Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[Mg].II.[OH-:11].[Na+].C([O:15][CH2:16]C)C>>[CH3:5][C:4]([CH3:7])([CH3:6])[CH2:3][CH2:2][C:16]([OH:15])=[O:11]
Reactant: [OH-]
Reactant: CC(C)(C)CCCl
Reactant: CCOCC
Agent: II
Agent: [Mg]
Agent: [Na+]
Product: CC(C)(C)CCC(=O)O
Reaction time: 1 h

Procedure:
1-Chloro-3,3-dimethylbutane (log) was added dropwise to magnesium turnings (2 g) with an initiating amount of iodine crystals in dry diethyl ether (100 ml) and Grignard formation allowed to proceed to completion over 1 hour. The mixture was poured onto dry ice (50 g) very slowly and 0.5 N sodium hydroxide added and the basic aqueous layer provided extracted with diethyl ether (x2). The basic aqueous layer was acidified and extracted with diethyl ether which was dried over magnesium sulphate, filtered then evaporated under vacuum to yield 7.2 g of 4,4-dimethyl pentanoic acid.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:11])[NH:4][C:3]1=[O:12].C(O)(=O)C.CO>[Cl-].[Na+].O.[Zn]>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:4][C:3](=[O:12])[CH2:2][C:10]=12
Reactant: O=C1Nc2nccc(Cl)c2C1(Br)Br
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Cc2c(Cl)ccnc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A mixture of 3,3-dibromo-4-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (0.745 g, 2.3 mmol), zinc dust (1.49 g, 23 mmol), acetic acid (10 mL) and methanol (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was then diluted with brine and extracted with ethyl acetate. The organic layer was further washed with brine, dried over anhydrous sodium sulfate, concentrated and dried in a vacuum oven to give 0.3 g (78%) of 4-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a tan solid. 1H NMR (360 MHz, DMSO-d6) δ 11.21 (s, br, NH), 8.01 (d, J=5.66 Hz, 1H), 7.23 (d, J=5.66 Hz, 1H), and 3.59 (s, 2H, CH,). MS m/e 168 [M+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=O)[NH2:19])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:24](OC)([N:26](C)C)[CH3:25].O.[NH2:32]N.[OH-].[Na+]>O>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[NH:26][C:24]([CH3:25])=[N:32][N:19]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CC(N)=O)cc1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nnc(Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2)[nH]1
Temperature: 120 °C
Yield: 59 %

Procedure:
tert-Butyl-[2-(4-carbamoylmethyl-phenoxy)-ethyl]-carbamate (605 mg, 2.05 mmol) and N,N-dimethylacetamide dimethylacetal (5 ml) were combined and heated to about 120° C. for about ninety minutes. The orange solution was then allowed to cool to room temperature and was concentrated in vacuo. The resulting oil was then dissolved in acetic acid (6 ml), and hydrazine hydrate (0.20 ml, 4.10 mmol) was added to the solution. The mixture was heated to about 90° C. for about ninety minutes and was then poured into water and brought to pH 7 by adding 5M sodium hydroxide. The material was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (silica gel; chloroform to 4% methanol/chloroform) to afford 403 mg (59% yield) of the desired product. LRMS ([M+H]+)=333.2.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[C@@H:24]([OH:38])[C@H:23]3[OH:39])=[C:15]([NH:40][CH2:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:14]=2)[CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[CH2:31]([O:30][C:28](=[O:29])[NH:27][C@H:25]1[CH2:26][C@@H:22]([N:19]2[CH:18]=[N:17][C:16]3[C:20]2=[N:21][C:13]([N:10]2[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]2)=[N:14][C:15]=3[NH:40][CH2:41][CH:42]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:23]([OH:39])[C@@H:24]1[OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)OCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)OCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {(R)-1-[9-((1R,2S,3R,4S)-4-benzyloxycarbonylamino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Intermediate L5) (1.24 g, 1.7 mmol) in MeOH (3 ml) is treated with 4M HCl in dioxane (5 ml) and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% HCl). The fractions are collected and the MeCN is removed in vacuo. The remaining aqueous portion is basified with saturated sodium bicarbonate solution and extracted with DCM. The combined organic extracted are dried (MgSO4) and concentrated in vacuo to afford the title product. MS (ES+) m/e 649 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:17])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([Cl:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CC(=O)O)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)Cl)cc1OC

