Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[F:31][C:32]1[C:33]([C:38]([NH:40][NH2:41])=O)=[N:34][CH:35]=[CH:36][CH:37]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:38]([C:33]3[C:32]([F:31])=[CH:37][CH:36]=[CH:35][N:34]=3)=[N:40][N:41]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: NNC(=O)c1ncccc1F
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCn2c(nnc2-c2ncccc2F)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
4-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37)(0.3 g, 1.031 mmol) was dissolved in Dichloromethane (DCM) (2.58 ml). triethyloxonium tetrafluoroborate (0.235 g, 1.237 mmol) was added and the solution was left to stir, under an argon atmosphere for 30 minutes. 3-Fluoro-2-pyridinecarbohydrazide (I31) (0.192 g, 1.237 mmol) was added and the solution was left to stir for a further 40 minutes. The solvent was removed under reduced pressure and 1-butanol (2.58 ml) was added. The reaction mixture was left to reflux at 120° C., under an argon atmosphere for 3.5 hours. The solvent was removed under reduced pressure to afford crude product in 0.887 g. The crude material was purified by flash chromatography (Biotage Isolera 4, 50 g cartridge) with a gradient of MeOH 0-10% in DCM. The solvent was removed under reduced pressure to afford 0.254 g of the desired compound. The isolated material was purified using MDAP to afford the purified product in 0.110 g.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)[CH:4]=1.C1([O:29][C:30](=O)[NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)C=CC=CC=1.NC1C=NC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:31][C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:19][CH2:18]2)[CH:4]=1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Cc1ccnc(Oc2cccc(C=C3CCNCC3)c2)c1
Agent: Cl
Agent: Nc1cccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccnc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnc4)CC3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Methyl-2-(3-piperidin-4-ylidenemethyl-phenoxy)-pyridine hydrochloride (530 mg, 1.5 mmol, from Step 5), pyridin-3-yl-carbamic acid phenyl ester (402 mg, 1.88 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-aminopyridine) and triethylamine (0.836 mL, 6.0 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 hours, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-5%, (8:1 EtOH:conc. NH4OH):DCM) to afford the desired product (429 mg) as a foamy white solid. MS (APCI 10V) AP+ 401.4, 281.2 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.35 (s, 3H) 2.45 (td, J=5.82, 0.99 Hz, 2H) 2.57 (td, J=5.81, 1.11 Hz, 2H) 3.51-3.57 (m, 2H) 3.61-3.67 (m, 2H) 6.44 (s, 1H) 6.73-6.80 (m, 1H) 6.90-6.95 (m, 2H) 6.97 (dt, J=5.18, 0.61 Hz, 1H) 7.08 (d, J=8.02 Hz, 1H) 7.30-7.42 (m, 2H) 7.91 (ddd, J=8.38, 2.58, 1.45 Hz, 1H) 7.98 (d, J=5.24 Hz, 1H) 8.16 (dd, J=4.81, 1.40 Hz, 1H) 8.58 (d, J=2.51 Hz, 1H)
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.S(Cl)(Cl)=O.[F:17][C:18]1[CH:19]=[C:20]([CH2:24]O)[CH:21]=[CH:22][CH:23]=1>>[N:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH2:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: OCc1cccc(F)c1
Reactant: O=C(O)C12CCN(CC1)CC2
Agent: Cl
Solvent: O=S(Cl)Cl
Product: O=C(OCc1cccc(F)c1)C12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.9 %

