Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([N:12]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:13]([CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:5]([N:12]([C:13]1([CH:15]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16]2)[CH2:2][CH2:1]1)[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)C(=O)C2CCN(Cc3ccccc3)C2)CC1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccccc2)C2(C3CCN(Cc4ccccc4)C3)CC2)CC1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A solution of ethylmagnesium bromide (3.0 M in ethyl ether, 13.0 mL, 39.1 mmol, 2.5 equiv) in THF (100 mL) was cooled to −78° C. To this was added a solution of titanium (IV) isopropoxide (4.8 mL, 16.3 mmol, 1.04 equiv) in THF (10 mL) dropwise with the temperature below −70° C. After stirring for thirty minutes, a solution of (R/S)-N-benzyl-N-(1-tert-butoxycarbonylpiperidin-4-yl)-1-benzylpyrrolidine-3-carboxamide (7.5 g, 15.6 mmol) in THF (10 mL) was added. The resulting solution was warmed to RT, heated at reflux for one hour. The mixture was then cooled to 8° C., and ethylmagnesium bromide (3.0 M in ethyl ether, 11.0 mL, 33.1 mmol, 2.1 equiv) was added, followed immediately by a solution of titanium (IV) isopropoxide (4.2 mL, 14.2 mmol, 0.91 equiv) in THF (10 mL). The reaction mixture was stirred at room temperature for one hour then partitioned between 1:1 EtOAc—H2O (500 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography (5:1 hexanes-EtOAc to 100% EtOAc) to give a pale yellow oil (4.7 g, 61%). ESI MS m/z 490.3 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.34-7.11 (m, 10H), 4.18-3.98 (br m, 1H), 3.92 (app s, 2H), 3.64 (app t, J=13.2, 1H), 3.55 (d, J=12.5, 1H), 3.00-2.78 (m, 4H), 2.75-2.37 (m, 4H), 2.33-2.21 (m, 1H), 2.10-1.89 (m, 2H), 1.73-1.62 (m, 2H), 1.50-1.37 (s+m, 11H), 1.37-1.14 (m, 2H), 0.71 (app s, 1H), 0.60-0.49 (m, 1H). 13C NMR (400 MHz, CDCl3) δ 154.20 (C═O), 143.1 (Ph), 138.8 (Ph), 128.5 (Ph), 128.4 (Ph), 127.9 (Ph), 127.7 (Ph), 126.6 (Ph), 125.9 (Ph), 78.8 (t-Bu), 60.6, 58.4, 55.5, 53.2, 48.9, 45.2, 43.3 (br), 42.7 (br), 38.6, 32.1 (br), 28.1 (t-Bu), 7.6 (c-Pr).
Reaction SMILES: C(OC(=O)N(C(C(=O)[NH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]3[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[C:15]([C:30]#[C:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[C:38]([CH3:42])=[N:37][CH:36]=[CH:35]3)[N:14]=1)C)C)(C)(C)C.[H][H].[OH-].[K+]>>[CH3:28][N:27]1[C:20]2[C:19]([C:17]3[CH:16]=[C:15]([C:30]#[C:31][C:32]4[CH:33]=[C:34]5[C:39](=[CH:40][CH:41]=4)[C:38]([CH3:42])=[N:37][CH:36]=[CH:35]5)[N:14]=[C:13]([NH2:12])[CH:18]=3)=[N:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:29])=[N:26]1
Reactant: Cc1nccc2cc(C#Cc3cc(-c4ncnc5c(C)nn(C)c45)cc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)n3)ccc12
Reactant: [H][H]
Agent: [K+]
Agent: [OH-]
Product: Cc1nccc2cc(C#Cc3cc(-c4ncnc5c(C)nn(C)c45)cc(N)n3)ccc12
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl-N-{1-[(4-{1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-[2-(1-methylisoquinolin-6-yl)ethynyl]pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate H2 (150 mg, 0.31 mmol) and potassium hydroxide (1 mol/l solution in MeOH:water=2:1, 3 ml, 3 mmol) is stirred at 60° C. for 2 days. The precipitate is collected and purified by NP chromatography to yield 4-{1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-[2-(1-methylisoquinolin-6-yl)ethynyl]pyridin-2-amine. Yield: 110 mg (89%). HPLC-MS: M+H=406; tR=1.07 min (METHOD—1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](I)[CH:4]=[N:3]1.[Br:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.BrC1C=C(C2C=NC=CC=2)C=CC=1>>[Br:8][C:9]1[CH:14]=[C:13]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cn1cc(I)cn1
Agent: Brc1cccc(-c2cccnc2)c1
Product: Cn1cc(-c2cccc(Br)c2)cn1

Procedure:
