Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[N:15]=[C:14]([S:16][CH3:17])[C:13]([C:18]#[N:19])=[CH:12][C:6]=1[C:7]([O:9]CC)=[O:8]>C(O)C.O>[NH2:4][C:5]1[N:15]=[C:14]([S:16][CH3:17])[C:13]([C:18]#[N:19])=[CH:12][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(C#N)c(SC)nc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1nc(N)c(C(=O)O)cc1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
3.08 g (2 eq) of lithium hydroxide monohydrate is added at room temperature to a solution of 8.7 g (36.7 mmol) of ethyl 2-amino-5-cyano-6-(methylthio)nicotinate in 87 ml of ethanol and 87 ml of water. The reaction mixture is stirred at 60° C. for 2 hours. The ethanol is evaporated and 1 N aqueous soda is added. The aqueous phase is washed with ethyl acetate and then re-acidified by adding 1 N aqueous hydrogen chloride (pH=1). The precipitate formed is filtered, rinsed with water and with diethyl ether and then dried under vacuum to yield 7.67 g (quantitative) of 2-amino-5-cyano-6-(methylthio)nicotinic acid in the form of a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23]S(C)(=O)=O)[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1>Cl.CO>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[CH:15][N:14]2[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH2:12][CH3:13])[CH2:9][C:10]#[N:11]
Reactant: CCC(CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: Cl
Solvent: CO
Product: CCC(CC#N)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of the product from Step C (250 mg, 0.59 mmol) and 4 N HCl/MeOH (10 mL) was stirred at room temperature for 2 h. After solvent was removed in vacuo, the residue was dissolved in ethyl acetate (20 mL), pH value adjusted to 9˜10 with a saturated sodium bicarbonate solution, dried over sodium sulfate, then filtered. After removing the organic solvent, the title compound as a colorless oil was obtained. LC/MS m/z=324.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=O)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Br)(Br)([Br:31])=O>CN(C)C=O>[Br:31][C:16]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)CCCC2
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: CCN(CC)c1ccccc1
Product: Clc1ccc(-n2nc3c(c2Br)CCCC3)cc1
Temperature: 25 °C

Procedure:
To 5.0 parts of 2-(4-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one [from Example 1(c)] with 3.0 parts of N,N-diethylaniline and 5.0 parts of dimethylformamide under nitrogen atmosphere was added 6.3 parts of phosphorous oxybromide. The mixture was heated to 130°-170° for two hours. After cooling to room temperature, the reaction mixture was extracted with 100 parts of diethyl ether, washed with water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. Recrystallization from methanol/water gave 2.7 parts of product, m.p. 101°-102°.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]=[C:16]([O:26][CH3:27])[N:15]=2)[CH2:10][CH:9]1[C:28](=[O:40])[NH:29][C:30]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32][CH:31]1[CH:33]=[CH2:34])=[O:7])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([O:37][C:35]([C:30]1([NH:29][C:28]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:17]=[C:16]([O:26][CH3:27])[N:15]=3)[CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:40])[CH2:32][CH:31]1[CH:33]=[CH2:34])=[O:36])[CH3:39]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc(OC)n2)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.8 %

