Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:12][CH2:11][CH2:10][C@:4]2([O:8][C:7](=[O:9])[NH:6][CH2:5]2)[CH2:3]1.[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[N:33][C:32]([O:35][CH2:36][CH3:37])=[CH:31][N:30]=1>CN(C)C=O.[NH4+].[Cl-]>[CH2:36]([O:35][C:32]1[N:33]=[CH:34][C:29]([CH2:28][N:6]2[CH2:5][C@@:4]3([CH2:10][CH2:11][CH2:12][C@@:2]([CH2:13][N:14]4[C:18]5[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)([CH3:1])[CH2:3]3)[O:8][C:7]2=[O:9])=[N:30][CH:31]=1)[CH3:37]
Reactant: CCOc1cnc(CBr)cn1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CNC(=O)O2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOc1cnc(CN2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of 1-{[(5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile (150 mg, 0.462 mmol) in N,N-Dimethylformamide (DMF) (2 mL) was added 60% sodium hydride in mineral oil (24.04 mg, 0.601 mmol) and stirred for 30 minutes. To the mixture was added 2-(bromomethyl)-5-ethoxypyrazine (120 mg, 0.555 mmol) and stirred overnight. The reaction was diluted with saturated NH4Cl and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated NaCl (2×), dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel ISCO chromatography (40 g silica gel, 40 mL/min, 0-10% MeOH/CH2Cl2 over 25 min) to afford 1-(((5S,7S)-3-((5-ethoxypyrazin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (125 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.35 (d, J=0.75 Hz, 1H), 8.21 (d, J=1.25 Hz, 1H), 8.13 (d, J=1.51 Hz, 1H), 7.83 (d, J=8.28 Hz, 1H), 7.59 (dd, J=8.28, 1.51 Hz, 1H), 4.31-4.41 (m, 4H), 4.12 (s, 2H), 3.21 (dd, J=23.09, 9.03 Hz, 2H), 1.81 (d, J=13.30 Hz, 1H), 1.49-1.74 (m, 4H), 1.22-1.46 (m, 6H), 1.02 (s, 3H). MS (m/z) 461.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[N:8]=[CH:7][N:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[N:8]=[CH:7][N:6]=1
Reactant: COc1ccc(Br)c(Nc2ncnc3cccc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Br)c(Nc2ncnc3cccc(OCC4CCNCC4)c23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
A mixture of 4-(2-bromo-5-methoxyanilino)-5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]quinazoline (0.108 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at ambient temperature for 1.5 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The resultant solid was isolated and dried under vacuum. The solid was dissolved in methylene chloride and few drops of a saturated methanolic ammonia solution was added. The solution was poured onto a chromatography column filled with silica and eluted with a 97:3 mixture of methylene chloride and a saturated methanolic ammonia solution. There was thus obtained the title compound (0.082 g); NMR Spectrum: (CDCl3) 1.2–1.4 (m, 2H), 1.9 (d, 2H), 2.3 (m, 1H), 2.65 (t, 2H), 3.12 (d, 2H), 3.84 (s, 3H), 4.2 (d, 2H), 6.61 (m, 1H), 6.93 (d, 1H), 7.5 (d, 2H), 7.68 (m, 1H), 8.22 (d, 1H), 8.68 (s, 1H); Mass Spectrum: M+H+ 443 and 445.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH2:13][O:14][CH3:15])=[O:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:38]([NH2:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([CH3:40])[CH3:39].Cl>CN(C=O)C.O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:47][C:38]([CH3:40])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:39])=[O:9])=[CH:5][C:4]=1[O:12][CH2:13][O:14][CH3:15])=[O:2]
Reactant: COCOc1cc(C(=O)O)ccc1C=O
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
4-Formyl-3-methoxymethoxybenzoic acid (2.57 g, 12.2 mmol) was dissolved in DMF (50 mL), and the solution was added with EDCI (4.68 g, 24.4 mmol), HOBT monohydrate (1.65 g, 12.2 mmol) and cumylamine (4.03 mL, 24.4 mmol), followed by stirring at room temperature for 4 hours. The reaction mixture was added with water (10 mL) and 1 mol/L hydrochloric acid (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate=95/5 to 80/20 to 70/30) to obtain 4-formyl-3-methoxymethoxy-N-(1-methyl-1-phenylethyl)benzamide (3.12 g, yield 78%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[O:29]=[C:30](C)[CH2:31][CH2:32][CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:30](=[O:29])[CH2:31][CH2:32][CH2:33][C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1CN(C(=O)CCCc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol), 4-(4-oxo-pentyl)-benzoic acid (58.3 mg, 0.30 mmol), HATU (114.0 mg, 0.30 mmol) and iPr2NEt (0.1 mL) in CH2Cl2 (2 mL) was stirred at rt 2 hrs. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and the residue was purified by RP-HPLC to rac-4-{4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-4-oxo-butyl}-benzoic acid (28.9 mg, 48.2%). HRMS (ES+) m/z Calcd for C33H30Cl2F2N2O3+H [(M+H): 599.1675; Found: 599.1674.