Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([OH:43])([C:39]([F:42])([F:41])[F:40])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:15][C:14]=1[Cl:44].[C:45]([Si:49]([CH3:52])([CH3:51])Cl)([CH3:48])([CH3:47])[CH3:46]>ClCCl>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:43][Si:49]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:52])[CH3:51])([C:35]([F:36])([F:37])[F:38])[C:39]([F:41])([F:42])[F:40])=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:20])=[CH:15][C:14]=1[Cl:44]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(N)c(Cl)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (4.22 mmol, 0.631 mL, 0.643 g) was added to a cooled (ice/slurry) solution of (4-amino-3-chlorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (3.25 mmol, 1.61 g) and tert-butyldimethylchlorosilane (4.22 mmol, 0.636 g) in dichloromethane (20 mL) under nitrogen. The resulting solution was stirred for 15 minutes prior to the removal of the external cooling bath. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with 0.5M hydrochloric acid (100 ml), 0.5M sodium hydroxide (100 ml) and brine (100 ml). The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum to give a crude oil. This oil was purified by SCX chromatography to afford the title compound (1.616 g).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[OH-:15].[Na+]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([OH:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: [OH-]
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2nc(Cl)nc(O)c2c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
A mixture of 2,4-dichloro-6-methoxyquinazoline (4.20 g, 18.5 mmol, 1.0 eq.) in THF (60 mL) and 1120 (60 mL) was treated with NaOH (4.00 g, 100 mmol, 5.4 eq.). The resulting mixture was stirred at 40° C. for 2 h. The reaction color turned to dark green and then a precipitate formed. After the reaction was completed, the mixture was cooled to room temperature. The precipitate was filtered off and the filtrate was concentrated down to 60 mL. The pH was then adjusted to 6 by adding 2N HCl in water. The precipitate which formed was collected and dried in vacuo to give 4.00 g of 2-chloro-6-methoxyquinazolin-4-ol as a grey solid (98%). LCMS m/z=211.1, 213.0 (M+1) (Method B) (retention time=1.11 min).
Reaction SMILES: [H-].[Na+].[OH:3][C:4](=[C:16]([C:19]#[N:20])[C:17]#[N:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.S(OC)(O[CH3:25])(=O)=O>C1COCC1>[CH3:25][O:3][C:4](=[C:16]([C:17]#[N:18])[C:19]#[N:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COc1ccc(CC(O)=C(C#N)C#N)cc1OC
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(Cc1ccc(OC)c(OC)c1)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 60% NaH (5.7 g, 0.14 mol) in THF (150 ml) at -78° C. under argon was added dropwise (1-hydroxy-(3,4-dimethoxyphenylethylidene))malononitrile (34.6 g, 0.14 mol) in THF (100 ml) over 1.25 hours. The reaction mixture was stirred for 2 hours and dimethyl sulfate (26.9 g, 0.21 mol) in THF (50 ml) was added over 30 minutes. The reaction mixture was warmed to room temperature and stirred for 24 hours. The solvents were removed in vacuo and the residue was partitioned between ether and water. The organic layer was separated and the aqueous layer was extracted with ether (3×150 ml). The ether layers were combined and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ether (6/4) to afford crude (1-methoxy-(3,4-dimethoxyphenylethylidene))malononitrile as a gold oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:18]=1)[C:7]([C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1)=O.ClC1C=CC(F)=C(C=1)C(C1C=NC=CC=1C(O)=O)=O>C(O)=O.Cl.[Cu].[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([CH:18]=1)[CH2:7][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: O=C(O)c1cnccc1C(=O)c1cc(Cl)ccc1F
Agent: [Cu]
Agent: Cl
Agent: O=C(O)c1ccncc1C(=O)c1cc(Cl)ccc1F
Solvent: O=CO
Product: O=C(O)c1cnccc1Cc1cc(Cl)ccc1F