The reaction of 1-methyl-4-iodopyrazole (Liljefors, S., and Gronowitz S. Chemica Scripta, 15, 102-9 (1980)) (1.3 g, 6.2 mmol) with 3-bromophenyl boronic acid (1.24 g, 6.2 mmol) using the procedure for the preparation of 3-(3'-bromophenyl)pyridine gave crude 4-(m-bromophenyl)-1-methylpyrazole which was chromatographed on a column of Bakers Silica Gel (60-200 mesh) packed and eluted with CH2Cl2. The less polar fractions contained undesired, incorrectly coupled products while the later more polar fractions contained the desired product (0.82 g, 56% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36]>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Temperature: 50 °C
Reaction time: 20 h
Yield: 109.4 %

Procedure:
N2-Butyl-8-(methyloxy)-9H-purine-2,6-diamine trifluoroacetate (5 g, 14.27 mmol) and potassium carbonate (4.93 g, 35.7 mmol) were suspended in DMF (40 ml) and heated to 50° C. under nitrogen for 30 mins. The mixture was cooled to room temperature, 1-bromo-4-chlorobutane (1.645 ml, 14.27 mmol) was added and stirring was continued at room temperature for 20 hours. The solvent was concentrated under vacuum and the residue was partitioned between DCM (100 ml) and water (100 ml). The layers were separated using a hydrophobic frit and the aqueous phase was re-extracted with DCM (100 ml). The combined organics extracts were concentrated in vacuo and the residue purified by chromatography using a FlashMaster apparatus (100 g silica cartridge) and using a DCM:methanol 0-25% gradient over 40 mins. The desired fractions were combined and concentrated under vacuum to give the impure title compound as a yellow oil (5.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH:10]([N:13]3C(=O)C4C(=CC=CC=4)C3=O)[CH:9]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C1C=C(c2ccc(F)cc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC1C=C(c2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To an ethanol solution (0.50 mL) of 2-[3-(4-fluorophenyl)cyclopent-2-en-1-yl]isoindoline-1,3-dione (10.0 mg, 0.0325 mmol) synthesized in Reference Synthesis Example 222, hydrazine monohydrate (3.16 μL, 0.0651 mmol) was added and the resultant mixture was stirred at room temperature for 1 day. Further, the reaction solution was stirred at 70° C. for 6 hours and then stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated under reduced pressure and was washed with chloroform to obtain a crude product of the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:5]=2[O:4][CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCC1>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10](/[CH:11]=[CH:14]/[C:15]([OH:17])=[O:16])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc2c1OCCO2
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNC1
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1cccc2c1OCCO2
Temperature: 0 °C

Procedure:
A mixture of 2,3-dihydrobenzodioxin-5-carboxaldehyde (Morishima, et al., Eur. Pat. Appl. 309,766, Apr. 5, 1989) (9.25 g, 56.4 mmol), malonic acid (11.73 g, 112.8 mmol), pyrrolidine (1 mL), and pyridine (25 mL) was heated to reflux for 2 hr, cooled, and then poured into ice water (300 mL). The white precipitate was filtered, washed with 1N HCl, and air dried (9.83 g, 84.6%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.ClNC(=O)CCC(N)=O.[CH3:20][CH:21]([OH:24])[C:22]#[CH:23]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH:23]=[C:22]([CH:21]([OH:24])[CH3:20])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: ON=Cc1ccc(F)cc1
Agent: NC(=O)CCC(=O)NCl
Solvent: ClCCl
