Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:6])[CH:4]=O)[CH3:2].[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:10][C:9]=1[C:23]([F:26])([F:25])[F:24].[OH-].[Na+]>ClCCl>[Cl:7][C:8]1[CH:22]=[CH:21][C:11]([O:12][C:13]2[N:18]=[CH:17][C:16]([N:19]=[CH:4][N:3]([CH2:1][CH3:2])[CH3:6])=[C:15]([CH3:20])[CH:14]=2)=[CH:10][C:9]=1[C:23]([F:26])([F:24])[F:25]
Reactant: CCN(C)C=O
Reactant: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)ncc1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(C)C=Nc1cnc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
In a 25 ml single-necked round-bottomed flask, ethylmethylformamide (349 mg) is solubilized in dry dichloromethane (4 ml) at ambient temperature (colourless solution). Under stirring phosphorous oxide chloride (0.37 ml) is added dropwise by syringe. Stirring at ambient temperature is continued for 1 hour, whereupon a pink-orange solution is obtained. To this solution, 6-(4-Chloro-3-trifluoromethyl-phenoxy)-4-methyl-pyridin-3-ylamine (605 mg) dissolved in 1.0 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at an ambient temperature for 1 hour. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 10 minutes. The mixture is then extracted with dichloromethane (2×50 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this gum by flash chromatography over silica gel with hexane/ethyl acetate 1:1 (v:v) gives 0.67 g of the compound as a brownish oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:23]=[N:24][N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([N:35]3[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]3)=[N:27][C:26]=12.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C(Cl)Cl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:23]=[N:24][N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([N:35]3[CH2:36][CH2:37][CH:38]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH2:39][CH2:40]3)=[N:27][C:26]=12
Reactant: O=C1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccccc1-c1nnn2c1nc(N1CCC(N3CCOCC3)CC1)c1ccccc12
Reaction time: 48 h
Yield: 71 %

Procedure:
Sodium triacetoxyborohydride (0.53 g, 2.75 mmol) was added portionwise over 10 min to a solution of 3-(2-fluorophenyl)-5-(4-oxopiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.30 g, 0.83 mmol) and morpholine (0.36 g, 4.1 mmol) in CH2Cl2 (5 ml) and the mixture was allowed to stir for a further 48 h. The mixture was diluted with CH2Cl2 (150 ml), washed with water (50 ml) and brine (50 ml), dried over MgSO4 and evaporated to give a yellow oil. Purification by flash column chromatography on silica eluting with CH2Cl2:MeOH (98:2) followed by trituration with diethyl ether gave 3-(2-fluorophenyl)-5-[4-(morpholin-4-yl)piperidin-1-yl]-[1,2,3]triazolo[1,5-α]quinazoline (0.255 g, 71%) as a white solid. δH (400 MHz; CDCl3) 1.78-1.88 (2H, m), 2.04-2.08 (2H, m), 2.43-2.53 (1H, m), 2.58-2.68 (4H, m), 3.07-3.14 (2H, m), 3.75-3.78 (4H, m), 4.17-4.22 (2H, m), 7.19-7.30 (2H, m), 7.33-7.39 (1H, m), 7.61 (1H, ddd, J=8, 8 and 1), 7.88 (1H, ddd, J=8, 8 and 1), 8.00 (1H, d, J=8), 8.13 (1H, ddd, J=7, 7 and 2), 8.69 (1H, d, J=8); m/z (ES+) 433 (M+H+).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:22]3[CH:23]=[N:24][C:25]4[N:26]([C:32](=[O:34])[NH2:33])[CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=3)[C:19]=2[C:20]#[N:21])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:36](F)(F)C(O)=O>C(Cl)Cl>[C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:22]3[CH:31]=[C:30]4[C:25](=[N:24][CH:23]=3)[N:26]([C:32]([NH2:33])=[O:34])[CH2:27][CH2:28][CH2:29]4)[C:19]=2[C:20]#[N:21])[CH2:12][CH2:13]1)(=[O:5])[CH3:36]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2C#N)CC1
Solvent: ClCCl
Product: CC(=O)N1CCC(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2C#N)CC1
Reaction time: 16 h

Procedure:
The crude 5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-4-cyano-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.22 mmol) is dissolved in DCM (2.0 mL) and trifluoroacetic acid (0.5 mL) is added. The mixture is stirred for 16 hrs and all the solvent is removed in vacuo. The residue is dissolved in MeOH and is passed through StratoSpheres SPE PL-HCO3 cartridge. The solution is concentrated to give the crude 6-(4-cyano-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide which is used without purification.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:9]1([NH:22][CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH:7]=[CH2:8].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:6]([C:9]1([N:22]([CH2:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH:26]=[CH:27][N:28]3[S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=2)(=[O:34])=[O:35])[C:1](=[O:4])[CH:2]=[CH2:3])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)[CH:7]=[CH2:8]
