Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[CH:10]=[C:11]([C:19](OC)=[O:20])[C:12]([C:15](OC)=[O:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>C1COCC1>[CH2:23]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[C:11]([CH2:19][OH:20])[CH:10]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1CO
Temperature: -50 °C
Reaction time: 3 h

Procedure:
A 100-L, four-necked, round-bottomed flask was charged with dimethyl 4-(dibenzylamino)benzene-1,2-dicarboxylate in 38 L of THF from the previous step. While cooling with a dry ice-acetone bath (ca. −50° C.), a solution of lithium aluminum hydride (LiAlH4) in THF (1.0 M, 26 L) was added dropwise via an addition funnel keeping the internal temperature <5° C. (ca. 1.5 h addition). The resulting reaction mixture was aged at −12 to 1° C. for 3 h. Additional LiAlH4 (1.2 L) was added via addition funnel and the reaction mixture was allowed to slowly warm to room temperature over 16 h. A solution of aqueous THF (1.03 L of water diluted with 4 L of THF) was then added slowly keeping the internal temperature <15° C. Next, 1.03 L of a 15% NaOH solution were added in one portion followed by the addition of 3.1 L of water in 5 portions. [note, the reaction mixture gets extremely thick during the second water addition step] The reaction mixture was allowed to warm to room temperature, and then filtered through Solka-Floc® with the aid of 40 L of THF [note, the filtration is slow, ca. 5 h] and concentrated to ca. 21 L (ca. 3 volumes). Toluene (56 L, 8 volumes) was added and the solution was concentrated to ca. 35 L (ca. 5 volumes). Seed crystals were then added to initiate crystallization and the reaction mixture was further concentrated to ca. 28 L (4 volumes). Heptane (70 L) was then added over 90 min and the crystallization was aged at room temperature until <3% of the dial remained in the mother liquor (ca. 3 h). The crystals were collected by filtration, washed with 20 L of a 1:2 toluene:heptane solution and 30 L of heptane, and dried under vacuum with a nitrogen sweep to give the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](Br)[CH:18]=[CH2:19].Cl.CCOCC>O1CCCC1.CCCCCC>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:19][CH:18]=[CH2:17])[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCBr
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A solution of diphenylacetic acid (250 g., 1.17 mol ) in 2.4 L of tetrahydrofuran was stirred at 0° C. under argon while 0.94 L of a 2.5M solution on n-butyllithium in hexane was added dropwise. After 1 hour, allyl bromide (142.5 g, 1.17 mole) was added in one portion. After 15 minutes, 500 mL of 10% hydrochloric acid was added, along with ether (2 L). The layers were separated, the aqueous layer extracted with ethyl ether (1×250 mL), the organic layers combined, washed with brine, dried (MgSO4), and filtered. Concentration afforded 296 g (99%) of an off-white solid, mp 134°-137° C. 1H NMR (CDCl3)δ 7.3 (m, 10H), 5.6 (m, 1H), 4.9 (bs, 2H), 3.2 (d, 2H).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:6])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(Br)cc1
Agent: [Pd]
Solvent: CO
Product: NCC(=O)c1ccc(Br)cc1
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a solution of compound 2-azido 4′-bromoacetophenone (1.0 g, 4.17 mmol) in MeOH (20 mL), Pd/C (10%, 100 mg) was added to the solution. The mixture was degassed and stirred under hydrogen system for 4 hours. The mixture was filtered and evaporated in vacuo without further purification to obtain 2-amino 4′-bromoacetophenone (0.535 g, 2.499 mmol, 60% yield). 1H NMR (d-MeOH) 4.63 (d, J=4.8 Hz, 2H), 7.62 (d, J=7.2 Hz, 2H), 8.03 (d, J=7.2 Hz, 2H) ppm.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].C(N[C:16]1[CH:25]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[C:23]([O:30]C(=O)C)=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20]([CH3:34])=[N:21]2)(=O)C>C(O)(=O)C.O>[C:27]([NH:26][C:24]1[C:23](=[O:30])[C:22]2[N:21]=[C:20]([CH3:34])[CH:19]=[CH:18][C:17]=2[C:16](=[O:2])[CH:25]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Nc1cc(NC(C)=O)c2ccc(C)nc2c1OC(C)=O
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 56 %

