Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCC[CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=2)[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:11]1=[O:31].Cl.C(N(CC)CC)C.C(OC(=O)C)(=O)C>CO.ClCCl>[CH3:3][C:2]([O:7][CH2:8][CH2:9][N:10]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=2)[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:11]1=[O:31])=[O:1]
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)C1(CCNCC1)C(=O)N2CCOC1CCCCO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)OCCN1C(=O)C2(CCNCC2)c2cc(C(=O)OC(C)(C)C)ccc21
Reaction time: 0.5 h

Procedure:
1-(tetrahydropyran-2-yl-oxy-ethyl)-5-tert-butoxycarbonyl-spiro[indoline-3,4′-piperidin]-2-one (0.021 g, 0.05 mmol) was dissolved in methanol (2 mL). To the reaction mixture was then added at room temperature aqueous 1.0N HCl (80 μL) and the reaction mixture was stirred for 30 minutes. The reaction mixture was then partitioned with aqueous Na2CO3 and ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a solid. The solid was then dissolved in dry dichloromethane (2 mL). To the reaction mixture was then added at 0° C. triethylamine (0.12 g, 0.12 mmol) and acetic anhydride (0.02 g, 0.2 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for 30 minutes and 18 hrs at room temperature. The reaction mixture was then partitioned with aqueous Na2CO3 and dichloromethane. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a gum.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:4][CH2:3]1.[CH3:17][C:18]1[C:26]2[CH2:25][O:24][C:23](=[O:27])[C:22]=2[CH:21]=[CH:20][C:19]=1[C@H:28]1[CH2:30][O:29]1.CCN(C(C)C)C(C)C>C(O)C>[OH:29][C@H:28]([C:19]1[C:18]([CH3:17])=[C:26]2[C:22](=[CH:21][CH:20]=1)[C:23](=[O:27])[O:24][CH2:25]2)[CH2:30][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:4][CH2:3]1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: O=C1Nc2ccccc2C12CCNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCC3(CC2)C(=O)Nc2ccccc23)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
Commercially available spiro[indoline-3,4′-piperidin]-2-one hydrochloride (500 mg, 2.10 mmol) was combined with 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4A) (398 mg, 2.10 mmol) and DIEA (439 μL, 2.51 mmol) in ethanol (7 mL) and heated at 80° C. for 3 h. The reaction mixture was concentrated and purified by MPLC eluting first with 30% ethyl acetatehexanes and then with 10% methanol/DCM to afford the title compound which was a mixture of regioisomers. MS-ESI (m/z): 393 (M+1)+;
Reaction SMILES: [Si](I)(C)(C)C.[CH3:6][O:7][C:8](=[O:46])[C@@H:9]([NH:38]C(OC(C)(C)C)=O)[CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:30]4[O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:29]=4[CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH3:6][O:7][C:8](=[O:46])[C@@H:9]([NH2:38])[CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:30]4[O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:29]=4[CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H](N)CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
TMS-I (870 mg, 0.63 mL, 4.35 mmol) was added dropwise to a stirred solution of (2R)-methyl-2-tert-butoxycarbonylamino-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionate (2.24 g, 3.96 mmol) in anhydrous methylene chloride (50 mL). The reaction mixture was stirred at room temperature for 20-30 mins (TLC control), and then diluted with water (50 mL). Saturated sodium bicarbonate solution was added to adjust the solution to pH 8-9. The reaction mixture was extracted with diethyl ether (2×50 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound has a pale yellow solid (1.76 g, 95%); Rf: 0.20 (5% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz): δ 8.00 (3H, d, J=8 Hz, Ar—H), 7.94 (1H, d, J=8 Hz, Ar—H), 7.76 (2H, d, J=9 Hz, Ar—H), 7.64 (4H, m, Ar—H), 7.34-7.51 (5H, m, Ar—H), 3.81 (2H, s, PhCH2S), 3.75 (3H, s, OMe), 3.67 (1H, m CHN), 2.91 (1H, dd, J=15, 5 Hz, CHHCHN), 2.86 (1H, dd, J=15, 8 Hz, CHHCHN), 1.91 (2H, s, NH2); ESI-LCMS e/z calcd for C29H25NO3S 467.586, found 468 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[C:11]([OH:13])=[O:12])([O-:7])=[O:6].[CH3:21]COC(C)=O>CO>[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[C:11]([O:13][CH3:21])=[O:12])([O-:7])=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Yield: 100 %

