Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:17][C:18]([F:21])([F:20])[F:19].B1C2CCCC1CCC2.[OH-:31].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:31])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:17][C:18]([F:20])([F:19])[F:21]
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
To the solution of 1-chloro-2-(trifluoromethoxy)-4-(4-vinylphenoxyl)benzene (1.2 g, 3.81 mmol) in dry THF (10 mL), was added 9-BBN (15.25 mL, 7.63 mmol) at 0° C. The mixture was stirred at room temperature overnight. aq. NaOH (6.5 mL, 19.50 mmol), and 30% H2O2 (2.0 mL, 19.58 mmol) were added. The reaction mixture was heated at 55° C. for 4 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (450 mg, 1.353 mmol, 35.5% yield) as a white oil.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)Cc1cccc(OC)c1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1cccc(OC)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3-methoxy-phenyl)-acetic acid methyl ester (1.07 g, 5.94 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (14.8 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.37 g, 6.53 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.16 mL). The reaction mixture was stirred at −78° C. for 3 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. At this time, the reaction was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution. This solution was diluted with water (100 mL) and extracted into ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid methyl ester (1.39 g, 89.1%) as a clear oil: EI-HRMS m/e calcd for C16H22O3 (M+) 262.1568, found 262.1561.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:21]I>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:21])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CI
Reactant: CCc1ccc(Nc2nc(C)nc3ccccc23)cc1
Product: CCc1ccc(N(C)c2nc(C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (4-ethyl-phenyl)-(2-methyl-quinazolin-4-yl)-amine (122 mg, 0.46 mmol) and methyl iodide (0.2 ml, 3.25 mmol) by a procedure similar to example 36. 1H NMR (CDCl3): 7.74 (d, J=8.1 Hz, 1H), 7.54-7.49 (m, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.09-6.92 (m, 4H), 3.61 (s, 3H), 2.73-2.63 (m, 5H), 1.26 (d, J=7.5 Hz, 3H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]2.[CH2:26]([NH:29][C:30]1[C:31]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:27][CH3:28]>C1COCC1.ClCCl>[CH3:28][CH2:27][CH2:26][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([C:23]([C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:14]([F:13])=[CH:15][C:16]=3[CH:17]=2)=[O:25])[CH2:38][CH2:37]1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: CCCNc1cccnc1N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCNc1cccnc1N1CCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
1,1'-carbonyldiimidazole (0.48) is added to a 20°-25° solution of 5-fluoroindole-2-carboxylic acid (I, 0.53 g) in THF (6 ml). After 1 hour of stirring the above reaction is added dropwise via cannula to a solution of [3-(propylamino)-2-pyridinyl]piperazine (II, PREPARATION 7, 0.72 g) in THF (6 ml) at -10° (ice/acetone bath). The reaction is stirred for 30 minutes at -10°, slowly warming to 20°-25°, and stirred 4 hours. The reaction is diluted with dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (40 ml), saline (40 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography (40 g silica gel) eluting with ethyl acetate/hexane (1/1). The appropriate fractions are pooled and concentrated to give the title compound, mp 196°-198°; IR (mineral oil) 3200, 2920-3000, 1630 and 1424 cm-1 ; NMR (300 MHz, CDCl3) 9.82, 7.72, 7.35, 7.27, 7.03, 6.95, 6.86, 6.78, 4.32, 4.09, 3.21, 3.08, 1.71 and 1.05 δ; CMR (300 MHz, CDCl3) 162.3, 159.5, 149.7, 137.4, 135.1, 132.3, 130.7, 127.5, 127.4, 120.4, 116.3, 113.4, 112.9, 112.7, 112.5, 106.1, 105.8, 105.1, 105.0, 49.0, 45.2, 22.5 and 11.6 δ; MS (m/e) 382, 381, 190, 176, 164, 162, 134 and 120.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14](Cl)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[NH3:23]>O>[CH2:2]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:23]2[CH2:11][CH2:12][N:7]([CH3:5])[CH2:8][CH2:9]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: N
Reactant: CCOC(=O)N1CCN(CC(Cl)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: O
Product: CCOC(=O)N1CCN(CC(c2ccc(F)cc2)N2CCN(C)CC2)CC1
Temperature: 65 °C

Procedure:
To 7.6 g of 1-ethoxycarbonyl-4-[2-chloro-2-(4-fluorophenyl)ethyl]piperazine hydrochloride were poured 5 ml of 25% aqueous ammonia solution and water and, after extraction with ether, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 20 ml of benzene, and 5.4 ml of 1-methylpiperazine was added, followed by heating at 65° C. for 3.5 hours. To the reaction solution were poured 25% aqueous ammonia solution and water and, after extraction with ether, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=4:1) to give 6.58 g of 1-ethoxycarbonyl-4-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine as an oil.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[O:12][CH2:13][C:14]3[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:25][NH:24][C:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:11]([NH:10][C@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[O:12][CH2:13][C:14]=2[CH:20]=1)=[NH:22]
Reactant: N#Cc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 81.2 %