Product: CC(O)c1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a stirred solution of 4-fluorobenzaldehyde oxime (0.2 g, 1.4 mmol) in DCM (10 mL) was added N-chlorosuccinamide (0.1 g, 1.4 mmol) and the reaction stirred for 1 hour at room temperature. But-3-yn-2-ol (0.23 g, 1.68 mmol) was added and the reaction mixture stirred at reflux for 3 h. After completion of the reaction (as monitored by TLC), the mixture was extracted with DCM (3×100 mL), the organic layer washed with water (100 mL) followed by brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (60-120 mesh; using 50% ethyl acetate in hexanes) to obtain 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanol as liquid (0.15 g, 50% yield). 1H NMR (400 MHz, CDCl3): δ 7.76 (dd, 2H), 7.05 (t, 2H), 6.48 (s, 1H), 5.04 (q, 1H), 1.63 (d, 3H).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([C:12]2[CH2:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CI>C1COCC1>[CH3:1][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1=C(c2ccccc2)Cc2ccccc21
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(c2ccccc2)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Butyllithium (2.5 M in hexanes, 3.0 mL, 7.6 mmol was added dropwise to a suspension of 2-phenylindene (1.382 g, 7.2 mmol) in THF (50 mL) at −78 C. Upon addition of n-butyllithium the reaction mixture turned a dark orange color and 2-phenylindene dissolved. When the addition of the reagents was complete the solution was allowed to warm to room temperature and stirred for 30 minutes. CH3I (1.3 mL, 22 mmol) was added to this solution dropwise and the light brown reaction mixture was heated to 40° C. and stirred for 24 hours. After that the solvents were removed in vacuo and the light brown solid was recrystallized from EtOH (25 mL) at room temperature affording white needles (1.075 g, 75% yield). 1H NMR (CDCl3, 20° C., 300 MHz): Λ 7.52-7.19 (overlapping signals from aromatic protons, 9H), 3.74 (s, 2H), 2.31 (s, 3H). 13C {1H} NMR (CDCl3, 20° C., 75 MHz): δ□1147.49 (C), 142.42 (C), 140.31 (C), 137.56 (C), 134.70 (C), 128.37 (CH), 128.24 (CH), 126.63 (CH), 126.40 (CH), 124.74 (CH), 123.32 (CH), 119.11 (CH), 40.96 (CH2), 11.94 (CH3).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=1)=[O:30].C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1cccc(O)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccc(O)c2)CC1
Yield: 13.5 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.96 g) as a starting compound, 6-bromo-1-(3-hydroxyphenyl)-1-hexanone (0.70 g) and potassium carbonate (1.60 g) were reacted and purified in the same manner as in Example 172 to give 0.17 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-hydroxyphenyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([OH:52])[CH3:51]>[Na]>[CH2:50]([O:52][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1)[CH3:51]
Reactant: CCO
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: [Na]
Product: CCCn1c(=O)cc(OCC)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Yield: 69 %

Procedure:
6-Chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)-biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.8 g) was dissolved in a solution of sodium metal (69 mg) in ethanol (10 mL) and the mixture was heated under reflux for 14 hours with stirring. The reaction mixture was concentrated to dryness and the resulting residue was dissolved in methylene chloride-water. The solution was acidified with 1N hydrochloric acid (1.5 ml), extracted and the organic layer was separated. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give white amorphous powders (0.36 g, 69%). M.p. 108°-119° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=2)[NH:20][CH:19]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC.C(OCC)(=O)C>CN(C=O)C>[CH:28]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[C:16]([C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:17])=[CH2:29]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1ccc2[nH]cc(C(=O)[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A solution (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl )-5-bromo-1H-indole (Example 