Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:13][C:14]#[C:15][CH3:16].[Br:17][C:18]1[NH:19][C:20]([C:25]#[N:26])=[C:21]([C:23]#[N:24])[N:22]=1>O.C(OCC)(=O)C>[Br:17][C:18]1[N:19]([CH2:13][C:14]#[C:15][CH3:16])[C:20]([C:25]#[N:26])=[C:21]([C:23]#[N:24])[N:22]=1
Reactant: N#Cc1nc(Br)[nH]c1C#N
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC#CCn1c(Br)nc(C#N)c1C#N
Temperature: 50 °C

Procedure:
69.8 g of potassium carbonate and 50 ml N,N-dimethylformamide solution of 74 ml of 1-bromo-2-butyne were added to a 520 ml N,N-dimethylformamide solution of 90.6 g of 2-bromo-1H-imidazole-4,5-dicarbonitrile [CAS No 50847-09-1], and the mixture was heated at 50° C. for 8 hours. 1 L of ethyl acetate and 500 ml of water were added to the solution, and the organic layer was washed twice with 500 ml of water and then with 500 ml of a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 48.0 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (1:4).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:24])=[C:4]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[I:25][C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[NH:28][N:27]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.CCOC(C)=O>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([CH:8]([C:6]3[C:5]([O:11][CH3:12])=[C:4]([CH:13]4[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]4)[C:3]([F:24])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:27]=[C:26]([I:25])[C:34]=12
Reactant: COc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 140 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
To a mixture of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate (0.77 g, 2.0 mmol, racemic intermediate from Example 13, Step 6), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.58 g, 2.2 mmol) in N,N-dimethylformamide (6.9 mL) was added potassium iodide (34 mg, 0.20 mmol) and cesium carbonate (0.99 g, 3.0 mmol). The resulting mixture was heated at 140° C. and stirred for 3 h. After cooling, the clear solution was taken into water and ethyl acetate (EtOAc). The solid was diluted with water and EtOAc, and stirred until dissolved. The organic layers were combined, concentrated and purified on silica gel (eluting with 0 to 100% EtOAc in hexanes) to give the desired product (0.55 g, 45%). LCMS calculated for C22H26ClFN6O3 (M+H)+: m/z=603.1; Found: 602.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.ClCCl.CCCCCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([C:10]#[N:11])[CH2:12][CH:14]2[CH2:15][OH:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClCC1CO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: ClCCl
Product: N#C[C@]1(c2ccc(Cl)c(Cl)c2)CC1CO
Temperature: -25 °C
Yield: 407.9 %

Procedure:
3,4-Dichlorophenyl acetonitrile (3 g, 1.6 mmole) was dissolved in dry tetrahydrofuran (THF, 25 mL) under nitrogen atmosphere. The solution was cooled to −25° C. Soda amide (0.6235, 1.6 mmol) was added portion wise maintaining the temperature of the reaction mass −25° C. The reaction mixture was allowed to warm to room temperature and maintained for 2 hours. It was then cooled to −25° C. A solution of S-(+) epichlorohydrin (1.49 g, 1.6 mmol) in tetrahydrofuran (5 mL) was added drop wise at −25° C. followed by the portion wise addition of soda amide (0.6235, 1.6 mmol). The temperature of the reaction mass was then gradually raised to room temperature over a period of 8 hours. The reaction was monitored by TLC (dichloromethane/hexane (1:1)). The reaction mass was quenched with saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate (3×50 mL).The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 4.0 g of crude oil. The crude oil was purified by column chromatography (silica gel, dichloromethane/hexane (9:1) to yield 1.58 g (40%) of product. 1H NMR: δ(300 MHz,CDCl3): 1.57-1.72(3H,m), 1.88-1.99 (1H,m), 3.72-3.79 (1H,dd, J=12.08,8.4 Hz), 4.06-4.12 (1H,dd, J=12.08,4.95 Hz), 7.13-7.17 (1H,m) 7.39-7.52 (2H,m).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:19]=[CH:18][C:10]2[N:11]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[N:12]=[N:13][C:9]=2[C:8]=1[C:20]([F:23])([F:22])[F:21])(=O)=O.[C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:15]1([CH2:14][N:11]2[C:10]3[CH:18]=[CH:19][C:7]([C:27]#[C:26][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[C:8]([C:20]([F:23])([F:22])[F:21])[C:9]=3[N:13]=[N:12]2)[CH2:17][CH2:16]1
Reactant: O=S(=O)(Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F)C(F)(F)F
Reactant: C#Cc1cccnc1
Agent: [Cu]I
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1c(C#Cc2cccnc2)ccc2c1nnn2CC1CC1
Temperature: 90 °C

