Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][C:24]([N:27](S(C)(=O)=O)[S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][N:22]=3)=[C:17]([F:36])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CS(C)=O>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][N:22]=3)=[C:17]([F:36])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N(S(C)(=O)=O)S(C)(=O)=O)cn2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(NS(C)(=O)=O)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 18.7 h
Yield: 86 %

Procedure:
To a 20 mL vial containing N-(tert-butyl)-3′-fluoro-4′-(5-(N-(methylsulfonyl)methylsulfonamido)pyrazin-2-yl)-[1,1′-biphenyl]-2-sulfonamide (38 mg, 0.068 mmol) were added a stir-bar and DMSO (1 mL). The mixture was sonicated until homogeneous, and then treated with NaOH (0.23 mL, 0.23 mmol, 1.0 N). The mixture was stirred at rt for 18.7 h before passing it through a syringe filter and subjecting it to HPLC purification thus yielding the title compound (28 mg, 86%). MS (ESI): mass calcd. for C21H23FN4O4S2, 478.11; m/z found, 479.1 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 11.29 (s, 1H), 8.82-8.72 (m, 1H), 8.46 (d, J=1.5, 1H), 8.07 (dd, J=7.9, 1.4, 1H), 7.98-7.91 (m, 1H), 7.71-7.65 (m, 1H), 7.65-7.58 (m, 1H), 7.43-7.32 (m, 3H), 7.05 (s, 1H), 3.41 (s, 3H), 1.03 (s, 9H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li+].CCC[CH2-].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[CH2:27][CH2:26]2.Cl[CH2:34][C:35](=[O:37])[CH3:36].[Cl-].[Na+]>O1CCCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[CH:27]([CH2:34][C:35](=[O:37])[CH3:36])[CH2:26]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CC(=O)CCl
Agent: CC(C)[N-]C(C)C
Agent: [CH2-]CCC
Agent: [Cl-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(CC(C)=O)C2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
A solution of LDA, prepared at 0° from 4.25 ml of diisopropyl-amine and 18.8 ml of N-butyllithium (1.6N in hexane), in 60 ml of anhydrous tetrahydrofuran, was added dropwise while stirring during 15 minutes to a solution, cooled to -70°, of 3.24 g of 5-methoxy-1-indanone in 350 ml of anhydrous tetrahydrofuran. After 45 minutes, a solution of 1.6 ml of chloroacetone in 60 ml of anhydrous tetra-hydrofuran was added dropwise to the solution during 15 minutes and the mixture was subsequently stirred at room temperature for 2 hours. The reaction mixture was poured on to 150 ml of ice, 150 ml of saturated sodium chloride solution were added and the mixture was extracted twice with 300 ml of diethyl ether each time. The combined organic phases were washed once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (hexane/diethyl ether 3:7). 1.4 g (32%) of (RS)-5-methoxy-2-(2-oxopropyl)-1-indanone were obtained as a solid with m.p. 73°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]4[NH2:19])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:22])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[NH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH2:3][C:2](=[O:22])[NH:1]4)[CH:11]=2)[NH:15][N:14]=1
Reactant: Nc1n[nH]c2ccc(-c3cccc4[nH]ccc34)cc12
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: Nc1n[nH]c2ccc(-c3cccc4c3CC(=O)N4)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To the suspension of 5-(1H-indol-4-yl)-1H-indazol-3-ylamine (0.82 g, 3.33 mmol) in t-BuOH: ethanol: acetic acid (20.5 mL: 12 mL: 6 mL) was added pyridinium tribromide (3.17 g, 9.9 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, it immediately became a dark pink color. Zinc dust (excess) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off and the solvent was removed under reduced pressure. The residue was washed with ample of water. The solid was triturated with DCM to give 0.563 g (77%) of 4-(3-amino-1H-indazol-5-yl)-1,3-dihydro-indol-2-one.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].O.[OH-].[Li+].Cl>CN(C=O)C.C1COCC1.O.CO.C(OCC)(=O)C>[CH:5]1([CH2:4][O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: Cc1cc(O)ccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(OCC2CC2)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A suspension of (bromomethyl)cyclopropane (20.0 g, 148 mmol), 4-hydroxy-2-methylbenzoic acid (10.1 g, 66.4 mmol) and potassium carbonate (22.0 g, 159 mmol) in DMF (150 mL) was stirred at 60° C. overnight. Ethyl acetate was added thereto, the mixture was left standing, and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To the obtained residue were added methanol (50 mL), water (50 mL), THF (100 mL) and lithium hydroxide monohydrate (3.00 g, 71.4 mmol), and the mixture was stirred at 50° C. for 3 hr. After being allowed to cool to room temperature, the mixture was acidified with 1N hydrochloric acid, and the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (13.5 g, yield 92%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(Cl)C=1C#[N:21].C1(S)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]=1[C:14]#[N:21]
Reactant: N#Cc1c(Cl)cccc1Cl
Reactant: O=c1c2ccccc2sc2cccc(Cl)c12
Agent: Sc1ccccc1
Product: N#Cc1c(Cl)cccc1Sc1ccccc1