Procedure:
This compound was prepared by the oxidation of the corresponding acylamido with potassium dichromate in glacial acetic acid. Into a 1000 ml Erlenmeyer flask, 240 ml of glacial acetic acid, and 5,7-diacetamido-2-methyl-8-acetoxyquinoline (31) (prepared as described in Example 31) (6.3 g, 2.0 mmol) were added. To the resulting suspension, a solution of potassium dichromate (17.64 g) in 200 ml of water was added. This black solution was magnetically stirred at room temperature for 20-24 hours. The solution was then poured into 900 ml of water and extracted with dichloromethane (5×200 ml). The organic extracts were washed with a solution of 5% sodium carbonate in a saturated salt solution (3×300 ml). The organic layer was dried overnight with anhydrous magnesium sulfate. The magnesium sulfate was filtered off, and the solvent was evaporated to leave an orange/yellow solid. The solid 7-acetamino-2-methylquinoline-5,8-dione (27) was dried overnight under vacuum. 2.6 g of product was obtained for a yield of 56%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:18][CH:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]1[C:34]([S:35][C:36]2[CH:41]=[C:40]3[O:42][CH2:43][O:44][C:39]3=[CH:38][C:37]=2I)=[N:33][C:27]2[C:28]([NH2:32])=[N:29][CH:30]=[N:31][C:26]1=2)[CH3:20].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:37]2[C:36]([S:35][C:34]3[N:25]([CH2:24][CH2:23][CH2:22][NH:21][CH:19]([CH3:20])[CH3:18])[C:26]4[C:27]([N:33]=3)=[C:28]([NH2:32])[N:29]=[CH:30][N:31]=4)=[CH:41][C:40]3[O:42][CH2:43][O:44][C:39]=3[CH:38]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C

Procedure:
3,5-Bis(trifluoromethyl)phenylboronic acid (22.6 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (0.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 4:5:2:1) to give 24.4 mg (70%) of DZ2-391. 1H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.79 (s, 3H), 7.12 (s, 1H), 6.86 (s, 1H), 6.09 (s, 2H), 5.71 (br s, 2H), 4.07 (t, J=6.6 Hz, 2H), 2.82 (septet, J=6.2 Hz, 1H), 2.49 (t, J=6.5 Hz, 2H), 1.95 (m, 2H), 1.12 (d, J=6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 154.1, 152.3, 151.5, 149.6, 148.6, 147.5, 142.1, 137.2, 131.2 (q, J=33 Hz), 129.6, 123.1 (q, J=270 Hz), 121.3, 119.6, 119.4, 114.9, 110.8, 102.4, 49.5, 42.8, 40.6, 28.8, 21.7; HRMS (ESI) m/z [M+H]+ calcd. for C26H25F6N6O2S, 599.1664; found. 599.1653; HPLC: method A Rt=7.45, method B Rt=9.38.
Reaction SMILES: [CH2:1]=O.[C:3]1([N:9]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:10]2=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Ni].C(O)C>[CH3:1][N:20]1[CH2:19][CH2:18][C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]=2[CH2:22][CH2:21]1
Reactant: c1ccc(-n2c3c(c4ccccc42)CCNCC3)cc1
Reactant: C=O
Agent: [Ni]
Solvent: CCO
Product: CN1CCc2c(n(-c3ccccc3)c3ccccc23)CC1

Procedure:
19.8 ml of a 35% formaldehyde solution and a spoonful of Raney Nickel are added to 20.4 g 1,2,3,4,5,6-hexahydro-6-phenylazepino[4,5-b]indole in 385 ml ethanol. The mixture is hydrogenated at room temperature. The mixture is then filtered and the filtrate concentrated to give a residue which is partitioned between ether and water. The ether phase is dried over sodium sulphate and concentrated to give the title compound as an oil which is converted into the hydrochloride, m.p. 236°-238° (from ether/ethanol).
Reaction SMILES: [NH2:1][C:2]1[C:11](C#N)=[C:10]2[C:5]([CH2:6][CH:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=32)=[CH:4][N:3]=1>Br.C(O)(=O)C>[Cl:25][C:20]1[CH:19]=[C:18]([CH:7]2[CH2:6][C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[CH:11][C:10]=3[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]2=3)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: N#Cc1c(N)ncc2c1-c1ccccc1C(c1ccc(Cl)c(Cl)c1)C2
Agent: Br
Solvent: CC(=O)O
Product: Nc1cc2c(cn1)CC(c1ccc(Cl)c(Cl)c1)c1ccccc1-2
Temperature: 200 °C
Yield: 25.3 %

