Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:33][CH2:32][N:31]2[S:34]([CH3:37])(=[O:36])=[O:35])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:33][CH2:32][N:31]2[S:34]([CH3:37])(=[O:35])=[O:36])=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)N1CCC1c1ccc(Br)cc1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCN4S(C)(=O)=O)cc3)cc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 61.4 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (100 mg, 0.311 mmol), 2-(4-bromophenyl)-1-(methylsulfonyl)azetidine (108.2 mg, 0.373 mmol), 2.0M potassium carbonate solution (0.5 mL, 1.0 mmol), and Pd(dppf)Cl2 (30 mg, 0.03 mmol) in toluene/ethanol (1.44 mL/0.48 mL) was stirred at 110° C. for 2.5 hours. TLC (petroleum ether/ethyl acetate=3:1) showed that the reaction was complete. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by prep-TLC to give the title compound (80 mg, 62% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.30-12.10 (s, 1H), 8.2 (s, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 7.55 (d, 2H), 7.45 (d, 2H), 5.35 (m, 1H), 4.32 (m, 1H), 4.0 (m, 1H), 3.75 (s, 3H), 3.15 (m, 2H), 3.05 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:13]=1)[C:8]([Cl:20])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Yield: 83 %

Procedure:
A stirring mixture of 68.2 g (0.29 mole) of 3,5-diacetoxybenzoic acid and 21 ml (0.29 mole) of thionyl chloride in 150 ml of dry benzene was heated in an oil bath at 80°-90° C. for 2 hours. After cooling the benzene was removed in vacuo to leave 3,5-diacetoxybenzoyl chloride as a tan, solid which was recrystallized from cyclohexane as colorless crystals, mp 87°-89° C., 61.8 g (83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Br[C:11]1[CH:20]=[N:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:17]2[CH:18]=[N:19][CH:20]=[CH:11][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccncc1Br
Product: COC(=O)c1ccncc1NCc1ccc(Cl)cc1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 4-chlorobenzylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.94 (d, 1H, J=5.0 Hz), 7.82 (br s, 1H), 7.62 (d, 1H, J=5.0 Hz), 7.24-7.32 (m, 4H), 4.47 (d, 2H, J=5.7 Hz), 3.89 (s, 3H). [M+H] calc'd for C14H13ClN2O2, 277, 279. Found 277, 279.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[N:9]1[C:18]2[C:13](=[CH:14][N:15]=[C:16]3[NH:21][CH:20]=[CH:19][C:17]3=2)[C:12](=[O:22])[CH:11]=[CH:10]1.[F:23][C:24]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.B.N1C=CC=CC=1C.C(=O)([O-])O.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[F:23][C:24]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:6]1[CH2:7][CH2:8][C@@H:3]([CH3:2])[C@@H:4]([N:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]4[NH:21][CH:20]=[CH:19][C:17]4=3)[C:12](=[O:22])[CH:11]=[CH:10]2)[CH2:5]1
Reactant: O=Cc1cccc(F)c1F
Reactant: C[C@@H]1CCNC[C@@H]1n1ccc(=O)c2cnc3[nH]ccc3c21
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: Cc1ccccn1
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CCN(Cc2cccc(F)c2F)C[C@@H]1n1ccc(=O)c2cnc3[nH]ccc3c21
Yield: 26 %

