Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[CH2:8]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:21]=[CH:22][C:23]([N:24]=[C:27]=[S:28])=[CH:25][CH:26]=2)[CH2:18][CH2:19]1)[CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C=CCCCC[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCCCC[C@H]1CC[C@H](c2ccc(N=C=S)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.36 ml of triethylamine in 15 ml of chloroform was treated dropwise at -10° C. with a solution of 2.18 g of p-[trans-4-(5-hexenyl)cyclohexyl]aniline in 20 ml of chloroform. After 5 minutes the mixture was treated with a solution of 690 μl of thiophosgene in 10 ml of chloroform, warmed to room temperature and stirred for 2 hours. Thereafter, the reaction mixture was partitioned between water and chloroform. The organic phase was dried over magnesium sulphate and concentrated. Chromatographic separation on 140 g of silica gel using ethyl acetate/petroleum ether (vol. 5:95) and subsequent crystallization from 80 ml of methanol and low temperature filtration gave 1.24 g of p-[trans-4-(5-hexenyl)cyclohexyl]phenylisothiocyanate (purity 100%) as a milky liquid of m.p. (C-N) 15.2° C. and cl.p. (N-I) 46.1° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:24]=O)=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH3:23])[N:18]=[CH:17]4)[N:8]=2)[CH:6]=1.Cl.[NH:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:24][N:27]2[CH2:30][CH:29]([OH:31])[CH2:28]2)=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH3:23])[N:18]=[CH:17]4)[N:8]=2)[CH:6]=1
Reactant: OC1CNC1
Reactant: Cc1cn(-c2ccnc(Nc3ccc4c(cnn4C)c3)n2)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccnc(Nc3ccc4c(cnn4C)c3)n2)cc1CN1CC(O)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a slurry of intermediate 13 (0.45 g, 1.3 mmol), 3-azetidinol hydrochloride (0.3 g, 2.7 mmol) and triethylamine (0.76 mL) in 50 mL of dichloromethane, was added NaBH(OAc)3 (0.86 g, 4.5 mmol) at room temperature. The reaction was stirred for 12 hour at room temperature and then quenched with 1N—NaOH. It was extracted with dichloromethane (×2) and washed with brine. The collected organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by column chromatography to afford desired Compound No. 143 as a pale yellow solid (0.27 g, 51%); MS (ESI) m/z 391 [M+H]+.]+; 1H NMR (300 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.48 (d, 1H, J=5.4 Hz), 8.30 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.62 (m, 2H), 7.12 (d, 1H, J=5.4 Hz), 5.34 (m, 1H), 4.19 (m, 1H), 4.04 (s, 3H), 3.49 (m, 2H), 3044 (s, 2H), 2.77 (m, 2H), 2.29 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:2]=1[O:1][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 155.8 %

Procedure:
2,4-dihydroxy-benzoic acid (35) (2 g, 13 mmol) in THF (250 mL) was mixed with cesium carbonate (16.9 g, 52 mmol) and benzyl bromide (6.2 mL, 52 mmol). The reaction mixture was refluxed overnight and then cooled down to room temperature. Cesium carbonate was filtered off through filter paper. The solvent was removed under reduced pressure. Liquid-liquid extraction was performed using 200 mL of CHCl3 and H2O (100 mL×3). The organic layer was dried over MgSO4. After filtering off the MgSO4, the organic layer was concentrated to give compound 36 (4.3 g) as a solid. LC-MS (ESI): m/e=425.2 [M+1]+
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[C:32]([C:36]1[S:37][CH:38]=[C:39](/[CH:41]=[CH:42]/[C:43]2[C:44]([OH:54])=[N:45][N:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:47]=2)[N:40]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([C:36]1[S:37][CH:38]=[C:39](/[CH:41]=[CH:42]/[C:43]2[C:44]([O:54][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:45][N:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:47]=2)[N:40]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Reactant: CC(C)(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(C(C)(C)C)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.49 g), 4-[(E)-2-(2-tert-butyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol hydrochloride (1.32 g), potassium carbonate (1.00 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl {4-[4-({4-[({4-[(E)-2-(2-tert-butyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (1.11 g, yield 45%) as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][CH:14]3[N:9]([CH2:10][CH2:11][C:12](=O)[CH2:13]3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:19]1([N:18]=[C:12]2[CH2:11][CH2:10][N:9]3[CH:14]([CH2:15][CH2:16][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8]3)[CH2:13]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCN2CC(c3ccccc3)CCC2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(N=C2CCN3CC(c4ccccc4)CCC3C2)cc1

