Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([O:24][CH3:25])=[N:17][C:18]([NH:21][CH2:22][CH3:23])=[N:19][CH:20]=3)=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[CH2:22]([NH:21][C:18]1[N:17]=[C:16]([O:24][CH3:25])[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)[CH:7]=3)=[CH:14][N:13]=2)=[CH:20][N:19]=1)[CH3:23]
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(Cl)c3)cn2)c(OC)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)cn2)c(OC)n1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
A mixture of 5-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-N-ethyl-4-methoxypyrimidin-2-amine (0.090 g, 0.25 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.060 g, 0.28 mmol), and K2CO3 (0.10 g, 0.76 mmol) in 5:1 dioxane/water (6 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.03 g, 0.025 mmol), sparged again with Ar and heated at 90° C. for 7 h. The mixture was cooled to RT, quenched with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain N-ethyl-4-methoxy-5-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (80 mg, 79%). MS (ESI) m/z: 404.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH2:18])=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:24][C:25]1[C:26]([CH2:31]Br)=[CH:27][CH:28]=[CH:29][CH:30]=1.O>CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([N:18]4[CH2:31][C:26]5[C:25](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:24]4)=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: BrCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1Cc2ccccc2C1
Reaction time: 3 h

Procedure:
To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under N2. The mixture was heated to 65 C. for 3 hours. α,α'-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 70 C. for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1% CH3OH: 99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184°-185° C.
Reaction SMILES: CON(C)[C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC#N>CCOCC>[CH:14]1([O:13][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=2[O:11][CH3:12])[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(C(=O)N(C)OC)cc1OC1CCCC1
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc(C(=O)c2ccccc2)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
To an ice bath cooled stirred solution of N-methoxy-N-methyl-3-cyclopentoxy-4-methoxybenzamide (1.2 g, 4.3 mmol) in 15 mL of anhydrous ether was added a 3 M solution of phenylmagnesium bromide (3.6 mL, 10.8 mmol) in ether dropwise over a 20 minute period. A white gum precipitated from the mixture and dry THF (6 mL) was added to facilitate stirring. The reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. The reaction was then quenched at 0° C. with a saturated aqueous solution of ammonium chloride (8 mL). The resulting mixture was allowed to warm to room temperature and was diluted with ethyl acetate (10 mL). The organic layer was separated and sequentially washed with 1 N citric acid (2×10 mL), saturated NaHCO3(aq) (2×10 mL), and brine (2×10 mL). The organic layer was then dried over MgSO4, filtered and concentrated in vacuo to give a viscous oil. The crude product was purified by flash column chromatography (silica gel, methylene chloride) and the resulting product was then dried in vacuo (40° C., <1 mmHg) to afford 0.75 g (60%) of a slightly impure product as a white solid: mp 73.5-75.0° C.; 1H NMR (CDCl3) δ 7.80-7.72 (m, 2H), 7.63-7.15 (m, 5H), 6.94-6.79 (m, 1H), 4.91-4.78 (m, 1H), 3.92 (s, 3H), 2.09-1.50 (m, 8H) also some impurity in the aromatic region; 13C NMR (CDCl3) δ 195.7, 153.9, 147.5, 138.3, 131.8, 129.7, 128.1, 125.1, 120.3, 115.5, 110.3, 80.5, 56.1, 32.7, 24.1; HPLC (Waters Nova-Pak/C18 column, 3.9×150mrn, 4 micron, 1 mL/min, 60/40, CH3CN/0.1% H3PO4(aq)) 6.2, min 99%.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[CH2:30]([O:32][CH2:33][CH2:34][N:35]1[CH2:44][CH2:43][C:42]2[C:41]([C:45](O)=[O:46])=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]1=[O:48])[CH3:31].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:45]([C:41]1[C:42]2[CH2:43][CH2:44][N:35]([CH2:34][CH2:33][O:32][CH2:30][CH3:31])[C:36](=[O:48])[C:37]=2[CH:38]=[CH:39][CH:40]=1)=[O:46])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: CCOCCN1CCc2c(C(=O)O)cccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCCN1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 20 h
Yield: 29.5 %