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]2)[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:37]([CH:34]3[CH2:35][CH2:36][N:31]([CH:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)[CH2:32][CH2:33]3)=[O:38])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C2CCOCC2)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C3CCOCC3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(4-chloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(tetrahydro-pyran-4-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a white solid. MS m/e: 544.2 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:17]3([CH2:21][O:20][C:19]([N:22](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18]3)[C:13]3([CH2:16][O:15][CH2:14]3)[C:9]3([CH2:12][CH2:11][CH2:10]3)[O:8][C:5]2=[CH:6][CH:7]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1(C)C=CC=CC=1.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>[F:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1[C:2]1[CH:3]=[C:4]2[C:17]3([CH2:21][O:20][C:19]([NH2:22])=[N:18]3)[C:13]3([CH2:16][O:15][CH2:14]3)[C:9]3([CH2:10][CH2:11][CH2:12]3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC1(CCC1)C21COC1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(F)c(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)C2(CCC2)O3)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
A mixture of di-tert-butyl (6′-bromotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl)imidodicarbonate (14.1 mg), 2-fluoro-5-methoxyphenylboronic acid (12.7 mg), PdCl2(PPh3)2 (5.3 mg) and 1M aqueous Na2CO3 (0.1 mL) in dioxane (0.4 mL) was stirred for 2 hours at 100° C. The mixture was filtered by using Chem Elut cartridges (Agilent Technologies) and washed with CHCl3. The filtrate was evaporated to give a brown oil. The oil was dissolved in toluene (0.5 mL) and to the mixture was added silicagel (neutral; 50 mg). The mixture was stirred for 1 hour at 100° C. The mixture was filtered and washed with CHCl3. The filtrate was evaporated. The residue was purified with HPLC (Column: Waters SunFire™ Prep C18 OBD™ 5 micrometer, 19×100 mm; MeOH/0.1% aqueous HCOOH 11/89 to 95/5(v/v)) and afforded 6′-(2-fluoro-5-methoxyphenyl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (1.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][NH2:38])=[CH:32][CH:31]=1.C(Cl)CCl.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:38][CH2:37][CH2:36][C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: NCCc1ccncc1
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)NCCc4ccncc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
The mixture of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (50 mg, 0.12 mmol), 2-(pyridin-4-yl)ethanamine (50 mg, 0.41 mmol), EDC (50 mg, 0.26 mmol) and 1-methyl-1H-imidazole (50 mg, 0.61 mmol) in 25 mL of DCM was stirred at room temperature overnight. Excess of DCM was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (3:1) to give 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(pyridin-4-yl)ethyl)piperidine-3-carboxamide (25 mg, 39%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 9.64 (s, 1H), 8.85 (s, 1H), 8.46-8.44 (m, 2H), 8.02-8.01 (m, 1H), 7.71-7.69 (m, 1H), 7.33-7.21 (m, 3H), 6.92 (d, 1H, J=9.0 Hz), 4.64-4.63 (m, 2H), 3.75 (s, 3H), 3.73 (s, 3H), 3.35-3.30 (m, 2H), 2.98-2.91 (m, 2H), 2.77-2.75 (m, 2H), 2.51 (brs, 1H), 1.82-1.42 (m, 4H). LC-MS: 520 [M+H]+, 260 [M/2+H]+, 518 [M−H]−, tR=1.29 min. HPLC: 97.55% at 214 nm, 97.72% at 254 nm, tR=3.51 min.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2[CH:6]=[N:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9](=[O:10])[C:4]=2[C:3]=1[CH2:28][CH2:29][CH2:30][CH3:31].BrC1N(COCC[Si](C)(C)C)C2C=NN(COCC[Si](C)(C)C)C(=O)C=2C=1C.[CH:60]1([O:63][C:64]2[CH:65]=[C:66](B3OC(C)(C)C(C)(C)O3)[CH:67]=[CH:68][C:69]=2[O:70][CH3:71])[CH2:62][CH2:61]1.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[CH2:28]([C:3]1[C:4]2[C:9](=[O:10])[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[CH:6][C:5]=2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:2]=1[C:66]1[CH:67]=[CH:68][C:69]([O:70][CH3:71])=[C:64]([O:63][CH:60]2[CH2:61][CH2:62]2)[CH:65]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC1CC1