Procedure:
U.S. Pat. No. 3,711,513 teaches the preparation of 1-chloro-thioxanthone by reacting 2,6-dichloro-benzonitrile with an alkali metal salt of thiophenol to obtain 2-chloro-6-phenylthio-benzonitrile, which is reacted with polyphosphoric acid to give 1-chloro-9-imino-thioxanthene, this latter product being hydrolysed to 1-chloro-thioxanthone.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].[CH3:22][NH:23][CH2:24][CH2:25][OH:26].[H-].[Na+]>C(Cl)Cl.CO.O>[F:21][C:18]1[CH:17]=[CH:16][C:12]2[C:13](=[O:14])[N:23]([CH3:22])[CH2:24][CH2:25][O:26][C:11]=2[C:19]=1[F:20]
Reactant: CNCCO
Reactant: O=C(Cl)c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN1CCOc2c(ccc(F)c2F)C1=O
Reaction time: 20 h
Yield: 21.1 %

Procedure:
DIPEA (0.68 mL, 3.9 mmol) was added to a solution of 2,3,4-trifluorobenzoyl chloride (500 mg, 2.6 mmol) in DCM (5 mL) followed by the addition of N-methylethanolamine (0.31 mL, 3.9 mmol). The mixture was stirred for 20 hours. The solution was diluted with methanol (10 mL) and passed through an ISOLUTE® SCX-2 SPE column. The solution was evaporated. The residue was dissolved in DMF and sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.7 mmol) was added portionwise over 5 minutes. The resulting mixture was stirred for 20 hours. Water (100 mL) was added dropwise and the mixture was extracted with ether (3×200 mL). Combined ethereal extracts were dried (MgSO4) and evaporated. The residue was purified by column chromatography (eluting with 1:1 ethyl acetate:isohexane to neat ethyl acetate) to afford the title compound (117 mg, 20%) as a colourless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:26][NH2:27]>>[C:15]1([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:26][NH2:27])[N:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nccc(N2CCC[C@@H]2COc2cccc3ccccc23)n1
Reactant: NN
Solvent: O
Product: NNc1nccc(N2CCC[C@@H]2COc2cccc3ccccc23)n1
Yield: 88.7 %

