Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[OH:37]>CCOCC>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[O:37][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: COC(C1=CN(C)CS1)c1ccccc1CCl
Reactant: Oc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(C1=CN(C)CS1)c1ccccc1COc1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To 0.25 g (1 mmol) of 5-(2-chloromethyl-α-methoxybenzyl)-3-methylthiazole, 2 ml of N,N-dimethylformamide, 0.28 g (2 mmol) of potassium carbonate and 0.33 g (2 mmol) of 2,5-dichlorophenol were added and stirred at 80° C. for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and recrystallized from ether/n-hexane to give 5-[2-(2,5-dichlorophenoxymethyl)-α-methoxybenzyl]-3-methylthiazole (0.28 g, 74.0%) as colorless crystals. mp. 78.5-79.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.O.C([O-])(O)=O.[Na+].[CH3:23][CH2:24]O>CCOCC>[CH2:23]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([OH:11])[CH:4]=1)[CH3:24]
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(Cl)c(O)c1

Procedure:
A solution of 4-chloro-3-hydroxy-benzoic acid (29.3 mmol) in EtOH (110 mL) is treated with conc. sulfuric acid (23.6 mL) and heated to reflux for 16 h. Water (600 mL), NaHCO3 (100 g) and ether (300 mL) are added successively, the layers are separated and the aqueous layer is extracted twice with ether. The combined organic layers are washed twice with brine, dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (CDCl3): δ=7.73 (s, 1H); 7.58 (d, J=8.3 Hz, 1H); 7.40 (d, J=8.3 Hz, 1H); 5.87 (s, 1H); 4.39 (q, J=7.0 Hz, 2H); 1.41 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:39])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:29](=[O:38])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=2)[CH2:25][CH2:26][CH2:27]Cl)=[CH:20][CH:19]=1)(C)(C)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.Cl.CO.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:29](=[O:38])[CH:24]([C:21]2[CH:22]=[CH:23][C:18](/[CH:17]=[CH:16]/[C:15](=[O:39])[NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[NH2:7])=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:32][CH:33]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCCCl)C(=O)Nc2ccc(Br)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCCN2CCOCC2)C(=O)Nc2ccc(Br)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of (E)-[2-(3-{4-[1-(4-bromo-phenylcarbamoyl)-4-chloro-butyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (187.5 mg, 0.3 mmol) in DMF (3 mL), morpholine (261 mg, 3 mmol) was added. Then the solution was stirred at 80 degrees Celsius overnight. A solution of 1.25 M HCl/MeOH (4 mL) was added to the residue, the solution was stirred for 4 h at ambient temperature. After reaction, the solution was neutralized with solid NaHCO3. The final product was obtained by preparative HPLC. MS: calc'd 577 (MH+), exp 577 (MH+). 1H NMR (d6-DMSO, 400 MHz), 10.33 (s, 1H), 9.57 (broad s, 2H), 7.61 (d, 1H, J=15.6 Hz), 7.59-7.54 (m, 4H), 7.49-7.46 (m, 4H), 7.36 (d, 1H, J=7.6 Hz), 6.99 (t, 1H, J=7.6 Hz), 6.91-6.84 (m, 2H), 6.71 (broad s, 1H), 3.96 (d, 2H, J=12.0 Hz,), 3.75 (t, 1H, J=7.2 Hz,), 3.62 (t, 2H, J=12.0 Hz), 3.40 (broad s, 2H), 3.14 (t, 2H, J=7.6 Hz), 3.03 (broad s, 2H), 2.09-2.04 (m, 1H), 1.78-1.71 (m, 1H), 1.67-1.57 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=O)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O.[IH:27]>C1C=CC=CC=1.CO>[IH:27].[O:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:3]([N:4]([CH3:6])[CH3:5])[N:2]([CH3:8])[CH3:1])[CH2:21][CH2:20]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CN(C)C(=O)N(C)C
Agent: I
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: CN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of tetramethylurea (10.4 g, 10.7 ml) in dry benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.2 g) in dry benzene (100 ml) in the presence of phosphorus oxychloride (8.3 ml) for 30 hours at 65°-70° C. gave an oil which was purified by column chromotography on a neutral alumina column (100 g) eluted with hexane to give as an oil. A solution of this base (2.5 g) in methanol (10 ml) was treated with 57% hydroiodic acid (1.3 ml) to give 2-(2-morpholinophenyl)-1,1,3,3-tetramethylguanidine hydroiodide as a pale yellow crystalline solid (m.p. 215°-216° C.) which was recrystallised from a 2:3 mixture of methanol and ether.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[C:3]=1[CH:4]=O.[SH:19][CH2:20][C@H:21]([NH:28][C:29](=[O:31])[CH3:30])[C:22]1[O:26][N:25]=[C:24]([CH3:27])[N:23]=1>>[OH:1][C:2]1[C:3]([CH2:4][S:19][CH2:20][C@H:21]([NH:28][C:29](=[O:31])[CH3:30])[C:22]2[O:26][N:25]=[C:24]([CH3:27])[N:23]=2)=[C:6]([C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[C:7]([CH3:12])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: CC(=O)N[C@@H](CS)c1nc(C)no1
