Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].S(=O)(=O)(O)[O-].[Na+].CN(C1C=CC=CN=1)C.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH:32]S(O)(=O)=O>O.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O.C(OCC)(=O)C.CCCCCC.C(Cl)Cl>[C:24]([NH:23][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:32]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=S(=O)(O)O
Agent: O=[Mo](=O)([O-])[O-]
Agent: CN(C)c1ccccn1
Agent: O=S(=O)([O-])O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
A solution containing 10.3 g of (V) in the form of sodium salt in 100 ml of water is cooled to 0-5° C. and adjusted to pH 2-3 with a 2 M sodium bisulfate solution. The reaction mixture is stirred at 0° C. for 15 minutes and then CH2Cl2 (70 ml) is added. The two phases are separated and the aqueous layer extracted once with CH2Cl2 (1×50 ml). The combined organic phases are washed with a saturated solution of NaCl (1×25 ml) (360 g/l) and dried over anhydrous Mg2SO4 (3 g, KF 0.12%). After filtration, the solution is concentrated under vacuum at room temperature until 100 mL. To the yellow solution 12 g of (VI) are added, followed by 0.175 g (1.42 mmol) of dimethylaminopyridine (DMAP) and, after complete dissolution of the reagent, 5.88 g of dicyclohexylcarbodiimide (DCC). The reaction mixture is stirred at room temperature for an hour. No starting (VI) is detected by TLC (ethyl acetate/hexane:1/2, detection by spraying with a solution containing H2SO4 (31 mL), ammonium molybdate (19 g) and (NH4)4Ce(SO4)4.2 H2O (1.9 g) in water (500 mL) and heating at 130° C. for 5 min). The precipitate of dicyclohexylurea (DCU) formed is filtered off and washed with CH2Cl2 (1×20 mL). The chloromethylene solution is evaporated to dryness yielding 24 g of (VII).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:30]=[CH:31]/[CH2:32]O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(Br)(Br)(Br)[Br:35]>C1C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:23]=[C:24](/[CH:30]=[CH:31]/[CH2:32][Br:35])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(/C=C/CO)cc1OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccc(/C=C/CBr)cc1OC
Reaction time: 1 h

Procedure:
3.67 g of triphenylphosphine was added to a solution of 1.94 g of (E)-3-(3,4-dimethoxyphenyl)allyl alcohol and 3.98 g of carbon tetrabromide dissolved in 20 ml of benzene, with ice-cooling in a nitrogen atmosphere. The mixture was stirred for 1 hour at the same temperature to obtain a benzene solution of (E)-3-(3,4-dimethoxyphenyl)allyl bromide. To this solution were added 1.11 g of triethylamine and a solution of 3.15 g of 5-(piperazin-1-yl)-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine dihydrate dissolved in 12 ml of benzene, with ice-cooling. The mixture was stirred for 2 hours at room temperature. To the reaction mixture was added 30 ml of water. The resulting insolubles were removed by filtration. An organic layer was separated and to the layer was added 30 ml of water. The mixture was adjusted to pH 1.0 with dilute hydrochloric acid. The aqueous layer was separated and 30 ml of ethyl acetate was added thereto. The mixture was adjusted to pH 8.0 with a 10% aqueous sodium hydroxide solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/acetone=2/1) to obtain 2.52 g of 5-[4-{(E)-3-(3,4-dimethoxyphenyl)allyl}piperazin-1-yl]-10,11-dihydo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine. It was recrystallized from a mixed solvent of ethyl acetate and n-hexane to obtain 2.13 g of colorless crystals having a melting point of 135°-136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:12]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.200 g; 1.32 mmol), benzeneboronic acid (0.323 g; 2.65 mmol), copper acetate (0.481 g; 2.65 mmol) and pyridine (0.214 mL; 2.65 mmol) in dichloromethane (8 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent 5 to 40% ethyl acetate in heptane) to yield 0.164 g (54%) of the title compound as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:9]=1)[CH:5]=[O:6].[CH2:15](O)[CH2:16][OH:17]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:17][CH2:16][CH2:15][O:6]2)[CH:7]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(OC(F)(F)F)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1cc(Br)cc(C2OCCO2)c1
Yield: 53.7 %