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Zinc-copper couple (0.75 g) is added to a stirred mixture of 4-(5-chloro-2-fluorobenzoyl)nicotinic acid and 3-(5-chloro-2-fluorobenzoyl)isonicotinic acid of Preparative Example 18 (94/6 on a molar base; 0.60 g) in 75% formic acid. The exothermic and effervescent reaction mixture is stirred for 15 min before heating to 80° C. for 2 hours. After cooling to 40° C., the mixture is filtered through a sintered glass funnel. The solid is washed with 75% formic acid (1×5 mL) and ethyl acetate (2×5 mL). The mixture is concentrated by roto-evaporation to about 2 mL. The orange oil obtained is dissolved in 0.5N HCl (3 mL) and extracted with ethyl acetate (3×10 mL), then saturated with NaCl and extracted with ethyl acetate/1,2-dimethoxyethane (2×5 mL). The combined extracts are dried with Na2SO4 and the solvents removed by roto-evaporation to yield a yellow foam. The foam (0.541 g) is recrystallized in hot acetonitrile (1 mL) to yield 4-(5-chloro-2-fluorobenzyl)nicotinic acid (0.142 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:6]=1[Cl:13])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)CCl>[C:1]([NH:4][C:5]1[C:6]([Cl:13])=[CH:7][C:8]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][Cl:18])=[C:9]([OH:11])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)CCCCCl
Reactant: COc1ccc(Cl)c(NC(C)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)Nc1cc(O)c(C(=O)CCCCCl)cc1Cl
Temperature: 25 °C
Reaction time: 168 h
Yield: 70.2 %

Procedure:
N-Acetyl-2-chloro-5-methoxyaniline (10.0 g, 50 mmol), aluminum chloride (13.3 g, 100 mmol), and 5-chloropentanoyl chloride (11.7 g, 75 mmol) were combined in ethylene dichloride (100 mL) and the mixture was stirred at room temperature and under nitrogen for 7 days. The mixture was then poured onto crushed ice and extracted into methylene chloride. The methylene chloride extract was washed with water and then dried. The solvent was evaporated in vacuo. Crystallization of the residue from ethyl acetate/hexane gave 1-(4-acetylamino-5-chloro-2-hydroxyphenyl)-5-chloropentan-1-one (10.18 g, 35.1 mmol), m.p. 126°-128° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CNc1ccc(-c2ccc(F)cc2)nc1
Reactant: Nc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ccc(-c2ccc(F)cc2)nc1)Nc1cccnc1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 98 mg (0.27 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 51.2 mg (0.54 mmol) 3-aminopyridine. Yield: 2.56 mg.
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].C(O)CCC.[CH2:35](Br)[CH2:36][CH2:37][CH2:38][CH3:39]>O>[CH2:1]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCBr
Reactant: CCCCCCCCCCc1ccc2nc(-c3ccc(O)cc3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCc1ccc2nc(-c3ccc(OCCCCC)cc3)ccc2c1
Yield: 83.8 %

Procedure:
To a solution 0.8 g of 6-decyl-2-(4-hydroxyphenyl)quinoline and 170 mg potassium hydroxide in i2 ml of butanol, 0.5 g of pentyl bromide was added, followed by heat refluxing for 4 hours. After the reaction, the reaction mixture was poured into water and subjected to extraction with toluene. The organic layer was washed with water, dried with anhydrous sodium sulfate and subjected to distilling-off of the solvent, followed by purification by silica gel column chromatography and recrystallization to obtain 0.8 g of 6-decyl-2-(4-pentyloxyphenyl)quinoline. This compound showed the following phase transition series.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:14]([O:16]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:7])([CH3:4])[CH3:3].[NH2:37][C@H:38]([C:46]([O:48][CH3:49])=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.C(N(CC)CC)C>CN(C)C=O>[NH:26]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[C@H:13]([C:14]([NH:37][C@H:38]([C:46]([O:48][CH3:49])=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
25.0 g of Z-Lys(BOC)-ONP and 10.7 g of H-Phe-OMe.HCl in 70 ml of dimethylformamide are mixed with 6.9 ml of triethylamine at room temperature whilst stirring and the mixture stirred for a further 18 hours. After dilution with ethyl acetate the mixture is washed with potassium carbonate solution until free of nitrophenol, extracted by shaking with 0.1 M citric acid and water, dried over sodium sulphate and evaporated to dryness in vacuo. The protected dipeptide of melting point 78°-80° C. crystalises from ethyl acetate-hexane. Rf = 0.45 in a thin layer chromatogram on silica gel in the system chloroform-acetone (8:2).
