Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8](=[O:19])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:10][C:5]2=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:9]2[CH2:10][C:5]3[C:6](=[N:7][C:2]([C:37]4[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][C:29]5[O:28][C:27]([C:24]6[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=6)=[C:31]([C:32]([NH:34][CH3:35])=[O:33])[C:30]=5[CH:36]=4)=[CH:3][CH:4]=3)[C:8]2=[O:19])=[CH:13][CH:14]=1
Reactant: O=C1c2nc(Cl)ccc2CN1Cc1ccc(F)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)C(=O)N(Cc3ccc(F)cc3)C4)cc12
Yield: 27.2 %

Procedure:
A solution of 2-chloro-6-(4-fluorobenzyl)-5H-pyrrolo[3,4-b]pyridin-7(6H)-one (70 mg, 0.25 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (152 mg, 0.30 mmol), K3PO4.3H2O (200 mg, 0.76 mmol), Pd2(dba)3 (23 mg, 0.03 mmol) and X-Phos (23 mg, 0.06 mmol) in dioxane/H2O (2 mL/0.5 mL) was stirred at 110° C. for 1 hour. After the reaction, the mixture was filtered and the filtrate was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The organic layer was washed with brine (10 mL*3), dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the product of 5-(6-(4-fluorobenzyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (42 mg, yield: 27%). 1H-NMR (CDCl3, 400 MHz) δ 7.97˜8.02 (m, 3H), 7.82˜7.88 (m, 2H), 7.64 (s, 1H), 7.33˜7.36 (m, 2H), 7.22 (t, J=8.8 Hz, 2H) 7.18 (t, J=8.4 Hz, 2H), 6.08 (br s, 1H), 4.86 (s, 2H), 4.34 (s, 2H), 3.16 (s, 3H), 3.01 (d, J=4.8 Hz, 3H), 2.99 (s, 3H). MS (M+H)+: 617.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]([C:22]1[N:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[N:25]=[C:24]([CH:31]=O)[CH:23]=1)[CH2:20][CH3:21]>>[C:27]([N:26]1[C:22]([CH2:19][CH2:20][CH3:21])=[CH:23][C:24]([CH2:31][NH:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][CH2:14]2)=[N:25]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCCc1cc(C=O)nn1C(C)(C)C
Reactant: NCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Product: CCCc1cc(CNCCN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1C(C)(C)C
Yield: 95.6 %

Procedure:
Compound 50 was prepared using the same method as that of Example 1 except that 4-(4-nitrophenyl)piperazin-1-ylethylamine and 5-propyl-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[H-].[Na+].[CH:13]1([S:19](Cl)(=[O:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN(C)C=O.C(O)C>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[S:19]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:21])=[O:20]
Reactant: CNCCc1ccncc1
Reactant: O=S(=O)(Cl)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(CCc1ccncc1)S(=O)(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
N-Methyl-2-(4-pyridyl)ethylamine (5 g) was added dropwise over 15 minutes to a stirred suspension of sodium hydride (1.77 g, 50% dispersion in oil) in dry N,N-dimethylformamide (80 ml) (DMF) containing absolute ethanol (2 drops) under dry nitrogen at room temperature. Upon gentle warming to 50° for 1 hour the coloured anion was generated. After cooling to 0°, cyclohexanesulphonyl chloride (6.71 g) was added dropwise over 45 minutes then the stirred mixture allowed to attain room temperature over 18 hours. The yellow solution was then added to ice-water (200 ml), filtered, extracted with chloroform (25 ml×4), the organic phase dried (MgSO4) and concentrated in vacuo. Residual DMF was distilled from the product at 0.7 mm.Hg and the remaining viscous oil column-chromatographed upon silica (150 g) by elution with chloroform. Evaporation of the primary fractions (200 ml×3) afforded crystalline N-methyl-N-(2-[4-pyridyl]ethyl)cyclohexanesulphonamide (8.67 g), m.p. 94°- 6°.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])=[CH:10][CH:11]=3)[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 2-{4-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]-phenoxy}-2-methyl propionic acid ethyl ester (345.2 mg, 0.711 mmol) in ethanol (8.9 mL) was treated with NaOH (aq) (0.854 mL of a 5M solution), and heated at reflux for 1 h. The hot solution was acidified to pH 1 with 1M HCl (6 mL). The mixture was cooled to ambient temperature, then further cooled to 0° C. before filtering the product. Following washing with H2O, the product was dried under vacuum at 50° C. to yield 226.2 mg (70%) as a white, crystalline solid: Rf=0.2 in 6:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.21 (s, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.64-7.62 (m, 3H), 7.48 (t, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 2H), 7.35 (t, J=7.2 Hz, 1H), 6.88-6.77 (m, 4H), 4.18 (t, J=6.4 Hz, 2H), 2.99 (t, J=6.4Hz, 2H), 2.44 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](S(C)(=O)=O)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[O:18]1CCOCC1>>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:18])[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2ccnc(S(C)(=O)=O)n2)s1
Reactant: C1COCCO1
Product: Cc1nc(C)c(-c2cc[nH]c(=O)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
4-(2,4-dimethyl-thiazol-5-yl)-2-methanesulfonyl-pyrimidine (288 mg, 1.07 mmol) was dissolved in dioxane (13 ml) and then 2N NaOHaq (6 ml, 12 mmol) was added. After stirring at room temperature for 1 hour, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue was purified by flash chromatography with DCM-MeOH (9-1) to give 166 mg of the title compound. (75% yield).
Reaction SMILES: ClCCC1OC=[N:6]C=1C.[N+:10]([CH:13]=[C:14]([NH:27][CH3:28])[NH:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][C:21]1[O:25][CH:24]=[N:23][C:22]=1C)([O-:12])=[O:11].NC1OC(CCCl)=CN=1>>[N+:10]([CH:13]=[C:14]([NH:27][CH3:28])[NH:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][C:21]1[O:25][C:24]([NH2:6])=[N:23][CH:22]=1)([O-:12])=[O:11]
Reactant: CNC(=C[N+](=O)[O-])NCCSCCc1ocnc1C
Reactant: Cc1ncoc1CCCl
Agent: Nc1ncc(CCCl)o1
Product: CNC(=C[N+](=O)[O-])NCCSCCc1cnc(N)o1