Procedure:
1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl trifluoromethanesulfonate (25 mg, 0.064 mmol), 3-ethynylpyridine (13.3 mg, 0.128 mmol), triethylamine (116 μL, 0.835 mmol), tetra-n-butyl ammonium iodide (0.1 equiv), and copper (I) iodide (4 mg, 0.019 mmol) were combined in DMF (0.64 mL) and the mixture was sparged under nitrogen. Tetrakis(triphenylphosphine) palladium (0) (7.4 mg, 0.0064 mmol) was added, the mixture was sparged under nitrogen and then heated at 90° C. for 18 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with water and brine. The organic extract was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (0-55% EtOAc in hexanes), providing the titled compound as a light yellow solid: 1H-NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.61 (dd, J=4.9, 1.7 Hz, 1H), 7.87 (dt, J=7.9, 2.0 Hz, 1H), 7.76 (s, 2H), 7.34 (dd, J=7.9, 4.9 Hz, 1H), 4.58 (d, J=7.2 Hz, 2H), 1.41 (m, 1H), 0.66-0.73 (m, 2H), 0.51-0.55 (m, 2H) ppm; LRMS (ES+) m/z 343.1 [(M+H)+; calculated for C18H14F3N4: 343.2].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[C:11]([CH3:24])[CH:10]=2)=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:24][C:11]1[CH:10]=[C:9]([O:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[CH:7][N:6]=2)[CH:14]=[CH:13][C:12]=1/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18]
Reactant: CCCCOC(=O)/C=C/c1ccc(Oc2ccc(O)cn2)cc1C
Reactant: Cc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)/C=C/c1ccc(Oc2ccc(OCc3ccc(C)cc3)cn2)cc1C
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
To a DMF (40 mL) solution of butyl (E)-3-{4-[(5-hydroxypyridin-2-yl)oxy]-2-methylphenyl}prop-2-enoate (3.54 g) was added NaH (60% in oil) (467 mg) at 0 ° C. After stirring for 10 minutes, 1-(bromomethyl)-4-methylbenzene (2.10 g) was added, and the resultant mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added saturated aqueous NH4Cl, and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt =9/1 to 3/1) to afford butyl (E)-3-[2-methyl-4-({5-[(4-methylbenzyl)oxy]pyridin-2-yl}oxy)phenyl]prop-2-enoate as a yellow solid (4.72 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.[F:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:23]2[CH2:24][CH2:25][CH:20]([F:19])[CH2:21][CH2:22]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: FC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCC(F)CC1
Temperature: 40 °C
Yield: 100.1 %

Procedure:
A solution of 4-chloro-2-fluoro-1-nitro benzene (0.30 g, 1.7 mmol) in toluene (5 mL) was treated with solid Na2CO3 (0.40 g, 3.7 mmol) and 4-fluoropiperidine hydrochloride (0.25 g, 1.8 mmol). The reaction was heated to 40° C. for 6 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.44 g, 99%) as a bright yellow oil. 1H-NMR (CDCl3; 400 MHz): δ 7.79 (d, 1H, J=8.8 Hz), 7.10 (d, 1H, 2.0 Hz), 6.97 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 4.97-4.79 (m, 1H), 3.26-3.17 (m, 2H), 3.06-2.99 (m, 2H), 2.14-1.97 (m, 4H). LC-MS (ESI, m/z): Calcd. for C11H12ClFN2O2, 225.2 (M-Cl+2H), found 225.2.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH3:8][CH:9]([C:11](=O)[CH2:12][CH2:13][CH3:14])[CH3:10].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[C:1]([C:3](=[C:11]([CH2:12][CH2:13][CH3:14])[CH:9]([CH3:10])[CH3:8])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: CCCC(=O)C(C)C
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCC(=C(C#N)C(=O)OC)C(C)C
Temperature: 25 °C