Reactant: C=CC(=O)Cl
Reactant: C=CCC1(NCc2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC1(N(Cc2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)C(=O)C=C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Acryloyl chloride (0.360 g, 0.401 mmol) was added at 0° C. to a stirred solution of tert-butyl 4-allyl-4-((1-tosyl-1H-indol-4-yl)methylamino)piperidine-1-carboxylate (0.2 g, 0.382 mmol), diisopropylethylamine (0.32 mL, 1.91 mmol) in DCM (5.0 mL). The reaction mixture was stirred at 0° C. for 30 min and was then allowed to warm to rt and stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: 5% ethyl acetate in hexane) to yield the title compound as a white solid (0.16 g, 72%). LCMS RtA=0.774, [M+H-Boc]+=477.9
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23].O>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH3:23])[CH2:11][CH2:10]1
Reactant: CCI
Reactant: Fc1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN1CCC(c2cccc(F)c2F)CC1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
To a solution of 4-(2,3-difluorophenyl)piperidine (0.41 g, 2.08 mmol) in acetonitrile (4 ml), was added potassium carbonate (0.57 g, 4.16 mmol) and 1-iodoethane (0.163 ml, 2.12 mmol) and the mixture was heated to 120° C. in a sealed tube under microwave radiation for 1200 s. Water (50 ml) was added and the mixture was extracted with ethylacetate (3×40 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The oily residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (0.31 g). MS m/z (reL. intensity, 70 eV) 225 (M+, 20), 224 (14), 211 (13), 210 (bp), 127 (8).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3C[C:13]4C=C[C:23]([O:26]C)=[CH:22][C:14]=4[C:15]([CH3:21])([CH3:20])[C:16]=3[NH:17]2)=[CH:9][CH:8]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C(OCC)C.O>[F:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3[C:23](=[O:26])[C:22]4[CH:2]=[CH:1][C:5]([O:4][CH3:3])=[CH:13][C:14]=4[C:15]([CH3:20])([CH3:21])[C:16]=3[NH:17]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(F)ccc3c1C2
Reactant: C1CCOC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(F)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under nitrogen atmosphere, to the THF (1.8 mL)-water (0.18 mL) solution of 3-fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole (Compound V2, 72.4 mg, 0.245 mmol), DDQ (122.4 mg, 0.539 mmol) was added and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added with diethyl ether and 0.5 N aqueous solution of sodium hydroxide (2 mL), and the resulting mixture was extracted twice with diethyl ether. The organic layer was washed twice with 0.5 N aqueous solution of sodium hydroxide (2 mL) and subsequently twice with brine (2 mL), and dried over sodium sulfate. After concentration under reduced pressure, hexane/ethyl acetate (5:1) and diethyl ether were added to the obtained crude product, and the solid was triturated. After removing the supernatant and drying under reduced pressure, the title compound was obtained (yellow solid, 57.0 mg, 75%).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C:15](=[CH2:16])[C@@H:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[CH:18]=2)[C@H:13]([O:33]CC2C=CC=CC=2)[C@@H:12]([O:41]CC2C=CC=CC=2)[C@@H:11]1[O:49]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C@@H:14]2[C:15](=[CH2:16])[C@H:10]([CH2:9][OH:8])[C@@H:11]([OH:49])[C@H:12]([OH:41])[C@H:13]2[OH:33])=[CH:18][C:19]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=1
