Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.C([SiH](CC)CC)C.[Na].O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19]2
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: CC[SiH](CC)CC
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(c3)CCN4)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
After dissolving 6,7-dimethoxy-4-(5-indolyloxy)quinoline (30 mg, 0.0780 mmol, described in WO9717329, p. 52) in trifluoroacetic acid (0.9 ml), triethylsilane (45 ml, 0.2808 mmol, 3.0 eqM) was added while cooling on ice, and the mixture was stirred for 4 hours and 30 minutes at room temperature under a nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate, neutralized with saturated sodium bicarnobate water, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/ethanol system) to obtain the title compound (20 mg, 0.0620 mmol, 66.28%) as light yellow crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[O:21]=[C:22]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][CH:32]=O)=[CH:30][C:25]=2[CH2:24][O:23]1.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[N:15]1([CH2:14][CH2:13][C:4]2[CH:5]=[CH:6][C:7]3[C:8](=[O:12])[O:9][CH2:10][C:11]=3[C:3]=2[CH3:2])[CH2:20][CH2:19][N:18]([CH2:32][CH2:31][C:29]2[CH:28]=[CH:27][C:26]3[C:22](=[O:21])[O:23][CH2:24][C:25]=3[C:30]=2[CH3:34])[CH2:17][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1c(CCN2CCN(CCc3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O

Procedure:
A mixture of 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride (62 mg, 0.21 mmol), (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (40 mg, 0.21 mmol), and sodium triacetoxyborohydride (67 mg, 0.32 mmol) in DCM (5 mL) was stirred overnight with a drop of acetic acid. LC showed formation of the desired product, which was purified by mass-directed HPLC (0.1% TFA in water and acetonitrile). LC-MS (IE, m/z): 435 [M+1]+. (0.076 μM)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:10]/[CH:11]=O.[C:21]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH3:24])=[O:22]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:24][O:23][C:21](=[O:22])/[CH:25]=[CH:11]/[CH:10]=[C:9](/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])\[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COc1ccc(/C(=C\C=O)c2ccccc2OC)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)c1ccccc1OC
Yield: 76.1 %

Procedure:
As described in Example 99, (E)-3-(2-methoxyphenyl)-3-(4-methoxyphenyl)-2-propenal (5 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (6.83 g) in a mixture of carbon tetrachloride (50 ml) and dichloromethane (25 mL) for 4 days at room temperature. The crude ester was isolated in the usual way and was crystallized from 2-propanol-hexane to provide 4.6 g of (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester. Recrystallization of a sample from the same solvents gave the analytical specimen, mp 99.5°-102.5° C.
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1ccccc1Cl)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 66 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used o-chlorophenyl boronic acid. The title compound (107 mg) was obtained as a white solid, (yield=66%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:11]1[NH:15][CH:14]=[C:13]([C:16]([O:18]CC)=O)[C:12]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=2[F:41])=[O:29])=[CH:23][CH:22]=1)(=[O:10])[NH2:9]>>[F:41][C:32]1[CH:33]=[CH:34][C:35]([C:37]([F:38])([F:40])[F:39])=[CH:36][C:31]=1[NH:30][C:28](=[O:29])[NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:12]2[C:13]([C:16]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:18])=[CH:14][NH:15][C:11]=2[C:8]([NH2:9])=[O:10])=[CH:22][CH:23]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Product: CN1CCN(C(=O)c2c[nH]c(C(N)=O)c2-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)CC1

Procedure:
The process is performed in a manner similar to that described in Example 39 but starting with N-methylpiperazine and ethyl 5-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxylate. After a similar work-up, 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carboxamide is obtained; ES+: m/z=533 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Cl[CH:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:9]#[N:10]
Reactant: N#CCc1ccccc1Br
Reactant: ClC(c1cccnc1)c1cccnc1
Solvent: C1CCOC1
Product: N#CC(c1ccccc1Br)C(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of (2-bromophenyl)acetonitrile (1.05 g, 5.38 mmol) in THF (20 mL) at 0° C. was added L DS (5.9 mL, 1.0 M). The mixture was stirred at 0° C. for 30 min followed by the addition of a solution of 3-[chloro(pyridin-3-yl)methyl]pyridine (1.1 g, 5.38 mmol) in THF (5 mL). The mixture was stirred at 0° C. for 2 h and the reaction was quenched with water (20 mL) and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (3% MeOH in CH2Cl2) to give 2-(2-bromophenyl)-3,3-dipyridin-3-ylpropanenitrile. 1H-NMR (500 MHz, CDCl3) δ 8.57-8.54 (m, 3H), 8.26 (d, 1H, J=2.0, 2.0), 7.76 (d, 1H, J=7.8), 7.73 (d, 1H, J=8.1), 7.59 (d, 1H, J=7.8), 7.34-7.11 (m, 5H), 5.12 (d, 1H, J=6.1), 4.58 (d, 1H, J=6.1). LRMS m/z (M+H) Calcd: 364.3, found: 363.9.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C(O)c1cc(F)c2cccnc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(F)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 5-fluoro-8-hydroxyquinoline-7-carboxylic acid (0.311 g) of Preparation 4 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-di-methylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried. The crude product is recrystallized from EtOAc/hexanes to yield 0.207 g of the title product as an off-white solid.
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+:15].[O:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Na:15][N:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:20]1(=[O:8])[O:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C(c1ccccc1)c1ccc[nH]1
Reactant: [Na+]
Reactant: C1CCOC1
Agent: [H-]
Product: O=C(c1ccccc1)c1cccn1[Na]
Product: O=C1CCCO1