Procedure:
Poured into a suspension of 255 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 113.5 mg of 2-(2-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 9 mg of hydroxybenzotriazole, 104 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 7.6 cm3 of dichloromethane is 0.3 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The reaction mixture is kept stirring for 20 h at a temperature close to 20° C. The suspension obtained is filtered and the precipitate is washed once with 5 cm3 of dichloromethane, twice with 5 cm3 of diisopropyl ether, then dried under vacuum. 82 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-2-(2-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white powder.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10](F)=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2].C([OH:23])C#CC.[K].CC(C)([O-])C>CS(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10]([OH:23])=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC#CCO
Reactant: CCN1CCC(c2cccc(C(C)=O)c2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CS(C)=O
Product: CCN1CCC(c2cccc(C(C)=O)c2O)CC1

Procedure:
Preparation according to Example 5: 1-[3-(1-ethylpiperidin-4-yl)-2-fluorophenyl]ethanone (12 mg, 0.048 mmol), dimethylsulfoxide (1 ml), 2-butyn-1-ol (6.7 mg, 0.096 mmol), potassium-tertbutoxide (11 mg, 0.096 mmol). MS m/z (relative intensity, 70 eV) 247 (M+, 57), 232 (bp), 218 (28), 147 (24) 84 (67).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[C:18]=3[O:24]C)[C:11]([CH3:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(O)(=O)C.O.C(=O)(O)[O-].[Na+]>Br>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[C:18]=3[OH:24])[C:11]([CH3:26])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1c(Br)cccc1NN=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(Br)c1O

Procedure:
A solution of 1-(3,4-dimethylphenyl)-3-methyl-4-(3-bromo-2-methoxyphenyl)hydrazono-5-pyrazolone(5 g) prepared as in Example 2, in 48% aqueous hydrobromic acid (200 mL) and glacial acetic acid (50 mL) was stirred and heated under reflux for about 80 hours. The reaction mixture was concentrated under vacuum to obtain a thick residue. Water (40 mL) was added and basified to pH 7-8 using saturated solution of sodium bicarbonate (20 mL). The mixture was filtered to give an orange solid, which was washed with water (25 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours. Yield: 3.5 g
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[I:29])=[O:9])=O)[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl>O>[CH:1]1([C:4]2[O:9][C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([S:19]([C:22]3[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=3)(=[O:20])=[O:21])[CH:14]=[C:13]4[I:29])=[N:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NNC(=O)C4CC4)ccc32)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(C5CC5)o4)ccc32)cc1
Temperature: 110 °C
Yield: 52.2 %

Procedure:
In a 50 mL RBF, N′-(cyclopropanecarbonyl)-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (1.13 g, 2.159 mmol) was treated with POCl3 (5 mL, 53.6 mmol), under argon. The flask was fitted with a reflux condenser. The reaction was stirred and heated at 110° C. for 1.25 h. The crude material was treated with water and extracted with EtOAc. The organic layer was washed with brine, dried, filtered and concentrated to 20 mL of solvent. When about 20 mL of solvent remained, a brown solid precipitated and was collected by filtration. The mother liquor was purified with flash chromatography to give 2-cyclopropyl-5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (570 mg, 1.128 mmol, 52.2). MS (ESI, pos. ion) m/z: 506.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.94-8.03 (m, 3H), 7.85 (s, 1H), 7.43 (d, J=8.0 Hz, 2H), 2.28-2.37 (m, 4H), 1.09-1.21 (m, 4H).
Reaction SMILES: O[C:2]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[NH:13]C(OC(C)(C)C)=O)([CH3:7])[CH2:3][CH:4]([CH3:6])[CH3:5].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH:2]([CH3:7])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CC(C)(O)c1sccc1NC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC(C)c1sccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
In 10 ml of methylene chloride, 1.2 g of 2-(1-hydroxy-1,3-dimethylbutyl)-3-t-butoxycarbonylaminothiophene was dissolved, 0.44 g of triethylsilane and 4.3 g of trifluoroacetic acid were added, and the mixture was stirred at the room temperature for 20 hours. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.43 g of the product as a crystal.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:16][CH3:17])=[C:11]([CH2:14][CH3:15])[CH:12]=2)[C:6](=[O:7])[O:5]1)#[N:2].C[O-].[Na+]>Cl>[C:1]([CH:3]1[C:6](=[O:7])[C:8]2[C:13](=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([CH2:16][CH3:17])[CH:9]=2)[C:4]1=[O:5])#[N:2]
Reactant: CCc1cc2c(cc1CC)C(=CC#N)OC2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCc1cc2c(cc1CC)C(=O)C(C#N)C2=O
Yield: 77.8 %

