Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([C:7](O)=O)[CH2:6][CH2:5][CH2:4]1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:19][NH:20][C:21]([NH2:23])=[O:22].C([O-])(O)=O.[Na+].[OH-].[Na+].Cl>C(Cl)Cl.O.CCOC(C)=O.CN(C=O)C>[F:1][C:2]([F:11])([F:10])[C:3]1([C:7]2[NH:23][C:21](=[O:22])[NH:20][N:19]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)C1(C(F)(F)F)CCC1
Reactant: NNC(N)=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(C2(C(F)(F)F)CCC2)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To a 0° C. solution of 1-trifluoromethyl-1-cyclobutylcarboxylic acid (1.50 g, 8.92 mmol) in DCM (15 mL) was added oxalyl chloride (1.50 g, 11.82 mmol) followed by catalytic amount of DMF. The reaction mixture was stirred at RT for 1 h. The solvent from the reaction mixture was completely evaporated. In a different flask, a suspension of semicarbazide hydrochloride (1.50 g, 13.45 mmol) in water (15 mL) was treated with NaHCO3 (1.50 g, 17.86 mmol) and stirred at RT for 30 minutes till a clear solution forms. To this solution was added the above acid chloride dissolved in EtOAc (20 mL) and the resultant mixture was stirred at RT over night. The organic layer was separated and the aqueous layer was extracted with DCM (2×10 mL). The combined organics were concentrated and the residue was treated with sodium hydroxide (1.50 g, 37.5 mmol) in water (15 mL), heated at 100° C. for 3 h, and stirred for 20 h at RT. The reaction mixture was acidified with conc. HCl to pH 1 and stirred at RT for 1 h. The reaction mixture was concentrated to a small volume under high vacuum and diluted with MeOH. The separated solids were filtered and washed with methanol. The filtrate was evaporated and further dried by azeotropic distillation from toluene to provide 5-(1-(trifluoromethyl)cyclobutyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.05 g, 57%) as a light brownish residue, suitable for use without further purification. MS (ESI) m/z: 208.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C@H:12]([CH3:17])[CH2:11]3)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(=O)(O)[O-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C1COCC1.O>[CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C@H:12]([CH3:17])[CH2:11]3)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)C[C@@H](C)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc2c(c1)C[C@@H](C)N2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (2R)-5-(2,5-dimethyl-1H-pyrrol-1yl)-2,3-dihydro-2-methyl-1H-indole (Step 2, 0.100 g, 0.442 mmol) in THF/H2O (8:1, 4.5 mL) is added sodium bicarbonate (0.072 g, 0.884 mmol) followed by benzyl chloroformate (80 μL, 0.53 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 mins and at ambient temperature for 2 h and is then concentrated under reduced pressure. The residue is taken up in CH2Cl2 (40 mL), washed with H2O (2×10 mL) and saline (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a Biotage Flash 40S 40 g silica gel cartridge (1% EtOAc/Hexanes) to give the title compound, MS (ESI+) for C23H24N2O2 m/z 361 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:34])[N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29](=[O:31])[CH3:30])[C@@H:24]([CH3:32])[CH2:23][C@H:22]4[NH2:33])=[CH:15][CH:14]=2)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl[C:88]1[CH:93]=[CH:92][C:91]([F:94])=[CH:90][N:89]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9](=[O:34])[N:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29](=[O:31])[CH3:30])[C@@H:24]([CH3:32])[CH2:23][C@H:22]4[NH:33][C:88]3[CH:93]=[CH:92][C:91]([F:94])=[CH:90][N:89]=3)=[CH:17][CH:18]=2)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)N1c2ccc(-c3ccc(CN(C)C(=O)OCc4ccccc4)cc3)cc2[C@H](N)C[C@@H]1C
Reactant: Fc1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(CN(C)C(=O)OCc4ccccc4)cc3)cc2[C@H](Nc2ccc(F)cn2)C[C@@H]1C
Temperature: 110 °C
Reaction time: 22 h
Yield: 35 %