Procedure:
Using 5-(2-chloroethyl)-4-methyloxazole as starting material in the procedure of Example 21 the product is 1-nitro-2-methylamino-2-[2-(2-(4-methyl-5-oxazolyl)ethyl)thioethylamino]-ethylene. Also, using 2-amino-5-(2-chloroethyl)oxazole (prepared by reacting 2-amino-5-(2-hydroxyethyl)oxazole with thionyl chloride) in the procedure of Example 21 gives 1-nitro-2-methylamino-2-[2-(2-(2-amino-5-oxazolyl)ethyl)thioethylamino]ethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH:17]=[O:18])[CH:10]=1.B(Cl)(Cl)Cl.C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH:22]=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:17]=[O:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1C=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)ccc1O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a cooled (0° C.), stirred solution of 2-[3,5-dichloro-4-(3-formyl-4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (0.4 g) in dichloromethane (10 mL) was added 1M boron trichloride in dichloromethane (4 mL). The resulting orange slurry was stirred at ambient temperature for 5 h, ice added and the reaction stirred an additional 1 h. The two phase solution was diluted into ethyl acetate and washed with water, brine, dried (Na2SO4), concentrated in vacuo to afford the title compound of Step B as an off-white solid, 0.4 g (m.p. 146-150° C.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].ClCCl.CO>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([CH2:20][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: c1c[nH]nn1
Reactant: COC(=O)c1cc(CCl)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(Cn2ccnn2)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine triazole (0.72 g, 10.4 mmol) and dimethylformamide (6 mL). Cool in an ice bath and add sodium hydride (0.42 g, 60% i oil, 10.4 mmol). After 30 minutes, warm to ambient temperature. Add a solution of methyl 2-methoxy-5-chloromethylbenzoate (1.85 g, 6.74 mmol) in dimethylformamide (6 mL). Heat to 75° C. After 3 hours, partition the reaction mixture between water and ethyl acetate. Extract the organic layer with water, dry over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 95/5 dichloromethane/methanol containing 0.5% concentrated aqueous ammonia to give methyl 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoate: Rf=0.l (silica gel, 1/1 hexane/ethyl acetate).
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:17])[CH2:14][CH2:15][CH3:16].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.[Zn+2].[I-].[I-]>[NH2:6][CH2:5][C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(=O)c1ccccn1
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCCC(O)(CN)c1ccccn1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
TMSCN (1.10 mL, 8.25 mmol) followed by ZnI2 (163 mg, 0.51 mmol) were sequentially added to neat 1-(pyridin-2-yl)butan-1-one (1.131 g, 7.58 mmol) with stirring under Ar. The reaction was stirred at RT for 1 hour. THF (13 mL) was added to cyanohydrin, then this was slowly added dropwise over 10 min via cannula to LAH (462 mg, 12.17 mmol) in THF (30 mL) with stirring under Ar. The reaction warmed as addition progressed. Once the addition ended, the reaction was heated to reflux for 1 hour, then cooled to RT then cooled in ice. To the cooled reaction mixture was added with stirring Na2SO4.10H2O. The reaction stirred overnight and was allowed to warm to RT as the bath warmed. The reaction was filtered, solid washed with EtOAc, the organic phase extracted with 10% HCl (2×), aqueous extracts combined and washed with Et20. The aqueous phase was basified to pH ˜12 with 5M NaOH, saturated with NaCl, and then extracted with Et2O (3×). Combined extracts were dried (MgSO4), filtered and concentrated to afford 695 mg of 1-amino-2-(pyridin-2-yl)pentan-2-ol as an oil. 1H NMR showed this to be a 1:1.6 mixture of ROTMS:ROH:1H NMR for desired product: 1H NMR (400 MHz, CDCl3) δ ppm 8.53 (m, 1H), 7.64 (td, J=7.58, 1.77 Hz, 1H), 7.58 (dt, J=7.83, 1.14 Hz, 1H), 7.10 (ddd, J=7.33, 4.80, 1.26 Hz, 1H), 3.32 (d, J=13.64 Hz, 1H), 2.87 (d, J=13.64 Hz, 1H), 0.75 (m, 3H)
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[Br:14]Br>C(Cl)(Cl)Cl>[CH:9]1[C:4]([C:2]([CH2:1][Br:14])=[O:3])=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([OH:10])[CH:8]=1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
In 50 ml. of chloroform was dissolved 5.4 g. of 4-hydroxy-3-nitroacetophenone and then 5 ml. of chloroform solution of 4.8 g. of bromine was added dropwise to the solution gradually. Thereafter, the mixture was stirred for 15 minutes and concentrated under a reduced pressure to form yellow crystals. By recrystallizing the product from benzene-n-hexane, 6.3 g. of the crystals of α-bromo-4-hydroxy-3-nitroacetophenone melting at 69°-71° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)[C:11]#N)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=[CH:25][C:26](=C)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=3)[CH:25]=[C:26]([CH3:27])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C=C(C)C=O
Reactant: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1Cl
Product: COc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1Cl