Procedure:
A mixture of 3-cyanomethylene-5,6-diethylphthalide (4.7 g; 0.021 mole) and methanolic sodium methoxide (from sodium [0.48 g] and methanol [21 ml]) was refluxed for 20 mins., cooled, and the red solution poured into 5N hydrochloric acid (100 ml). The precipitated yellow solid was filtered off and dried in vacuo over P2O5 /NaOH to yield 3.711 g (79%) of material of m.p. 172°-173° C. (d). (Found; C, 73.60; H, 5.94; N, 6.13; C14H13NO2 requires; C, 73.99; H, 5.77; N, 6.16%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:14][C:15]([F:33])([F:32])[C:16]([C:19]1[CH:28]=[CH:27][C:26]2[CH2:25][C@H:24]([C:29](O)=[O:30])[CH2:23][CH2:22][C:21]=2[N:20]=1)([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:29]([CH:24]3[CH2:23][CH2:22][C:21]4[N:20]=[C:19]([C:16]([CH3:18])([CH3:17])[C:15]([F:33])([F:32])[F:14])[CH:28]=[CH:27][C:26]=4[CH2:25]3)=[O:30])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Reactant: CC(=O)N1CCc2ccc(N)cc21
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: CN1CCCC1=O
Product: CC(=O)N1CCc2ccc(NC(=O)C3CCc4nc(C(C)(C)C(F)(F)F)ccc4C3)cc21
Temperature: 60 °C
Reaction time: 1.3 h
Yield: 64.1 %

Procedure:
To a mixture of 1-acetyl-6-amino-indoline (32 mg, 0.18 mmol), (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (40 mg, 0.14 mmol) was added HATU (79 mg, 0.21 mmol) in NMP (0.7 mL), followed by N,N-diisopropylethylamine (73 μL, 0.42 mmol). After 1.3 h, the reaction was heated to 60° C. After 25 h, the material was filtered and purified by reverse-phase HPLC (40-75% ACN in 0.1% HCO2H/H2O). The fractions were stirred with MP-carbonate resin (1.0 g, 3.0 mmol/g) overnight, filtered and concentrated to afford the amide (40 mg, 64%) as a solid foam. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.21 (d, J=1.8 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.38 (dd, J=1.8, 8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 4.09 (t, J=8.5 Hz, 2H), 3.08 (t, J=8.5 Hz, 2H), 3.02-2.85 (m, 4H), 2.85-2.74 (m, 1H), 2.18-2.12 (m, 1H), 2.16 (s, 3H), 1.93-1.82 (m, 1H), 1.55 (s, 6H); m/z=446.5 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1)=[O:4].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([C:15]3[S:14][CH:18]=[CH:17][N:16]=3)=[CH:26][CH:25]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: O=Cc1ccc(-c2nccs2)cc1
Reactant: COC(=O)c1ccc(CCCN)s1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CCCNCc2ccc(-c3nccs3)cc2)s1