Procedure:
A flask was charged with phenylmethyl({4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}methyl)methylcarbamate (for a preparation see intermediate 80) (100 mg, 0.219 mmol), sodium tert-butoxide (31.5 mg, 0.328 mmol), racemic BINAP (6.80 mg, 10.93 μmol), tris(dibenzylideneacetone)dipalladium(0) (10.01 mg, 10.93 μmol) and 2-chloro-5-fluoropyridine (0.033 mL, 0.328 mmol), then filled with toluene (2 mL) and the resulting mixture was stirred at 110° C. for 22 h then cooled to room temperature and partitioned between water (20 mL) and EtOAc (60 mL). The layers were separated and the aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with brine (30 mL), dried over MgSO4 and concentrated in vacuovacuo. Purification of this residue on SP4 using a 25 G silica cartridge (gradient:10 to 50% AcOEt in Hexanes) following by another purification using a 12 G silica cartridge (gradient:10 to 50% AcOEt in Hexanes) gave phenylmethyl[(4-{(2S,4R)-1-acetyl-4-[(5-fluoro-2-pyridinyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}phenyl)methyl]methylcarbamate (60 mg, 35%)
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[CH:28]=[CH:27][N:26]([CH3:29])[C:25](=[O:30])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[CH:28]=[CH:27][N:26]([CH3:29])[C:25](=[O:30])[CH:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: Cn1ccc(Cl)cc1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCO[C@@H]1CN(c2ccn(C)c(=O)c2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 16 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (50 mg, 0.15 mmol), 4-chloro-1-methylpyridin-2(1H)-one obtained in Example (137a) (25 mg, 0.17 mmol) and sodium carbonate (78 mg, 0.74 mmol) were suspended in DMSO (1 mL). The suspension was subjected to the same operation as in Example (131b) to obtain 9.8 mg of the title compound as a pale brown amorphous solid (16%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[OH:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[O:12][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccncc2cc1Br
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccncc4cc3Br)c2cc1OC
Temperature: 140 °C
Reaction time: 7 h
Yield: 44.6 %

Procedure:
7-Bromo-6-hydroxyisoquinoline (11 mg), 4-chloro-6,7-dimethoxyquinoline (31 mg), and 4-dimethylaminopyridine (17 mg) were suspended in o-dichlorobenzene (2 ml), and the mixture was stirred at 140° C. for 7 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (9 mg, yield 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][CH:20]=2)=[CH:15][CH:14]=1)=O>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[O:23][CH:22]=[N:21][CH:20]=4)=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(-c2cnco2)cc1
Product: Cc1ccc2nc(-c3ccc(-c4cnco4)cc3)cn2c1
Yield: 43.6 %

Procedure:
The procedure of Referential Example 1 was repeated, except that 2-amino-5-methylpyridine (54 mg) and 2-bromo-1-[4-(1,3-oxazol-5-yl)phenyl]-1-ethanone (133 mg), which had been produced in Referential Example 10, were used, to thereby yield the title compound (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38]([CH2:39][CH3:40])=[O:41])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: CCC(=O)O
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(N)(=O)=O)cnn23)c1
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 92 %

