Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH:7]=[CH:8][C@H:9](O)[C@@H:4]2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:31][C:32]1[C:37]2[N:38]=[CH:39][NH:40][C:36]=2[C:35]([F:41])=[CH:34][N:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH:7]=[CH:8][C@@H:9]([N:40]3[C:36]4[C:35]([F:41])=[CH:34][N:33]=[C:32]([F:31])[C:37]=4[N:38]=[CH:39]3)[C@@H:4]2[O:3]1.[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH:7]=[CH:8][C@@H:9]([N:38]3[C:37]4[C:32]([F:31])=[N:33][CH:34]=[C:35]([F:41])[C:36]=4[N:40]=[CH:39]3)[C@@H:4]2[O:3]1
Reactant: Fc1ncc(F)c2[nH]cnc12
Reactant: CC1(C)O[C@H]2[C@@H](O)C=C[C@H]2O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(F)cnc(F)c43)C=C[C@H]2O1
Product: CC1(C)O[C@H]2[C@H](n3cnc4c(F)ncc(F)c43)C=C[C@H]2O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (1-1) (250 mg, 1.6 mmol, 1 equiv) was dissolved in dry THF (8 mL). Triphenylphosphine (630 mg, 2.4 mmol, 1.5 equiv) was added, followed by 4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-4, 300 mg, 1.9 mmol, 1.2 equiv). The mixture was cooled to 0° C. and DIAD (470 μL, 2.4 mmol, 1.5 equiv) was added dropwise. The resulting mixture was stirred at ambient temperature for 2 hours. The solvent was removed at reduced pressure and the yellow residue was purified via flash chromatography on a 80 g silica gel column (gradient elution 0 to 100% ethyl acetate in hexanes) to yield 1-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-1H-imidazo[4,5-c]pyridine (2-2) and 3-[(3aS,4R,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-4,7-difluoro-3H-imidazo[4,5-c]pyridine (2-1) as a 1:1 regioisomeric mixture. 1H NMR (2-2) (500 MHz, CDCl3): δ 7.82 (s, 1H); 7.86 (m, 1H); 6.42 (d, J=5.7 Hz, 1H); 6.05 (s, 1H); 5.75 (s, 1H); 5.44 (d, J=5.5 Hz, 1H); 4.68 (d, J=5.7 Hz, 1H); 1.51 (s, 3H); 1.37 (s, 3H). LRMS m/z (M+H) 294.0 found, 294.1 required. 1H NMR (2-1) (500 MHz, CDCl3): δ 7.90 (s, 1H); 7.84 (m, 1H); 6.42 (d, J=5.7 Hz, 1H); 6.05 (s, 1H); 5.75 (s, 1H); 5.44 (d, J=5.5 Hz, 1H); 4.68 (d, J=5.7 Hz, 1H); 1.51 (s, 3H); 1.37 (s, 3H). LRMS m/z (M+H) 294.0 found, 294.1 required.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([Mg]Br)[CH3:12].O>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH2:11][CH3:12])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CCC(O)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 15 g (73.9 mmol) 5-bromo-2-fluorobenzaldehyde in diethyl ether (100 ml) at 0° C. were slowly added 27.1 ml (81.3 mmol) of ethyl magnesium bromide (3 M solution in diethyl ether). After stirring at 0° C. for 3 h, water (20 ml) was carefully added upon which a white precipitate formed. The solid was filtered off and washed with tert-butylmethyl ether. The combined filtrates were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude title compound thus obtained (16.1 g, 93% of th.) was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.[C:26]1([Li])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.C1CCCCC1.C(OCC)C>[C:16]1([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:5]3[S:1][C:2]4[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=4[CH:4]=3)[OH:7])[CH2:9][CH2:10]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1cc2ccccc2s1)C1CCN(CCc2ccccc2)CC1
Reactant: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)(c1cc2ccccc2s1)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Dissolve [benzo[b]thiophene-2-yl][1-(2-phenylethyl)-4-piperidinyl]methanone (3.5 g, 10.01 mmol) in anhydrous tetrahydrofuran (100 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, phenyllithium (6 mL of a 2.0M solution in cyclohexane/ethyl ether, 12.0 mmol) and stir at -78° C. for 5 hours. Remove the ice bath and allow to warm to room temperature. Pour into saturated ammonium chloride (100 mL) and stir for 20 minutes. Separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, wash with water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (50% ethyl acetate/hexane) and recrystallize (isopropanol) to give the title compound as a white solid; mp 144°-146° C.