Procedure:
A mixture of methyl cyanoacetate (1.98 g), 2-methylhexan-3-one (3.76 g), ammonium acetate (0.196 g) and glacial acetic acid (0.288 ml) in toluene (10 ml) was stirred and heated at reflux with removal of water using a Dean and Stark apparatus for 6 hours. After cooling to room temperature the mixture was diluted with ethyl acetate and washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and pentane (2%) to give methyl 2-cyano-3-propyl-4-methylpent-2-enoate (as a mixture of E and Z isomers) (2.11 g) as a colourless oil.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1.[CH3:15]O>>[CH3:15][O:11][C:10]([C:9]1[CH:13]=[CH:14][C:6](=[O:5])[NH:7][CH:8]=1)=[O:12]
Reactant: O=C(O)c1ccc(O)nc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(=O)[nH]c1
Yield: 68 %

Procedure:
Thionyl chloride (6.3 mL, 86.33 mmol) was added dropwise to a solution of 6-hydroxynicotinic acid (10.0 g, 71.94 mmol) in methanol at 0° C. The mixture was heated to reflux for 6 hours, the solvent was removed and standard extractive work up provided the title compound as a brown solid (7.5 g, 68%). m.p. 166-172° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H), 6.37 (d, J=9.3 Hz, 1H), 7.79 (dd, J=2.7, 9.5 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H); IR (KBr) ν 3050, 2965, 1712, 1651, 1433, 1300, 1106 cm−1; MS 154 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][CH2:19][CH3:20])[C:3]1=[O:21].C(N(CC)C(C)C)(C)C.[CH2:31]([NH:33][C:34](=[O:49])[NH:35][C:36]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:37]=1[C:38](O)=[O:39])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:38]([C:37]3[CH:41]=[C:42]([C:45]([F:47])([F:48])[F:46])[CH:43]=[CH:44][C:36]=3[NH:35][C:34]([NH:33][CH2:31][CH3:32])=[O:49])=[O:39])[C:3]2=[O:21])[C@H:8]([CH2:18][CH2:19][CH3:20])[CH2:9]1)([CH3:16])[CH3:17]
Reactant: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: CCNC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)NCC)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-3-amino-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]pyrrolidin-2-one (77 mg, 0.26 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.32 mL), 2-(3-ethylureido)-5-(trifluoromethyl)benzoic acid (80 mg) and HATU (129 mg). The reaction was stirred at RT for 14 h, diluted with water, filtered, and purified by RP-HPLC to afford 1-{2-[((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)-2-oxopyrrolidin-3-yl)carbamoyl]-4-(trifluoromethyl)phenyl}-3-ethylurea. MS found: (M+H)+=554.4. [Note: for larger scale preparations, the reaction was frequently run with CH2Cl2 as a co-solvent, and the following aqueous workup was used before RP-HPLC purification. Volatiles were removed and the residue was dissolved in EtOAc. The organic phase was washed with sat. NaHCO3, water, 1N HCl, sat. NaCl, and then dried (MgSO4), filtered, and concentrated in vacuo.]
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1Br
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Temperature: 25 °C
Yield: 95 %

