Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([CH2:21][CH2:22][CH:23]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25](=O)[NH:24]4)[NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>>[CH3:1][N:2]([CH3:31])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[N:20]=[C:19]([CH2:21][CH2:22][CH:23]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25](=[S:41])[NH:24]4)[NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(C)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=O)N4)nc3c2)cc1
Product: CN(C)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCC4CCCCC(=S)N4)nc3c2)cc1
Yield: 63.6 %

Procedure:
The title compound is synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 85 mg of N,N-dimethyl-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide (compound B5) and 82 mg of Lawesson's reagent. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-5 vol. % ethanol) affords 56 mg of the title compound as a light yellow, waxy solid. ESI-MS: 458.3 (MH+). TLC: Rf=0.46 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: BrCS[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCSc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
51.3 g (300 mmol) of m-bromomethylthiobenzene was added dropwise to a dichloromethane (350 ml) solution containing 47.9 g (359.6 mmol) of aluminum chloride and 42.4 g (300 mmol) of benzoyl chloride which was cooled to 0° C. After addition, the resulting mixture was stirred for 2 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (35) as 58.1 g (189 mmol, yield of 63%) of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:20]([C:12]2[S:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:22])=[O:21])=[C:5]([NH:10][S:20]([C:12]2[S:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:21])=[O:22])[CH:4]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: COc1ccc(N)c(N)c1
Product: COc1ccc(NS(=O)(=O)c2cc3ccccc3s2)c(NS(=O)(=O)c2cc3ccccc3s2)c1

Procedure:
N,N′-(4-methoxy-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (472 mg) was prepared as in Example 31 using 4-methoxybenzene-1,2-diamine and benzothiophene-2-sulfonyl chloride as requisite starting materials.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:12]=[C:13]1[CH2:16][CH2:15][CH2:14]1>>[CH3:12][C:13]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: C=C1CCC1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Product: CC1(c2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred mixture of benzene (5.0 ml, 56 mmol) and Sulfuric acid (1.17 ml, 21.9 mmol) was cooled to 0° C. and treated dropwise with a solution of Methylenecyclobutane (1.00 ml, 10.8 mmol) in Benzene (3.0 ml, 34 mmol) over-1 h. Upon completion of the addition, the reaction mixture was stirred an additional 1 h while being warmed to RT. The mixture extracted with 15 ml of hexane. The organic phase was washed with 10 ml H2O and 10 ml sat NaHCO3, dried over Na2SO4, filtered and concentrated to yield a colorless liquid. The liquid was purified by kugelrohr distillation (5-10 torr) to yield the desired compound as a colourless liquid. First fraction was collected at 75-85° C. as a colorless liquid (330 mg) of product as a colorless liquid. 1-(1-methylcyclobutyl)-4-nitrobenzene
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:37])[C:18]([N:20]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]#[C:27][C:28]3[S:32][CH:31]=[N:30][CH:29]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:38][CH3:39].[OH-].[K+]>O1CCOCC1.O.Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:37])[C:18]([N:20]([C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]#[C:27][C:28]3[S:32][CH:31]=[N:30][CH:29]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:38][CH3:39]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCCOCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCOCC#Cc1cncs1)C(C)(C)C)CC2
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A solution of 293 mg of 8c in 3 ml of dioxane was mixed with a solution of 100 mg of KOH in 1 ml of water and stirred at 55° C. for 1 hr. After this period all ester had disappeared according to TLC. The reaction mixture was cooled, diluted with 10 ml of water and cold 0.5N HCl was added until pH 3. The product was extracted into ethyl acetate. The combined organic layers were once washed with water, dried and concentrated. The amorphous product 8d thus obtained was used without further purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C:49]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][Si:60]([C:73]([CH3:76])([CH3:75])[CH3:74])([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:57]=2)[CH:52]=[CH:51][CH:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:10])[C:11]([NH:48][C:49]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][Si:60]([C:73]([CH3:76])([CH3:75])[CH3:74])([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH:57]=2)[CH:52]=[CH:51][CH:50]=1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)[Si](Oc1ccc2cccc(N)c2c1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reaction time: 3 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)alanine (220 mg, 1.16 mmol) in dry CH2Cl2 (2 mL) under argon were added PYBOP (604 mg, 1.16 mmol), 1-amino-7-(tert-butyldiphenylsilyloxy)naphthalene hydrochloride, as described above in Step C, (250 mg, 0.58 mmol), and N,N-diisopropylethylamine (0.40 mL, 2.3 mmol). The reaction mixture was stirred for 3 hrs, then partitioned between CH2Cl2 (250 mL) and 10% aqueous citric acid (75 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with CH2Cl2-20% ethyl acetate to yield the desired product as a white foam.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:32][O:33][C:34]([C:36]1[NH:37][C:38](=[O:50])[NH:39][C:40]=1[CH2:41][S:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)=[O:35].[CH3:51][C:52]1[CH:61]=[C:60]([CH2:62]O)[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[N:53]=1>C1COCC1.CN(C=O)C>[CH3:32][O:33][C:34]([C:36]1[NH:37][C:38](=[O:50])[NH:39][C:40]=1[CH2:41][S:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH2:62][C:60]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[N:53]=[C:52]([CH3:51])[CH:61]=2)=[CH:45][CH:44]=1)=[O:35]
Reactant: COC(=O)c1[nH]c(=O)[nH]c1CSc1ccc(O)cc1
Reactant: Cc1cc(CO)c2ccccc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c(=O)[nH]c1CSc1ccc(OCc2cc(C)nc3ccccc23)cc1
Reaction time: 2 h
Yield: 8 %

