mixture is diluted with water (100 ml) and extracted with diethyl ether (2×30 ml). The aqueous phase is acidified with concentrated hydrochloric acid, the insoluble is filtered, washed with water and dried at 80° C. under vacuum to give 2-(6-methoxy-2-naphthyl)-propionic acid (2.18 g; 9.5 mmol; yield 95 %), m.p. 154°-155° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH:10]=[CH:9]3.[C-:19]#[N:20].[K+].O>CN(C)C=O>[C:19]([CH2:2][CH2:3][CH:4]1[O:18][C:7]2=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=[C:6]2[CH2:5]1)[NH:12][C:11](=[O:17])[CH:10]=[CH:9]3)#[N:20]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CCCl)C2
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CCC#N)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
2-(2-Chloroethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.5 g) was dissolved in dimethylformamide (50 ml). To the solution, potassium cyanide (2.0 g) was added and stirred at 100° C. for three hours. After the reaction was completed, the reaction liquid was condensed under reduced pressure. Water was added thereto and extraction was performed with chloroform. The chloroform phase was dried and condensed under reduced pressure. The residue was recrystallized from a solvent mixture of chloroform-ether to obtain 1.4 g of 2-(2-cyanoethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as pale yellow prisms (96.8%).
Reaction SMILES: [C:1]([NH:9][NH:10][C@@H:11]1[C:16]2[CH:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:15]=2[O:14][C:13]([CH3:24])([CH3:23])[C@H:12]1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)(Cl)Cl>[C:32]([N:10]([C@@H:11]1[C:16]2[CH:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:15]=2[O:14][C:13]([CH3:23])([CH3:24])[C@H:12]1[OH:25])[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NNC(=O)c2ccccc2)[C@@H]1O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N(NC(=O)c1ccccc1)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
Trans-4-(2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (320 mg) was dissolved in 1 ml of chloroform, 0.5 ml of pyridine was added, and 0.28 ml of acetyl chloride was added with stirring under ice cooling. After stirring at room temperature for 80 minutes, the solvent was distilled off under reduced pressure and the residue was dissolved in 5 ml of methanol. The solution was treated with 5 ml of 1N-sodium hydroxide at room temperature for 30 minutes. After the methanol had been distilled off, the residue was shaken together with ethyl acetate-water and the organic layer was washed with an aqueous solution of sodium chloride and subsequently concentrated. This was recrystallized from hexane-ethanol (1:1) to give 170 mg of trans-4-(1-acetyl-2-benzoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.monohydrate as white crystals, m.p. 212°-213° C.