Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:14]#[N:15])[C:11]([OH:13])=O)[CH:3]=1.S(Cl)(Cl)=O.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>Cl>[CH2:20]([NH:24][C:11](=[O:13])[C:10](=[C:4]1[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2]([CH3:1])=[CH:3]1)[C:14]#[N:15])[CH2:21][CH2:22][CH3:23]
Reactant: CC1=CC(=C(C#N)C(=O)O)CC(C)(C)C1
Reactant: CCCCN
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCCNC(=O)C(C#N)=C1C=C(C)CC(C)(C)C1

Procedure:
2(3,5,5-trimethyl-2-cyclohexenylidene) cyanoacetic acid (0.2 mol) and thionyl chloride (50 mls) were refluxed together for 1 hr. The acid chloride was then added dropwise with stirring to n-butylamine (0.4 mol) in petroleum ether (340 mls). The flask may have to be cooled with an ice bath. After addition, 1N HCl (150 mls) was added and the mixture stirred. The mixture was allowed to separate and the upper layer was washed until acid free. It was then treated with 1.4 g activated carbon, then n-butyl (3,5,5-trimethyl-2-cyclohexenylidene) cyanoacetamide was isolated. Ref. J. Am. Chem. Soc., 1949, 71, 2215.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][OH:51])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cr](O)(O)(=O)=[O:53].CC(O)C>CCOCC>[C:1]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([OH:53])=[O:51])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=[Cr](=O)(O)O
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO
Solvent: CCOCC
Solvent: CC(C)O
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Yield: 89 %

Procedure:
The alcohol (40) (1.73 g, 2.41 mmol) was dissolved in ether (200 ml) at 30° C. and treated with chromic acid (4 ml of a 0.67M solution; 2.68 mmol). The resulting solution was allowed to stir and cool to room temperature over two hours during which time two further 1 ml portions of chromic acid were added. Propan-2-ol (5 ml) was then added and the ethereal solution washed with water four times, then dried, filtered and evaporated to leave the title compound (41) as a white powder (1.57 g; 89%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].[CH3:8][C:9]([CH:11]=O)=O>>[OH:6][C:5]1[C:3]([CH3:4])=[N:2][C:9]([CH3:11])=[CH:8][N:7]=1
Reactant: C[C@H](N)C(N)=O
Reactant: CC(=O)C=O
Agent: Cl
Product: Cc1cnc(O)c(C)n1

Procedure:
The title-compound was prepared from alanine amide hydrochloride and pyruvic aldehyde as described by Karmas and Spoerri, J. Am. Chem. Soc., 1952, 74, 1580 m.p.=149.5°-151° C. (Lit. 146°-147° C.).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])OC2C=CC(Cl)=CC=2)[O:7][N:6]=1)([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[C:37]([F:43])=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[C:37]([F:43])=[C:38]([NH:39][C:11]([NH:10][C:8]2[O:7][N:6]=[C:5]([C:2]([F:1])([CH3:3])[CH3:4])[CH:9]=2)=[O:20])[CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)on1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3F)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
A mixture of 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (prepared as described in Example 257A) (213 mg, 0.714 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared as described in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure to the crude product. Purification via silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea (147 mg, 64%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.55 (brs, 1H), 8.89 (brs, 1H), 8.58 (s, 1H), 8.03 (m, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.20 (s, 1H), 4.00 (s, 6H), 1.69 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 486 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=O)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].O[NH:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[NH:29].[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[O:22][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[N:27]=2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: N=C(NO)c1ccccn1
Reactant: CCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCCc2nc(-c3ccccn3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C

Procedure:
To a mixture of ethyl 5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (120 mg, 0.32 mmol) and of N-hydroxy-2-pyridinecarboximidamide (50 mg, 0.36 mmol) in EtOH (2 ml) was added a 21% (w/v) solution of sodium ethoxide in EtOH (0.225 ml, 0.62 mmol) and then heated in a sealed vial in a microwave oven at 140° C. for 10 min. The cooled mixture was evaporated to dryness and the residue partitioned between chloroform (5 ml) and saturated aqueous ammonium chloride (5 ml). The organic phase was evaporated to dryness and the crude product subjected to purification by MDAP. Product containing fractions were combined and evaporated to dryness. The product was triturated to a solid in a small amount of diethyl ether then dried to reveal the title compound as a white solid (44 mg, 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)(=[O:16])=[O:15]
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(NS(C)(=O)=O)cc1

