Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:11])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 408 %

Procedure:
To a solution of 4-chloro-benzaldehyde oxime (20 g, 0.13 mol) in anhydrous dimethylformamide (80 ml) was added N-chlorosuccinimide (3.51 g, 0.03 mol, 0.2 eq) at room temperature. Subsequently, HCl gas drawn from the headspace of concentrated hydrochloric acid was bubbled through the reaction mixture. Then, additional N-chlorosuccinimide (14.06 g, 0.11 mol, 0.8 eq) was then added in four portions and the mixture was stirred at room temperature for twenty hours before it was poured into ice-water (200 ml) and extracted twice with methyl t-butyl ether. The combined organic layers were washed with water and brine, and then dried and concentrated to give the title compound as a white solid (23.26 g): 1H NMR (CDCl3, 200 MHz): δ=7.97 (s, 1H), 7.77 (m, 2H), 7.36 (m, 2 H). 13C NMR (CDCl3, 50 MHz): δ=139.37, 137.10, 130.99, 128.94, 128.57
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[C:8]([F:17])=[C:9]([CH2:14][C:15]#[N:16])[CH:10]=[C:11]([F:13])[CH:12]=1)(C)C.[CH3:20][O:21][CH2:22][CH2:23]Br.[F-].[K+]>CN(C=O)C>[F:17][C:8]1[C:7]([O:6][CH2:23][CH2:22][O:21][CH3:20])=[CH:12][C:11]([F:13])=[CH:10][C:9]=1[CH2:14][C:15]#[N:16]
Reactant: COCCBr
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(CC#N)c1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(F)cc(CC#N)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.7 %

Procedure:
To a solution of (3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,5-difluorophenyl)acetonitrile (1.22 g, 4.30 mmol) in DMF (10 mL) was added 2-bromoethyl methyl ether (485 μl, 5.16 mmol) and potassium fluoride (0.5 g, 8.6 mmol). The mixture was stirred at room temperature for 15 hrs. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford an orange oil, which was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes gave 690 mg, 3.04 mmol (71%) of (2,5-difluoro-3-{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile as a colorless oil. 1H NMR (CDCl3): 6.75-6.69 (m, 2H), 4.17-4.15 (m, 2H), 3.78-3.74 (m, 4H), 3.44 (s, 3H); MS (EI) for C11H11NO2F2: 228 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:28][CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: CN(C)CCCN
Product: CN(C)CCCNc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1
Yield: 44 %

Procedure:
Following the procedure described above in Example 34, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with N1,N1-dimethylpropane-1,3-diamine. The crude product was purified by flash column chromatography (15% methanol in methylene chloride) to give a yellow solid (0.040 g, 44%). 1H NMR (400 MHz, chloroform-D) δ ppm 1.8 (m, 2 H) 2.3 (s, 6 H) 2.4 (t, J=6.4 Hz, 2 H) 3.2 (t, J=6.6 Hz, 2 H) 3.5 (s, 1 H) 6.3 (s, 1 H) 7.1 (m, 2 H) 7.2 (t, J=8.6 Hz, 1 H) 7.3 (dd, J=6.3, 2.8 Hz, 1 H) 8.4 (s, 1 H) 9.0 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:43]=[C:42](Br)[CH:41]=[CH:40][C:39]=1[F:45]>>[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:43]=[C:42]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:33])[CH2:31][CH3:32])[CH:41]=[CH:40][C:39]=1[F:45]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: COC(=O)Cc1cc(Br)ccc1F
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1ccc(F)c(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (5-bromo-2-fluoro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:15])=[CH2:14])[CH:8]=1)([CH3:6])[CH3:5])=C=O.[OH-].[K+]>CC(O)(C)C>[C:13]([C:9]1[CH:8]=[C:7]([C:4]([NH2:1])([CH3:6])[CH3:5])[CH:12]=[CH:11][CH:10]=1)([CH3:15])=[CH2:14]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: C=C(C)c1cccc(C(C)(C)N)c1
Yield: 37.7 %

