Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH2:4]([OH:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>C(N(CC)CC)C>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]#[C:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:12])[CH:15]=1
Reactant: C#CCCCCCCO
Reactant: Brc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCCCCC#Cc1cccnc1
Yield: 91.1 %

Procedure:
A flame-dried, 22-L flask equipped with a mechanical stirrer, condenser, and a gas inlet tube dipping below the surface of the solvent was charged with 4.0 L of methylene chloride, 1.25 L of triethylamine, 385 g of 7-octyn-1-ol, and 285 mL (456 g) of 3-bromopyridine. The reagents were rinsed into the flask with an additional 100 mL of methylene chloride. Argon was bubbled through the reaction mixture for 30 minutes. The flask was evacuated for 3 minutes at 70 mm. The vacuum was released by bubbling in argon. This process was repeated six times and then 42 g of dichlorobis(triphenyl phosphine)palladium (II) and 4 g of cuprous iodide were added. The mixture was heated at a gentle reflux for 18 hours and cooled to 20°. To the mixture was added, with vigorous stirring, 8.0 L of ether. A small amount of yellowish-white solid was removed by filtration and washed with 2×1.5 L=3.0 L of ether. The combined filtrate was washed with 3.0 L of deionized water and 2×3.0 L=6.0 L of 1N hydrochloric acid. The combined aqueous solutions were washed with 2×2.5 L=5.0 L of ether. The organic solutions were discarded and the aqueous solution was made strongly basic by the addition of 2.50 L of 20% sodium hydroxide solution. The resulting mixture was extracted with 3×4.0 L=12.0 L of methylene chloride. The extracts were dried over sodium sulfate and filtered through Celite. Solvent removal on a rotary evaporator at 45° gave 534.2 g (91% yield) of a pale brown 8-(3-pyridinyl)-7-octyn-1-ol having a strong odor of 3-bromopyridine. No further purification of this material was undertaken.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:7][C:8]=1[CH2:9]O)([CH3:3])[CH3:2].CCN(CC)CC.CS(Cl)(=O)=O.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([C@@H:40]2[CH2:42][C@H:41]2[C:43]([OH:45])=[O:44])=[CH:36][CH:35]=1>ClCCl.O>[CH:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:7][C:8]=1[CH2:9][NH:33][C:34]1[CH:35]=[CH:36][C:37]([C@@H:40]2[CH2:42][C@H:41]2[C:43]([OH:45])=[O:44])=[CH:38][CH:39]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 19.7 %

Procedure:
To a solution of {(4-isopropyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (0.10 g, 0.331 mmol) in dichloromethane (3 mL) was added Et3N (0.04 g, 0.39 mmol) and the mixture cooled to 0° C. The mixture stirred for 15 min after which methanesulfonyl chloride (0.04 g, 0.36 mmol) was added followed 30 min later by the addition of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.09 g, 0.49 mmol). The solution stirred for 24 h after which it was poured into H2O, the organics extracted with dichloromethane, dried over MgSO4, and the solvents reduced in vacuo. The crude material was purified on silica gel eluting with an increasing gradient from hexanes to 30% ethyl acetate/hexanes to give the title compound as a yellow powder (0.03 g, 16%). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 6.62 (d, J=8.6 Hz, 2H), 4.47 (s, 2H), 3.50-3.47 (m, 1H), 3.18-3.15 (m, 1H), 2.53-2.51 (m, 1H), 1.80-1.77 (m, 1H), 1.61-1.58 (m, 1H), 1.37-1.26 (m, 7H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:11][CH2:12][NH2:13].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:3]=12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(CCN)[nH]c2ccccc12
Solvent: C1CCOC1
Product: Cc1c2n(c3ccccc13)C(=O)NCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of 2-(3-methylindol-2-yl)ethylamine (1.74 g) in tetrahydrofuran (200 ml) at room temperature was added 1,1'-carbonyldiimidazole (1.6 g) in small portions. After one hour of stirring, the reaction mixture was evaporated in vacuo. The residue was dissolved in toluene and the solution was evaporated in vacuo. The oil obtained was heated at 100° C. for 40 minutes and then cooled. Purification of the residue with silica gel column chromatography (chloroform) gave 3,4-dihydro-5-methylpyrimido[1,6-a]indol-1(2H)-one (0.8 g).
