Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].ON1C2C=CC=CC=2N=N1.CN(CCCN=C=NCC)C.Cl.[NH2:46][C@H:47]([C:54]([O:56][CH3:57])=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.Cl.CN1CCOCC1>C(Cl)Cl>[N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:46][C@H:47]([C:54]([O:56][CH3:57])=[O:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:10])[CH3:7])=[O:4]
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 1,500 g (4.68 mmoles) of Z-(L)-Pro-(L)-AlaOH (Sigma) in 60 ml of dry methylene chloride (CH2Cl2) was brought, under stirring and in an argon atmosphere, to the temperature of the ice and salt bath. The following were then added in succession: 0.800 g (4.73 mmoles) of commercial 1-hydroxybenzotriazole (HOBt) and 0.900 g (4.69 mmoles) of N-(dimethylaminopropyl)-N'-ethylcarbodiimide.HCl (EDC). Keeping the temperature under control, the mixture was left under stirring for 10 minutes and then the following were added in succession: 0.940 g (4.66 mmoles) of (L)-PhgOMe.HCl (Bachem) and 0.520 ml (4.72 mmoles) of 4-methylmorpholine (NMM), maintaining the temperature for a further 2 hours. The mixture was then left under stirring and static argon for 12 hours with the temperature free to rise to room temperature. The solid white precipitate was filtered away and washed with a little CH2Cl2. The latter was put back into the filtered reaction solution, which was extracted in succession using 5% NaHCO3 (3×30 ml); saturated aqueous NaCl (2×30 ml); 4% KHSO4 (3×30 ml) and finally saturated aqueous NaCl (2 ×30 ml), discarding the aqueous phases. The organic phase extracted was left in a cold chamber under argon and on anhydrous Na2SO4 for 12 hours. The desiccant was then filtered away, the solution concentrated to a small volume and the dense residual liquid was ground with anhydrous ethyl ether a number of times, decanting each time and discarding the ether phase. The residual solid was left for 24 hours under vacuum on P2O5. 1.630 g (74.8%) of an analytically pure powdery white solid were recovered.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH:26]=1.O>CN(C)C=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[CH:24]=[N:23][CH:22]=[C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[CH:26]=2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: ClCc1cncc(-c2ccc(Cl)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cncc(COc3ccc(CCCCn4ccnn4)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A solution of 85 mg (0.39 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 16 mg (0.39 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.39 mmol) 3-Chloromethyl-5-(4-chloro-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water and n-heptane. The residue was dried at 40° C. to give 108 mg (67%) of the title compound as light brown powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([Cu])#[N:11]>CN(C=O)C.CCOC(C)=O.[Cu]I>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c(F)c1
Yield: 101.4 %

Procedure:
2-Fluoro-4-iodoaniline (5.0 g, 21 mmol) was dissolved in 20 mL dry DMF. To it were added CuCN (3.8 g, 42 mmol) and catalytic amount of CuI (200 mg). The slurry was refluxed for 1 hour. Diluted with EtOAc. Filtered through celite. Concentrated in vacuuo to yield solid 4-amino-3-fluorobenzonitrile (2.9 g, 100%). ES-MS: (M+H)+ 137.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[C:18](=S)=[S:19]>N1C=CC=CC=1>[CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:18](=[S:19])[NH:17][N:16]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S=C=S
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Solvent: c1ccncc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(=S)[nH]nc12
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of (2e)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (1.90 g, 8.04 mmol) and carbon disulfide (0.58 ml, 9.64 mmol) in pyridine (30 ml) was stirred at 60° C. for 3 hours. After cooling to room temperature, the solid formed was filtered and dried to yield the desired product (1.90 g, 84.9%). LCMS calculated for: C11H14N6OS (M+H) 280.1. found: 280.1.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([OH:8])=[CH:6][CH:7]=1.O[CH:11]1[CH2:15][CH2:14][O:13][CH2:12]1>>[Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([O:8][CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(O)ccc1Br
Reactant: OC1CCOC1
Product: Cc1nc(OC2CCOC2)ccc1Br

