Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Zn+2:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[C:11]2[NH:15][C:14]([C:16]([C:50]3[CH:55]=[CH:54][C:53]([C:56]#[C:57][Si](C)(C)C)=[CH:52][CH:51]=3)=[C:17]3[N:49]=[C:20]([C:21]([C:41]4[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=4[F:48])=[C:22]4[NH:40][C:25](=[C:26]([C:32]5[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=5[F:39])[C:27]5[CH:28]=[CH:29][C:30]=1[N:31]=5)[CH:24]=[CH:23]4)[CH:19]=[CH:18]3)=[CH:13][CH:12]=2.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C1COCC1.CO>[Zn+2:1].[C:56]([C:53]1[CH:54]=[CH:55][C:50]([C:16]2[C:17]3[NH:49][C:20](=[CH:19][CH:18]=3)[C:21]([C:41]3[C:42]([F:48])=[CH:43][CH:44]=[CH:45][C:46]=3[F:47])=[C:22]3[N:40]=[C:25]([CH:24]=[CH:23]3)[C:26]([C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])=[C:27]3[NH:31][C:30]([CH:29]=[CH:28]3)=[C:10]([C:4]3[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])[C:11]3=[N:15][C:14]=2[CH:13]=[CH:12]3)=[CH:51][CH:52]=1)#[CH:57]
Reactant: C[Si](C)(C)C#Cc1ccc(-c2c3nc(c(-c4c(F)cccc4F)c4ccc([nH]4)c(-c4c(F)cccc4F)c4nc(c(-c5c(F)cccc5F)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(-c2c3nc(c(-c4c(F)cccc4F)c4ccc([nH]4)c(-c4c(F)cccc4F)c4nc(c(-c5c(F)cccc5F)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of Zn-3 (82 mg, 93.2 μmol) in THF (9 mL) was added a suspension of K2CO3 (30 mg, 217 μmol) in methanol (3 mL). The mixture was stirred for 1 h at room temperature in the dark. Then CH2Cl2 (20 mL) was added. The mixture was washed with aqueous 5% NaHCO3 solution (20 niL) and dried (Na2SO4). Purification by column chromatography (silica, CH2Cl2/hexanes 1:2) afforded 58 mg (71.6 μmol, 77%) of the title compound as a red-purple solid.
Reaction SMILES: O([C:3](C)(C)C)[K].[CH:7]1[C:12]2[CH2:13][C@H:14]3[N:19]([CH2:20][CH:21]4[CH2:23][CH2:22]4)[CH2:18][CH2:17][C@:16]45[C@H:24]([C:26]([CH2:28][CH2:29][C@@:15]34[OH:30])=O)[O:25][C:10]([C:11]=25)=[C:9]([OH:31])[CH:8]=1.C(O)(=O)C.[ClH:36]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1CCCO1.O>[CH2:3]=[C:26]1[C@@H:24]2[O:25][C:10]3[C:11]4[C@:16]52[CH2:17][CH2:18][N:19]([CH2:20][CH:21]2[CH2:22][CH2:23]2)[C@H:14]([CH2:13][C:12]=4[CH:7]=[CH:8][C:9]=3[OH:31])[C@:15]5([OH:30])[CH2:29][CH2:28]1.[ClH:36]
Reactant: CC(C)(C)O[K]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC1CCCO1
Product: C=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Methyltriphenylphosphonium bromide (MTPPB, 112.9 g) was suspended in 2-methyltetrahydrofuran (MTHF, 245 ml). Keeping the temperature in the range 20-25° C., KO-t-Bu (38.7 g) was charged in portions under inert atmosphere in one hour. The suspension was stirred for two hours. An anhydrous solution of naltrexone (35 g) in MTHF (144 ml) was then added over a period of one hour at 20-25° C. The suspension was maintained under stirring overnight. The mixture was then treated with a solution of glacial acetic acid (17.7 g) in MTHF. Water was then added and the pH was adjusted to 9-10. The phases were separated, the lower aqueous phase was discarded and the organic phase was washed twice with water. The organic phase was concentrated to residue under vacuum and then diluted with dichloromethane (175 ml) to give a clear solution. Concentrated aqueous hydrochloric acid (HCl 37%, 10.1 g) was added over one hour at 20-25° C. The suspension was stirred and then filtered and washed with dichloromethane and acetone. The product was dried affording 38.1 g of Nalmefene HCl.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:9].[NH2:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:29])[CH:12]=1>>[CH:24]1([O:23][C:16]2[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[C:20]3[C:15]=2[NH:14][C:13](=[O:29])[CH:12]=[C:11]3[NH:10][C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=2[CH3:9])[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COc1ccc2c(N)cc(=O)[nH]c2c1OC1CCCC1
