Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].C(OC[CH2:11][C:12]1[NH:13][C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[N:16]=1)C.[C:26]([N:45]1[C:49]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:56]2[CH:63]=[CH:62][C:59]([CH2:60]Br)=[CH:58][CH:57]=2)=[N:48][N:47]=[N:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)(=O)C>CN(C)C(=O)C.O>[CH2:2]([O:4][CH2:11][C:12]1[N:13]([CH2:60][C:59]2[CH:58]=[CH:57][C:56]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=3[C:49]3[N:45]([C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:46]=[N:47][N:48]=3)=[CH:63][CH:62]=2)[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]([C:17]([OH:20])([CH3:18])[CH3:19])[N:16]=1)[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
217 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 450 mg of ethyl 2-ethoxyethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [prepared as described in Preparation 44(iii)] in 5 ml of N,N-dimethylacetamide, and the mixture was stirred for 30 minutes. At the end of this time, a solution of 1.47 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 10 ml of N,N-dimethylacetamide was added dropwise to the mixture. The mixture was stirred at room temperature for 2 hours, after which it was mixed with ethyl acetate and water and shaken. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.2 g of the title compound as an amorphous powder.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2cccc([N+](=O)[O-])c2)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([Si]([C:11]#[C:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH2:38][CH:39]([OH:50])[CH2:40][NH:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=3)[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][C:21]([C:26]#[C:27][Si](C(C)C)(C(C)C)C(C)C)=[CH:20][CH:19]=3)(C(C)C)C(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C>C1COCC1.CCOC(C)=O>[C:26]([C:21]1[CH:20]=[CH:19][C:18]2[N:17]([CH2:38][CH:39]([OH:50])[CH2:40][NH:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[CH:43]=3)[C:16]3[C:24]([C:23]=2[CH:22]=1)=[CH:25][C:13]([C:12]#[CH:11])=[CH:14][CH:15]=3)#[CH:27]
Reactant: COc1cccc(NCC(O)Cn2c3ccc(C#C[Si](C(C)C)(C(C)C)C(C)C)cc3c3cc(C#C[Si](C(C)C)(C(C)C)C(C)C)ccc32)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#Cc1ccc2c(c1)c1cc(C#C)ccc1n2CC(O)CNc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 27 h
Yield: 71.9 %

Procedure:
The title compound of Example 100 was prepared as follows. To a solution of 1-(3,6-bis((triisopropylsilyl)ethynyl)-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (0.0152 g, 0.0215 mmol) in 200 μL anhydrous THF, a solution of TBAF in THF (1 M, 64.5 μL, 0.0645 mmol) and acetic acid (2.5 μL, 0.0430 mmol) were added. The mixture was sealed and stirred under N2 atmosphere at rt for 27 h until TLC showed the complete disappearance of starting material. The crude was diluted with 10 mL EtOAc and washed with saturated NaHCO3 (3×10) mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford white solid as product (0.0061 g, yield 71.9%).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][NH2:7].[OH-:8].[Na+].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:10]([NH:6][NH:7][C:10](=[O:8])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(C=Cc1ccccc1)NNC(=O)C=Cc1ccccc1
Reaction time: 2 h
Yield: 54.4 %

Procedure:
A solution of 9.5 g of hydrazine sulfate and 8.0 g of sodium hydroxide in 83 ml of water was stirred at 20° -30° C while cooled with ice. To the resulting solution were slowly added dropwise 25 g of cinnamoyl chloride and 7.5 g of sodium hydroxide in 20 ml of water. After completion of the addition, the mixture was stirred at 20° -30° C for 2 hours. The produced precipitate was collected by filtration and washed with water. The so obtained product was then recrystallized twice from acetic acid (first grade, prepared and sold by Wako Junyaku Kabushiki Kaisha, Japan, the same in the following) and dried under reduced pressure to yield 11.6 g of N,N'-biscinnamoylhydrazine as white needles, m.p. 267° - 268° C. Analysis: Calculated for C18H16N2O2 : C, 73.97%; H, 5.48%, N, 9.5%, Found: C, 74.17%; H, 5.55%; N, 9.69%.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:19])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:20]([O-])=O.[Na+].[CH3:24][C:25]1[CH2:26][C:27](=[O:43])[N:28]([C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[C:35]([CH3:40])([CH3:39])[CH2:34][C:33]3([CH3:42])[CH3:41])[N:29]=1.C(=O)(O)[O-].[Na+]>Cl>[OH:19][C:4]1[C:3]([NH:2][N:20]=[C:26]2[C:27](=[O:43])[N:28]([C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[C:35]([CH3:40])([CH3:39])[CH2:34][C:33]4([CH3:42])[CH3:41])[N:29]=[C:25]2[CH3:24])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1
Reactant: CC1=NN(c2ccc3c(c2)C(C)(C)CC3(C)C)C(=O)C1
Reactant: Cc1cc(N)c(O)c(-c2cccc(C(=O)O)c2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=NN(c2ccc3c(c2)C(C)(C)CC3(C)C)C(=O)C1=NNc1cc(C)cc(-c2cccc(C(=O)O)c2)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.1 %