Reactant: COc1cc(O)c(C=O)c(-c2nc(C)no2)c1C
Product: COc1cc(O)c(CSC[C@H](NC(C)=O)c2nc(C)no2)c(-c2nc(C)no2)c1C

Procedure:
2-Hydroxy-4-methoxy-5-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde and (R)-N-[2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl)-ethyl]-acetamide were subjected in an analogous manner to the procedure described in Example 1(g) to yield (R)-N-[2-[6-hydroxy-4-methoxy-3-methyl-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzylsulfanyl]-1-(3-methyl-1,2,4-oxadiazol-5-yl)-ethyl]-acetamide as an oil.
Reaction SMILES: FC1C=CC(C2C3C(=CC(C#N)=CC=3)CO2)=CC=1.Cl[CH2:20][CH2:21][CH2:22][C:23]1([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:31]2[C:26](=[CH:27][C:28]([C:32]#[N:33])=[CH:29][CH:30]=2)[CH2:25][O:24]1.[I-:41].[Na+]>CC(C)=O>[I:41][CH2:20][CH2:21][CH2:22][C:23]1([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:31]2[C:26](=[CH:27][C:28]([C:32]#[N:33])=[CH:29][CH:30]=2)[CH2:25][O:24]1
Reactant: N#Cc1ccc2c(c1)COC2(CCCCl)c1ccc(F)cc1
Reactant: [I-]
Agent: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccc2c(c1)COC2(CCCI)c1ccc(F)cc1
Yield: 181 %

Procedure:
1-3-Iodopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (14a). A solution/suspension of 1-(3-chloropropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (20 g, 35 mmol, 80% pure) and sodium iodide (285 g, 1.9 mol) in dry acetone (200 ml) was heated at reflux for 24 h. The mixture was evaporated, and partitioned between ether and water. The ether layer was separated, and was washed successively with water and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated to give 1-(3-iodopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (25.8 g, 99%, 80% pure) as a thick oil. 1H NMR (CDCl3) δ 1.6-1.9 (m, 2H), 2.21 (ddd, 1H), 2.31 (ddd, 1H), 3.16 (td, 2H), 5.12 (dt, 1H), 5.21 (dt, 1H), 7.02 (t, 2H), 7.41 (d, 2H), 7.43 (d, 1H), 7.51 (s, 1H), 7.62 (dq, 1H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[Cl:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(Cl)c(NC(=O)OC(C)(C)C)c1
Reactant: [H][H]
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Cl)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (E)-ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)acrylate (6-3) (1.0 equiv.) in ethyl acetate/ethanol (1:1, 0.3 M) was added Wilkinson's catalyst (0.10 equiv.). Hydrogen gas was introduced via a ballon, and the reaction was stirred at room temperature for 24 hours. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated in vacuo and purified by Combiflash using 0-10% ethyl acetate in hexane to give ethyl 3-(3-(tert-butoxycarbonylamino)-4-chlorophenyl)propanoate (6-4) as a solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH3:13])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O1CCOCC1>[CH3:13][NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: CNc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Solvent: C1COCCO1
Product: CNc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-methylamino-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 278°-280° C.) and piperazine in dioxane at 80° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:6])=[CH2:5].[CH3:8][O:9][C:10](=[O:13])[CH2:11][SH:12].N1CCCCC1.C[O-].[Na+]>CO>[CH3:8][O:9][C:10]([CH:11]1[C:3](=[O:2])[CH:4]([CH3:6])[CH2:5][S:12]1)=[O:13]
Reactant: COC(=O)CS
Reactant: C=C(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C1SCC(C)C1=O

Procedure:
100 g (1 mole) of methacrylic acid methyl ester are added dropwise to 106 g of thioglycolic acid methyl ester and 1 ml of piperidine. The reaction mixture is added dropwise to a solution of 40 g of sodium methylate in 200 ml of methanol. The mixture is stirred for a further half an hour, poured onto water, acidified and extracted with methylene chloride and the organic phase is washed with water and dried with sodium sulfate. After distillation, 4-methyl-3-oxotetrahydro-2-thiophencarboxylic acid methyl ester is obtained (bp. 110° to 115°/14 Pascal).
