Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17](C=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:24])[NH:3]1.C1(P(=[CH:44][C:45]([O:47][CH3:48])=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:49]1COCC1>>[CH3:48][O:47][C:45](=[O:46])[CH:44]=[CH:49][C:17]12[CH2:16][CH2:15][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:24])[NH:3][C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:19][CH2:18]1)[CH2:21][CH2:20]2
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(C=O)(CC3)CC4)nc21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(C=CC(=O)OC)(CC3)CC4)nc21
Temperature: 25 °C

Procedure:
4-(2,6-Dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde (900 mg, 2.73 mmol) was dissolved in 25 mL of THF and methyl (triphenylphosphoranylidene)acetate (1.83 g, 2 eq) was added. The resulting reaction mixture was stirred under reflux for 18 h. It was then cooled to rt and purified by preparative HPLC using a mixture of aqueous acetonitrile to afford 300 mg of the desired product.
Reaction SMILES: [OH:1][C@@:2]([CH3:53])([C:5](=[O:52])[C@@H:6]([NH:11][C:12]([C@@H:14]([NH:22][C:23](=[O:51])[C@@H:24]([NH:29][C:30](=[O:50])[C@@H:31]([NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:3][I:4].[C:54](Cl)(Cl)=[O:55].[CH2:58]([OH:61])[C:59]#[CH:60]>ClCCl.CN(C1C=CN=CC=1)C>[C:54](=[O:55])([O:61][CH2:58][C:59]#[CH:60])[O:1][C@:2]([CH3:53])([CH2:3][I:4])[C:5](=[O:52])[C@H:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[NH:11][C:12](=[O:13])[C@H:14]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:22][C:23](=[O:51])[C@H:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[NH:29][C:30](=[O:50])[C@H:31]([CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:44][CH2:45][O:46][CH2:47][CH2:48]1
Reactant: O=C(Cl)Cl
Reactant: C#CCO
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CI
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCOC(=O)O[C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
(2S)—N—((S)-1-((2S,4S)-2-hydroxy-1-iodo-2,6-dimethyl-3-oxoheptan-4-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide (1.18 g, 1.39 mmol) was dissolved in dichloromethane. DMAP (1.92 g, 13.9 mmol) was added and the mixture cooled to 0° C. Phosgene solution (20% in toluene, 3.75 mL, 5.52 mmol) was added dropwise and the reaction stirred at 0° C. for 30 minutes. Propargyl alcohol (0.802 ml, 13.9 mmol) was added and the mixture stirred at room temperature for 16 hours. The reaction was diluted with 200 mL dichloromethane, washed with 1 N HCl (50 ml) and brine (50 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by prep HPLC to afford 230 mg of white solid. 1H NMR (DMSO-d6): δ 8.37 (d, J=8.5 Hz, 1H), 8.18 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.28-7.08 (m, 10H), 5.19 (s, 2H), 4.89-4.83 (m, 1H), 4.57-4.51 (m, 4H), 4.37-4.28 (m, 2H), 3.87-3.79 (m, 4H), 3.65-3.31 (m, 793H), 2.96-2.90 (m, 4H), 2.80-2.76 (m, 1H), 2.50-2.42 (m, 6H), 1.89-75 (m, 2H), 1.58-1.30 (m, 9H). 0.86-0.74 (m, 12H).
Reaction SMILES: [OH2:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][CH:21]([NH2:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>CS(C)=O>[CH3:20][CH:21]([N:31]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:1])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Reactant: O
Reactant: COc1ccc(CC(C)N)cc1
Solvent: CS(C)=O
Product: COc1ccc(CC(C)N=C(OCc2ccccc2)C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3.08 g of 2-benzyloxyphenylglyoxal hydrate (crude oil) are dissolved in 10 ml of dimethylsulfoxide, and 2.1 g of α-methyl-4-methoxyphenethylamine are added thereto. The mixture is stirred at room temperature for 45 minutes, whereby a solution of α-(α-methyl-4-methoxyphenethylimino)-2-benzyloxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:39])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@H:32]4[CH3:37])[N:19]=3)[CH:14]([CH3:38])[CH2:13]2)=[N:9][C:10]=1Br)=[O:4].[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Cl:39])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:21]=[C:20]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH:32]4[CH3:37])[N:19]=3)[C@H:14]([CH3:38])[CH2:13]2)=[N:9][CH:10]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1nc(Cl)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOC[C@H]4C)n3)C(C)C2)nc1Br
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCOCC4C)n3)[C@H](C)C2)c(Cl)n1