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3-chloro-4-methoxyphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly yellow powder (yield 37%), melting at 160-163° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].CN(C)C=[O:15]>>[Cl:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([OH:15])[C:3]=1[C:4]#[N:5]
Reactant: CN(C)C=O
Reactant: Cc1cc(Cl)c(C#N)c(Cl)n1
Product: Cc1cc(O)c(C#N)c(Cl)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 2,4-dichloro-6-methylnicotinonitrile (12.0 g, 64.2 mmol), CsOAc (37.0 g, 193.0 mmol) in N,N-dimethylformamide (50 mL) was stirred at 80° C. overnight under N2. The mixture was partitioned between water (800 mL) and ethyl acetate (800 mL), the organic layer was dried and concentrated to afford 2-chloro-4-hydroxy-6-methylnicotinonitrile (9.0 g brown solid, 84.1% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C@H:13]1[CH2:17][O:16][C@:15]2([CH2:23][CH2:22][C@@H:21]3[NH:24][C@@:18]2([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:19][C@H:20]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:14]1.N(C(OCC)=O)=N[C:42](OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>O1CCCC1>[CH3:42][O:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:10])[F:11])=[CH:4][C:3]=1[C@H:13]1[CH2:17][O:16][C@:15]2([CH2:23][CH2:22][C@@H:21]3[NH:24][C@@:18]2([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:19][C@H:20]3[S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:14]1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@@]21C[C@@H](c2cc(OC(F)(F)F)ccc2O)CO1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1[C@H]1CO[C@]2(CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of (1R*,2R*,4S*,5S*,6R*)-2′,3′,4′,5′-tetrahydro-4′-(2-hydroxy-5-trifluoromethoxyphenyl)-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2′-furan] (Example 10; 60 mg, 0.11 mmol), diethyl azodicarboxylate (0.04 ml, 0.25 mmol), triphenylphosphine (68 mg, 0.26 mmol), methanol (0.2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature overnight then concentrated in vacuo and treated with methanol (2 ml) followed by 4M aqueous Na
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7]([NH2:11])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[BrH:14].BrBr>C(O)(=O)C>[NH2:11][C:7]1[C:6]([C:12]#[N:13])=[CH:5][C:4]([C:1](=[O:3])[CH2:2][Br:14])=[C:9]([CH3:10])[N:8]=1
Reactant: CC(=O)c1cc(C#N)c(N)nc1C
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1nc(N)c(C#N)cc1C(=O)CBr
Temperature: 45 °C
Reaction time: 5 h

Procedure:
2.7 g (15.4 mmol) of 5-acetyl-2-amino-3-cyano-6-methyl-pyridine are suspended in 110 ml of glacial acetic acid, and 1.9 ml (16.2 mmol) of 48% strength HBr are added. Then 5.2 g (32.4 mmol) of bromine are added, and the mixture is stirred at 45° C. for five hours. After cooling, the mixture is filtered with suction and the filter cake is stirred with NaHCO3 solution, filtered with suction and dried. Recrystallization from ethanol is used for purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11](C(O)=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.Cl>ClCCl.O1CCOCC1>[NH:11]1[CH2:10][CH2:9][CH:8]([N:5]2[CH2:4][CH2:3][S:2](=[O:1])(=[O:17])[CH2:7][CH2:6]2)[CH2:13][CH2:12]1
Reactant: O=C(O)N1CCC(N2CCS(=O)(=O)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S1(=O)CCN(C2CCNCC2)CC1
Reaction time: 18 h