Procedure:
To a solution of compound 13a (1.0 g, 1.81 mmol) in DCM (30 ml) was added triethylsilane (0.53 g, 4.53 mmol) and TFA (20 ml) and the mixture was stirred at room temperature for 1 hour. The solution was evaporated under reduced pressure and co-evaporated two times with toluene which gave the title compound (1.2 g), (M+H)+496.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[CH3:52][O:53][CH2:54][CH2:55][CH2:56][NH2:57]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[S:20][C:19]([C:21]([NH:57][CH2:56][CH2:55][CH2:54][O:53][CH3:52])=[O:22])=[CH:18][CH:17]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(C(=O)O)s3)nc12
Reactant: COCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCCNC(=O)c1ccc(-c2cc(NC3CC3)n3ncc(C=O)c3n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (30 mg, 0.091 mmol), EDCI (19 mg, 0.10 mmol), Et3N (14 μL, 0.10 mmol), and HOBt (14 mg, 0.10 mmol) in 2 mL of DMF pre-stirred for 5 minutes was added 3-methoxypropylamine (10 μL, 0.10 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate, washed with H2O, brine, dried over MgSO4, filtered, and evaporated to dryness to provide 30 mg of 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-N-(3-methoxypropyl)thiophene-2-carboxamide (83%). LCMS (M+1=400)
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:16]O)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[N:3]1[C:2]([Cl:1])=[N:6][N:5]([CH3:7])[C:4]1=[O:8]
Reactant: Cc1cccc(CO)c1-n1c(Cl)nn(C)c1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(CBr)c1-n1c(Cl)nn(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of the title compound of Step D (3.0 g, 12 mmol) in dichloromethane (56 mL) cooled to 0° C. under a nitrogen atmosphere was added triphenylphosphine (3.72 g, 14 mmol) followed by carbon tetrabromide (5.9 g, 18 mmol). The mixture was allowed to warm to room temperature and was stirred for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (2:1 hexanes:ethyl acetate) to afford 3.19 g of the title compound of Step E as a light yellow powder. 1H NMR (CDCl3): δ 7.3-7.39 (m,3H), 4.35 (AB q,2H), 3.56 (s,3H), 2.16 (s,3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH:9]2[CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[CH2:12][CH2:11][N:10]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:2]=1.C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][N:10]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1COc1cccnc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCNCC1COc1cccnc1
Temperature: 80 °C
Yield: 87.1 %

Procedure:
Palladium hydroxide on carbon (˜10% palladium, 0.170 g, 0.12 mmol) was added to a solution of 1-tert-butyl 4-benzyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (0.649 g, 1.52 mmol) and ammonium formate (0.191 g, 3.03 mmol) in EtOH (10 mL), and the reaction mixture was heated to 80° C. for 2 h. Upon cooling to rt, the reaction mixture was diluted with EtOAc (40 mL) and washed with water (3×30 mL) and brine (30 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure, yielding 388.4 mg (87%) of the desired product as a white, waxy solid. LC-MS: RT=3.90 min, [M+H]+=294.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:30][OH:31].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:31][NH:30][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
To a solution of compound 12f (125 mg, 0.287 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (199 mg, 2.87 mmol) and a freshly prepared solution of sodium methoxide in methanol (99 mg, 4.30 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13f (20 mg, yield 16%). HPLC 85.42% (Rt=14.11 min).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=S(=O)(NCC(Cc1cccnc1)c1ccc(OCc2ccccc2)cc1)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=S(=O)(NCC(Cc1cccnc1)c1ccc(O)cc1)c1ccc(Cl)cc1
Yield: 59 %

Procedure:
The N-[2-(4-benzyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide (170 mg) was dissolved in 10 ml of ethanol, followed by addition of 0.2 g of 10% palladium carbon, and stirred for catalytic reduction via hydrogen at 55° C. overnight, to obtain 82 mg of N-[2-(4-hydroxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([NH:10][C:11]([C:13]3[CH:39]=[CH:38][N:16]4[C:17](=[O:37])[C:18](/[CH:28]=[CH:29]/[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:19]([N:21]5[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH2:22]5)[N:20]=[C:15]4[CH:14]=3)=[O:12])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)[C:42]([N:44]=C=O)=[O:43]>C(OCC)(=O)C>[NH2:44][C:42]([O:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:19]2[N:20]=[C:15]3[CH:14]=[C:13]([C:11]([NH:10][C:7]4[S:8][CH:9]=[C:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[N:6]=4)=[O:12])[CH:39]=[CH:38][N:16]3[C:17](=[O:37])[C:18]=2/[CH:28]=[CH:29]/[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:22]1)=[O:43]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(O)C2)nc2cc(C(=O)Nc3nc(C4CCC4)cs3)ccn2c1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(OC(N)=O)C2)nc2cc(C(=O)Nc3nc(C4CCC4)cs3)ccn2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl (E)-3-[8-{[(4-cyclobutyl-1,3-thiazol-2-yl)amino]carbonyl}-2-(3-hydroxypiperidino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-2-propenoate (16 mg, 0.029 mmol) was dissolved in ethyl acetate (3 ml), added with trichloroacetyl isocyanate (10 μl) under ice cooling, stirred at 0° C. for 1 hour, then further added with trichloroacetyl isocyanate (10 μl), and further stirred for 30 minutes. Then, the reaction solution was concentrated under reduced pressure, and the resulting residue was added with methanol (2 ml), water (0.2 ml) and sodium formate (12 mg) at room temperature and stirred at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (chloroform:methanol=30:1) to obtain 20 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:37]1([CH2:43][CH2:44]N)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C1COCC1>[N:37]1([CH2:43][CH2:44][NH:18][C:16]([C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][N:12]3[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=2[O:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:17])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NCCN1CCCCC1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCN3CCCCC3)cc21
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with 2-piperidin-1-yl-ethylamine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-6 as an oil in 100% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N-]C(C)C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[CH:28][CH:25]1[CH2:24][CH2:23][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:27][CH2:26]1)[CH2:6]2
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1cc2c(cc1OC)C(=O)C(=CC1CCN(Cc3ccccc3)CC1)C2