Procedure:
rac-1-[(3R,4R)-4-methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one hydrochloride (18 mg, 0.057 mmol) and 2,3-difluorobenzaldehyde (10 mg, 0.070 mmol) in a mixture of methanol (1 mL)/acetic acid (1 mL) was stirred with 2-picoline borane (10 mg, 0.094 mmol) at room temperature for one day. After addition of saturated aqueous sodium hydrogen carbonate and 1 M aqueous sodium hydroxide, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (chloroform/methanol=20/1 (v/v)) to give rac-1-[(3R,4R)-1-(2,3-difluorobenzyl)-4-methylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (less polar fraction: 6.1 mg, yield 26%) as a pale yellow solid and rac-1-[(3R,4R)-1,4-dimethylpiperidin-3-yl]-1H-pyrrolo[2,3-h][1,6]naphthyridin-4(7H)-one (more polar fraction: 5.9 mg, yield 35%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[C:25]([F:40])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd+2].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:39][C:38]1[C:23]([NH:22][C:2]2[N:3]=[CH:4][C:5]3[N:6]([CH3:21])[C:7](=[O:20])[C:8]4([CH2:19][CH2:18]4)[CH2:9][N:10]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)[C:11]=3[N:12]=2)=[CH:24][C:25]([F:40])=[C:26]([CH:37]=1)[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1)=[O:28]
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1
Agent: [Pd+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CN1CCC(NC(=O)c2cc(Cl)c(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)cc2F)CC1
Temperature: 100 °C
Yield: 59.9 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 85 mg, 0.30 mmol), 4-amino-5-chloro-2-fluoro-N-(1-methyl-4-piperidyl)benzamide (Intermediate 173; 101 mg, 0.33 mmol) and XANTPHOS (16 mg, 0.03 mmol) were dissolved in 1,4-dioxane (7.5 mL). Caesium carbonate (210 mg, 0.59 mmol) was added and the system purged with a stream of nitrogen for 15 minutes before tris(dibenzylideneacetone) palladium (II) (17 mg, 0.02 mmol) was added. The apparatus was evacuated and backfilled with nitrogen (×3) and then heated at 100° C. for 3 hours. The mixture was cooled, filtered and the filtrate absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (100 mg, 60%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:7]=1.[CH3:30][C@@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:32]4[C@H:31]([CH3:30])[CH2:35][O:34][C:33]4=[O:36])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][O:10][C:9]3=[O:13])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCOC3=O)CC2)c(C)c1
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3N3CCOC3=O)CC2)c(C)c1
Yield: 40.8 %

Procedure:
To a mixture of 3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one (207 mg) described in Preparation Example 120, (R)-4-methyloxazolidin-2-one (50.6 mg) described in Preparation Example 25, cesium carbonate (228 mg), tris(dibenzylideneacetone)dipalladium (0) chloroform (51.8 mg) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (24 mg) was added toluene (1 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After evaporation of the solvent, the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (97.5 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[OH:34])[N:17]=2)[CH2:12]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].ClC([O-])=O>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][C@@H:11]([NH:10][C:36](=[O:37])[O:38][CH2:39][CH3:40])[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N[C@@H]1CCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Temperature: -40 °C
Yield: 93.2 %

Procedure:
At RT, diisopropyl ethylamine (130 μL, 0.74 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (125 mg, 0.37 mmol) in THF (10 mL), and the reaction was cooled to −40° C. Ethyl chloroformate (33 μL in 0.33 mL THF, 0.34 mmol) was added dropwise over a period of 10 minutes. After addition of the chloroformate was complete, the reaction mixture was warmed to RT, quenched with H2O, and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-10% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 to give (R)-ethyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 10) (130 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=8.6 Hz, 1H), 7.58-7.57 (m, 2H), 7.38-7.29 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.72-6.67 (m, 1H), 4.25-4.21 (m, 1H), 4.16-4.13 (m, 2H), 4.07-3.97 (m, 3H), 3.84-3.82 (m, 1H), 2.52 (s, 3H), 2.24-2.16 (m, 1H), 2.04-2.00 (m, 1H), 1.16 (t, J=7.1 Hz, 3H) ppm. LC/MS: m/z 411.3 (M+H)+ at 2.24 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Mg+2].[Br-].[Br-].[Li]CCCC.[O:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.I[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:36]([O:35][C:33]([N:30]1[CH2:31][CH2:32][CH:27]([CH:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:10]4[O:9][CH:13]=[CH:12][N:11]=4)=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)[CH2:28][CH2:29]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(I)cc3)CC2)CC1
Reactant: c1cocn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3ccc(-c4ncco4)cc3)CC2)CC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A −10° C. solution of MgBr2 (37 mg; 0.202 mmol) in THF (1 mL) was treated with nBuLi (0.333 mL; 1.82M; 0.606 mmol) The solution was stirred at −10° C. for 1 hr. A solution of oxazole (42 mg; 0.606 mmol) in THF (0.5 mL) was added and the solution was stirred at 25° C. for 2 hr. This solution was added to a refluxing solution of tert-butyl 1′-(4-iodophenyl)-4,4′-bipiperidine-1-carboxylate (285 mg; 0.606 mmol) and PdCl2(dppf) (495 mg; 0.606 mmol) in THF (4 mL). The mixture was refluxed 1 hr. The reaction was partitioned between CH2Cl2 and water. The organic was dried over magnesium sulfate, filtered and evaporated to a solid. The solid was chromatographed (PTLC; 40:1 CH2Cl2/MeOH) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.CCN(CC)CC.CC(OC(C)=O)=O>Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](=[CH:17]\[C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)/[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=Cc1ccco1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)/C(=C/c1ccco1)c1ccc(Br)cc1
Temperature: 140 °C