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: Cc1c(Br)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CCCCc1c(-c2ccc(OC)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 87.6 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(a) except for using 530 mg (0.999 mmol) of 2-bromo-3-butyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 22-(b) in place of 2-bromo-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, and using 435 mg (1.50 mmol) of 2-(3-cyclopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference Example 1-(e) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 537 mg of the title compound was obtained as a brownish oil. (Yield: 88%)
Reaction SMILES: COC1C2C(=CC=CC=2)C(O)=CC=1.[CH3:14][O:15][C:16]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32](=[O:33])/[C:18](=[C:19]2\[CH:20]=[C:21]([O:30][CH3:31])[C:22]3[C:27]([C:28]\2=[O:29])=[CH:26][CH:25]=[CH:24][CH:23]=3)/[CH:17]=1>[Ag]=O.C(Cl)(Cl)Cl>[CH3:31][O:30][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]([OH:29])=[C:19]([C:18]2[CH:17]=[C:16]([O:15][CH3:14])[C:39]3[C:34]([C:32]=2[OH:33])=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:20]=1
Reactant: COC1=C/C(=C2/C=C(OC)c3ccccc3C2=O)C(=O)c2ccccc21
Agent: O=[Ag]
Agent: COc1ccc(O)c2ccccc12
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(OC)c3ccccc3c2O)c(O)c2ccccc12

Procedure:
Under an atmosphere of nitrogen, a mixture of 5.0 g of 4-methoxy-1-naphthol and 50 mL chloroform was mechanically stirred with 10.0 g silver oxide until the conversion to Russig's Blue was complete. The unreacted silver oxide was filtered and washed with chloroform. The filtrate and chloroform washings were combined and stirred with 4.9 g of 4-methoxy-1-naphthol until the solution turned gray. The solution was then concentrated to 50 mL and the resulting precipitate was filtered, washed with chloroform and dried to yield 3.18 g of 1,1'-dimethoxy-3,3'-binaphthyl-4,4'-diol as a light gray solid. The structure was confirmed by NMR.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:16][CH2:17][CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[N:7]([CH2:16][CH2:17][CH3:18])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cnc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 7-bromoquinazolin-4(3H)-one (0.2 g, 0.89 mmol) and DMF (20 mL) was added sodium hydride (85 mg, 3.5 mmol) in portions. The reaction mixture was stirred at room temperature for 15 min. 1-iodopropane (0.18 g, 1.1 mmol) was added dropwise. After stirring for 30 min., the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 267, 269 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1.[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:14])=[C:6]([Br:12])[CH:5]=1
Reactant: COC(=O)c1cc(F)c(O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(F)c(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.9 %

Procedure:
5.0 g of 3-Bromo-5-fluoro-4-hydroxy-benzoic acid methyl ester were dissolved using 50 ml of acetone. Then, 8.3 g of K2CO3 and 2.5 ml of CH3I were added and the reaction mixture stirred at room temperature for 48 h. The reaction mixture was then filtrated and evaporated. Chromatography on silica gel using EA/HEP 1:2 yielded 2.0 g of the title compound, oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH2:20][CH2:19][CH:18]([C:21](OC)=[O:22])[CH2:17][CH:16]=1.CO.[BH4-].[Li+].C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:13][CH2:14]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH:16]=1
Reactant: COC(=O)C1CC=C(c2ccc3c(nnn3CC3CC3)c2Cl)CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: OCC1CC=C(c2ccc3c(nnn3CC3CC3)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 4-[4-chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]cyclohex-3-ene-1-carboxylate (Example 1, 0.22 g, 0.64 mmol) was dissolved in dichloromethane (10 mL), treated with methanol (0.031 mL, 0.77 mmol, 1.2 equiv) and then lithium borohydride (17 mg, 0.77 mmol, 1.2 equiv). The mixture was stirred at ambient temperature for 30 minutes. To the mixture, eight additional portions of lithium borohydride (17 mg, 0.77 mmol, 1.2 equiv) and eight additional portions of methanol (0.031 mL, 0.77 mmol, 1.2 equiv) were added over 4 hours. The mixture was treated with sodium bicarbonate (20 mL, aqueous saturated), stirred for 18 hours and poured into water (100 mL), which was extracted with ethly acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 7.87 (1H, d, J=8.6 Hz), 7.41 (1H, d, J=8.6 Hz), 5.75-5.72 (1H, m), 4.61 (2H, d, J=7.3 Hz), 3.44-3.37 (1H, m), 3.36-3.32 (1H, m), 2.43-2.33 (1H, m), 2.33-2.23 (2H, m), 1.94-1.85 (2H, m), 1.82-1.74 (1H, m), 1.47-1.34 (2H, m), 0.58-0.53 (2H, m), 0.49-0.45 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 318.1368 [(M+H)+; calculated for C17H21ClN3O: 318.1368].