Reaction SMILES: CN(C)CCCN=C=NCC.[ClH:12].Cl.Cl.[CH3:15][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][C:40]=1[CH3:41])[CH2:19][C@H:20]1[NH:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]#[C:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2([CH3:37])[CH3:36])[CH2:21]1.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:52]=1)[C:47](O)=[O:48].ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[ClH:12].[ClH:12].[F:42][C:43]([F:57])([F:58])[C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([C:53]([F:56])([F:54])[F:55])[CH:52]=1)[C:47]([N:25]1[CH2:24][CH2:23][N:22]([CH2:26][C:27]#[C:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][C:31]2([CH3:37])[CH3:36])[CH2:21][C@H:20]1[CH2:19][C:18]1[CH:38]=[CH:39][C:40]([CH3:41])=[C:16]([CH3:15])[CH:17]=1)=[O:48]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3(C)C)CCN2)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 153486.91 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.22 ml) was added over 5 minutes to a mixture of (3R)-3-(3,4-dimethylbenzyl)-1-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine trihydrochloride (0.48 g) and 3,5-bis(trifluoromethyl)benzoic acid (0.27 g), 1-hydroxybenzotriazole (0.15 g) and triethylamine (0.35 ml) in dichloromethane (10 ml). After 2 hours of stirring at room temperature, the reaction mixture was directly purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40:1). The fractions containing the objective compound was collected and evaporated under reduced pressure. The residue was treated with 4N hydrogen chloride in ethyl acetate and recrystallized from a mixture of acetone and water to give colorless crystals of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(3,3-dimethylmorpholino)-2-butynyl]-piperazine dihydrochloride (525 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([CH:24]=C)=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.CC#N.O.C[N+]1([O-])CC[O:35]CC1>[Os](=O)(=O)(=O)=O.CC(C)=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([CH:24]=[O:35])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cc(OCc2ccc(C)nc2C)cc2scc(CC(=O)OC)c12
Agent: O=[Os](=O)(=O)=O
Solvent: CC#N
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(C=O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.5 %

Procedure:
To a mixture of methyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-4-vinyl-1-benzothiophen-3-yl)acetate (459 mg), CH3CN (2 mL), water (2 mL) and acetone (2 mL) were added osmium(VIII) oxide (7% microcapsule, 907 mg) and NMO (439 mg) at room temperature. The mixture was stirred at room temperature for 20 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was poured into aqueous solution of Na2S2O3 at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. To a mixture of the residue, THF (3 mL) and water (3 mL) was added sodium periodate (802 mg) at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was quenched with aqueous solution of Na2S2O3 at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine twice, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (293 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[OH:12].[Cl:13][C:14]1[CH:15]=[C:16](O)[CH:17]=[CH:18][CH:19]=1>CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=1
Reactant: Oc1cccc(Cl)c1
Reactant: OC1CCNc2ncc(Br)cc21
Solvent: CO
Solvent: ClCCl
Product: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Yield: 60 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (225 mg) was reacted with 3-chlorophenol (0.30 mL) as in General Procedure 12. Basic alumina chromatography using a gradient of 0-1% methanol/methylene chloride as the eluting solvent gave the title compound as a white film (60% yield). LCMS: m/z=339 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00 (m, 1H), 2.21 (m, 1H), 3.40 (m, 1H), 3.51 (m, 1H), 5.04 (s, 1H), 5.27 (t, J=3.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 7.00 (m, 2H), 7.24 (m, 1H), 7.48 (d, J=2.1 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:13].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[NH2:10][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([CH3:13])[C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C#N)cc(N)c1N
