Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][CH3:31])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide (30 mg, 0.074 mmol) in DMF (3 mL) was added NaH (8.9 gm, 0.37 mmol) at rt. After 30 min, MeI (11.5 mg, 0.09 mmol) was added, and the reaction mixture was heated at rt for 2 h. After cooling to rt, the reaction mixture was quenched with MeOH, then poured into water (100 mL). The reaction mixture was extracted with EtOAc, washed with brine, and dried over Na2SO4. Concentration in vacuo followed by flash chromatography afforded the title product. LC-MS: 416 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 6.85 (d, 1H), 4.40 (d, 1H), 4.10 (m, 1H), 3.65 (m, 4H), 3.45 (m, 1H), 3.36 (s, 3H), 3.20 (m, 4H), 2.15 (m, 1H) 2.05 (m, 1H), 1.50–1.90 (m, 6H), 1.40 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40](NC2C=CN(C)N=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[C:55]([O:59][C:60]([N:62]1[CH:66]=[CH:65][C:64]([NH2:67])=[N:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56].CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[C:55]([O:59][C:60]([N:62]1[CH:66]=[CH:65][C:64]([NH:67][C:40](=[O:41])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)=[N:63]1)=[O:61])([CH3:58])([CH3:56])[CH3:57]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 99.3 %

Procedure:
Triphenylphosphine (1.61 g, 6.15 mmol) was dissolved in methylene chloride (60 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (1.24 g, 6.97 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 1.36 g, 4.1 mmol) was then added and it was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for another 30 min. The mixture was cooled to 0° C. and 3-amino-pyrazole-1-carboxylic acid tert-butyl ester (0.75 g, 4.1 mmol) was added followed by N-methyl-morpholine (540 μL, 4.92 mmol). The mixture was continued to stir at 0-4° C. for 4 h. The reaction was diluted with ethyl acetate (150 mL), washed with water (50 mL), aqueous 0.1 M hydrochloric acid (2×50 mL) and saturated aqueous brine solution (2×50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (Merck silica gel 60, 40-63 μm; 5% ethyl acetate/hexanes to 25% ethyl acetate/hexanes) afforded 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazole-1-carboxylic acid tert-butyl ester (2.02 g, 99%) as a light yellow oil: ESI-LRMS m/e calcd for C23H30ClN3O5S [M+] 495.2, found 496.4 [M+H+], 395.5 [M−CO2tBu+H+].
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.[C:14]([O-])(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].S([O-])(OC(C)(C)S(OC1C=CC(O)=CC=1)(=O)=O)(=O)=O.Cl>O>[C:14]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])(=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C[C@@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCC(=O)[O-]
Agent: CC(C)(OS(=O)(=O)[O-])S(=O)(=O)Oc1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(=O)N[C@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
D-alanine 1.78 g (0.02 mol) and triethylamine 2.8 ml (0.02 mol) were dissolved in 60 ml of water. Myristate of 4-hydroxyphenyldimethylsulfomethyl sulfate 9.52 g (0.02 mol) was added to the solution, and the mixture was stirred for 12 hours at room temperature. The solution reacted was adjusted to pH 2 or 3 with 1N-HCl and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and freed of solvent in vacuo. The oily residue obtained was purified by column chromatography (column: 2.5×15 cm) on 50 g of silica gel and N-myristoyl-D-alanine 3.6 g was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[F:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:24]=[CH:23]2.[F-].[K+].COCCOC.O.CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([S:12][C:4]1[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]2=[C:2]([C:19]2[C:18]([F:17])=[C:27]3[C:22]([CH:23]=[CH:24][C:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:26]3)=[CH:21][CH:20]=2)[N:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Sc1nc(Br)c2c(N)nccn12
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)(C)Sc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2F)c2c(N)nccn12

Procedure:
Into a 10 mL microwave vessel was added 1-bromo-3-tert-butylsulfanyl-imidazo[1,5-a]pyrazin-8-ylamine (23 mg, 0.000076 mol), 8-fluoro-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (0.032 g, 0.000092 mol), potassium fluoride (0.0089 g, 0.00015 mol), DME (2 mL, 0.02 mol), H2O (0.3 mL, 0.02 mol), DMF (0.34 mL, 0.0044 mol) and the reaction mixture was degassed 3×. Pd(PPh3)4 (0.02 g, 0.00002 mol) was then added to the reaction mixture and the vessel was sealed. The reaction mixture was microwaved on 300 watts, 100° C. for 30 min. Reaction mixture was concentrated in vacuo. Purification by Gilson HPLC eluting with 10→75% acetonitrile: H2O afforded the compound with pinacole impurity. The compound was then passed through a 2 g silica gel cartridge eluting with 6% EtOAc in hexanes followed by 4% MeOH in DCM to afford the pure compound as a yellow solid. 1H NMR (400 MHz, CD3OD-d4): δ=1.43 (s, 9H), 7.22 (d, J=5.05 Hz, 1H), 7.50-7.59 (m, 3H), 7.68-7.74 (m, 1H), 7.90-7.96 (m, 2H), 8.20 (d, J=8.59 Hz, 1H), 8.26 (d, J=7.83 Hz, 2H), 8.51 (dd, J=8.84, 1.26 Hz, 1H). MS(ES+):m/z 444.17 (100)[MH+]. HPLC: tR=3.24 min (Open Lynx polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH:11]([Cl:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:13][CH2:11][CH2:12][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1O
Reactant: CC(Cl)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccccc1OCCCl
Temperature: 25 °C
Yield: 34.9 %

