Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11]([N:13]1[C@@H:25]([C:26]([NH:28][CH3:29])=[O:27])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14]1)=[O:12].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH:2]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11]([N:13]1[C@@H:25]([C:26]([NH:28][CH3:29])=[O:27])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14]1)=[O:12])=[O:1]
Reactant: CNC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)c1occc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CNC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)c1occc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of product (6-A) (2.2 g, 5.56 mmol) in acetone (20 ml) was added TsOH (191 mg, 1.11 mmol), and the solution was stirred at ambient temperature for 3 h. The reaction was quenched by saturated NaHCO3 (20 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated and purified by CC (DCM:MeOH=300:1 to 100:1) to give product (7-A) (1.8 g, 92%) as a brown solid. LC-MS (M+H)+=352.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:24]([Sn](CCCC)(CCCC)C#CC)[CH2:25][CH2:26]C.C(OCC)(=O)C.CCCCCC>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]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:24]#[C:25][CH3:26])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1oc2cccc(OS(=O)(=O)C(F)(F)F)c2c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC#Cc1cccc2oc(C(=O)OCC)c(C)c12
Yield: 14 %

Procedure:
To 3-methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid ethyl ester (550 mg, 1.6 mmol, 1 eq), the product of Example 20, Step 1, in 5 mL of toluene under nitrogen was added 60 mg of Pd(PPh3)4 (0.05 mmol, 0.03 eq) and tributyl-prop-1-ynyl-stannane (0.55 mL, 1.8 mmol, 1.13 eq). The resulting reaction mixture was heated to reflux for 18 h. After work up and column chromatography (3% ethyl acetate/hexane), 3-methyl-4-prop-1-ynyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 14% yield (56 mg). 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (t, J=7.1 Hz, 3 H) 2.1 (s, 3 H) 2.8 (s, 3 H) 4.5 (q, J=7.1 Hz, 2 H) 7.3 (m, 2 H) 7.5 (dd, J=7.6, 1.8 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.C(O)(=O)C.[NH3:21]>>[Cl:11][C:9]1[CH:10]=[C:2]([NH2:21])[C:3](=[CH:7][C:8]=1[S:12]([CH3:15])(=[O:14])=[O:13])[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Reactant: N
Agent: Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cc(C(=O)O)c(N)cc1Cl
Temperature: 0 °C
Yield: 64 %

Procedure:
A solution of 2,4-dichloro-5-methylsulfonylbenzoic acid (Example 1, Step B) (60 g.; 0.267 mole) in aqueous ammonia (28%, 900 ml.) is heated in an autoclave at 180° C. for 12 hours. The cooled reaction mixture is poured into ice (3 kg.) and concentrated hydrochloric acid (1.3 liters) which causes the product to precipitate 42 g. (64% yield) of 4-chloro-5-methylsulfonylanthranilic acid, m.p. 286.5°-288.5° C. after recrystallization from acetic acid.
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.NC1C=CC=CC=1.CC(C)([O-])C.[Na+].Br[CH2:42][CH2:43][F:44]>CN(C=O)C.O>[O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:42][CH2:43][F:44])[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1
Reactant: FCCBr
Reactant: Fc1ccc(Nc2cc(Nc3ccc(OCC4CO4)cc3)ncn2)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: FCCN(c1cc(Nc2ccc(OCC3CO3)cc2)ncn1)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a solution of 4-[4-(2,3-epoxypropoxy)anilino]-6-(2,4-difluoroanilino)pyrimidine (prepared by an analogous procedure to Reference Examples 9 and using the appropriate aniline) (1.4 g) in DMF (11 ml) at 0° C. was added sodium tert-butoxide (580 mg) and the mixture stirred for 10 minutes. To a portion of this solution (2.2 ml) was added 1-bromo-2-fluoroethane (0.11 ml) and the reaction stirred for 1 hour. The solution was then poured into water and extracted with EtOAc. The organic extract was dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with DCM:MeOH; 125:2 to give the product (237 mg, 75%) as a colourless oil. NMR: 2.65 (2H, m), 2.81 (2H, m), 3.79 (1H, dd), 4.01-4.18 (2H, m), 4.51 (2H, t), 4.67 (2H, t), 5.40 (1H, s), 6.82 (2H, d), 7.21 (1H, m), 7.30-7.59 (4H, m), 8.20 (1H, s), 8.84 (1H, s).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:44])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:39][CH2:40][O:41][CH2:42][CH2:43]5)[CH2:33]4)=[O:44])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.9 %

