Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)[N:3]=1.I[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[O:30][C:29]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)=[N:28][N:27]=3)[CH:24]=2)[N:19]([S:41]([C:44]2[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH:18]=1.CN(C=O)C>O1CCOCC1.CC(C)=O.CCOC(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.[Cu]I>[F:14][C:11]1([F:15])[CH2:12][CH2:13][N:8]([C:4]2[N:3]=[C:2]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[O:30][C:29]([NH:31][CH2:32][C:33]6[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=6)=[N:28][N:27]=5)[CH:24]=4)[N:19]([S:41]([C:44]4[CH:45]=[CH:46][C:47]([CH3:48])=[CH:49][CH:50]=4)(=[O:43])=[O:42])[CH:18]=3)[CH:7]=[N:6][CH:5]=2)[CH2:9][CH2:10]1
Reactant: FC1(F)CCN(c2cncc(Cl)n2)CC1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(N5CCC(F)(F)CC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 125 °C
Yield: 85.8 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-6-(4,4-difluoropiperidin-1-yl)pyrazine (300 mg, 1.28 mmol) and (Me3Sn)2 (0.32 mL, 1.54 mmol) in p-dioxane (2.5 mL) followed by Pd(PPh3)4 (60 mg, 0.05 mmol). The reaction was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 125° C. for 30 min. The mixture was cooled to RT and 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.615 g, 1.024 mmol) was added followed by DMF (1 mL), CuI (244 mg, 1.28 mmol) and Pd(PPh3)4 (59 mg, 0.05 mmol). The reaction was heated in a microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 125° C. for 0.5 h. It was diluted with 5 mL of acetone and 10 mL of EtOAc, filtered through a pad of Celite. The filtrate was concentrated. The residue was loaded on a silica gel column and eluted with 50% EtOAc in DCM followed by 10-20% MeOH in EtOAc to give 5-(3-(6-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (590 mg) as a brown amorphous solid that was used in the next step without further purification. MS (ESI, pos. ion) m/z 672.0 (M+1).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[C:31]=2[F:38])=[CH:26][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl:39][CH:40]([CH:44]([CH3:46])[CH3:45])[C:41](O)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:39][CH:40]([CH:44]([CH3:46])[CH3:45])[C:41]([O:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:25][CH:26]=2)=[C:31]([F:38])[C:32]=1[F:37])=[O:42]
Reactant: CCCCCCCOc1ccc(-c2ccc(O)c(F)c2F)cc1
Reactant: CC(C)C(Cl)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2ccc(OC(=O)C(Cl)C(C)C)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 0.1 mol of DCC in methylene chloride is added to a mixture of 0.1 mol of 4'-heptyloxy-2,3-difluorobiphenyl-4-ol, 0.1 mol of optically active 2-chloro-3-methylbutyric acid (prepared from valine) and a catalytic amount of DMAP in 250 ml of methylene chloride at 0° C. The mixture is then stirred at room temperature for 12 hours, the precipitate is subsequently filtered off with suction and the filtrate is worked up in the customary manner to give 4-(p-heptyloxyphenyl)-2,3-difluorophenyl 2-chloro-3-methylbutyrate.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:31])=[C:25]([S:27](Cl)(=[O:29])=[O:28])[CH:26]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:31])=[C:25]([S:27]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:16]=[CH:17][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=3)[N:14]=2)(=[O:29])=[O:28])[CH:26]=1
Reactant: Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-ylamine (0.08 g) and 5-fluoro-2-methyl-benzenesulfonyl chloride (0.07 g) as a light yellow solid (0.1 g). MS (ESI−): 439.1 ([M−H]−)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:24]([NH:31][C:9]1[C:10]([F:16])=[C:11]([F:15])[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][N:4]2[CH:1]1[CH2:2][CH2:3]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O

