Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH:3]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH:7]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].C(N(CC)CC)C>C(#N)C>[CH3:13][C:8]1[CH:7]=[C:6]([C:4]2[N:20]=[C:21]([NH2:23])[S:22][C:3]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:11]=[C:10]([CH3:12])[CH:9]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C)cc(C(=O)C(Br)c2ccncc2)c1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.4 %

Procedure:
To a solution of 2-bromo-1-(3,5-dimethylphenyl)-2-(4-pyridyl)ethanone hydrobromide (5.0 g, 13 mmol) and thiourea (1.0 g, 14 mmol) in acetonitrile (60 mL) was added dropwise triethylamine (1.9 ml, 14 mmol) and the mixture was stirred at room temperature for 3 h. The solvent was concentrated under reduced pressure and a saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and the solvent was evaporated. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (2.0 g, 7.2 mmol, yield 55%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:4]1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29]O.CCN(CC)CC>>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][N:3]([CH3:2])[CH2:4]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCCC(COc2ccc(NC=C3C(=O)Nc4ccc(F)cc43)cc2)C1
Yield: 77.2 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine hydrochloride (688 mg, 1.2 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.23 mmol, 1 equiv.) with the addition of anhydrous Et3N (2.25 equiv.) are reacted to give the named compound as a yellow solid (657 mg, 77%).
Reaction SMILES: CC(N(C)C)=O.[CH3:7][C:8]1[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[C:10]([OH:20])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2.F[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:7][C:8]1[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[C:10]([O:20][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2
Reactant: COc1cccc(-c2c(C)cc3cc(OC)ccc3c2O)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2c(C)cc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)c1
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
A dimethylacetamide solution (2 mL) of 3-methyl-6-(methyloxy)-2-[3-(methyloxy)phenyl]-1-naphthalenol (247) (0.072 g, 0.25 mmol, 1 equiv) was treated with 4-fluorobenzaldehyde (0.030 mL, 0.27 mmol, 1.1 equiv) followed by cesium carbonate (0.096 g, 0.29 mmol, 1.2 equiv). After 10 min at gentle reflux, the mixture was diluted with H2O (2 mL) and extracted with EtOAc (3×5 mL). The pooled organic portions were dried (Na2SO4) and concentrated. Radial chromatography (SiO2, 1 mm plate, 80:20; hexanes/EtOAc) afforded the title compound (248) as a pale yellow oil (0.060 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 9.80 (s, 1H), 7.68-7.59 (m, 4H), 7.19-7.14 (m, 2H), 7.05 (dd, J=9.2, 2.4 Hz, 1H), 6.78-6.65 (m, 5H), 3.93 (s, 3H), 3.64 (s, 3H), 2.26 (s, 3H). TLC (75:25; hexanes/EtOAc): Rf=0.55.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[O:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH3:35])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COCCOCOc1cc2ccc(-c3ccc(CO)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COCCOCOc1cc2ccc(-c3ccc(C=O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
2.63 g (5.9 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzenemethanol and 40 ml of dichloromethane were introduced into a round-bottomed flask and 4.2 g of pyridinium dichromate were added. The reaction mixture was stirred at room temperature for twelve hours, was filtered through silica and the filtrate was evaporated. The solid obtained was recrystallized from heptane and 490 mg (19%) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzaldehyde were collected, which compound had a melting point of 83°-4° C.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)=O)[C:4]([O:6]CC)=[O:5].[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27])([O-:22])=[O:21].[OH-].[Na+]>C(O)C>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[NH:27][C:26]([C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=3)=[N:2][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1)[CH3:19]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OCC)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(-c2[nH]c(-c3cccc([N+](=O)[O-])c3)nc2C(=O)O)cc1