Procedure:
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((1R,3S)-3-(morpholinomethyl)cyclopentylcarbamoyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 20, 0.22 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.05 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as an eluent to furnish the title compound (0.14 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.88-0.96 (m, 9H); 1.25-1.39 (m, 11H); 1.43-1.88 (m, 24H) 2.21-2.47 (m, 8H); 2.86-3.10 (m, 3H); 3.15-3.72 (m, 7H); 4.60 (s, 1H); 4.74 (s, 1H); ES Mass: 622 (100%), [M+Na] 645; HPLC: 98.6%.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:3].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.N1C2C(=CC=CC=2)CC=1.C([Al](Cl)Cl)C>ClCCCl>[CH3:1][C:2]1[CH2:3][CH:12]2[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]2[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]=1
Reactant: C=C(C)C1CCCCC1=O
Reactant: c1ccc2[nH]ccc2c1
Agent: C/C1=C\CCCCC(=O)N2c3ccccc3CC2C1
Agent: C1=Nc2ccccc2C1
Agent: CC[Al](Cl)Cl
Solvent: ClCCCl
Product: CC1=CCCCCC(=O)N2c3ccccc3CC2C1

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cyclohexanone (0.88 g, 6.38 mmol), 1H-indole (0.90 g, 7.65 mmol) which was in situ isomerized to 3H-indole, and EtAlCl2 (0.81 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a white solid (1.25 g, 77% yield).
Reaction SMILES: [C:1]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:21])[C:2]1[C:3](=[CH:7][C:8](=[C:12]([CH:20]=1)[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[C:9]([O-:11])=[O:10])[C:4]([O-:6])=[O:5].S(Cl)([Cl:29])=O>CN1C(=O)CCC1>[Cl-:29].[Cl-:29].[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[C:12]1[C:8](=[CH:7][C:3](=[C:2]([CH:20]=1)[C:1]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[C:4]([O-:6])=[O:5])[C:9]([O-:11])=[O:10]
Reactant: O=S(Cl)Cl
Agent: CCCCOC(=O)c1cc(C(=O)OCCCC)c(C(=O)[O-])cc1C(=O)[O-]
Solvent: CN1CCCC1=O
Product: [Cl-]
Temperature: 0 °C

Procedure:
Next, the NMP solution (θ) of di-n-butyl pyromellitate was added to the NMP solution (η) of di-n-butyl 3,3′,4,4′-diphenylether-tetracarboxylate, and the flask containing them was cooled to 0° C., to which was dropwise added 20.56 g (0.173 mols) of thionyl chloride, and reacted therewith for 1 hour to obtain a mixed solution (ι) of di-n-butyl 3,3′,4,4′-diphenylether-tetracarboxylate dichloride and di-n-butyl pyromellitate dichloride.
Reaction SMILES: [C:1]([C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:8][C:3]1([C:1]#[C:2][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:20]/[C:21]2[NH:22][CH:23]=[CH:24][C:25]=2[O:26][CH3:27])/[C:13](=[O:19])[NH:14]3)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C#CC1(O)CCCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC3(O)CCCC3)c21

Procedure:
Using Method D above, 1-ethynyl-cyclopentanol (86.3 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.31 mmol) (Starting Material 1 above) using DPPFPdCl2 (12.6 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 2 days to yield (Z)-1,3-dihydro-4-[(1-hydroxycyclopentyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 43 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([OH:30])[CH:29]=1>>[ClH:1].[Cl:31][C:27]1[C:26]([Cl:32])=[CH:25][C:24]([NH:23][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:29][C:28]=1[OH:30]
Reactant: Nc1cc(O)c(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Agent: Cl
Product: Oc1cc(Nc2ncnc3sc4c(c23)CCNC4)cc(Cl)c1Cl