Procedure:
480 mg of 2-chloro-4-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin1-yl]pyrimidine are warmed at 80° C. for 6 h with 5 g of hydrazine hydrate, giving 420 mg of {4-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin1-yl]pyrimidin-2-yl}hydrazine;
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:4].[C:22]([O:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[C:22]([O:26][C:27](=[O:28])[NH:29][CH2:30][C:31](=[O:32])[NH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:3](=[O:4])[NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)([CH3:25])([CH3:23])[CH3:24]
Reactant: NC(C(=O)Nc1ccc2[nH]ncc2c1)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(=O)NC(C(=O)Nc1ccc2[nH]ncc2c1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 2-amino-2-(3-chloro-phenyl)-N-(1H-indazol-5-yl)-acetamide (0.17 mmol) and tert-butoxycarbonylamino-acetic acid (0.17 mmol) in THF (2 mL) was added HOBt (0.18 mmol). The reaction mixture was cooled to 0° C. and EDC (0.18 mmol) was added and the reaction mixture was left to stir overnight. The reaction mixture was then concentrated in vacuo and the residue was was partitioned between EtOAc and brine. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc:hexanes (80:20) to give the title compound in 55% yield.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)[CH:12]=2)[C:7]([CH3:29])([CH3:28])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][CH2:15][NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=3)[CH:12]=2)[C:7]([CH3:29])([CH3:28])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(NCCc2ccc3c(c2)N(C(C)C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N1CCC(C)(C)c2ccc(CCNc3ccc(C(=O)O)cc3)cc21
Temperature: 50 °C
Reaction time: 48 h
Yield: 99.9 %

Procedure:
A solution ethyl 4-[(1-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)ethylamino]-benzoate (Compound 35, 5.6 mg, 0.0142 mmol) of 7 in ethanol (1 mL) was treated with 2N KOH (0.5 mL) and stirred at 50° C. for 2 days. The solvent was removed under reduced pressure and the residue was washed with ethyl acetate and acidified with 2N HCl. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% ethyl acetate in hexane, Rf=0.11) to give the title compound (5.2 mg, quant.) as a pale yellow solid:
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[CH3:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH2+:24][CH2:23][CH2:22]3)[CH:16]=2)[N:12]=[C:11]([C:27]2[O:31][N:30]=[C:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=3)[N:28]=2)[N:10]=1.C=O.[BH3-]C#N.[Na+]>CCO>[CH3:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH3:2])[CH2:23][CH2:22]3)[CH:16]=2)[N:12]=[C:11]([C:27]2[O:31][N:30]=[C:29]([C:32]3[CH:33]=[CH:34][C:35]([O:38][C:39]([F:42])([F:40])[F:41])=[CH:36][CH:37]=3)[N:28]=2)[N:10]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(N2CC[NH2+]CC2)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1ccnc(N2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 45 %

Procedure:
The mixture of 4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazin-1-ium trifluoroacetate (100 mg, 0.2 mmol), formaldehyde (0.5 mL, 6.0 mmol, 38% in H2O) and paraformaldehyde (100 mg, 3.3 mmol) in EtOH (1 mL) was stirred at RT, then treated with NaBH3CN (63 mg, 1.0 mmol) in one portion. The mixture was stirred at RT for 3 h, and then concentrated under reduced pressure to give the crude product, which was purified by pre-HPLC (Mobile phase: A=10 mM NH4HCO3/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to afford 5-(5-methyl-1-((2-(4-methylpiperazin-1-yl)pyridin-4-yl) methyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (45 mg, 45%). MS (ES+) C23H23F3N8O2 requires: 500. found: 501 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.22 (d, J=8.3 Hz, 2H), 8.08 (d, J=5.3 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 6.77 (s, 1H), 6.42 (d, J=5.3 Hz, 1H), 5.50 (s, 2H), 3.50-3.48 (m, 4H), 2.58 (s, 3H), 2.41-2.32 (m, 4H), 2.20 (s, 3H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=[CH:11]2.[CH3:21][NH:22][C:23](=[O:31])[C:24]1[CH:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1>CS(C)=O>[CH3:21][NH:22][C:23]([C:24]1[CH:29]=[C:28]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=[CH:11]3)[CH:27]=[CH:26][N:25]=1)=[O:31]
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CNC(=O)c1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1
Temperature: 100 °C