Procedure:
Ethyl 5-(4-ethoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylate obtained by reacting and treating ethyl 2-hydroxyimino-3-(4-ethoxyphenyl)-3-oxopropionate and 3-nitrobenzylamine in the same manner as in Starting Material Synthetic Example 1 is dissolved in ethyl alcohol and 1 M aqueous sodium hydroxide solution is added. The mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-ethoxyphenyl)-2-(3-nitrophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[CH2:25][O:26][CH2:27][CH:28]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:24]3[CH2:25][O:26][CH2:27][CH:28]=3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOC1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOC3)cc2C1

Procedure:
Prepared in analogy to Example A49(a) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and tributyl-(2,5-dihydro-furan-3-yl)-stannane. Off-white solid. MS (m/e): 268.3 ([{37Cl} M+H−Me2C═CH2]+, 32%), 266.1 ([{35Cl}M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:38]([O-])=[O:39].[NH4+]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH:19]1[CH2:20][CH2:21][N:22]([CH:38]=[O:39])[CH2:23][CH2:24]1)[C:14](=[O:25])[N:13]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:12]2=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[O-]
Reactant: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCNCC3)c2=O)cc1OC
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c3cc(OCc4ccccc4)ccc3n(C3CCN(C=O)CC3)c2=O)cc1OC
Yield: 97.9 %

Procedure:
A mixture of 0.6 g of 6-(benzyloxy)-3-(3,4-dimethoxybenzyl)-1-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione obtained in stage 1.7 and 0.113 g of ammonium formate in 5 ml of ACN is irradiated under a microwave field at 140° C. for 1 h 00. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 0.62 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:29][CH2:30][CH3:31])=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1COCC1.N1C=CN=C1.[C:42]([Si:46](Cl)([CH3:48])[CH3:47])([CH3:45])([CH3:44])[CH3:43]>CCOC(C)=O.CCCCCCC.O>[Si:46]([O:28][C@@H:26]([CH3:27])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH2:29][CH2:30][CH3:31])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)=[O:13])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:48])[CH3:47]
Reactant: CCCc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCCc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A 250 mL round bottom flask was charged with N′-((2R,3S)-2-(3-chloro-4-cyano-2-propylphenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (intermediate 1119-B) (0.710 g, 1.61 mmol) and THF (20 mL) at room temperature. Imidazole (0.440 g, 6.47 mmol) and tert-butyldimethyl silyl chloride (0.730 g, 4.84 mmol) were then added to the mixture which was stirred at room temperature for 48 h. Water (20 mL) was then added to the mixture followed by heptane (50 mL) and stirred for 30 min at room temperature. EtOAc (50 mL) was then added and the phases were partitioned. The organic extract was separated, dried over Na2SO4, and concentrated to furnish a yellow solid. The crude material was purified by flash column chromatography [SiO2, EtOAc-hexanes (20%:80%)→EtOAc-hexanes (50%:50%)→EtOAc-hexanes (60%:40%) as eluent] to afford the title compound as a light yellow solid with other minor impurities (0.750 g, 84% yield), which was immediately taken to the next synthetic step.