Procedure:
A solution of 2-benzoylpyrrole (II, 20.0 g, 117 mmoles) in 50 mL of anhydrous tetrahydrofuran was added dropwise to a nitrogen blanketed stirred suspension of sodium hydride (129 mmoles) in 300 mL of anhydrous tetrahydrofuran over the course of 30 minutes. The reaction mixture was stirred under a nitrogen atmosphere for 1 hour after which gas evolution had ceased. The tetrahydrofuran was then evaporated under reduced pressure to leave the 1-sodio-2-benzoylpyrrole as a yellow solid gamma-Butyrolactone (11.0 g, 128 mmoles) was added to the solid and this mixture was protected from moisture with a calcium sulfate drying tube and heated to 135° C. for 5 hours. After being cooled to room temperature, the resulting solid was dissolved in 1% aqueous sodium hydroxide (500 mL) and extracted with ethyl ether (2×300 mL). The aqueous phase was then acidified to pH 2 by dropwise addition of concentrated hydrochloric acid with vigorous stirring. The acidified aqueous solution was extracted with two portions of ethyl acetate (350 mL, 150 mL) and the combined ethyl acetate extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 4-(2-benzoylpyrrol-1-yl)butyric acid (III, 27.61 g, 92%). 1H NMR (CDCl3): delta 2.18 (m, 2H), 2.40 (t, J=7 Hz), 4.48 (t, J=7 Hz, 2H), 6.17 (m, 1H), 6.75 (m, 1H); 6.99 (m, 1H), 7.41-7.55 (complex m, 3H), 7.77 (m, 2H). This acid was of sufficient purity to proceed with the esterification step without further purification.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.C([BH3-])#N.[Na+]>C(O)(C(F)(F)F)=O>[CH2:1]1[CH:13]2[CH:5]([C:6]3[C:11]([NH:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][NH:2]1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)NC1CNCCC21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a solution of 2,3,4,9-tetrahydro-1H-beta-carboline (0.100 g, 0.581 mmol) in TFA (1 mL) was added sodium cyanoborohydride (0.109 g, 1.74 mmol) and the reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by using preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 35 cm; 5-100% acetonitrile—0.1M ammonium acetate over 20 min, 100% acetonitrile hold 10 minutes, 21 mL/min) to give 2,3,4,4a,9,9a-hexahydro-1H-beta-carboline (0.073 g, 0.42 mmol) as a brown oil; RP-HPLC (Table 1, Method a) Rt 1.35 min; m/z: (M+H)+ 175.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([OH:18])[CH2:10][N:11]1[CH:15]=[N:14][C:13]([CH:16]=O)=[N:12]1.[Cl-].[CH3:26][O:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([OH:18])[CH2:10][N:11]1[CH:15]=[N:14][C:13]([CH:16]=[CH:32][C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:53][CH:52]=2)=[N:12]1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ncn(CC(O)(Cn2cncn2)c2ccc(F)cc2F)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(C=Cc2ncn(CC(O)(Cn3cncn3)c3ccc(F)cc3F)n2)cc1
Reaction time: 20 h