Procedure:
A mixture of ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (28.2 g) prepared in Referential Example 1 (2), benzylamine (9.8 ml), anhydrous potassium carbonate (23.6 g), and acetonitrile (140 ml) was heated at 100°-110° C. for 1 hour to give ethyl 5-benzylamino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (21.4 g), which was recrystallized from ethanol, m.p. 134°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:13])[CH:10]([Cl:12])[Cl:11])=[CH:5][CH:4]=1.O[C:15](C)([CH3:24])[C:16]([C:18]1C=CC=C[CH:19]=1)=O.OC(CC)(CC)C(C1C=CC=CC=1)=O.OC(CCC)(CCC)C(C1C=CC=CC=1)=O.C(C1C=CC(C(=O)C(O)(C)C)=CC=1)(C)C.C(C1C=CC(C(=O)C(O)(CC)CC)=CC=1)(C)C.C(C1C=CC(C(=O)C(O)(C)CC)=CC=1)CCC.C(C1C=CC(C(=O)C(O)(C)C)=CC=1)CCCCCCCCCCC.O(C1C=CC(C(=O)C(Br)Br)=CC=1)C1C=CC=CC=1.BrC(Br)C(C1C=CC=CC=1)=O.ClC(Cl)C(C1C=CC=CC=1)=O.CC(C)C(C1C=CC=CC=1)=O.C1(C2C=CC(C(=O)C(CCCC)CCCC)=CC=2)CCCCC1.C1(C(C2C=CC=CC=2)=O)C=CC=CC=1.OC1CCCCC1>>[O:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:13])[CH:10]([Cl:11])[Cl:12])=[CH:7][CH:8]=1)[C:1]1[CH:19]=[CH:18][CH:16]=[CH:15][CH:24]=1
Reactant: CC(C)(O)C(=O)c1ccccc1
Reactant: COc1ccc(C(=O)C(Cl)Cl)cc1
Agent: CC(C)C(=O)c1ccccc1
Agent: CC(C)c1ccc(C(=O)C(C)(C)O)cc1
Agent: CCC(O)(CC)C(=O)c1ccc(C(C)C)cc1
Solvent: OC1CCCCC1
Product: O=C(c1ccc(Oc2ccccc2)cc1)C(Cl)Cl

Procedure:
p-methoxy-2,2-dichloroacetophenone; 2-hydroxy-2,2-dimethylacetophenone; 2-hydroxy-2,2-diethylacetophenone; 2-hydroxy-2,2-dipropylacetophenone; p-isopropyl-2-hydroxy-2,2-dimethylacetophenone; p-isopropyl-2-hydroxy-2,2-diethylacetophenone; p-n-butyl-2-hydroxy-2-methyl-2-ethylacetophenone; p-dodecyl-2-hydroxy-2,2-dimethylacetophenone; p-phenoxy-2,2-dibromoacetophenone; 2,2-dibromoacetophenone; 2,2-dichloroacetophenone; 2,2-dimethylacetophenone; 2-hydroxy-2,2-cyclohexylacetophenone; p-cyclohexyl-2,2-dibutylacetophenone; 2-2,dimethoxy-2-phenylacetophenone; and 1-hydroxycyclohexane phenyl ketone.
Reaction SMILES: [Br:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([O:15][CH2:16][C@@H:17]2[CH2:19][O:18]2)=[CH:4][CH:3]=1.NCC1CCN([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=2[S:36]([NH2:39])(=[O:38])=[O:37])CC1>>[Br:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:13][CH2:12][CH:7]2[CH2:8][CH2:9][N:39]([S:36]([C:29]3[CH:28]=[CH:33][C:32]([O:34][CH3:35])=[CH:31][CH:30]=3)(=[O:37])=[O:38])[CH2:5][CH2:6]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(S(N)(=O)=O)c(N2CCC(CN)CC2)c1
Reactant: Brc1ccc(OC[C@@H]2CO2)c2c1[nH]c1ccccc12
Product: COc1ccc(S(=O)(=O)N2CCC(CNCC(O)COc3ccc(Br)c4[nH]c5ccccc5c34)CC2)cc1
Yield: 77.4 %