Reaction SMILES: [Li+].[OH-].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C@@H:22]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:23][NH:24][C:25]([CH3:38])([CH3:37])[CH2:26][C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[C:30]([O:32]C)=[O:31])=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[CH:17]=[CH:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C1COCC1.CO.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C@@H:22]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH2:23][NH:24][C:25]([CH3:38])([CH3:37])[CH2:26][C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[C:30]([OH:32])=[O:31])=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[CH:17]=[CH:16]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 89.1 %

Procedure:
Solid LiOH (370 mg, 15.4 mmol) was added to a stirring solution of Intermediate 100 (950 mg, 1.55 mmol) in THF/MeOH/H2O (15 mL, 3/1/1) at rt. The reaction mixture was stirred over night then pH was adjusted to 1 with 1 N HCl. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give crude acid (1.09 g) as yellow solid. Recrystallization (CH2Cl2/Et2O) afforded the title compound (830 mg, 89%) as off white solid. ES/MS calcd. for C35H45N2O5Si+ 601.3. Found m/z=601.3 (M+H)+.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7](=[NH:9])[NH2:8])=[CH:3]1.[Cl:10][C:11]([SH:14])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[S:14][N:8]=[C:7]([C:4]2[CH:5]=[CH:6][S:2][CH:3]=2)[N:9]=1
Reactant: N=C(N)c1ccsc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(-c2ccsc2)ns1
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of thiophene-3-carboximidamide hydrochloride (2.00 g, 12.3 mmol) and perchloromethyl mercaptan (1.32 ml, 12.3 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.46 g, 61.5 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.57 g (59.5%) of the desired product as an oil.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[CH:6]1([P:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)([SH:14])=[S:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:6]1([P:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)([S:14][CH2:1][CH2:2][CH2:3][CH3:4])=[S:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: S=P(S)(C1CCCCC1)C1CCCCC1
Reactant: CCCCBr
Product: CCCCSP(=S)(C1CCCCC1)C1CCCCC1

Procedure:
n-Butyl bromide was reacted with the ammonium salt of dicyclohexylphosphinodithioic acid to obtain n-butyl dicyclohexylphosphinodithioate, a viscous liquid, b.p. 167°-175° C at 0.15 mm., which on testing lasted 900 hours longer than the control. The total number of hours required to reach failure was 2.8 times that of the control.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@H:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3]1.[CH3:18][NH:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:18][N:19]([CH3:20])[CH:2]1[CH2:6][CH2:5][C@H:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3]1
Reactant: CNC
Reactant: N#Cc1ccc2[nH]cc([C@H]3CCC(=O)C3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CN(C)C1CC[C@H](c2c[nH]c3ccc(C#N)cc23)C1
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
(1S)-3-(3-oxocyclopentyl)-1H-indole-5-carbonitrile (112 mg, 0.5 mMol) and dimethylamine (2.0 M solution in THF, 2.5 mL, 5.0 mMol) were dissolved in ethanol (2 mL). After stirring for 15 min, sodium triacetoxyborohydride (424 mg, 2.0 mMol) was added and the reaction continued for 2 h. The reaction was then diluted with water (5 mL) and made acidic (pH 3) with 6 M HCl. The reaction was then adjusted to pH 10 with sodium carbonate. It was extracted two times with ethyl acetate (50 mL) and the extracts were dried over sodium sulfate, concentrated in vacuo, and dried under high vacuum to give (1S)-3-(3-dimethylaminocyclopentyl)-1H-indole-5-carbonitrile (125 mg, 100%) as a cis/trans diastereomeric mixture. 1H NMR (500 MHz, d4-MeOH) δ 8.02 (0.7 H s), 7.99 (0.3 H, s), 7.46 (0.3 H, s), 7.44 (0.7 H, s), 7.35 (1 H, dd, J=8.24 1.53), 7.24 (0.7 H, s), 7.20 (0.3 H, s), 3.49 (0.3 H, m), 3.36 (0.7 H, m), 2.83 (0.2 H, m), 2.75 (0.8 H, m), 2.39 (1 H, m), 2.31 (6 H, s), 2.21 (1 H, m), 2.05 (1 H, m), 1.80 (2 H, m), 1.66 (1 H, m).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:28])[CH:20](Br)[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.O>O1CCCC1>[CH3:17][O:18][C:19](=[O:28])[CH:20]([N:12]1[C:11](=[O:14])[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:13]1)[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1ccc(Oc2ccccc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1nc(Oc2ccccc2)ccc1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