Procedure:
To a solution of 1-(1-isocyanato-1-methyl-ethyl)-3-isopropenyl-benzene (10 g, 50 mmol) in t-BuOH (1000 mL) was added KOH (40.0 g, 71.6 mmol). The mixture was stirred at reflux for 3 h. The resultant mixture was cooled down to room temperature, concentrated and dissolved in CH2Cl2. Solid residue was filtered off and the organic layer was adjusted to pH<7 using cone. HCl. The ammonium salt was extracted with water. The aqueous layer was made basic using an aqueous NaOH solution [5% w/w, 200 ml] and free based amine was then extracted with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(3-isopropenyl-phenyl)-1-methyl-ethylamine (3.3 g, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH2:23](O)[CH3:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:23][CH3:24])=[O:10])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
A solution of 43 g (200 mmol) of 4-bromophenylacetic acid and 0.2 g of conc. H2SO4 in 470 ml of ethanol was refluxed for 16 hours. The reaction mixture was cooled to ambient temperature, stirred with 6 g of solid K2CO3 for 30 minutes and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (200 ml), washed with 10% aqueous NaHCO3 (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:44])[NH:6][C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][CH2:28][N:29]([CH2:37][CH2:38][O:39][CH3:40])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:43])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:42]=[CH:41][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][NH:29][CH2:37][CH2:38][O:39][CH3:40])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:43])[CH:8]=2)=[O:44])[CH2:3][CH2:2]1
Reactant: COCCN(CCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNCCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reaction time: 18 h
Yield: 48.1 %

Procedure:
To a solution of 287 (840 mg, 1.35 mmol) in DCM (25 mL) was added TFA (10 mL) and the reaction mixture was stirred for 18 h. The reaction mixture was concentrated, diluted with water and 4N NaOH to pH 13 to form a precipitate which was collected by filtration, washed with water, and dried and purified twice by Biotage (SNAP 50 g; MeOH/DCM: 1/99 to 15/85 over 20 CV) to produce a material that upon trituration with MeOH afforded the title compound 288 (338 mg, 0.65 mmol, 48% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.54-8.49 (m, 2H), 8.30 (s, 1H), 8.19 (d, J=8.2 Hz, 1H), 7.81 (dd, J=8.0, 2.2 Hz, 1H), 7.73 (dd, J=13.5, 2.5 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (bd, J=8.6 Hz, 1H), 6.63 (d, J=5.5 Hz, 1H), 6.58 (bd, J=2.5 Hz, 1H), 3.37 (t, J=5.7 Hz, 2H), 3.23 (s, 3H), 2.84-2.73 (m, 4H), 2.68 (t, J=5.7 Hz, 2H), 2.59-2.51 (m, 1H), 2.00-1.50 (m, 1H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H).). MS (m/z): 522.6 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]#[N:15])=[CH:11]2)=[CH:6][CH:5]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CS(C)=O>[CH2:16]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]#[N:15])=[CH:11]2)=[CH:6][CH:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc2ccc(O)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc2ccc(OCc3ccccc3)cc2c1
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Sodium hydride (151 mg, 60% in mineral oil, 3.77 mmol) is added to a stirring solution of 7-hydroxy-2-naphthonitrile (530 mg, 3.14 mmol) in DMSO (10 mL). After the bubbling subsides, benzyl bromide (448 μL, 3.77 mmol) is added and the resulting mixture is allowed to stir for 4 hours. The reaction mixture is poured into water and extracted with ether. The ether layer is dried (Na2SO4), filtered, and concentrated to dryness. The product is purified by column chromatography (step gradient, 25 to 50% CH2Cl2 in hexanes) to give 7-benzyloxy-2-naphthonitrile (735 mg, 90%) as a white solid. HRMS (EI) calculated for C18H13NO: 259.0997, found 259.0993.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:13]=1[CH2:14]Br>CN(C=O)C>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:13]=1[CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: N#CCc1ccc(O)cc1
Solvent: CN(C)C=O
Product: N#CCc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-Hydroxyphenyl)acetonitrile (5 g, 37.5 mmol) and K7CO3 (6.74 g, 48.8 mmol) in dry DMF (20 ml) was added 2,6-Difluorobenzyl bromide (7.77 g, 37.5 mmol). The reaction mixture was stirred for 4 hours at room temperature and concentrated in vacuo. The crude residue was taken in EtOAc and washed with water and brine. The aqueous layer was washed one more time with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:29])[C@@H:14]([OH:28])[CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5](OC)=[O:6].O>C1COCC1>[OH:26][C@@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:20]([CH2:19][CH2:18][C@@H:17]3[C@@H:16]2[CH2:15][C@H:14]([OH:28])[C@@:13]2([CH3:29])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][OH:6])[CH2:25]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 103.5 %