Procedure:
3,4-Dimethoxyphenylacetic acid (6.47 g, 0.033 mole) was dissolved in 50 ml of dry benzene and refluxed for 2 hr. with excess thionyl chloride (25 ml). The solvent and SOCl2 were removed on a rotary evaporator. Two additional quantities of dry benzene were added to the residue, followed by rotary evaporation which yielded 3,4-dimethoxyphenylacetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH2:6][O:7][CH3:8].Cl.O.C1C[O:23][CH2:22]C1>>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:22]1=[O:23])[CH2:6][O:7][CH3:8]
Reactant: C1CCOC1
Reactant: COCC(CC(=O)OC)Nc1ccccc1N
Agent: Cl
Solvent: O
Product: COCC(CC(=O)OC)n1c(=O)[nH]c2ccccc21
Reaction time: 16 h
Yield: 58 %

Procedure:
To a solution of 3-(2-Amino-phenylamino)-4-methoxy-butyric acid methyl ester (320 mg, 1.3 mmol) in THF (5.0 mL) is added CDT (440 mg, 2.7 mmol) at room temperature. The mixture is stirred at the same temperature for 16 hours. Then 5 mL of 1.0 M HCl solution is added along with 20 mL of water. The mixture is extracted with EtOAc (3×25 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography affords 205 mg (58%) of 4-Methoxy-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyric acid methyl ester.
Reaction SMILES: C[C:2]1[CH:13]=[CH:12][C:5]([CH2:6]OS(C)(=O)=O)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH3:17]N(C=O)C.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K].Cl>CCCCCC.C(OCC)(=O)C>[CH3:17][CH:6]([N:26]1[C:22](=[O:32])[C:23]2[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:25]1=[O:27])[C:5]1[CH:12]=[CH:13][CH:2]=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(COS(C)(=O)=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(c1cccc([N+](=O)[O-])c1)N1C(=O)c2ccccc2C1=O

Procedure:
Methanesulfonic acid 4-methyl-3-nitro-benzyl ester (0.45 g, 1.83 mmol) was added to anhydrous DMF (20 mL), under argon, and potassium phthalimide (0.34 g, 1.83 mmol) was added. The reaction mixture was heated to 60EC for 12 h. The reaction mixture was cooled and poured into 1N HCl and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (4:1 hexane/ethyl acetate) Yield 0.45 g. 1H NMR (CDCl3, 300 MHz): δ 2.58 (s, 3H), 4.88 (s, 2H), 7.30 (d, J=7 Hz, 1H), 7.57 (d, J=7 Hz, 1H), 7.24-7.77 (m, 2H), 7.84-7.89 (m, 2H), 8.02 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:24]1[C:25]2[CH:32]=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.N12CCN(CC1)CC2>CC#N>[N:27]1[CH:26]2[NH:30][CH:31]=[CH:32][CH:25]2[C:24]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[S:11])=[CH:3][C:2]=2[F:1])=[N:29][CH:28]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(OC2=NC=NC3NC=CC23)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16 %

Procedure:
To a mixture 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (24 mg, 0.075 mmol, Compound A of Example 3), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (11 mg, 0.075 mmol, commercially available) and 1,4-diazabicyclo[2.2.2]octane (DABCO, 8.4 mg, 0.075 mmol) was added MeCN (2 mL). The reaction was stirred at RT for 4 h and concentrated in vacuo. The residue was purified reverse phase preparative HPLC to give the title compound (5.3 mg, 16%) as a white solid. 1H NMR (CDCl3) δ 12.46 (s, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 7.95 (dd, 1H, J=11.6, 2.8 Hz), 7.43 (m, 1H), 7.34 (m, 1H), 7.29 (m, 4H), 7.13 (app. T, 2H, J=8.6 Hz), 6.80 (s, 1H), 3.72 (s, 2H); MS(ESI+) m/z 440 (M+H)+.
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(N(CC)CC)C.[CH:25]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:29]=1[O:30][C:31](Cl)=[O:32])([CH3:27])[CH3:26]>ClCCl.CN(C1C=CN=CC=1)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:25]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:29]=1[O:30][C:31]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:32])([CH3:27])[CH3:26]
Reactant: O=C(OCc1ccccc1)c1ccccc1O
Reactant: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Oc1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57 %