Reaction SMILES: [CH2:1]([N:3]([CH:11]([C:19]1[NH:20][C:21](=[O:37])[C:22]([OH:36])=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:26])[N:24]=1)[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][OH:16])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(C#N)(C)=O.C(Cl)Cl.O>[CH3:38][S:39]([O:37][C:21]1[C:22]([O:36][S:39]([CH3:38])(=[O:41])=[O:40])=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:26])[N:24]=[C:19]([CH:11]([N:3]([C:4]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:10])[CH2:1][CH3:2])[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][O:16][S:39]([CH3:38])(=[O:41])=[O:40])[N:20]=1)(=[O:41])=[O:40]
Reactant: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Agent: CC(=O)C#N
Solvent: O
Solvent: ClCCl
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](COS(C)(=O)=O)OC)c1nc(OS(C)(=O)=O)c(OS(C)(=O)=O)c(C(=O)NCc2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl ethyl[(4S)-1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)-5-hydroxy-4-methoxypentyl]carbamate (30 g, 57.4 mmol) in AcCN (500 mL) at 0° C. was added TEA (48 mL, 344 mmol) followed by a dropwise addition of a solution of MsCl (22.37 mL, 287 mmol) in DCM (15 mL). The resulting mixture was stirred at 0° C. for 30 minutes, then diluted with H2O (˜100 mL) and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was used in the next step without further purification. LC-MS: 757.5 (M+1).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:12][CH3:13])=[C:9]([CH3:11])[CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH:14](=O)[CH:15]([CH3:17])[CH3:16]>>[C:1]([C:6]1[NH:7][C:8]([CH2:12][CH3:13])=[C:9]([CH3:11])[C:10]=1[CH2:14][CH:15]([CH3:17])[CH3:16])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cc(C)c(CC)[nH]1
Reactant: CC(C)C=O
Product: CCOC(=O)c1[nH]c(CC)c(C)c1CC(C)C

Procedure:
The crude product, obtained in Example 68 but using 2-carbethoxy-4-methyl-5-ethylpyrrole and isobutyraldehyde, solidified at 0° C. after distillation (70° C. 1 × 10-4 mm). It was recrystallized twice from methanol, m.p. 53°-55° C. (12%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH2:38]([O:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:37]=[CH2:36]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)cc1O
Reactant: C=CCBr
Product: C=CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1C(=O)OCC

Procedure:
Prepared from ethyl 2-hydroxy-4-[N-(α-phenyl-2-piperidinobenzyl)-aminocarbonylmethyl]-benzoate, using allyl bromide.
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:10](=[O:12])[CH3:11])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.O1CCCC1.C1CNC(=O)C1.[Br:30][Br-]Br>CCOCC>[Br:30][CH2:11][C:10](=[O:12])[C:2]([OH:1])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(=O)C(O)(CN1CCCCC1)c1ccccc1
Agent: O=C1CCCN1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CBr)C(O)(CN1CCCCC1)c1ccccc1

Procedure:
2-Hydroxy-2-phenyl-1-piperidino-3-butanone (2.47 g, 10 mmole) is added to 50 mL of dry tetrahydrofuran (THF). The solution is stirred and a solution of pyrrolidone hydrotribromide (5 g, 10 mmole) in 100 mL of dry. THF is added dropwise over a period of 2 hours. After being refluxed for 4 hours, the reaction mixture is allowed to cool. Ether is added and the solution washed twice with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the product purified by flash column chromatography to give 4-bromo-2-hydroxy-2-phenyl 1-piperidino-3-butanone.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2CCO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.C(N)C>>[C:1]([C:5]1[N:6]=[C:7]([NH:22][CH2:23][CH3:24])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CCN