Procedure:
A suspension of LiA1H4 (0.15 g, 3 mols. equiv.) in dry THF (25 ml) was stirred under nitrogen whilst standing in an ice/methanol bath. Methyl deoxycholate (5b) (0.5 g, 1.2 mmol) in dry THF (30 ml) was then added dropwise and the resultant mixture stirred at ambient temperature for 2.5 hours. Water was then introduced carefully to the mixture until all the excess LiA1H4 had been destroyed. The resultant mixture was acidified with 2M HCl and extracted into EtOAc (3×). The combined organic extracts were washed with water (2×), dried and evaporated to give a white foam (0.47 g, 100%). Recrystallisation of 0.41 g from ethyl acetate afforded pure 3α,12α,24-trihydroxy-5β-cholane (7b)8 (0.30 g, 73%): m.p. 110°-116° C. [Lit8 107°-114° C.); 1H nmr (90 MHz; CDCl3 /DMSO d6) δ 0.67 (3H, s, 18-CH3), 0.90 (3H, s, 19-CH3), 3.2-3.7 (1H, m, 3β-H), 3.4-3.6 (2H, t(broadened), 24-CH2), 3.8-4.0 (1H, m, 12β-H); IR (KBr) 3366 (OH's) cm-1.
Reaction SMILES: Br.[CH2:2]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:21]([N:10]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COc1cccc(CCNCCc2ccccc2)c1
Reactant: CCCCCI
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCN(CCc1ccccc1)CCc1cccc(OC)c1