Procedure:
A mixture of quinuclidine-4-carboxylic acid hydrochloride (100 mg, 0.52 mmol) and thionyl chloride (500 μl, 6.85 mmol) was refluxed for 2 hours. The reaction was cooled to room temperature, and the solvent was accurately removed. The residue was suspended in dry DCM and treated with (3-fluorophenyl)methanol (65.8 mg, 0.52 mmol). The reaction was stirred at room temperature for 24 hours. The solvent was evaporated, and the residue was dissolved in water (1 ml), basified with NaHCO3 and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain 3-fluorobenzyl quinuclidine-4-carboxylate (41 mg, 29.8% yield), which was used in the next step without any further purification.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.[CH2:19]([O:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1N)[CH:20]=[CH2:21]>N1C=CC=CC=1>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[CH:20]([CH2:21][O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:11])[CH3:10])[CH2:19]1
Reactant: C=CCOc1ccccc1N
Reactant: CC1(C)CCCC(C)(C)N1O
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1OCC1COc2ccccc21
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To a solution of 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 3.1 g (30 mmol) of tert-butyl nitrite and 7.5 mg (0.012 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) in 100 mL of pyridine at 65°-70° C. under a nitrogen atmosphere is added dropwise over 20 minutes a solution of 5.6 g (25 mmol) of 2-allyloxyaniline in 20 mL of pyridine. The evolution of gas is observed during the addition of the 2-allyloxyaniline. After the addition is complete, the reaction mixture is kept at 65°-70° C. for an additional forty minutes until gas evolution subsided. After cooling to ambient temperature, the reaction mixture is then concentrated. The residue obtained is purified by vacuum flash chromatography (heptane) to give 2.3 g of a viscous liquid in 63.7% yield. The structure is confirmed by 1Hnmr and elemental analyses.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C(#N)C>[OH:11][C:7]1[CH:6]=[C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1cccc(O)c1
Solvent: CC#N
Product: Oc1cccc(-c2cn3cc(I)ccc3n2)c1
Temperature: 110 °C
Yield: 60.7 %

Procedure:
987 mg (corresponding to 4.55 mmol) of 2-bromo-3′-hydroxyacetophenone and 1.00 g (corresponding to 4.55 mmol) of 2-amino-5-iodopyridine were dissolved in 50 mL of acetonitrile. The resulting solution was heated under reflux in an oil bath at 110° C. for 2 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 1 mL of methanol. Then, about 10 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 927 mg (corresponding to 2.76 mmol) of 2-(3′-hydroxyphenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 8, Step 2).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.Br[C:13]1[CH:14]=[CH:15][C:16]([O:19][C@H:20]2[CH:27]3[CH2:28][N:23]4[CH2:24][CH:25]([CH2:29][CH:21]2[CH2:22]4)[CH2:26]3)=[N:17][CH:18]=1.[NH:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.N>>[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C@H:20]4[CH:27]5[CH2:28][N:23]6[CH2:24][CH:25]([CH2:29][CH:21]4[CH2:22]6)[CH2:26]5)=[N:17][CH:18]=3)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: Brc1ccc(OC2C3CC4CC2CN(C4)C3)nc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Product: c1cc2cc(-c3ccc(OC4C5CC6CC4CN(C6)C5)nc3)ccc2[nH]1

Procedure:
Prepared from the product of Example 9F (45 mg, 0.14 mmol) and 5-indolylboronic acid (33 mg, 0.204 mmol; Maybridge) according to Method E: 1H NMR (300 MHz, CHCl3) δ ppm 1.76-1.86 (m, 2H), 2.26 (s, 2H), 2.39 (d, J=11.5 Hz, 2H), 3.26-3.44 (m, 5H), 5.37 (t, J=3.2 Hz, 1H), 6.61 (t, J=2.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 7.25-7.30 (m, 1H), 7.31-7.41 (m, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.86 (dd, J=8.5, 2.7 Hz, 1H) MS (DCI/NH3) m/z=346 (M+H)+; Anal. Calcd. for C22H22N3O.1.6H2O: C, 70.79; H, 6.80; N, 11.26. Found: C, 70.78; H, 6.44; N, 10.91.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(=O)(O)[O-].[K+].[I:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>CC(C)=O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([I:13])=[CH:15][CH:16]=1
Reactant: COC(CN)OC
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(CNC(=O)c1ccc(I)cc1)OC
Yield: 96.8 %