Reaction SMILES: [Na:1].[NH2:2][C:3]1[C:4]([F:13])=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[CH2:8][C:9]#[N:10].C([O:19][N:20]=O)CC(C)C>C(O)C>[Na:1].[NH2:2][C:3]1[C:4]([F:13])=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[C:8](=[N:20][OH:19])[C:9]#[N:10]
Reactant: CC(C)CCON=O
Reactant: N#CCc1cc(N)c(F)cc1Cl
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)c1cc(N)c(F)cc1Cl

Procedure:
0.3 g of sodium in 20 ml of absolute ethanol is introduced, with stirring, into a three-necked flask. There are then added slowly dropwise at room temperature, with stirring, firstly 1.8 g of 5-amino-2-chloro-4-fluorobenzyl cyanide and subsequently 1.5 ml of isopentylnitrite. The reaction solution is stirred at room temperature for a further 15 hours, and afterwards concentrated by evaporation. The residue is is taken up in glacial acetic acid, stirred up and filtered to thus obtain 2.2 g of the sodium salt of 5-amino-2-chloro-4-fluorobenzoyl cyanide which melts at 263°-264° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:10])[CH2:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O.[C:33]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>O1CCCC1.C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]([CH3:10])[C:8](=[C:33]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC1=CC(C(C)(C)C)=CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 2.73 g of 3-tert-butyl-1-methyl-cyclopentadiene (20.1 mmol) was dissolved in 30 ml of dehydrated tetrahydrofuran in a nitrogen atmosphere. To the solution, 13.5 ml of n-butyl lithium/hexane solution (1.58M: 21.3 mmol) was gradually added dropwise in an ice bath and stirred at room temperature for 3 days. To the reaction solution, 10.5 ml of hexamethyl phosphoramide (60.4 mmol) was added and stirred at room temperature for 1 hr. To the solution, a solution prepared by dissolving 3.87 g of benzophenone (21.2 mmol) in 40 ml of dehydrated tetrahydrofuran was gradually added dropwise in an ice bath and stirred at room temperature over night. To the resulting reaction mixture, 50 ml of a hydrochloric acid aqueous solution (1N) was gradually added dropwise in an ice bath and stirred at room temperature for some time. Diethyl ether was added to the mixed solution to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution, water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a dark-red liquid. The liquid was purified with a column chromatography using 300 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure, and thereby the aimed compound was obtained in an amount of 3.28 g (10.9 mmol) as a reddish-orange solid (yield: 54%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@@H:7]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:49][C:50]1[S:51][CH:52]=[C:53]([CH2:55][CH2:56]O)[N:54]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:29])[C@@H:7]([NH:19][S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:56][CH2:55][C:53]2[N:54]=[C:50]([NH2:49])[S:51][CH:52]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1nc(CCO)cs1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(O)cc1)NS(=O)(=O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCc2csc(N)n2)cc1)NS(=O)(=O)c1ccccc1
Reaction time: 72 h

Procedure:
To a stirred solution of 5-2 (0.14 g, 0.32 mmol) and PPh3 (0.11g, 0.41 mmol) in THF (2 mL) at ambient temperature was added a solution of 5-4 (56 μg, 0.39 mmol) DEAD (67 μL, 0.42 mmol) in THF (2 mL) dropwise over a 15 min period. After 72 h, the reaction mixture was diluted with EtOAc and then washed with H2O, sat. NaHCO3, 10% KHSO4 and brine, dried (MgSO4) and concentrated. After two flash columns: silica, 85% EtOAc/hexanes; silica, 5% to 30% isopropanol/CHCl3), 5-5 was obtained as a yellow oil. Rf 0.19 (silica, 85% EtOAc/hexanes).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][Zn+])=[CH:34][CH:33]=1>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:38]=[CH:39][C:32]([Cl:31])=[CH:33][CH:34]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(Cl)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-chloro-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 3): tR=1.01 min.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:15]=[C:14]([NH:16][C:17](=[O:24])[CH2:18][C:19](OCC)=[O:20])[NH:13][N:12]=2)[C:8]([CH3:25])=[N:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.O.Cl>CO.O1CCCC1>[CH2:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:15]=[C:14]3[N:16]=[C:17]([OH:24])[CH:18]=[C:19]([OH:20])[N:13]3[N:12]=2)[C:8]([CH3:25])=[N:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(=O)Nc1cc(-c2nc(CC(C)C)cnc2C)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: Cc1ncc(CC(C)C)nc1-c1cc2nc(O)cc(O)n2n1
Temperature: 25 °C

Procedure:
A suspension of ethyl 3-{[3-(6-isobutyl-3-methylpyrazin-2-yl)-1H-pyrazol-5-yl]amino}-3-oxopropanoate (1.13 g, 3.29 mmol) and triethylamine (1.38 mL, 9.88 mmol) in methanol (9 mL), tetrahydrofuran (9 mL), and water (9 mL) was refluxed for 2 h. After being cooled to ambient temperature, the reaction mixture was acidified to pH 2 with 2N aqueous hydrochloric acid and concentrated in vacuo. The residue was triturated with water to give 2-(6-isobutyl-3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidine-5,7-diol. MS (APCI): m/z 300 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:27][C:28]([NH2:30])=[S:29])([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.Br[CH2:32][C:33](=O)[C:34]([F:37])([F:36])[F:35]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:27][C:28]2[S:29][CH:32]=[C:33]([C:34]([F:37])([F:36])[F:35])[N:30]=2)([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: NC(=S)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Solvent: CCO
Product: Fc1cc(C(F)(F)F)cc(C(Cc2ccccc2)(Nc2nc(C(F)(F)F)cs2)c2ccc(Cl)cn2)c1
Temperature: 80 °C
Yield: 61.1 %

Procedure:
To 1-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)thiourea (15 mg, 0.033 mmol) in ethanol (1 mL) in a two dram vial was added 3-bromo-1,1,1-trifluoropropan-2-one (6.3 mg, 0.033 mmol). The vial was heated in a shaker at 80° C. for 2 hours. The reaction was concentrated and crude mixture was purified by silica gel ISCO chromatography (4 g column) using hexanes/EtOAc (0-25% over 20 min) to give the N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-4-(trifluoromethyl)thiazol-2-amine as a white foam (11 mg, 61% yield). LCMS: 4.3 min [M+1] 456.1 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 3.58 (d, J=13.21 Hz, 1H), 4.60 (d, J=12.96 Hz, 1H), 6.46 (d, J=7.58 Hz, 2H), 6.88 (s, 1H), 7.05 (t, J=7.46 Hz, 2H), 7.10-7.15 (m, 2H), 7.24-7.29 (m, 2H), 7.35 (d, J=9.78 Hz, 1H), 7.64-7.71 (m, 2H), 8.01 (s, 1H), 8.31 (d, J=2.20 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]4[O:20][C:21](Br)=[CH:22][C:16]=4[C:15]3=[O:24])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]4[O:20][C:21]([C:30]5[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=5)=[CH:22][C:16]=4[C:15]3=[O:24])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)Cn1ncc2cc(-n3ccc4oc(Br)cc4c3=O)ccc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)Cn1ncc2cc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)ccc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
To a solution of methyl-2(5-(2-bromo-4-oxofuro[3,2-c]pyridine-5(4H)-yl)1H-indazol-1-yl)acetate (0.77 g, 19 mmol) in DMSO (44 mL) was added 4-chlorophenyl boronic acid (0.32 g, 2.1 mmol), K2CO3 (0.52 g, 3.8 mmol) and bis(triphenylphosphine)palladium (II) chloride (0.13 g, 0.19 mmol). The solution was evacuated for 15 minutes under high vacuum then backfilled with argon. The process was repeated three times. The reaction mixture was stirred at 90° C. for 2 h; then the reaction mixture was diluted with H2O (20 mL) and extracted with CH2Cl2 (3×40 mL). The extracts were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/MTBE, 100:0 to 1:1) yielded the title compound (0.38 mg, 46%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.77-7.63 (m, 4H), 7.53-7.41 (m, 4H), 7.35 (d, J=7.5 Hz, 1H), 6.68 (dd, J=7.5, 0.9 Hz, 1H), 5.22 (s, 2H), 3.78 (s, 3H); ESI MS m/z 434 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18]([OH:20])=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH:25](I)(C)[CH3:26]>>[CH2:25]([O:19][C:18](=[O:20])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])[CH3:26]
Reactant: CC(C)I
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)O)c(C)c1C
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid and isopropyl iodide is converted to
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N+:25]([O-])=O)=[CH:17][CH:16]=2)[CH:10]=[CH:9][N:8]=1)=[O:5].C(=O)([O-])[O-].[Na+].[Na+]>CC(O)=O.[Fe]>[NH2:25][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:14][CH2:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: COCC(=O)Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(COc2ccc(N)c3ccccc23)ccn1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
A suspension of the nitroarene (63) (30.0 g, 82.0 mmol) and iron powder (22.8 g, 408 mmol) in AcOH (300 mL) was heated at 50° C. for 1.5 hr, and was then cooled to RT. Solid sodium carbonate was added portionwise to the reaction mixture until effervescence was no longer observed. The mixture was extracted with ethyl acetate (2×700 mL) and the combined organic extracts were washed with saturated aqueous sodium carbonate and with brine and then dried (MgSO4). Evaporation in vacuo furnished the title compound (Intermediate M) as a brown solid (25.0 g, 77%): m/z 338 (M+H)+ (ES+).