Procedure:
Using 7-(2-chloro-5-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.08 g, 0.147 mmol) obtained in Example 12 step 5 and propionic acid (0.055 mL, 0.737 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.081 g, 92%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][C:12]2[C:13](=[O:18])[C:14](=[O:17])[C:15]=2[CH3:16])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:5][NH:6]2.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(#N)C.C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:10]([NH:11][C:12]2[C:13](=[O:18])[C:14](=[O:17])[C:15]=2[CH3:16])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][CH2:20][CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:5][NH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(Nc2ccc3[nH]cc(CCCO)c3c2C)c(=O)c1=O
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(Nc2ccc3[nH]cc(CCCOS(C)(=O)=O)c3c2C)c(=O)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To an ice-cold suspension of 4-methyl-5-(1,2-dioxo-4-methyl-3-cyclobuten-3-yl)amino-3-(3-hydroxypropyl)indole (0.235 g, 0.79 mmol) in 5 mL of acetonitrile-THF (4:1) was added triethylamine (0.132 mL, 0.95 mmol), followed by methanesulfonyl chloride (0.074 mL, 0.95 mmol). The mixture was stirred at 0° C. for 2 h and then the cooling bath was removed and stirring continued at room temperature for 17 h. Another 0.026 mL (0.19 mmol) of triethylamine and 0.015 mL (0.19 mmol) of methanesulfonyl chloride were then added and stirring was continued for 30 min. The resulting mixture was diluted with ethyl acetate, washed (H2O×2; brine), dried (Na2SO4) and evaporated to give a gum. This material was chromatographed (SiO2 /ethyl acetate-dichloromethane, 1:1) to give to give the title compound (0.270 g, 91%) as an off-white foam. An analytical sample was obtained by crystallization from ether to give an off-white solid, mp 130°-131° C. (dec): IR (KBr) 3240 (br), 1792, 1727, 1590, 1330, 920 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ 11.01 (br s, 0.75H), 10.95 (br s, 0.25H), 10.58 (s, 0.75H), 10.31 (s, 0.25H), 7.23-7.13 (m, 2H), 6.94 (d, J=8.5 Hz, 0.75H), 6.88 (d, J=8.6 Hz, 0.25H), 4.29 (t, J=6.3 Hz, 2H), 3.19 (s, 3H), 2.96 (m, 2H), 2.50 (s, 3H), 2.24 (s, 0.75H), 2.02 (m, 2H), 1.56 (s, 2.25H). Anal. Calcd for C18H20N2O5S: C, 57.43; H, 5.36; N, 7.44. Found: C, 57.16; H, 5.00; N, 7.34.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:7]=1.[F:36][C:37]1[CH:38]=[C:39]([CH:55]=[CH:56][CH:57]=1)[CH2:40][N:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[N:42]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:44]4[CH:43]=[N:42][N:41]([CH2:40][C:39]5[CH:55]=[CH:56][CH:57]=[C:37]([F:36])[CH:38]=5)[CH:45]=4)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:7]=1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cnc(NC(=O)OC(C)(C)C)c(F)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(NC(=O)OC(C)(C)C)c(F)c4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl (3-fluoro-5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)carbamate (intermediate 66T) (150 mg, 0.24 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (82 mg, 0.27 mmol) using Pd(PPh3)2Cl2 (8 mg, 0.012 mol) and sodium carbonate (76 mg, 0.72 mmol) in toluene/ethanol/water (10/10/2 mL) to afford 122 mg (crude) of the titled compound. MS: m/z=657.2 (M+1).
Reaction SMILES: CS(C)=O.[H-].[Na+].[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:35]([C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)(=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O.O1CCCC1>[N:45]1[CH:46]=[CH:47][CH:48]=[C:43](/[C:35](/[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:15]\[CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:44]=1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)c1cccnc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCC/C=C(/c1ccccc1)c1cccnc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To dimethylsulfoxide (40 ml) was added dropwise sodium hydride (1.0 g), and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, to which was added 5-carboxypentyltriphenyl phosphonium bromide (9.5 g, 21 mmoles) and the mixture was stirred for 5 minutes. To the reaction mixture was added a tetrahydrofuran solution (10 ml) of 3.7 g (0.02 mole) of 3-benzoylpyridine. The mixture was stirred for 30 minutes at room temperature, followed by addition of water (100 ml), which was subjected to extraction twice with ethylacetate (50 ml). The aqueous layers were combined and adjusted to pH 6 with 2N HCl, which was subjected to extraction with ethyl acetate. The organic layers were combined and washed with water and dried (magnesium sulfate). The solvent was then evaporated off, and the residue was subjected to silica-gel chromatography, using ethanolethyl acetate (1:5) as eluant to yield (E)+(Z)-7-(3-pyridyl)-7-phenyl-6-heptenoic acid (Ia-3, Ia-4 in Table 3) (4.5 g 79%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:18](C)=[C:17]2[N:8]([C:9](=[O:20])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1)=O)C.[OH-].[K+]>>[OH:3][CH2:4][C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[O:20])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1
Reactant: CCOC(=O)c1nn2c(=O)[nH]c3ccccc3c2c1C
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12

Procedure:
Following the procedure of Example 25, but substituting 2[(acetoxy)methyl]pyrazolo[1,5-c]quinazoline-5(6H)-one for 1-methylpyrazolo[1,5-c]quinazoline-5(6H)-one-2-carboxylic acid ethyl ester in Example 25 and using a mole ratio of 2 to 1 for the quantity of potassium hydroxide to ester, the title compound is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[N:5]([CH:18]=[N:19][CH:20]=2)[C:6]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2[N:5]3[CH:18]=[N:19][CH:20]=[C:4]3[C:3]([Cl:2])=[CH:8][C:7]=2[C:9](=[O:11])[CH3:10])[CH2:13][CH2:14]1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCNCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(C)=O)CC1
Reaction time: 0.08 h
Yield: 77 %

Procedure:
1-(8-Chloro-5-piperazin-1-ylimidazo[1,5-a]pyridin-6-yl)ethanone hydrochloride was dissolved in methylene chloride (1.0 mL) and N,N-diisopropylethylamine (45 μL, 0.26 mmol) was added. To the reaction mixture, acetyl chloride (5.5 μL, 0.077 mmol) was added and the mixture was stirred for 5 minutes. Evaporation and purification by preparative LCMS (pH 10) gave the desired compound (13 mg, 77%). LCMS calculated for C15H18ClN4O2 (M+H)+: m/z=321.1. found: 320.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Sn](C)(C)C)[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:26]=1.[F-].[Cs+]>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:29]2[CH:30]=[CH:25][CH:26]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:28]=2)[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1cccc(OCCCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([Sn](C)(C)C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(OCCCc3ccccc3)c2)c1
Temperature: 50 °C