Procedure:
A solution of 2-aminoacetaldehyde dimethylacetal (12.3 mL, 112 mmol) in a mixture of acetone (50 mL) and aqueous potassium bicarbonate (12 g, 122 mmol in 110 mL of water) was stirred and cooled to −5° C., as a solution of 4-iodobenzoyl chloride (25 g, 94 mmol) was added dropwise. The cooling bath was removed and the reaction stirred for 3 hours. The reaction was concentrated and diluted with water. The resulting solid was isolated by filtration and dried to give 30.5 g of N-(2,2-dimethoxyethyl)-4-iodobenzamide, 1H NMR (400 MHz, CDCl3) δ 7.78 (d, 2H), 7.46 (d, 2H), 6.34 (s, 1H), 4.44 (t, 1H), 3.58 (t, 2H), 3.42 (s, 6H) ppm.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:36]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(OCC4C=CC=CC=4)=C(OCC4C=CC=CC=4)C=3)N=2)CC1)=O)(C)(C)C>>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:36][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c3c2CCNCC3)cc1
Yield: 20 %

Procedure:
The title compound (22 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 3,4-bis(benzyloxy)benzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also provided 2-(3,4-bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C34H32ClN3O2, 549.22; found, m/z 550.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.16 (m, 14H), 6.86 (d, J=8.3 Hz, 1H), 6.65 (d, J=1.9 Hz, 1H), 6.56 (dd, J=8.3, 1.9 Hz, 1H), 5.13 (s, 2H), 4.99 (s, 2H), 4.97 (s, 2H), 2.78-2.76 (m, 2H), 2.73-2.71 (m, 2H), 2.65 (m, 4H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][OH:10]>>[C:1]1([C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][O:10]1)=[O:8]
Reactant: CO
Reactant: OCc1ccccc1
Product: O=C1OCc2ccccc21

Procedure:
The procedure as described in F is repeated, except that 50 ml of benzyl alcohol are used instead of methanol, to give a phthalide compound of the formula ##STR16## m.p. 183°-184° C.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:21][C:22]1([CH3:30])[O:27][C:26](=[O:28])[CH2:25][C:24](=[O:29])[O:23]1>>[OH:19][C:1](=[C:25]1[C:26](=[O:28])[O:27][C:22]([CH3:30])([CH3:21])[O:23][C:24]1=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCCC=CCCCCCCCC(=O)Cl
Product: CCCCCCCCC=CCCCCCCCC(O)=C1C(=O)OC(C)(C)OC1=O
Yield: 88.4 %