Reactant: C=C1[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1c1ccc(Cl)c(Cc2ccc(CC)cc2)c1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: C=C1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1c1ccc(Cl)c(Cc2ccc(CC)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a solution of ((1S,2R,3R,4R,6S)-4-(benzyloxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)-5-methylenecyclohexane-1,2,3-triyl)tris(oxy)tris(methylene)tribenzene (34, 24 mg, 31.4 mmol) in anhydrous DCM (0.8 mL) in a vial at −78° C. under a nitrogen blanket was added BCl3 (1 M in DCM, 0.25 mL) drop-wise over 15 minutes. The resulting mixture was stirred at −78° C. for 30 minutes and gradually warmed to −20° C. The resulting mixture was stirred at −20° C. for another 30 minutes. At this time, LC-MS indicated that the reaction was complete. The solution was cooled to −78° C. and methanol (1 mL) was slowly added. The resulting solution was warmed to room temperature and concentrated under reduced pressure. The residue was dissolved in 0.5 mL of 1:1 DCM:MeOH and loaded on a preparative TLC plate, which was developed in 15:1 (DCM:MeOH) to obtain 9 mg (71%) of compound 35 as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.29-6.89 (m, 7H), 4.80 (s, 1H), 4.28 (s, 1H), 3.95 (m, 4H), 3.64 (m, 2H), 3.51(m, 3H), 3.22 (m, 1H), 2.58 (q, J=7.2 Hz, 2H), 2.25 (m, 1H), 1.18 (t, J=7.5 Hz, 3H). LC-ESI-MS m/z 425 (M+Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[N:57]1([C:63](=[O:65])[CH3:64])[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:63]([N:57]1[CH2:62][CH2:61][N:60]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH2:59][CH2:58]1)(=[O:65])[CH3:64]
Reactant: CC(C)(C)N(Cc1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Reactant: CC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CN(C(C)(C)C)S(=O)(=O)Cc3ccccc3)cc2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
In a vial, N-[(4-bromophenyl)methyl]-N-tert-butyl-1-phenylmethanesulfonamide (186 mg; 0.47 mmol), palladium(II) acetate (5 mg, 0.023 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (22 mg, 0.047 mmol) sodium tert-butoxide (61 mg, 0.61 mmol) were weighed out and the vial was purged with nitrogen. 1,4-Dioxane (3 mL) and 1-piperazin-1-ylethanone (78 mg, 0.61 mmol) were then added and the reaction was stirred at 100° C. for 16 hours. The reaction was filtered through diatomaceous earth, concentrated and purified by preparative reverse phase HPLC to yield 141 mg of N-(4-(4-acetylpiperazin-1-yl)benzyl)-N-tert-butyl-1-phenylmethanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.47-7.33 (m, 5H), 7.27-7.16 (m, 2H), 6.96-6.83 (m, 2H), 4.41 (s, 2H), 4.16 (s, 2H), 3.62-3.49 (m, 4H), 3.19-3.09 (m, 2H), 3.09-2.95 (m, 2H), 2.03 (s, 3H), 1.33 (s, 9H); LCMS (m/z) ES+ 444.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[NH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: Nc1cccs1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Product: CCOC(=O)C(=CNc1cccs1)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)3-ethoxyacrylate (5.0 g)and 2-aminothiophene (2.22 g), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2-thienyl)aminoacrylate, which is then treated with 60% sodium hydride as in Reference Example 22 to give ethyl 1-(2-thienyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.05 g), as white powder (recrystallized from ethyl acetate - n-hexane), m.p. 198°-200° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:8]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]([CH2:17]C3C=CC=CC=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C(OC(C1C(OC(=O)C(C)(C)C)=C2C(Br)=C(Br)N(C)C2=CN=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:8]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]([CH3:17])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c(C)c(C)n2Cc2ccccc2)c1OC(=O)C(C)(C)C
Agent: CCOC(=O)c1ncc2c(c(Br)c(Br)n2C)c1OC(=O)C(C)(C)C
Product: CCOC(=O)c1ncc2c(c(C)c(C)n2C)c1OC(=O)C(C)(C)C

Procedure:
Prepared in analogy to that of 1-benzyl-4-(2,2-dimethyl-propionyloxy)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester from 2,3-Dibromo-4-(2,2-dimethyl-propionyloxy)-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester. The title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.53 (s, 3H), 4.42 (q, 2H, J=7.0 Hz), 3.76 (s, 3H), 2.34 (s, 3H), 2.29 (s, 3H), 1.46 (s, 9H), 1.41 (t, 3H, J=7.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11])(=[O:14])[CH3:13]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A mixture of 10 g. 4-hydroxy-3-chlorobenzoic acid and 50 ml. of acetic anhydride is refluxed for two hours. Excess acetic anhydride is distilled under vacuum and the residue diluted and stirred with a mixture of methanol (100 ml.) and water (20 ml.) at about 50° for 30 minutes. The mixture is then reduced to low volume under vacuum, water added and the precipitated crystals filtered. Recrystallization from toluene gives 6.5 g. (52% yield) m.p. 162°-163° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]Br.[Cl:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][SiH:20](Cl)[CH2:19][CH2:18]2)=[CH:10][C:9]=1[F:24]>>[Cl:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][C@H:17]2[CH2:22][CH2:21][Si@H:20]([CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1])[CH2:19][CH2:18]2)=[CH:10][C:9]=1[F:24]