Procedure:
The title compound was prepared from 3-bromo-6-hydroxy-2-methylpyridine and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N[C@H](C(O)=O)C[SeH].[Li]CCCC.[CH3:49][S:50]C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:9]1[S:50][CH3:49])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSC
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Cc4ccccc4)cn(C(=O)OC(C)(C)C)c23)CC1
Agent: N[C@@H](C[SeH])C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1c(Cc2ccccc2)c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2n1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester (186 mg, 0.38 mmol) in THF (5 ml) was cooled to −78° C., and Sec-BuLi (1.4 ml, 1.4 M in cyclohexane) was added. After stirring at −78° C. for 20 minutes, 1 ml of dimethyl sulfide was added and the reaction was allowed to warm up to room temperature for 30 minutes. H2O was slowly added, followed by EtOAC. The organic layer was separated and washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo to give crude 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-methylsulfanyl-indole-1-carboxylic acid tert-butyl ester as an oil (277 mg), which was used without further purification.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(CC)C(C)C)(C)C.[OH:30][C:31]1([CH3:35])[CH2:34][NH:33][CH2:32]1>C(Cl)(Cl)Cl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:33]1[CH2:34][C:31]([OH:30])([CH3:35])[CH2:32]1)=[N:6]2
Reactant: CC1(O)CNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(C)(O)C3)nc2c1C#N
Temperature: 100 °C
Yield: 92.1 %

Procedure:
Under nitrogen atmosphere, 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (216 mg, 0.753 mmol) was dissolved in N,N-dimethylsulfoamide (10 ml), then N,N-diisopropylethylamine (584 μl, 3.35 mmol) and 3-hydroxy-3-methylazetidine (132 mg, 1.51 mmol) dissolved in N,N-dimethylsulfoamide (5 ml) were added, followed by stirring under heat at 100° C. for 20 hours. After cooling, diluting with chloroform and washing with water, the organic layer was dried over anhydrous magnesium, sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (234 mg, 92%) as a white solid.
Reaction SMILES: [NH2:1][C@:2]([C:6]([OH:8])=[O:7])([CH3:5])[CH2:3][CH3:4].[OH-].[Na+].[Cl:11][CH2:12][C:13](Cl)=[O:14].Cl>>[Cl:11][CH2:12][C:13]([NH:1][C@:2]([C:6]([OH:8])=[O:7])([CH3:5])[CH2:3][CH3:4])=[O:14]
Reactant: CC[C@@](C)(N)C(=O)O
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC[C@@](C)(NC(=O)CCl)C(=O)O
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a well-stirred mixture chilled to 0° C. to 5° C. (ice bath) of racemic isovaline ((R,S) 2-amino-2-methylbutanoic acid) (350 g, 2.99 mole) and 2N aqueous sodium hydroxide (1.5 L) were added simultaneously chloroacetyl chloride (373 g, 3.31 mole) and 2N aqueous sodium hydroxide (1,718 ml, 3.44 mole) over 1.5 hours . The base was added at such a rate as to keep the reaction mixture basic at all times. The reaction mixture was warmed up to room temperature, treated with concentrated aqueous hydrochloric acid until acidic to litmus paper. A white solid formed which was separated by filtration and dried to yield 454 g (78.5%) of the expected racemic N-chloroacetylisovaline ((R,S) 2-chloroacetamido-2-methylbutanoic acid).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6](C)[CH2:5][CH2:4]1)#[N:2].Cl.C(C1(C2C=CC=CC=2SC2C=CC=CC=2)CCN(C)CC1)#N.Cl[C:47]([O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:48]>C(Cl)Cl>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6]([C:47]([O:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:48])[CH2:5][CH2:4]1)#[N:2]
Reactant: CN1CCC(C#N)(c2ccccc2Sc2ccccc2)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N#CC1(c2ccccc2Sc2ccccc2)CCN(C(=O)Oc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2.5 g of 4-cyano-1-methyl-4-(2-phenylthiophenyl)piperidine, free base of Example 3, and 1.7 g of phenyl chloroformate in 50 ml of methylene chloride is permitted to stand for 24 hours before being poured onto 100 g of ice. Thereafter, the mixture is extracted with 50 ml of methylene chloride and the organic solution is successively washed twice with 50 ml portions of water, washed once with 40 ml saturated sodium bicarbonate solution, washed once with 40 saturated sodium chloride solution, dried and evaporated. The residue is chromatographed through a silica gel column, first with an ether eluant and then with an ether-hexane (1:1) mixture eluant, until there is no indication of contamination by thin layer chromatography. Thereafter, the product is chromatographed through the same absorbent, ether eluant to provide 4-cyano-1-phenoxycarbonyl-4-(2-phenylthiophenyl)piperidine.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[OH:15].Br[CH2:17][CH2:18][OH:19]>CN(C=O)C.CCOC(C)=O>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:17][CH2:18][OH:19]
Reactant: OCCBr
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCOc1ccc(F)cc1F
Temperature: 120 °C
Yield: 63 %

