Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:21][C:20]([OH:22])([CH2:19][CH2:18][NH:17][C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1)[CH3:23]
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Reactant: CC(C)(O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(O)CCNc1ccc(C#Cc2ccccc2)nn1
Yield: 26.9 %

Procedure:
A solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (125 mg, 0.582 mmol) and 4-amino-2-methylbutan-2-ol hydrochloride (244 mg, 1.75 mmol, 3 equiv.) and triethylamine (206 mg, 284 ml, 2.04 mmol, 2 equiv.) in 1.25 ml of pyridine was heated 20 hours at 85° C. The solvent was removed in vaccuo. The residue was taken up in ethyl acetate/methanol, adsorbed onto 4 g of silica and purified on a 20 g flash chromatography column using a heptane/ethyl acetate 85:15 to 15:85 gradient to yield 44 mg (27% yield) of the title compound as a crystalline white solid, MS: m/e=282.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:7]=1.C(=O)([O-])O.[Na+].[Cl:35][CH2:36][CH2:37][C:38](Cl)=[O:39]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:38](=[O:39])[CH2:37][CH2:36][Cl:35])([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN(C(=O)CCCl)[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of [(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine (7.98 g, 16.5 mmol) in a mixture of chloroform (52 ml) and saturated sodium hydrogen carbonate solution (78 ml) was treated dropwise at 0° C. with 3-chloropropanoyl chloride (2.57 g, 19.8 mmol). The reaction mixture was left to warm to room temperature and vigorous stirring continued for 16 hours. For the workup, the layers were separated, the aqueous layer extracted with chloroform (100 ml), thereupon, the combined organic layers dried over sodium sulfate and evaporated at reduced pressure. After chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 60/10 as the eluent, besides recovery of 57% of the starting material, N-[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-3-chloro-N-(4-methoxy-benzyl)-propionamide (intermediate C9A) was obtained as a colourless viscous oil (2.08 g, 22% of theory). MS (ISP): m/z=536.2, 538.3 [M−Cl+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][C:8]23[CH2:22][CH:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=42)[C:14]2[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2]1.[CH2:23]=O.Cl>C(O)=O>[CH3:23][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][C:8]23[CH2:22][CH:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=42)[C:14]2[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2]1
Reactant: c1ccc2c(c1)C1CC2(CC2CNCCO2)c2ccccc21
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CCOC(CC23CC(c4ccccc42)c2ccccc23)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 9-(2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (200 mg), formic acid (600 mg) and 37% formalin (0.25 ml) was stirred at 80° C for 2 hours. 4N Hydrochloric acid was added to the cooled reaction mixture, and the reaction mixture was evaporated to dryness. The residue was diluted with water, basified with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(4-methyl-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 136° - 137° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([F:35])[CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[C:28]([F:35])[CH:27]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccc(Cl)cc1F
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(Cl)cc1F
Yield: 53.1 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-chloro-2-fluorophenylboronic acid (available from Combi-Blocks Inc.; 70 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-fluoro-biphenyl-2-carboxylic acid (0.6 mg, 0.3%). The same compound was also prepared using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode when 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 4-chloro-2-fluorophenylboronic acid (available from Combi-Blocks Inc.; 87 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-fluoro-biphenyl-2-carboxylic acid (63.6 mg, 53%). The second sample was characterized by 1H NMR: (300 MHz, DMSO-d6) δ 13.22 (br s, 1H), 8.50 (d, J=4.9 Hz, 2H), 8.26-8.37 (m, 2H), 8.09 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.37-7.60 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](I)[CH:10]=1)[C:5]([OH:7])=[O:6].B(O)(O)[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1.C(O)C.O>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>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cc(Br)cc(C(=O)O)c2)cc1
Temperature: 85 °C

Procedure:
A pressure vial was charged with 3-bromo-5-iodo-benzoic acid (7.60 g, 23.2 mmol), p-tolylboronic acid (3.16 g, 23.2 mmol), tetrakis(triphenylphosphine)palladium(0) (1.34 g, 1.16 mmol), cesium carbonate (8.33 g, 25.6 mmol), toluene (99.0 mL, 930 mmol), ethanol (27.1 mL, 465 mmol) and water (12.6 mL, 697 mmol) and the reaction stirred at 85° C. over nights. The reaction mixture was filtered over celite and the solvent removed to get the crude product as a brown solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8]CC)=O)[CH3:2].[OH-].[Na+].O.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[N:38]1([C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C1COCC1.CN(C=O)C>[CH2:12]([O:11][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([N:41]1[CH2:40][CH2:39][N:38]([C:44]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:45])[CH2:43][CH2:42]1)=[O:8])[CH3:13]
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(CC(=O)N1CCN(C(=O)OCc2ccccc2)CC1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
Part A: To a solution of ethyl 3,3-diethoxypropionate (90% tech.) (5.28 g, 25 mmol) in 50 mL of THF was added 1.00 N sodium hydroxide in water (25.00 mL, 25 mmol), and the resulting mixture was stirred at 25° C. for 18 h. The mixture then was concentrated under vacuum to afford a residual white solid. This solid was dissolved in 50 mL of DMF. To the solution was added EDCI (5.75 g, 30.0 mmol), 1-hydroxybenzotriazole (4.56 g, 33.8 mmol), and benzyl piperazine-1-carboxylate (5.51 g, 25.0 mmol), and the resulting mixture was stirred at 25° C. for 24 h. The reaction mixture was concentrated under vacuum, and the residue was diluted with water. The aqueous mixture was extracted with ethyl acetate, and the combined extracts were washed aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 10-40% ethyl acetate/chloroform) furnished 8.00 g (88%) of benzyl 4-(3,3-diethoxypropanoyl)piperazine-1-carboxylate as an oil; 1H NMR (500 MHz, CDCl3) δ 57.34 (m, 5H), 5.14 (s, 2H), 4.90 (t, 1H, J=5.5 Hz), 3.73-3.46 (m, 12H), 2.68 (d 2H, J=5.5 Hz), 1.19 (t, 6H, J=7.0 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: c1cc(C2CO2)ccn1
Reactant: CN1CCc2[nH]c3ccc(C(F)(F)F)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(C(F)(F)F)ccc3n2CC(O)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 3.937 mmol) in DMF (10 mL) was added sodium hydride (472 mg, 11.81 mmol) in portions at RT. After stirring at RT for 15 min, the suspension was allowed to cool to 0° C. and 4-(oxiran-2-yl)pyridine (762 mg, 6.299 mmol) was added dropwise into the reaction mixture, which was stirred at RT overnight. The reaction mixture was poured into ice-cooled water and extracted with EtOAc (3×50 mL). The organic layer was washed with water (2×50 mL), dried over anhydrous sodium sulfate and concentrated. The solid obtained was re-crystallized in DCM-diethyl ether to yield 2-(2-methyl-8-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.59 (d, 2H), 7.4 (s, 1H), 7.39 (d, 1H), 7.3 (d, 1H), 7.19 (d, 2H), 4.68 (m, 1H), 4.1 (m, 2H), 3.4 (dd, 2H), 2.82 (m, 1H), 2.74 (bs, 2H), 2.6 (m, 1H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers 6a and 6b.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Br[CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([O:9]CC)=O>C1COCC1.C(O)C>[C:13]1([CH2:12][CH:6]2[NH:4][CH2:1][CH2:2][NH:3][C:7]2=[O:9])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(Br)Cc1ccccc1
Reactant: NCCN
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1NCCNC1Cc1ccccc1

Procedure:
Ethylenediamine (25 g.) is added to a stirred solution of ethyl 2-bromo-3-phenylpropionate (XXVII, Example 61, 14.0 g.) in THF (100 ml.) and ethanol (300 ml.). After 20 hours at 20°-25° the solvents are removed under reduced pressure and the residual oil is partitioned between ethyl acetate-1N sodium hydroxide solution. The ethyl acetate extract is washed with water, saline, and concentrated. The residual oil is applied to a silica gel column which is eluted with chloroform-methanol (9/1). Fractions containing the product are pooled, concentrated to a residue and recrystallized from ethyl acetate-SSB to give 3-(phenylmethyl)piperazinone, m.p. 92°-93°.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[C:13]=2[CH2:20][CH3:21])=[CH:8][CH:7]=1>C(OCC)(=O)C>[CH2:20]([C:13]1[C:14]([CH2:18][C:1]#[N:2])=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[CH:10]=[CH:11][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)[CH3:21]
Reactant: CCc1c(CCl)cccc1-c1ccc(OC)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1c(CC#N)cccc1-c1ccc(OC)cc1
Reaction time: 3 h
Yield: 83 %

Procedure:
An aqueous solution (7 ml) of potassium cyanide (829 mg, 12.7 mmol) was added dropwise to a solution of 3′-(chloromethyl)-2′-ethyl-1,1′-biphenyl-4-yl methyl ether (3.32 g, 12.7 mmol) obtained in Example (90-4) in N,N-dimethyl sulfoxide (7 ml) at 80° C., and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=9/1-3/1) to give (2-ethyl-4′-methoxy-1,1′-biphenyl-3-yl)acetonitrile (2.65 g, yield: 83%).