Procedure:
13.4 g of N-phenethyl-3-methoxyphenethylamine hydrobromide [prepared as in French patent No. 2,356,417, Example 1], 200 ml of acetone, 22 ml of pentyl iodide and 29.3 g of potassium carbonate were refluxed for 4 hours and were vacuum filtered. The filter was washed with acetone and the filtrate was concentrated to dryness under reduced pressure. The 30 g of residue were chromatographed on silica (eluant: cyclohexane - ethyl acetate 7-3) to obtain 11.4 g of pure N-pentyl-N-phenethyl-3-methoxy-phenethylamine.
Reaction SMILES: O[Li].O.O.[C:5]([O:9][C:10]([N:12]([CH3:47])[C@@H:13]([CH3:46])[C:14]([NH:16][C@H:17]1[CH2:23][O:22][C:21]2[C:24]([C:28]([O:30]C)=[O:29])=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[O:43][CH3:44])[C:18]1=[O:45])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([O:9][C:10]([N:12]([CH3:47])[C@@H:13]([CH3:46])[C:14]([NH:16][C@H:17]1[CH2:23][O:22][C:21]2[C:24]([C:28]([OH:30])=[O:29])=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[O:43][CH3:44])[C:18]1=[O:45])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: COC(=O)c1cccc2c1OC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N2Cc1c(OC)ccc2ccccc12
Agent: [Li]O
Solvent: CO
Solvent: O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c(C(=O)O)cccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
LiOH.H2O (9.1 mg, 217 μmol, Eq: 1.5) and H2O (1 mL) were added to a solution of (S)-methyl 3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-5-((2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylate (95 mg, 145 μmol, Eq: 1.00) in MeOH (4 mL). The mixture was heated to 50° C. After 2 h, LiOH.H2O (18 mg, 429 μmol, Eq: 2.95) was added and the temperature was increased to 60° C. After 4 h, the mixture was concentrated to a volume of approximately 1.5 mL. This mixture was acidified to pH 2 with 1 N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 filtered and concentrated to give a material that was purified by silica gel chromatography to afford (S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-5-((2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylic acid (31 mg, 37%) as an off-white foam.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O>O1CCOCC1>[CH:10]1([NH:16][C:2]2[N:4]=[C:5]([NH:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:7]=[C:8]([NH:16][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[N:1]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1COCCO1
Solvent: O
Product: C1CCC(Nc2nc(NC3CCCCC3)nc(NC3CCCCC3)n2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
18.5 g (0.1 mol.) of cyanuric chloride were dissolved in 400 mL of 1,4-dioxane. The mixture solution was warmed to 50° C. While stirring, the warmed solution was dropwise added with 60.2 g (0.6 mol.) of cyclohexylamine over two hours in such a manner that the reaction temperature did not raise over 50° C. While continuing further stirring, the temperature was raised to 85° C. and 60.2 g (0.61 mol.) of cyclohexylamine by keeping the temperature. Thereafter, the temperature was again raised and the reaction was carried out at the reaction temperature of 95° C. for six hours. 230 g of water were added to the reaction solution so that the temperature did not fall less than 90° C. and then, cooled. to the room temperature while stirring. Product was separated, from the reaction solution through filtration and washed with each 150 mL of water four times. The filtered product was dried at 70° C. for six hours under vacuum to obtain 34.2 g of 2,4,6-tris(cyclohexylamino)-1,3,5-triazine (yield: 225° C.)
Reaction SMILES: C(OC(O)[CH2:5][C:6]([F:9])([F:8])[F:7])C.[CH3:11][C@@H:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]1([C@H:12]([N:19]=[CH:5][C:6]([F:7])([F:8])[F:9])[CH3:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(O)CC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](N=CC(F)(F)F)c1ccccc1
Reaction time: 3 h

Procedure:
To solution of (trifluoromethyl)acetaldehyde ethyl hemiacetal (1.2 equiv.) in toluene is added (R)-(+)-α-methylbenzylamine (1 equiv.) and catalytic amount of p-toluenesulfonic acid. The solution is heated at reflux under a Dean-Stark apparatus. After 3 hr, the reaction flask is fitted with a short-path condenser and the reaction contents were fractionally distilled to give the title compound as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:15][CH:14]=1
Reactant: COc1ccc(S)cc1
Reactant: Ic1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(Sc2ccc3[nH]ccc3c2)cc1
Yield: 89.3 %

Procedure:
The general procedure in example 39 was followed. 5-Iodoindole (243 mg, 1.0 mmol), 4-methoxythiophenol (123 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 5-(4-methoxyphenyl)sulfanylindole (228 mg, 90% yield) as white solid. Column chromatographic solvent (hexane/ethyl acetate=5/1). Rf=0.3 (hexane/ethyl acetate=5/1). 1H NMR (CDCl3, 300 MHz) δ 8.14 (brs, 1 H), 7.69 (s, 1 H), 7.30 (d, 1 H, J=8.4 Hz), 7.12-7.28 (m, 4 H), 6.79 (dt, 2 H, J=2.1 Hz, 9.0 Hz), 6.47-6.49 (m, 1 H), 3.76 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 158.7, 135.2, 132.1, 128.9, 128.8, 126.5, 126.2, 125.2, 124.9, 114.8, 112.1, 102.9, 55.7. IR (neat, cm−1) 3417 (broad), 2958, 2939, 2834. MS (EI) m/z (relative intensity) 255 (100), 223 (15). HRMS (EI), Cald. for C15H13NOS 255.0712; Found 255.0702. Anal. Cald. for C15H13NOS, Cald. C: 70.56, H: 5.13; Found C: 70.37, H: 5.09.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12](O)=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34].[CH:36]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:42][S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccccc1N1CCN(c2cccc(C3CC(C)(C)c4cc(F)cc(C(=O)O)c4N3)c2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2cccc(C3CC(C)(C)c4cc(F)cc(C(=O)NS(=O)(=O)C5CC5)c4N3)c2)CC1
Yield: 29.7 %