Procedure:
To a cooled (0° C.) solution of benzyl salicylate (0.77 g, 3.3 mmol) in dichloromethane (6 mL) was added triethylamine (0.52 mL, 3.7 mmol) and a catalytic amount of DMAP. To this mixture a suspension of compound (104) (0.9 g, 3.7 mmol, crude product from last step) in dichloromethane (4 mL) was further added. The reaction was allowed to warm to room temperature slowly and stirred for 14 h. The reaction mixture was then diluted with 10% aqueous citric acid solution (10 mL) and extracted with ethyl ether (2×40 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by radial chromatography on silica gel (eluting with ethyl acetate/hexane) to afford 0.8 g (57% yield over two steps) of the title compound (105).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=S)[C:5]=3[CH:19]=[CH:20][CH:21]=2.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1.C(O)C>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[N:30][CH2:29][CH2:28][CH2:27][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)[C:5]=3[CH:19]=[CH:20][CH:21]=2
Reactant: NCCCn1ccnc1
Reactant: S=C1c2cccc3c(Cl)ccc(c23)N1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCO
Product: Clc1ccc2c3c(cccc13)C(=NCCCn1ccnc1)N2Cc1ccccc1
Yield: 64.8 %

Procedure:
A mixture of 3.1 g of 6-chloro-1-(phenylmethyl)benz[cd]indole-2(1H)-thione (Cr), 1.4 g of 1H-imidazole-1-propanamine, 250 ml of ethanol, 75 ml of dimethylformamide, and 3.5 g of mercuric acetate is reacted as described in Example 3, giving 2.6 g of the desired product, mp 147°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:32])[CH:24]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 83.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), m-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.057 g (83%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:8][C:7]1[C:2]([NH:14][NH2:15])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: NN
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Solvent: CCO
Solvent: O
Product: NNc1ncc(C(F)(F)F)cc1Cl
Yield: 70.9 %

Procedure:
A reaction flask was loaded with 2,3-dichloro-5-(trifluoromethyl)pyridine (10.8 g) and ethanol (25 ml), followed by dropwise addition of hydrazine monohydrate (3 g) to the flask in 5 minutes with stirring. The resultant mixture was heated and stirred at 40 to 60° C. for 2.5 hours. Thereafter, the heating was stopped, and the reaction mixture was left to cool. The precipitated white crystals were filtrated for collection and dried to give 3-chloro-2-hydrazino-5-(trifluoromethyl)-pyridine (7.5 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:17]=[C:11]2[C:12](=[O:16])[NH:13][CH2:14][CH2:15][N:10]2[N:9]=1)=[O:7])[CH3:4].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.O>[CH2:3]([O:5][C:6]([C:8]1[CH:17]=[C:11]2[C:12](=[O:16])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:15][N:10]2[N:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2n(n1)CCNC2=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2n(n1)CCN(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (0.16 g, 4.0 mmol) was added to a stirred solution of 4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.7 g, 3.35 mmol) in DMF (14 mL) at 0° C. The mixture was stirred at room temperature for 1 hour and then benzyl bromide (0.48 mL, 4.0 mmol) was added. The mixture was stirred at room temperature for 16 hours, diluted with H2O and extracted with DCM. The organic layer was separated, washed with brine, dried (NaSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield 4,5,6,7-tetrahydro-4-oxo-5-(phenylmethyl)-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.83 g, 83% yield) as a white oil. C16H17N3O3 LCMS: Rt 1.79, m/z 300 [M+H]+ (see LCMS Method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[N:5]2.[H-].[Na+].CI.[CH3:31]N(C)C=O>O>[CH3:31][N:12]([C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=1)[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]1[CH:6]=[N:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: CCOC(=O)C(C)Oc1cccc(Nc2cnc3cc(Cl)ccc3n2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)C(C)Oc1cccc(N(C)c2cnc3cc(Cl)ccc3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 2-{3-[N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate (10 mmole), sodium hydride (10 mmole), methyl iodide (50 mmole) and dimethylformamide (50 ml) was stirred at room temperature for a period of 3 hours. Water was added to the reaction mixture and the precipitated product was collected by filtration. The product was purified by chromatography over alumina (eluent dichloromethane) to give ethyl 2-{3-[N-methyl-N-(6-chloroquinoxalin-2-yl)amino]phenoxy}propionate as an oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](Cl)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[N:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([O:26][C:27]4[CH:28]=[C:29]5[C:33](=[N:34][CH:35]=4)[NH:32][CH:31]=[CH:30]5)=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:24][CH3:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-6-methoxyquinazoline (224 mg, 0.61 mmol), (prepared as described for the starting material in Example 28), 5-hydroxy-7-azaindole (91 mg, 0.68 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (94 mg, 0.68 mmol) in DMA (5 ml) was stirred at 85° C. for 2 hours, allowed to cool to ambient temperature and the solvent evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (95/5) to give a white solid. This was triturated with acetone, filtered and dried to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline (227 mg, 80%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: CN1CCN(c2c(C=O)c3ccccc3n2-c2ccc(C(C)(C)C)cc2)CC1

