Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][CH2:28]C)=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:32](N)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][NH:26][CH:27]([CH3:28])[CH3:32])=[CH:23][CH:24]=3)=[CH:30][CH:31]=2)=[CH:6][CH:7]=1
Reactant: CCCNCc1ccc(CNCCOc2ccc(C#Cc3ccc(Cl)cc3)cc2)cc1
Reactant: CC(C)N
Product: CC(C)NCc1ccc(CNCCOc2ccc(C#Cc3ccc(Cl)cc3)cc2)cc1

Procedure:
Compound 4 was synthesized using the procedure described for Compound 2 except that isopropylamine was used in the last reductive amination step. Compound 4 was obtained as a yellow gum. MS 433; 1H NMR (CDCl3) δ 4.10 (t, 2H), 3.86 (d, 2H, becomes singlet with D2O exchange), 2.80 (m, 1H), 1.09 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](=[CH2:27])[CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:28])[CH:11]=2)[CH:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16](=[CH2:27])[CH2:17][CH2:18][NH2:19])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:28])[CH:11]=2)[CH:6]=1
Reactant: C=C(CCNC(=O)OC(C)(C)C)c1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(CCN)c1c(C)c(CC(=O)OC)cc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
To a solution of [4-(3-tert-butoxycarbonylamino-1-methylene-propyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.79 g, 2.0 mmol) in methylene chloride (28.5 mL) was added trifluoroacetic acid (7.5 mL, 98 mmol). The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum and the resulting brown residue was dissolved in toluene. The solvent was again removed under vacuum, then dissolved in methylene chloride (−5 mL) with heating. The mixture was diluted with hexanes (˜10 mL). As a result, some oil precipitated. The mixture was diluted with dichloromethane and the dark brown solution was stored in the refrigerator for 15 hours; however, further precipitation of the product was not successful. The solvent was removed and the crude mixture (1.1 g) was purified using flash chromatography (80 g ISCO column, 0-100% methylene chloride in hexanes followed by 0-20% methanol in methylene chloride) to afford [4-(3-amino-1-methylene-propyl)-6-fluoro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (0.502 g, 75%) as a white, amorphous, and hygroscopic solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.64-7.71 (m, 1H), 7.55-7.59 (m, 1H), 7.32-7.38 (m, 1H), 7.16 (td, J=8.5, 2.3 Hz, 1H), 5.53 (s, 1H), 5.09 (s, 1H), 3.77-3.81 (m, 2H), 3.67-3.71 (m, 4H), 2.99 (d, J=6.0 Hz, 2H), 2.65 (t, J=7.4 Hz, 2H), 2.28 (s, 4H).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[O:9][N:10]=[C:11]([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:21]([N:14]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[O:9][N:10]=[C:11]([CH3:13])[CH3:12])(=[O:23])[CH3:22]
Reactant: CC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N(C(=NC1CCCCC1)ON=C(C)C)C1CCCCC1
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 1,3-dicyclohexyl-O—(N-isopropylideneamino)-isourea (Cmpd. 3) (16.7 g, 60 mmol) and 4-dimethylaminopyridine (180 mg) in pyridine (40 ml) is added acetic anhydride (8.9 ml, 90 mmol). The mixture is stirred 2 h and then evaporated under reduced pressure. The residue is diluted with hexane (150 ml), washed with water (5×20 ml), dried over MgSO4 and evaporated. The solid residue is recrystallized from hexane to afford 13.3 g of the title compound as white crystals, mp 74-78° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.I[CH2:12][CH:13]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>C1COCC1>[CH2:22]([CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: c1ccsc1
Reactant: CCCCCCCCC(CI)CCCCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCC(CCCCCC)Cc1cccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A solution of thiophene (46.4 g, 551 mmol., 2.50 equiv.) and THF (300 mL) was cooled to −78° C. n-Butyllithium (2.5 M in hexanes, 212 mL, 528 mmol., 2.40 equiv.) was added over 1 hour. The mixture was stirred for an additional 30 minutes at −78° C. before a solution of 1-iodo-2-hexyldecane (90.0 g, 220 mmol., 1.00 equiv) in THF (200 mL) was added slowly over 1 hour. After stirring for 1 hour at −78° C., the reaction mixture was warmed to ambient temperature and stirred for 18 hours. Water (200 mL) was added and the organic material was extracted with Et2O (3×250 mL), washed with additional water, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting brown residue was purified by silica gel column chromatography (hexanes) to give a pale yellow oil (52.03 g, 77% yield). 1H NMR (500 MHz, CDCl3) δ 7.12 (dd, J=5.2, 1.2 Hz, 1H), 6.92 (m, 1H), 6.76 (dd, J=3.4, 0.9 Hz, 1H), 2.76 (d, J=6.7, 2H), 1.62 (b, 1H), 1.33-1.21 (m, 24H), 0.91-0.87 (m, 6H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OCC)(=O)C>C1COCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)OCC
Yield: 92.8 %