Procedure:
Add thionyl chloride (2 mL) dropwise to the solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.5 g, 6.4 mmol) in methanol (20 mL), reflux for 5 hrs. TLC (PE:EtOAc=1:1) shows the reaction is complete. Concentrate under reduced pressure to give the crude product (1.8 g, 100%) which is used in next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][N:10]=[CH:9][C:8]=2[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[C:12]2[S:11][N:10]=[CH:9][C:8]=2[C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c2cnsc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c2cnsc12
Yield: 68.5 %

Procedure:
200 g of 7-nitro-4-hydroxy-1,2-benzisothiazole, 260 g of benzyl bromide and 210 g of potassium carbonate in 2.5 l of acetone are refluxed for 12 hours. The entire mixture is then concentrated to one liter under reduced pressure, the residue is poured into a threefold amount of water and the batch is repeatedly extracted with methylene chloride. The combined organic phases are dried over magnesium sulfate and freed from solvent under reduced pressure. The crude product is recrystallized from a mixture of methanol and tetrahydrofuran. 200 g (70% of theory) of 7-nitro-4-benzyloxy-1,2-benzisothiazole of melting point 158°-160° C. are obtained.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.O=P(Cl)(Cl)Cl.[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[C:34]2[C:25](=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=1.O>C(Cl)Cl>[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21]1[C:34]2[C:25](=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]([CH:9]=[O:10])=[CH:23][CH:22]=1
Reactant: CN(C=O)c1ccccc1
Reactant: COCCOc1cccc2cc3ccccc3cc12
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COCCOc1ccc(C=O)c2cc3ccccc3cc12
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a 1 L 3-necked RB flask equipped with overhead stirrer, condenser, addition funnel and N2 inlet line with bubbler was added N-methylformanilide (Aldrich, 72 g, 0.53 mol, 65.75 mL) and CH2Cl2 (150 mL). After cooling to 0°, POCl3 (Aldrich, 69.0 g, 0.44 mol, 42 mL) was added dropwise (maintaining the reaction mixture at 0°) over 20 min. The solution was allowed to warm to RT and a solution of 1-[(2-methoxy)ethoxy]anthracene (1B, 60.0 g, 0.24 mol) in CH2Cl2 (200 mL) added dropwise over 10 min. The solution warmed and turned a deep red color during this addition. The reaction mixture was refluxed for 5 h, cooled and hydrolyzed by the dropwise addition of H2O (50 mL) over 1 h. The H2O was then removed and the volume of the solution reduced to 200 mL. the solution was applied to a plug of SiO2 (1 kg) and chromatographed using CH2Cl2 followed by EtOAc as the eluting solvents. The appropriate fractions were combined and the solvent removed by rotary evaporation to give a yellow oil which solidified upon cooling. Recrystallization (abs. EtOH) gave 40.87 g (60.7%) of yellow 4-[2-(methoxy)ethoxy]-1-anthracenecarbaldehyde, m.p. 72°-74°, (C,H).
Reaction SMILES: F[C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[N:4]([CH2:12][C:13]([F:16])([F:15])[F:14])[C@H:5]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:6][OH:7].[H-].[Na+]>C1COCC1>[CH2:8]([C@H:5]1[N:4]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:3]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:2]=2[O:7][CH2:6]1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)C[C@H](CO)N(CC(F)(F)F)c1ccc([N+](=O)[O-])cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1COc2cc([N+](=O)[O-])ccc2N1CC(F)(F)F
Yield: 47.5 %