Procedure:
A solution of 3-bromo-5-trifluoromethoxybenzaldehyde (20, 2.00 g, 7.43 mmol), ethylene glycol (2.31 g, 37.2 mmol), para-toluenesulfonic acid (50 mg, 0.26 mmol) in anhydrous toluene (50 mL) was refluxed using a Dean-Stark apparatus for 3 h. The solution was concentrated and the product purified by silica gel chromatography eluting with 0-10% EtOAc in hexanes to afford the title compound (1.25 g, 54%) as a clear, colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.57 (t, J=1.5 Hz, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 5.79 (s, 1H), 4.12-4.01 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:25])=[C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:14]=2)=[CH:4][CH: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>N1C=CC=CC=1>[Cl:25][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([NH:1][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[CH:3][CH:4]=2)=[CH:14][C:13]=1[NH:15][C:16]([C:18]1[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=1)=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc(N)nc3)ccc2Cl)n(C)n1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(Cl)c(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Yield: 85.8 %

Procedure:
In the same manner as in Reference Example 4 and using N-{5-[(6-aminopyridin-3-yl)oxy]-2-chlorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (300 mg, 0.838 mmol), p-toluenesulfonyl chloride (176 mg, 0.922 mmol) and pyridine (4 mL) as starting materials, the title compound (368 mg, 86%) was obtained as a white solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][NH:9][CH:10]=2)[CH2:5][CH2:4]1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>CN(C)C=O.[Cl-].[Na+].O>[CH:3]1([C:6]2[C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][N:9]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH2:4][CH2:5]1
Reactant: COC(=O)c1c[nH]cc1C1CC1
Reactant: Clc1ccnc2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2ccnc3ccccc23)cc1C1CC1
Temperature: 40 °C
Reaction time: 0.3 h

Procedure:
0.208 g (6.5 mmol) of sodium hydride at 75% by weight in liquid petroleum jelly is added to a solution of 1.07 g (6.5 mmol) of 4-cyclopropyl-3-methoxycarbonyl-1H-pyrrole in 20 mL of dimethylformamide at a temperature in the region of 20° C. under an argon atmosphere. After the reaction mixture has been stirred at a temperature in the region of 40° C. for 0.3 hour, 1.07 g (6.5 mmol) of 4-chloroquinoline and 10 mL of dimethylformamide are added. After stirring for 6 hours at a temperature in the region of 120° C., the reaction mixture is poured into 200 mL of brine and then extracted with 100 mL and then 50 mL of ethyl acetate. The organic extracts are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The oily residue is purified by chromatography on silica gel [eluent: dichloromethane/ethyl acetate (75/25 by volume)]. After the fractions containing the expected product have been concentrated to dryness under reduced pressure (2.7 kPa), 1.2 g of 4-cyclopropyl-3-methoxycarbonyl-1-(quinolin-4-yl)-1H-pyrrole are obtained in the form of a thick clear oil, which is used directly in the following step.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:32][CH:29]2[CH2:31][CH2:30]2)=[O:20])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Reactant: NC1CC1
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NC2CC2)C1(C)C