Procedure:
Diethyl malonate (31.15 g, 194.48 mmoles) was first transferred at 0° C. to a stirring suspension of sodium hydride (4.67 g, 194.58 mmoles) in dry THF (200 mL). To this resulting mixture, was added dropwise (at 0° C.) a solution of t-butyl bromoacetate (23.00 g, 117.91 mmoles). Formation of a white precipitate was instantly observed. The mixture was then stirred at room temperature until complete consumption of the starting material (1.5 hours as confirmed by TLC: 20% ethyl acetate: 80% hexanes). The solvent was then evaporated and the residue was taken-up in 500 mL diethyl ether. This organic phase was washed with water (3×300 mL) and washed once with brine (200 mL) before being dried (anhydrous MgSO4) and evaporated. The obtained residue was first purified by distillation to remove excess malonate and then by flash chromatography (SiO2, 15% ethyl acetate: 85% hexanes) to afford 30.00 g (92.8% yield) of the desired compound as an oil: IR (film) 2982, 1733, 1258, 1152, 1037 cm−1; 13C NMR (CDCl3, 100 MHz) 169.5, 168.1, 80.8, 61.2, 47.7, 33.9, 27.6.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]([C:64](=[O:88])[C@@H:65]([NH2:87])[CH2:66][CH2:67][CH2:68][O:69][Si:70]([C:83]([CH3:86])([CH3:85])[CH3:84])([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:60][CH2:59]1)=[O:57])[CH2:52][CH2:53][CH3:54]>CN(C=O)C.C(Cl)CCl>[CH2:51]([O:55][C:56]([N:58]1[CH2:59][CH2:60][N:61]([C:64](=[O:88])[C@@H:65]([NH:87][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=2)=[O:28])[CH2:66][CH2:67][CH2:68][O:69][Si:70]([C:83]([CH3:86])([CH3:85])[CH3:84])([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:62][CH2:63]1)=[O:57])[CH2:52][CH2:53][CH3:54]
Reactant: Cc1ccc2c(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 385 mg 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 10 ml DMF were added 215 mg HOBt, 270 mg EDC and 0.4 ml DIPEA. After 20 minutes 506 mg 4-[(S)-2-Amino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoyl]-piperazine-1-carboxylic acid butyl ester hydrochloride were added and the mixture stirred for 12 h. The reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product thus obtained was pure enough for the following transformation. Yield: 850 mg.
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].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][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])=[CH:26][CH:25]=1
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: COc1ccc(CNc2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1
Yield: 60 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 4-methoxy-benzylamine according to the GPA affording 24.7 mg (60%) of a red powder. Rt=4.97 min.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[O:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[NH:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].Cl>N1C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[O:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:13]([S:34]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=2)(=[O:36])=[O:35])[CH2:12]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CNC(c2ccc(Cl)c(Cl)c2)O1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2C[C@@H](CCO[Si](C)(C)C(C)(C)C)OC2c2ccc(Cl)c(Cl)c2)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
1.00 g (2.72 mmole) of 2-[(5R)-(3,4-dichlorophenyl)oxazolidin-5-yl]ethanol t-butyldimethylsilyl ether [prepared as described in the first part of Example 1(f)] was dissolved in 10 ml of pyridine, and 773 mg (3.27 mmole) of 3,4-dimethoxybenzenesulfonyl chloride were added to the resulting solution, whilst ice-cooling. The mixture was then stirred for 2 hours under a nitrogen atmosphere. At the end of this time, the reaction mixture was poured into 100 ml of ice-cooled 10% w/v aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 10:1 to 2:1 by volume as the eluent, to give 1.27 g of the title compound as white crystals.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2cc(C(C)=O)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)c1cc2ccc(C(=O)O)cc2o1
Reaction time: 8 h
Yield: 93124.7 %

