Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:21]([C:34](OCC)=[O:35])=[CH:20]2.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:6]([NH:5][C:34]([C:21]2[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:23]3[C:19]([CH:20]=2)=[CH:18][C:17]([F:16])=[CH:25][CH:24]=3)=[O:35])[CH:7]=1
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1cnc2ccccc2c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cnc2ccccc2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
1.19 mL (2.38 mmol) of a 2M solution of trimethylaluminium in toluene are added dropwise to a solution, stirred at 0° C. under an inert atmosphere, of 0.274 g (1.9 mmol) of 3-aminoquinoline in 40 mL of dry toluene. The mixture is then stirred at 50° C. After 15 minutes, a solution of 0.5 g (1.59 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (WO2006/024776) in 10 mL of toluene is added dropwise. 15 mL of 1N hydrochloric acid solution and 100 mL of ethyl acetate are added to the mixture. The organic phase is separated out and then washed successively with 20 mL of 1N hydrochloric acid solution, 20 mL of water and 20 mL of saturated sodium chloride solution, and then concentrated under reduced pressure. The product thus obtained is triturated in 10 mL of hot toluene. A precipitate is collected by filtration. After drying, 295 mg of the expected product are thus isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=O)[CH3:15])[CH:9]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[C:14](=[C:21]2/[C:20](=[O:22])[NH:19][C:18](=[O:23])[S:17]/2)/[CH3:15])[CH:9]=1
Reactant: CC(=O)c1cccc(-c2ccccc2Cl)c1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: C/C(=C1/SC(=O)NC1=O)c1cccc(-c2ccccc2Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 1-(2′-chloro-1,1′-biphenyl-3-yl)ethanone (145 mg, 0.63 mmol) and 2,4-thiazolidinedione (67 mg, 0.57 mmol) in xylene (1.9 mL), sodium acetate (38 mg, 0.28 mmol) and acetic anhydride (53 μL, 0.57 mmol) were added and the solution was heated in a sealed tube for 16 h. It was then cooled to rt, partitioned between ethyl acetate and water, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. Finally filtered, concentrated and purified by chromatography. (hexanes:ethyl acetate; 4:1) to give the product as a solid.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[O:6]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[CH:1](=[N:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C=NCc1cccc(Oc2ccccc2)c1
Reaction time: 0.33 h
Yield: 98 %

Procedure:
38 g (0.528 mol) of isobutyraldehyde is added dropwise within 30 minutes, with stirring, to a solution of 99.5 g (0.5 mol) of 3-phenoxybenzylamine in 100 ml of toluene. After completion of the dropwise addition, stirring is continued for 20 minutes at room temperature, and the water which has formed (about 8.5 g) is separated in a separating funnel. The toluene with the unreacted isobutyraldehyde and residual water is then removed by rotation in a water-jet vacuum, and the residue is distilled in an oil-pump vacuum to yield 124 g (0.49 mol) of N-isobutylidene-(3-phenoxybenzylamine) as a colourless, mobile liquid, corresponding to a yield of 97.8% of theory; b.p. 85° C./4 Pa; nD20 =1.5666.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][O:10]2)=[CH:5][N:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+].Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[N:12]([C@@H:9]([C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:11][OH:10])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc([C@@H]2CO2)cn1
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COc1ccc([C@@H](CO)N=[N+]=[N-])cn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
To a stirred solution of (R)-2-methoxy-5-(oxiran-2-yl)pyridine (1.02 g, 6.75 mmol) in acetonitrile (100 mL) were added sodium azide (1.8 g, 27 mmol) and lithium perchlorate (11 g, 0.10 mol) and the mixture was stirred at 60° C. for 4 h. TLC indicated completion of the reaction. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was treated with water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with aq. NaHCO3 and brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (0-50% EtOAc/hexane) to give a light yellow oil (0.9 g, 69%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)(=[O:27])=[O:26]
Reactant: COC(=O)COc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1ccc(CCCOS(C)(=O)=O)cc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
A solution of methyl [4-(3-hydroxypropyl)phenoxy]acetate (4.5 g, 20.5 mmol) in dichloromethane (50 ml) was treated at 0° C. with triethylamine (4.36 g, 43.1 mmol) followed by methanesulfonyl chloride (3.99 g, 34.8 mmol) added dropwise over 5 min. After 30 min at 0° C., the reaction mixture was diluted with dichloromethane, washed with 1N hydrochloric acid, water and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 8:18) gave 5.51 g (89%) of the title material as a white solid: mp 49-51° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.Cl.[C:45]1([CH:51]([C@H:53]2[CH2:57][CH2:56][CH2:55][NH:54]2)[OH:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:54]2[CH2:55][CH2:56][CH2:57][C@@H:53]2[CH:51]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[OH:52])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Reactant: OC(c1ccccc1)[C@H]1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC[C@@H]2C(O)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (22 mg, 0.11 mmol) in acetonitrile (5 mL) was added o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (45 mg, 0.14 mmol, 1.3 eq.), pyridine (34 μL, 0.42 mmol, 4 eq.), and phenyl[(2R)-pyrrolidin-2-yl]methanol hydrochloride (25 mg, 0.12 mmol, 1.1 eq.). The reaction mixture was stirred at ambient temperature for 20 h and at 40° C. for an additional 2 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to yield the product as a white solid. HRMS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1625.
Reaction SMILES: C(O[C:4](OCC)([CH3:17])[CH2:5][CH2:6][N:7]1[CH:12]=[C:11]([C:13]#[N:14])[C:10](=[O:15])[NH:9][C:8]1=[O:16])C.[O:21]1CCOCC1>>[O:16]=[C:8]1[NH:9][C:10](=[O:15])[C:11]([C:13]#[N:14])=[CH:12][N:7]1[CH2:6][CH2:5][CH2:4][CH:17]=[O:21]
Reactant: CCOC(C)(CCn1cc(C#N)c(=O)[nH]c1=O)OCC
Reactant: C1COCCO1
Product: N#Cc1cn(CCCC=O)c(=O)[nH]c1=O
Temperature: 60 °C