Procedure:
Starting from 9-octadecenoyl chloride (15 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione (8 g), 5-(1-hydroxy-9-octadecenylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (18 g) was obtained as an oil according to similar manner to that of Preparation A-2 (1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].[Cl:11][C:12]1[CH:13]=[C:14]2[N:35](COCC[Si](C)(C)C)[C:34]([O:44][C@H:45]3[CH2:54][O:53][C@H:52]4[C@@H:47]([O:48]C(C5C=CC=CC=5)[O:50][CH2:51]4)[CH2:46]3)=[N:33][C:15]2=[N:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)Cl.O.CC([P+](Cl)(C(C)(C)C)C(C)(C)C)(C)C.C1C=CC(C2C(N)=CC=CC=2)=CC=1.[Pd+2]>[Cl:11][C:12]1[CH:13]=[C:14]2[NH:35][C:34]([O:44][C@@H:45]3[CH2:46][C@H:47]([OH:48])[C@@H:52]([CH2:51][OH:50])[O:53][CH2:54]3)=[N:33][C:15]2=[N:16][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[F:10])=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(Br)c(F)c1
Reactant: CC1(C)OB(c2ccc(-c3nc4nc(O[C@H]5CO[C@@H]6COC(c7ccccc7)O[C@H]6C5)n(COCC[Si](C)(C)C)c4cc3Cl)cc2)OC1(C)C
Agent: [Pd+2]
Agent: CC(C)(C)[P+](Cl)(C(C)(C)C)C(C)(C)C
Agent: Nc1ccccc1-c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)c(F)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Placed 4-bromo-3-fluorobenzonitrile (15 mg, 0.075 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (6 mg, 0.012 mmol) into a reaction vessel in a dry-glove box. Then 6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano-[3,2-d][1,3]dioxin-7-yl)oxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (45 mg, 0.062 mmol) was added as a solution in anhydrous dioxane (0.50 mL) which had been degassed. To this mixture was added a solution of degassed, aqueous 1N K3PO4 (0.19 mL, 0.19 mmol). The reaction vessel was sealed and heated to 80° C. with stirring. After 16 hours, the mixture was allowed to cool to room temperature, then diluted with DCM (2.0 mL) and water (1.0 mL), and vigorously stirred for 30 minutes. The organic layer was separated and concentrated under reduced pressure. The resultant oil was dissolved in DCM (1.0 mL), and SiliaMetS® Dimercaptotriazine (100 mg) was added. The resulting suspension was stirred for 2 hours at 35° C. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The resultant residue was dissolved in DCM (0.50 mL) and TFA (0.50 mL) and stirred at room temperature. After 3 hours the mixture was concentrated under reduced pressure. The resultant oil was dissolved in methanol (0.50 mL), then a 5N aqueous solution of NaOH (0.10 mL) was added and the mixture was allowed to stir at room temperature. After 15 minutes the solution was acidified with a few drops of formic acid and diluted with DMSO. The resulting mixture was filtered to remove solids and purified via reverse phase preparatory HPLC using MeCN/water/formic acid as the mobile phase. The fractions containing product were combined and concentrated under reduced pressure to provide the title compound as a white solid. LC-MS: calculated for C25H20ClFN4O4 494.12, observed m/e: 495.12 (M+H)+ (Rt 0.48/2 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[C:11]([Cl:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:11]([Cl:24])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(OCc2ccccc2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of tert-butyl 3-[4-(benzyloxy)-2-chlorophenyl]propanoate (22.5 g) in dichloromethane (67.6 mL) was added trifluoroacetic acid (24.8 mL), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-[4-(benzyloxy)-2-chlorophenyl]propanoic acid (13.5 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([F:17])[F:16])[CH3:12]>[Cu].CS(C)=O>[CH2:11]([O:13][C:14](=[O:19])[C:15]([F:17])([F:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc([N+](=O)[O-])cc1
Temperature: 55 °C
Reaction time: 15 h

Procedure:
According to the Kumadaki method (supra) and the above-described scheme, 4-iodonitrobenzene (Compound 1b; 249.0 mg, 1.0 mmol), bromodifluoroacetic acid ethyl ester (203 mg, 1.0 mmol), copper powder (128 mg, 2.0 mmol) and DMSO (2.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 15 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2,2-difluoro-2-(4-nitrophenyl)acetic acid ethyl ester (Compound 2b) was obtained with a yield of 58%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[F:12]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 110 °C