Procedure:
Methyl 2-acetyl-1-benzofuran-6-carboxylate (155 mg, 0.71 mmol) is dissolved in MeOH (3 ml) and H2O (0.5 ml). 2N NaOH (0.39 ml, 0.78 mmol) is added drop-wise, and the reaction is stirred overnight. The volatiles are removed in vacuo, and the residue is dissolved in H2O (3 ml). Concentrated HCl is used to adjust the pH to 3, and the resulting precipitate is isolated via filtration and dried overnight to afford 135 g (93%) of 2-acetyl-1-benzofuran-6-carboxylic acid as a yellow solid. MS for C11H8O4, (ESI−) m/z: 202.7 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:65][C:66]([CH3:70])([CH3:69])[CH2:67][NH2:68]>C(Cl)Cl>[OH:65][C:66]([CH3:70])([CH3:69])[CH2:67][NH:68][C:28]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]1)=[O:30]
Reactant: CC(C)(O)CN
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC(C)(C)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.14 mmol) in methylene chloride (10 mL), HATU (Aldrich, 105 mg, 0.28 mmol) was added followed by the addition of DIPEA (0.34 mmol) and 2-hydroxy-2-methyl-propylamine (Matrix, 25 mg, 028 mmol). The mixture was stirred at rt 1 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 35-50% EtOAc/hexanes) to give a white solid. 50 mg.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:9])[CH3:8].C([Li])CCC.[Cl:15][CH:16]([C:20]1[O:25][C:24](=[O:26])[C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([F:34])([F:33])[F:32])[C:22]=2[N:21]=1)[CH:17]([CH3:19])[CH3:18]>CCCCCC.O1CCCC1>[Cl:15][CH:16]([CH:17]([CH3:19])[CH3:18])[C:20]([NH:21][C:22]1[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](=[O:26])[CH2:8][C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:9])=[O:25]
Reactant: CC(C)C(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Reactant: CC(=O)Nc1nccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 82.6 %

Procedure:
10.6 g of N-(2-thiazolyl)-acetamide, 325 ml of tetrahydrofuran and 106 ml of n-butyllithium in hexane titrating 1.4M and 11.4 g of 2-(1-chloro-2-methylpropyl)-8-(trifluoromethyl)-4H-3,1-benzoxazin-4-one of Step A in solution in 80 ml of tetrahydrofuran were reacted by the procedure of Step A of Example 6 of Belgian Pat. No. 896,941 to obtain 13.8 g of 2-[(2-chloro-1-oxo-3-methylbutyl)-amino]-β-oxo-N-(2-thiazolyl)-3-(trifluoromethyl)-benzene propanamide melting at 186° C.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Na]>C(O)(=O)C>[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [Na]
Solvent: CC(=O)O
Product: Cc1cccc(C2=CCNc3c(C(N)=O)cnn32)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
7-[3-Methylphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamine (prepared as described in Example 1) is stirred as a suspension in gacial acetic acid (cooled in an ice bath) under nitrogen and then excess sodium cyanoborohydide is added to the reaction mixture in portions. After one hour of stirring in the ice bath, the mixture is stirred at room temperature for 19 hours. This solution is evaporated to dryness, then water is added and the white precipitate which forms is collected by filtration and washed with an aqueous saturated solution of sodium bicarbonate, and finally with water. The solid is collected by filteration and dried to give 4,5-dihydro-7-(3-methylphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][C:13]2=[O:16])=[CH:8][CH:7]=1.BrBr.C(OCC)(=O)C>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:15]2[C:14]3[C:13](=[O:16])[NH:12][CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1nc2ccc3c(c2s1)C(=O)NCC3
Temperature: -10 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Potassium thiocyanate (8.62 g, 0.088 mol) was added to a stirred solution of 7-amino-3,4-dihydroisoquinolin-1(2H)-one (I-66a: 1.8 g, 0.01 mol) in acetic acid (60 mL) at −10° C. and this was followed by the addition of bromine (5.33 g, 0.033 mol). The resulting reaction mass was stirred at −10° C. for 3 hours and further at room temperature overnight. The reaction was monitored by TLC (100% ethyl acetate). The reaction mass was diluted with ice water and filtered. The resulting mixture was basified at 0° C. using KOH solution to pH 10 and extracted using ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 1.4 g of the product (58.33% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][CH3:13])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:38]1[N:46]2[C:41]([C:42]3([CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[O:43][C:44]3[CH:50]=[C:49]([C:51]([O:53][CH3:54])=[O:52])[CH:48]=[CH:47][C:45]=32)=[CH:40][CH:39]=1.CCN(CC)CC>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:57]2[CH2:58][CH2:59][C:42]3([O:43][C:44]4[CH:50]=[C:49]([C:51]([O:53][CH3:54])=[O:52])[CH:48]=[CH:47][C:45]=4[N:46]4[CH:38]=[CH:39][CH:40]=[C:41]34)[CH2:55][CH2:56]2)=[O:9])=[CH:5][C:4]=1[O:12][CH3:13])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Reactant: CCc1ccc(C(=O)O)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)OC)ccc2-n2cccc23)cc1OC
Yield: 95.5 %