5a, 252 mg, 0.59 mmol), tributyl(vinyl)tin (0.20 mL, 0.68 mmol) and tetrakistriphenyphosphine palladium (0) (84 mg, 0.073 mmol) in anhydrous DMF (3 mL) was stirred at 95-100° C. for 1 day. After cooling to room temperature, the product was taken into ethyl acetate, filtered through celite, washed with water (2×) and brine (1×), dried over sodium sulfate and the solvent was removed in vacuo. Flash chromatography on silica gel (60-100% ethyl acetate in hexanes) yielded (R)-5-vinyl-3-[(N-carbobenzyloxypyrrolidin-2-yl)carbonyl]-1H-indole (115 mg, 52%). A solution of LAH (0.77 mL, 1M in THF, 0.77 mmol) was added slowly to a cooled (0° C.) solution of (R)-5-vinyl-3-[(N-carbobenzyloxypyrrolidin-2-yl) carbonyl]-1H-indole (115 mg, 0.31 mmol) in THF (5 mL). Once the addition was completed, the reaction mixture was stirred at reflux for 2 h prior to quenching with sodium sulfate decahydrate. The product was taken into ethyl acetate, filtered to remove the solid residue, and the solvent was removed in vacuo. Flash chromatography on silica gel (5% 2M methanolic ammonia in dichloromethane) yielded (R)-5-vinyl-3-[(N-methylpyrrolidin-2-yl) methyl]-1H-indole (52 mg, 71%). HRMS-FAB+ for C16H20N2 : calculated MH+ :241.17047; found MH+ :241.17036.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5]([Si:9]([CH3:12])([CH3:11])Cl)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Si:9]([O:4][CH2:3][CH2:2][Br:1])([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:12])[CH3:11]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCBr
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 2-bromoethanol (50 g, 0.40 mol) in CH2Cl2 (50 mL) was added t-butyldimethyl-chlorosilane (63.4 g, 0.42 mol), triethylamine (45.4 g, 0.45 mol) and dimethylaminopyridine (0.5 g). After stirring overnight the reaction mixture was washed 3× with water. The organic fraction was dried with Na2SO4, filtered, and concentrated in vacuo to provide 85 g of the title compound as a light yellow oil.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C@:21]2([CH3:30])[CH2:26][S:25](=[O:28])(=[O:27])[CH2:24][C:23]([NH2:29])=[N:22]2)[CH:20]=1>>[NH2:29][C:23]1[CH2:24][S:25](=[O:27])(=[O:28])[CH2:26][C@:21]([C:19]2[CH:20]=[C:15]([NH:14][C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:1])[F:13])=[CH:9][N:8]=3)=[O:12])[CH:16]=[CH:17][C:18]=2[F:31])([CH3:30])[N:22]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)CC(N)=N1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)CS(=O)(=O)CC(N)=N1
Yield: 52 %

Procedure:
Prepared from 5-(difluoromethoxy)picolinic acid (69.7 mg, 369 μmol, Eq: 1.00) and (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (100 mg, 369 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (85 mg, 192 μmol, 52.1% yield) as a white foam. MS (ISP): m/z=443.4 [(M+H)].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1.[CH3:31][N:32]=[C:33]=[O:34]>CC(C)=O>[CH3:31][NH:32][C:33](=[O:34])[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:16][CH2:17]2)=[O:11])=[CH:29][CH:30]=1
Reactant: CN=C=O
Reactant: NCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: CC(C)=O
Product: CNC(=O)NCCCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1

Procedure:
1-{1-[4-(3-Aminopropoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.5 g), methylisocyanate (0.15 ml) and acetone (10 ml) are heated at 100° C. for 18 hours in an autoclave. Acetone is distilled off and the residue is purified by silica gel column chromatography (solvent: methylene chloride:methanol=100-50:1) to give 1-{1-[4-(3-(3-methylureido)propoxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (0.19 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[C@H:10]([CH3:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of (R)-1-benzyl-3-methylpiperazine (10 g, 52.6 mmol) in dichloromethane (30 mL) at room temperature