Procedure:
K2CO3 (1.07 g, 7.78 mmol) was added to a solution of 2,4-difluoro phenol (0.84 g, 6.48 mmol) in dry DMF (15 ml). 2-Bromoethanol (0.81 g, 6.48 mmol) was added, and the mixture was heated overnight at 120° C. The mixture was cooled, taken up in EtOAc, extracted with water (20 ml), saturated NaCl (4×20 ml), dried over MgSO4, and evaporated under reduced pressure. The product was purified by column chromatography on silica (Hexane:EtOAc 3:1) to give the desired product in 63% yield
Reaction SMILES: NC(N)=O.[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([N:15]=[C:16]=[O:17])[CH2:10]2.Cl.[F:19][CH2:20][CH2:21][NH2:22].C(N(C(C)C)CC)(C)C>>[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([NH:15][C:16]([NH:22][CH2:21][CH2:20][F:19])=[O:17])[CH2:10]2
Reactant: NCCF
Reactant: O=C=NC1Cc2cccc(Br)c2C1
Agent: Cl
Agent: NC(N)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCF)NC1Cc2cccc(Br)c2C1

Procedure:
The title urea was generated from 4-bromo-2-isocyanato-indan (12.00 mmol), fluoroethyl amine hydrochloride (1.20 g, 90% purity, 10.85 mmol) and diisopropylethyl amine (4.20 mL, 24.11 mmol) according to the protocol described in general procedure G. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ 2.64-2.94 (m, 2H), 3.06-3.42 (m, 4H), 4.28-4.40 (m, 2H), 4.5 (t, 1H, J=5.0 Hz), 6.0 (t, 1H, J=5.6 Hz), 6.4 (d, 1H, J=7.0 Hz), 7.1 (t, 1H, J=7.9 Hz), 7.2 (d, 1H, J=7.3 Hz), 7.4 (d, 1H, J=7.9 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[F:16])\[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[F:16])\[CH2:7][Br:18])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(F)c1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(F)c1F
Yield: 39.6 %

Procedure:
To a stirred mixture of (E)-3-(2,3-difluoro-phenoxy)-but-2-enoic acid ethyl ester (8.01 g, 0.033 mol) in carbon tetrachloride (30 mL) under a nitrogen atmosphere was added N-bromosuccinimide (8.91 g, 0.050 mol) and benzoyl peroxide (810 mg, 0.003 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2,3-difluoro-phenoxy)-but-2-enoic acid ethyl ester (4.20 g, 40%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:22])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].[N:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:30][C:31]([SH:34])=[N:32][N:33]=2)=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[C:16]1([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:22])[C:2]([S:34][C:31]3[NH:30][C:29]([C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)=[N:33][N:32]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Reactant: Sc1nnc(-c2ccncc2)[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Sc1nnc(-c2ccncc2)[nH]1
Temperature: 55 °C
Yield: 27 %

Procedure:
A solution of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (150 mg, 0.46 mmol, from Step 1 below), 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (82 mg, 0.46 mmol), and triethylamine (64 □L, 0.46 mmol) dissolved in DMF (5 mL) was heated to 55° C. under N2 for 8 h. The resulting mixture was concentrated and purified by Prep HPLC to give the title compound (58 mg, 27%) as a pale yellow solid. 1H NMR (DMSO-d6): δ 1.62-1.82 (m, 12H), 2.03-2.11 (m, 8H), 2.51 (m, 1H), 2.87 (d, 1H, J=17.5 Hz), 3.11 (d, 1H, J=17.5 Hz), 5.55 (s, 1H), 8.01 (d, 2H, J=5.8 Hz), 8.84 (d, 2H, J=5.8 Hz). ESIMS: MH+ 467.15
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][NH2:28])=[O:26])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:30](OC)(OC)OC>>[CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]5[O:26][CH:30]=[N:28][N:27]=5)[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(OC)OC
Reactant: NNC(=O)c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Agent: Cl
Product: c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)cc(-c2nnco2)n1