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of 4-amino-3-methyl-5-nitro-benzonitrile (3.24 g, 18.3 mmol) in ethanol (80 mL) was added tin chloride dihydrate (8.67 g, 49.75 mmol). The reaction mixture was heated to reflux for 14 h, then cooled to room temperature, and concentrated in vacuum. The residue was diluted with ethyl acetate (100 mL) and treated with triethylamine (20 mL). The resulting slurry was filtered through a pad of celite and the filtercake was rinsed with three-portion ethyl acetate (50 mL). The filtrate was washed with saturated NaHCO3, water, and brine, then dried over Na2SO4 and filtered. After removal of solvent, the residue was purified by flash chromatography on silica gel (30%-50% EtOAc/hexane) to yield the title compound (2.17 g, 81%) as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 6.94 (1H, s), 6.85 (1H, s), 2.16 (3H, s). LCMS (M+H)+ m/z 148 (t=0.67 min.).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](NC(c2ccccc2)c2ccccc2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
A solution of 200 mg (0.551 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 110 mg (0.606 mmol) of benzophenone in 5 ml of toluene are kept at reflux for 18 hours. The reaction mixture is then concentrated in a rotary evaporator and dissolved in 3 ml of methanol, and 69 mg (1.10 mmol) of sodium cyanoborohydride are added at RT. The reaction mixture is adjusted to pH=5 with 80 μl of acetic acid and stirred at RT for 68 hours. The title compound ##STR98## is obtained as white foam (120 mg, 41%). TLC: toluene/ethyl acetate (7:3) Rf =0.79, FD-MS: M+ =528,530; IR: 1630 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)c2ccccc2c1O
Reaction time: 1 h

Procedure:
4-Chloro-1-naphthol , 9 g, in 100 ml acetic acid was cooled to 15° C. and 3.25 ml concentrated nitric acid in 20 ml acetic acid was added dropwise over 15 minutes. After 1 hour, the reaction mixture was poured into 600 ml chilled water. The precipitate was filtered off, washed with water and dried to give a crude product. The product was partially purified by extracting with boiling hexane to obtain 3.5 g. Further purification was accomplished by dissolving in 10 ml chloroform, absorbing on 15 g silica and loading on a column of 90 g silica gel, equilibrated with hexane. The product was eluted with 5% ethyl acetate in hexane to give 0.8 g of 4-chloro-2 nitro-1-naphthol after evaporation, m.p. 142°-3° (d) .
Reaction SMILES: Cl.[CH:2]12[CH2:9][CH2:8][CH:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[CH2:10][C@@H:11]([C:13]1[C:14]([CH3:23])=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[O:17][CH2:16]2)[OH:12].[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:28]=[N:27][N:26]=[N:25]1>>[N:24]1([C:29]2[CH:30]=[CH:31][C:32]([S:35]([N:6]3[CH2:7][CH:2]4[CH2:9][CH2:8][CH:5]3[CH2:4][N:3]4[CH2:10][C@@H:11]([C:13]3[C:14]([CH3:23])=[C:15]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[O:17][CH2:16]4)[OH:12])(=[O:37])=[O:36])=[CH:33][CH:34]=2)[CH:28]=[N:27][N:26]=[N:25]1
Reactant: O=S(=O)(Cl)c1ccc(-n2cnnn2)cc1
Reactant: Cc1c([C@@H](O)CN2CC3CCC2CN3)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CN2CC3CCC2CN3S(=O)(=O)c2ccc(-n3cnnn3)cc2)ccc2c1COC2=O

Procedure:
5-((1R)-2-(5-(4-(1H-Tetrazol-1-yl)phenylsulfonyl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1 (3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 14 starting from 5-((1R)-2-(2,5-diazabicyclo[2.2.2]octan-2-yl)-1-hydroxyethyl)-4-methylisobenzofuran-1(3H)-one hydrochloride (INTERMEDIATE 16) and commercially available 4-(1H-tetrazol-1-yl)benzene-1-sulfonyl chloride.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14](OCCC)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][OH:21].[OH-:22].[Na+].Cl>O>[CH2:20]([O:21][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([OH:22])[CH3:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CO
Reactant: CCCOC(C)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
3.45 g (0.01 mol) of unreacted ester (-)-4-benzyloxy-4'-(1-acetoxyethyl)biphenyl obtained in Example 12 was added into a mixture of 50 ml of methanol and 25 ml of a 20% sodium hydroxide solution and stirred at 30°-40° C. for 2 hours. The reaction mixture was added with 200 ml of water, adjusted to pH 4 with 4N hydrochloric acid and extracted with 500 ml of ether. The organic layer was washed with water and concentrated under reduced pressure to give 3.0 g (99% yield) of (-)-4-benzyloxy-4'-(1-hydroxyethyl)biphenyl as a white solid. By using 1.22 g (4 mmol) of this product as starting material, the alkylation, debenzylation and after-treatments of Example 19 were carried out to obtain 0.47 g (91% yield) of (-)-4-hydroxy-4'-(1-(2s-methylbutyloxy)ethyl)biphenyl. nD20 =1.5479, [α]D20 = -60.0° (c=1, CHCl3).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11]/[C:12]/2=[CH:15]\[C:16](Cl)=[O:17])=[CH:7][CH:6]=1>ClCCl.C(OCC)(=O)C>[F:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11]/[C:12]/2=[CH:15]\[C:16]([N:2]([CH3:3])[CH3:1])=[O:17])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=C(Cl)/C=C1\CCCc2ccc(F)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)/C=C1\CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
Dimethylamine (3 ml, 0.045 mol, Kodak) was added to a chilled (ice bath) solution of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetyl chloride (2.3 g, 0.010 mol) in dichloromethane (35 ml). The reaction was warmed to 25° C. and stirred for 1.5 h. The volatiles were removed by spin evaporation in vacuo to give a beige residue. This residue was dissolved in ethyl acetate (200 ml), washed with deionized water (50 ml), and the organic layer was concentrated by spin evaporation in vacuo. The residue was chromatographed on Silica Gel 60 using a step gradient from ethyl acetate-hexanes/1:5 to ethyl acetate. Fractions containing (e)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamide were combined and concentrated by spin evaporation in vacuo to a white solid. Recrystallization from dichloromethane-hexanes gave 1.62 g (70%) of (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)-N,N-dimethylacetamide as a white crystalline solid; m.p., 66-70° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C1(S([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](B(O)O)=[CH:39]2)(=O)=O)C=CC=CC=1.[OH-].[K+]>>[NH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:39]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4c[nH]c5ccccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.1 g) was reacted with 1-(phenylsulfonyl)-3-indoleboronic acid via General Procedure A to yield 56.9 mg 133 following phenylsulfonyl group deprotection with aqueous potassium hydroxide at 50° C. for 2 hours then reverse phase HPLC purification. MS (Q1) 487.3 (M)+