Procedure:
In a manner similar to preparation 3, react 4-aminobenzeneacetic acid, methyl ester with methanesulfonyl chloride, and pyridine to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9](Br)[CH3:10])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH3:10])=[CH:4][N:3]=1
Reactant: CC(Br)c1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(±)-2,4-Dichloro-5-(1-bromoethyl)-pyrimidine (1.97 g; 7.70 mmol) (from Example 1c supra) was dissolved in acetonitrile (21 mL). p-Anisidine (0.95 g; 7.70 mmol) (Aldrich), potassium carbonate (1.17 g; 8.48 mmol) and potassium iodide (0.32 g; 1.93 mmol) were added and the mixture was stirred at room temperature. After 16 hours, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromatography (Biotage 40M, 20:80 to 25:75 ethyl acetate-hexanes gradient) gave (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amine. (Yield 1.82 g; 76.3%).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[CH:5]=[C:4]([CH2:9][C:10](=O)[CH3:11])[O:3]1.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[CH:17][N:16]=1.O>O1CCOCC1>[Cl:14][C:15]1[CH:20]=[C:19]([N:21]2[C:10]([CH3:11])=[CH:9][C:4]([OH:3])=[CH:5][C:6]2=[O:8])[C:18]([CH3:22])=[CH:17][N:16]=1
Reactant: CC(=O)CC1=CC(=O)OC(C)(C)O1
Reactant: Cc1cnc(Cl)cc1N
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(Cl)cc1-n1c(C)cc(O)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a screw top vial with rubber septa inset was added 2,2-dimethyl-6-(2-oxo-propyl)-[1,3]dioxin-4-one, prepared as described in Organic Letters, 11(21), 4910-4913; 2009, (500 mg, 2.7 mmol) and 2-chloro-5-methyl-pyridin-4-ylamine (575 mg, 4 mmol, 1.5 eq). The mixture was dissolved in anhydrous 1,4-dioxane (10 mL). Once the mixture was homogeneous the vial was placed on a stirrer/hot plate preset to 90° C. The reaction vessel was heated at this temperature for 3.5 h. The reaction vial was removed from heat and analyzed by HPLC which showed that the reaction was >95% complete. The vial was placed back on the hot plate. To the heated mixture was added H2SO4 (250 μL) and the reaction was heated for 1 h. The reaction vial was removed from the heat and after cooling to ambient temperature, the dioxane was removed by passing a stream of air over the top of the open vial to give a brown residue. Water (˜4 mL) was added to the vial, and the mixture was stirred for 30 min. The resulting tan solid was filtered off with washing from additional water and the diethyl ether to give the desired product (531 mg, 57% based on being the sulfate salt) as a tan solid which by HPLC was ˜95% pure: MS (ES) m/e 250 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH3:11]>O1CCOCC1>[NH2:11][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: N
Solvent: C1COCCO1
Product: N#Cc1cnc(N)nc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a solution of 2,4-dichloropyrimidine-5-carbonitrile (600 mg, 3.45 mmol) in dioxane (20 ml) was added a 0.5M solution of NH3 in dioxane (20 ml, 10 mmol) and the mixture stirred at room temperature for 4 h. A mixture of two isomers were obtained and separated by column chromatography using a mixture of hexane/ethyl acetate (from 0% to 45% of ethyl acetate). The title compound (304 mg, 56% yield) was found to be the less polar isomer.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([CH:24]=[O:25])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CCOCC>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([CH:24]([OH:25])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(C(O)c2ccccn2)C1
Temperature: -78 °C

Procedure:
To 1.51 g (9.55 mmol) bromopyridine in 50 mL ether at −20° C. was added 6 mL (1.6 M in hexane, 9.6 mmol) n-butyl lithium, after 10 minutes the mixture was cooled to −78° C. and 1.61 g (8.7 mmol) 3-formyl-azetidine-1-carboxylic acid tert-butyl ester in 20 mL ether was added. The mixture was stirred and allowed to warm to room temperature, quenched with 50 mL 1 M sodium bicarbonate solution and then extracted with 50 mL DCM. The organic layer was dried over Na2SO4. After filtration and evaporation of the solvent the desired product was purified by column chromatography (silica, heptane/EtOAc 1:1 to EtOAc).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([OH:9])[CH3:8])[CH2:3][CH2:2]1.[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O.CCN(CC)CC>ClCCCl>[OH:9][CH:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])[CH2:2][CH2:3]1)[CH3:8]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(O)C1CCNCC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
(±)-1-(4-Piperidinyl)ethanol (see reference: WO 9725992A, 12.44 g, 65.7 mmol) in 1,2-dichloroethane (500 mL) was stirred at room temperature and BOC2O (14.36 g, 65.8 mmol) was added followed by Et3N (19 mL, 136 mmol). The stirred mixture was heated at gentle reflux for 15 min and then allowed to cool to room temperature and stirred overnight. The solution was washed twice with 10% citric acid, once with 10% Na2CO3, dried over MgSO4, filtered and concentrated to afford (±)-1,1-dimethylethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate (14 g, 93% yield) as a light amber oil. 1H NMR (400 MHz, DMSO-d6): δ 4.35 (d, 1H, J=4.8 Hz), 3.92 (m, 2H), 3.32 (m, 1H), 2.59 (m, 2H), 1.68 (m, 1H), 1.47 (m, 1H), 1.34 (s, 9H), 1.25 (m, 1H), 1.08-0.88 (m, 2H), 0.97 (d, 3H, J=6.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34](O)=[O:35].CCN=C=NCCCN(C)C>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35]
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccccc4F)c3)c2c1
Yield: 13.8 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-fluorophenylacetic acid (0.11 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 30 mg (12% yield) of the title compound. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.2 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.45 (t, 1H), 7.45-7.29 (m, 3H), 7.25-7.15 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 389 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[CH:3]=1.[N:17]([O-])=[O:18].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4](=[O:16])[C:3]=1[N:17]=[O:18]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)n(Cc2ccccc2)c(=O)[nH]1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1[nH]c(=O)n(Cc2ccccc2)c(=O)c1N=O