Procedure:
3-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-(trimethylstannyl)pyridine (75 mg, 176 μmol), 1-iodo-3-(3-phenylpropoxy)benzene (59 mg, 174 μmol, 1.0 equiv.) and anhydrous DMF (2 mL) were placed in a 25 mL round-bottom flask with magnetic stirrer. To this mixture were added rapidly copper(I) iodide (3.3 mg, 0.02 mmol, 0.10 equiv.), cesium fluoride (53 mg, 0.35 mmol, 2.0 equiv.), and Pd(PPh3)4 (10.1 mg, 0.01 mmol, 0.05 equiv.). The flask was fitted with a three-way stopcock with nitrogen balloon, and the atmosphere was exchanged. The reaction mixture was heated at 50° C. for 6 h. The bulk of solvent was pumped off at room temperature with an oil pump. The reaction progress was monitored by TLC (EtOAc/petroleum ether 1:1). The residue was chromatographed on silica gel with EtOAc/petroleum ether/Et3N 2:3:0.05. This resulted in 55 mg (66%) of 3-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-5-[3-(3-phenylpropoxy)phenyl]pyridine as a colorless oil. 1H NMR (CDCl3, TMS, 300 MHz) δ 8.48 (s, 1H), 8.33 (s, 1H), 8.02 (s, 1H), 7.57 (br s, 1H), 7.39 (t, 1H, J=8.0 Hz), 7.34-7.19 (m, 4H), 7.16 (d, 1J, J=8.1 Hz), 7.10 (s, 1H), 6.96 (dd, 1H, J=2.1, 8.1 Hz), 4.55 (br m, 1H), 4.43 (br m, 1H), 4.22 (dd, 1H, J=2.5, 10.0 Hz), 4.04 (t, 2H, J=6.3 Hz), 3.91 (t, 2H, J=7.5 Hz), 2.85 (7, 2H, J=7.5 Hz), 2.36 (m, 2H), 2.15 (m, 3H), 1.41 (s, 9H).
Reaction SMILES: Br.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:24]C)=[C:7]([CH:23]=1)[CH2:8][C:9]1(O)[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.O>C(O)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:24][C:9]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[CH2:8][C:7]=2[CH:23]=1
Reactant: COc1ccc(F)cc1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.1 %

Procedure:
Hydrobromic acid (48%, 60 mL) was added to a solution of the crude tert-butyl 4-(5-fluoro-2-methoxybenzyl)-4-hydroxypiperidine-l-carboxylate (86 g) in acetic acid (300 mL). The mixture was heated at reflux for 5 hours. Further hydrobromic acid (48%, 60 mL) was added and reflux continued for 24 hours. The mixture was cooled to room temperature, added to water (2 L) and extracted with tert.-butyl methyl ether (2×500 mL). The aqueous phase was adjusted to pH>10 by addition of 50 wt. % sodium hydroxide solution and extracted with tert.-butyl methyl ether (2L+1L). Organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residual solid was crystallised from tetrahydrofuran/tert.-butyl methyl ether (4:1, 500 mL) to give the title compound (20 g). 1H-NMR (CD3OD, 400 MHz): δ 6.92-6.87 (m, 1H); 6.81-6.75 (m, 1H); 6.64 (dd, J=4.2, 8.7 Hz, 1H); 3.08-2.98 (m, 4H); 2.89-2.81 (m, 2H); 1.91-1.83 (m, 2H); 1.78-1.69 (m, 2H).
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[N:25]=1.[F:48][CH:49]([F:70])[CH2:50][NH:51][C:52]([NH:54][C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH:56]=1)=[O:53]>>[F:48][CH:49]([F:70])[CH2:50][NH:51][C:52]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:24]2[CH:29]=[C:28]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]3[CH3:47])[N:25]=2)=[CH:57][CH:56]=1)=[O:53]
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCC(F)F)cc2)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCC(F)F)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Yield: 23 %

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-2-yl)-3-methylmorpholine (intermediate 16) and 1-(2,2-difluoroethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 20). Purification was achieved using flash chromatography (20-90% EtOAc in petroleum ether (40:60). The material was further purified by prep HPLC (low pH) to afford a white solid (20 mg, 23%).