Procedure:
Cs2CO3 (52.0 g, 160 mmol) was added to a solution of 6-hydroxy-1-naphthoic acid (10 g, 53.0 mmol) in DMSO (140 mL). After stirring vigorously for 15 min N-methyl-4-chloropicolinamide (10.8 g, 61.0 mmol) was introduced and the mixture was heated at 100° C. for 10 h. After cooling to RT, the mixture was filtered through a plug of silica gel (10:1:0.5; CH2Cl2,CH3OH, AcOH). The filtrate was concentrated and triturated with EtOAc to provide the title compound as a slightly pink solid. MS (ESI, pos. ion) m/z: 323.3 (M+1). Mass Calc'd for C18H12N2O4: 322.31.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([NH:30][C:27]3[CH:28]=[N:29][C:24]([N:21]4[CH2:20][CH2:19][O:18][CH2:23][CH2:22]4)=[CH:25][CH:26]=3)=[O:17])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: Cc1cc(-c2ccc(CC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCOCC4)nc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)acetic acid 73-1 (40 mg, 0.18 mmol), 6-morpholinopyridin-3-amine (40 mg, 0.22 mmol) and HATU (80 mg, 0.21 mmol) in 2 mL DMF was added DIEA (104 μL, 0.6 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give the title compound 73 as white solid. MS m/z 389.19 (M+1); 1H NMR 400 MHz (DMSO-d6) δ11.30 (s, 1H), 8.82 (d, 1H, J=6.4 Hz), 8.57 (d, 1H, J=2.4 Hz), 8.35 (m, 1H), 8.24 (dd, 1H, J1=6.4 Hz, J2=1.6 Hz), 8.19 (dd, 1H, J1=10.0 Hz, J2=2.8 Hz), 8.02 (m, 2H), 7.63 (m, 2H), 7.42 (d, 2H, J=9.6 Hz), 3.87 (s, 2H), 3.75 (m, 4H), 3.66 (m, 4H), 2.80 (s, 3H).
Reaction SMILES: O[C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:7]2[C:8]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=3[S:10][C:6]=2[C:5]([C:19]#[N:20])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc(O)c2c1sc1cc(C(F)(F)F)ccc12
Product: N#Cc1cnc(Cl)c2c1sc1cc(C(F)(F)F)ccc12
Reaction time: 0.17 h

Procedure:
A suspension of 1-hydroxy-7-(trifluoromethyl)[1]benzothieno[3,2-c]pyridine-4-carbonitrile in POCl3 (1 M) was placed in a microwave reactor at 210° C. (normal absorption) for 10 min. The reaction mixture was carefully poured onto ice, stirred for 10 min and the solid filtered off to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH:10]2[CH2:12][CH2:11]2)[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15].CC(=CC)C.P([O-])([O-])(O)=[O:22].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:5]=[C:4]([C:13]([OH:22])=[O:14])[C:3]=1[Cl:15]
Reactant: Nc1c(F)c(CC2CC2)nc(C=O)c1Cl
Reactant: O=P([O-])([O-])O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: Nc1c(F)c(CC2CC2)nc(C(=O)O)c1Cl
Temperature: 70 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-6-(cyclopropylmethyl)-5-fluoropicolinaldehyde (63 mg, 0.276 mmol) and t-butanol (1.378 mL). The mixture was treated with H2O (0.459 mL), 2-methylbut-2-ene (0.3 mL, 0.276 mmol), sodium hydrogenphosphate (78 mg, 0.551 mmol), and finally sodium chlorite (74.8 mg, 0.827 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was evaporated to dryness under N2. Purification via reverse phase chromatography yielded 4-amino-3-chloro-6-(cyclopropylmethyl)-5-fluoropicolinic acid (6.2 mg, 9.5%); 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 5.00 (m, 2H), 2.70 (dd, J=7.0, 2.6 Hz, 2H), 1.17-1.02 (m, 1H), 0.60-0.48 (m, 2H), 0.27 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −139.97; ESIMS m/z 243.2 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([C:13]2[CH:12]=[CH:11][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)cncc1Cl
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1c(Cl)cncc1-c1ccc2ccccc2c1
Temperature: 150 °C
Yield: 52.4 %