Procedure:
A stirred suspension of 2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazine-6-carbonitrile (example 117) (310 mg, 1.07 mmol), hydroxylamine hydrochloride (275 mg, 3.96 mmol), sodium carbonate (227 mg, 2.14 mmol) in ethanol (4 ml) and water (4 ml) was heated under reflux conditions for 17 h, water (10 ml) was added, the precipitate was collected by filtration, washed with water and hexane. The crude product was further purified by crystallization (diethyl ether/methanol 10:1) to yield the title compound as white solid (280 mg, 81%). MS (ISP): m/e=323.3 (M+H+); m.p. 206° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:4]=1[CH2:5][NH:6][C:7](=[NH:12])[NH:8][C:9]([NH2:11])=[S:10].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:30]=[CH:29][C:24]([C:25](=O)[CH2:26]Br)=[CH:23][CH:22]=1.C(O)(=O)C>O1CCOCC1>[CH3:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:5][NH:6][C:7]([NH:8][C:9]1[S:10][CH:26]=[C:25]([C:24]2[CH:29]=[CH:30][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:22][CH:23]=2)[N:11]=1)=[NH:12]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(OC)c1CNC(=N)NC(N)=S
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 52.9 %

Procedure:
Preparation took place analogously to Example 3 by reaction of 140 mg (0.52 mmol) N-[[(2,6-dimethoxybenzyl)amino](imino)methyl]thiourea with 140 mg (0.52 mmol) 4-(trifluoromethyl)phenacyl bromide. The educts were suspended in 3 ml dioxane, were added to 0.3 ml acetic acid and were heated for 40 minutes in the microwave (radiation 300 Watt). The mixture was subsequently concentrated and the crude product obtained was purified by chromatography on silica gel (dichloromethane/methanol 1-4%). Stirring of the yellow foam obtained with methyl tert.-butyl ether yielded 120 mg of a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: COC(=O)c1sc(Br)cc1OC(C)c1ccccc1Cl
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: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2cnc3[nH]ccc3c2)cc1OC(C)c1ccccc1Cl
Temperature: 140 °C
Yield: 45.3 %

Procedure:
5-Bromo-3-[1-(2-chloro-phenyl)-ethoxy]-thiophene-2-carboxylic acid methyl ester (200 mg, 0.53 mmol, 1.0 Eq.), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (195 mg, 0.80 mmol, 1.5 Eq.) and Pd(PPh3)4 (61 mg, 0.05 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and ethanol (0.4 mL). 2M K2CO3 (0.8 mL, 1.60 mmol, 3.0 Eq.) was added and the reaction heated under microwave conditions at 140° C. for 10 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/petroleum Ether) to give the sub-title compound as a yellow solid (100 mg, 0.24 mmol, 45%); 1H NMR (400 MHz, CDCl3) δ1.75(3H, d), 3.94 (3H, s), 5.88 (1H, q), 6.64 (1H, d), 6.94 (1H, s), 7.26-7.34 (2H, m), 7.38-7.44 (2H, m), 7.71 (1H, dd), 8.17 (1H, d), 8.44 (1H, d).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:12]([CH2:18]OC)[CH2:13][Si](C)(C)C)([CH3:11])([CH3:10])[CH3:9].[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:8]([N:12]1[CH2:13][C@@H:28]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[C@H:29]([C:30]([O:32][CH3:33])=[O:31])[CH2:18]1)([CH3:9])([CH3:10])[CH3:11]
Reactant: COC(=O)/C=C/c1ccc(F)cc1
Reactant: COCN(C[Si](C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(C)(C)C)C[C@H]1c1ccc(F)cc1
Reaction time: 18 h
Yield: 75.1 %

Procedure:
Trifluoroacetic acid (38.9 mL, 0.505 mmol) was added to a solution of the product of step B (1.03 g, 5.05 mmol) and methyl (2E)-3-(4-fluorophenyl)prop-2-enoate (1.00 g, 5.05 mmol) in methylene chloride (10 mL) at ambient temperature. After 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the crude residue by medium pressure liquid chromatography on silica gel (gradient elution; 0–9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) furnished the title compound as a colorless liquid (1.06 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[O:31]C)=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.B(Br)(Br)Br.O>ClCCl>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:22]=3[OH:31])=[O:19])=[CH:15][CH:16]=2)[NH:4][N:3]=1
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(-c2ccnc3[nH]nc(N)c23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Nc1n[nH]c2nccc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4O)cc3)c12
Reaction time: 0.5 h

