Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH2:23]Br>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[C:17]2[C:16](=[CH:21][CH:20]=1)[CH2:15][N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH3:13])=[CH:8][CH:7]=1)(=[O:10])=[O:11])[CH2:23]2
Reactant: Clc1ccc(CBr)c(CBr)c1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(Cl)cc3C2)cc1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
To a suspension of 60% sodium hydride (3.0 g, 0.125 mmol) in mineral oil in 80 ml of anhydrous DMF (100 ml) was dropwise added a solution of para-toluene sulphonamide (5.6 g, 32.60 mmol) in 30 ml of DMF over 1 hour with vigorous stirring at room temperature. After the addition, the mixture was stirred for 1 hour at room temperature and another 1 hour heating at 90° C. To this mixture was added dropwise a solution of 1,2-bis-bromomethyl-4-chloro-benzene (4 g, 14.18 mmol) in 20 ml of anhydrous DMF at 60° C. and then stirred overnight at room temperature. The resultant mixture was poured onto ice and the resulting precipitate was collected by filtration. The precipitate was washed with 1N hydrochloric acid, 5% sodium carbonate and brine then dried (MgSO4), filtered and evaporated to give 2.8 g of 5-Chloro-2-(toluene-4-sulphonyl)-2,3-dihydro-1H-isoindole as a pale yellow solid. MS: [M+H]+ 308.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CS[C:14](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:14]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: NCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Yield: 83.7 %

Procedure:
A solution of 4-nitrobenzylamine (5.24 g, 34.4 mmol) and S-methyl-N,N′-bis(tert-butoxycarbonyl)isothiourea (5.00 g, 17.2 mmol) in THF (60 ml) was stirred at 55° C. for 9 hours and at room temperature for 11 hours. The reaction mixture was concentrated under reduced pressure, was then mixed with ethyl acetate (150 ml) and was washed with 1 N hydrochloric acid (30 ml×3) and an aqueous saturated solution of sodium chloride (30 ml) in the order. The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, 150 g: ethyl acetate/hexane 1/9→1/6). The objective fractions were concentrated under reduced pressure, diisopropyl ether was added to the residue and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain N-(4-nitrobenzyl)-N′,N″-bis(tert-butoxycarbonyl)guanidine (5.67 g, 14.4 mmol, 83%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])[CH2:46][CH2:45]1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Yield: 8.7 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(2-methoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (6.1 mg, 8.7%) as light yellow oil. MS m/e=521.4 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][N:22]=[CH:21]1>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]1[N:20]([CH3:19])[CH:21]=[N:22][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1cncc1-c1cc2nc(Cl)ccc2n1Cc1ccccc1
Temperature: 110 °C
Reaction time: 7 h

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.10 g, 0.31 mmol, from Example 62, Step 2) and 1-methyl-5-(tributylstannyl)-1H-imidazole (0.12 g, 0.31 mmol, Aldrich) in toluene (6.0 mL) was degassed by a stream of nitrogen through the solution. Tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) was added and the mixture was stirred at 110° C. for 7 hours. Toluene was removed in vacuo, and the residue was dissolved in MeCN and filtered. Flash chromatography, eluting with a gradient from 0-70% EtOAc in hexanes afforded product as a white solid (35 mg, 35%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN([CH2:32][CH3:33])CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([N:24]1[CH2:23][CH2:22][N:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)[CH2:26][CH2:25]1)([O:3][CH2:4][C:33]1[CH:32]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2N2CCNCC2)CC1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 4-[2-(N-boc-piperidin-4-yloxy)-phenyl]-piperazine (1.5 g, 4.1 mol, 1.0 eq.) in DCM (20 mL) was added Et3N (0.8 mL, 5.74 mmol, 1.4 eq.), di-carbobenzoyloxy anhydride (1.4 g, 4.9 mmol, 1.2 eq.) and DMAP (25 mg, 0.2 mmol, 0.5 eq.). The mixture was stirred at r.t. overnight. The solution was diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound (2.03 g, 4.1 mmol, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][N:13]([C:14]([C:16]4[C:17]([CH3:21])=[N:18][O:19][CH:20]=4)=[O:15])[C:7]3([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:6][N:5]2[CH:30]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:31]1([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[O:10])[N:8]4[CH2:11][CH2:12][N:13]([C:14]([C:16]5[C:17]([CH3:21])=[N:18][O:19][CH:20]=5)=[O:15])[C:7]4([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:6][N:5]3[CH:30]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(C23Cn4cc(N)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(C23Cn4cc(NC5CCCCC5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1