A solution of 6-phenoxy-2H-pyridazin-3-one (0.78 g, 4.18 mmol) in tetrahydrofuran (21 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (0.2 g, 5.0 mmol). The reaction was stirred at 0° C. for 5 min and then at 25° C. for 35 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 1.08 g, 4.59 mmol). The reaction was then warmed to 50° C. where it stirred overnight. After this time, the reaction was cooled to 25° C., poured into water (100 mL), and extracted into methylene chloride (3×100 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with methylene chloride and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 80 g, 20-40% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(6-oxo-3-phenoxy-6H-pyridazin-1-yl)-propionic acid methyl ester (1.03 g, 72%) as a light yellow oil. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.98 (d, 2H), 1.32-1.71 (m, 7H), 1.71-1.84 (m, 1H), 1.84-2.05 (m, 1H), 3.59 (s, 3H), 5.19 (dd, J=10.9, 3.9 Hz, 1H), 7.10-7.18 (m, 3H), 7.22 (t, J=7.5 Hz, 1H), 7.42 (t, J=7.5 Hz, 2H), 7.48 (d, J=9.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][S:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][S:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCSc1ccncc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSc1ccncc1
Temperature: 90 °C
Yield: 2.8 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), 4-(2-chloroethylthio)pyridine hydrochloride (252 mg, 1.2 mmol) and potassium carbonate (454 mg, 3.3 mmol) in NMP (30 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methanol mixtures (100/0 increasing to 75/25) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(4-pyridylthio)ethoxy)quinazoline (13 mg, 3%). m.p. 182-186° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3ccccc3F)c2C(N)=O)cc1
Yield: 89 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 1.91 g (7.01 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 57 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 2.47 g of 1-(4-t-butylbenzyl)-4-(2-fluorobenzoylamino)-5-imidazolecarboxamide (yield 89%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[S:20][C:21]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)=[N:22][N:23]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.O1CCOCC1.[OH-].[Na+]>O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]5[S:20][C:21]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)=[N:22][N:23]=5)[CH:17]=4)[NH:12][CH:11]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(-c5ccccc5)s4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2nnc(-c3ccc4[nH]cc(-c5cncc(C6CC6)n5)c4c3)s2)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
In a 20 mL glass microwave tube 2-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-5-phenyl-1,3,4-thiadiazole (190 mg, 0.346 mmol) was treated with dioxane (2.5 mL) and 1N NaOH (0.75 mL) and heated in the microwave to 100° C. for 10 min. The mixture was treated with H2O, extracted with EtOAc (2×15 mL), washed with brine, dried over MgSO4, filtered and concentrated affording 2-(3-(6-cyclopropylpyrazin-2-yl)-1H-indol-5-yl)-5-phenyl-1,3,4-thiadiazole (89 mg, 65%) as a yellow amorphous solid. (ESI, pos. ion) m/z: 396.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.06 (1H, br. s.), 9.13 (1H, s), 8.96 (1H, s), 8.43 (1H, d, J=2.5 Hz), 8.40 (1H, s), 7.99-8.08 (2H, m), 7.89-7.96 (1H, m), 7.58-7.69 (4H, m), 2.23-2.32 (1H, m), 1.17-1.30 (4H, m).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([O:21]C)=[O:20].O.O[Li].O.Cl>C1COCC1>[F:24][C:2]([F:1])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)Cc1ccc(Oc2ccccn2)cc1OCC(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Oc2ccccn2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)phenylacetate (0.45 g, 1.3 mmol) from Step 3 above in THF (4 mL) and water (1 mL) was added LiOH·H2O (0.065 g, 1.5 mmol). The mixture was stirred at ambient temperature for 14 h. The solution was adjusted to pH 3 by the addition of 5 N aqueous HCl and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 0-20% MeOH:CH2Cl2 to give 2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)-phenylacetic acid as a gum (HPLC retention time=5.4 min (method A)).
Reaction SMILES: Br[C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[C:34]([N:36](C)C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([F:20])[C:13]=1[N:12]1[C:3]2[C:2]([C:34]#[N:36])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[C:4]=2[C:10]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:23][CH:22]=2)=[N:11]1
Reactant: COc1ncc(Br)c2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1F
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ncc(C#N)c2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1F
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-(7-bromo-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)morpholine (93 mg) obtained in Step B of Example 218 in DMA (3 mL) were added tetrakis(triphenylphosphine)palladium(0) (43 mg) and zinc cyanide (33 mg) at room temperature, and the mixture was stirred under microwave irradiation at 120° C. for 30 min. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (77 mg).