Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([OH:17])=O.[C:22]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([NH:31][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])=[O:17]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
A solution of N-(3,4-dichlorobenzyl)indole-2-carboxylic acid (0.23 g), benzenesulphonamide (129 mg), dimethylaminopyridine (0.22 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g) in dichloromethane was allowed to stir for 24 hours at room temperature. 2N HCl was added and the reaction stirred vigorously for 2 hours, then extracted with dichloromethane. Combined organic extracts were dried (MgSO4) and concentrated to yield the desired end product as a white crystalline solid (122 mg, 32%); NMR δ(CD3SOCD3) 5.65 (s, 2H), 6.73 (dd, 1H), 7.12 (m, 2H), 7.30 (t, 1H), 7.38 (d, 1H), 7.56 (m, 4H), 7.70 (m, 2H), 7.91 (d, 2H); M/z (−) 457 (M−H+).
Reaction SMILES: [C:1](N)(=[O:3])[CH3:2].C=O.O.[NH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11].C(NCC(O)=O)(=O)C>COCCOC>[C:1]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2]
Reactant: O=C(O)CNCC(=O)O
Reactant: CC(N)=O
Agent: C=O
Agent: CC(=O)NCC(=O)O
Solvent: O
Solvent: COCCOC
Product: CC(=O)N(CC(=O)O)CC(=O)O
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII) (11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72 mole), DME (90 mL), and CO2 (CO)8 (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345 kPa) CO:H2 (95:5) at 25° C. for 30 min. HPLC analysis of this stream gave an 89% yield of (XVI), 1% (XIV), and 8% (XVIII).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])=[CH:6][CH:5]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(CCBr)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(CCBr)cc1

Procedure:
A solution of [4-(2-bromoethyl)phenyl]acetic acid (48.6 g., 0.2 mole) and sulfuric acid (1.5 ml.) in ethanol (400 ml.) is boiled under reflux for 6 hours. About 300 ml. of the ethanol is removed by distillation at reduced pressure. The residue is diluted with 400 ml. of water. The oily ester is taken up in ether, washed with water and brine, and dried over magnesium sulfate. Evaporation of the ether leaves the title compound as an oil which can be purified by distillation in vacuo.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][CH2:8]2)[CH:2]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([CH3:41])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]2[CH2:51][CH2:52][CH2:53][S:54](Cl)(=[O:56])=[O:55])(=[O:44])=[O:43])=[C:37]([CH3:58])[CH:36]=1>C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH3:58])[C:38]([S:42]([N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]2[CH2:51][CH2:52][CH2:53][S:54]([N:13]2[CH2:12][CH2:11][C:10]3([CH2:9][CH2:8][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[CH2:15][CH2:14]2)(=[O:55])=[O:56])(=[O:44])=[O:43])=[C:39]([CH3:41])[CH:40]=1
Reactant: c1cncc(C2(OCCN3CCCC3)CCC3(CCNCC3)CC2)c1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCS(=O)(=O)N2CCC3(CC2)CCC(OCCN2CCCC2)(c2cccnc2)CC3)c(C)c1
Reaction time: 1 h
Yield: 47 %

Procedure:
9-(Pyridin-3-yl)-9-(2-(pyrrolidin-1-yl)ethoxy)-3-azaspiro[5.5]undecane (0.26 mmol, 1 eq) was dissolved in methylene chloride (3 ml) at 0° C., triethylamine (1.04 mmol, 4 eq) was added, and 3-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)propane-1-sulfonyl chloride (0.26 mmol, 1 eq), dissolved in methylene chloride (2 ml) was added to the mixture. After 1 h at room temperature, the mixture was diluted with methylene chloride (20 ml). The organic phase was washed with water (10 ml) and saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (1-5% methanol in methylene chloride). Yield: 47%. MS, Rt=3.6 min, m/z=731.5 [MH]+.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[Cl-].[NH4+:17]>CS(C)=O>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([NH2:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cccc2ccccc12
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1ccc([N+](=O)[O-])c2ccccc12
Reaction time: 1 h