Procedure:
A mixture of 2-amino-6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[f]isoquinoline-1-carbonitrile (186 mg, 0.510 mmol) in 48% hydrobromic acid (1 mL) and 33% wt hydrogen bromide in acetic acid (1 mL) was heated to 200° C. for 45 minutes under microwave irradiation. The mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was removed and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC using dichloromethane-methanol (19:1) as eluent to provide 6-(3,4-dichlorophenyl)-5,6-dihydrobenzo[f]isoquinolin-2-amine as an off-white solid (44 mg, 25%). 1H NMR 400 MHz (DMSO-d6) δ 7.80 (d, J=7.6 Hz, 1H), 7.74 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.41 (t, J=7.2 Hz, 1H), 7.34 (m, 2H), 7.07 (d, J=7.6 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 6.87 (s, 1H), 5.78 (s, 2H), 4.30 (m, 1H), 2.98 (d, J=5.6 Hz, 2H). LCMS m/e 341 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.CCCCCC.[CH3:22][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29]>O1CCCC1>[CH3:22][NH:23][C:24](=[O:29])[CH2:25][CH2:26][C:27](=[O:28])[C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10]
Reactant: COc1cccc(OC)c1
Reactant: CN1C(=O)CCC1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)CCC(=O)c1c(OC)cccc1OC
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A solution of 1,3-dimethoxybenzene (89 ml, 0.064 mole) in dry tetrahydrofuran (480 ml) was added during 10 minutes to a stirred solution of n-butyl lithium in hexane (350 ml, 0.6 mole) under an atmosphere of nitrogen. The stirred mixture was heated under reflux for 90 minutes, then a solution of N-methyl succinimide (77 g, 0.68 mole) in dry tetrahydrofuran was added dropwise. The mixture was heated under reflux for an additional hour and then allowed to stand overnight. The supernatant was decanted and the residue was hydrolysed with 20% aqueous ammonium chloride solution (280 ml) and extracted with chloroform. The washed and dried extract was evaporated and the residue recrystallised from ethyl acetate to give N-methyl 3-(2,6-dimethoxybenzoyl)-propionamide (15 g, 10%, m.p. 134° ). (Found: C, 62.18; H, 6.73; N, 5.54; C13H17NO4 requires C, 62.14; H, 6.82; N, 5.57%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].Br[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(=O)CC>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[O:13][CH2:15][C:16]#[N:17])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(O)cc([N+](=O)[O-])c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: N#CCOc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 61.8 %

Procedure:
3,5-Dinitrophenol (15.0 g) and 10.75 g of bromoacetonitrile were dissolved in 85 ml of 2-butanone and the solution was treated with 33.78 g of potassium carbonate. The heterogenous mixture was stirred and heated at 70° C. for 5 hours, cooled to room temperature, poured into ethyl acetate, washed with water, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography eluting with dichloromethane/hexane (3:1) to give 11.24 g of (3,5-dinitrophenoxy)-acetonitrile as a light yellow solid.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11]([NH2:13])=[NH:12])[CH2:3]2.C[O-].[Na+].CN(C)[CH:19]=[CH:20][C:21]([C:23]1[N:30]2[C:26]([O:27][CH:28]=[CH:29]2)=[N:25][C:24]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=O>C(O)C>[F:37][C:34]1[CH:33]=[CH:32][C:31]([C:24]2[N:25]=[C:26]3[N:30]([C:23]=2[C:21]2[CH:20]=[CH:19][N:13]=[C:11]([NH:10][C@@H:4]4[CH:5]5[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]5)[CH2:3]4)[N:12]=2)[CH:29]=[CH:28][O:27]3)=[CH:36][CH:35]=1
Reactant: N=C(N)NC1CN2CCC1CC2
Reactant: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nc2occn12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2nc3occn3c2-c2ccnc(N[C@H]3CN4CCC3CC4)n2)cc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A 5 L 3-neck round bottom flask is charged with the N-1-azabicyclo[2.2.2]oct-3-ylguanidine hydrochloride (261.5 g, 1.277 mol) and absolute ethanol. Sodium methoxide (21% by weight) (405 ml, 1.08 mol) is added dropwise over 15 min. The 3-(dimethylamino)-1-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]prop-2-en-1-one (232.1 g, 0.776 mol) is then added in portions so that no reaction mixture temperature change is observed. The reaction mixture is then refluxed for 5 hours and cooled to room temperature. Solvent is removed in vacuo and the residue partitioned between 1N NaOH and ethyl acetate. The resulting solids are filtered, washed with water, ethyl acetate, and then dried. The solids are then mostly dissolved in hot isopropyl alcohol and filtered through celite while hot. The isopropyl alcohol solution is concentrated to dryness and the solids dried under vacuum to give the desired pyrimidine compound (143.8 g) as a tan solid in 46% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][C:11]23[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2NO)[CH:5]=[CH:6][CH:7]=1.O.[NH2:25]N>C(O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([NH2:25])[C:11]23[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ONC1CCCCC12C=Nc1ccc(-c3cccc(Cl)c3)cc12
Reactant: NN
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: NC1=Nc2ccc(-c3cccc(Cl)c3)cc2C12CCCCC2
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 65.2 %