Procedure:
0.786 g of tert-butyl ester of 4-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-piperidine-1-carboxylic acid is put in 5 ml of dichloromethane. 12.3 ml of 4M hydrochloric acid in dioxane is added at room temperature. The solution is stirred for 18 h and evaporated to dryness. The product thus obtained is returned to the basic state by means of tetraalkylammonium carbonate resin at a rate of 2 g per mmol. 0.555 g of 4-piperidin-4-yl-thiomorpholine 1,1-dioxide is obtained.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CO>[CH3:7][O:6][C:1](=[O:5])[CH:2]([CH3:4])[CH2:3][NH:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(C)C(=O)OC
Reactant: NCc1ccccc1
Solvent: CO
Product: COC(=O)C(C)CNCc1ccccc1
Yield: 76.4 %

Procedure:
Methyl methacrylate (64.2 ml, 60.07 g, 0.6 mole) was added slowly at 0° C. (ice bath) to benzylamine (54.6 ml, 53.6 g, 0.5 mole) in 200 ml of methanol. The reaction solution was heated to reflux overnight. After being cooled, the solution was concentrated under vacuum to remove the excess of methyl methacrylate and methanol. Unreacted benzylamine was removed by heating the residue in a Kugelrohr oven under vacuum to yield the crude 3-phenylmethylamino-2-methyl-propanoic acid methyl ester (79.2 g, 76.41%).
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Li]CCCC.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:39])=[CH:34][CH:33]=1>C1COCC1>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:38]([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[OH:39])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1cccnc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A suspension of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (214.5 mg, 0.495 mmol, Intermediate 3: step c) in dry THF (5 mL) was heated with a heat gun to form a solution. The solution was cooled in a dry ice-acetone bath for 2 minutes, then a solution of n-BuLi (2.5 M in hexanes, 0.18 mL, 0.45 mmol) was added dropwise by syringe. After 1 minute, a solution of (4-chlorophenyl)(pyridin-3-yl)methanone (0.117 mg, 0.541 mmol) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath that was allowed to warm to room temperature. The reaction was quenched with saturated ammonium chloride. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 50-100% EtOAc-hexanes) followed by reverse-phase chromatography (acetonitrile with 0.05% TFA in water). Product fractions were mixed with saturated aqueous sodium bicarbonate and DCM, the layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, and concentrated to provide the title compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([CH2:8][NH:9][C:10]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[S:34][C:10]([C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1ccc(C(=O)NCC(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)c1ccc(-c2ncc(-c3ccc(Cl)cc3)s2)cc1
Yield: 89 %

Procedure:
In the same manner as in Example 111, ethyl 4-[N-(4-chlorobenzoylmethyl)carbamoyl]benzoate was reacted with Lawesson's reagent to obtain ethyl 4-[5-(4-chlorophenyl)-2-thiazolyl]benzoate. The product was recrystallized from xylene-isopropyl ether. Yield: 89%. Pale yellow prisms. Melting point: 167 to 168° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:9]([N:12]=C=O)(=[O:11])=[O:10]>C1(C)C=CC=CC=1>[C:1]1([O:7][S:9](=[O:11])(=[O:10])[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccccc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
To a solution of 4.98 g of phenol in 9 ml of toluene, a solution of 7.49 g of chlorosulfonyl isocyanate in 5 ml of toluene was added dropwise at an inner temperature of 45° C. or lower. After the completion of dropwise addition, the mixture was heated in an oil bath at 110° C. and continuously stirred for 12 hours. The reaction solution was ice-cooled and the insoluble matter was removed by filtration, and then the filtrate was heated in an oil bath at 40° C. While stirring vigorously, 1.2 ml of water was slowly added dropwise. The reaction solution was ice-cooled and the deposited crystal was collected by filtration, washed with toluene and then dried under reduced pressure to obtain 6.46 g of the desired compound as a colorless crystal having a melting point of 78 to 80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:16][C:15]2[CH:17]=[C:18]([C:21]([F:23])([F:24])[F:22])[CH:19]=[CH:20][C:14]=2[O:13][CH3:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,5-dichlorophenyl isocyanate (0.94 g, 5.0 mmol) in toluene (10 ml) was added to a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.96 g, 5.0 mmol) in toluene (10 ml). The reaction was stirred at RT for 1 hour and the product filtered off. 1.20 (63%) of the title compound was isolated.