Agent: Cl
Product: CCNc1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and ethanamine hydrochloride and isolated as white solid (1.1 mg, 7%). MS (m/e): 345.3 (MH+).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][P:7]([OH:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3].[CH:11]([NH2:14])([CH3:13])[CH3:12]>O>[CH2:1]([NH:5][CH2:6][P:7]([OH:10])([OH:9])=[O:8])[C:2]([OH:4])=[O:3].[CH:11]([NH3+:14])([CH3:13])[CH3:12]
Reactant: CC(C)N
Agent: O=C(O)CNCP(=O)(O)O
Solvent: O
Product: CC(C)[NH3+]

Procedure:
Glyphosate acid (275.2 g technical grade, about 87.2% purity, commonly referred to as a “wet cake”) was suspended in 183.9 g of water. Isopropylamine (83.9 g, one (1) equivalent based on the gae of the glyphosate) was slowly added to this glyphosate suspension, while maintaining mixture below about 50° C. to provide a concentrated glyphosate isopropylammonium salt solution. Then 60 g of tallowamine ethoxylate (10 EO) was added to the glyphosate isopropylammonium salt solution. The resulting concentrate had a density of 1.207 g/ml, a pH of 4.58 and contained 480 gae/l glyphosate. The resulting concentrate was found to be a clear, homogeneous solution with a cloud point greater than about 55° C. The resulting concentrate was also stable when stored at −10° C. for 14 days, with no signs of crystallization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1)([O-:3])=[O:2].C=O.[BH3-][C:24]#N.[Na+].CC(O)=O>CC#N>[CH3:24][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][O:7][C:6]1[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: [BH3-]C#N
Reactant: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCCC1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6 mmol) was dissolved in CH3CN (20 ml) and formaldehyde (2.4 ml, 37% aqueous) was added. NaBH3CN (607 mg) was added, an exotherm was observed. The pH is monitored every 15 min and adjusted to ˜7 with AcOH. After 45 min, the mixture was concentrated in vacuo and the residue is dissolved in EtOAc, washed with 6N NaOH, 1N NaOH, and 2N HCl (3×). The acid washings were combined, adjusted to ˜pH 10 with solid Na2CO3 and extracted with EtOAc (2×). The EtOAc fractions were combined, dried with Na2SO4, and purified with flash chromatography (SiO2, 95:5:0.5 CH2Cl2:MeOH:NH4OH) to afford 1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([C:8]([CH2:16][CH2:17][CH3:18])([CH2:12][CH2:13][CH2:14][CH3:15])C(O)=O)[CH3:7].[N-:19]=[N+]=[N-].[Na+].[OH-].[Na+]>CCOCC.C(Cl)(Cl)Cl>[CH2:6]([C:8]([NH2:19])([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][CH3:15])[CH3:7]
Reactant: CCCCC(CC)(CCC)C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCCC(N)(CC)CCC
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Into a three-necked flask equipped with a mechanical stirrer and a condenser, were introduced 70 ml of chloroform, 18 ml of concentrated sulphuric acid (d = 1.83) and 11g (0.06 mol) of 2-ethyl-2-n-propylhexanoic acid prepared as described above. The mixture was heated to 50° C and while stirring 7.5 g of sodium azide in powder form were added. The operation of addition lasted 90 minutes after which the reaction mixture was heated to 50° C for 2 hours. The mixture was then neutralized with a 40% aqueous solution of sodium hydroxide previously cooled to 0° C. The amine was extracted with ether and the ethereal phase was washed with water and dried over magnesium sulphate. The ether was evaporated out under vacuum and the oil so obtained was taken up in dry ether, which provided 1-ethyl-1-n-propyl-n-pentylamine in free base form.