Procedure:
A mixture of 4-bromophenylacetic acid (12.90 g, 60.0 mmol), 2-furancarboxaldehyde (6.0 mL, 72.0 mmol), NEt3 (12.0 mL, 86.4 mmol), and Ac2O (12.0 mL, 127.2 mmol) were heated at 140° C. (bath) with stirring for 1¾ h. The reaction mixture was cooled in an ice bath, before being treated with 2M HCl (30 mL) to adjust the pH to 1. A solid precipitated out of solution. This solid was extracted into Et2O (500 mL). The Et2O layer was washed with H2O (100 mL), before being extracted with 5% w/v aqueous Na2CO3 solution (5×100 mL). The aqueous extracts were washed with Et2O (2×50 mL), before being carefully acidified with AcOH to pH 6. The cream solid generated was collected, washed with H2O, and recrystallised from MeOH—H2O to give the title compound: m/z (ES+)=604.0 [2M+NH4]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1C1CCCCC=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:37]=[CH:36][C:35](B(O)O)=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[N:33]2>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:35]1[CH:36]=[CH:37][C:28]([F:27])=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)c2cccnc12
Reactant: Cc1cc2ccccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2ccccc2c(-c2ccc(F)c3cccnc23)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-Butoxy-2-(1-(5-fluoroquinolin-8-yl)-3-methylnaphthalen-2-yl)acetic acid (10) was prepared following the procedure to make (S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6 except 5-fluoroquinolin-8-ylboronic acid was used instead of cyclohexenylboronic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 8.81 (d, J=8.2 Hz, 1H), 8.70 (dd, J=3.3 Hz, J=4.7 Hz,1H), 8.09 (t, J=6.2 Hz, 1H), 7.92 (m, 2H), 7.78 (m, 1H), 7.63 (t, J=9.0 Hz, 1H), 7.42 (t, J=7.0 Hz, 1H), 7.18 (t, J=7.8 Hz,1H), 6.84 (d, J=7.6 Hz, 1H), 5.18 (s, 1H), 2.68 (s, 3H), 0.80 (s, 9H). 19F-NMR: 377 MHz, (CD3OD) δ: −77.9, −123.2. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H25FNO3: 418.47. found: 418.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].Cl.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=O.[OH-].[K+].C(Cl)(=O)C>O.C(O)C>[CH2:31]([O:30][C:24]([C:25]1[NH:9][C:6]2[C:7]([C:26]=1[CH3:28])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)=[O:29])[CH3:32]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(N)cc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: CC(=O)Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2cc(C(F)(F)F)c(OC)cc2c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.3 %