Procedure:
The title compound of Step A was prepared from 5-(3-amino-propyl)-thiophene-2-carboxylic acid methyl ester, of Preparation 5, and 4-thiazol-2-yl-benzaldehyde, of Preparation 25, using the method described in Example 1, Step A, except N,N-diisopropylethylamine was used in place of triethylamine. 1H NMR (400 MHz, CDCl3) δ 8.97-7.32 (m, 7H), 6.72 (d, 1H, J=4 Hz), 3.82 (s, 3H), 3.70 (s, 2H), 2.91 (t, 2H, J=7 Hz), 2.62 (t, 2H, J=7 Hz), 1.90 (m, 2H); MS 373 (M+1).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]=[N:17][N:18]3[C:23]=2[C:22]2[CH:24]=[CH:25][NH:26][C:21]=2[N:20]=[CH:19]3)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.CO>[C:15]1([CH:12]2[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]2)[N:16]=[N:17][N:18]2[C:23]=1[C:22]1[CH:24]=[CH:25][NH:26][C:21]=1[N:20]=[CH:19]2
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: OC1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Yield: 74.6 %

Procedure:
1-{4-[(tert-Butyldimethylsilyl)oxy]cyclohexyl}-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine (500 mg, 1.35 mmol) in a mixture of dichloromethane (5 mL) and methanol (5 mL) was stirred with pyridinium p-toluenesulfonate (338 mg, 1.35 mmol) at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→1/1 (v/v)-ethyl acetate) to give the title compound as a colorless solid (259 mg, yield 75%).
Reaction SMILES: [CH:1]12[CH:9]([CH2:10][C:11](Cl)=[O:12])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[NH2:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[CH2:26][CH3:27]>>[CH:1]12[CH:9]([CH2:10][C:11]([NH:14][N:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]3[CH2:26][CH3:27])=[O:12])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2
Reactant: CCc1nc2ccccc2c(=O)n1N
Reactant: O=C(Cl)CC1C2CCCC1CCC2
Product: CCc1nc2ccccc2c(=O)n1NC(=O)CC1C2CCCC1CCC2

Procedure:
The product from Example 56D and 3-amino-2-ethylquinazolin-4(3H)-one (Aldrich) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.5 Hz, 1 H) 1.40-1.59 (m, 4 H) 1.63-1.97 (m, 10 H) 1.99-2.09 (m, 1 H) 2.51-2.56 (m, 2 H) 2.56-2.67 (m, 1 H) 2.67-2.80 (m, 1 H) 7.53 (t, J=7.0 Hz, 1 H) 7.67 (d, J=7.8 Hz, 1 H) 7.80-7.89 (m, 1 H) 8.11 (dd, J=8.1, 1.4 Hz, 1 H) 10.95 (s, 1 H); MS (ESI+) m/z 354 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10]O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[BrH:12]>>[BrH:12].[Br:12][CH2:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2
Reactant: OCc1ccc2[nH]ncc2c1
Agent: Br
Product: BrCc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79 %

Procedure:
1H-indazole-5-ylmethanol (100 mg, 0.675 mmol) was added to a 48% aqueous hydrogen bromide solution (2.0 ml) at room temperature and stirred at room temperature for 15 hours and then at 50° C. for 5 hours. Subsequently, the reaction solution was filtered and the resulting solid was dried under reduced pressure to obtain 5-(bromomethyl)-1H-indazole hydrobromide (156 mg, 79%).
Reaction SMILES: CN1C=CN=C1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[CH3:12][O:13][CH2:14][CH2:15][OH:16].O>ClCCl>[CH3:7][S:8]([O:16][CH2:15][CH2:14][O:13][CH3:12])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COCCO
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: COCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
1-Methylimidazole (50 g) and methanesulfonyl chloride (66 g) were mixed in dichloromethane in a 500 mL two-bulb flask. After adding ethylene glycol monomethyl ether (42 g) dropwise at 10° C., the mixture was stirred at room temperature for 4 hours. After the reaction was completed, water was added. After stirring for 10 minutes, the solvent layer in which the product was dissolved was separated from the aqueous layer in which the byproduct was dissolved. The product was yielded by removing the solvent at room temperature using an evaporator (yield: 98%), and the byproduct 1-methylimidazolium chloride was recovered as 1-methylimidazole using 40 wt % NaOH aqueous solution and used again (yield: 95%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.Br[C:13]1[CH:14]=[CH:15][C:16]([O:19][C@H:20]2[CH:27]3[CH2:28][N:23]4[CH2:24][CH:25]([CH2:29][CH:21]2[CH2:22]4)[CH2:26]3)=[N:17][CH:18]=1.[NH:30]1[C:38]2[C:33](=[CH:34][C:35](B(O)O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.N>>[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C@H:20]4[CH:27]5[CH2:28][N:23]6[CH2:24][CH:25]([CH2:29][CH:21]4[CH2:22]6)[CH2:26]5)=[N:17][CH:18]=3)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1ccc(OC2C3CC4CC2CN(C4)C3)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Product: c1cc2cc(-c3ccc(OC4C5CC6CC4CN(C6)C5)nc3)ccc2[nH]1