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[O:9][C:8]2[S:10][C:11]([CH3:15])([CH3:14])[C@H:12](Br)[C:7]=2[C@@H:6](O)[CH:5]=1.[N-:17]=[N+:18]=[N-:19].[Na+].CN(C)C=[O:24]>O>[N:17]([C@H:6]1[CH:5]=[C:4]([Br:3])[O:9][C:8]2[S:10][C:11]([CH3:15])([CH3:14])[C@H:12]([OH:24])[C:7]1=2)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)SC2=C([C@H]1Br)[C@@H](O)C=C(Br)O2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1(C)SC2=C([C@@H](N=[N+]=[N-])C=C(Br)O2)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride, 60% in mineral oil, (134 mg, 3.36 mmol) was added to a solution of 16 (1.15 g, 3.36 mmol) in N,N-dimethylformamide (25 ml) at 0° C. and stirred at rt for 2 h. The reaction was cooled to 0° C. and sodium azide (635 mg, 10.8 mmol) in water (2 ml) was added. After stirring at rt for 1 h, the resultant solution was poured into water (150 ml). The product was extracted with dichloromethane (50 ml), washed several times with water and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product as a brown oil, 1.0 g (98%), which was used without further purification. 1H NMR (CDCl3): d 1.31 (s, 3 H), 1.48 (s, 3 H), 2.42 (d, J=5.3 Hz, H), 3.72 (d of d, J=7.5 and 5.3 Hz, 1 H), 4.21 (d, J 7.5 Hz, 1 H) and 6,76 (s, 1 H); IR (neat) 3600-3200, 2101, 1663, 1568 and 1470 cm-1 ; MS: m/z 303 MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1O)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC.CN(C)[CH:22]=[O:23]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:23][CH3:22])[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A mixture of 3-fluoro-4-hydroxybenzoic acid (500 mg, 3.2 mmol), cesium carbonate (3.1 g, 9.6 mmol) and iodomethane (440 μl, 7.0 mmol) in dimethylformamide (7 mL) was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and washed with 5% aqueous lithium chloride, 1N aqueous sodium hydroxide, brine, then dried over anhydrous sodium sulfate. Filtration and concentration afforded 534 mg, 2.9 mmol (92%) of methyl 3-fluoro-4-(methyloxy)benzoate. MS (EI) for C9H9FO3: 185 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH:12]=O)[N:11]=1)=[O:5].Cl.[NH2:30][OH:31].N1C=CC=CC=1>CCO.C(Cl)Cl>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10](/[CH:12]=[N:30]\[OH:31])[N:11]=1)=[O:5]
Reactant: NO
Reactant: O=Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: O=C(Nc1nc(/C=N\O)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Into a solution of Compound 67 (180 mg, 0.44 mmol) in 3 mL of EtOH was added hydroxylamine hydrochloride (60 mg, 0.9 mmol) and pyridine (0.5 mL). The solution was stirred at room temperature for 2 hours. The reaction was diluted with 20 mL of CH2Cl2, and the solution was washed with 10 mL of water and dried (Na2SO4), filtered and concentrated. The residue was purified on silica (eluted with 5-100% ethyl acetate in hexane) to give Compound 72 (98 mg, 52%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.Cl[C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][N:24]=1>C(O)CCC>[OH2:12].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:23]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=[CH:25][N:24]=3)[CH2:18][CH2:17]2)[N:3]=1.[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:23]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=[CH:25][N:24]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: Clc1nccc(-c2ccccc2)n1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4nccc(-c5ccccc5)n4)CC3)nc(N)c2cc1OC
Product: O
Yield: 63 %

Procedure:
4-Amino-6,7-dimethoxy-2-piperazino-quinazoline (3.44 g, 0.012 mole) and 2-chloro-4-phenylpyrimidine (2.5 g, 0.011 mole) (J. Chem. Soc., 2328 (1951)) in n-butanol (250 ml) were heated under reflux for six hours. After cooling the solid product was collected, washed with diethylether, and partitioned between chloroform and saturated aqueous sodium carbonate solution. The chloroform layer was separated, the aqueous layer extracted with chloroform and the combined chloroform layers were washed with water, dried (Na2SO4) and evaporated in vacuo. The residue (5 g) was chromatographed on silica eluting with chloroform and chloroform-methanol (97.5:2.5 by volume). Appropriate fractions were combined, evaporated and the resulting solid crystallized from dimethylformamide (DMF)/diethyl ether to give 4-amino-6,7-dimethoxy-2-[4-(4-phenylpyrimidin-2-yl)-piperazino] quinazoline hemihydrate, (2.28 g), m.p. 250° C. (dec).