Procedure:
A mixture of 6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), cyclopropane sulfonic acid amide (76 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid {6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-amide (36 mg, 30%) as a light yellow solid: MS (ESI) M+1=577.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([NH2:6])[CH3:5].[CH3:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[C:13]([CH3:16])[C:14]=1[F:15].C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:7])[C@H:4]([NH:6][C:11]1[CH:12]=[C:13]([CH3:16])[C:14]([F:15])=[C:9]([CH3:8])[CH:10]=1)[CH3:5]
Reactant: Cc1cc(B(O)O)cc(C)c1F
Reactant: COC(=O)[C@@H](C)N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 39 h
Yield: 37.5 %

Procedure:
To a suspension of (R)-2-amino-propionic acid methyl ester (0.200 g, 1.940 mmol), 3,5-dimethyl-4-fluorophenylboronic acid (0.652 g, 3.880 mmol), Cu(OAc)2 (0.388 g, 2.134 mmol), and molecular sieves 4 Å (1.456 g) in 15 mL of dichloromethane, was added triethylamine (0.54 mL, 3.880 mmol). After stirring at room temperature under O2 for 39 h, the reaction mixture was filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes to give the title compound as brown oil (0.164 g, 38% yield). LC-MS: tR=8.1 min; m/z 226 (M+H)+.
Reaction SMILES: [C@H:1](Br)([C:7]([OH:9])=[O:8])[C@H:2](Br)[C:3]([OH:5])=[O:4].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>>[CH2:11]([NH:18][CH:2]([CH:1]([NH:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@@H](Br)[C@@H](Br)C(=O)O
Agent: Cl
Product: O=C(O)C(NCc1ccccc1)C(NCc1ccccc1)C(=O)O
Temperature: 50 °C

Procedure:
To a mechanically stirred solution of meso-2,3-dibromosuccinic acid (27.6 g, 0.100 mol) in alcohol (200 ml) was slowly added benzylamine (85 g, 0.80 mol) at ambient temperature. After complete addition the mixture was refluxed overnight. A heavy precipitate of salts appeared. The mixture was cooled to 50° C. and concentrated hydrochloric acid was added until pH was 4-5. The precipitate was filtered off, washed several times with water and alcohol and dried.
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:8]=1[OH:21])=CC>C(OCC)(=O)C.C(O)(=O)C>[OH:21][C:8]1[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][CH:11]=[CH:12][C:7]=1[CH:4]=[O:1]
Reactant: O=[O+][O-]
Reactant: CC=Cc1cccc(Oc2ccccc2C)c1O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccccc1Oc1cccc(C=O)c1O

Procedure:
Ozone gas was introduced into a solution of 2-(1-propenyl)-6-(o-tolyloxy)phenol (13.7 g) in a mixture of ethyl acetate (300 ml) and acetic acid (50 ml) at 0°-3° C. with stirring for an hour. The reaction mixture was washed with water, aqueous sodium bicarbonate and saline successively, dried over magnesium sulfate and when evaporated. The oily residue (12.9 g) was dissolved in diethyl ether, and the solution was washed with water, dried over magnesium sulfate and evaporated. The oily residue (11.7 g) was pulverized and recrystallized from methanol to give 2-hydroxy-3-(o-tolyloxy)benzaldehyde (4.8 g). mp 56°-58° C.