Procedure:
The product from Example 173 and cyclopropylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.30-0.42 (m, 2H), 0.47 (s, 3H), 0.56-0.60 (m, 2H), 0.90 (7.3 Hz, 3H), 1.17 (s, 3H), 1.18 (s, 3H), 1.23-1.44 (m, 3H), 1.56 (s, 9H), 1.56-1.67 (m, 3H), 1.95-2.07 (m, 1H), 2.56-2.67 (m, 4H), 2.71-2.82 (m, 1H), 7.63 (d, J=4.0 Hz, 1H), 8.50 (s, 1H). (ESI+) m/z 434 (M+H)+. Anal. calcd. for C24H39N3O2S: C, 66.47; H, 9.06; N, 9.69. Found: C, 65.95; H, 9.13; N, 9.44.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:5][N:6]=1.[CH2:11]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>N1C=CC=CC=1>[C:7]([C:4]1[S:3][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=2)(=[O:31])=[O:30])=[N:6][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
2-Amino-5-tert-butyl-1,3,4-thiadiazole (204 mg, 1.3 mmol) was suspended in pyridine (0.5 mL). p-Dodecylbenzenesulfonyl chloride (300 mg, 0.87 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred at this temperature for 1 h. The reaction mixture was then added to aqueous 10% HCl (5 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered, and volatiles evaporated to yield a solid mass. Chromatography on silica gel (70-230 mesh) eluted with 2% MeOH in CH2Cl2 gave the product (350 mg, 0.75 mmol, 87%). Recrystallization from hexanes:ethyl acetate (3:7) gave an analytical sample, mp 117-118° C.; 1H NMR (500 MHz, CDCl3) δ 0.88 (3, t, J=6.5 Hz), 1.20-1.36 (18, m), 1.38 (9, s), 1.56-1.64 (2, m), 2.63 (2, t, J=7.5 Hz), 7.25 (2, d, J=8.0 Hz), 7.86 (2, d, J=8.0 Hz), 12.24 (1, br s); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 31.1, 31.8, 35.8, 36.5, 126.5, 128.7, 138.5, 148.1, 167.8, 168.0; MS (ESI+, m/z) Calcd for C24H40N3O2S2 466.3. found 466.2 (M+H)+. HRMS (ESI+, m/z) Calcd for C24H40N3O2S2 466.2562. found 466.2562 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[N:9]([CH:16]=[C:17]([OH:19])[CH:18]=3)[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH:11]=3)=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:19][C:17]1[CH:18]=[C:8]2[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:15]3[C:10](=[CH:11][CH2:12][CH2:13][CH2:14]3)[N:9]2[CH:16]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1cc2c(-c3ccncc3)c3c(n2c1)=CCCC3
Product: CCOC(=O)C(C)(C)Oc1cc2c(-c3ccncc3)c3c(n2c1)=CCCC3

Procedure:
The above compound was prepared from 7,8-dihydro-9-(4-pyridyl)-6H-pyrrolo[1,2-a]-indole-2-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]2[N:27](C3CCCCO3)[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:34])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:34][C:11]1[CH:12]=[C:13]([O:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@@H]3CCC[C@H]3c3ccnn3C3CCCCO3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@@H]1CCC[C@H]1c1ccn[nH]1
Yield: 98.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)-4-({(1R,2S)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]cyclopentyl}oxy)benzenesulfonamide (227 mg, 0.348 mmol) prepared in Example 149d, triethylsilane (0.60 mL), trifluoroacetic acid (4.0 mL) and dichloromethane (6.0 mL), to yield the title compound (143 mg, 98%) as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=1[Cl:43])C1C=CC=CC=1.B(Cl)(Cl)Cl.C(Cl)Cl>C(Cl)Cl.CCOC(C)=O>[Cl:43][C:10]1[CH:11]=[C:12]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:36][CH3:37])=[O:35])=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCc4ccccc4)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A solution of 6-(N-(4-(benzyloxy)-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.300 g, 0.485.mmol) in anhydrous DCM (12 mL) was cooled in an ice water bath and treated with 1M BCl3/DCM (2.00 mL, 2.00 mmol). After stirring in the ice bath for 10 minutes the solution was allowed to warm to RT. This solution was then combined with the solution from an analogous 50 mg scale reaction and poured into 50 mL of stirred ice water. The mixture was diluted with 50 mL of EtOAc, stirred vigorously for several minutes and the phases separated. The EtOAc solution was washed with water (2×), brine (1×), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from DCM to 1:1 DCM/EtOAc) followed by recrystallization from hexane/EtOAc to afford the title compound (0.110 g, 37%) as a white powder. Impure fractions from the above chromatography were combined, concentrated, and subjected to RP-HPLC purification (C18, MeCN/water/0.1% formic acid) to afford an additional portion of the title compound (0.107 g, 36%) for a total yield of 73%. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.45 (s, 1H) 8.40-8.48 (m, 1H) 8.18 (s, 1H) 7.90-8.01 (m, 2H) 7.61 (d, J=2.6 Hz, 1H) 7.34-7.45 (m, 3H) 7.14 (s, 1H) 6.96 (d, J=8.8 Hz, 1H) 3.30 (s, 3H) 2.82 (d, J=4.6 Hz, 3H) 2.20-2.34 (m, 1H) 0.77-1.09 (m, 3H) 0.43 (br. s., 1H). LCMS (m/z, ES+)=529 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)(O)[O-].[Na+]>CCO>[CH2:25]([O:24][C:22]([C:21]1[N:12]=[C:8]2[CH:7]=[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]3[C:10](=[CH:11][C:2]([I:1])=[CH:3][CH:4]=3)[N:9]2[CH:20]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(-c2ccccc2)c2ccc(I)cc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cn2c(cc(-c3ccccc3)c3ccc(I)cc32)n1
Temperature: 80 °C