Procedure:
3′-Amino-2′-hydroxy-5′-methyl-biphenyl-3-carboxylic acid hydrochloride 11f (155 mg, 0.56 mmol) was dissolved in 1.9 mL of hydrochloric acid (1 N) upon cooling by an ice-water bath, followed by dropwise addition of 1.2 mL of aqueous sodium nitrite (42 mg, 0.61 mmol). After the mixture was stirred for 20 minutes, 5-methyl-2-(1,1,3,3-tetramethyl-indan-5-yl)-2,4-dihydro-pyrazol-3-one 19d (135 mg, 0.5 mmol) was added. The mixture was adjusted to pH 8˜9 by batch addition of aqueous sodium bicarbonate (700 mg, 8.33 mmol). The generated bubbles were quenched with 2 mL of ethanol. The reaction mixture was warmed up to room temperature and reacted overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was dissolved in 30 mL of water. After mixing well, the mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid, filtered and dried. The crude product was purified by HPLC to obtain the title compound 2′-hydroxy-5′-methyl-3′-{N′-[3-methyl-5-oxo-1-(1,1,3,3-tetramethyl-indan-5-yl)-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-biphenyl-3-carboxylic acid 20 (50 mg, yield 19.1%) as a red solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([O:12]C(=O)C)=[CH:8][C:7]=1[O:16][CH:17]([CH3:19])[CH3:18].Cl>C1COCC1.CO.O>[CH3:3][O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[O:16][CH:17]([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc(OC(C)=O)cc1OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(O)cc1OC(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 115 %