Procedure:
Stir a solution of 6′-bromo-3′-chloro-4-[6-(4-fluoro-phenyl)-2-(3-(R)-methyl-morpholin-4-yl)-pyrimidin-4-yl]-3-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (3 g) in 100 mL of THF with 5% palladium on carbon (300 mg) under 1 atmosphere of hydrogen gas for several days. Filter the mixture through celite and concentrate under reduced pressure. Partition the residue between saturated NaHCO3 solution and EtOAc. Dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify using flash column chromatography eluting with a gradient EtOAc/hexanes solvent system to give the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:8]=2[CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][C:5]1=[O:26])(=[O:3])[CH3:2].[O:27]1CCCC1>Cl>[C:1]([NH:4][CH2:13][CH2:12][CH2:11][C:10]([C:9]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:8]=1[CH:7]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:6][C:5]([OH:27])=[O:26])=[O:14])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)N1CCCC(=O)c2ccc(Cl)cc2C(c2ccccc2)CC1=O
Agent: Cl
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1C(CC(=O)O)c1ccccc1

Procedure:
A solution of 3.30 g (0.009 mol) of 4-acetyl-11-chloro-1-phenyl-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione in 40 ml of tetrahydrofuran and 20 ml of 2N hydrochloric acid is stirred at room temperature for two days. Then, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with hexane-ethyl acetate (1:1) and crystallization from ethyl acetate/hexane gives 2-(4-acetamidobutyryl)-5-chloro-β-phenylhydrocinnamic acid as white crystals with melting point 114°-116°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].[S:11]([CH2:21][N+:22]#[C-:23])([C:14]1[CH:20]=[CH:19][C:17](C)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[C-:24]#N.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:5]2[O:6][CH:23]=[N:22][C@@H:21]2[S:11]([C:14]2[C:15]([CH3:24])=[CH:16][CH:17]=[CH:19][CH:20]=2)(=[O:12])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: [C-]#N
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)[C@H]1N=CO[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In a manner analogous to Preparation 1, 3,4-dichlorobenzaldehyde (0.56 g, 3.20 mmol), tosylmethylisocyanide (0.75 g, 3.84 mmol) and NaCN (0.02 g, 0.40 mmol) gave the desired compound as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=8.3 Hz, 2H), 7.50 (d, J=8.3 Hz, 1H), 7.35 (m, 3H), 7.15 (m, 2H), 6.00 (d, J=6.2 Hz. 1H), 4.96 (dd, J=6.2, 1.7 Hz, 1H), 2.47 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:14]([C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=2)[OH:15])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: O=Cc1cccc(F)c1
Product: OC(c1cccc(F)c1)c1cnc(Cl)nc1Cl
Yield: 79 %

Procedure:
The compound was prepared from 5-bromo-2,4-dichloropyrimidine (Aldrich) and 3-fluorobenzaldehyde (Aldrich) in 79% yield in an analogous manner as described in Example 1. 1H NMR (300 MHz, CDCl3) δ 8.85 (s, 1H), 7.35 (m, 1H), 7.14 (m, 3H), 7.14 (m, 3H), 6.077 (s, 1H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@H:15]([CH3:32])[C@H:16]([C@H:18]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[N:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])(=O)=O>C(Cl)Cl.CCOC(C)=O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@H:15]([CH3:32])[C@H:16]([C@H:18]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[N:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[O:17][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of tert-butyl (4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-1-hydroxy-2-methyl-3-oxopropyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (2.0 g, 4.3 mmol) in DCM (40 mL) at −40° C., 2,6-lutidine (0.90 mL, 7.8 mmol) was added, followed by tert-butyldimethylsilyl trifluoromethanesulfonate (1.4 mL, 6.0 mmol). The mixture was stirred at −40° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with a saturated aq. NaHCO3 and brine, then dried over MgSO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-20% EtOAc in hexanes) to afford the sub-title compound (2.2 g, 88%). LCMS calc. for C30H49N2O7Si (M+H)+: m/z=577.3. found 577.3.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.C(N(CC)C(C)C)(C)C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:23]=1[NH2:35].C(OCC)(=O)C>CN(C)C=O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([NH:35][C:23]1[C:24]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[F:21])=[O:11]
Reactant: Nc1c(F)cc(F)cc1N1CCOCC1
Reactant: O=C(O)CC1CC2CCC1C2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CC2CCC1C2)Nc1c(F)cc(F)cc1N1CCOCC1
Reaction time: 0.03 h
Yield: 51 %