Procedure:
The title compound was prepared in analogy to Example 65A from tert-butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (300 mg, 0.92 mmol) and 5-amino-2,3-dichlorophenol hydrochloride from Example 68A (296 mg, 1.38 mmol) to yield 395 mg (99%).
Reaction SMILES: [CH2:1]([CH:5]1[N:9]=[CH:8][C:7](Cl)([CH2:10][C:11]([O:13]C)=[O:12])[N:6]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4].C(C1N=CC([Cl:39])(CC(O)=O)N1CC1C=CC([N+]([O-])=O)=CC=1)CCC>>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[C:8]([Cl:39])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1N=CC(Cl)(CC(=O)O)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCC1N=CC(Cl)(CC(=O)OC)N1Cc1ccc([N+](=O)[O-])cc1
Product: CCCCc1nc(Cl)c(CC(=O)O)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
Methyl 2-butyl-5-chloro-1-(4-nitrobenzyl)-imidazole-5-acetate was also prepared by the procedure described in Example 2Part B from 2-butyl-5-chloro-1-(4-nitrobenzyl)imidazole-5-acetic acid. NMR (200 MHz, CDCl3) δ 8.23 (d, 2H, J=10Hz); 7.20 (d, 2H, J=10Hz); 5.21 (s, 2H); 3.75 (s, 3H); 3.67 (s, 2H); 2.58 (t of t, 2H, J=7Hz); 1.32 (q of t, 2, J=7Hz); 0.86 (t, 3H, J=7Hz). Mass Calcd. for C17H20ClN3O4 ; 365.1142. Found 365.1132.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[C:17]2[NH:16][C:15]([CH3:18])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[CH2:19]([O:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[CH3:20]>O>[Cl:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][C:25]4[CH:35]=[CH:36][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=4)=[CH:28][CH:29]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOc1ccc(Oc2ccc(CCl)cc2)cc1
Reactant: Cc1nc2cccc(Cl)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Oc2ccc(Cn3c(C)nc4c(Cl)cccc43)cc2)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a mixture of anhydrous N,N-dimethylforamide (10 ml) and sodium hydride (62% oil suspension; 0.071 g), 4-chloro-2-methylbenzimidazole (0.304 g) was added while stirring, and the stirring was continued at room temperature for 1 hour. The resultant mixture was cooled to 5°-10° C., and a solution of 4-(4-ethoxyphenoxy)benzyl chloride (0.400 g) in anhydrous N,N-dimethylformaide (10 ml) was dropwise added thereto in 30 minutes, followed by stirring at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water (100 ml) and extracted with toluene (30 ml) two times. The toluene extract was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 4-chloro-1-[4-(4-ethoxyphenoxy)benzyl]-2-methylbenzimidazole (0.204 g) as a colorless liquid. nD26.5 1.6087.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].C(=O)=O.CC(C)=O.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[C:17](=[O:18])[CH2:16][Br:15])[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: O=C(Br)CBr
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: C=CCN(CC=C)C(=O)CBr
Temperature: 25 °C

Procedure:
A 78-g (0.8 mol) sample of diallylamine was added dropwise to a stirred and cooled (dry-ice/acetone bath) solution of 80 g (0.4 mol) bromoacetylbromide in 200 ml methylene dichloride. The reaction mixture was allowed to warm to about 25° C. and stirred overnight. The reaction mixture was then washed with water, aqueous sodium bicarbonate, again with water, dried over magnesium sulfate and evaporated under reduced pressure to give 38 g N,N-diallyl-α-bromoacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[CH2:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][Cl:22])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(C)(CCCl)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CCCl)C(=O)CSc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
86.7 g (0.6 mole) of 4-chlorothiophenol and 82.8 g (0.6 mole) of potassium carbonate in 500 ml of toluene are heated under reflux for 2 hours, using a water separator. 91.5 g (0.5 mole) of 1,5-dichloro-3,3-dimethyl-2-pentanone in 200 ml of toluene are then added at 100° C. The reaction mixture is stirred at 100° C. for 5 hours and is then allowed to cool, and is stirred with 500 ml of water. The organic phase is separated off, washed with dilute sodium hydroxide solution and with water, dried over sodium sulphate and concentrated. 137.4 g (94.4% of theory) of 1-(4-chlorophenylthio)-5-chloro-3,3-dimethyl-2-pentanone of refractive index nD20 1.5628 are obtained. ##STR95##
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][Zn+])([CH3:5])([CH3:4])[CH3:3].Br[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[N:16][CH:17]=1.O>C1COCC1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:18][C:15]1[N:16]=[CH:17][C:12]([CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[CH:13][CH:14]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(F)nc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
(2-tert-Butoxy-2-oxoethyl)zinc(II) chloride (0.5M in ethyl ether) (Rieke Metals, Inc., Lincoln, Nebr.; 73.9 mL, 36.9 mmol) was added to a mixture of 5-bromo-2-fluoropyridine (Acros, Morris Plains, N.J.; 2.92 mL, 28.4 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.; 0.201 g, 0.284 mmol) in THF (150 mL) and the resulting yellow solution was stirred at 65° C. for 1.5 h in a flask fitted with an air-cooled reflux condenser. Water (200 μL) was added to the reaction, and the resulting mixture was concentrated onto silica gel and chromatographically purified (silica gel, 0 to 30% EtOAc/hexanes) to provide tert-butyl 2-(6-fluoropyridin-3-yl)acetate (2.43 g, 11.50 mmol, 40.5% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.74 (td, J=8.0, 2.5 Hz, 1H), 6.90 (dd, J=8.4, 2.9 Hz, 1H), 3.52 (s, 2H), 1.44 (s, 9H). m/z (ESI, +ve) 212.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[N:4][CH:3]=1.Cl[CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1.CC(C)([O-])C.[K+].O1CCOCC1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([CH:14]=1)[C:8](/[N:7]=[C:5]1\[S:6][C:2]([Cl:1])=[CH:3][N:4]\1[CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1)=[O:18]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(Cl)s1
Reactant: ClCc1cscn1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(Cl)cn1Cc1cscn1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of Example 83A (1001 mg, 3.33 mmol), commercially available 4-(chloromethyl)thiazole (574 mg, 3.33 mmol), potassium t-butoxide (354 mg, 3.33 mmol) and tetrabutylammonium iodide (492 mg, 1.33 mmol) in anhydrous toluene (30 mL)/dioxane (10 mL) was refluxed for 15 h. The mixture was then cooled to room temperature, washed with water, brine, dried with anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by using an Analogix® Intelliflash280 ™ (SiO2, 0-70% ethyl acetate in hexanes) to afford the title compound. 800 mg, 60% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.79 (s, 3H), 5.54 (s, 2H), 7.13 (d, J=8.7 Hz, 1H), 7.49 (dd, J=8.7, 2.8 Hz, 1H), 7.70 (dd, J=16.3, 2.4 Hz, 2H), 7.91 (s, 1H), 9.10 (d, J=2.0 Hz, 1H). MS (DCI) m/z 401 (M+H)+; Anal. Calculated for C15H11Cl2N3O2S2: C, 45.01; H, 2.77; N, 10.50. Found: C, 44.83; H, 2.71; N, 10.16.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([Sn:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9].[CH3:14][C:15](OC(C)=O)=[O:16].CCN(CC)CC.CCOC(C)=O.O>C(Cl)Cl>[C:15]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([Sn:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9])(=[O:16])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: C[Sn](C)(C)c1ccc(F)c(CN)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cc([Sn](C)(C)C)ccc1F
Reaction time: 3 h
Yield: 72.7 %