Reactant: Cc1cncc(C)c1Br
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OC1CCCC1

Procedure:
The title compound was prepared from 4-bromo-3,5-dimethylpyridine and 4-amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (Example 1, Step 6) following the procedure outlined in Example 8. 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.44 (s, 1H), 8.40 (s, 2H), 7.88 (d, 1H), 7.03 (d, 1H), 4.96 (m, 1H), 4.51 (s, 1H), 3.90 (s, 3H), 2.13 (s, 6H), 1.80-1.54 (m, 8H); MS (ESI): 380.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][N:28]=2)[CH:23]=[CH:22]1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:25]=[C:24]4[CH:23]=[CH:22][NH:21][C:29]4=[N:28][CH:27]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Product: COc1cccc(Nc2nc(-c3cnc4[nH]ccc4c3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with 7-azaindole-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 121. NMR: (CDCl3): 3.91 (s, 3H, CH3), 4.15 (s, 3H, CH3), 6.66 (m, H, ArH), 6.89 (m, H, ArH), 7.17 (m, H, ArH), 7.24 (s, H, ArH), 7.38-7.42 (m, 3H, 3×ArH), 7.51 (s, H, ArH), 9.04 (sbr, H, NH), 9.13 (m, H, ArH), 9.56 (m, H, ArH). MS: (ESI+) MH+=372.25
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[CH:22]=[CH:21][C:20]([O:23]COC)=[C:19]([O:27][CH3:28])[CH:18]=4)=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([NH:38][CH2:39][C:40](O)=[O:41])(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C1C=CN=CC=1)C>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:12]=[C:11]3[C:16]([C:8](/[CH:7]=[CH:6]/[C:5]4[CH:29]=[CH:30][C:2]([NH:1][C:40](=[O:41])[CH2:39][NH2:38])=[CH:3][CH:4]=4)=[N:9][NH:10]3)=[CH:15][CH:14]=2)=[CH:18][C:19]=1[O:27][CH3:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COCOc1ccc(-c2ccc3c(C=Cc4ccc(N)cc4)n[nH]c3c2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2ccc3c(/C=C/c4ccc(NC(=O)CN)cc4)n[nH]c3c2)ccc1O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3-(4-aminostyryl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole (90 mg, 0.224 mmol) was dissolved in dichloromethane (2 mL) and was treated with Boc-glycine (196 mg, 1.12 mmol, 5 equiv), DMAP (82 mg, 3 equiv) and HATU (426 mg, 5 equiv). The mixture was allowed to stir for 30 min. The mixture was partitioned between ethyl acetate and water. The organic material was concentrated, taken up in methanol (5 mL) and was treated with potassium carbonate (100 mg). The mixture was heated to 50° C. for 3 d. The resulting mix was-again partitioned between ethyl acetate and water. The organic material was concentrated, and purified by silica (109 mg, 66%): Rf sm 0.32, p 0.46 (ethyl acetate-hexane 6:4); 1H NMR (300 MHz, CDCl3) δ 8.18 (bs, 1H), 8.03 (d, 1H, J=8.1 Hz), 7.56 (m, 5H), 7.40 (m, 3H), 7.20 (m, 3H), 5.29 (s, 2H), 5.20 (bs, 1H), 3.98 (s, 3H), 3.96 (d, 2H), 3.54 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:15]([F:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:9]=1.[NH2:28][C@H:29]([CH3:42])[CH2:30][N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41].C(=O)([O-])O.[Na+]>O1CCOCC1>[O:41]=[C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39](=[O:40])[N:31]1[CH2:30][C@H:29]([NH:28][C:8]1[C:15]([F:16])=[CH:14][C:11]([C:12]#[N:13])=[C:10]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:9]=1)[CH3:42]
Reactant: N#Cc1cc(F)c(Cl)nc1Nc1ccc2ncccc2c1
Reactant: C[C@@H](N)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](CN1C(=O)c2ccccc2C1=O)Nc1nc(Nc2ccc3ncccc3c2)c(C#N)cc1F
Temperature: 140 °C
Yield: 73 %

Procedure:
Potassium carbonate (115 mg) and 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (50 mg) were added to a tube containing a 1,4-dioxane (2 ml) solution containing (R)-2-(2-aminopropyl)isoindoline-1,3-dione (52 mg) and the tube was sealed, followed by stirring with heating at 140° C. for 13 hours. The reaction solution was adjusted to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:2), and a yellow solid of (R)-6-((1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (57 mg) was thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](Cl)=[N:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:22]3[CH2:23][CH2:24][N:19]([C:14]4[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][N:15]=4)[CH2:20][CH2:21]3)[NH:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2cc(Br)ccc2[nH]1
Reactant: Clc1cccnc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccnc1N1CCN(c2nc3ccc(Br)cc3[nH]2)CC1

Procedure:
The 5-bromo-2-chloro-1H-benzoimidazole (0.115 g, 0.5 mmol, Example 23b), 1-(3-chloropyridin-2-yl)piperazine (0.198 g, 1 mmo, Example 3b) and N,N-diisopropylethylamine (0.35 mL, 2 mmol, Aldrich) were reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 207-208° C. MS (ESI; pos.,ion) m/z: 394 (M+1).
Reaction SMILES: [C:1]([C@@H:4]([NH:12][S:13]([C:16]1[S:17][C:18]([Cl:21])=[CH:19][CH:20]=1)(=[O:15])=[O:14])[C@H:5]([CH3:11])[CH2:6][C:7]([F:10])([F:9])[F:8])(=[O:3])[CH3:2].[CH3:22][Mg]Br.CCOC(C)=O.CCCCCC>C1COCC1>[Cl:21][C:18]1[S:17][C:16]([S:13]([NH:12][C@H:4]([C:1]([OH:3])([CH3:22])[CH3:2])[C@H:5]([CH3:11])[CH2:6][C:7]([F:10])([F:9])[F:8])(=[O:15])=[O:14])=[CH:20][CH:19]=1
Reactant: C[Mg]Br
Reactant: CC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)s1)[C@H](C)CC(F)(F)F
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](CC(F)(F)F)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(C)(C)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 46.9 %

Procedure:
A solution of N-[(1S,2R)-1-acetyl-4,4,4-trifluoro-2-methylbutyl]-5-chlorothiophene-2-sulfonamide (prepared as in Example 17, 0.100 g, 0.275 mmol) in THF (5 mL) was stirred under nitrogen at 0° C. Methyl magnesium bromide (3.0 M in ethyl ether, 0.266 mL, 0.824 mmol,) was added dropwise and the resulting solution was stirred for 19 h at 25° C. After this time period, the reaction was complete by TLC (1:2 EtOAc/hexane). The solution was quenched with saturated aqueous NH4Cl (10 mL) and extracted with ether (40 mL). The organic layer was washed with brine (20 mL) and then dried over MgSO4 to obtain a crude oil (0.110 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:4 EtOAc-hexanes, to afford 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(1-hydroxy-1-methylethyl)2-methylbutyl]thiophene-2-sulfonamide as a white solid (0.049 g, 46.6%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([N:13]([CH:31]=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([C:8]1([N:13]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=CN(C1(C(=O)OC(C)(C)C)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCN(C1(C(=O)OC(C)(C)C)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of 1-{(2-Ethoxycarbonyl-vinyl)-[4-(4-fluoro-phenoxy)-benzenesulfonyl]-amino}-cyclopentanecarboxylic acid tert-butyl ester (1.23 g, 2.3 mmole) in 50 mL ethanol with 723 mg 5% Pd/C catalyst was hydrogenated at ambient temperature until HPLC indicated that the reaction was complete. The catalyst was filtered and the filtrate evaporated to give an oil which was submitted to chromatography over silica gel, eluting with 105 ethyl acetate in hexane. 1-{(2-Ethoxycarbonyl-ethyl)-[4-(4-fluoro-phenoxy)-benzenesulfonyl]-amino}-cyclopentanecarboxylic acid tert-butyl ester was isolated as a colorless oil (875 mg, 71% yield). 1H NMR (CDCl3) □ 7.75-7.80 (m, 2H), 6.86-7.01 (m, 6H), 4.09 (q, J=7.2, 2H), 3.44-3.48 (m, 2H), 2.66-2.72, m, 2H), 2.09-2.15 (m, 2H), 1.52-1.74, m, 4H), 1.43 (s, 9H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[S:11][C:10]([NH2:12])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][CH2:17][CH2:18]Br>C(OCC)(=O)C>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[S:11][C:10](=[NH:12])[N:9]([CH2:18][CH2:17][O:16][CH3:15])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Nc1ncc(Cc2ccc(F)cc2)s1
Solvent: CCOC(C)=O
Product: COCCn1cc(Cc2ccc(F)cc2)sc1=N