Procedure:
1-(3,3-Diethoxy-butyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile (Prep 54, 200 mg, 0.71 mmol) was dissolved in dioxane (8 mL) and 1N HClaq (1 mL) was added. The mixture was warmed at 60° C. for 20 minutes. The solvents were evaporated, the residue was submitted to lyophilization, to give 150 mg of the title compound that was used in the next step without further purification (quantitative yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl.[CH2:13](O)[CH3:14]>>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:13][CH3:14])=[O:8])=[CH:10][CH:11]=1
Reactant: CCO
Reactant: NCc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(CN)cc1

Procedure:
3 g (19.9 mmol) of 4-aminomethylbenzoic acid was suspended in 100 ml of ethanol. 10 ml of ethanol containing 25% of hydrogen chloride was added to the suspension, and they were heated under reflux for 8 hours. The solvent was evaporated, and the title compound was obtained by the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant.
Reaction SMILES: [C:1]([C:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11](OC)[O:12]C)[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([C:4]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11]=[O:12])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(CC(=O)OC)C(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Product: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(C=O)CC(=O)OC
Temperature: 28 °C
Reaction time: 12 h

Procedure:
Methyl 4-acetyl-4-tert-butoxycarbonyl-3-dimethoxymethyl-6-nonynoate (546 mg) is dissolved in 30 ml of tetrahydrofuran, and 25 ml of 1.5% aqueous solution of perchloric acid is added to the solution. The mixture is stirred at 28° C. for 12 hours. Subsequently the reaction mixture is neutralized with sodium bicarbonate and concentrated in a vacuum. The residue is extracted with ethyl acetate. The extract is dried and then concentrated to give methyl 4-acetyl-4-tert-butoxycarbonyl-3-formyl-6-nonynoate (compound (8), R1 =t-Bu, R2 =CH3) in a yield of 98.0%.
Reaction SMILES: [OH:1][CH:2]([CH2:23][OH:24])[CH2:3][S:4]([CH2:7][CH2:8][C:9]([NH:12]C(=O)OCC1C=CC=CC=1)([CH3:11])[CH3:10])(=[O:6])=[O:5].[H][H]>CO.[Pd]>[NH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][S:4]([CH2:3][CH:2]([OH:1])[CH2:23][OH:24])(=[O:6])=[O:5]
Reactant: CC(C)(CCS(=O)(=O)CC(O)CO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)CC(O)CO
Reaction time: 2 h

Procedure:
A solution of benzyl 4-(2,3-dihydroxypropylsulfonyl)-2-methylbutan-2-ylcarbamate (2.34 g, 10.4 mmol) in methanol (50 ml) was purged with nitrogen and palladium on carbon (10%, 230 mg) was added. The suspension was put under a blanket of hydrogen (1.3 atmospheres) and stirred for 2 hours. The suspension was filtered through Celite® and concentrated in vacuo to afford the title compound which was used without further purification. LRMS (ESI/APCI) m/z 226 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1.[H-].[Na+].F[C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:25]=1[CH:26]=[O:27]>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][O:20][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:35])[F:34])[C:25]=1[CH:26]=[O:27]
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=Cc1c(F)cccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1c(OCc2cccc(OCc3ccc4ccccc4n3)c2)cccc1C(F)(F)F
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
[3-(Quinolin-2-ylmethoxy)-phenyl]-methanol (300 mg, 1.13 mmol, example 48) is dissolved in DMF (6 mL) and sodium hydride (60%, 60 mg, 1.5 mmol) is added and allowed to stir 20 min. 2-Fluoro-6-(trifluoromethyl)benzaldehyde (0.30 mL, 2.2 mmol) is added and the reaction is heated at 90° C. for 5 h. The reaction is partitioned between ethyl acetate (200 mL) and water (200 mL), dried over magnesium sulfate, filtered, concentrated in vacuo and purified by column chromatography (silica, 25% ethyl acetate in hexanes) to provide the title compound; MS (ESI) 438 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:17][CH:18]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:20](=[O:21])[CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1cccc(F)c1
Reactant: CCOC(=O)c1ccc(C)[nH]1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2cccc(F)c2)c(C)[nH]1
Yield: 78 %