Reaction SMILES: [C:1]1([C:7]2C=CC3C(=CC(C(O)=O)=CC=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:21][C:22](=[O:32])C1C=CC(C=O)=C(N)C=1.[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](=O)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[OH-].[K+]>C(O)C>[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][C:47]2[C:42]([CH:41]=1)=[CH:43][C:44]([C:22]([OH:32])=[O:21])=[CH:45][CH:46]=2
Reactant: O=C(Cc1ccccc1)c1ccccc1Br
Reactant: COC(=O)c1ccc(C=O)c(N)c1
Reactant: O=C(O)c1ccc2ccc(-c3ccccc3)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccccc3Br)cc2c1
Yield: 40 %

Procedure:
Following the same reaction procedure and workup as for Compound 405f (235 mg, 1.31 mmol) of Compound 53 was reacted with the product of the previous reaction, Compound 424b (360 mg, 1.31 mmol), in ethanol (12 mL) using 10% w/v KOH in ethanol (1.1 mL) to produce the title compound (210 mg, 40% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])=[CH:21][CH:20]=1)=[O:10].C(N(CC)CC)C.[O:47]1[CH2:51][CH2:50][CH2:49]C1.O.[C:53](Cl)(=[O:56])[CH:54]=[CH2:55]>>[C:53]([O:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:51](=[O:47])[CH:50]=[CH2:49])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])=[CH:21][CH:20]=1)=[O:10])(=[O:56])[CH:54]=[CH2:55]
Reactant: C=CC(=O)Cl
Reactant: C1CCOC1
Reactant: O=C(OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCO)CCCCCCO
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)OCCCCCCC(CCCCCCOC(=O)C=C)C(=O)OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
First, 2.6 g of 6-[2,3-difluorobiphenyl-4'-yl]oxyhexyl 2,2-bis(6-hydroxyhexyl)acetate, 1.2 g of triethylamine, and 100 ml of tetrahydrofuran were placed in a 200 ml flask. Then, a small amount of tetrahydrofuran in which 1.1 g of acryloyl chloride was dissolved was added dropwise to the mixture under ice water cooling. The resultant mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with diluted hydrochloric acid and water in this order, and then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/toluene=1/9) to obtain 0.9 g of 6-[2,3difluorobiphenyl-4'-yl]oxyhexyl 2,2-bis(6-acryloyloxyhexyl)acetate (Y: 28%). The compound thus obtained was liquid at room temperature. The compound thus obtained had a purity of 99% by HPLC and of 1 spot by TLC.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6][C@@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:18]([O-])=O)=[C:14]([F:17])[CH:15]=3)[CH:10]=[C:9]2[C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[CH2:4][O:3]1>C(O)C>[NH2:18][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[F:17])[N:8]([CH2:7][C@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:26])[O:6]1)[C:9]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[CH:10]2
Reactant: CC1(C)OC[C@H](Cn2c(C(C)(C)CO)cc3cc([N+](=O)[O-])c(F)cc32)O1
Solvent: CCO
Product: CC1(C)OC[C@H](Cn2c(C(C)(C)CO)cc3cc(N)c(F)cc32)O1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