Procedure:
Bicyclo[2.2.1]hept-2-yl-acetic acid (0.20 mL), N,N-diisopropyl-ethylamine (0.50 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (0.55 g) were mixed in dry N,N-dimethylformamide (3 mL) and stirred under argon for 2 minutes. 2,4-Difluoro-6-morpholin-4-yl-phenylamine (0.20 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture, which was stirred at 60° C. under argon for 16 hours. Ethyl acetate (20 mL) was added and the organic phase was washed with saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), brine/water (1:1, 20 mL), dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 0.17 g (51% yield) of the title compound as a white solid. LC-MS (m/z) 351 (MH+); tR=2.94, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.12 (m, 4H), 1.41 (m, 4H), 1.87 (m, 1H), 1.99 (d, 2H), 2.13 (dd, 1H), 2.20 (m, 1H), 2.27 (dd, 1H), 2.88 (t, 4H), 3.70 (t, 4H), 6.72 (m, 1H), 6.89 (dt, 1H), 9.10 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O>ClCCl.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[C:6]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH2:7][Br:20])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=C(C)Oc1cccc2c1CCCC2
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: ClCCl
Product: CCOC(=O)C=C(CBr)Oc1cccc2c1CCCC2
Temperature: 45 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A solution of 3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (0.69 g, 2.65 mmol) in dichloromethane (14 mL) was treated with N-bromosuccinimide (0.50 g, 2.80 mmol) and 2,2′-azobis(2,4-dimethylvaleronitrile) (31.6 mg, 0.12 mmol). The reaction was then warmed to 45° C. where it stirred overnight. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane, and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded impure 4-bromo-3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (638.8 mg, 71%) as a yellow oil. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([C:11]#[N:12])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=Cc1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 87.6 %

Procedure:
4-Chloro-3-fluorobenzaldehyde (1.0 g, 6.3 mmol) was added to a solution of ethyl 2-cyanoacetate (0.71 g, 6.3 mmol) and piperidine (0.081 ml, 0.82 mmol) in toluene (10 mL) at room temperature. The mixture was heated at 100° C. for 7 hours. Upon cooling to room temperature, the mixture was concentrated in vacuo and rinsed with hexane to give ethyl 3-(4-chloro-3-fluorophenyl)-2-cyanoacrylate (1.4 g, 88%). LCMS (APCI+) [M+H]+ 253.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH2:3]1.[C:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])[NH2:14]>>[ClH:23].[C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[S:12][CH:11]=[CH:10][C:5]2=3)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])[NH2:14]
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Reactant: CN1CCC(O)c2ccsc2C1
Product: CN1CCC(Oc2ccc(C(N)=O)cc2Cl)c2ccsc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 22) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][S:20][C:21]2[NH:25][N:24]=[C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[N:22]=2)=[CH:17][CH:16]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][S:20][C:21]2[NH:25][N:24]=[C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:22]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1n[nH]c(SCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CSc2nc(CCC(=O)O)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 3-[5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]-1H-1,2,4-triazol-3-yl]propionate (550 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hrs. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated to give 3-[5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]-1H-1,2,4-triazol-3-yl]propionic acid as crystals. Recrystallization from methanol-ethyl acetate gave colorless prism crystals (410 mg, yield 79%). melting point: 170–171° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)=[O:5])C.[ClH:29]>C(O)C>[ClH:29].[C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH:13]([OH:26])[CH2:14][NH:15][CH:16]([CH3:25])[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:9][CH:8]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)Cc1ccc(OCC(O)CNC(C)CCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CC(CCc1ccccc1)NCC(O)COc1ccc(CC(=O)O)cc1
Yield: 49 %

Procedure:
In this example, 3 g of 1-(4-ethoxycarbonylmethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol (Compound 14) is dissolved in 20 ml of ethanol and then 20 ml of concentrated hydrochloric acid is added thereto. The mixture is heated under reflux for 3 hours. The solvent is then distilled away from the reaction solution under reduced pressure, and the residue is recrystallized from tetrahydrofuran-ether to obtain 1.5 g of 1-(4-carboxymethylphenoxy)-3-(1-methyl-3-phenylpropylamino)-2-propanol hydrochloride. (Yield: 49%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]2[N:16]=[C:15]3[N:18]([C:22]4[C:23]([CH3:31])=[N:24][C:25]([N:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=4)[CH2:19][CH2:20][CH2:21][N:14]3[C:13]=2[C:12]([CH:32]([OH:35])[CH2:33][CH3:34])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:1]([O:35][CH:32]([C:12]1[C:13]2[N:14]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]4[C:23]([CH3:31])=[N:24][C:25]([N:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=4)[C:15]3=[N:16][C:17]=2[C:9]([Cl:8])=[CH:10][CH:11]=1)[CH2:33][CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(N(C)C)nc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.4 %