Procedure:
To a solution of DEAD (81 mg, 0.46 mmol) in 3 mL of THF at 0° C. was added PPh3 (120 mg, 0.46 mmol). After dissolution of PPh3, 4d (100 mg, 0.31 mmol) was added and the solution was stirred for 15 min. (2-methyl-4-quinolinyl)methanol was then added as a solid. After stirring for 2 h, 3 mL of DMF was added to aid dissolution. The mixture was stirred at room temperature overnight before it was quenched with water. The solution was extracted with CH2Cl2 and the organic layer was dried over MgSO4. After filtration and concentration, the residue was purified by flash column chromatography to provide 5-[4-(2-methyl-quinolin-4-ylmethoxy)-phenylsulfanylmethyl]-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid methyl ester 4e (11 mg, 8%). MS (ESI+) (M+1)=436.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Li]CCCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cnc2ccccn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2ccccn12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 3-bromoimidazo[1,2-A]pyridine (0.10 g, 0.51 mmol) in THF (7.0 mL) under nitrogen atmosphere was cooled to −78° C. followed by dropwise addition of n-BuLi (1.30 M in hexane, 0.46 mL, 0.66 mmol). The resulting solution was stirred at same temperature for 45 min followed by addition of tributyltin chloride (0.14 mL, 0.53 mmol). The reaction mixture was then allowed to come to room temperature (45 min). After the completion of reaction (TLC monitoring), the reaction mixture was again cooled to −78° C. and quenched with dropwise addition of saturated NH4Cl solution. The reaction mixture was then extracted with EtOAc (2×25 ml). The combined organics was dried (Na2SO4), filtered and concentrated. The residue was used as such without further purification. MS: 409.10 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH:4]=[C:3]2[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][C@:2]12[C:8]([CH3:9])([CH3:10])[C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(C2=C[C@H]3CC[C@]2(C)C3(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(C2C[C@H]3CC[C@]2(C)C3(C)C)cc1

Procedure:
A mixture of Example 372B (100 mg) and 10% Pd/C (20 mg) in ethyl acetate (5 mL) and ethanol (5 mL) at room temperature was stirred under H2 for 18 hours, filtered, and concentrated to provide the desired product. MS (DCI(+)) m/e 245 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][Cl:20])=[O:17]>C(OCC)C>[C:16](=[O:17])([O:3][C@H:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:4])[O:18][CH2:19][Cl:20]
Reactant: O=C(Cl)OCCl
Reactant: CCOC(=O)[C@H](C)O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)[C@H](C)OC(=O)OCCl
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.1 %

Procedure:
To the mixture of ethyl (S)-lactate (23.6 g), pyridine (15.8 g) and diethyl ether (400 ml) was added dropwise a solution of chloromethyl chloroformate (25.6 g) in diethyl ether (100 ml) under ice cooling over the period of 40 minutes. After stirring at room temperature for 14 hours, the resulting solid was removed off by filtration. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (250 ml). The solution was washed with water (150 ml×2) and a saturated sodium chloride aqueous solution (150 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain chloromethyl [(1S)-1-(ethoxycarbonyl)ethyl] carbonate (38.5 g) as a colorless liquid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc2cc(Cl)c(Cl)cc2s1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5cc(Cl)c(Cl)cc5s4)cc3CC[C@@H]12
Yield: 30.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2,5,6-trichloro benzothiazole (110 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 54 mg (31%) of the title compound as an amorphous foam. FDMS: m/e=463.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]2=[O:11])[CH2:13][CH2:14][C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:21]3)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: BrCCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCc1ccccc1C2