Procedure:
This compound was prepared according to the procedure described in EXAMPLE 41 (Structure 24 of Scheme V) from (2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-4-methyl-1-pentanol (1.95 g, 5.76 mmol) in 30 mL THF and NaH (1.4 g, 35 mmol) in 25 mL THF heated at reflux for 1 hr to afford 0.87 g (50%) of (3R)-3,4-dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine, a yellow oil. Data for (3R)-3,4-dihydro-3-isobutyl-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: Rf0.6 (3:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, 1H, J=9.1, 2.7), 7.71 (d, 1H, J=2.5), 6.72 (d, 1H, J=9.1), 4.30 (dd, 1H, ABx, J=11.0, 1.5), 4.19–4.06 (m, 1H), 4.06–4.01 (m, 1H), 3.82–3.73 (m, 1H), 3.53–3.47 (m, 1H), 1.71–1.61 (m, 2H), 1.38–1.29 (m, 1H), 0.99 (d, 3H, J=6.5), 0.96 (d, 3H, J=6.5).
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[N:33]=[C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[N:38]=3)[NH:35][N:36]=2)[CH2:28][CH2:27]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1.CC(O)=O>[CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:26]4[CH2:27][CH2:28][CH:29]([C:32]5[N:33]=[C:34]([C:37]6[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:45])([F:46])[F:44])[N:38]=6)[NH:35][N:36]=5)[CH2:30][CH2:31]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: FC(F)(F)c1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6cccc(C(F)(F)F)n6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-methyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (300 mg, 0.95 mmol) and 2-(5-piperidin-4-yl-2H-[1,2,4]triazol-3-yl)-6-trifluoromethyl-pyridine hydrochloride salt (662 mg, 1.43 mmol) in NMP (8.1 mL) was treated with Et3N (0.32 mL), followed by AcOH (98 μL) and the mixture was stirred overnight at rt. NaBH(OAc)3 (222 mg) was added and the mixture stirred for 3 hours. The mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution, the organic phase washed with brine and concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([CH:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[CH:18]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([O:15][CH:19]([C:17]#[CH:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)=[O:14]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCCF
Solvent: ClC(Cl)Cl
Product: C#CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCCF)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step F of Example 9, (1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid and α-ethynyl-3-phenoxy-benzyl alcohol were reacted to obtain α-ethynyl-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+47°±1.5° (c=1% in CHCl3).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[OH:16][CH2:17][C:18]1([C:21]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH2:20][CH2:19]1>>[OH:16][CH2:17][C:18]1([C:21]2[CH:26]=[CH:25][C:24]([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][C:3]=3[C:8]3[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=3)=[CH:23][CH:22]=2)[CH2:20][CH2:19]1
Reactant: OCC1(c2ccc(B(O)O)cc2)CC1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C2(CO)CC2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-(1-(hydroxymethyl)cyclopropyl)phenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H18N4O, 331. Found, 331.
Reaction SMILES: [C:1]1([C:7]([S:9][CH2:10][C:11]([OH:13])=[O:12])=[S:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:18]O>>[C:1]1([C:7]([S:9][CH2:10][C:11]([O:13][CH3:18])=[O:12])=[S:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CSC(=S)c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CSC(=S)c1ccccc1
Yield: 98 %

Procedure:
2-((Phenylcarbonothioyl)thio)acetic acid (10 g, 47.1 mmol) was dissolved in 200 mL of methanol followed by the dropwise addition of thionylchloride (16 g, 120 mmol) at room temperature. The reaction mixture was refluxed for 4 hours. The reaction mixture was concentrated in vacuo and ethyl acetate was added. The mixture was washed with sat. aq. NaHCO3 and brine and dried over Na2SO4. The reaction mixture was concentrated in vacuo to afford Methyl 2-((phenylcarbonothioyl)thio)acetate 2 as brown oil (10.5 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[S:17][C:18]([N+:21]([O-])=O)=[CH:19][N:20]=1.[Cl-].[NH4+].C(O)C.O>[Fe].CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:16]1[S:17][C:18]([NH2:21])=[CH:19][N:20]=1
Reactant: COc1cc2nccc(Sc3ncc([N+](=O)[O-])s3)c2cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Sc3ncc(N)s3)c2cc1OC
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 29.8 %

Procedure:
After suspending 6,7-dimethoxy-4-(5-nitrothiazol-2-ylsulfanyl)quinoline (699 mg, 2.00 mmol), iron (559 mg, 10.0 mmol) and ammonium chloride (1.07 g, 20.0 mmol) in an ethanol (20 ml)-water (5 ml) mixed solvent, the suspension was heated and stirred at 80° C. for 20 minutes. After completion of the reaction, the reaction mixture was filtered with celite and washed in an ethyl acetate-tetrahydrofuran mixed solvent. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:methanol=30:1), and the fraction containing the target substance was concentrated to obtain the title compound (190 mg, 0.595 mmol, 30%) as yellowish-brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([CH3:26])=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH:41]1[CH2:46][OH:47])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=3[C:29]([F:31])([F:32])[F:30])[N:8]=[C:9]4[CH3:26])[C:18](=[O:25])[N:19]=2)[CH2:42][CH:41]1[CH2:46][OH:47])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C)nn3Cc2ccc(Cl)cc2C(F)(F)F)S1
Reactant: CC(C)(C)OC(=O)N1CCNCC1CO
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=C3SC(N4CCN(C(=O)OC(C)(C)C)C(CO)C4)=NC3=O)cc12

