Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]1[NH:15][C:16](=[O:18])[CH2:17][N:9]1[CH2:8]2)([O-])=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]1[NH:15][C:16](=[O:18])[CH2:17][N:9]1[CH2:8]2
Reactant: [H][H]
Reactant: O=C1CN2Cc3cc([N+](=O)[O-])ccc3N=C2N1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc2c(c1)CN1CC(=O)NC1=N2

Procedure:
To a suspension of 9.18 g. (3.4×10-2 mole) of 7-Nitro-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one hydrochloride in 95% ethanol (300 ml.) was added 10 ml. of concentrated hydrochloric acid and 0.45 g. of 10% Pd/C catalyst. The mixture was placed on a Paar hydrogenator, shaken until theoretical hydrogen absorbed, removed and water (150 ml.) added to effect dissolution of precipitate. The mixture was filtered under suction, the catalyst washed with 95% ethanol and the mixture evaporated to dryness yielding 9.02 g. of a yellow powder. Purification of the free base was effected yielding 7-Amino-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one; m.p. >275°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:24][C:25](=[O:40])[CH2:26][N:27]2[C:35]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=3[C:29]([C:36]([F:39])([F:38])[F:37])=[N:28]2)C2N(C3C=CC(OC)=CC=3)C=CN=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:50][C:51](C(N)CC3C=C(F)C=C(F)C=3)=[CH:52][N:53]=2)=[CH:45][CH:44]=1.FC(F)(F)C1C2CCCCC=2N(CC(O)=O)N=1>>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]2[O:50][C:51]([CH:10]([NH:24][C:25](=[O:40])[CH2:26][N:27]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[C:29]([C:36]([F:38])([F:39])[F:37])=[N:28]3)[CH2:9][C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=3)=[CH:52][N:53]=2)=[CH:47][CH:48]=1
Reactant: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1
Agent: Cl
Agent: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)NC(Cc1cc(F)cc(F)c1)c1cnc(-c2ccc(Cl)cc2)o1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 19E and 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.35 (s, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.69-6.52 (m, 3H), 5.24 (q, J=7.6 Hz, 1H), 4.69 (s, 2H), 3.09 (ddd, J=33.5, 13.7, 7.3 Hz, 2H), 2.54 (m, 2H), 2.42-2.37 (m, 2H), 1.81-1.70 (m, 4H). MS (m/z) 565.1 [M+H]+.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2[CH2:16][OH:17])[CH2:3][CH2:2]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:6]=2[CH:16]=[O:17])[CH2:3][CH2:2]1
Reactant: OCc1cc(OC(F)(F)F)ccc1OC1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
Sulfur trioxide pyridine complex (0.90 g, 5.7 mmol) was added to a solution of 2-cyclopropoxy-5-(trifluoromethoxy)benzenemethanol (Description 13, 393 mg, 1.6 mmol) and triethylamine, (1.54 mL, 11.1 mmol) in dimethylsulfoxide (3 mL) and the mixture was stirred at room temperature for 45 min. Further triethylamine (0.44 mL, 3.2 mmol) and sulfur trioxide pyridine complex (0.126 g, 0.8 mmol) were added and the mixture was stirred at room temperature for 30 min. The mixture was poured into aqueous citric acid (10%, 50 mL) and extracted with ethyl acetate. The combined organic fractions were washed with aqueous citric acid (10%, 3×50 mL) and water (3×50 mL), dried (Na2SO4), and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (0.326 g, 84%). 1H NMR (360 MHz, CDCl3) δ0.86 (4H, m), 3.82-3.9 (1H, m), 7.42 (2H, m), 7.62 (1H, d, J 2.5 Hz), and 10.36 (1H, s).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[CH3:9][O:10][N:11]=[C:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]Cl)[C:13]1[O:18][CH2:17][CH2:16][O:15][N:14]=1.O>CN(C)C=O>[O:15]1[CH2:16][CH2:17][O:18][C:13]([C:12](=[N:11][O:10][CH3:9])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]=[O:5])=[N:14]1
Reactant: CON=C(C1=NOCCO1)c1ccccc1CCl
Reactant: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C1=NOCCO1)c1ccccc1C=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
19.5 g (0.14 mol) of N-methylmorpholine N-oxide are added to a solution of 15 g (0.056 mol) of (2-chloromethyl-phenyl)-(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methanone O-methyl oxime in 150 ml of dimethylformamide and the mixture is stirred at 120° C. for 2 hours. After cooling, the mixture is poured into 1000 ml of water and extracted three times with 200 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and concentrated under reduced pressure. The residue is stirred with diisopropyl ether and the solid formed is filtered off with suction. 10.5 g (76% of theory) of 2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzaldehyde are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[N:44]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]5[CH:27]=[CH:26][S:25][CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)n[nH]c12
Yield: 8.9 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indazole-7-carboxamide (Example 48a) (0.05 mmol) in DMF (2 mL) was reacted with K2CO3 (14 mg, 0.1 mmol), triethyl amine (42 uL, 0.3 mmol) and morpholine (22 uL, 0.25 mmol) to afford the title compound (2.3 mg, 8.8%).
Reaction SMILES: [C:1](=[O:13])([O:5][C:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:2][CH2:3]Cl.N1C(C)=CC=CC=1C.[I-:22].[Na+]>CC(C)=O.CCCCCC>[C:1](=[O:13])([O:5][C:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:2][CH2:3][I:22]
Reactant: CC1(OC(=O)OCCl)CCCCC1
Reactant: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1cccc(C)n1
Solvent: CC(C)=O
Product: CC1(OC(=O)OCI)CCCCC1
Reaction time: 1.5 h