Procedure:
4-Methoxy-3-trifluoromethyl-phenylamine (5 g, 26 mmol) in 12 mL water was cooled to −5 degrees C. (Ice/Methanol bath). Conc. HCl was added dropwise (7 ml), and the reaction mixture was stirred for five minutes. A solution of NaNO2 (2.0 g, 29 mmol) dissolved in 3 ml water was added dropwise over 10 minutes, and the reaction mixture was stirred for 30 min. Sodium acetate (1.8 g, 22 mmol) was then added, and stirring was continued at −5 degrees C. In a separate flask, ethyl alpha-acetoacetate (4.55 g, 29 mmol) in 20 ml absolute ethanol was stirred, and KOH (1.6 g, 29 mmol) dissolved in 3 ml water was added, followed by ice (30 g). The resulting diazonium salt was added quickly to the reaction mixture, rinsing in with 5 ml EtOH, and the reaction mixture was stirred at zero degrees C. for 3.5 hours, then stored at −10 C) for 16 hours. The reaction mixture was warmed to room temperature and extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. Solvent was removed under reduced pressure to leave a liquid residue. In a separate flask 100 ml EtOH and 21 ml acetyl chloride were mixed, with cooling in an ice bath, then heated to 70 degrees C. The liquid residue was added via pipette over 15 minutes to the acetyl chloride solution. This reaction mixture was heated to reflux for 2.5 hours, cooled, evaporated under reduced pressure. The residue was purified by column chromatography (10% ethyl acetate/hexane) to give 3.0 g 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester, 38% as a white solid and triturated with diethyl ether to give 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (1.0 g) as a white solid, and 5-Methoxy-3-methyl-4-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (14%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][N:35]=[CH:36][N:23]5[CH:22]=[CH:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:38].CCOC(C)=O>CO.C(Cl)Cl>[ClH:38].[C:28]1([C:27]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)=[N:19][C:20]3[CH:21]=[CH:22][N:23]4[CH:36]=[N:35][N:34]=[C:24]4[C:25]=3[CH:26]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5cnnc5c4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4ccn5cnnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl{1-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6b) (1.07 g, 2.177 mmol) in MeOH (5 mL) and DCM (15 mL) was added a 4N solution of HCl in EtOAc (5.44 mL, 21.77 mmol). The sealed reaction mixture was permitted to stir at room temperature. After 4 hours the reaction mixture was filtered to give 1-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine hydrochloride (1-15) as a tan solid. HRMS (M+H)+: observed=392.1872, calculated=392.1870.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH2:18].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(-c2cccnc2)nc2ccc(Br)cc12
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(-c2cccnc2)nc2ccc(Br)cc12
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
A 100 mL round bottom flask was fitted with a reflux condenser and charged with 6-bromo-2-(pyridin-3-yl)quinazolin-4-amine (2.45 g, 8.14 mmol), acetic anhydride (5.81 g, 57.0 mmol) and acetic acid (30 mL). The reaction mixture was stirred at 90° C. for 20 min and then cooled to room temperature. A precipitate formed during the reaction and was collected by filtration and washed with water (100 mL). The solid was dried at 60° C. to give N-(6-bromo-2-(pyridin-3-yl)quinazolin-4-yl)acetamide as a white powder (1.83 g, 66%). 1H NMR (300 MHz, CDCl3) δ 9.72 (s, 1H), 8.84-8.69 (m, 3H), 8.22 (s, 1H), 8.02-7.90 (m, 2H), 7.53-7.41 (m, 1H), 2.83 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](F)=[O:6].[CH3:14][OH:15]>C(N(CC)CC)C>[Br:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([O:15][CH3:14])=[O:6]
Reactant: O=C(F)c1cc(F)c(F)c(Br)c1F
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(F)c(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
772 g of 3-bromo-2,4,5-trifluoro-benzoyl fluoride are added dropwise to 1460 ml of methanol and 340 g of triethylamin, while cooling with ice. The mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated in vacuo and the resulting residue is taken up in water and methylene chloride. The water is extracted with methylene chloride once more. The organic phase is dried with Na2CO3 and concentrated in vacuo. The resulting residue is distilled in vacuo.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[NH:55]1[CH:59]=[N:58][C:57]([C:60](O)=[O:61])=[N:56]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:60]([C:57]2[N:58]=[CH:59][NH:55][N:56]=2)=[O:61])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1nc[nH]n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2nc[nH]n2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1H-1,2,4-triazole-3-carboxylic acid as starting materials in 43% yield. LCMS for C27H28ClN10O2 (M+H)+: m/z=559.2.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:22](NC1C=C(C(O)=O)C(=CC=1)C(O)=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCC.CC(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCCCC.CC(C)CCCCCCCCCCCCCNC1C=C(C(O)=O)C(=CC=1)C(O)=O.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C(=CC=1)C(O)=O)CCCCCCCCCCCCCCCCCC>>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCNc1ccc(C(=O)O)c(C(=O)O)c1
Reactant: CCCCCCCCNc1ccc(C(=O)O)c(C(=O)O)c1
Agent: CC(C)CCCCCCCCCCCCCNc1ccc(C(=O)O)c(C(=O)O)c1
Agent: CCCCCCCCCCC(C)Nc1ccc(C(=O)O)c(C(=O)O)c1
Agent: CCCCCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(C(=O)O)c1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(C(=O)O)c1

Procedure:
Similarly, the diethyl 4-alkylaminophthalates described in Example 11 give, respectively, 4-octylaminophthalic acid, 4-nonylaminophthalic acid, 4-decylaminophthalic acid, 4-undecylaminophthalic acid, 4-(1-methylundecyl)aminophthalic acid, 4-dodecylaminophthalic acid, 4-tridecylaminophthalic acid, 4-tetradecylaminophthalic acid, 4-pentadecylaminophthalic acid, 4-(14-methylpentadecyl)aminophthalic acid, 4-heptadecylaminophthalic acid, 4-octadecylaminophthalic acid, and 4-nonadecylaminophthalic acid.