Procedure:
To a solution of 2-methoxyphenol (14.4 g, 116 mmol) in 2-butanone (200 mL) was added bromochloroethane (69.0 g, 480 mmol) followed by the addition of potassium carbonate (40.0 g, 280 mmol). The reaction mixture was mechanically stirred and heated to reflux for 24 h, then cooled to room temperature. The solids were filtered off and the solvent was removed under vacuum. The residue was dissolved in diethyl ether and washed with 10% of NaOH, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel column chromatography (25% EtOAc/hexane) afforded 7.55 g (35%) of a solid: mp 36-38°C. (Lit.2 41-43° C,); 1H NMR (DMSO, 400 MHz), 3.75 (s, 3H), 3.91 (dd, 2H), 4.20 (dd, 2H), 6.86-6.99 (m, 4H); MS (EI) m/z 186 (M+).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].[Si:18]([O:25][CH2:26][CH:27]1[CH:31]([CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:30][C:29]([CH2:41]Br)=[CH:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Si:18]([O:25][CH2:26][CH:27]1[CH:31]([CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:30][C:29]([CH2:41][N:7]2[C:8]([S:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])=[CH:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Reactant: CCc1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2ccccc2)n(CC2=CC(CO[Si](C)(C)C(C)(C)C)C(CO[Si](C)(C)C(C)(C)C)C2)c(=O)[nH]c1=O

Procedure:
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione (0.16 g, 0.66 mmol) and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide (0.30 g, 0.66 mmol) in dimethylformamide (10 ml) were heated at 50° C. for overnight in the presence of sodium bicarbonate (66 mg, 0.79 mmol). After the concentration of dimethylformamide, 1-{[3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl}-5-ethyl-6-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF (10 ml) was reacted with n-tetrabutylammonium fluoride at room temperature for 1 hr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product (48 mg).
Reaction SMILES: [S:1](OCCOC1C=CC(C)=CC=1)(=[O:4])(=[O:3])[NH2:2].[CH3:16][C:17]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[CH2:18][OH:19].S(Cl)(=O)(=O)N.ClS(N=C=O)(=O)=O.C(N(CC)CC)C.O>C(#N)C>[S:1]([O:19][CH2:18][C:17]([CH3:16])([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20])(=[O:4])(=[O:3])[NH2:2]
Reactant: CC(C)(CO)Oc1ccccc1
Reactant: Cc1ccc(OCCOS(N)(=O)=O)cc1
Agent: NS(=O)(=O)Cl
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(COS(N)(=O)=O)Oc1ccccc1
Yield: 28 %

Procedure:
This compound was prepared by the procedure used to synthesize 2-(4-methylphenoxy)ethanol sulfamate in Example 33. Thus, 13.2 g (0.0794 mole) of 2-methyl-2-phenoxypropanol was reacted with sulfamoyl chloride prepared from 26.5 ml (0.298 mole) of chlorosulfonyl isocyanate (98%, Aldrich), 33.9 g (0.336 mole) of triethylamine, and 5.3 g (0.294 mole) of water in 250 ml of acetonitrile. The 12.4 g of a viscous, oily residue obtained was purified by high pressure liquid chromatography (Waters Associates Prep LC/System 500A; PrePAK 500® silica; methylene chloride), then by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride). Fractions containing title compound were combined and the solvent was evaporated under reduced pressure to give 5.4 g (28%) of a viscous oil.
Reaction SMILES: [I-].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([CH3:11])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].S(Cl)([Cl:15])(=O)=O>C(O)(=O)C>[Cl-:15].[Cl:15][CH2:3][C:2]([C:5]1[CH:10]=[CH:9][N+:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1cc[n+](C)cc1
Agent: [I-]
Solvent: CC(=O)O
Product: C[n+]1ccc(C(=O)CCl)cc1
Product: [Cl-]
Temperature: 25 °C