Procedure:
A mixture of 1-(2,4-difluorophenyl)-2-(3-formyl-1,2,4-triazol-1-yl)-1-(1,2,4-triazol-1-ylmethyl)ethanol (0.6 g), p-methoxybenzyl-triphenylphosphonium chloride (1.68 g), potassium carbonate (0.5 g) and methanol (10 ml) was heated at 60°-70° for 2 hours, then left at room temperature for 20 hours. The reaction mixture was filtered, the separated solids were washed with methanol, and the combined organic solutions were evaporated to dryness. The residue was purified by medium pressure liquid chromatography on silica, eluting with chloroform, to give 1-(2,4-difluorophenyl)-2-[3-(4-methoxystyryl)-1,2,4-triazol-1-yl]-1-(1,2,4-triazol-1-ylmethyl)ethanol, m.p. 150°-152°.
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[CH:5]=[C:6]([Cl:14])[C:7]2[O:11][C:10]([CH3:12])=[CH:9][C:8]=2[CH:13]=1.[N+]([O-])([O-])=O.[Na+]>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([Cl:14])[C:7]2[O:11][C:10]([CH3:12])=[C:9]([I:1])[C:8]=2[CH:13]=1
Reactant: II
Reactant: Cc1cc2cc(Cl)cc(Cl)c2o1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1oc2c(Cl)cc(Cl)cc2c1I
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A suspension of 1.7 mmol of pulverized iodine in 10 ml of glacial acetic acid is admixed with 3 mmol of 5,7-dichloro-2-methylbenzofuran [42969-85-7] and with 0.3 mmol of sodium nitrate. The mixture is stirred at 85° C. for 6 hours. If necessary further sodium nitrate is added after 1 hour. The reaction mixture is cooled to room temperature and quenched with 10% sodium hydrogen sulphite solution, and tert-butyl methyl ether is added. The phases are separated and the aqueous phase is extracted with tert-butyl methyl ether (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([NH2:25])[N:14]([CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:13]=2)=[CH:8][CH:7]=1.[OH2:34].C(Cl)Cl>Cl.FC(F)(F)C(O)=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[C:17]([OH:34])=[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:1]=[N:25][C:15]=3[N:14]([CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:13]=2)=[CH:8][CH:7]=1
Reactant: Nc1c(C#Cc2ccccc2)c(-c2ccc(F)cc2)nn1CCN1CCOCC1
Reactant: O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1c(-c2ccccc2)nnc2c1c(-c1ccc(F)cc1)nn2CCN1CCOCC1
Temperature: -10 °C

Procedure:
To a cooled (cooling bath −10° C.) stirred suspension of sodium nitrite (82 mg, 1.2 mmol) in conc. HCl (2.6 mL) was added a solution of 3-(4-fluorophenyl)-1-(2-morpholinoethyl)-4-(phenylethynyl)-1H-pyrazol-5-amine (129 mg, 0.33 mmol) in trifluoroacetic acid (0.5 ml) and the reaction mixture was allowed to warm to ambient temperature over 2 h. Water and CH2Cl2 were added. The aqueous phase was extracted with CH2Cl2 (×3) and the organic phases combined, dried over MgSO4, filtered and evaporated. The crude material was purified by preparative HPLC to give 3-(4-fluorophenyl)-1-(2-morpholinoethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-4-ol as a solid (27.8 mg) which was used as such in the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([OH:19])([CH2:15][C:16](O)=[O:17])[CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([OH:19])([CH2:15][CH2:16][OH:17])[CH2:8]2
Reactant: COc1ccc(OC)c2c1CCC(O)(CC(=O)O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c2c1CCC(O)(CCO)C2