Procedure:
A mixture of 6-bromo-indan-1-one (3.57 g, 17 mmol), 1-(2-bromo-ethyl)-2-bromomethyl-benzene (4.7 g, 17 mmol) in THF (50 mL) was added NaH (816 mg, 34 mmol) at room temperature, the mixture was refluxed for 2 hours. The mixture was quenched with water, concentrated, then extracted with DCM, washed with brine, dried over Na2SO4, concentrated to 6-bromo-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalen]-1(3H)-one (1.8 g, 33%).
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](O)=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>CN(C=O)C.CCOC(C)=O>[CH3:29][C:28]1[CH:27]=[CH:26][O:25][C:24]=1[C:22]([NH:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[CH:10]=[N:9][CH:8]=[C:7]([CH:12]=2)[C:5]([N:4]=[S:2]([CH3:1])([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][C:38]([N:68]3[CH2:73][CH2:72][O:71][CH2:70][CH2:69]3)=[O:39])=[CH:34][CH:35]=2)=[O:3])=[O:6])[CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: C1COCCN1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)N4CCOCC4)cc3)c2)c1
Reaction time: 0.33 h
Yield: 40.9 %

Procedure:
3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)phenyl]propanoic acid (0.050 g, 0.090 mmol) was dissolved in DMF (1 mL) then treated with BOP (0.051 g, 0.117 mmol) and TEA (0.050 mL, 0.360 mmol) and allowed to stir for 20 min. Morpholine (0.015 mL, 0.180 mmol) was then added and the reaction was allowed to stir for an additional 4 h. The resulting reaction mixture was dissolved in EtOAc (5 mL) and then extracted with brine (2×5 mL). The organic layer was then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude mixture was then purified via column chromatography (silica gel, gradient eluant mixture of MeOH in EtOAc: 0% to 0% MeOH) give the title compound (0.023 g, 41%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])[C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@H:20]3[C:26]([CH3:28])([CH3:27])[C@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
Trifluoroacetic acid (10 mL) was added slowly to a cooled (0° C.) solution of N′-(2-fluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜5.3 mmol) in dichloromethane (10 mL), and the resulting solution was stirred at 0° C. for 10 min and then at room temperature for 3.5 h. The solvent was evaporated and dichloromethane (80 mL) was added. The solution was washed with water (4×20 mL) and brine (20 mL), dried (magnesium sulfate), filtered, and evaporated to give an orange foam. This was triturated with 10% ethyl acetate/hexane (25 mL) and the mixture was cooled in an ice-bath at 0° C. for 1 h. The solid was filtered off and dried to give (4R,7S)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (890 mg, 58%) as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Cu][C:26]#[N:27].Cl>O>[C:26]([C:8]1[CH:7]=[C:6]([CH3:11])[C:5]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:24])#[N:27]
Reactant: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: N#C[Cu]
Agent: Cl
Solvent: O
Product: COc1ccc(S(=O)(=O)Nc2c(C)cc(C#N)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.7 %