Reaction SMILES: [C:1]1(/[C:7](/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26]Br)=[CH:20][CH:19]=2)=[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:28]>C(O)C>[C:1]1(/[C:7](/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH2:28])=[CH:20][CH:19]=2)=[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Solvent: CCO
Product: NCCOc1ccc(/C(=C(/CCO)c2ccccc2)c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
10.0 g of Z-1,2-diphenyl-1-[4-(bromoethoxy)phenyl]-1-buten-4-ol is added to200 ml of ethanol saturated with ammonia gas. The solution is stirred for 3hours at 90° C. in an autoclave. The solvent is evaporated and the residue is dissolved in ethyl acetate in the presence of 2M sodium hydroxide solution by warming the solution on a water bath. The organic layer is washed with water. The precipitated product is filtered off. The yield is 5.1 g (60%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[C:21]([C:25](O)=[O:26])[NH:22]2)=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:25]([C:21]2[NH:22][C:23]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[C:16]([Cl:15])[CH:24]=3)=[O:26])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc3ccc(Cl)cc3[nH]2)C1

Procedure:
68.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 6-chloro-1H-indole-2-carboxylic acid to give (R)-3-{[(6-chloro-1H-indole-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale yellow solid. MS376.1 ([M−H]−)
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].C[Mg]Cl.Cl[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[C:1]([N:5]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][N:7]=1)[C:17](=[O:18])[O:19][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1NC(C)(C)C
Reactant: COC(=O)Cl
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)N(c1ncccc1C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To N-(tert-butyl)-3-methylpyridin-2-amine (67) (16.78 g, 92% wt, 102 mmol) in THF (100 ml) was addition MeMgCl (44.3 mL, 3M, 133 mmol) in THF under −10° C. over 5 min. The reaction mixture was warmed up to room temperature and aged for 80 min, then cooled to −20 to −15° C. and methyl chloroformate (8.7 ml, 112 mol) was added over 10 min under −8° C. The reaction mixture was gradually warmed up and aged overnight at room temperature. The reaction mixture was quenched by addition of 15% aqueous citric acid (13 mL), water (40 mL) and MTBE (33 mL) at 0° C. The organic layer was separated and washed with water (50 mL), saturated NaHCO3/water (1:3, 50 ml), brine (50 mL) and water (50 mL), in turns. The organic layer was concentrated and flushed with THF to give 68 (19.3 g, 92%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:13]=1[O:14][CH:15]1[CH2:18][N:17](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16]1>C(Cl)Cl>[Cl:11][C:12]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:13]=1[O:14][CH:15]1[CH2:18][N:17]([C:1]([Cl:4])=[O:2])[CH2:16]1
Reactant: Cc1cccc(Cl)c1OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cccc(Cl)c1OC1CN(C(=O)Cl)C1
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
A mixture of 13.9 g (0.14 mole) of phosgene and 17.3 g (0.125 mole) of potassium carbonate in 140 mL of methylene chloride was stirred under nitrogen for 30 min then cooled in an ice water bath while 46.5 g (0.125 mole) of 3-(2-chloro-6-methylphenoxy)-1-(diphenylmethyl)azetidine in 140 mL of methylene chloride was added dropwise. After stirring for 16 h the excess phosgene was destroyed by adding small pieces of ice. Water was added to dissolve the inorganic material and the methylene chloride portion was separated, dried (filtered through Whatman PS paper) and concentrated in vacuo, 65.8 g. The oily residue was triturated with 300 mL of 30/60 pet ether and then with 300 mL of hexanes, both at ambient temperature. The remaining yellow residue was triturated with boiling hexanes and the hot solution decanted (4×200 mL). Upon cooling an orange oil separated which was removed from the hexanes solution by decanting. After decanting again, the hexanes solution was cooled in an ice bath and decanted to remove all traces of the impure orange oil. The volume of hexanes was reduced to 75 mL by heating under a stream of nitrogen. Upon cooling, crystalline product was obtained in 2 fractions (10.8 g and 5.5 g). Rework of the filtrate and the ambient temperature filtrates (300 mL of pet ether and 300 mL of hexanes) yielded an additional 6 g of product for a total yield 22.3 g crude (68.6%), mp 67°-69° . A sample was recrystallized for analysis from hexanes, mp 70°-71.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[N-:39]=[N+:40]=[N-:41].[Na+]>>[N:39]([CH2:2][CH2:3][CH2:4][S@:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Agent: [Na+]