Procedure:
15.5 g of 5,8-dimethoxy-1,2,3,4-tetrahydro-2-hydroxy-2-naphthaleneacetic acid in 150 ml of tetrahydrofuran were added dropwise within 15 minutes to 3.32 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The reaction mixture was heated to reflux for 1 hour and then cooled. After the dropwise addition of 15 ml of ethyl acetate and 20 ml of water the suspension was filtered and the filtrate was concentrated. The product was purified by column chromatography (silica gel, chloroform/methanol 30:1). There was obtained 5,8-dimethoxy-1,2,3,4-tetrahydro-2-hydroxy-2-naphthaleneethanol, m.p. 121°-122°.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:8](=[O:24])[CH:7]=1.[OH-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:8](=[O:24])[CH:7]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate (14 g, 35.0 mmol) (from step 2) was taken up in THF (25 ml) and H2O. 2.5 N NaOH (aq.) was added and the reaction stirred for 30 minutes at room temperature. The reaction was made acidic via the addition of concentrated HCl. The product was extracted with ethyl acetate. The ethyl acetate extraction was dried over Na2SO4, filtered, and the solvent removed in vacuo. Upon vacuum removal of the solvent, the product crashed out of the ethyl acetate. This precipitate was collected on a filter pad and washed with a 50 ethyl acetate/hexanes to yield a white powder (9 g, 7%). 1H NMR (300 MHz, CDCl3) δ 8.01 (dd, J=, 1.61 Hz, 1H), 7.84 (d, J=1.61 Hz, 1H), 7.52-7.47 (app q, J=8.26, 1H), 7.43 (d, J=8.06 Hz, 1H), 7.00-6.88 (m, 2H), 6.19 (d, J=2.62 Hz, 1H), 6.05 (dd, J=2.62, 1.81 Hz, 1H), 5.17 (s, 2H), 2.19 (s, 3H), 1.90 (s, 3H); ES-HR/MS m/z 386.12 (M+H calcd for C21H18F2NO4 requires 386.1198).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:19][C:20]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:21][CH:22]=3)[S:17][C:10]=12.C1(C)C=CC=CC=1.C(O)C.[C:42]1([CH2:48][C:49]([N:51]=[C:52]=[S:53])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:31][C:52]([NH:51][C:49](=[O:50])[CH2:48][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[S:53])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[O:19][C:20]([CH2:23][N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:21][CH:22]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)o2)CC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=S)NC(=O)Cc6ccccc6)cc5F)c4s3)o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a 5 mL round bottom flask was added 3-fluoro-4-(2-(5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine (32 mg, 0.0713 mmol) and 1:1 toluene/ethanol (1 mL). 2-Phenylethanoyl isothiocyanate (25.3 mg, 0.143 mmol; prepared according to the procedure described by J. Org. Chem. 1964, 29, 1115-1119) was added as a solution in toluene (0.5 mL). After stirring for 30 minutes at room temperature, the crude was concentrated in vacuo. The crude was dissolved in MeOH and purified by preparative TLC, eluting with 9:1 CH2Cl2/MeOH. The product was collected at Rf 0.4 just above the unreacted starting material at Rf 0.3 to provide the product (5 mg, 10%) as a white solid. LRMS (APCI+) m/e 626 (M+1) detected; 1H NMR (CDCl3, 400 MHz) δ 9.98 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.22 (s, 1H), 7.75 (d, J=13.7 Hz, 1H), 7.62 (s, 1H), 7.45 (m, 2H), 7.24 (m, 2H), 7.07 (t, J=8.6 Hz, 2H), 6.71 (s, 1H), 6.35 (s, 1H), 3.66 (s, 2H), 2.58 (m, 8H), 2.29 (s, 3H), 1.79 (m, 4H).
Reaction SMILES: [CH:1]1(B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Br[C:14]1[C:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][N:16]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([F:33])[CH:32]=2)[N:15]=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH:1]1([C:14]2[C:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][N:16]([C:27]3[CH:28]=[N:29][CH:30]=[C:31]([F:33])[CH:32]=3)[N:15]=2)[CH2:3][CH2:2]1.[F:33][C:31]1[CH:32]=[C:27]([N:16]2[CH:17]=[C:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH:14]=[N:15]2)[CH:28]=[N:29][CH:30]=1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2cncc(F)c2)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cn(-c2cncc(F)c2)nc1C1CC1
Product: CC(C)(C)OC(=O)Nc1cnn(-c2cncc(F)c2)c1
Temperature: 100 °C
Yield: 71.9 %
Yield: 28.2 %

Procedure:
To a suspension of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.087 g, 6.47 mmol) in toluene (13.69 ml) was added tert-butyl (3-bromo-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)carbamate (1.1 g, 3.08 mmol) followed by ethanol (6.84 ml) and 2 M aqueous potassium carbonate (3.08 mL, 6.16 mmol). The solution was degassed by applying vacuum and then purging with nitrogen (3 times). To the reaction mixture was added palladium tetrakis (0.178 g, 0.154 mmol) and the flask was heated at 100° C. under nitrogen for 36 hours. Water (5 mL) was added and the mixture was extracted with ethyl acetate. The combined organics were concentrated and chromatographed (0-100% ethyl acetate/hexanes) to give tert-butyl (3-cyclopropyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)carbamate (705 mg, 2.215 mmol, 71.9% yield) as a yellow solid and tert-butyl (1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-yl)carbamate (242 mg, 0.870 mmol, 28.2% yield) as a yellow solid.
Reaction SMILES: ClC(OCC(C)C)=[O:3].[C:9]([N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CN1CCOCC1.[CH2:29]([NH2:39])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>C1COCC1>[C:29]([NH2:39])(=[O:3])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1.[C:9]([N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17])([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CC(C)COC(=O)Cl
Agent: CN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: NC(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Isobutyl chloroformate (226 μL, 1.73 mmol) was added to a solution of N-Boc sarcosine (1.73 mmol) and N-methylmorpholine (192 μL, 1.73 mmol) in THF. After two minutes, piperonylamine (216 mL, 1.73 mmol) was added and the mixture allowed to warm to room temperature. After thirty minutes, the reaction mixture was passed through a bed of Celite and all volatiles were removed under reduced pressure to yield N-Boc sarcosine piperonyl amide (531 mg, 95%) as a white solid. 1H NMR: (CDCl3) δ2.41 (s,3), 3.28 (s,2), 4.39 (d,2), 5.95 (s,2), 6.80 (m,3), 7.43 (bs,1), 9.04 (bs,1).