Procedure:
To a solution of 1-[4-(3-amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea, described in Example 5, in 6 mL of dichloromethane at −40° C. are added dropwise 1.6 mL of 1M boron tribromide solution, and the temperature is allowed to return to 20° C. After 30 minutes, the reaction is cooled on an ice bath and water is then added. After stirring for 15 minutes, the mixture is filtered off and the insoluble orange material is washed with water and with dichloromethane. The solid is purified on a prepacked Biotage KP-Sil column of 60 Å SiO2 32-63 μm (eluent: 95/5 then 90/10 then 80/20 then 70/30 dichloromethane/solution A; solution A=38/17/2 dichloromethane/methanol/aqueous ammonia). 29 mg of a yellow powder of 1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-hydroxy-5-trifluoromethylphenyl)urea are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]([OH:16])=O)[CH3:2].[CH2:17]([O:19][C:20]([C:22]1([NH2:31])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18].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>[CH2:17]([O:19][C:20]([C:22]1([NH:31][C:14]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][C:4]=2[O:3][CH2:1][CH3:2])=[O:16])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CCOc1ccc2ccccc2c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2c(OCC)ccc3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 2-ethoxy-naphthalene-1-carboxylic acid (335 mg, 1.55 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (318 mg, 1.55 mmol), HATU (886 mg, 2.33 mmol) in anhydrous DMF (8 mL) is added DIPEA (385 μL, 2.33 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (45) as white solid (420 mg, 67%).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].C(O)CCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:5][CH2:6][CH2:1][CH3:7])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: Cc1ccccc1
Reactant: CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCO
Product: CCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 70 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (440 g, 5.0 mol), n-butanol (371 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (40 mmHg, 93 to 100° C.) to give butyl pyruvate (505 g, yield: 70%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: CN(C)CCN
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-(dimethylamino)ethylamine according to general procedure 1 providing the amino compound (456 mg, 74%) as a white solid; Rf=0.43 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J=9.6 Hz, 1H), 7.46 (s, 1H), 6.77 (d, J=9.7 Hz, 1H), 3.83 (t, J=5.9 Hz, 2H), 3.48 (t, J=6.0 Hz, 2H), 3.01 (s, 6H); ES-MS: (M+H)=284, 286 m/z.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:53]=[C:48]3[CH2:49][O:50][CH2:51][CH2:52][N:47]3[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:33][CH2:32][N:24]3[C:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]=4[CH:31]=[C:23]3[C:22]2=[O:34])=[N:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:53]=[C:48]3[CH2:49][O:50][CH2:51][CH2:52][N:47]3[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCOC3)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 61 %

Procedure:
Following the procedures as described in Example 113j, reaction of 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (200 mg, 0.52 mmol) and 129c (170 mg, 0.52 mmol) gave 129d as a yellow solid (185 mg, 61%). LCMS: [M+H]+ 584
Reaction SMILES: C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:9][O:10][N:11]=[CH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[CH2:30][CH2:31][CH3:32]>CO>[CH3:9][O:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[CH2:30][CH2:31][CH3:32]
Reactant: CCCc1nc2c(N)nc3cccnc3c2n1CCCC=NOC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.8 %

Procedure:
Sodium cyanoborohydride (0.54 g, 8.64 mmol, 3 eq) and acetic acid (7 mL) were added to a solution of 4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyraldehyde O-methyloxime (0.94 g, 2.88 mmol, 1 eq) in methanol (7 mL) and stirred at ambient temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (60 mL) and saturated aqueous sodium bicarbonate (40 mL). The phases were separated and the aqueous phase was adjusted to pH ˜8 with solid sodium bicarbonate and extracted with dichloromethane (2×20 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 1.01 g of 1-[4-(methoxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]-1,5-naphthyridin-4-amine as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[C:12]#[N:13])[S:10][C:6]=2[CH:5]=1)([OH:3])=[O:2].[OH2:26]>S(=O)(=O)(O)O>[C:1]([C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9](=[C:11]([C:14]3[N:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=3)[C:12]([NH2:13])=[O:26])[S:10][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: N#CC(=C1Nc2ccc(C(=O)O)cc2S1)c1nccc(C(F)(F)F)n1
Reactant: O
Agent: O=S(=O)(O)O
Product: NC(=O)C(=C1Nc2ccc(C(=O)O)cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 2-[6-carboxybenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)-acetonitrile (620 mg, 1.70 mmol) in concentrated sulfuric acid (5 mL), was heated to 50° C. for 10 hr. The mixture was cooled to room temperature and added dropwise to rapidly stirred room-temperature water (100 mL). The precipitate that formed was collected by filtration, washed with water and hexanes, and dried under vacuum to give 2-[6-carboxybenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (587 mg, 90% yield) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[CH:4][CH:3]=1
Reactant: Clc1ccccc1I
Reactant: Clc1ccc2cc[nH]c2c1
Product: Clc1ccc2ccn(-c3ccccc3Cl)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-chloro-2-iodobenzene: ESMS m/e: 262.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7]2[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.B(Br)(Br)Br.ClCCl.[Cl-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(OC)cc1Nc1ccc(F)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.7 %

Procedure:
Methyl 2-(4-fluoroanilino)-4-methoxybenzoate 2.2 g was added to 1.0 mol/L boron tribromide/dichloromethane 24 mL, and it was stirred at room temperature for 5 hours. Saturated sodium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=5:1] to give methyl 2-(4-fluoroanilino)-4-hydroxybenzoate 0.60 g of purple solid.