Procedure:
2-Bromo-1-fluoro-4-nitrobenzene (15 g, 68.2 mmol), 2,4-difluorophenol (7.82 mL, 82 mmol), and cesium carbonate (26.7 g, 82 mmol) were combined in DMSO (75 mL), heated at 110° C. for 1 hour, and then cooled. To the cooled reaction mixture was added water (1000 mL) and saturated aqueous sodium chloride (1000 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered, and concentrated under reduced pressure to give a crude solid which was used in the next step without additional purification.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C@@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O>Br>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C@@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1CCC(C)(C)C
Agent: Br
Product: CC(C)(C)CC[C@@H]1C[C@@H](c2cc(=O)[nH]o2)CCN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
(2R,4S)-Methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (62 mg, 0.2 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 4 mL) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated and the compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×19 ID mm) using a gradient of 5-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 15 minutes with a flow of 19 mL/min. 5-((2R,4S)-2-(3,3-Dimethylbutyl)piperidin-4-yl)isoxazol-3(2H)-one (39.8 mg, 79%) was isolated as a white solid. 1H NMR (600 MHz, cd3od) δ 0.92 (s, 9H), 1.20-1.34 (m, 2H), 1.56-1.69 (m, 2H), 1.83-1.90 (m, 1H), 2.05-2.13 (m, 1H), 2.14-2.21 (m, 1H), 2.26-2.34 (m, 1H), 3.05-3.19 (m, 2H), 3.25-3.34 (m, 2H), 5.75 (s, 1H). HRMS Calculated for [C14H24N2O2+H]+: 253.1916. Found: 253.1925
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[C:14]([CH:22]2[CH:31]3[CH2:32][CH:33]=[CH:34][CH:30]3[C:29]3[CH:28]=[C:27]([C:35](=[O:37])[CH3:36])[CH:26]=[CH:25][C:24]=3[NH:23]2)=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1)(C)C.O>CO>[C:12]([C:13]1[C:14]([CH:22]2[CH:31]3[CH2:32][CH:33]=[CH:34][CH:30]3[C:29]3[CH:28]=[C:27]([C:35](=[O:37])[CH3:36])[CH:26]=[CH:25][C:24]=3[NH:23]2)=[CH:15][C:16]2[O:20][CH2:19][O:18][C:17]=2[CH:21]=1)#[CH:11]
Reactant: CC(=O)c1ccc2c(c1)C1C=CCC1C(c1cc3c(cc1C#C[Si](C)(C)C)OCO3)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cc2c(cc1C1Nc3ccc(C(C)=O)cc3C3C=CCC31)OCO2
Reaction time: 2 h
Yield: 74.6 %

Procedure:
Potassium carbonate (0.058 g, 0.42 mmol) was added to the 1-[4-(6-trimethylsilanylethynyl-benzo[1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-yl]-ethanone (0.090 g, 0.21 mmol) in methanol (4 mL) and stirred for 2 hr. The reaction mixture poured into water (25 mL) and the product was extracted with chloroform (3×5 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 10% EtOAc/Hexanes to give the product as a colorless solid (0.056 g, 75%)
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([NH:19][C:20]3[N:40]=[C:23]4[C:24]([C:28]5[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=5[O:35][CH2:36][CH:37]([F:39])[F:38])=[CH:25][CH:26]=[CH:27][N:22]4[N:21]=3)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:34][C:32]1[CH:31]=[CH:30][C:29]([O:35][CH2:36][CH:37]([F:39])[F:38])=[C:28]([C:24]2[C:23]3[N:22]([N:21]=[C:20]([NH:19][C:17]4[CH:16]=[CH:15][C:12]5[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=5[CH:18]=4)[N:40]=3)[CH:27]=[CH:26][CH:25]=2)[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(Cl)ccc5OCC(F)F)cccn4n3)cc2CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)COc1ccc(Cl)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12

Procedure:
{8-[5-Chloro-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine was prepared from 7-{8-[5-chloro-2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.117 g, 205 mmol) and trifluoroacetic acid (0.5 mL) in a manner analogous to Example 312 to give product (0.045 g, 47%). MP=102-105° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.52 (s, 1H), 8.78 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.50 (d, 1H), 7.40 (m, 2H), 7.30 (d, 1H), 7.05 (t, 1H), 7.00 (d, 1H), 6.25 (br m, 1H), 4.35 (m, 2H), 3.10 (br m, 1H), 2.79 (br m, 8H). MS=470 (MH)+.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH:10]1[CH2:12][CH2:11]1>>[CH:10]1([CH2:9][C:1]2([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: O=C(O)C1CCC1
Reactant: BrCC1CC1
Product: O=C(O)C1(CC2CC2)CCC1

Procedure:
The title compound was prepared according to the procedure described for Intermediate 15.1 from cyclobutanecarboxylic acid and (bromomethyl)cyclopropane.