Procedure:
To a turbid solution of 5′-(3-Chlorophenyl)-N-hydroxyspiro[cyclohexane-1,3 -[3H]indol]-2-amine (0.500 g; 1.53 mmol) in 25 mL of ethanol was added hydrazine hydrate (0.600 mL; 12.24 mmol). The solution was warmed to 55° C., where Raney-nickel (50% in water) was added to the reaction to keep a constant evolution of gas. After 45 minutes, the hot reaction mixture was filtered through a Celite plug and rinsed with a copious amount of hot methanol. The filtrate was concentrated in vacuo to give 0.890 g of an opaque solid. The product was purified by flash silica gel chromatography, (eluant, 2% to 8% methanol-methylene chloride with 0.1% ammonium hydroxide) to afford 0.310 g (65%) of the desired product as a white solid. Mp. 118-120° C. 1H NMR δ (300 MHz, DMSO-d6) 1.31-1.46 (m, 2H), 1.70-1.93 (m, 8H), 7.0 (d, 1H), 7.1 (br, 2H 2NH), 7.31-7.34 (dt, 1H, J=8 Hz), 7.41-7.46 (t, 2H), 7.55-7.58 (d, 1H), 7.62 (s, 1H), 7.72 (s, 1H); MS (ECI(+ve)) m/z 311 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[O-:17][CH2:18][CH3:19].[Na+].[Na].ClCCO>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:19][CH2:18][OH:17])=[CH:10][CH:11]=1
Reactant: CC[O-]
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Agent: OCCCl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: OCCOc1ccc(Oc2cc(F)cc(F)c2)cc1

Procedure:
4-(3,5-Difluorophenoxy)phenol (9.0 g, 40.5 mmol) was added to an ethanolic solution of sodium ethoxide prepared from ethanol (40 ml) and sodium (939 mg, 40.9 mmol). To the resultant solution, 2-chloroethanol (3.26 g, 40.5 mmol) was dropwise added with stirring under reflux. After completion of the addition, the resultant mixture was stirred under reflux for 4 hours. After allowed to cool, ethanol was removed, and the residual oil was dissolved in toluene. The toluene layer was washed with water once, a 20% aqueous potassium hydroxide solution two times and a saturated aqueous sodium chloride solution once in order and dried over anhydrous magnesium sulfate. Removal of the solvent gave 2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (6.50 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:21])C(=O)C1>CC#N.C(OCC)(=O)C>[Br:21][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc(C2CCOCC2)cn1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ncc(C2CCOCC2)nc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine (2.8 g, 15.6 mmol) in CH3CN (52 mL) was added NBS (2.78 g, 15.62 mmol) in two portions at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with ethyl acetate and was washed with saturated sodium carbonate solution, water, brine, dried and concentrated. The crude 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine (3.9 g, 97%) was used for the next step without further purification. LCMS (m/z): 258/260 (MH+), 0.52 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (s, 1H), 4.90 (br. s., 2H), 4.14-4.02 (m, 2H), 3.59-3.43 (m, 2H), 2.83 (d, J=5.5 Hz, 1H), 1.91-1.77 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[C:13]([C@:17]2([CH3:37])[CH2:22][CH2:21][N:20]([CH2:23][C@@H:24]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH2:19][C@@H:18]2[CH3:36])[CH:14]=[CH:15][CH:16]=1)(=O)C.O>CO>[OH:10][C:11]1[CH:12]=[C:13]([C@:17]2([CH3:37])[CH2:22][CH2:21][N:20]([CH2:23][C@@H:24]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]([O:27][CH3:28])=[O:26])[CH2:19][C@@H:18]2[CH3:36])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(OC(C)=O)c2)[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Potassium carbonate (0.156 g, 0.001 mol, 3 eq) was added to a solution of 5b (0.160 g, 0.0003 mol, 1 eq) in methanol (15 mL). The suspension was stirred under nitrogen for 2 h. Water (50 mL) was added and the suspension was extracted with ethyl acetate (100 mL). The organic solution was washed with brine (50 mL), separated and dried over sodium sulfate. Evaporation of the solvent afforded the methyl ester 6b as a solid (0.060 g, 41% yield). Rf 0.30 (hexane/EtOAc=8:2). 1H NMR δ (CDCl3) 0.73 (d, 3H), 1.26 (s, 3H), 1.51 (d, 1H), 1.94 (m, 1H), 2.20-2.35 (m, 2H), 2.40-2.50 (m, 2H), 2.55-2.70 (m, 2H), 2.80-3.00 (m, 3H), 3.58 (s, 3H), 6.60 (d, 1H), 6.75 (s, 1H), 6.85 (d, 1H), 7.10-7.30 (m, 7H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:10][C:9]([C:11]([NH2:13])=[O:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH:30]=[N:31][NH:32]3)O1>>[NH:32]1[C:33]2[C:29](=[C:28]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:5]4[O:10][C:9]([C:11]([NH2:13])=[O:12])=[CH:8][C:6]=4[N:7]=3)[CH:36]=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: NC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Product: NC(=O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2o1