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH:15]2[CH2:17][CH2:16]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[OH-].[Na+]>CO>[CH:15]1([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1cc2ccccc2c(C2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2ccccc2c(C2CC2)n1

Procedure:
350 mg (1.54 mmol) 1-cyclopropyl-isoquinoline-3-carboxylic acid methyl ester was dissolved in 10 mL MeOH and treated with 2.50 mL 4 M aqueous NaOH solution at RT for 12 h. The solvent was removed by distillation, the residue taken up in water, acidified with 4 M aqueous hydrochlorid acid and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[C:12]=1[CH3:19])#[N:10].CN(C)CCN(C)C.[C:28]1([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]I)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1.O>[C:28]1([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:19][C:12]2[C:13]([C:17]#[N:18])=[CH:14][CH:15]=[CH:16][C:11]=2[C:9]#[N:10])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1c(C#N)cccc1C#N
Reactant: ICCCCCCCCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(C#N)c1CCCCCCCCCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of lithium diisopropylamide 1.5M in tetrahydrofuran (6 ml, 9 mmol) was added dropwise to a stirred solution of 2,6-dicyanotoluene (0.85 g, 6 mmol) and tetramethyl ethylenediamine (1.04 g, 9 mmol) in dry tetrahydrofuran (50 ml), cooled to -70° C. under nitrogen. After one hour, 8-phenyloctyl iodide (2.15 g, 6.8 mmol) was added dropwise at -70° C. to the intense blue suspension, then allowed to warm to 0° C. over one hour. Water (100 ml) was added (cautiously at first) to the brown mixture and then extracted with diethyl ether (50 ml). The extracts were washed with 2M hydrochloric acid, dried, filtered and evaporated to a brown oil (2.67 g). Purified by chromatography on flash silica eluting with dichloromethane gave 2-(9-phenylnonyl)-1,3-benzenedicarbonitrile as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[O:8])[CH2:6]Br.[N-:12]=[N+:13]=[N-:14].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=[O:8])[CH2:6][N:12]=[N+:13]=[N-:14]
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCC(=O)c1cccc(Br)c1
Yield: 99.3 %

Procedure:
A solution of 20.2 g (73 mmol) of 3-bromophenacyl bromide and 5.42 g (83 mmol) of sodium azide was stirred at RT for 90 min in methanol. The solvent was removed under reduced pressure and the crude product was partitioned between ethyl acetate (200 ml) and water (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford the title compound (17.4 g, 99%) as a light yellow solid. 1H NMR (400 MHz, d6-DMSO): δ 8.10 (d, J=1.0, 1H), 7.90–7.97 (m, 2H), 7.22 (t, J=7.9, 1H), 4.93 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9](=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:21][C:22]([F:26])([F:25])[CH2:23]I.O>CN(C)C=O>[F:21][C:22]([F:26])([F:25])[CH2:23][N:10]1[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]1=[O:18]
Reactant: FC(F)(F)CI
Reactant: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2ccccc2)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a suspension of 5.13 g of 4-phenyl-6-chloro-2(1H)-quinazolinone in 60 ml of dimethylformamide was added 0.85 g 62% sodium hydride, and the resulting mixture was stirred at 100° C. for 30 minutes. Thereafter, 10.0 g of 2,2,2-trifluoroethyl iodide was added and the mixture was stirred at 140° C. for 8 hours. After cooling, the reaction mixture was poured into 300 ml of water and the resulting mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was absorbed on a silica gel column, eluted with chloroform to obtain 3.5 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-2(1H)-quinazolinone which was recrystallized from ethanol to give pale yellow leaflets melting at 185.0°-186.0° C., and 2.0 g of 2-(2,2,2-trifluoroethoxy)-4-phenyl-6-chloroquinazoline which was recrystallized from ethanol to give pale yellow needles melting at 113.0°-114.0° C.