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with 1-methyl piperazine as described in Step 2 of Example 29 to afford 1-(4-tert-butylphenyl)-2-(4-methyl-piperazin-1-yl)-1H-indole-3-carboxaldehyde as a light brown solid. TLC (silica gel, ethyl acetate-16.5% methanol-0.8% 7N methanolic ammonia); Rf 0.23; ESI/MS 376 (M+H), RT 3.4 min; NMR 10.14 (1H, s); 8.12 (1H, d, J=9 Hz); 7.67 (2H, d); 7.45 (2H, d); 7.19 (2H, m); 6.92 (1H, d, J=6 Hz); 3.26 (4H, m); 2.18 (7H, m); 1.37 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=3)[CH:8]=2)[N:3]=1.C([NH2:28])(=O)C.C([O-])([O-])=O.[K+].[K+]>>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH:22]([CH3:23])[CH3:24])[N:13]=[C:12]([C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[N:3]=[C:2]([NH2:28])[CH:11]=[CH:10]4)[C:20]=12
Reactant: CC(N)=O
Reactant: CC(C)n1nc(-c2ccc3nc(Cl)ccc3c2)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)n1nc(-c2ccc3nc(N)ccc3c2)c2c(N)ncnc21
Temperature: 200 °C
Yield: 45.9 %

Procedure:
3-(2-chloroquinolin-6-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA130, 50 mg, 0.15 mmol), acetamide (174 mg, 3.0 mmol) and K2CO3 (104 mg, 0.75 mmol) were combined and heated to 200° C. under an argon atmosphere for one hour. Reaction was cooled, then extracted with H2O and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA146 (22 mg, 46% yield). ESI-MS (M+H)+ m/z calcd 320.2, found 320.4.
Reaction SMILES: O1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11](=[O:21])[CH2:12][NH:13]C(=O)OC(C)(C)C)=[C:4]2C=C1.[ClH:22].[O:23]1CCO[CH2:25][CH2:24]1>C(O)C>[ClH:22].[NH2:13][CH2:12][C:11]([NH:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:25]=[CH:24][O:23][C:4]=12)=[O:21]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccnc2occc12
Agent: Cl
Solvent: CCO
Product: NCC(=O)Nc1ccnc2ccoc12
Temperature: 25 °C

Procedure:
Tert-Butyl 2-(furo[2,3-b]pyridin-4-ylamino)-2-oxoethylcarbamate (350 mg, 1.2 mmol) was placed in ethanol (96%) (3.0 ml) and hydrogen chloride in dioxane (5.0 ml, 20.00 mmol) was added after which the resulting mixture was stirred at room temperature over night. The solids were filtered off, washed subsequently with EtOH and diethylether and dried in a stream of air. 230 mg of a white powder was obtained (1.01 mmol, 84%). MS (ESI) m/z=191.9 [M+1]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:10](=O)([O-])[O-].[Na+].[Na+].O.CCO[CH2:20][CH3:21]>>[CH2:1]([N:3]([CH2:10][C:20]#[CH:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccccc1
Reactant: CCOCC
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C#CCN(CC)c1ccccc1
Reaction time: 40 h
Yield: 56 %

Procedure:
The procedure follows that of (Reppe and Mitarbeiter, Annalen der Chemie, 596:38-75 (1955)). Ethylaniline (37.1 g, 0.300 Moles) and Benzenesunfonylchloride (60.7 g, 0.300 Moles); are combined in a 500 mL Erlenmeyer flask. To this is added 125 mL of 13% Sodium Carbonate and 100 mL of water and the mixture stirred for 40 hours. The mixture was extracted with ether, dried and 97 mL Acetic anhydride added, the ether evaporated, thinned with benzene and finally extracted with 3:1 Hydrochloric acid. The acidic solution was back extracted with about 30 mL of benzene before being neutralized with Sodium Carbonate, let settle overnight and finally steam distilled. The distillate was extracted with ether and the ether evaporated to 26.8 g (56% yield) of pale yellow liquid IR (neat) 3291, 3062, 3027, 2972, 2931, 2113, 1600, 1505, 1457, 1377, 1348, 1275, 1244, 1185, 1127, 1039, 1009, 750, 692, 651 cm-1 ; 1H NMR (CDCl3) δ1.27 (t, J=7.3) 2.23 (t, J=2.5, 1), 3.49 (q, J=7.2), 4.06 (d, J=2.5), 6.89 (m, 3), 7.29 (m, 2); 13C NMR (CDCl3)2 δ12.9 (--CH3), 40.1 (N--CH2 --), 46.0 (N--CH2 --), 72.1 (yneC-), 80.8 (yneC), 114.4 (arom), 118.2 (arom), 129.6 (arom), 148.3 (arom).