Procedure:
Prepared from 1-bromo-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.050 g, 0.15 mmol) and (4-aminomethyl-1-piperidinyl) 4-methoxybenzenesulfonamide (0.085 g, 0.3 mmol) of according to procedure used for Example 2 to give 0.035 g of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[CH3:10][C:11]([S:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:16][S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)N=Cc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a stirred solution of 5-Bromo-pyridine-2-carbaldehyde (2.0 g, 10.753 mmol) in CH2Cl2 (20 mL) and 2-Methyl-propane-2-sulfinic acid amide (2.602 g, 21.505 mmol) is added CuSO4 (5.589 g, 21.505 mmol) at room temperature. Resulting reaction mixture is stirred at room temperature for 3 hours. Reaction mixture is filter through celite. Diluted with water and extracted with CH2Cl2. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 5% ethyl acetate in hexane to afford the title compound (2.5 g): 1H-NMR (400 MHz, DMSO-d6) δ: 1.19 (s, 9H), 8.03 (d, J=8.52 Hz, 1H), 8.25-8.27 (dd, J=2.32 Hz, J=8.32 Hz, 1H), 8.44 (s, 1H), 8.90 (d, J=1.84 Hz, 1H). LC-MS (m/z): [M+H]=291.1.
Reaction SMILES: P(Cl)(Cl)Cl.O[CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9].P(Cl)(Cl)[Cl:22].CN(C=O)C.C([O-])(O)=O.[Na+]>O.CC(OC)(C)C.CN(C=O)C>[Cl:22][CH2:6][CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19]
Reactant: ClP(Cl)Cl
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A 3-N 100 mL flask was charged with PCl3 (2.8 mL, 31.6 mmol) and dry DMF (32 mL) then stirred at RT for 1 h. In a separate 50 mL flask, farnesol (Ex-1B-5) (10.0 g, 45.2 mmol) and DMF (10 mL) was charged. The PCl3/DMF solution was then transferred to the farnesol, solution and the resulting dark orange solution was stirred for 1 h. The reaction was quenched by addition of solid NaHCO3 (2.5 g, 63.2 mmol). The solvent was removed by high vacuum rotary evaporation to yield an oily orange residue. To the residue was added MTBE (40 mL) and water (40 mL). The aqueous phase was washed with MTBE (3×20 mL). The MTBE layers were combined, washed with brine (2×20 mL), dried over MgSO4, filtered and finally concentrated by rotary evaporation to yield 1-chloro-3,7,11-trimethyl-dodeca-2,6,10-triene (Ex-1B-6) as a yellow oil (9.89 g, 92%). 1H NMR (400 MHz, CDCl3) δ (ppm): 5.47 (broad-t, J=8.3 Hz, 1H), 5.15-5.07 (m, 2H), 4.12 (d, J=8.1 Hz, 2H), 2.18-1.95 (m, 8H), 1.75 (s, 3H), 1.70 (s, 3H), 1.62 (s, 6H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C([O:37][C:38](=[O:53])[CH2:39][CH2:40][C@@H:41]([C:50](O)=[O:51])[NH:42]C(OC(C)(C)C)=O)(C)(C)C>>[ClH:28].[NH2:42][C@H:41]([C:50](=[O:51])[NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)[CH2:40][CH2:39][C:38]([OH:53])=[O:37]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: N[C@@H](CCC(=O)O)C(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and tert-butoxycarbonyl-L-glutamic acid 5-tert-butyl ester by using the same method as in Example 96.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10]2[C:15]3[N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:17]=[N:18][C:14]=3[CH:13]=[C:12]([C:25]([F:28])([F:27])[F:26])[CH:11]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.N1CCCC[CH2:30]1>>[C:19]1([N:16]2[C:15]3[C:10]([C:9]#[C:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:30][CH2:3][CH2:2]4)=[CH:11][C:12]([C:25]([F:28])([F:27])[F:26])=[CH:13][C:14]=3[N:18]=[CH:17]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C1CCNCC1
Reactant: FC(F)(F)c1cc(C#CCN2CCOCC2)c2c(c1)ncn2-c1ccccc1
Product: FC(F)(F)c1cc(C#CCN2CCCCC2)c2c(c1)ncn2-c1ccccc1
Yield: 17 %

Procedure:
This was prepared in a similar manner to 7-(3-(4-morpholinyl)prop-1-ynyl)-1-phenyl-5-trifluoromethylbenzimidazole using piperidine in place of morpholine to realise the desired product (13 mg, 17%) m/z, 384.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=[O:27])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH2:26][OH:27])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(C=O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(CO)c2[nH]c(=O)n3c2c1OCC3c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde (15 mg, 0.040 mmol) from Example 137, Step 3 was stirred in ethanol (0.58 mL), followed by addition of sodium tetrahydroborate (2.3 mg, 0.060 mmol). The mixture was stirred at room temperature for 1 h. Purification by preparative LCMS (pH 10) afforded the title compound. LCMS calc. for C20H19N4O4 (M+H)+: m/z=379.1. found: 379.2.
Reaction SMILES: [CH3:1][S:2](Br)(=[O:4])=[O:3].OO.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>[N+](C)([O-])=O.C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:1][S:2]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Br
Reactant: C=Cc1ccccc1
Agent: OO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)C=Cc1ccccc1
Reaction time: 50 h