Procedure:
0.1N NaOH (10 mL, 1 mmol) was added to a solution of 4-Acetoxy-2-isopropoxy-benzoic acid methyl ester (0.910 g, 3.6 mmol) in THF (1 mL) and MeOH (1 mL). Reaction was stirred for three days at room temperature. Reaction solution was concentrated by rotary evaporation and resulting residue was dissolved in water. The solution was neutralized with 1N HCl and a precipitate formed. Collected precipitate and washed with water and hexane. Obtained 0.870 g of 4-Hydroxy-2-isopropoxy-benzoic acid methyl ester in quantitative yield.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9]2)(=[O:3])[CH3:2].[Si:18](OS(C(F)(F)F)(=O)=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[Si:18]([O:3][C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9]2)=[CH2:2])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccc2cccc(C(C)=O)c2n1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2ccc(C(=O)OC)nc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of methyl 8-acetylquinoline-2-carboxylate (1.98 g, 8.64 mmol) in DCM (25 mL) at 0° C. was added TEA (1.56 mL, 11.23 mmol) followed by TBSOTf (1.66 mL, 9.50 mmol). The reaction mixture was stirred at 0° C. for 50 min. The mixture was then partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted with DCM (2×). The combined organic layers were then dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give methyl 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)quinoline-2-carboxylate as a brown oil: 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.12 (dd, J=7.3, 1.3 Hz, 1H), 7.80 (dd, J=8.1, 1.3 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 6.12 (s, 1H), 4.99 (s, 1H), 4.05 (s, 3H), 1.01 (s, 9H), 0.28 (s, 6H). m/z (ESI, +ve ion) 344.0 (M+H)+. This oil was taken up in THF (10 mL), treated with water (2.5 mL, 138 mmol) and NBS (1.61 g, 9.07 mmol), and stirred at RT for 20 min. The reaction mixture was then partitioned between water and Et2O, and the organic layer was separated and sequentially washed with saturated NaHCO3, water, and brine, then dried over MgSO4, filtered, and concentrated in vacuo to give methyl 8-(2-bromoacetyl)quinoline-2-carboxylate as a greenish-brown solid. This material was used without purification in the subsequent step assuming the theoretical yield: 1H NMR (400 MHz, CDCl3) δ ppm 8.40 (d, J=8.6 Hz, 1H), 8.30 (d, J=7.0 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.76 (t, J=7.6 Hz, 1H), 5.32 (br. s., 2H), 4.08 (s, 3H). m/z (ESI, +ve ion) 308.0/310.1 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]4[NH:21][C:20]([NH:22]C(=O)OC)=[N:19][C:16]4=[N:17][CH:18]=3)=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:28]1[C:37]2[CH2:36][CH2:35][C@H:34]([CH2:38][CH3:39])[CH2:33][C:32]=2[N:31]=[CH:30][N:29]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O.CO>[CH2:38]([C@@H:34]1[CH2:33][C:32]2[N:31]=[CH:30][N:29]=[C:28]([N:5]3[CH2:6][C:7]4[CH:12]=[C:11]([C:13]5[CH:14]=[C:15]6[NH:21][C:20]([NH2:22])=[N:19][C:16]6=[N:17][CH:18]=5)[CH:10]=[CH:9][C:8]=4[O:2][CH2:3][CH2:4]3)[C:37]=2[CH2:36][CH2:35]1)[CH3:39]
Reactant: COC(=O)Nc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2[nH]1
Reactant: CC[C@H]1CCc2c(Cl)ncnc2C1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc5nc(N)[nH]c5c4)cc3C2)C1
Temperature: 25 °C

Procedure:
A mixture of methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridin-2-yl]carbamate hydrochloride (84 mg, 0.23 mmol, (7S)-4-chloro-7-ethyl-5,6,7,8-tetrahydroquinazoline (reagent preparation 3) (35 mg, 0.18 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.90 mmol) in N-methyl-2-pyrrolidone (2.0 mL) was reacted in a microwave apparatus (250 W) for 5 min. at 110° C. After cooling to room temperature the reaction mixture was diluted with methanol (2 mL) and purified by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) to give 6-{4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-imidazo[4,5-b]pyridin-2-amine. 1H NMR (400 MHz, Methanol-d4): 8.33 (s, 1H), 8.13 (brs, 1H), 7.63 (s, 1H), 7.50 (brs, 1H), 7.31 (d, 1H), 7.04 (d, 1H), 4.75 (b, 2H), 4.44 (m, 1H), 4.24 (m, 1H), 3.99 to 3.86 (m, 2H), 2.94 to 2.86 (m, 2H), 2.60 (m, 1H), 2.28 (m, 1H), 1.97 (m, 1H), 1.75 (m, 1H), 1.36 (m, 2H), 1.14 (m, 1H), 0.97 (t, 3H); MS (EI) for C25H27N7O: 442 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[C:4](=O)[CH2:3]1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.C([BH3-])#N.[Na+]>CO.O>[CH3:1][C:2]1([CH3:12])[O:7][C:6]2[CH:8]=[CH:9][S:10][C:5]=2[CH:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:3]1
Reactant: CC1(C)CC(=O)c2sccc2O1
Reactant: C1CCNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)CC(N2CCCC2)c2sccc2O1
Reaction time: 24 h
Yield: 53.6 %