was added triethylamine (10.6 g, 106 mmol) and the reaction mixture was stirred for 1 h. To the reaction mixture was added (BOC)2O (13.7 g, 62.8 mmol) and the contents were stirred for further 4 h. The reaction mixture was quenched in water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography eluting with 10% ethyl acetate in n-hexanes to afford 13.0 g of (R)-tert-butyl 4-benzyl-2-methylpiperazine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH:11]1([NH2:14])[CH2:13][CH2:12]1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:14][CH:11]1[CH2:13][CH2:12]1)[C:5]#[N:6]
Reactant: NC1CC1
Reactant: N#Cc1ccc(F)c(Br)c1
Solvent: CO
Product: N#Cc1ccc(NC2CC2)c(Br)c1
Yield: 118.9 %

Procedure:
A solution of 3-bromo-4-fluorobenzonitrile (9.33 mmol) and cyclopropylamine (7.90 g, 136 mmol) in methanol (60 mL) was heated to 60° C. for 20 hours and concentrated. The concentrate was purified by flash column chromatography with 96:4 hexane/ethyl acetate to provide 2.63 g of the desired product. MS (ESI(+)) m/z 239 (M+H)+;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:19]=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:13]=1.[OH-].[K+].O>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]([C:26]2[C:20]3[C:21](=[N:22][CH:23]=[C:18]([C:14]4[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=4)[CH:19]=3)[NH:24][CH:25]=2)[OH:8])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cccc(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 3-nitrobenzaldehyde (534, 1.08 g, 7.17 mmol) in methanol (34 mL) was added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 1.08 g, 5.52 mmol, prepared as described in Example 17) and potassium hydroxide (1.55 g, 27.6 mmol). The reaction was stirred at room temperature for four hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The mixture was purified by silica gel column chromatography eluting with 4% methanol in dichloromethane to provide two different compounds, a white solid (P-1399, R═H, 1.20 g, 63%) MS (ESI) [M+H+]+=347.2, and a light yellow solid (535, R=Me, 0.434 g, 22%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH:12]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:7][CH:6]=1.[N:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[N:37]1([C:43]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:23])[Cl:24])=[O:18])[CH2:13][CH:12]3[O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[CH:9][CH:10]=2)=[O:44])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(OCCOc1ccc(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2OCc2ccc3ccccc3c2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 11.3 %

Procedure:
A solution of 250 mg (0.56 mmol) of 2,2,2-trichloroethyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 20 ml of toluene was treated in succession with 250 ml (2.8 mmol, 5.0 eq.) of morpholine-4-carbonyl chloride, 375 mg (3.08 mmol, 5.5 eq.) of 4-dimethylaminopyridine and 20 μl (0.075 mmol, 0.13 eq.) of dibutyltin diacetate. This mixture was boiled under reflux for 64 hours. In the course of the reaction a further 125 ml (1.40 mmol, 5.0 eq.) of morpholine-4-carbonyl chloride and 188 mg (1.56 mmol, 2.3 eq.) of 4-dimethylaminopyridine were added and the mixture was boiled under reflux for a further 24 hours. The reaction mixture, cooled to room temperature, was poured into 100 ml of an ice/water mixture, stirred for 5 minutes and extracted three times with methylene chloride. The organic phases were each washed once with water and saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The crude product (546 mg) was separated on silica gel using a 9:1 mixture of hexane and acetone as the eluent. There were obtained 42 mg (14% of theory) of 2,2,2-trichloro-ethyl (3RS,4RS)-4-[4-[2-(morpholin-4-ylcarbonyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 665.3, 667 (M+H)+.