Procedure:
Acetic anhydride (0.30 mL, 3.15 mmol) was added to a stirred solution of 1-{9-chloro-1-[6-(dimethylamino)-2-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (103 mg, 0.258 mmol) in pyridine (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 6 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-90% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate to give the title compound as a colorless crystal (86.9 mg, 0.197 mmol, 76%)
Reaction SMILES: [OH-:1].[Na+].C[C:4]([CH:6]1[CH:8]([CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[C:7]1([CH3:15])[CH3:14])=[O:5].[CH3:16]O>>[CH3:14][C:7]1([CH3:15])[CH:8]([CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[CH:6]1[C:4]([O:5][CH3:16])=[O:1].[CH3:14][C:7]1([CH3:15])[CH:8]([CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[CH:6]1[C:4]([OH:5])=[O:1]
Reactant: CC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Product: CC1(C)C(CC(Cl)(Cl)Cl)C1C(=O)O
Product: COC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Reaction time: 0.5 h

Procedure:
To 250 ml of methanol solution containing 36 g of sodium hydroxide were added 26.8 g of 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropyl methyl ketone (purity: 97.9%, cis/trans ratio: 91.5/8.5) under cooling with ice, and then 27.6 g of chlorine gas were absorbed from the surface of the solution for 100 minutes and stirred for 30 minutes. Then 25.2 g of sodium sulfite (7 hydrate) and 200 ml of water were added and the mixture was stirred for 30 minutes to decompose excess hypochlorite. Then the reaction mixture was made acidic with conc. hydrochloric acid. After separating lower organic layer deposited, water layer was subjected to extraction with ether, and the ether layer was mixed with the separated organic layer and washed with sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. After distilling off the ether, vacuum distillation was carried out to obtain 8.3 g of methyl 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropanecarboxylate, b.p. 77°-86° C./0.4 mmHg, cis/trans ratio 88/12, purity 87.8%, yield 26.3% and 15 g of 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropanecarboxylic acid, b.p. 104°-120° C./0.4 mmHg, cis/trans ratio 82.8/17.2, purity 91.8%, yield 52.0%. Further, the sodium bicarbonate aqueous wash solution was acidified to obtain 1.4 g of 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropanecarboxylic acid.
Reaction SMILES: Br[CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:3]1.[CH3:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18].[CH2:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:22]>CN1CCCC1=O.C(Cl)Cl>[CH3:15][C:16]([CH3:20])([C:17]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1)=[O:18])[CH2:19][N:26]1[CH2:27][CH2:28][N:23]([CH2:21][CH3:22])[CH2:24][CH2:25]1
Reactant: CC(C)(C)C=O
Reactant: Cc1ccc(N2CCNC(Br)C2)cc1
Reactant: CCN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCN1CCN(CC(C)(C)C(=O)N2CCN(c3ccc(C)cc3)CC2)CC1
Temperature: 200 °C
Reaction time: 0.33 h
Yield: 54 %

Procedure:
3-Bromo-1-(4-methylphenyl)piperazine-2,2-dimethylpropan-1-one (Example 37, step 1; 2.00 g, 5.92 mmol) was dissolved in N-methylpyrrolidinone (10 mL). N-Ethylpiperazine (1.50 mL, 11.8 mmol) was added. The reaction mixture was split into four batches and each was heated at 200° C. for 15 minutes in a Biotage Initiator microwave at high absorption. The reaction mixtures were combined and dissolved in DCM (300 mL), and washed with water (2×80 mL), brine (100 mL), dried (MgSO4) and then concentrated in vacuo. The residue was purified by reverse phase column chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (100 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo, to give a colourless oil which was recrystallised from heptane to give 1-{2,2-dimethyl-3-[4-(4-methylphenyl)piperazin-1-yl]-3-oxopropyl}-4-ethylpiperazine (1.19 g, 48%) as a white solid.