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10](C)C(=O)O[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]([NH:22][CH2:23][CH2:24][NH2:25])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15](=[O:16])[NH:22][CH2:23][CH2:24][NH:25][C:7](=[O:14])[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:11]=1[NH2:10])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cn1c(=O)oc(=O)c2cccc(Cl)c21
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cccc(Cl)c1N
Yield: 84 %

Procedure:
Starting from 8-chloro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione and N-Boc-ethylenediamine and using Procedure S, the title intermediate was obtained as a colourless solid (264 mg; 84% yield).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C=C.[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>[Br-].C([N+](CC)(CC)CC)C>[C:28]([O:32][CH3:33])(=[O:31])/[CH:29]=[CH:30]/[CH:1]=[CH:2]/[CH3:3]
Reactant: C=CCCl
Reactant: C=CC(=O)OC
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=CCO
Product: C/C=C/C=C/C(=O)OC
Temperature: 120 °C

Procedure:
Quantities of 1.9 grams alyl allyl chloride dimer, 2.75 grams tetraethyl ammonium bromide, 5.25 grams of triphenyl phosphine, 45 cc allyl alcohol, and 60 cc methyl acrylate are introduced into a reaction chamber and heated to 120°C for 20 hours. Methyl sorbate is produced to the extent of 10% by weight of the final reaction solution.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:24])[CH:13]=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Reactant: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Product: Cc1nc(C(=O)Nc2cnn(Cc3nc(C(C)(F)F)cs3)n2)c(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Following general procedure Z2, starting from 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10](OCC)(OCC)(OCC)[CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(OCCCCCCCC)(=O)C1C(=CC=CC=1)C(OCCCCCCCC)=O>[CH3:10][C:11]12[O:7][CH2:6][C:3]([CH2:8][OH:9])([CH2:4][O:5]1)[CH2:2][O:1]2
Reactant: OCC(CO)(CO)CO
Reactant: CCOC(C)(OCC)OCC
Agent: CCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC12OCC(CO)(CO1)CO2
Yield: 85 %

Procedure:
Pentaerythritol (13.6 g, 0.1 mol), triethyl orthoacetate (16.22 g, 0.1 mol, 18.3 mL), pyridine p-toluenesulfonate (PPTS) (0.5 g, 2 mmol) and 100 mL of dioctyl phthalate were mixed in a 250 mL, round-bottom flask fitted with a regular distillation apparatus. The mixture was heated to 130°-140° C. and ethanol was slowly distilled. When the amount of ethanol was close to the theoretical value the pressure was reduced to <0.1 torr and the product was distilled in vacuo. The white product which distilled crystallized in the condenser to give 13.6-14.9 g of MHTBO. Yield: 85-93%. The compound can be recrystallized from toluene but can be used directly. Mp: 110°-112° C.
Reaction SMILES: O[CH:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:5][CH2:6]1
Reactant: COc1ccccc1N1CCN(CC(O)c2ccccc2)CC1
Reactant: C1CCNC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CC(c2ccccc2)N2CCCC2)CC1
Temperature: 0.5 °C

Procedure:
A mixture of 1-(2-hydroxy-2-phenylethyl)-4-(2-methoxyphenyl)-piperazine (5.65 g; 0.018 m), triphenylphosphine (5.69 g, 0.022m) and pyrollidine (15 ml; 0.18 m) in dichloromethane (100 ml) was stirred at 0.5° C. and a solution of diethylazodicarboxylate (3.8 ml, 0.024 m) in dichloromethane (5 ml) was added over 5 minutes. The resulting yellow solution was stirred at ambient temperature for 48 hrs. The residue on evaporation was partitioned between ether and 3N aq. hydrochloric acid. The combined HCl layers were washed with ether and then basified with ammonia and shaken with 3 portions of ether. The ether layers were washed well with water and dried over magnesium sulfate to give an oil which was chromatographed to give 0.96 g of the title compound. The crude oil in ethanol was acidified with ethanolic hydrogen chloride. The solvent was evaporated, and the residual foam solidified when triturated with ethanol and ether. The solid was recrystallised from ethanol to give the title compound as the dihydrochloride (0.45 g), m.p. 214°-18° C(d).