Procedure:
According to the process disclosed in U.S. Pat. No. 4,895,841, 5,6-dimethoxy-1-indanone was condensed with 1-benzyl-4-formylpiperidine in the presence of lithium diisopropylamide to give 5,6-dimethoxy-2-[[1-benzyl-4-piperidinyl]methylene]-1-indanone, which was then reduced with platinum oxide catalyst to give donepezil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([C:11](=[O:14])[CH2:12][OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[C:17]([F:36])[CH:16]=3)[CH:9]=[C:10]([CH:11]([OH:14])[CH2:12][OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C(=O)CO)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Nc1ncnn2c(C(O)CO)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
To a stirred solution of Example 234 (150 mg, 0.30 mmol) in THF (2 mL) at 0° C., was added DIBAL-H (2.96 mL, 2.96 mmol, 1.0 M in THF). The reaction was allowed to stir for 30 min while warming to rt. The mixture was quenched with MeOH (1 mL) and diluted with EtOAc (300 mL) and saturated aq sodium potassium tartrate (200 mL). This solution was stirred at 50° C. for 17 hr. The mixture was allowed to cool and the organic phase was washed with brine (50 mL), dried (Na2SO4) and concentrated to dryness. The residue was purified by preparative HPLC using a gradient elution from 10% to 70% acetonitrile to obtain 31 mg (20%) of the desired product. 1H-NMR (DMSO-d6) δ 9.51 (br s, 1H), 9.35 (br s, 1H), 8.73 (d, J=6.0 Hz, 1H), 8.35 (t, J=8.7 Hz, 1H), 7.98 (s, 1H), 7.62-7.55 (m, 1H), 7.49-7.47 (m, 1H), 7.41-7.27 (m, 2H), 6.76 (s, 1H), 5.27 (t, J=5.7 Hz, 1H), 4.59-4.58 (m, 1H), 4.11 (s, 1H), 3.39 (d, J=6.9 Hz, 2H); MS [M+H]+=509.2; LCMS RT=2.98 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[OH:24])[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: Nc1ccc(F)cc1O
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Temperature: 140 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (500 mg), 2-amino-5-fluor-phenol (265 mg) and p-toluenesulfonic acid (75 mg) in dioxane (5 ml) was stirred at 140° C. for 15 minutes under microwave radiation. The reaction mixture was allowed to cool, filtered and the filtercake was washed with dioxane, MeOH and diethyl ether to give the desired product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([O:15]CC)=[O:14])=[CH:6]2>Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1
Agent: Br
Product: O=C(O)c1cnc2ccc(O)cc2c1