Procedure:
15.78 g 4-Acetyl-1-methylpyridinium iodide were suspended in 60 ml acetic acid and 15.0 g sulfuryl chloride were added. The mixture was stirred at ambient temperature for several hours and cooled to 0° C. The crystals were filtered, washed with acetic acid and dried.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][NH2:5].Cl.Cl.[OH-].[Na+].[C:13](=[O:16])(O)[OH:14].[CH:17]1[C:29]2[CH:28]([CH:30]3CC(=O)NC3=O)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>O>[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][NH:5][C:13]([O:14][CH2:30][CH:28]1[C:29]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:16]
Reactant: O=C1CC(C2c3ccccc3-c3ccccc32)C(=O)N1
Reactant: O=C(O)O
Reactant: NCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 1 h

Procedure:
Cupric sulphate (1.4 g, 5.5 mM) in (5.5 cm3) water was added to a stirred solution of H-Dab-OH.2HCl (2 g, 0.5 mM) and NaOH (0.8 g. 0.02 mM) in water (44 cm3), and the resulting mixture stirred for one hour. 9-Fluorenyl succinimide carbonate (3.2 g) was then added dropwise with vigorous stirring and the resulting mixture stirred at room temperature for three days. The precipitate resulting was filtered, washed with water and dried. Excess ethylene diamine tetraacetic acid disodium salt was then added to one liter of boiling water, and the suspension kept at boiling point for ten minutes. The product was filtered, washed with water and dried in high vacuo over phosphorus pentoxide, (3.4 g. 94%), m.p., 166° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[O:18]1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1.C(#N)C>O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:25]2[CH2:26][CH2:27][C:22]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:23][CH2:24]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A mixture of 10 g (0.057 mol) of p-fluorophenyl methyl sulfone, 8.72 g (0.063 mol) of K2CO3, 24.66 g (0.172 mol) of 1,4-dioxa-8-azaspiro[4.5]-decane and 50 ml of acetonitrile is stirred overnight at 90°-100° C. After cooling, the mixture is diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ethyl ether affords 13.11 g (77%) of title compound as a white solid: m.p. 192°-194° C.; IR (KBr) 1588, 1369, and 1290 cm-1 ; NMR (CDCl3) δ 7.74 (m, 2H), 6.96 (m, 2H), 4.02 (s, 4H), 3.54 (m, 4H), 3.03 (s, 3H), and 1.81 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (20.0 g, 102 mmol) in DMF (400 ml) at 0° C. was added NaH (60% mineral oil dispersion; 4.87 g, 122 mmol) slowly (CAUTION: GAS EVOLUTION). The reaction mixture was stirred at 0° C. for 2 h. Benzenesulfonyl chloride (17.0 ml, 132 mmol) was added dropwise, and the reaction mixture was allowed to warm to ambient. After 1 hour the reaction mixture was cooled in an ice bath, and 100 mL of water was added slowly (CAUTION: GAS EVOLUTION, EXOTHERM). The reaction mixture was partitioned between ethyl acetate (500 mL) and brine (600 mL). The organic layer was washed with additional brine (500 mL), followed by saturated aqueous ammonium chloride (250 mL). The first and 3rd aqueous layers were combined and back-extracted with ethyl acetate (500 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to a thick slurry. EtOAc (100 mL) was added, followed by hexanes (100 mL). The mixture was filtered, and the filter cake was rinsed with 1:1 EtOAc/Hexanes (50 mL) to afford 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as a grey solid. The filtrate can be concentrated and purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford additional product. LRMS (ESI) calculated for C13H9BrN2O2S [M+H]+, 337.0; found 336.9.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])[CH2:2]1.C1(S(O[CH2:32][CH2:33][CH2:34][C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][CH:36]=2)(=O)=O)C=CC=CC=1>CN(C)C=O.C(N(CC)CC)C>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([CH2:34][CH2:33][CH2:32][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[CH2:16][C:15]4[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=4)[C:9]3=[O:21])[CH2:2]2)=[CH:36]1
Reactant: O=S(=O)(OCCCc1c[nH]c2ccccc12)c1ccccc1
Reactant: COc1cc2c(cc1OC)C(=O)N(CC1CCCNC1)C2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(=O)N(CC1CCCN(CCCc3c[nH]c4ccccc34)C1)C2

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-5,6-dimethoxy-1-oxo-1,3-dihydro-isoindole and 3-(3-benzenesulphonyloxy-propyl)-indole in dimethylformamide and triethylamine analogously to Example 1.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[CH:6][CH:7]=1.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[CH3:17][C:16]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:20][N:19]=1
Reactant: CC(=O)NN
Reactant: Clc1ccc(-c2ccc(Cl)c(Cl)c2)nn1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc(Cl)c(Cl)c3)nn12