Procedure:
To chlorosulfonic acid (100 mL) cooled to 0° C. was added 2-bromobenzoic acid (20.0 g, 99.5 mmol) portionwise over 10 minutes. The reaction mixture was warmed to room temperature and then to reflux cautiously over 30 minutes in 10° C. increments, followed by reflux for 16 hours. After cooling to room temperature the solution was quenched in 1 mL portions into ice-water (2 L). Further ice was added as necessary to keep the temperature below 5° C. The resulting precipitate was filtered under vacuum and dried in a vacuum oven for 4 hours to give the title compound as a tan solid in 95% yield, 28.6 g.
Reaction SMILES: N#N.[F:3][CH:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[N:10]1.[NH4+].[Cl-]>CCO.O.[Fe]>[F:3][CH:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]1
Reactant: CC(F)CCCCn1cc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(F)CCCCn1cc(N)cn1
Temperature: 75 °C
Reaction time: 0.67 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-(5-fluoro-hexyl)-4-nitro-1H-pyrazole (135 mg, 0.63 mmol), iron powder (106 mg, 1.88 mmol) and NH4Cl (169 mg, 3.13 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 40 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1M NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a red solid. LC-MS-conditions 02: tR=0.60 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:42][C:43]1[CH:55]=[CH:54][CH:53]=[CH:52][C:44]=1[O:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([N:49]1[CH2:48][CH2:47][CH:46]([O:45][C:44]2[CH:52]=[CH:53][CH:54]=[CH:55][C:43]=2[Cl:42])[CH2:51][CH2:50]1)=[O:8])[CH3:2]
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: CCOC(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a stirred solution of malonic acid monoethyl ester (1.2 g, 0.0089 mole) in DMF (10 mL) was added DIPEA (2.5 g, 0.02 mole), HOBt (1.3 g, 0.0097 mole) and EDCI.HCl (1.9 g, 0.0097 mole). After 2 minutes 4-(2-chloro-phenoxy)-piperidine hydrochloride (2 g, 0.0081 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (60% ethyl acetate in hexane) to afford 1.1 g (42%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester. LC-MS purity: 326.11 (M+1)+, 90.2%. To a stirred solution of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid ethyl ester (1.1 g, 0.0034 mole) in a mixture of THF (20 mL), methanol (4 mL) and H2O (4 mL) was added LiOH.H2O (0.286 g, 0.0068 mole) at ambient temperature. The resulting mixture was stirred for 30 minutes. Volatiles were then evaporated and the resulting residue was diluted with water, acidified with 10% aqueous HCl solution. The resulting precipitate was isolated by filtration and dried to afford 0.75 g (75%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2([CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[N:12]=[C:11]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH2:22][CH2:21]2)[CH:10]=1>ClC1C=CC(Cl)=CC=1Cl.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)[N:12]2[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14][C:13]=12
Reactant: COc1ccccc1C1=CC(N2CCN(Cc3ccc(C)cc3)CC2)=NC12C=CC(=O)C=C2
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: COc1ccccc1-c1cc(N2CCN(Cc3ccc(C)cc3)CC2)n2ccc(=O)ccc12
Yield: 64.3 %

Procedure:
A solution of 4-(2-methoxyphenyl)-2-[4-(4-methylbenzyl)-1-piperazinyl]-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (2.8 g) in 1,2,4-trichlorobenzene (80 cc) is heated for 4 hours at a temperature of about 210° C. After evaporation to dryness under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C., the residue obtained is dissolved in methylene chloride (50 cc) and the solution is poured into silica (60 g) contained in a column 2 cm in diameter. Elution is first performed with a mixture of methylene chloride and methanol (99:1 by volume) (200 cc); the corresponding eluates are rejected. Elution is then performed with a mixture of methylene chloride and methanol (99:1 by volume) (450 cc) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. After recrystallization of the residue in acetonitrile (75 cc), 1-(2-methoxyphenyl)-3-[4-(4-methylbenzyl)-1-piperazinyl]-7H-pyrrolo[1,2-a]azepin-7-one (1.8 g), m.p. 186° C., is obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[OH:24])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([O:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[C:16]([NH:15][C:7]1[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=1)=[O:25])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)c2cc(Cl)ccc2O)cc(C(C)(C)C)c1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Yield: 66.1 %