Procedure:
To a solution of 7-amino-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]-pyrazin-5-one (33 mg, 0.081 mmol) in CH2Cl2 (0.5 mL) was added cyclohexanone (9 μL, 0.081 mmol), acetic acid (7 μL, 0.12 mmol) followed by sodium triacetoxyborohydride (26 mg, 0.12 mmol). After stirring the mixture for three further hours, cyclohexanone (20 μL, 0.18 mmol) was added followed by the addition of additional acetic acid (20 μL, 0.34 mmol). The mixture was quenched with a saturated aqueous solution of NaHCO3. Additional CH2Cl2 (3 mL) was added and the organic layer separated, the aqueous layer was further extracted with CH2Cl2 (3 mL). The organic layers were combined dried (Na2SO4), filtrated, concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, gradient 0-10% MeOH in EtOAc) and reverse phase chromatography (Biotage SP4, 12 g C18 cartridge; gradient ACN in water). The compound 7-(cyclohexylamino)-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (112) was isolated as a solid (1.6 mg, yield 1%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.[NH2:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([NH:15][C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:18][CH:17]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: FC(F)(F)COc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 2,4-dichloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazine (10 g, 40.3 mmol) in THF (100 mL) was added tert-butyl 4-aminobenzoate (7.79 g, 40.3 mmol) and Hunig's Base (7.04 mL, 40.3 mmol). The resulting mixture was stirred for 16 h. The precipitate was filtered and washed with Et2O, dried, then washed with water and dried to give the tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (10.6 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.[CH:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([CH3:23])[CH3:22].N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][C:4]3[C:5]4[C:10](=[N:9][CH:8]=[CH:7][N:6]=4)[N:1]=[CH:2][N:3]=3)=[CH:15][CH:16]=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)cc1
Reaction time: 20 h
Yield: 10.7 %

Procedure:
4-[2-(Pteridin-4-ylamino)-ethyl]-phenol (500 mg, 1.9 mmol), 4-isopropylphenylboronic acid (400 mg, 2.4 mmol), anh. Cu(OAc)2 (360 mg, 2.0 mmol) and powdered, freshly activated 4 Å molecular sieves (approximately 1 g) were combined in CH2Cl2 (15 mL), treated with pyridine (920 μL, 900 mg, 11.4 mmol) and sealed and stirred for 20 h with a moisture trap. The reaction was suction filtered and the filtrate shaken with dilute aqueous NH4OH. The organic phase was washed with H2O and brine and concentrated in vacuo. The residue was purified by preparative RP-HPLC using 80% MeCN/H2O to yield {2-[4-(4-isopropylphenoxy)-phenyl]-ethyl}-pteridin-4-yl-amine (78 mg, 11%) as a tan solid: mp 105-106.5° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[N:29]=[C:30]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:31](C(OC(C)(C)C)=O)[C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[N:29]=[C:30]([CH2:39][N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[NH:31][C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCOCC2)nc2nc(Cl)ccc21
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4[nH]c(CN5CCOCC5)nc4n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (300 mg, 0.96 mmol) and tert-butyl 5-chloro-2-(morpholin-4-ylmethyl)-1H-imidazo[4,5-b]pyridine-1-carboxylate (340 mg, 0.96 mmol) as starting materials.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:20]2[CH:41]=[CH:42][C:43]([Cl:45])=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([N:25]([C:1](=[O:3])[CH3:2])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=2)[C:20]2[CH:41]=[CH:42][C:43]([Cl:45])=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
Add acetyl chloride (0.3 mmol) followed by pyridine (0.3 mmol) to a solution of 5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.05 g, 0.1 mmol) in dichloromethane (1 mL). After stirring at room temperature for 24 h remove solvent under vacuum. Chromatograph the product over silica gel using ethyl acetate/hexane (10-40%) to elute. This affords the title compound (0.04 g, 71%) as an oil which foams under vacuum: MS (ES+): 563 (M−H).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([C:19]1[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]([O:32]C)=[O:31]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([C:19]1[CH:20]=[C:21]([Br:27])[C:22]([O:26][CH2:29][C:30]([OH:32])=[O:31])=[C:23]([Br:25])[CH:24]=1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=C(c1cc(Br)c(O)c(Br)c1)c1c(Cc2ccccc2)sc2ccccc12
Product: O=C(O)COc1c(Br)cc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1Br

Procedure:
This compound was prepared from (2-benzyl-benzo[b]thiophen-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone and methyl bromoacetate in substantially the same manner, as described in Example 20, and was obtained as an off-white solid, mp 162-163° C., MS m/e 558 (M)+; Analysis for: C24H16Br2O4S Calc'd: C, 51.45; H, 2.88 Found: C, 51.15; H, 2.71
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].B(Br)(Br)Br.O>ClCCl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Then, 21.60 g of 4-(4-propylphenyl)anisole was dissolved in 45 mL of dichloromethane, and the resultant solution was cooled with ice. Then, 35.79 g of boron tribromide was added to the solution at such a rate that the inside temperature did not exceed 10° C., followed by stirring at room temperature for 1 hour. Water was added to separate the mixture into layers, and an organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine and dried by adding sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to yield 15.91 g of 4-(4-propylphenyl)phenol.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:32]=[C:31]([C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH2:34])[N:30]=[CH:29][C:28]=3[N:41]=2)=[C:21]([F:42])[CH:20]=1>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:32]=[C:31]([C:33]4([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:1][CH2:34]4)[N:30]=[CH:29][C:28]=3[N:41]=2)=[C:21]([F:42])[CH:20]=1
Reactant: C=C(c1ccccc1)c1cc2sc(-c3ccc(C4OCCCO4)cc3F)nc2cn1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2cnc(C3(c4ccccc4)CC3)cc2s1
Reaction time: 4 h