Procedure:
2-Chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carboxamide was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to give, after purification by reverse HPLC, 291. MS (Q1) 365 (M+)
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:26])=[C:8](C(OCC)=O)[C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:27]1[CH:28]=[N:29][NH:30][CH:31]=1.[OH-].[Na+].C1(OC2C=CC=CC=2)C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1>CS(C)=O.O.C(O)=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:26])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:27]1[CH:28]=[N:29][NH:30][CH:31]=1
Reactant: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)c(Br)c2c1NS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: c1ccc2ncccc2c1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2c(Br)c(-c3cn[nH]c3)sc2n1
Temperature: 150 °C
Yield: 54.8 %

Procedure:
A mixture of ethyl 3-bromo-6-methyl-4-[(phenylsulfonyl)amino]-2-(1H-pyrazol-4-yl)thieno[2,3-b]pyridine-5-carboxylate (Description 69) (6.1 g, 11.70 mmol) in DMSO (120 mL) and aqueous NaOH (5M) (9.36 mL, 46.8 mmol) was heated at 150° C. for ca. 2.5 h. After cooling to RT, the mixture was diluted with water (100 mL) and acidified with formic acid. The mixture was extracted with 20% MeOH in DCM (75 mL×5) and the combined organics dried and concentrated. Water (100 mL) was added to the residue and a precipitate crashed-out which was filtered and rinsed with water (50 mL×3). The solid was dried and then taken-up in diphenyl ether (74.4 mL, 468 mmol) and quinoline (13.86 mL, 117 mmol). The resulting mixture was then heated at 200° C. for ca. 5 h. After cooling to RT, the mixture was purified via normal phase chromatography, eluting with 0-100% ethyl acetate in DCM, to give the title compound (2.88 g). LCMS (A) m/z: 449/451 [M+1]+, Rt 1.05 min (acidic).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:7][CH:6]=1)C.[ClH:17]>>[ClH:17].[CH2:12]([C:8]1[C:9]([CH3:11])=[CH:10][C:5]([C:4]([OH:16])=[O:3])=[CH:6][N:7]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1cnc(CC(C)C)c(C)c1
Agent: Cl
Product: Cc1cc(C(=O)O)cnc1CC(C)C

Procedure:
A solution of 6-isobutyl-5-methyl-nicotinic acid ethyl ester (3.75 g, 16.95 mmol) in 12.5% aq. HCl (50 mL) is stirred at 65° C. for 24 h before the solvent is evaporated. The residue is dried under HV to give 6-isobutyl-5-methyl-nicotinic acid hydrochloride (3.55 g) as a white powder; LC-MS: tR=0.57 min, [M+1]+=194.25.