Procedure:
Slurry 6-amino-3-(phenylmethyl)-pyrimidine-2,4-dione (1.1 g=5 mmol) in 50 ml water. Add NaNO2 (0.63 g=9.1 mmol), warm to 75° C. and add acetic acid (2.6 ml=45 mmol) in 30 ml water over two hours. Collect the product, water wash and dry over P2O5 to give title compound as an orange solid. EI MS: M+=246.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:15]Br>O1CCOCC1>[Br:15][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Cc1cccc(S(C)(=O)=O)c1
Reactant: BrBr
Solvent: C1COCCO1
Product: CC(=O)C(Br)c1cccc(S(C)(=O)=O)c1
Temperature: 25 °C

Procedure:
A stirred solution of 1-(3-methanesulphonyl-phenyl)-propan-2-one (176b) (0.25 g, 1.18 mmol) in dioxane (10 ml) at 5° C. is treated with bromine (0.131 g, 0.82 mmol) added in two portions. The reaction is stirred and allowed to warm up to room temperature. The solvent is removed in vacuo to yield an orange oil of the titled compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[NH:6][CH:7]=[C:8]([C:10](=O)[CH2:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=2)[CH:9]=1)(=[O:4])=[O:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][S:2]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]([CH3:19])([CH3:20])[CH3:21])[C:15]([OH:22])=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=2)[CH:9]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)c1cc(CC(=O)c2c[nH]c(S(C)(=O)=O)c2)cc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)c1cc(CCc2c[nH]c(S(C)(=O)=O)c2)cc(C(C)(C)C)c1O

Procedure:
For example, using 2-methylsulfonyl-4-[2-(3,5-di-t-butyl-4-hydroxyphenyl)-1-oxo-ethyl]pyrrole in this general reaction together with eight molar equivalents of LAH yields 2-methylsulfonyl-4-[2-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]pyrrole (a compound according to Formula X wherein: m is 2; n is 0; R is H; and X is SO2CH3 ; and Y and Z are each H). Likewise, using 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole in this general reaction together with eight molar equivalents of LAH yields 3-(3,5-di-t-butyl-4-hydroxybenzyl)pyrrole (a compound according to Formula X wherein: m is 1; n is 0; R is H; and X, Y and Z are each H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:32]([O:33]C(OC)=O)=[CH:31][C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]([F:38])[CH:5]=1.O.Cl>CO>[ClH:3].[Cl:3][C:4]1[C:32]([OH:33])=[CH:31][C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]([F:38])[CH:5]=1
Reactant: COC(=O)Oc1cc(Nc2ncnc3cc(OCCCc4ccncc4)c(OC)cc23)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCCCc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 150.4 %