Procedure:
A solution of 4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridine-2-carbohydrazide (8 mg, 0.019 mmol, 1.0 eq) and 0.1 mL of 4 M hydrogen chloride in 1 mL trimethyl orthoformate was heated in the microwave at 120° C. for 1200 seconds. The crude product was purified by reverse phase prep HPLC to give the title compound. MH+=392.0
Reaction SMILES: [OH:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)C(Cl)=O.CO>C(Cl)Cl>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:12])[C:10]([F:11])=[C:2]([OH:1])[C:3]=1[F:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(F)c(F)c(O)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
A solution of 3-hydroxy-2,4,5-trifluorobenzoic acid (50 g, 0.26 mol) (prepared in an analogous manner to that described in Eur. Pat. Publication 271275) in methylene chloride (500 mL) was added oxalyl chloride (79 g, 0.62 mol). This solution was stirred at room temperature for 18 hours, cooled to 5° C. and then treated dropwise with methanol (100 mL). The mixture was stirred at room temperature for 2 hours, refluxed for 0.5 hour, cooled and concentrated. The residue was partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was dried (MgSO4) and concentrated to provide 16.7 g of the desired 3-hydroxy-2,4,5-trifluorobenzoic acid methyl ester. Acidification of the bicarbonate layer, extraction with ether and concentration provided an additional 37 g of desired product as indicated by NMR, This material was not purified further but carried into the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[C:4]([C:9]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2OC)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[C:24]1C(OC)=C(C(CBr)=CC=1)C(OC)=O.C1(S)CCCCC1>>[Br:1][C:2]1[C:3]([O:22][CH3:24])=[C:4]([C:9]([CH2:12][S:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Reactant: COC(=O)c1c(CSc2ccccc2OC)ccc(Br)c1O
Agent: SC1CCCCC1
Product: COC(=O)c1c(CSC2CCCCC2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and cyclohexanethiol and used without further purification.
Reaction SMILES: C(N(CC)CCC[N:7]1[C:15]2[C:10](=[C:11]([Cl:16])[CH:12]=[CH:13][CH:14]=2)[C:9](NCCCN(CC)CC)=[N:8]1)C.[ClH:28].C(OCC)C>C(O)C>[ClH:16].[ClH:28].[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[N:8][NH:7]2
Reactant: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2cccc(Cl)c12
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Clc1cccc2[nH]ncc12

Procedure:
In 50 ml of absolute ethyl alcohol was dissolved 3.2 g of the 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-4 -chloroindazole, and into the solution was introduced dried hydrogen chloride gas under cooling with ice. Then to the solution was added anhydrous diethyl ether to separate crystals. The crystals were obtained by filtration and dried to give 1-(3-diethylaminopropyl)-3-diethylaminopropylamino)-4-chloroindazole dihydrochloride having the following analytical value.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.[OH-:13].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[NH:3][C:4](=[O:13])[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1cc2nc(Cl)nc(Cl)c2s1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2nc(Cl)[nH]c(=O)c2s1
Temperature: 25 °C
Yield: 92 %

Procedure:
A mixture of 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (450 mg, 2.05 mmol), aqueous NaOH (1N, 4 mL) and THF (4 mL) was stirred at room temperature under N2. The reaction was monitored by HPLC until the reaction was completed. Then the mixture was neutralized to PH 5 by addition of 2N aqueous HCl. The solid was filtrated and dried to give 380 mg of 2-chloro-6-methylthieno[3,2-d]pyrimidin-4(3H)-one (yield was 92%) as a yellow solid. MS obsd. (ESI+) [(M+H)+]: 201.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.CN(C)C=O.O.[C:15]1([CH3:23])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1>>[CH3:23][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1
Reactant: Cc1cc(C)cc(C)c1
Reactant: ClCc1c[nH]cn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(Cc2c[nH]cn2)c(C)c1

Procedure:
3.0 g of 4-chloromethylimidazole hydrochloride are suspended in 20 ml of mesitylene. 5 ml of dimethylformamide are added and the reaction mixture is refluxed for 12 hours, then cooled. 30 ml of water are added, the layers are separated, and the aqueous phase is washed with chloroform. The aqueous solution is then made alkaline with sodium carbonate solution and extracted with chloroform. The combined chloroform extracts are washed with water and evaporated to dryness. The residue, which is crude 4-(2',4',6'-trimethylbenzyl)imidazole, is converted to the hydrochloride by treatment with concentrated hydrochloric acid. The hydrochloride salt melts at 166°-169° C.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH:22]2[O:24][CH2:23]2)=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:23][CH:22]([C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:26][CH:25]=3)[O:24][C:14]2=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: COc1ccc(C2CO2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1ccc(N2CC(c3ccc(OC)cc3)OC2=O)cc1
Yield: 14.5 %

Procedure:
In a 20 ml-three necked flask, 0.013 g of lithium chloride and 3.8 ml of DMF were placed. To the mixture, a solution of 1.09 g (6.22 mM) of 4-butylphenyl isocyanate and 6.20 mM of optically active 4-methoxystyrene oxide in 1.3 ml of DMF was added dropwise in 12 minutes under refluxing and stirring in nitrogen atmosphere, followed by refluxing for 50 minutes under stirring. After the reaction, the reaction mixture was left standing for cooling, then poured into water, and subjected to extraction with ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain a residue The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=10/1) and recrystallized from methanol to obtain 0.29 g of optically active 3-(4-butylphenyl)-5-(4-methoxyphenyl)-2-oxazolidinone (Yield: 14.5%).