Reactant: Fc1cc(OCC2CC[SiH](Cl)CC2)cc(F)c1Cl
Reactant: CC(C)CCBr
Product: CC(C)CC[Si@H]1CC[C@H](COc2cc(F)c(Cl)c(F)c2)CC1

Procedure:
The general procedure of Example 1 was repeated using 3-methylbutyl bromide and 4-(4-chloro-3,5-difluorophenyloxymethyl)-1-chloro-1-silacyclohexane, thereby obtaining the intended product.
Reaction SMILES: [NH2-].[Na+].[C:3]1(=[O:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.N.[C:14]1([CH3:29])[CH:19]=[CH:18][C:17]([C:20](OC2C=CC=CC=2)=[O:21])=[CH:16][CH:15]=1.Cl>CCOCC>[C:14]1([CH3:29])[CH:19]=[CH:18][C:17]([C:20]([CH:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:3]2=[O:12])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)Oc2ccccc2)cc1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: N
Agent: [NH2-]
Solvent: CCOCC
Product: Cc1ccc(C(=O)C2Cc3ccccc3C2=O)cc1
Reaction time: 1 h

Procedure:
To a suspension of 7.8 g. of sodium amide in 100 ml. anhydrous ether under an atmosphere of nitrogen is added 13.2 g. of indan-1-one. Ammonia is evolved and the mixture is stirred and heated under reflux until evolution ceases, after about 1 hour. A solution of 21.2 g. of phenyl p-toluate in 250 ml. of ether is then added dropwise over a period of 15 min. and the resulting mixture is heated under reflux for 11/2 hr. It is then cooled and poured onto 500 g. of ice, and then made slightly acidic by the addition of 2N hydrochloric acid. The organic layer is separated and washed twice with a 10% solution of sodium bicarbonate and once with water. It is then shaken with a saturated aqueous solution of cupric acetate, and the 2-phase system is stirred vigorously overnight. The resulting brown solid produced is filtered off and added to a stirred mixture of 250 ml. of ether and 100 ml of 2N hydrochloric acid. After 1 hr. the ether layer is separated, washed with sodium bicarbonate solution and water and dried over sodium sulfate. Removal of the ether gives a crude crystalline residue which can be recrystallized from ether to give the title product (m.p. 103°-105°).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20](Br)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[N:7]([C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:32]4[C:27]([O:26][CH3:25])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ncccc1-c1cnc2ccc(N3CC[C@H](N(C)C(=O)OC(C)(C)C)C3)nn12
Temperature: 150 °C
Yield: 77.7 %

Procedure:
A mixture of [(S)-1-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert butyl ester (83 mg, 0.21 mmol), 2-methoxypyridine-3-boronic acid (43 mg, 0.28 mmol), K2CO3 (87 mg, 0.63 mmol) and dichlorobis(triphenylphosphine)palladium(II) (7.4 mg, 0.011 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the organic layer was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (69.3 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.50 (s, 9H) 2.11-2.29 (m, 2H) 2.84 (s, 3H) 3.40 (dd, J=10.48, 6.95 Hz, 1H) 3.46-3.53 (m, 1H) 3.67-3.74 (m, 2H) 4.08 (s, 3H) 4.94 (br. s., 1H) 6.61 (d, J=9.60 Hz, 1H) 7.03 (dd, J=7.58, 4.80 Hz, 1H) 7.77 (d, J=9.85 Hz, 1H) 8.12-8.18 (m, 2H) 8.86 (dd, J=7.58, 1.77 Hz, 1H). LRMS (ESI) m/z 425.3 [(M+H)]+, calc'd for C22H28N6O3: 424.51.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][C@H:13]([OH:15])[C@@H:12]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:29]([O:15][C@H:13]1[CH2:14][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[CH2:10][CH2:11][C@@H:12]1[C:16]1[N:20]([CH3:21])[N:19]=[CH:18][CH:17]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cn1nccc1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nccc1[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1OC(=O)c1ccccc1
Yield: 71.6 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 107a by using the (1S*,2R*,5R*)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (774 mg, 2.49 mmol) prepared in Example 160a, triethylamine (2.08 mL, 14.9 mmol), benzoyl chloride (1.45 mL, 12.6 mmol) and dichloromethane (8.0 mL), to yield the title compound (739 mg, 72%) as a colorless oil.