Procedure:
A mixture of 3-aminomethyl-4-fluoro-1-trimethylstannylbenzene (505.4 mg, 1.76 mmol), Ac2O (215.3 μL, 2.28 mmol) and NEt3 (489 μL, 3.51 mmol) was stirred at room temperature in CH2Cl2 (18 mL). After 3 h, extractive EtOAc/H2O workup followed by flash chromatography (EtOAc/Hexanes, 40:60) provided the title compound (422 mg, 73%) as an oil. 1H NMR (DMSO, 400 MHz): 8.29 (br s, 1H), 7.41 (d, J=7.52 Hz, 1H), 7.45-7.30 (m, 1H), 7.14 (dd, J=10.9, 8.2 Hz, 1H), 4.27 (d, J=5.47 Hz, 2H), 1.85 (s, 3H), 0.26 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:17]S(C)=O>C1COCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][C:12]2([O:16][CH2:17]2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CS(C)=O
Reactant: O=C1CCCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCCC3(CO3)C2)cc1
Reaction time: 1 h
Yield: 71 %

Procedure:
Sodium hydride (583 mg, 14.6 mmol) in DMSO (6 mL) was heated to 55 C. for 1 h. The reaction mixture is cooled to 0 C. and Me3SI (3 g, 14.62 mmol) dissolved in THF (9.8 mL) was added dropwise. 1-Benzyl-piperidine-3-one (1.5 g, 6.64 mmol) dissolved in DMSO (10 mL) was added 15 minutes later. After completion of addition the reaction proceded at RT. After 30 min. the reaction was quenched with water. The aqueous layer was extracted with hexanes. Combined organic layers were dried over Na2SO4 and concentrated. The crude material was purified using silica gel chromatography (9:1 DCM:hexanes in 2 M ammonia in EtOH) to yield 5-benzyl-1-oxa-5-aza-spiro[2.5]octane (960 mg, 71%). MH+ (204).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=O)=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:7]=1>>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]#[N:12])=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: Cc1ccc(-c2cc(Cl)ccc2C(N)=O)cc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2cc(Cl)ccc2C#N)cc1

Procedure:
26 ml of thionyl chloride was dropwise added to 8.9 g of 4-chloro-2-(4-methylphenyl)benzamide, and the mixture was heated under reflux for 2.5 hr. Excess thionyl chloride was distilled off as much as possible by making use of toluene. The residue was recrystallized from a mixed solvent of tetrahydrofuran-isopropyl ether-n-hexane to prepare 7.2 g of a product.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([C:12]3([OH:19])[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]1=[O:20])[CH3:2].[NH:21]1[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[O:27])[CH2:22]1>>[CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([C:12]3([OH:19])[CH2:17][CH2:16][CH:15]([N:21]4[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=5)=[O:27])[CH2:22]4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]=2[O:5][C:4]1=[O:20])[CH3:2]
Reactant: CCn1c(=O)oc2ccc(C3(O)CCC(=O)CC3)cc21
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CCn1c(=O)oc2ccc(C3(O)CCC(N4CC(NC(=O)CNC(=O)c5cccc(C(F)(F)F)c5)C4)CC3)cc21

Procedure:
The title compound was prepared as a white solid by reductive amination of 3-ethyl-5-(1-hydroxy-4-oxo-cyclohexyl)-3H-benzooxazol-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.