Procedure:
A mixture of 3,5-dichloroisonicotinonitrile (0.300 g, 1.734 mmol), naphthalen-2-ylboronic acid (0.328 g, 1.908 mmol), potassium phosphate (0.736 g, 3.47 mmol) and palladium tetrakis(triphenylphosphine) (0.100 g, 0.087 mmol) was pumped and backfilled with nitrogen 3 times. N,N-Dimethylacetamide (6 mL) was added. The mixture was again pumped and backfilled with nitrogen 3 times. The reaction tube was sealed and heated to 150° C. under microwave for 30 min. The mixture was diluted with ethyl acetate (80 mL), washed with 1:1 mixture of brine and water (30 mL), brine (30 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with toluene and eluting with 10-35% ethyl acetate in hexanes, gave 3-chloro-5-(naphthalen-2-yl)isonicotinonitrile as a white solid (240.5 mg, 46% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (1H, s), 8.81 (1H, s), 8.00-8.15 (2H, m), 7.87-8.00 (2H, m), 7.67 (1H, dd, J=8.53, 2.01 Hz), 7.53-7.64 (2H, m); MS (ES+) m/z: 265 (M+H); LC retention time: 4.066 min (analytical HPLC Method A).
Reaction SMILES: [CH2:1]([C:7]1[O:8][C:9](I)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>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>[CH2:1]([C:7]1[O:8][C:9]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(I)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(-c2ccco2)o1
Yield: 174.1 %

Procedure:
Pd(PPh3)4 (1.15 g, 1 mmol, 5% mol) was added to 2-tributyltinfuran (7.05 g, 20 mmol) and 2-hexyl-5-iodofuran (5.5 g, 20 mmol) in dry toluene (150 mL) and the reaction mixture was refluxed under N2 for 5 h. The mixture was then cooled, separated with hexane, the organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (elution with hexane) to afford 3.8 g of 5-hexyl-2,2′-bifuran (88%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.35 (d, J=1.1 Hz, 1H), 6.39-6.45 (m, 3H), 6.00 (d, J=3.2 Hz, 1H), 2.62 (t, J=7.6, 2H), 1.64 (td, J=2H), 1.28-1.34 (m, 6H) 0.87 (t, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 156.3, 147.0, 144.8, 141.3, 111.3, 106.5, 105.9, 104.1, 31.6, 28.9, 28.1, 28.0, 22.6, 14.1 ppm. HRMS (FD): m/z calcd for C14H18O2: 218.1307. found 218.1315.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][NH:4][N:3]=1.I[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu](Cl)Cl.C(OCC)(=O)C.C(#N)C>[Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CC(=O)Nc1c[nH]nc1Cl
Reactant: Ic1cccnc1
Agent: Cl[Cu]Cl
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Reaction time: 2 h
Yield: 64.6 %

Procedure:
A 250-mL, 3-neck round bottom flask was charged with N-(3-chloro-1H-pyrazol-4-yl)acetamide (4.8 g, 30.1 mmol), copper(II) chloride (0.404 g, 3.01 mmol), 3-iodopyridine (7.40 g, 36.1 mmol), potassium phosphate (7.66 g, 36.1 mmol) and acetonitrile (100 mL). N,N′-Dimethylethane-1,2-diamine (1.33 g, 15.0 mmol) was added and the mixture was heated at 80° C. for 18 hours, at which point thin layer chromatography analysis [Eluent: ethyl acetate] indicated that a trace amount of starting material remained and a major product formed. It was filtered through a pad of Celite® and the Celite® pad rinsed with acetonitrile (50 mL). Water (300 mL) was added to the filtrate and the resulting suspension was stirred for 2 hours and filtered. The resulting solid was rinsed with water (2×20 mL) and dried under vacuum at room temperature to afford a white solid (4.60 g, 65%): mp 169-172° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.05 (dd, J=2.8, 0.8 Hz, 1H), 8.82 (s, 1H), 8.54 (dd, J=4.7, 1.4 Hz, 1H), 8.20 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.54, (ddd, J=8.3, 4.7, 0.8 Hz, 1H), 2.11 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 168.12, 147.46, 139.42, 135.46, 133.60, 125.47, 124.21, 122.21, 120.16, 22.62; EIMS m/z 236 ([M]+).