Procedure:
3.5 g of 1-nitronaphthalene and 3.3 g of N,N-tetramethylenethiocarbamoylsulphenamide, dissolved in 15 ml of dimethyl sulphoxide, are added dropwise to a vigorously stirred suspension of 6 g of potassium hydroxide in 50 ml of dimethyl sulphoxide, the temperature being kept at 20° to 25° C. When the addition has ended the mixture is stirred for a further 60 minutes, poured into 400 ml of a saturated aqueous ammonium chloride solution and extracted with methylene chloride. After drying and removing the solvent, 4-nitro-1-naphthylamine is obtained with a melting point of 190° to 192° C. The yield is 2.9 g (77%). 1Nitro-2-napthylamine is additionally obtained in a yield of about 2%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH:13]([C:15]1[CH2:16][O:17][CH2:18][CH2:19][CH:20]=1)=O>C(O)C>[F:12][C:11]1[C:2]([NH:1][CH2:13][C:15]2[CH2:16][O:17][CH2:18][CH2:19][CH:20]=2)=[CH:3][C:4]2[O:8][C:7](=[O:9])[NH:6][C:5]=2[CH:10]=1
Reactant: Nc1cc2oc(=O)[nH]c2cc1F
Reactant: O=CC1=CCCOC1
Solvent: CCO
Product: O=c1[nH]c2cc(F)c(NCC3=CCCOC3)cc2o1
Yield: 27.9 %

Procedure:
To a solution of 6-amino-5-fluoro-benzoxazolin-2-one (0.97 g, 5.7 mmole) and 3-formyl-5,6-dihydro-2H-pyran (0.71 g, 6.3 mmole) in ethanol (40 ml) were added molecular sieves (4A, 1 g). The mixture was heated under reflux for 3 hours. Upon cooling, the reaction mixture was filtered and the filtrate was concentrated to yield a solid product, which was washed with ethanol. This product was dissolved in methanol (200 ml) and then sodium borohydride was added in portions at room temperature. Stirring was continued for hours. The reaction mixture was concentrated and water was added. The organic material was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was recrystallized from methanol to afford 420 mg of the title product (28%): m.p. 175°-176° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=[CH:9]2)[CH2:3][CH2:4][CH3:5].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=[CH:9]2)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1ccc2c(C(=O)OC)cccc2c1
Agent: O=C(O)c1cccc2ccccc12
Product: CCCC(O)c1ccc2c(C(=O)O)cccc2c1

Procedure:
In accordance with the procedure of Example 1, step 4, methyl 6-(1-hydroxybutyl)-1-naphthoate (14 mg, 0.05 mmol) was converted into 13 mg (98%) of 641-hydroxybutyl)-1-naphthoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:6]=1.CN(C=O)C.[C:24]1(OB(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].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.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.O.C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:5]2[CH:6]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:3]=[C:4]2[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:10]=1
Reactant: OB(O)Oc1ccccc1
Reactant: COC(=O)c1cc(Br)cn1Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)cn1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 36.7 %