Reaction SMILES: C([O:8][C:9](=[O:33])[CH2:10][C@@H:11]([N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:17]1)[C:12]([NH:14][CH3:15])=[O:13])C1C=CC=CC=1>C(O)(=O)C>[CH3:15][NH:14][C:12](=[O:13])[C@H:11]([N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[CH:17]1)[CH2:10][C:9]([OH:33])=[O:8]
Reactant: CNC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Solvent: CC(=O)O
Product: CNC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Yield: 90 %

Procedure:
According to the procedure described in Example 7(a), N-methyl-3(R)-[3-[4-(pyndin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester was hydrogenolyzed in acetic acid to yield in 90% yield N-methyl-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow amorphous solid. 1HNMR (DMSO-d6): δ 8.58 (d, 2H, J=5.9 Hz), 7.75 (d, 2H, J=8.1 Hz), 7.71 (d, 2H, J=6.2 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.29 (s, 1H), 6.77 (t, 1H, J=2.2 Hz), 6.42 (t, 1H, J=2.2 Hz), 4.80 (d, 1H, J=10.7 Hz), 3.16 (dd, 1H, J=15.8, 11.0 Hz), 2.36 (s, 3H). Anal. Calculated for C20H19N3O3•1.0 H2O•0.33 AcOH: C, 64.08; H, 5.81; N, 10.85. Found: C, 64.23, 64.16; H, 5.66, 5.67; N, 10.83, 10.78.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=3[OH:26])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34](=O)([O-])[O-].[Cs+].[Cs+].ClCI>O1CCCC1>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=4[O:26][CH2:34]3)[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Agent: ClCI
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a mixture of 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one (10.6 g, 24.4 mmol) and cesium carbonate (23.8 g, 73.1 mmol) in tetrahydrofuran (100 mL) was added chloroiodomethane (6.35 g, 36.6 mmol) under nitrogen. The mixture was stirred at ambient temperature for 3 h, then filtered through a pad of silica and rinsed with tetrahydrofuran (500 mL). The filtrate was concentrated in vacuo to dryness. The residue was recrystallized from diethyl ether (20 mL) to afford 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (7.9 g, 72%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.41-7.27 (m, 10H), 7.15 (dd, J=7.1, 1.5 Hz, 1H), 7.07 (s, 1H), 7.05-6.92 (m, 2H), 6.55-6.49 (m, 2H), 6.34 (s, 1H), 4.86 (ABq, 2H), 3.80 (s, 3H), 2.01 (s, 3H); 13C NMR (75 MHz, CDCl3) δ178.1, 160.2, 159.2, 141.8, 137.8, 137.4, 132.9, 128.70, 128.66, 128.48, 128.46, 128.2, 128.0, 127.9, 124.2, 123.8, 123.1, 119.6, 112.2, 93.8, 80.4, 58.7, 57.7, 55.6, 16.1; MS (ES+) m/z 448.3 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:27]=[C:28]([O:32][CH3:33])[CH:29]=[CH:30][CH:31]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4ccccc4Cl)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12e and 3-bromoanisole
Reaction SMILES: CN(C)CCCN=C=NCC.[OH:12][CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][NH:19][CH2:20]2)[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])([OH:23])[CH2:15]1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C@H:40]([CH3:44])[C:41](O)=[O:42]>ClCCl.O.OC1C2N=NNC=2C=CC=1>[OH:12][CH2:13][CH:14]1[CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([C:41](=[O:42])[C@H:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[CH3:44])[CH2:20]2)[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])([OH:23])[CH2:15]1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: COc1ccccc1C1(O)CC(CO)CC2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1[C@H](C)C(=O)N1CC2CC(CO)CC(O)(c3ccccc3OC)C2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
2.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide are added to a solution of 2.77 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol, 1.80 g of (S)-2-(2-methoxyphenyl)propionic acid and 30 mg of hydroxybenzotriazole hydrate in 80 cm3 of dichloromethane. After stirring at 20° C. for 20 hours, the reaction mixture is washed with 40 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, height 40 cm) in a mixture of cyclohexane and ethyl acetate (30:70 by volume) and then in a mixture of ethyl acetate and methanol (90:10 by volume). Evaporation of the eluent and drying. I under reduced pressure (2.7 kPa) give 3.6 g of 6-hydroxymethyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol (mixture of the 2 diastereoisomers, 3aR,4R,6S,7aS,S and 3aS,4S,6R,7aR, S) in the form of a white solid. M.p.K =178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:16]([Cl:17])=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=2[Cl:18])=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:16]([Cl:17])=[CH:15][C:12]([CH2:13][Cl:21])=[CH:11][C:10]=2[Cl:18])=[CH:4][CH:3]=1