Procedure:
A solution of 5,6-dihydro-5,5-dimethylthieno[3,2-b]pyran-7-one (1.0 g, 5,5 mmol), pyrrolidine (2.3 ml, 27.4 mmol) sodium cyanoborohydride (0.345 g, 5,5 mmol) and 1N aqueous hydrochloric acid (5,5 ml, 5,5 mmol) in methanol (15 ml)-was stirred at rt for 1 day. Additional sodium cyanoborohydride (0.345 g, 5,5 mmol) was added and the solution was stirred an additional 1 day; additional sodium cyanoborohydride (1.0 g, 15.9 mmol) was added again and the mixture stirred 5 additional days. The mixture was poured into water (100 ml) and extracted with dichloromethane. The dichloromethane solution was washed with water and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by medium pressure chromatography using 2% methanol in dichloromethane as the eluant to give the product 0.70 g (54%) as a yellow solid; mp 49°-50° C.; IR(KBr): 2971, 1560 and 1394 cm-1 ; MS:m/z 238 (MH+); H NMR-(CDCl3): δ 1.27(s,3H), 1.45(s3H), 1.80(m,4H), 1.91(m,2H), 2.76(m,4H), 4.09(m,1H), 6.57(d,J=5.4 Hz,1H), and 7.04(d,J=5.4 Hz,1H).
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([C:8]2[S:12][CH:11]([NH2:13])[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][O:16][CH2:17][CH2:18][Br:19]>>[BrH:19].[F:14][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[S:12][C:11](=[NH:13])[N:10]([CH2:18][CH2:17][O:16][CH3:15])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC1NC=C(C2CCC(F)(F)CC2)S1
Reactant: COCCBr
Product: Br
Product: COCCn1cc(C2CCC(F)(F)CC2)sc1=N

Procedure:
A mixture of Example 184E and commercially available 2-bromoethyl methyl ether (Aldrich) was processed using the method described in Example 46A to afford the title compound. MS (ESI+) m/z 277 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:19]=[C:20]=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O:24]CC)C>>[CH2:11]([N:19]1[C:20](=[O:21])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:24])[S:10]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOCC
Reactant: S=C=NCc1ccccc1
Reactant: O=C=NCCc1ccccc1
Product: O=c1sn(CCc2ccccc2)c(=O)n1Cc1ccccc1