Procedure:
To a mixture of methyl 4-bromo-1-(4-chlorobenzyl)-1H-pyrrole-2-carboxylate (0.72 g) and DMF (21 mL) were added phenylboric acid (0.30 g), sodium carbonate (0.58 g), water (3.0 mL), and tetrakis(triphenylphosphine) palladium (0.13 g), followed by stirring at 100° C. for 24 hours. To the reaction mixture were added ethyl acetate and water, and the insoluble materials were separated by filtration through Celite. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0 to 10%) to obtain methyl 1-(4-chlorobenzyl)-4-phenyl-1H-pyrrole-2-carboxylate (0.26 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[I-].[Na+]>COCCOC>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([CH:22]=[N:23][NH:24]5)=[CH:20][CH:19]=4)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]3)=[CH:7][C:6]=2[O:27][CH3:28])[CH2:32][CH2:31]1
Reactant: OC1CCNCC1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCC(O)CC1
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 505.8 mg (5.0 mmol) of 4-hydroxypiperidine and 75.0 mg (0.5 mmol) of sodium iodide in 5 mL of DME was heated at 135° C. for 16 hr. The work up gave 97.9 mg (42.8%) of the product as a off white solid, m.p. 174° C. (dec.), mass (electrospray, m/e): M+H 459.0.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(O)C>[C:6]1([C:4]2[C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[NH:19][CH2:16][CH2:17][N:18]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccccc1F
Reactant: NCCN
Solvent: CCO
Product: c1ccc(C2=NCCNc3ccccc32)cc1
Temperature: 180 °C

Procedure:
A 5 mL microwave tube was charged with 2-fluorobenzophenone (0.40 g), ethylene diamine (0.40 g) and ethanol (4 mL). The mixture was heated in a microwave at 180° C. for 10 minutes. The contents were concentrated to an oil and dissolved in methylene chloride. The resulting solution was purified by silica gel chromatography. Any unreacted benzophenone was eluted with methylene chloride and then the desired product was eluted with 70% ethyl acetate in hexanes. Desired fractions were concentrated to provide 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine as a yellow crystalline solid. H1 NMR (d6-dmso): 7.30-7.42 (m, 5H), 7.12 (dd, 1H), 6.78 (d, 1H), 6.75 (d, 1H), 6.49 (dd, 1H), 6.05 (br t, 1H), 3.84 (m, 2H), 3.56 (m, 2H).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].O>C1COCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C. and with cooling, 156.32 g (620 mmol) of tert-butyl diethylphosphonoacetate were added dropwise to a suspension of 23.71 g (593 mmol) of sodium hydride (60% in mineral oil) in 1.0 liters of THF. After the addition had ended, the mixture was stirred at 0° C. for 30 min and a solution of 100.0 g (539 mmol) of 4-chloro-3-nitrobenzaldehyde in 200 ml of THF was then added. The reaction mixture was heated at RT overnight, and water and ethyl acetate were then added. The organic phase was removed, dried with magnesium sulphate and concentrated under reduced pressure. The residue was recrystallized from isopropanol. Drying under high vacuum gave 144.0 g (94.2% of theory) of the target product.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]#[CH:20])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.C1(C)C=CC(S(O)(=O)=[O:30])=CC=1>COCCOC>[C:1]1([S:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[S:17][CH:18]=[C:19]([CH2:20][OH:30])[C:15]=3[CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C#CCSc1ccc(OS(=O)(=O)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: O=S(=O)(Oc1ccc2scc(CO)c2c1)c1ccccc1
Reaction time: 2 h
Yield: 187.8 %

Procedure:
The compound (3) (65.47 g, 183 mmol) obtained in above (2) was dissolved in 1,2-dimethoxyethane (1.6 L) and the solution was refluxed for 4 hours. To the solution were added water (64 ml) and p-toluenesulfonic acid monohydrate (19.2 g, 100 mmol) and refluxing was continued for 2 hours. The reaction mixture was concentrated under reduced pressure. After water (200 ml) was added to the resulting oil, the mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to provide 60.18 g of the title compound (4) as oil. Crude yield: 103%.
Reaction SMILES: [F:1][C:2]1([F:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([CH:13]([CH3:15])[CH3:14])[C:4](=[O:16])[CH2:3]1.[2H]C1([2H])C([2H])([2H])C2C(=CC=C(F)C=2)[C@H](C(C)C)[C@]1([CH2:36][C:37]([OH:39])=[O:38])O>>[F:17][C:2]1([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C@H:5]([CH:13]([CH3:15])[CH3:14])[C@:4]([CH2:36][C:37]([OH:39])=[O:38])([OH:16])[CH2:3]1
Reactant: CC(C)[C@@H]1C(=O)CC(F)(F)c2cc(F)ccc21
Reactant: [2H]C1([2H])c2cc(F)ccc2[C@H](C(C)C)[C@@](O)(CC(=O)O)C1([2H])[2H]
Product: CC(C)[C@H]1c2ccc(F)cc2C(F)(F)C[C@]1(O)CC(=O)O