(S)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (500 mg, 1.4 mmol) was dissolved ethanol (15 mL) and the reaction was flushed with N2. Then Pd—C (50 mg, 5% wt) was added. The reaction was flushed with nitrogen again and then stirred under H2 (atm). After 1 hour only partial conversion to the product was observed by LCMS. The reaction was filtered through Celite and concentrated. The residue was resubjected to the conditions above. After 1 hour LCMS indicated complete conversion to product. The reaction mixture was filtered through Celite. The filtrate was concentrated to yield the product as a black solid (420 mg, 91%). ESI-MS m/z calc. 336.2. found 337.5 (M+1)+. Retention time 0.90 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J=12.6 Hz, 1H), 6.76 (d, J=9.0 Hz, 1H), 6.03 (s, 1H), 4.78 (br s, 1H), 4.46 (s, 2H), 4.41-4.27 (m, 3H), 4.06 (dd, J=6.1, 8.3 Hz, 1H), 3.70-3.67 (m, 1H), 3.53 (dd, J=10.7, 17.2 Hz, 2H), 1.40 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:23]([C:20]2([CH3:19])[CH2:22][CH2:21]2)(=[O:25])=[O:24])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: CC1(S(=O)(=O)Cl)CC1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: CC1(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)CC1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 1-methyl-cyclopropanesulfonylchloride to obtain the desired product. 1H NMR (300 MHz, CDCl3): δ 7.42 (dd, J=1.8 & 10.5 Hz, 1H), 7.36 (ddd, J=2.4, 4.5 & 9.0 Hz, 1H), 7.27 (d, J=6.0 Hz, 1H), 7.07 (dd, J=9.3 & 17.7 Hz, 1H), 6.24 (dt, J=2.1, 8.7 & 17.4 Hz, 1H), 5.86 (br s, 1H), 1.43 (s, 3H), 1.33 (t, J=5.4 Hz, 2H), 0.75 (dd, J=5.1 & 6.3 Hz, 2H); m/z=481 [M−1]−.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH3:38])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[C:34]([F:36])[C:31]([C:32]#[N:33])=[C:30]([Cl:37])[CH:29]=2)=[N:24]1>>[Cl:37][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C@@H:21]([NH:20][C:9]([C:7]3[N:8]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=3)=[O:11])[CH3:38])[N:24]=2)[CH:35]=[C:34]([F:36])[C:31]=1[C:32]#[N:33]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1C1CC1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C2CC2)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (1.41 mmol, 400 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.41 mmol, 395 mg). The product was purified by flash-chromatography. Yield 249 mg. 1H-NMR (400 MHz; CDCl3): δ −0.01 (s, 9H), 0.93 (t, 2H), 0.99 (d, 4H), 1.23 (d, 3H), 1.88-1.95 (m, 1H), 3.52 (t, 2H), 4.29-4.40 (m, 2H), 4.47-4.54 (m, 1H), 5.33 (s, 2H), 6.59 (d, 1H), 7.35 (d, 1H), 7.49-7.51 (m, 2H), 7.58 (d, 1H), 7.72 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1C=CC=CC=1.BrCC#[N:21].C(=O)([O-])[O-].[K+].[K+]>CO.[Pd].C(C(C)=O)C>[C:2]([CH2:1][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)#[N:21]
Reactant: N#CCBr
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CO
Product: N#CCOc1cccc2cc[nH]c12

Procedure:
A solution of 7-benzyloxyindole (0.5 g, 2.24 mmol) in methanol (100 ml) is hydrogenated at 60 psi (4.38 Kg/cm2) over 10% palladium on charcoal (50 mg) for 4 hours. The catalyst is filtered off and the filtrate was evaporated. A stirred solution of the residue and bromoacetonitrile (0.16 ml, 2.3 mmol) in methyl ethyl ketone (5 ml) is heated under reflux with solid anhydrous potassium carbonate (0.62 g, 4.5 mmol) for 2 hours, cooled, poured onto ice-hydrochloric acid and extracted with dichloromethane. The extract is dried and evaporated and the residue is chromatographed on silica in ethyl acetate-hexane (1:2) to give a pale solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](SC)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:29][O:30][C:31]1[C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][N:34]=[C:33]([NH2:50])[N:32]=1>COCCOC.C(OCC)(=O)C.CSC.[Cu]Br.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>[CH3:29][O:30][C:31]1[C:36]([C:16]2[N:17]=[C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][CH2:9]4)=[CH:13][C:14]=3[N:15]=2)=[CH:35][N:34]=[C:33]([NH2:50])[N:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N)nc1OC