Procedure:
A solution of 4-ethyl-3-methoxy-benzoic acid (450 mg, 2.5 mmol), HATU (940 mg, 2.5 mmol), methyl spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-7′-carboxylate (830 mg, 2.5 mmol), and Et3N (1.7 mL, 9.9 mmol) in DMF (8 mL) was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organics were dried over sodium sulfate, filtered and evaporated to yield a crude mixture that was purified by silica gel chromatography eluting with 0-30% EtOAc in hexanes to yield methyl 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylate (1.1 g, quant). ESI-MS m/z calc. 460.5, found 461.5 (M+1)+; Retention time: 2.08 minutes (3 min run).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:16]3[N:15]=[C:14]([S:23][CH3:24])[C:13]=2[C:25]#[N:26])[CH2:10][CH2:9]1.N1CCCCC1>C(O)C.O>[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[C:7]4[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]4)=[C:16]3[N:15]=[C:14]([S:23][CH3:24])[C:13]=2[C:25]#[N:26])[CH2:9][CH2:10]1
Reactant: O=C1CNC(=O)N1
Reactant: CSc1nc2c(C=O)cnn2c(NC2CC2)c1C#N
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: CSc1nc2c(C=C3NC(=O)NC3=O)cnn2c(NC2CC2)c1C#N
Temperature: 80 °C
Reaction time: 10 h
Yield: 83.7 %

Procedure:
Hydantoin (366 mg, 3.7 mmol) and 7-(cyclopropylamino)-3-formyl-5-(methylthio)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (1 g, 3.7 mmol) were dissolved in ethanol (18.5 mL) along with piperidine (3.7 mL, 3.7 mmol). The reaction was heated at 80° C. After 10 hours, the reaction was cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was dried in vacuo to give the intermediate, 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-5-(methylthio)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (1.1 g, 83% yield). LCMS (M+1=356)
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]CC)=[O:15])[CH:12]=2)[N:7]([CH3:19])[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[N:7]([CH3:19])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C)c2ccc(C(=O)OCC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1cn(C)c2ccc(C(=O)O)cc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
To a mixture of ethyl 3-butyl-1-methyl-1H-indole-5-carboxylate (0.294 g) in methanol (20 mL) was added 1N NaOH (10 mL). The mixture was stirred at 50° C. for 18 h, cooled to room temperature and poured into 1N HCl (50 mL). The mixture was extracted with ethyl acetate and the ethyl acetate extract was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 0.234 g (89%) of the title compound: 1H NMR (CD3OD) δ 0.965, 1.42, 1.69, 2.76, 3.77, 7.02, 7.35, 7.84, 8.29.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>ClCCl>[N:9]1([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COc1cccc(N2CCCC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(N2CCCC2)c1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a stirring solution of 1-(3-methoxy-phenyl)-pyrrolidine (354 mg, 2 mmol) in dichloromethane (30 ml) at 0° C. was added BBr3 (4.0 ml, 4 mmol, 1 M solution in dichloromethane) in a dropwise fashion. The resulting solution was stirred over night at room temperature and then poured into ice water (30 ml). The aqueous mixture was extracted with dichloromethane (3×). The combine organic layers were washed with brine (1×), dried over sodium sulfate, and filtered. The dichloromethane filtrate was concentrated to afford the title compound as an oil (317 mg, 97%). MS(ES) m/e 164.2 ([M+H]+).
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[N:11]=[CH:12][C:13]3[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:14]=3[N:15]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>CN(C)C=O>[CH2:23]([CH:22]([N:16]1[C:14]2[N:15]=[C:10]([NH:9][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:11]=[CH:12][C:13]=2[CH:19]=[CH:18][C:17]1=[O:20])[CH2:25][CH3:26])[CH3:24]
Reactant: CCC(Br)CC
Reactant: O=c1ccc2cnc(Nc3ccccc3)nc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1c(=O)ccc2cnc(Nc3ccccc3)nc21
Temperature: 60 °C
Yield: 22.4 %

Procedure:
To a suspension of NaH (33 mg of a 60% suspension of NaH in mineral oil) in 7 mL of dimethylformamide was added 2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one (154 mg, 0.65 mmol). The reaction mixture was heated to 60° C. resulting in a clear solution. The solution was cooled slightly, and 3-bromopentane (125 μL, 1.01 mmol) was added. The reaction was heated at 60° C. for 30 minutes, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with 1:1 ethyl acetate:hexane to provide 45 mg (23%) of 8-(1-ethylpropyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one , mp 116-118° C.