Procedure:
Carboxylic acid 15c is prepared from 12b in a manner analogous to that of Example 1, step 2 for acid 15b.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]3[C:25]([C:26]([O:28]C)=O)=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:30]>CO>[C:26]([C:25]1[C:19]2[O:18][C:17]([CH:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:16][CH2:15]3)=[N:21][C:20]=2[CH:22]=[CH:23][CH:24]=1)(=[O:28])[NH2:30]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 37 %

Procedure:
Methyl 2-(1-(benzyloxycarbonyl)piperidin-4-yl)benzo[d]oxazole-7-carboxylate (560 mg, 1.4 mmol) was added to a solution of ammonium in methanol (10 mL) in a sealing tube and the mixture was stirred at room temperature for 2 days. The resulting mixture was evaporated and the crude product was purified by prep-HPLC to give benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate (200 mg, yield 37%). 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.94-1.98 (m, 2H), 2.18-2.22 (m, 2H), 3.06-3.12 (m, 2H), 3.20-3.23 (m, 1H), 4.26 (brs, 2H), 5.16 (s, 2H), 6.30 (s, 1H), 6.92 (s, 1H), 7.32-7.38 (m, 5H), 7.42-7.46 (t, J=8.0 Hz, 1H), 7.84-7.87 (dd, J1=8.0 Hz, J2=1.2 Hz, 1H), 8.06-8.08 (dd, J1=8.0 Hz, J2=1.2 Hz, 1H); LC-MS (ESI) m/z: 380 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[C:5]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][N:26]([CH3:54])[C:27](=[O:53])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)=[O:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:21]1[N:20]=[CH:19][C:18]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([NH:37][C:35](=[O:36])[NH:34][C:31]4[CH:30]=[CH:29][C:28]([C:27]([N:26]([CH3:54])[CH3:25])=[O:53])=[CH:33][CH:32]=4)=[CH:43][CH:42]=2)[N:11]=[C:10]3[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:23][CH:22]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Fc1ccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4cccc(-c5ccc(F)nc5)c4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-8-(6-fluoro-pyridin-3-yl)-4-morpholin-4-yl-quinazoline (70 mg, 0.000203 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido]-benzamide (100 mg, 0.0002436 mol), cesium carbonate (133 mg, 0.000406 mol), DMF (3.5 mL) and water (0.9 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (7 mg, 0.0000101 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 2% MeOH in chloroform) to yield the title compound as a light yellow solid [8 mg, 7%]. 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.95 (s, 1H), 8.60 (s, 1H), 8.43 (m, 1H), 8.28 (d, J=8.8 Hz, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.58 (m, 3H), 7.49 (m, 2H), 7.39 (m, 3H), 3.84 (s, 8H), 2.95 (s, 6H); LC-MS (ESI): Calculated mass: 591.2; Observed mass: 591.9 [M+H]+ (RT: 1.53 min).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.Br[C:20]1[C:21]([O:36][CH2:37][C:38]2[N:39]([CH2:43][CH3:44])[N:40]=[CH:41][N:42]=2)=[N:22][N:23]2[C:28]=1[CH:27]=[N:26][N:25]=[C:24]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35]>>[CH2:43]([N:39]1[C:38]([CH2:37][O:36][C:21]2[C:20]([C:6]3[O:7][CH:8]=[CH:9][CH:10]=3)=[C:28]3[N:23]([C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[N:25][N:26]=[CH:27]3)[N:22]=2)=[N:42][CH:41]=[N:40]1)[CH3:44]
Reactant: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccco1
Yield: 59 %