Procedure:
2M Aqueous sodium hydroxide (1.5 ml mmol) was added to a solution of 4-(4-chloro-2-fluoro-5-methoxycarbonyloxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline (1.28 g, 2.5 mmol) in methanol (13 ml) and the mixture stirred for 2 hours at ambient temperature. Water was added and the mixture was adjusted to pH7 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. This solid was dissolved in methylene chloride (30 ml) and methanol (5 ml) and a solution of 5M hydrogen chloride in isopropanol (2.5 ml) was added. The solution was diluted with isopropanol and concentrated under vacuum to a total volume of 10 ml. The resulting solid was collected by filtration, washed with isopropanol and then ether and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-(4-pyridyl)propoxy)quinazoline hydrochloride (924 mg, 70%). 1H NMR Spectrum: (DMSOd6) 2.3(t, 2H); 3.12(t, 2H); 4.0(s, 3H); 4.28(t, 2H); 7.18(d, 1H); 7.4(s, 1H); 7.52(d, 1H); 7.95(d, 2H); 8.32(s, 1H); 8.82(s, 1H); 8.84(d, 2H); 10.65(s, 1H); 11.65(br s, 1H) MS-ESI: 455 [MH]+
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[C:17]#[N:18]>C1COCC1>[F:1][C:2]1[C:11]2[N:10]([C:15]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:16]=3[C:17]#[N:18])[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: Fc1cccc2c1NCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cccc(F)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a flask charged with 5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (Combi-Blocks) (0.321 g, 2.096 mmol) was added THF (8.38 ml). The solution was cooled in an ice water bath prior to the addition of sodium hydride (60% in mineral oil) (0.092 g, 2.306 mmol). The resulting suspension was stirred for 30 mins at 0° C., the 30 mins at room temp. The resulting pale yellow suspension was cooled in an ice water bath prior to the addition of 2-fluoro-5-(trifluoromethyl)benzonitrile (Matrix Scientific) (0.436 g, 2.306 mmol). The mixture was stirred for 5 mins at 0° C., the 1 hr at room temperature when LC-MS indicated all starting material present. The tannish suspension was heated to reflux overnight providing a brown solution with about 80% conversion to product according to LC-MS. The mixture was cooled to room temperature and carefully added to ice water which was extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered and dried under reduced pressure. The crude residue was purified with a 25 g column (25 m spherical silica gel, Interchim) ramping EtOAc in heptane (0-35%, with 10% DCM throughout) providing product which had partially coeluted with starting amine. The material obtained was filtered through a 5 g SCX-2 column washing with MeOH. The MeOH wash contained product, obtained as an off-white solid 2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile (0.450 g, 1.396 mmol, 66.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91-3.97 (m, 2 H) 4.22 (br. s., 2 H) 6.68 (ddd, J=10.86, 8.22, 1.37 Hz, 1 H) 6.82 (dt, J=8.41, 1.37 Hz, 1 H) 7.00 (td, J=8.31, 5.97 Hz, 1 H) 7.14 (dd, J=8.71, 2.25 Hz, 1 H) 7.67 (ddd, J=8.73, 2.23, 0.59 Hz, 1 H) 7.90 (dd, J=1.57, 0.59 Hz, 1 H). m/z (ESI) 323.3 (M+H)+.
Reaction SMILES: C[N:2]1[CH2:12][C@H:11](C2C=CC=CC=2)[C:10]2[CH:9]=[C:8]([OH:19])[C:7](Cl)=[CH:6][C:5]=2CC1.CC([C@]1([OH:47])C[C@H]2N(C[C@H]3C4C2=CC=CC=4CCC2C=CC=CC3=2)CC1)(C)C>>[NH2:2][CH2:12][CH2:11][C:10]1[CH:5]=[CH:6][C:7]([OH:47])=[C:8]([OH:19])[CH:9]=1
Reactant: CN1CCc2cc(Cl)c(O)cc2[C@@H](c2ccccc2)C1
Reactant: CC(C)(C)[C@@]1(O)CCN2C[C@@H]3c4ccccc4CCc4cccc(c43)[C@H]2C1
Product: NCCc1ccc(O)c(O)c1

Procedure:
HEK cells were transfected with DNA encoding D1-NLS-GFP (2 micrograms), and D1-WT (6 micrograms) for 48 hours. These cells were treated 6 hrs after transfection with SCH-23390 (10 micromolar), or (+)butaclamol (10 micromolar). The medium containing antagonist was changed at 6, 22, 30 and 42 hours after transfection. Control cells received no antagonist treatment.
Reaction SMILES: [Mg].[O:2]([CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]I)[Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].C(Br)C.[CH2:23]1[O:26][CH:24]1[CH3:25]>C1COCC1>[O:2]([CH2:10][CH2:11][C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:23][CH:24]([OH:26])[CH3:25])[Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCC#CCCCCCI
Reactant: CC1CO1
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: CC(O)CCCCCCC#CCCO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To magnesium powder (830 mg, 35 mmol) and 18 (8.7 g, 23 mmol) in 40 mL of dry THF under nitrogen was added ethyl bromide (0.1 mL,=1.3 mmol). Grignard formation was maintained by refluxing for 3 hr. After the iodide (18) was consumed, 2.2 g (11.5 mmol) of cuprous iodide was added. The mixture was cooled in an ice-bath and stirred for 30 min. Propylene oxide (2.7 g, 46 mmol) diluted in 10 mL of dry THF was added dropwise, the reaction stirred for 30 min at 23° C. and then quenched with saturated aqueous ammonium chloride (100 mL). The ether extract (3×75 mL) of the aqueous mixture was washed with brine (3×75 mL). The isolated product was purified by chromatography9 on 180 g (20 cm×4.5 cm I.D. column) of silica gel (20% EtOAc in hexane) to give 3.3 g (46% yield) of 19.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH:29]([OH:31])[CH3:30])[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)CN
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Product: CC(O)CNc1nc(N2CCS(=O)CC2)c2ncnc(SCc3ccccc3)c2n1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine and 1-amino-2-propanol.