Procedure:
Using N-{3,5-bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
Reaction SMILES: C(NCC)C.[CH2:6]([O:13][NH:14][C@H:15]1[CH2:20][N:19](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH:18]([C:38](=[O:40])[NH2:39])[C:17]([CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH2:6]([O:13][NH:14][C@H:15]1[CH2:20][NH:19][CH:18]([C:38]([NH2:39])=[O:40])[C:17]([CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])=[CH:16]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1=C[C@@H](NOCc2ccccc2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1C(N)=O
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)(C)[Si](C)(C)OCC1=C[C@@H](NOCc2ccccc2)CNC1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Diethylamine (0.824 mL, 7.89 mmol) was added to a solution of (5R)-(9H-fluoren-9-yl)methyl 5-((benzyloxy)amino)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-carbamoyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 162, 0.968 g, 1.58 mmol) in DCM (20 mL) and the resulting solution was allowed to stir at room temperature overnight. The volatiles were removed by evaporation and the residue was purified on silica gel (0-12%, MeOH/DCM, UV 220 nm) to afford the title compound (0.564 g, 91%) as a yellow film.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[N:9]2)[CH2:4][O:3]1.O.[OH-].[Na+].CCCCCCC>C(OC)(C)(C)C>[CH3:1][C:2]1([CH3:17])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH2:4][O:3]1
Reactant: CC(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCCCCCC
Product: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Temperature: 62.5 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To a 5 L glass flask equipped with a mechanical stirrer and thermometer was charged with 584 g (315 g after corrected by wt %, 1.28 mol) of N-[1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-acetamide and 1.2 L of purified water. The mixture was agitated at 60-65° C. for 3 h, forming a homogeneous solution. After cooling the batch to 40-45° C., 214 g (5.14 mol) of NaOH (solid) was added in portions. The mixture was agitated at 90° C. for 24 h. The mixture was cooled to 20-25° C. and extracted with 2 kg of isopropyl acetate. The combined organic phase was concentrated by distillation in vacuo (35-45° C. (batch)/P<−0.1 MPa) to give a yellow oil. The residue was diluted with 414 g of methyl tert-butyl ether and 750 g of heptane subsequently. The resulting suspension was stirred at 20-25° C. for 15 h. The solids were collected by filtration and washed with 1100 g of methyl tert-butyl ether/heptane (1/2, v/v). The solids were dried in a vacuum oven (30-35° C./P≦−0.1 MPa) for ca. 24 h to afford 215 g (68% yield in 2 steps) of 1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine as an off-white solid. 1H-NMR (400 MHz, d6-DMSO): δ 7.31 (s, 1H), 5.38 (s, 1H), 4.55 (s, 2H), 4.26-4.32 (m, 1H), 3.92-3.98 (m, 3H), 3.7-3.73 (m, 1H), 1.31 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12].[OH:15][C:16]12[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[C:20]1([NH:29][C:30](=[O:32])[CH3:31])[C:19]1[CH:33]=[CH:34][C:35]([CH:37]([CH3:39])[CH3:38])=[CH:36][C:18]=1[O:17]2>C1COCC1>[C:8]([O:17][C:18]1[CH:36]=[C:35]([CH:37]([CH3:38])[CH3:39])[CH:34]=[CH:33][C:19]=1[C:20]1([NH:29][C:30](=[O:32])[CH3:31])[C:21](=[O:28])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]1=[O:15])(=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(=O)Cl
Reactant: CC(=O)NC12C(=O)c3ccccc3C1(O)Oc1cc(C(C)C)ccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.1 %

Procedure:
Triethylamine (0.24 ml, 1.77 mmol) and Valeroyl chloride (0.18 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (10 ml). The reaction mixture was stirred at room temperature for 12 hrs, concentrated in a vacuum to remove solvent. The reaction mixture was extracted with water and methylene chloride, and purified through silica gel column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.20 g, 32%).