Procedure:
This was prepared in 59% yield using a similar procedure to that described in Example 53 except using 2-(tributylstannyl)furan instead of 2-(tributylstannyl)pyridine and 3-bromo-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazine instead of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-pyrazolo[1,5-d][1,2,4]triazine. Data for title compound: mp=182-183° C. (CH2Cl2-EtOAc); 1H NMR (360 MHz, CDCl3) δ 1.39 (3H, t, J=7.3 Hz), 4.17 (2H, q, J=7.3 Hz), 5.59 (2H, s), 6.51 (1H, m), 6.70 (1H, m), 7.28 (1H, m), 7.39 (1H, dt, J=7.6 and 0.9 Hz), 7.56 (1H, m), 7.65 (1H, m), 7.81 (1H, m), 7.90 (1H, s), 9.69 (1H, s); MS (ES+) m/e 406 [MH]+; Anal. Found C, 58.57; H, 4.08; N, 23.87%. C20H16FN7O2.0.3H2O requires C, 58.48; H, 4.07; N, 23.87%.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[S:14](Cl)(=[O:16])=[O:15]>C1COCC1>[C:1]([NH:5][S:14]([C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[F:6])(=[O:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(S(=O)(=O)Cl)c(F)c1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice cooled solution of tert-butylamine (12.55 ml) in THF (60 ml) was added a solution of 2-fluoro-4-methylbenzene-1-sulfonyl chloride (5 g) in THF (25 ml), dropwise. After stirring for 15 min at 0° C., the reaction mixture was allowed to warm and stirred at room temperature for 2 hours. The HCl salt was removed by filtration and the filtrate was concentrated to give a yellow residue, which was triturated with Et2O and Hexanes to give 5.10 g N-tert-butyl-2-fluoro-4-methylbenzenesulfonamide as an off-white granular solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=2)[CH:19]=1.[Li+].[OH-]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=2)[CH:19]=1
Reactant: CCOC(=O)c1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cn12
Temperature: 85 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
To stirred solution of (R)-ethyl 6-(2-(2,5-difluorophenyl)pyrrolidin 1-yl)imidazo[1,2-a]pyridine-3-carboxylate (4.5 g, 12.12 mmol) in Ethanol was added 1M LiOH (0.87 g, 36.3 mmol) solution and stirred for 5 h at 85° C. Solvent was removed under reduced pressure and residue was dissolved in water, extracted unwanted impurities with Diethyl ether and water layer was acidified with 2N HCl and solid was collected by filtration. Solid was dried under high vacuum to afford (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Int-14) as pale yellow solid (3.5 g, 84.1% yield), MS (ESI): m/z 344.2 (M+H).
Reaction SMILES: C(OC(=O)[NH:10][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)([CH3:13])[CH3:12])C1C=CC=CC=1.CCO>[Pd].O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([C:11]([NH2:10])([CH3:12])[CH3:13])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(C(C)(C)NC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COc1cccc(C(C)(C)N)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A flask was charged with [1-(3-methoxy-phenyl)-1-methyl-ethyl]-carbamic acid benzyl ester (D100) (1 g, 3.34 mmol, 1 equiv), 10% palladium on charcoal (50% wet, 100 mg, 10% w/w), NH4COOH (2.1 g, 33 mmol, 10 equiv), EtOH (40 ml) and H2O (8 ml). The resulting mixture was stirred at 80° C. for 2 h, cooled to room temperature and the catalyst was filtered off using a pad of celite. Most of the EtOH was removed in vacuo and the residue was diluted with 1N HCl aqueous solution. The aqueous phase was extracted with AcOEt then basified to pH 13 and extracted twice with AcOEt. These combined organic layers were dried over MgSO4 and concentrated in vacuo to yield 1-(3-methoxy-phenyl)-1-methyl-ethylamine (F15) (290 mg, 53%) as a yellow gum.