Procedure:
4-[2-(3-Fluorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (114) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (3-fluorophenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/RT. Purification: recrystallization from ether/pentane. Yield: 78%. 1H (CDCl3, 400 MHz): δ 10.6 (NH, broad s), 7.30 (1H, s), 7.26 (1H, dd), 7.04 (1H, d), 6.99 (1H, d), 6.92 (1H, dd), 4.37 (2H, q), 4.07 (2H, s), 2.58 (3H, s), 1.39 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 193.5, 164.0, 161.6, 141.0, 137.4, 130.0, 125.3, 121.5, 120.5, 116.9, 116.4, 113.7, 61.0, 46.4, 14.4, 14.0 ppm. LC/MS: 98%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31](Cl)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:37]=[CH:36][C:19]3[NH:20][C:21]([NH:23][C:24]([C:26]4[N:27]=[C:28]5[CH:33]=[CH:32][C:31]([O:7][CH2:6][C@@H:2]6[CH2:3][CH2:4][CH2:5][O:1]6)=[N:30][N:29]5[CH:35]=4)=[O:25])=[N:22][C:18]=3[CH:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: OC[C@@H]1CCCO1
Reactant: O=C(Nc1nc2cc(-c3cc(F)cc(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc2cc(-c3cc(F)cc(Cl)c3)ccc2[nH]1)c1cn2nc(OC[C@@H]3CCCO3)ccc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-(tetrahydrofuran-2-yl-)-methanol (30.6 mg) in dry DMF (1 mL) NaH (12 mg, 60% dispersion in mineral oil) was added, and the mixture was stirred at room temperature for 20 minutes under nitrogen. To this mixture 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (44.0 mg) was added, and the mixture was warmed to 80° C. The reaction was monitored by LCMS until substantially complete. Then, 10 mL of water was added and the reaction mixture was stirred for 10 minutes. The reaction was then filtered through a fine fritted funnel and the crude product was washed with water. After air drying, the product 6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-5-fluoro-phenyl)-1H-benzoimidazol-2-yl]-amide (24.8 mg) was purified by column chromatography (prepacked silica column) using 9:1 DCM and 2N ammonia in methanol. LCMS (m/z): 507.9. 1H NMR (400 MHz, CDCl3) δ 11.23 (1H, br. s.) 10.25-10.73 (1H, m) 8.40 (1H, s) 7.74 (2H, d) 7.38-7.44 (2H, m) 7.19-7.25 (2H, m) 7.04 (1H, dt) 6.83-6.89 (1H, m) 4.24-4.42 (3H, m) 3.82-4.03 (2H, m) 1.91-2.17 (2H, m) 1.67-1.82 (2H, m).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].Br[C:10]1[C:15]([Br:16])=[CH:14][CH:13]=[CH:12][N:11]=1>C1COCC1>[Br:16][C:15]1[C:10]([CH2:7][C:6]#[N:8])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC#N
Reactant: Brc1cccnc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCc1ncccc1Br
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Dry THF (100 mL) was cooled to −78° C. and n-butyllithium (2.5 M in hexanes; 23 mL, 58 mmol) was added. Acetonitrile (3.3 mL, 64 mmol) was added dropwise maintaining the temperature below −60° C. A white precipitate formed and the reaction mixture was stirred at −78° C. for 45 min. A solution of 2,3-dibromopyridine (2.0 g, 8.4 mmol) in dry THF (10 mL) was added dropwise and the reaction mixture stirred at −78° C. for 1.5 h then allowed to warm to room temperature. The reaction was quenched by the dropwise addition of water. The aqueous was extracted with DCM (×3) and the combined organics washed with brine, dried (MgSO4) and concentrated in vacuo. (3-Bromo-pyridin-2-yl)-acetonitrile (Intermediate 1) was purified by flash column chromatography.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[OH:30][C:31]1([C:38]2[S:39][CH:40]=[CH:41][N:42]=2)[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1>>[OH:30][C:31]1([C:38]2[S:39][CH:40]=[CH:41][N:42]=2)[CH2:32][CH2:33][CH:34]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:35][CH2:36]1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(O)(c3nccs3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-hydroxy-4-thiazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:18])[C:9]([CH3:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)/C=C/C(O)=O>CCOC(C)=O.CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH2:18])[C:9]([CH3:10])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccccn1)C(N)c1cccc(F)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(c1ccccn1)[C@@H](N)c1cccc(F)c1