Procedure:
To a clear solution of potassium tert-butoxide (0.201 g, 1.79 mmol) and trimethylsulfoxonium iodide (0.394 g, 1.79 mmol) in 5 mL DMSO was added a cloudy mixture of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylvinyl)thiazolo[4,5-c]pyridine (0.500 g, 1.19 mmol) in 20 mL THF rapidly. After 4 h, the reaction mixture was partitioned between EA and sat'd aq NH4Cl, and the organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting material was taken up in DCM and was filtered. The filtrate was collected and adsorbed onto 2 g silica gel and dried in vacuo. The resulting material was purified by silica gel chromatography, 40 g, 0-100% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylcyclopropyl)thiazolo[4,5-c]pyridine as a white solid. MS (ESI) m/z: calculated: 432.1; Observed: 433.0 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH2:15])[CH:4]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:15][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(-c2ccccc2)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2)c(NC(=O)C(C)(C)C)c1
Yield: 93 %

Procedure:
A magnetically stirred solution of 4-methoxybiphenyl-2-ylamine (25.27 g, 127 mmol) in CH2Cl2 (300 mL)/pyridine (300 mL) at 0° C. under nitrogen was treated with pivaloyl chloride via syringe (16.8 g, 17.2 mL, 139 mmol). The resultant suspension was stirred for 12 h at room temperature and concentrated in vacuo. The residue was digested with CH2Cl2 (300 mL), washed with 1 N HCl (2×300 mL), 1 N NaOH (2×300 mL), H2O (300 mL), brine (300 mL), dried (K2CO3), filtered, and concentrated in vacuo to give 33.6 g (93%) of a white solid: 1H NMR (300 MHz, CDCl3) δ 1.07 (s, 9H), 3.83 (s, 3H), 6.69 (dd, J=8.5, 2 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.29-7.47 (m, 5H), 7.53 (br s, 1H), 8.13 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=2[C:17](Cl)=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:26][NH2:27].NN>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=2[C:17]([NH:26][NH2:27])=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)Cl)cc1
Reactant: NN
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)NN)cc1
Temperature: -10 °C
Yield: 85 %

Procedure:
The crude 2-(4-tert-butyl-benzenesulfonylamino)-5-chlorobenzoyl chloride was dissolved in dichloromethane (300 mL) and transferred to an addition funnel. Hydrazine hydrate (212 mL, 4.35 mol), dissolved in 1.2 L dichloromethane in a 4 L Erlenmeyer flask, was cooled to −10° C. in a dry ice-acetone bath and the acyl chloride solution was added in a slow stream to the stirring hydrazine solution over a 15 minute period. The cold bath was subsequently removed following the addition and LCMS analysis at 15 minutes indicated the reaction was complete. The resultant reaction mixture was quenched with water (500 mL), resulting in a voluminous white precipitate that was collected by vacuum filtration. The precipitate was slurried in 800 mL ethyl acetate and acetic acid was added while stirring until a homogeneous solution was formed. The solution was transferred to a separatory funnel and extracted with 3×100 mL of water. The aqueous phases were discarded and the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to produce 4-tert-butyl-N-(4-chloro-2-hydrazinocarbonyl-phenyl)benzenesulfonamide (71 g) in an 85% yield: HPLC retention time=2.49 minutes; MS (ES) M+H expected 382.0, found 382.0.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].C1(S)C=CC=CC=1.[CH3:38][Si:39]([CH2:42][SH:43])([CH3:41])[CH3:40]>>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][S:43][CH2:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)CS
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Agent: Sc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CSC[Si](C)(C)C)C1=O

Procedure:
The title compound was prepared from (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) by a procedure similar to the one described in Example 300, Step A, replacing benzenethiol with the appropriate amount of (trimethylsilyl)methanethiol.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]1[C:9]2([CH2:12][N:11]([C:13]([C:15]3[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=4[F:29])=[C:19]([F:30])[C:18]([F:31])=[CH:17][CH:16]=3)=[O:14])[CH2:10]2)[O:8]1.[N-:32]=[N+:33]=[N-:34].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:32]([CH:7]([C:9]1([OH:8])[CH2:10][N:11]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:31])=[C:19]([F:30])[C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:14])[CH2:12]1)[CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC2(C1)OC2CC1OCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC(CC1OCCO1)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 22 h
Yield: 73.7 %

Procedure:
6-{[2-(1,3-Dioxolan-2-ylmethyl)-1-oxa-5-azaspiro[2.3]hex-5-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline (31 mg, 0.057 mmol) was dissolved in dimethylformamide (0.5 mL) and sodium azide (20 mg, 0.308 mmol) was added. The mixture was stirred at ambient for 22 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with water, brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 3-[1-azido-2-(1,3-dioxolan-2-yl)ethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (25 mg, 0.042 mmol, 74% yield): MS (EI) for C21H19F3IN5O4: 590 (MH+).