Procedure:
Reagents: Benzyl-isothiocyanate (6.5 mmol, 0.85 mL), phenethylisocyanate (6.5 mmol, 0.89 mL) and SO2Cl2 (6.5 mmol, 0.52 mL) in diethyl ether (25 mL). Isolation: solvent evaporation. Purification: silica gel column chromatography (AcOEt/hexane, 1:4).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[NH2:18][C:19]([NH2:21])=[O:20].Cl.O>C(O)C.C(OCC)(=O)C>[CH2:6]([C:7]1[CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:21]=[C:19]([OH:20])[N:18]=1)[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCC(=O)CC(=O)CCCCCC
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCc1cc(CCCCCC)nc(O)n1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
Pentadecane-7,9-dione (60.0 g, 250 mmol) and 30 g (500 mmol) of urea were dissolved in 3750 mL of ethanol, and under a nitrogen atmosphere, 75 mL of concentrated hydrochloric acid was added, and the mixture was gradually heated until reflux, and allowed to reflux for 18.5 hours. After cooling down to room temperature, water and ethyl acetate were added, the oil phase was extracted, and washed with a saturated sodium bicarbonate solution and saturated saline in this order, and dried over magnesium sulfate and concentrated. The resultant concentrate was purified by a silica gel column (hexane•ethyl acetate) to obtain 31.2 g of 4,6-dihexylpyrimidin-2-ol.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH:5]([OH:30])[CH2:6][NH:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:23])[C:12]=2[C:11]([NH:24][CH2:25][CH:26]([OH:29])[CH2:27]Cl)=[CH:10][CH:9]=1>CO>[O:29]1[CH2:27][CH:26]1[CH2:25][NH:24][C:11]1[C:12]2[C:13](=[O:23])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:22])[C:21]=2[C:8]([NH:7][CH2:6][CH:5]2[O:30][CH2:4]2)=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NCC(O)CCl)ccc(NCC(O)CCl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1c2ccccc2C(=O)c2c(NCC3CO3)ccc(NCC3CO3)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (3.5 g) was added to a solution of 1,4-bis-(3-chloro-2-hydroxypropylamino)-9, 10-anthracenedione (8.3 g, 19.8 mmoles), the compound of Example 1, in MeOH (500 mL) at 60° C. The resulting blue solution was stirred at room temperature for 4 hours, and the solvent was removed under reduced pressure. The residual solid was then purified by flash column chromatography (silica gel, CH2Cl2 : MeOH/25:1). Recrystallization from CH2Cl2 : hexanes yielded the title compound 1,4-bis-(2, 3-epoxypropylamino)-9, 10-anthracenedione which is compound 3 in Scheme 2 (6.2 g, 89.37%), mp 189°-190° C.: 1H NMR (CDCl3) δ2.74 (m, 1H, CH2), 2.87 (m, 1H, CH2), 3.26 (m, 1H, CH), 3.57 (m, 1H CH2), 3.78 (m, 1H, CH2), 7.32 (s, 2H, Ar (2,3)), 7.71 (dd, J=3.2 Hz, 5.5 Hz, 2H, Ar (6, 7)), 8.34 (dd, J=3.2 Hz, 5.5 Hz, 2H, Ar (5, 8)), 10.76 (s, 2H, NH). Anal. Calcd for C20H18O4N2 ×0.25 H2O: C, 67.66; H, 5.25; N, 7.93. Found: C, 67.72; H, 5.55; N, 7.54. IR: 3400, 3070, 2910, 1640, 1220, 900.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>CN(C=O)C.[Cl-].[Cl-].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+2]>[CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:21]=[CH2:22])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(COc1ccc(Br)cc1[N+](=O)[O-])OCC
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(OCP(=O)(OCC)OCC)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
A solution of 2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmole, prepared as in Example 31, Step A from 2-fluoro-5-bromonitrobenzene) in DMF (5 mL) was treated with tributyl(vinyl)tin (1.2 mmole) and palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was heated at 60° C. under nitrogen for 6 h. Evaporation and chromatography gave 2-diethylphosphonomethyloxy-5-vinylnitrobenzene as an oil which was subjected to Step B of Example 31, Step B of Example 29, and Step D of Example 27 to give 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (34.1). mp>167° C.(dec.). Anal. calcd. for C11H12N3O4PS2: C: 38.26; H: 3.50; N: 12.17. Found: C: 37.87; H: 3.47; N: 11.93.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][C:19]1[C:20](B(O)O)=[CH:21][S:22][CH:23]=1>>[CH3:18][C:19]1[C:20]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:21][S:22][CH:23]=1
Reactant: Cc1cscc1B(O)O
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Cc1cscc1-c1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-methyl-3-thiopheneboronic acid to give [1-(4-methyl-thiophen-3-yl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 307(MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:74][C:75]([F:79])([F:78])[CH2:76][NH2:77]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:77][CH2:76][C:75]([F:79])([F:78])[F:74])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: NCC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)NCC(F)(F)F
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 2,2,2-trifluoroethanamine (9.0 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2,2,2-trifluoroethanamine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2,2,2-trifluoroethyl)acetamide. (16 mg, 0.032 mmol, 23%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1([CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Mg]Br>C(OCC)C.C(=O)=O.CC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccccc1[Mg]Br
Agent: O=C=O
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cc1ccccc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 5 h
Yield: 112.6 %

Procedure:
N-Boc-4-piperidone (Boc-29.155) (200 mg, 11.0 mmol) was dissolved in 5 ml of anhydrous ethyl ether, cooled in dry ice/acetone bath. 2-Tolylmagnesium bromide (550 μl, 2M in ethyl ether, 1.1 mmol) was added dropwise over 5 min. White precipitate was formed. After 5 h, remove the dry ice/acetone bath and rise to room temperature gradually. After 2 h, cooled in ice bath, 8 ml of saturated NH4Cl and 2 ml of H2O were added. The organic phase was separated and aqueous phase was extracted with 4×10 ml of Et2O. Combined with organic phase and washed with 8 ml of H2O and 10 ml of brine, dried over MgSO4. Concentrated and dried to obtain 361 mg of colorless oil. Separated by silica gel to obtain 4f (229.7 mg, 79% yield) as colorless oil. 1H NMR (CDCl3, 200 MHz) δ 1.47 (s, 9H), 1.93 (m, 4H), 2.60 (s, 3H), 3.27 (t, 2H, J=13.0 Hz), 3.96 (d, 2H, J=12.2 Hz), 7.15 (m, 3H), 7.35 (m, 1H).