Reaction SMILES: C(O[C:4](=[O:8])[O:5][CH2:6][CH3:7])C.[NH:9](CCO)[CH2:10][CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][N:9]1[CH2:7][CH2:6][O:5][C:4]1=[O:8]
Reactant: OCCNCCO
Reactant: CCOC(=O)OCC
Product: O=C1OCCN1CCO

Procedure:
This compound was prepared from diethylcarbonate and diethanolamine in accordance with the method of E. K. Drechsel in the Journal of Organic Chemistry 22 (1957), page 851. A clear, slightly colored liquid having a boiling point of 154° was obtained.
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[C:5](=[S:12])[NH:6][C:7](=[O:11])[NH:8][C:9]=1[CH3:10].[OH-].[K+]>>[CH3:10][C:9]1[NH:8][C:7](=[O:11])[N:6]=[C:5]([S:12][CH3:1])[C:4]=1[Cl:3]
Reactant: Cc1[nH]c(=O)[nH]c(=S)c1Cl
Reactant: CI
Agent: [K+]
Agent: [OH-]
Product: CSc1nc(=O)[nH]c(C)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
Methyl iodide (0.012 mol) was added to an aqueous solution prepared from 5-chloro-6-methyl-4-thiouracil (0.01 mol) and 0.725 M KOH (25 ml) and the reaction mixture was stirred at room temperature for 5 h. The solid precipitate formed was collected and was recrystallized from isopropanol; yield 65%, m.p. 268°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.C(OC(N1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])=O)C>ClC>[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([N:1]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: CCl
Product: O=C1c2ccccc2C(=O)N1C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 73.3 %

Procedure:
10.0 g of 3-amino-1-benzylpyrrolidine was dissolved into 10 ml of chloromethane, to which 12.4 g of N-ethoxycarbonylphthalimide was added and stirred at a room temperature for 10 hours. The solvent was distilled off, diethyl ether was added and insoluble matters were filtered out. The filtrate was concentrated and purified on silica gel column chromatography, to obtain 12.70 g of the above-captioned compound (yield: 73%)
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](O)=[O:4].[CH3:10][N:11]1[C@@H]2CC3C=CC(OC)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.C(OC(Cl)=O)C(C)C>C1COCC1>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([NH:11][CH3:10])=[O:4]
Reactant: CC(C)CC(Br)C(=O)O
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)C(Br)CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To the solution of DL-alpha-bromoisocaproic acid in THF (4 ml) was added N-methylmorphine (0.18 ml, 1.63 mmol), followed by dropwise addition of isobutylchloroformate (0.15 ml, 1.16 mmol). A white solid precipitate was formed. After stirring at RT for 1.5 h, the white solid was filtered. Methylamine (1 ml, 2N in THF) was added to the filtrate. The reaction mixture was concentrated after 0.5 hour. The resultant crude material was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4 and concentrated to give the title compound, 2-bromo-N,4-dimethylpentanamide, (0.18 g, 78%) as an oil.