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@](=O)(CCCN=[N+]=[N-])c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and sodium azide were converted to the title compound.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[C:3](=[O:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:20]1([N:23]2[CH2:28][C:27]3([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[O:26][CH2:25][C:24]2=[O:34])[CH2:22][CH2:21]1>CN(C)C=O.O.[Cl-].[Na+].O>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([N:31]2[CH2:32][CH2:33][C:27]3([O:26][CH2:25][C:24](=[O:34])[N:23]([CH:20]4[CH2:21][CH2:22]4)[CH2:28]3)[CH2:29][CH2:30]2)[C:3](=[O:5])[CH3:4])=[CH:7][CH:8]=1
Reactant: CC(=O)C(Br)c1ccc(Br)cc1
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C(c1ccc(Br)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-bromo-1-(4-bromophenyl)propan-2-one (0.225 mmol) in N,N-dimethylformamide (1 mL) was treated with potassium carbonate (0.676 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.237 mmol). The reaction mixture was stirred at room temperature overnight, at which point it was diluted with water (50 mL) and brine (20 mL). The aqueous mixture was extracted four times with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness in vacuo to afford the crude title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([O:8][CH:9](C)[CH3:10])=[O:7].[OH:33]S(O)(=O)=O.O>C(O)CO>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH2:10][OH:33])=[O:7]
Reactant: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: OCCO
Product: O=C(COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F)OCCO
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of isopropyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (II(d)) (0.63 g, 1.41 mmol, 1.0 eq) in ethylene glycol (30 mL) at room temperature was added H2SO4 (0.4 mL, 7.5 mmol, 5.3 eq) dropwise. The reaction mixture was stirred overnight at 10° C. then heated at 40° C. for 3 h. The reaction was then cooled to room temperature and poured into water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with 5% Na2CO3, water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 1:5 to 1:1) to give the title compound as an oil, which crystallised on standing to give a white solid (0.54 g, 85%).
Reaction SMILES: C(OO)(=O)C.O[C@@H:7]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:12]([O:13][C@@H:14]2[O:22][C@H:21]([CH2:23][OH:24])[C@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]2[OH:16])[C@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:29]([SH:31])[CH3:30].B(F)(F)F.CCOCC.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(Cl)Cl>[C@@H:14]1([O:13][C@@H:12]2[C@@H:25]([CH2:27][OH:28])[O:26][C@@H:7]([S:31][CH2:29][CH3:30])[C@H:8]([OH:9])[C@H:10]2[OH:11])[O:22][C@H:21]([CH2:23][OH:24])[C@H:19]([OH:20])[C@H:17]([OH:18])[C@H:15]1[OH:16]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Reactant: CCS
Agent: CC(=O)OO
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCS[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of β-lactose peracetate (50 g), ethanethiol (6.9 g, 822 ml) and 200 ml dry CH2Cl2 was added BF3 /Et2O (8.5 g, 7.3 ml) at RT. After 2 hours, TLC (toluene/ethyl acetate 2/3) showed no more reaction. The mixture was shaken with ca 500 ml 1M NaOH. The organic layer was directly evaporated and taken up in methanol (150 ml), then NaOMe in methanol (10 ml, 0.5M) was added and the mixture was stirred overnight at RT. The TLC (ethyl acetate/acetic acid/methanol/water 12/3/3/3) yields an Rf 0.41. The reaction mixture was neutralized with Dowex (50w×8, H+) filtered and concentrated The residue was recrystallized from ethanol (300 ml). Yield 16.4 g, 56%, mp 191°-192° C.