Procedure:
Prepared from the product of Example 9F (45 mg, 0.14 mmol) and 5-indolylboronic acid (33 mg, 0.204 mmol; Maybridge) according to Method E: 1H NMR (300 MHz, CHCl3) δ ppm 1.76-1.86 (m, 2H), 2.26 (s, 2H), 2.39 (d, J=11.5 Hz, 2H), 3.26-3.44 (m, 5H), 5.37 (t, J=3.2 Hz, 1H), 6.61 (t, J=2.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 7.25-7.30 (m, 1H), 7.31-7.41 (m, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.86 (dd, J=8.5, 2.7 Hz, 1H) MS (DCI/NH3) m/z=346 (M+H)+; Anal. Calcd. for C22H22N3O.1.6H2O: C, 70.79; H, 6.80; N, 11.26. Found: C, 70.78; H, 6.44; N, 10.91.
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][N:11]2[C:15]([CH:16]=O)=[CH:14][N:13]=[CH:12]2)=[CH:8][CH:7]=1)#[N:5].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCOC(C)=O>ClC(Cl)C>[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][N:11]2[C:15]([CH2:16][NH:3][CH3:2])=[CH:14][N:13]=[CH:12]2)=[CH:8][CH:7]=1)#[N:5]
Reactant: CN
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CNCc1cncn1Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of methylamine hydrochloride in 5 mL dichloroethane at 0° C. are added 4 Å sieves (0.5 g), followed by 1 mmol of the aldehyde from Step E and 1.5 mmol Na(OAc)3BH. The reaction is stirred for 10 minutes at 0° C., warmed to room temperature and stirred for 2 hours. The reaction is poured into EtOAc/ sat. NaHCO3 solution. The organic layer is washed with brine, dried (Na2 SO4), filtered, and concentrated in vacuo. The crude product is taken up in 10 mL dichloromethane and 2 mL n-propylamine, stirred at room temperature for 1 hour, concentrated in vacuo , and purified by flash chromatography.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O)(=O)C>O>[N:22]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc2c1=O
Temperature: 140 °C

Procedure:
A mixture of 100 mg (0.314 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 0.274 ml (3.14 mmol) of morpholine is heated at 140° C. (oil bath temperature) for 1 hour in a closed vial. After cooling, the residue is dissolved in water, the solution acidified with 2 M acetic acid to pH ˜5 and allowed to stand at room temperature. An orange precipitate forms which is filtered and recrystallized from DMSO/water yielding 81 mg of the title compound as an orange powder, m.p. >260° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([Cl:16])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl[C:23]([O:25][CH2:26][CH2:27][Cl:28])=[O:24]>ClCCl>[Cl:28][CH2:27][CH2:26][O:25][C:23]([NH:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([Cl:16])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:24]
Reactant: Cc1cccc(N)c1CNc1cccn2c(Cl)c(C)nc12
Reactant: O=C(Cl)OCCCl
Solvent: ClCCl
Product: Cc1cccc(NC(=O)OCCCl)c1CNc1cccn2c(Cl)c(C)nc12

Procedure:
According to the procedure indicated in Example 1a, 8-(2-amino-6-methylbenzylamino)-3-chloro-2-methylimidazo[1,2-a]pyridine (0.27 g) and 2-chloroethyl chloroformate (0.18 g) in dichloromethane (30 ml) give the title compound as a brown oil, which is used directly for further reaction in 2b.