Procedure:
Ethyl 6-methoxyquinoline-3-carboxylate (500 mg, 2.0 mmol) in 48% aq. HBr (5 mL) was subjected to MWI at 140° C. for 5 min. 6-Hydroxyquinoline-3-carboxylic acid precipitated from the reaction mixture and was collected by filtration. 1H NMR (300 MHz, CD3OD): δ 9.50 (d, 1H), 9.36 (d, 1H), 8.18 (d, 1H), 7.83 (dd, 1H), and 7.64 (d, 1H). LCMS: (FA) ES+ 190.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[I:11].CCO.[NH4+].[Cl-]>C1COCC1.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[I:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c(I)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Cl)c(I)c1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
1-Chloro-2-iodo-4-nitro-benzene (2.00 g, 7.09 mmol) was dissolved in THF (30 mL) at 60° C. and EtOH (35 mL) was added followed by NH4Cl (0.569 g, 10.6 mmol in 30 mL of water) and iron powder (1.58 g, 28.4 mmol). This mixture was stirred vigorously for 3 h and then cooled in 22° C. and filtered though celite rinsing with EtOAc. The solution was then concentrated to 30 mL in vacuo and then poured into a 1:1 solution of 1N NaOH/brine (100 mL). This mixture was then extracted with EtOAc (3×50 mL) and the organics were dried over anhydrous MgSO4. Filtration and concentration gave compound 801B as a yellow solid. No purification was necessary. HPLC: 100% at 2.310 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm), MS (ES): m/z 517.6 [M+Na]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[C:13]([CH3:25])[S:12][C:11]=2[CH:26]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:25][C:13]1[S:12][C:11]2[CH:26]=[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]3)[CH:8]=[CH:9][C:10]=2[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: OC1CCNCC1
Product: Cc1sc2cc(OCCCCN3CCC(O)CC3)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene and 4-hydroxy-piperidine were converted to yield 1-{4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-piperidin-4-ol as yellowish oil, MS: 464 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH:14][CH2:15][C@@H:16]1[O:21][C:20]2[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC1C=CC(O[CH2:35][C:36]#[N:37])=CC=1.Cl>CN(C=O)C>[CH2:7]([NH:14][CH2:15][C@H:16]1[CH2:17][O:18][C:19]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH2:35][C:36]#[N:37])[C:20]=2[O:21]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)O[C@@H](CNCc1ccccc1)CO2
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1c([N+](=O)[O-])ccc2c1O[C@@H](CNCc1ccccc1)CO2
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A 250 mL round bottomed flask equipped with a magnetic stir bar is charged with solid 95% potassium t-butoxide (1.57 g, 13.5 mmol) and DMF (6.5 mL), and the suspension is stirred until all the solids are dissolved. A DMF (4.0 mL) solution containing N-benzyl-1-[(2S)-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanamine (1.00 g, 3.3 mmol) and (4-chlorophenoxy)acetonitrile (1.12 g, 6.7 mmol) is added over 3 min. After 30 min, a 2 N aqueous solution of HCl is added until pH 1 is obtained (˜9 mL). The solution is transferred to a separatory funnel and extracted with toluene (2×10 mL) and discarded. The product-containing aqueous phase is adjusted to pH 10 by the addition of 10 N aqueous NaOH, and extracted with toluene (2×10 mL). The product-containing organic phases are combined and washed with water (15 mL) and then with brine (15 mL), and the volatiles are removed by evaporation to give the title compound (1.01 g, 88%) as a syrup. LCMS (Basic Method): 2.06 min, 340 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, J=9.1 Hz, 1H), 7.35-7.17 (m, 5H), 7.10 (d, J=9.1 Hz, 1H), 4.50-4.37 (m, 2H), 4.16 (dd, J=7.0, 11.4 Hz, 1H), 4.10 (s, 2H), 3.76 (s, 2H), 2.87-2.74 (m, 2H), NH not observed.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][C:7]=1[CH3:19])=[O:5])C.[OH-].[Na+]>CO>[C:15]([O:14][C:12]([NH:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:19])[N:8]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1sc(NC(=O)OC(C)(C)C)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)O
Temperature: 50 °C

Procedure:
A mixture of 2-tert-butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid ethyl ester (4.3 g) and sodium hydroxide (10 N, 2.5 mL) in MeOH (80 mL) is heated at 50° C. overnight. The mixture is cooled, concentrated in vacuo, diluted with water and acidified to pH 4-5 with 2 N HCl. The solid is collected by filtration and dried to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>C(O)C.C(O)(=O)C.C1COCC1.[Pd]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cc(F)ccc1Oc1ccccc1N
Reaction time: 20 h
Yield: 94.9 %

Procedure:
To a stirring solution of title compound 18 (3.48 g, 11.9 mmol) in ethanol (30 mL), acetic acid (1.0 mL) and THF (10 mL) was added palladium on charcol 10% (0.37 g, 10% w/w). The reaction mixture was stirred under hydrogen atmosphere for 20 hours. The catalyst was filtered and the filtrate was concentrated in vacuo. The residue was diluted with ether and this organic mixture was washed with a saturated aqueous solution of bicarbonate, water and brine then solvent evaporated to afford title compound 19 (2.95 g, 95%) as a beige solid. LRMS (ESI): (calc) 261.08. (found) 262.3 (MS)+.