Procedure:
(S)-1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine is prepared is prepared starting from racemic 1-(3-fluorophenyl)-2-methyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC chromatography. The free base was dissolved in EtOAc and a solution of fumaric acid (1.0 eq) in MeOH is added. The solvent is removed in vacuo and the residue is triturated with Et2O/hexanes (1:1), collected by filtration and air-dried. 1HNMR (300 MHz, DMSO-d6) δ 1.19 (s, 3 H), 1.31 (s, 3 H), 4.48 (s, 1 H), 6.55 (s, 2 H), 6.85-6.95 (m, 2 H), 7.01 (t, J=8.9 Hz, 1 H), 7.18-7.34 (m, 3 H), 7.64-7.77 (m, 1 H), 8.59 (d, J=3.8 Hz, 1 H). MS: m/z 245.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]([CH2:15][C@H:16]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:2]([F:1])([F:28])[C:3]([N:5]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N(C[C@H]1CCNC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido) methyl)pyrrolidine-1-carboxylate (1.28 g, 3.10 mmol) in dichloromethane (DCM) (12 mL) was added TFA (3 ml, 38.9 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dried under vacuum to give 950 mg of product as pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:17])([O-])=O.[CH2:18](OC(OCC)N(C)C)C.N1CCCC1>CN(C)C=O>[O:10]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[NH:1][CH:18]=[CH:17]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CCOC(OCC)N(C)C
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc3[nH]ccc3c2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A solution of 2-nitro-5-phenoxytoluene (2.06 g) in dimethylformamide (30 ml) containing dimethylformamide diethylacetal (1.57 g) and pyrrolidine (0.77 g) was heated at 120° C. for 2 hours. Solvent was removed at reduced pressure and the residue dissolved in methanol. Raney Nickel (one spatula measure) was added followed by hydrazine hydrate (3×0.5 ml portions, one portion every 30 minutes). The mixture was stirred for a further 1 hour after the final portion of hydrazine hydrate was added, the mixture filtered and solvent removed at reduced pressure. The residue was partitioned between water (100 ml) and diethyl ether (100 ml), the organic phase separated and dried (MgSO4), solvent removed at reduced pressure and the residue column chromatographed (silica gel, hexane →10% ethyl acetate/hexane eluant) to give 5-phenoxyindole (0.52 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([NH:7][C:8](=[O:12])[CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[H-].[Na+].[C:19](Cl)(=[O:23])[CH2:20][CH:21]=[CH2:22]>O1CCCC1>[C:10]([C:9](=[C:19]([OH:23])[CH2:20][CH:21]=[CH2:22])[C:8]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)=[O:12])#[N:11]
Reactant: C=CCC(=O)Cl
Reactant: N#CCC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(O)=C(C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
6.0 g (0.026 mole) of 4'-trifluoromethyl-cyanoacetanilide in 200 ml of dry tetrahydrofuran were stirred under nitrogen at room temperature and were treated with 1.95 g (0.065 mole) of sodium hydride 80% oil dispersion. The mixture was stirred for a further 30 minutes at room temperature and cooled to -50° C. before the dropwise addition of 3.3 g (0.033 mole) of 3-butenoyl chloride prepared as described in J. Chem. Soc. (1948), p. 661. The mixture was stirred at -50° C. for 2 hours, then was poured onto dilute hydrochloric acid/ice and filtered. The solid was chromatographed over silica gel eluting with dichloromethane to give 2.4 g (31%) of the title compound as colorless crystals and 3 g of starting material were recovered.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=O)[CH2:17][CH3:18]>O>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[N:2][OH:3])[CH2:17][CH3:18]
Reactant: NO
Reactant: CCC(=O)c1ccco1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=NO)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
Hydroxylamine hydrochloride (3.3 g, 47.8 mmol) and sodium acetate (3.9 g, 47.8 mmol) were added to 20 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(Furan-2-yl)propan-1-one (5.4 g, 43.5 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (20 mL) was added and the product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 6.1 g of the title compound.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:8]1[CH:9]=[CH:10][C:2]2[C:1]([C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:17][CH:16]=3)([C:15]3[CH:14]=[CH:13][C:12]([OH:18])=[CH:17][CH:16]=3)[O:6][C:4](=[O:5])[C:3]=2[CH:7]=1
Reactant: Oc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21

Procedure:
Phenolphthalein is synthesized by standard methods involving a condensation reaction with phthalic anhydride and phenol under appropriate reaction conditions. Substituted phenolpthalein derivatives are obtained from the correspondingly substituted phthalic anhydride and in a similar manner.