Procedure:
To a solution of 4.0 g (10 mmol) of the product of Example 10 in 60 mL of pyridi was added 2.0 g (22 mmol) of copper (I) cyanide and the resulting mixture was refluxed for 48 h. The reaction mixture was then cooled to room temperature, poured over cold water, stirred for 16 h and then carefully acidified with concentrated HCl solution. The resulting solid was filtered and washed with water, dissolved in chloroform, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether, filtered and dried to provide 2.0 g (58%) of the desired product as a white solid. m.p. 175° C.; Electrospray Mass Spec 347 (M+H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[C:21]([CH3:56])=[CH:22][C:23]([CH3:55])=[C:24]([CH:54]=2)[C:25]([NH:27][CH2:28][C:29]2([CH2:33][NH:34][C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:32][O:31][CH2:30]2)=[O:26])[CH:17]=[C:16](Cl)[N:15]=1.Cl>CN(C)C=O>[NH2:13][C:14]1[N:15]=[C:16]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:17]=[C:18]([C:20]2[CH:54]=[C:24]([C:25](=[O:26])[NH:27][CH2:28][C:29]3([CH2:33][NH:34][C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:32][O:31][CH2:30]3)[C:23]([CH3:55])=[CH:22][C:21]=2[CH3:56])[N:19]=1
Reactant: O=C(O)CCS
Reactant: Cc1cc(C)c(-c2cc(Cl)nc(N)n2)cc1C(=O)NCC1(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)COC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cc(SCCC(=O)O)nc(N)n2)cc1C(=O)NCC1(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)COC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
3-Mercaptopropionic acid (84 μl, 0.937 mmol) and cesium carbonate (316 mg, 0.970 mmol) were added to an N,N-dimethylformamide (1.0 ml) solution of 5-(2-amino-6-chloropyrimidin-4-yl)-2,4-dimethyl-N-{3-[(tritylamino)methyl]oxetan-3-ylmethyl}benzamide (119 mg, 0.192 mmol) obtained in Step 2 above. The resulting mixture was stirred at 80° C. for 1.5 hour. The reaction solution was slightly acidified with 1N hydrochloric acid, and the precipitated solid was collected by filtration. The separated solid was washed with water, and then dried under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=15:1) to yield 3-{2-amino-6-[2,4-dimethyl-5-({3-[(tritylamino)methyl]oxetan-3-ylmethyl}carbamoyl)phenyl]pyrimidin-4-ylsulfanyl}propanoic acid (77 mg) as a white solid material.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:17][CH3:18])=[CH:5][CH:4]=1.N1C(C)=CC=CC=1C.[F:27][C:28]([F:41])([F:40])[S:29]([O:32]S(C(F)(F)F)(=O)=O)(=[O:31])=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]=2[O:32][S:29]([C:28]([F:41])([F:40])[F:27])(=[O:31])=[O:30])=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([O:17][CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(OC)c2nc3ccccc3cc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COc1ccc(OC)c2c(OS(=O)(=O)C(F)(F)F)c3ccccc3nc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 1,4-dimethoxyacridine (prepared as described in Ionescu and Mester (1969)) (1.0 g, 3.9 mmol) in dry CH2Cl2 (18 ml) under N2 were successively added DMAP (95 mg, 0.8 mmol), 2,6-lutidine (0.6 ml, 55 mmol) and trifluoromethane-sulfonic anhydride (0.8 ml, 4.7 mmol) and the reaction mixture was stirred at 0° C. for 2 h and then for 1 h at rt. The solution was washed with H2O, dried and evaporated. The residue was purified by column chromatography when elution with hexane/CH2Cl2 (1:1) to give the title compound (1.3 g, 87%), as a yellow solid. IR (KBr): ν/cm−1=1253 (s, SO), 1030 (s, SO); 1H NMR (200 MHz, CDCl3): δH/ppm=4.04 (s, 3H, OCH3), 4.14 (s, 3H, OCH3), 6.83 (d, J=8.4 Hz, 1H, H-2), 7.01 (d, J=8.4 Hz, 1H, H-3), 7.68 (dd, J=8.5 and 7.8 Hz, 1H, H-7), 7.86 (dd, J=8.5 and 7.8 Hz, 1H, H-6), 8.22 (d, J=8.5 Hz, 1H, H-5), 8.43 (d, J=8.5 Hz, 1H, H-8); 13C NMR (50.3 MHz, CDCl3): δC/ppm=55.2 (q, OCH3) 56.3 (q, OCH3), 104.2 (d, C-2), 106.6 (d, C-3), 113.3 (s, C-9a), 118.5 (q, CF3), 119.1 (s, C-8a), 120.7 (d, C-7), 122.5 (s, C-4a), 127.6 (d, C-6), 129.8 (d, C-8), 130.9 (d, C-5), 144.2 (s, C-10a), 147.2 (s, C-1), 148.7 (s, C-4), 148.8 (s, C-9); MS (EI); m/z (%)=388 [M+1] (9), 387 [M+] (42), 254 (100), 226 (69); HRMS: calcd. for C16H12F3NO5S 387.0388; found 387.0394.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:14][Mg+].[Br-]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:13])([CH3:12])[CH:10]([OH:11])[CH3:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C=O)c1ccc(Cl)c(Cl)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)C(C)(C)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution of 2-(3,4-dichlorophenyl)-2-methylpropanal (47.13 g, 0.217 mol) in Et2O (223 mL) at 0° C. was added a 3.0M solution of MeMgBr (217 mL, 0.651 mol) in Et2O. After stirring 2 h at 0° C., the reaction mixture was warmed to room temperature over 1 h. Then the reaction mixture was cooled to 0° C., quenched with H2O (100 mL) and 3N HCl (200 mL), extracted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford the crude product, which was purified by column chromatography to yield 3-(3,4-dichlorophenyl)-3-methylbutan-2-ol (45.9 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 1H), 7.37 (d, 1H), 7.21 (dd, 1H), 3.83 (m, 1H), 1.31 (s, 3H), 1.29 (s, 3H), 1.05 (d, 3H).