Temperature: 85 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
A mixture of 5-(4-fluoro-benzyl)-thiazol-2-ylamine (330 mg, 1.59 mmol) and 2-bromoethyl methyl ether (0.50 mL, 5.34 mmol) was heated to 85° C. and stirred for 12 hours. The mixture was cooled to ambient temperature, diluted with 20 mL of ethyl acetate and washed with saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted with 2×20 mL ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 50% ethyl acetate in dichloromethane containing 0.5% Et3N) afforded 342 mg of the title compound: MS (LC/MS) m/z 267 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(NC2CCNC2)cc1
Yield: 215.9 %

Procedure:
To a solution of tert.butyl-3-(4-chloroanilino)-1-pyrrolidinecarboxylate (130 mg, 0.438 mmol) in CH2Cl2 (5 mL) was added CF3COOH (1 mL). After 30 min tie volatiles were removed in vacuo to give the subtitled product (186 mg) and was used directly in the next step.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1(=[CH:12][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cc1ccccc1
Reactant: C1CCNC1
Product: C(=C1CCCCC1)N1CCCC1
Reaction time: 12 h

Procedure:
Cyclohexanecarboxyaldehyde (23.2 g) and pyrrolidine (14.5 g) were dissolved in toluene (200 ml), and the mixture was heated under reflux using a Dean-Stark distillation apparatus. After 12 hours, the solvent was removed. The residue was distilled under reduced pressure (60° C., 1 mmHg) to give 22.6 g of 1-(cyclohexylidene-methyl)pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[CH3:28][CH:29]1[O:34][CH:33]([CH3:35])[CH2:32][NH:31][CH2:30]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15]([N:31]3[CH2:32][CH:33]([CH3:35])[O:34][CH:29]([CH3:28])[CH2:30]3)=[NH:19])=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CC1CNCC(C)O1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Solvent: CO
Product: CC1CN(C(=N)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC(C)O1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 2,6-dimethylmorpholine (28 μl, 0.23 mmol) via procedure W to afford 74 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,6-dimethylmorpholino)(imino)methyl)-benzamide. MS (Q1) 449 (M)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][NH:8][N:7]=1)[CH3:4].[Cl:18][C:19]1[N:24]2[CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=3)[N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[Cl:18][C:19]1[N:24]2[CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[C:34]([CH2:36][N:8]4[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([O:5][CH2:3][CH3:4])=[N:7]4)[CH:33]=[CH:32][N:31]=3)[N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccnc(OCc2cn3c(Cl)cccc3n2)c1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccnc(OCc3cn4c(Cl)cccc4n3)c2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
Sodium hydride (60%, oily, 160 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl)propionate (849 mg) and 5-chloro-2-(4-chloromethyl-2-pyridyloxymethyl)imidazo[1,2-a]pyridine (1230 mg) in N,N-dimethylformamide (20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (1570 mg, yield: 81%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][N:8]=[C:7]3[N:11]([CH3:21])[N:12]=[C:13]([C:14]4[CH:15]=[N:16][N:17]([CH3:20])[C:18]=4Br)[C:6]=23)[CH2:4][CH2:3][CH2:2]1.[CH:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.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>[N:1]1([C:5]2[N:10]=[CH:9][N:8]=[C:7]3[N:11]([CH3:21])[N:12]=[C:13]([C:14]4[CH:15]=[N:16][N:17]([CH3:20])[C:18]=4[C:27]4[CH:28]=[CH:29][C:24]([CH:22]=[O:23])=[CH:25][CH:26]=4)[C:6]=23)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ncc(-c2nn(C)c3ncnc(N4CCC4)c23)c1Br
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1ncc(-c2nn(C)c3ncnc(N4CCC4)c23)c1-c1ccc(C=O)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