Procedure:
The ketone (III) (5.25 g.) was dissolved in 100 ml. toluene and 2.13 g. aniline. A small amount of pTSA was added and the solution was refluxed overnight using a Dean-Starke trap. The solvent was removed in vacuo Yield, 6.9 g. The semi-solid still had some ketone present (IR spectrum) so the residue was recycled using 1 g. aniline. The reaction was worked up as above and the crude anil showed no ketone. Yield, 7.2 g. (6.97 g. theoretical; probably excess aniline present).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH2:18]([C@H:20]1[N:29]([CH:30]([CH3:32])[CH3:31])[C:28]2[N:27]=[C:26]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([C:43](O)=[O:44])=[C:38]4[C:42]=3[O:41][CH2:40][CH2:39]4)[N:25]=[CH:24][C:23]=2[N:22]([CH3:46])[C:21]1=[O:47])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH:17][C:43]([C:37]4[CH:36]=[CH:35][C:34]([NH:33][C:26]5[N:25]=[CH:24][C:23]6[N:22]([CH3:46])[C:21](=[O:47])[C@@H:20]([CH2:18][CH3:19])[N:29]([CH:30]([CH3:31])[CH3:32])[C:28]=6[N:27]=5)=[C:42]5[O:41][CH2:40][CH2:39][C:38]=45)=[O:44])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Reactant: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
(cis)-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (577 mg, 2.43 mmol), 7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (1 g, 2.43 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (780 mg, 2.43 mmol) and diisopropylethylamine (690 mg, 5.35 mmol) were dissolved in 40 mL of dichloromethane. The reaction mixture was stirred for 2 hours. The resulting solution was added with 50 mL of aqueous ammonia and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 44 (576 mg, yield: 38.0%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][C:4]=1F)#[N:2].[C:23]([O-])([O-])=[O:24].[K+].[K+]>CO.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][C:4]=1[O:24][CH3:23])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(ccn2-c2ccc(C#N)c(F)c2)c1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(ccn2-c2ccc(C#N)c(OC)c2)c1
Temperature: 75 °C
Yield: 102 %

Procedure:
A solution of 95 mg (0.32 mmol) of compound 9m was combined with 120 mg (0.87 mmol) of K2CO3 in 8 mL of MeOH and heated at 75° C. for 5 h. The mixture was cooled, diluted with water, and extracted with CH2Cl2. The organic solution was concentrated to give 100 mg (100%) of 9n as a white solid.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:9][C:10]([CH2:12][O:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][N+:29]([O-:31])=[O:30])=[O:11])([CH3:8])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:3][CH2:4][C:5]([NH:9][C:10]([CH2:12][O:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][N+:29]([O-:31])=[O:30])=[O:11])([CH2:6][OH:7])[CH3:8]
Reactant: CC1(NC(=O)COC(=O)c2ccccc2OC(=O)CCCCCO[N+](=O)[O-])COC(C)(C)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(CO)(CO)NC(=O)COC(=O)c1ccccc1OC(=O)CCCCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a solution of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid (2,2,5-trimethyl-[1,3]dioxan-5-yl carbamoyl)-methyl ester (5.5 grams) in a mixture of Methanol (55 ml) and water (2.5 ml), was added p-toluenesulfonic acid (0.2 grams) and stirred at room temperature for 2 hours. The reaction mixture poured onto cold water, extracted with Ethyl acetate, washed the organic layer with water, dried over Sodium sulphate and distilled under vacuum to get crude compound which was purified by column chromatography using Hexane:Ethyl acetate as eluant to get 1 grams of 2-(6-Nitrooxy-hexanoyloxy)-benzoic acid (2-hydroxy-1-hydroxy methyl-1-methyl-ethylcarbamoyl)-methyl ester as light yellow syrup. The product was characterized by 1H NMR (DMSO-d6) δ 1.16 (s, 3H, CH3), 1.45 (m, 2H, CH2), 1.70 (m, 4H, CH2X2), 2.64 (t, 2H, CH2), 3.50 (m, 4H, CH2X2), 4.55 (t, 2H, CH2), 4.70 (s, 2H, CH2), 4.80 (t, 2H, OH X2), 7.25 (d, 1H, Ar), 7.40 (m, 2H, Ar & NH), 7.70 (t, 1H, Ar), 8.00 (d, 1H, Ar).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH3:25])=[O:23])[CH2:3]1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O.Cl>N1C=CC=CC=1>[CH3:25][O:24][C:22]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([C:15](=[O:21])[CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C@H:4]([CH2:3][C@@H:2]([O:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:19][CH2:18]1)[CH2:5][CH2:6]3)=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 96 h

Procedure:
3β-Hydroxy-17β-methoxycarbonyl-5α-androstan-11-one (4.75 g.) and toluene-p-sulphonyl chloride (5 g.) in pyridine (50 ml.) were allowed to stand at room temperature for four days. Water (10 ml.) was added, the resulting solution was stirred for an hour and was then poured into stirred water (1.1). The mixture was acidified with hydrochloric acid and the product collected, washed well with water and dried over sodium hydroxide in vacuo. Recrystallisation from chloroform/hexane containing a trace of ether afforded pure title compound (3.4 g.) as needles; m.p. 158°-160°; [α]D + 42.5°, (c 1.09).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Cl.[NH+]1C=CC=CC=1.O>C(OC)(C)(C)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(F)c1C#N
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: COC(C)(C)C
Product: N#Cc1c(O)cccc1F
Temperature: 190 °C
Reaction time: 5 h