Procedure:
A mixture of 2.6 g. of 3-chloro-6-(3,4-dichlorophenyl)pyridazine and 1.8 g. of acetic acid hydrazide is heated in 50 ml. of n-butanol for 24 hrs. to give the product of the example.
Reaction SMILES: [CH2:1]=O.[CH:3](=[O:7])[CH:4]([CH3:6])[CH3:5].[CH2:8]([NH:15][CH:16]([CH3:18])[CH3:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:5][C:4]([CH3:1])([CH2:6][N:15]([CH:16]([CH3:18])[CH3:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]=[O:7]
Reactant: CC(C)C=O
Reactant: C=O
Reactant: CC(C)NCc1ccccc1
Product: CC(C)N(Cc1ccccc1)CC(C)(C)C=O

Procedure:
Under the same conditions as for the preparation of 2,2-dimethyl-3-(N-morpholino)propanal, 28.0 g (0.34 mol) of 36% aqueous formaldehyde were reacted with 25.4 g (0.35 mol) of isobutyraldehyde and 50.0 g (0.34 mol) of N-benzylisopropylamine, and worked up. The product distilled at a top temperature of 100° C. and a pressure of 4·10−2 mbar. Yield: 48.6 g (62% of theory) as a pale yellow, clear and almost odorless liquid which had an amine content of 4.28 mmol N/g.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([S:9][CH3:10])[S:8][C:4]=2[CH:3]=1.[Mn]([O-])(=O)(=O)=[O:14].[K+].[OH2:19]>C(O)(=O)C>[I:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([S:9]([CH3:10])(=[O:14])=[O:19])[S:8][C:4]=2[CH:3]=1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CSc1nc2ccc(I)cc2s1
Agent: [K+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1nc2ccc(I)cc2s1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
To a stirred, room temperature solution of 6-iodo-2-(methylthio)benzo[d]thiazole (Reference Example 6b, 1.22 g, 4.0 mmol) in acetic acid (100 mL) was added dropwise a solution of potassium permanganate (0.190 g, 1.2 mmol) in water (60 mL). The reaction mixture was stirred at room temperature for 68 hours, then quenched with aqueous sodium sulfite. The resulting mixture was vigorously stirred at room temperature overnight. The resulting precipitate was collected by filtration and rinsed with water. The solid was dissolved in ethyl acetate, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure to provide 6-iodo-2-(methylsulfonyl)benzo[d]thiazole. 1H NMR (300 MHz, CDCl3) δ ppm 3.41 (s, 3H), 7.93 (d, J=1 Hz, 2H), 8.38 (t, J=1 Hz, 1H); MS (DCI/NH3) m/z 340 (M+H)+, 357 (M+NH4)+.
Reaction SMILES: O.[CH3:2][N:3]1[C@H:13]2[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]4[O:22][C@H:7]5[C:8]([CH:10]=[CH:11][C@:12]2([OH:23])[C@:6]5([C:16]=34)[CH2:5][CH2:4]1)=[O:9].[H][H]>[Pd].C(O)(=O)C>[CH3:2][N:3]1[C@@H:13]2[CH2:14][C:15]3=[CH:20][CH:19]=[C:18]([OH:21])[C:17]4[O:22][C@H:7]5[C:8]([CH2:10][CH2:11][C@:12]2([OH:23])[C@:6]5([C:16]=43)[CH2:5][CH2:4]1)=[O:9]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@@H]1C5
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 30 °C

Procedure:
A hydrogenation vessel is charged with kg litre water and 0.73 kg acetic acid before adding 1 kg of 14-hydroxymorphinone prepared as in Example 1.1A and the mixture stirred until clear. 40 g of wet 10% Pd on carbon catalyst is added under a stream of nitrogen, and hydrogen supplied at 35-40 psi (2.41-2.76 bar). The temperature is maintained at 30±5° C. until hydrogen uptake stops, then the vessel is maintained at 35-40 psi (2.41-2.76 bar) and 30±5° C. for 3-4 hours. The reaction vessel is cooled to less than 25° C. and a sample subjected to HPLC to check for 14-hydroxymorphinone. If the 14-hydroxymorphinone area detected by HPLC is >0.1%, the hydrogenation is repeated.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][S:15][C:14]3=[O:19])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:20](=O)[CH2:21][CH2:22][CH3:23].N1CCCCC1>C(O)C>[CH:20](=[C:16]1[S:15][C:14](=[O:19])[N:13]([CH2:12][CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:17]1=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: O=C1CSC(=O)N1CCCc1cccc2nccn12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.51 g (5.5 mmol) of 3-[3-(imidazo[1,2-a]pyridin-5-yl)propyl]thiazolidine-2,4-dione and 0.50 ml (5.5 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.22 g (67.3%, light yellow oily substance) of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C(#N)C.O>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 80 °C
Yield: 118.2 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (10 g, 0.05 mol) in acetonitrile (150 mL) were added K2CO3(23 g, 0.16 mol) and 2-(chloromethyl) quinoline (14.2 g, 0.06 mol) under an inert atmosphere. The reaction mixture was then heated at 80° C. for 16 h, diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (19 g, 95%) as an oil.