4-(Azetidin-1-yl)-3-(5-bromo-1-methyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (C28) (345 mg, 0.991 mmol), (4-formylphenyl)boronic acid (163 mg, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (11.6 mg, 0.0100 mmol), and sodium carbonate (210 mg, 1.98 mmol) were combined in ethanol (10 mL). Water (2 mL) was added, and the reaction mixture was allowed to stir for 18 hours at 100° C. The reaction mixture was concentrated in vacuo and diluted with water. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel chromatography [Gradient: 0% to 100% (90:5:5 ethyl acetate/methanol/triethylamine) in heptane]. The product was obtained as a mixture with some impurities, and was used in the next step without additional purification. Yield: 270 mg, 0.723 mmol, 73%. APCI m/z 374.0 (M+1). 1H NMR (400 MHz, CD3OD), product peaks only: δ 2.25-2.34 (m, 2H), 3.8-4.0 (br m, 4H), 3.95 (s, 3H), 3.96 (s, 3H), 7.61 (br d, J=8.2 Hz, 2H), 7.76 (s, 1H), 7.92 (br d, J=8.4 Hz, 2H), 8.16 (s, 1H), 9.97 (s, 1H).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]>CC(C)=O>[I:1][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: [I-]
Reactant: O=C(CCCCl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCCI)c1ccccc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
Sodium iodide (1.64 g, 10.95 mmol, 2 equiv) was added to a solution of 4-chloro-1-phenylbutan-1-one (1 g, 5.475 mmol, 1 equiv) in acetone. The reaction mixture was refluxed for 16 h. After cooling to ambient temperature, it was evaporated under reduced pressure to remove all the acetone. The residue was worked up using ethyl acetate and sodium bisulfite, followed by a wash with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage falsh chromatography system (SNAP 50 g cartridge, Rf=0.4, 5%-30% ethyl acetate in hexanes) to afford the title compound as white solid (880 mg, 59%). The bottle containing the compound was wrapped in aluminium foil to stored in the freezer to avoid further darkening of the mixture; 1H NMR (400 MHz, DMSO-d6): δ 2.06-2.16 (m, 2H); 3.14 (t, 2H, J=3.2 and 4 Hz); 3.34 (t, 2H, J=6.8 and 7.2 Hz); 7.51-7.55 (m, 2H); 7.62-7.67 (m, 2H); 7.95-7.98 (m, 2H); MS for C10H11IO m/z 274.99 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:29])([CH3:28])[CH2:12][C@:13]([CH2:19]SC2C=CC(C)=CC=2)([OH:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.F[B-](F)(F)F.C[O+](C)C.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:28])([CH3:29])[CH2:12][C@:13]2([C:14]([F:17])([F:15])[F:16])[CH2:19][O:18]2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc(SC[C@](O)(CC(C)(C)c2cc(Br)cc3c2OCC3)C(F)(F)F)cc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C[C@]1(C(F)(F)F)CO1)c1cc(Br)cc2c1OCC2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 95 %

Procedure:
To a solution of (S)-4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol (11.1 g, 22.6 mmol) in 75 mL of anhydrous dichloromethane was added trimethyloxonium tetrafluoroborate (5.18 g, 35.0 mmol). The resulting suspension was stirred at room temperature for 4.5 hours. A solution of potassium carbonate (9.40 g, 68.0 mmol) in 75 mL of water was then added. After 13 hours, the reaction mixture was poured into 200 mL of saturated aqueous sodium bicarbonate solution and extracted with three 300 mL portions of dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 0%-2% EtOAc-hexanes) afforded the title compound as a clear oil (7.84 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[N:6][CH:5]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: C#C[Si](C)(C)C
Product: COC(=O)c1cncc(C#C[Si](C)(C)C)c1
Yield: 13.6 %

Procedure:
Under the conditions of example 21 B, 5 g of 5-bromonicotinic acid methyl ester is reacted with 2.43 g of trimethylsilylacetylene, worked up, and the crude product is chromatographed on silica gel with hexane/0-5% ethyl acetate. 734 mg of 5-(2-trimethlsilylethinyl)-nicotinic acid methyl ester is obtained as oil.