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CSC
Solvent: COCCOC
Product: COc1nc(N)ncc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (70 mg) in 1,2-dimethoxyethane (10 mL) was added 4-methoxy-5-tributylstannyl-pyrimidin-2-ylamine (131 mg) and copper(I)bromide-dimethyl sulfide (65 mg) and the reaction mixture was stirred at room temperature for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (9 mg) was then added and the reaction mixture was heated at reflux for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water (2×20 mL) and brine (2×20 mL). The organic phase was dried (MgSO4), reduced in vacuo and purified by column chromatography to give 293. NMR: (CDCl3) 2.58-2.62 (4H, m), 2.73 (3H, s, Me), 3.18-3.22 (4H, m), 3.76-3.80 (6H, m), 3.89-3.94 (7H, m), 4.98 (2H, br s, NH), 7.24 (1H, s, Ar) and 8.72 (1H, s, Ar). MS: (ESI+): MH+521.25
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[N:10]2)=[CH:5][CH:4]=1.[C:18]1([C@H:28]([NH2:30])[CH3:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.ClCCCl>[C:18]1([C@H:28]([NH:30][CH2:14][C:11]2[CH:12]=[CH:13][N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=3)[N:10]=2)[CH3:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccn(-c2ccc(C(F)(F)F)cc2)n1
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C[C@@H](NCc1ccn(-c2ccc(C(F)(F)F)cc2)n1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with 1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbaldehyde 65 (0.200 g, 0.833 mmol), (R)-1-(naphthalen-1-yl)ethanamine 39 (0.171 g, 0.999 mmol), sodium triacetoxyborohydride (0.353 g, 1.67 mmol), 4 mL of DCE, and 3 drops of AcOH. This mixture was stirred overnight at room temperature and then quenched with saturated aqueous NaHCO3. The mixture was extracted with DCM, dried, and concentrated. Purification by column chromatography on silica gel (10% to 50% EtOAc in hexanes) gave ((1R)-1-(1-naphthyl)-N-({1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}methyl)ethanamine 66. Mass spectrum, calculated for C23H20F3N3 395.2; found 396.2 (M++1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:4]=1.[Na+].[I-].[Si](Cl)(C)(C)C.CO>O.C(#N)C>[OH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:4]=1
Reactant: CCCCCC(=O)OCc1nccc(OC)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: CCCCCC(=O)OCc1nccc(O)n1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
3.1 g (13.0 mMol) hexanoic acid 4-methoxy-pyrimidin-2-ylmethyl ester and 5.85 g (39 mMol) NaI are dissolved in 130 ml (13 mMol) of a 0.1 M solution of water in acetonitrile at 60° C. Then 4.95 ml (39 mMol) Me3SiCl are added via syringe. The resulting suspension is stirred for 7 h at 60° C. and then cooled to rt again. Then 15 ml of MeOH are added dropwise. After stirring for 10 additional minutes, the reddish suspension is concentrated in vacuo. The residue is redissolved in 300 ml EtOAc and 100 ml sat. NaHCO3 solution, the aq. layer separated off and extracted with 2×300 ml EtOAc. The organic phases are washed with 50 ml of a 0.5 M solution of Na2S2O3 and brine, dried (Na2SO4) and concentrated. Crystallization from CH2Cl2 and hexane gives the title compound: m.p.: 78° C.; MS: [M+1]+=225.