Procedure:
7-Iodo-4-phenyl-quinolin-2-ylamine (100 mg, 0.29 mmol), ethyl bromopyruvate (0.05 mL, 0.43 mmol), and sodium bicarbonate (22 mg, 0.58 mmol) were dissolved in EtOH (2 mL) and heated to 80° C. for 3 hours. The mixture was concentrated and purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 1v.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:23][CH3:22])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Reactant: CN
Solvent: CCO
Product: CNc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Temperature: 90 °C

Procedure:
To 500 mg of 4-(3-bromo-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile in 15 mL of absolute ethanol was added 4 mL of 40% aqueous methyl amine. The sealed reaction was heated at 90° C. for 24 hours, stripped of solvents, and purified by flash chromatography on silica gel with a gradient of 0-1% methanol/chloroform followed by purification by preparative thin-layer chromatography with 5% methanol/chloroform to yield 86 mg of 4-(3-bromo-phenylamino)-6-methylamino-[1,7]naphthyridine-3-carbonitrile as an amorphous solid: melting point 250° C. (decomposed); mass spectrum (m/e): M+H 354.1, 356.1.
Reaction SMILES: C([N:8]([C:15]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[CH:33][CH:32]=1)([C:20]([F:30])([F:29])[C:21](=[O:28])N1CCCCC1)[C:16]([F:19])([F:18])[F:17])[S:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])C1C=CC=CC=1.[C:45]1([CH3:53])[CH:50]=[CH:49][C:48]([Mg]Br)=[CH:47][CH:46]=1>C1COCC1>[CH3:14][C:11]([S:9]([NH:8][C:15]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:42])[F:43])=[CH:35][CH:36]=1)([C:20]([F:30])([F:29])[C:21](=[O:28])[C:48]1[CH:49]=[CH:50][C:45]([CH3:53])=[CH:46][CH:47]=1)[C:16]([F:17])([F:18])[F:19])=[O:10])([CH3:12])[CH3:13]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)S(=O)N(Cc1ccccc1)C(c1ccc(OCCCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)C(=O)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C(F)(F)C(NS(=O)C(C)(C)C)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
Mg turnings were suspended in 0.1 N aq HCl for a few minutes, rinsed with water, MeOH and dried under vacuum. A flame dried flask equipped with a stir bar was charged with Mg turnings (0.243 g, 10 mmol), anhydrous THF (4.4 mL) and 4-bromotoluene (1.71 g, 10 mmol) in anhydrous THF (4.4 mL) followed by several drops of 1,2-dibromoethane. The reaction initiated in a few minutes and the mixture became warm. The approximate concentration of the Grignard reagent is 1 M. The mixture was diluted with 10 mL anhydrous THF to produce a clear solution of p-tolylmagnesium bromide (˜0.5 M). To a solution of Intermediate 103E (260 mg, 0.396 mmol) in THF (3959 μL) at 0° C. was added the freshly prepared p-tolylmagnesium bromide (3959 μL, 1.980 mmol). The reaction was warmed to rt, concentrated to half of the original volume, and stirred for 3 h. The reaction was cooled to 0° C., quenched with sat'd aq NH4Cl, and then diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (24 g silica gel, eluted with EtOAc in hexanes) to afford the desired product (60 mg, 24%) as a yellow gum. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.19 (s, 1H), 4.01 (br. s., 2H), 2.40 (s, 3H), 2.31 (dd, J=16.2, 10.2 Hz, 2H), 2.10-1.99 (m, 2H), 1.25 (s, 9H).
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]2[CH2:17][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]1[CH:6]=[CH:7]2)(=[O:3])[CH3:2].F>>[C:1]([N:4]1[CH:9]2[CH:8]3[CH:7]([CH2:6][CH:5]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17]3)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CC2C=CC1N(C(C)=O)C2Cc1ccccc1
Agent: F
Product: CCOC(=O)C1CC2C3CC1N(C(C)=O)C2Cc1ccccc13