Procedure:
130 mg of zinc chloride, 3.2 g (20 mmoles) of methanesulfonic acid bromide and 0.15 ml of 50% strength hydrogen peroxide are successively added to a solution of 2.1 g (20 mmoles) of styrene in 5 ml of nitromethane. After 50 hours at room temperature, the mixture is taken up in methylene chloride and the solution is washed with water. The crude 1-methylsulfonyl-2-bromo-2-phenylethane which remains after stripping off the methylene chloride is dissolved in 10 ml of benzene and dehydrobrominated by adding 25 mmoles of triethylamine. Distillation at from 121° to 124° C. at 0.01 mm Hg gives β-methylsulfonylstyrene, of melting point 77° - 79° C. (after recrystallization from ether). According to the NMR spectrum (J = 15.5 Hz), the product is in the trans-configuration.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:35]2[NH:39][N:38]=[CH:37][CH:36]=2)O1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:35]4[NH:39][N:38]=[CH:37][CH:36]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: CC1(C)OB(c2ccn[nH]2)OC1(C)C
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3ccn[nH]3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure in Example 93, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide was coupled with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give 310. MS (ESI) 436.1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Br)cc1
Yield: 43.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-bromophenyl)-5-methylpyrazole-4-carboxylic acid (0.6 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the title compound (0.5 g) was obtained, melting point: 250–252° C.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1CO>[CH3:20][S:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:12]2
Reactant: CSc1ccc2c(c1)cc(-c1ccccc1)n2S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: OCC1CCCO1
Product: CSc1ccc2[nH]c(-c3ccccc3)cc2c1
Temperature: 50 °C
Reaction time: 26 h
Yield: 89.5 %

Procedure:
To a solution of 1-benzenesulfonyl-5-methylsulfanyl-2-phenylindole (264 mg) in tetrahydrofuran-methanol (2/1, 6.9 mL) was added cesium carbonate (680 mg) at room temperature, and the mixture was stirred at 50° C. for 26 hours. The reaction mixture was allowed to cool to ambient temperature and concentrated under reduced pressure. 1 mol/L Hydrochloric acid was added to the residue and this resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (149 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[I:20].CN([CH:24]=[O:25])C>C1COCC1.O.C(O)(=O)C>[F:13][C:14]1[C:15]([I:20])=[CH:16][CH:17]=[CH:18][C:19]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Fc1ccccc1I
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: O=Cc1cccc(I)c1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (10.42 mL, 74.36) in THF (135 mL) under N2 in an ice bath at 0-5° C. was added dropwise over 10 min n-BuLi (42.25 mL, 67.6 mmol) and stirred at this temperature for 10 min. Cooled the reaction mixture to −78° C. in a dry ice/acetone bath and dropwise added 1-fluoro-2-iodobenzene (7.88 mL, 67.6 mmol) over 5 min. Stirred at this temperature for 1 h, dropwise added DMF (6.26 mL, 74.36 mL) over 5 min, and stirred for 10 min. Added Acetic Acid (13.5 mL) followed by H2O and extracted with Et2O (2×). The combined organic solution was washed (0.1 N HCl then brine), dried (MgSO4), filtered and concentrated. The crude benzaldehyde (16.9 g) was taken onto the next step without purification. 1H NMR was consistent with structure.
Reaction SMILES: C(OC([NH:8][N:9]([C:11]([C@@H:13]1[CH2:17][C@@H:16]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:15][N:14]1[S:28]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)(=[O:30])=[O:29])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:10][N:9]([C:11]([C@@H:13]1[CH2:17][C@@H:16]([S:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:15][N:14]1[S:28]([C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)(=[O:29])=[O:30])=[O:12])[NH2:8]
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)NC(=O)OC(C)(C)C)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)N)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Yield: 101.1 %

Procedure:
(Step 22) 2 g (3.4 mmol) (2S,4R)-N′-[4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-N′-methyl-hydrazinecarboxylic acid tert-butyl ester in 9 ml CH2Cl2 were treated with 3.4 ml TFA for 2 h. The solution was concentrated, redissolved in toluene and evaporated. The residue was dissolved in ethyl acetate and sat. aq. NaHCO3, the layers were separated and the inorganic one was extracted with ethyl acetate, the combined organic ones were washed wit brine, dried over Na2SO4 and concentrated yielding 1.67 g (quant) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid N-methyl-hydrazide as white solid, MS: 486 (MH+).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N3CCOCC3)c2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 4-morpholinecarbonyl chloride (370 μL) was added to a solution of 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (0.757 g) in chloroform (11 mL) and triethylamine (520 μL). The reaction mixture was stirred at ambient temperature for about 3 hours; then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was recrystallized from acetonitrile and dried in a vacuum oven at 60° C. for 24 hours to provide 0.7014 g of N-{2-[2-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}morpholine-4-carboxamide as a white powder, m.p. 205–207° C.