Reactant: OCc1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: ClCc1cc(Cl)c(Sc2ccc(Cl)cc2)c(Cl)c1
Yield: 100 %

Procedure:
4-(4-Chlorophenylthio)-3,5-dichlorobenzyl alcohol (1.28 g, 4.00 mmol) was added to stirred thionyl chloride (5.0 ml) at ambient temperature. The solution was refluxed 15 minutes, treated with dimethylformamide (1 drop), refluxed 15 minutes, treated with more dimethylformamide (1 drop), and refluxed 1 hour. Thionyl chloride was evaporated under a stream of nitrogen, hexane (5 ml) was added and evaporated under a stream of nitrogen, and the residue was dried under vacuum. Hexane (10 ml) was added, the mixture was filtered through anhydrous magnesium sulfate, and the magnesium sulfate was washed well with hexane. The combined filtrate and washes were evaporated under vacuum and dried at 35° C. under vacuum to provide 1.35 g (100%) of 4-(4-chlorophenylthio)-3,5-dichlorobenzyl chloride. The chloride was suspended in absolute ethanol (10 ml) and stirred at ambient temperature while sodium azide (720 mg, 11.1 mmol) was added. The mixture was refluxed 3 hours, kept 16 hours at - 20° C., and evaporated to dryness under vacuum at 30° C. The residue was treated with diethyl ether (50 ml), filtered, and washed with diethyl ether. The combined filtrate and washes were evaporated under vacuum and dried to provide 1.38 g (100%) of 4-(4-chlorophenylthio)-3,5-dichlorobenzyl azide as a colorless viscous oil; 60 MHz 'H NMR (CDCl3) 4.35 s (2H), 7.03 dm (J=8.5 Hz, 2H), 7.23 dm (J=8.5 Hz, 2H), 7.38 s (2H); IR (neat): 2110 cm-1.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([OH:22])=[CH:8][C:7]=1Cl.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([OH:22])=[CH:8][C:7]=1[O:3][CH2:2][CH2:1][OH:4]
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CN1CCCC1=O
Product: Nc1c(OCCO)cc(O)c2c1C(=O)c1ccccc1C2=O

Procedure:
47 parts of ethylene glycol, 13.7 parts of 1-amino-4-hydroxy-2-chloroanthraquinone, 24 parts of N-methylpyrrolidone, 1.2 parts of phenol and 6 parts of potassium carbonate are heated for 6 hours at 120°-125°C under nitrogen. After working up, 10.5 parts of 1-amino-2-(2'-hydroxyethoxy)-4-hydroxyanthraquinone are obtained.
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.Cl.CCN(CC)CC.[CH2:41]([S:43](Cl)(=[O:45])=[O:44])[CH3:42]>CO.C(Cl)Cl>[CH2:41]([S:43]([N:8]1[CH2:9][CH2:10][N:5]([CH2:4][C:3]2[C:2]([F:1])=[C:21]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH2:6][CH2:7]1)(=[O:45])=[O:44])[CH3:42]
Reactant: Cc1cc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)ccn1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCS(=O)(=O)N1CCN(Cc2cccc(NC(=O)Nc3ccnc(C)c3)c2F)CC1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate (600 mg, 1.35 mmol, 1.0 equiv) in MeOH (3 mL) was added HCl (4N in dioxane, 3 mL, 12 mmol, 8.9 equiv). After 1 h, the solvent was removed in vacuo. To this residue was added DCM (10 mL) and Et3N (875 μL, 6.28 mmol, 4.65 equiv), and the resulting solution was divided into two equal parts. To the resulting solution was added ethanesulfonyl chloride (90 μL, 0.95 mmol, 1.4 equiv) dropwise by syringe. After 30 min, the reaction was quenched by the addition of aq. satd. NaHCO3. The reaction was diluted with EtOAc, and washed twice with aq. satd. NaHCO3 and once with brine. The solution was then dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase preparative HPLC provided 1-(3-((4-(ethylsulfonyl)piperazin-1-yl)methyl)-2-fluorophenyl)-3-(2-methylpyridin-4-yl)urea (267 mg, 90%). LCMS m/z (APCI)=436.2 (M+H).