Procedure:
Cyclization of ethyl 2-acetyl-3-benzyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate, described in Example 1BQ, in the presence of hydrofluoric acid at 0°-15° C. using a procedure similar to that described in Example 2A affords ethyl 1-acetyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH3:19][N:20]1[N:24]=[N:23][C:22]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[N:21]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CN1C(=O)N(C)CC1.CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:29][C:28]4[CH:27]=[CH:26][C:25]([C:22]5[N:23]=[N:24][N:20]([CH3:19])[N:21]=5)=[CH:32][CH:31]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: Cn1nnc(-c2ccc(C=O)cc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CN1CCN(C)C1=O
Solvent: CC(=O)O
Product: Cn1nnc(-c2ccc(CNc3n[nH]c4ncnc(Nc5cccc(Cl)c5)c34)cc2)n1

Procedure:
Analogously to Example 34, 261 mg (1.00 mmol) of 3amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6), 282 mg (1.5 mmol) of 4-(2-methyl-2H-tetrazol-5-yl)-benzaldehyde and 180 mg of acetic acid are stirred in 39 ml of DMEU/methanol (1:2) at RT for 1 hour and then reacted with two 440 mg (7 mmol) portions of NaCNBH3. 4-(3-Chloro-phenylamino)-3-[4-(2-methyl-tetrazol-5-yl)-benzylamino]-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 232-235° C.; HPLC: tRet(grad20-100/20)=11.4; FAB-MS: (M+H)+=433.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[CH:4]([CH3:9])[CH:5]([CH3:8])[CH2:6][CH:7]=1>[Pd]>[CH3:9][C:4]1[C:5]([CH3:8])=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[OH:10]
Reactant: CC1=CCC(C)C(C)C1=O
Agent: [Pd]
Product: Cc1ccc(C)c(O)c1C
Yield: 96 %

Procedure:
1000 g of 2,5,6-trimethyl-2-cyclohexen-1-one is passed per hour per liter of catalyst at atmospheric pressure through an externally heated tube having a capacity of 250 cm3 and filled with a palladium/silica gel catalyst (0.2% by weight of palladium), the temperature being 300° C. The yield is 96% of 2,3,6-trimethylphenol. 4% of starting material is recovered and returned to the reaction.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].Cl.[NH2:15][OH:16].C(N(CC)CC)C>C(O)C>[NH2:2]/[C:1](=[N:15]\[OH:16])/[CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(/C(N)=N/O)C1
Yield: 75.9 %

Procedure:
In a 16 mL vial, tert-butyl 3-cyanoazetidine-1-carboxylate (190 mg, 1.04 mmol; which may be prepared as described in Step 2) was dissolved in ethanol (2.9 mL), then hydroxylamine hydrochloride (101 mg, 1.46 mmol) and triethylamine (247 μL, 1.77 mmol) were added. The reaction mixture was stirred at reflux for 3 h, cooled and concentrated. The residue was taken up in EtOAc and water, the aqueous layer extracted with EtOAc, dried over Na2SO4 and concentrated to give the product as a white solid (170 mg, 76%).