Procedure:
151 g (1 mol) of 2-fluoro-6-methoxybenzonitrile and 346.5 g (3 mol) of pyridinium hydrochloride were introduced into a 2 l flask and then slowly heated to 190° C. under a protective gas atmosphere and then stirred at this temperature for 5 h. The mixture was cooled by slowly stirring to room temperature overnight. Then 1000 ml of water were added, and the mixture was heated to 80° C. After adding 1000 ml of methyl tert.-butyl ether, the phases were separated and the aqueous phase was back-extracted twice with 500 ml of methyl tert.-butyl ether. The combined methyl tert.-butyl ether phases were washed once with 800 ml of 10% strength aqueous sodium hydroxide solution and once with 400 ml of water. The two aqueous phases were combined, adjusted to pH 2 with concentrated hydrochloric acid and washed three times with 500 ml of methylene chloride. Then, the combined organic phases were washed once with 10% strength hydrochloric acid. The organic phase was dried over sodium sulfate. Finally, the solvent was distilled off in vacuo. Yield: 120 g (87% of theory) of the desired product of purity >99% according to GC. 1H NMR (in D6 dimethylsulfoxide): δ=6.85 ppm (m, 2H, arom. H), 7.55 ppm (q, 1H, arom. H), 11.7 ppm (s, 1H, OH).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[C:15]([Cl:28])[CH:14]=1.[CH:29](N1CCCCC1)=[O:30].[Cl-].[NH4+]>O1CCCC1>[Si:21]([O:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:29]=[O:30])=[CH:14][C:15]=1[Cl:28])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1Cl
Reactant: O=CN1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C=O)cc1Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution (1.6 M, 8.3 ml) of n-butyl lithium/hexane was added to a solution of 4-bromo-1-((tert-butyldimethylsilyloxy)methyl)-2-chlorobenzene (4.03 g) in tetrahydrofuran (10 ml) under a nitrogen atmosphere at −60° C. and the mixture was stirred for 45 min. The reaction mixture was once heated to 0° C. and then cooled to −40° C. and 1-formyl piperidine (1.63 g) was dropwise added over 3 min. Then, the reaction mixture was heated to 0° C. over 2 hr. Aqueous ammonium chloride was added to the reaction mixture and the resulting product was extracted twice with hexane. The organic layers were combined, washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=30/1) to give the objective compound (2.49 g) as a colorless oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:77][CH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:77][CH:78]5[CH2:83][CH2:82][O:81][CH2:80][CH2:79]5)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCOCC1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a mixture of 0.0651 g (0.141 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0213 g (0.211 mmole) of 4-aminotetrahydropyran was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0631 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-217).
Reaction SMILES: [C:1]1([N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CS(C)=O>[C:27]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:14][C:11]5[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=5)[CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:21]=4)=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1nccc(-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)n1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)c2nccc(-c3ccc(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)cc3)n2)cc1
Reaction time: 5 h
Yield: 81 %

Procedure:
4-(4′-Diphenylaminobiphenyl-4-yl)pyrimidine-2-amine (100 mg, 0.24 mmol) and sodium hydroxide (38 mg, 0.96 mmol) were added in dimethylsulfoxide (1 mL), and mixed at 100° C. for 30 minutes. This solution was added with a solution of benzyl bromide (63.1 μL, 0.53 mmol) in dimethylsulfoxide (1 mL) at 100° C. for 30 minutes, followed by stirring for 5 hours. This solution was cooled and added with water (100 mL) and a saturated saline solution, and then allowed to stand for 24 hours. The precipitated crystalline material was purified by column chromatogram (silica gel, hexane: EtOAc=8:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
0.25 g (0.0011 mol) of 1-(4-chloro-benzyl)-piperidin-4-ol and 0.39 ml (0.0028 mol) of triethylamine were dissolved in 11 ml of toluene, treated with 0.184ml (0.0014mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.135 9 (39%) of 1-(4-chloro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([NH2:26])=[O:25])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[F:15])=[CH:11][C:10]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:9][CH:8]=3.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[F:15][C:14]1[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH:11]=3)[NH:6][C:5]=2[C:4]([C:24]([NH2:26])=[O:25])=[CH:3][C:2]=1[C:32]1[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
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: CO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4ccc(C(=O)N5CCOCC5)cc4c3c2F)cc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
3-Bromo-4-fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (25 mg, 0.059 mmol), 4-methoxyphenylboronic acid (13.56 mg, 0.089 mmol), Pd(Ph3P)4 (6.87 mg, 5.95 μmol) and Na2CO3(2M) (0.074 mL, 0.149 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was stirred at 105° C. for 3 hrs. The mixture was filtered through an ACRODISC® PTFE membrane (0.45 um) and purified using preparative HPLC to give 12.2 mg of titled product. MS (ESI) m/z 448.06 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.86 (bs, 1H), 8.31 (bs, 1H), 8.16 (d, 1H, J=9.1), 8.14 (s, 1H), 7.83 (d, 1H, J=8.6), 7.66 (d, 2H, J=8.2), 7.55(m, 2H), 7.11 (d, 2H, J=8.5), 3.84 (s, 3H), 3.7-3.5 (bm, 8H).