Procedure:
Chloromethyl 1-methylcyclohexyl carbonate (2.07 g) in acetone (7.5 ml) was treated with 2,6-lutidine (0.116 ml). Sodium iodide (2.25 g) was then added and the mixture was stirred for 1.5 h. More sodium iodide (1.5 g) was then added and stirring was continued. After a total of 2.5 h the acetone was removed and CH2Cl2/water were added and the layers separated. The dichloromethane layer was washed with 5% aqueous Na2S2O3, dried (MgSO4) and evaporated to leave an oil. This was taken up in hexane (50 ml) and loaded onto a silica gel column, and the column was eluted with 5% ethyl acetate in hexane to give iodomethyl 1-methylcyclohexyl carbonate containing some of the starting chloromethyl compound, δ(CDCl3) 1.26-1.35 (2H, m), 1.40-1.65 (9H, m, including s at δ 1.52), 2.10-2.20 (2H, m), 5.69 (s) and 5.91 (s) (together 2H, ratio 1:5) ppm.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[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>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2c(Br)cncc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Brc1cncc2cc(-c3ccccc3)ccc12
Yield: 71 %

Procedure:
A mixture of 4,7-dibromoisoquinoline (556 mg, 1.93 mmol), tetrakis(triphenylphosphine)-palladium(0) (73 mg, 3 mol %), phenylboronic acid (238 mg, 1.95 mmol), and aqueous sodium carbonate (Na2CO3) (3.9 mL, 1.0 M, 3.9 mmol) in DME (12 mL) was heated at reflux under nitrogen for 20 h. The mixture was diluted with ethyl acetate (EtOAc) (100 mL), washed with water (30 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexanes-EtOAc (95:5 to 80:20) as eluant to give 4-bromo-7-phenylisoquinoline (389 mg, 1.37 mmol) as a straw-colour solid; 1H (δ, CDCl3, 300 MHz) 7.4-7.6 (3H, m), 7.65-7.75 (2H, m), 8.1 (1H, d), 8.15 (1H, s), 8.2 (1H, d), 8.7 (1H, s), 9.2 (1H, s); LRMS 283, 284, 286.
Reaction SMILES: ClC1C=CC(C(C2C=CC(Cl)=CC=2)[N:9]2[CH2:12][CH:11]([C:13]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10]2)=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:9]1[CH2:12][CH:11]([C:13]([C:19]2[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=2)([OH:18])[C:14]([CH3:15])([CH3:16])[CH3:17])[CH2:10]1
Reactant: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 210 mg (0.59 mmol) of tert-butyl 3-[1-(3,5-difluorophenyl)-1-hydroxy-2,2-dimethylpropyl]azetidine-1-carboxylate (2) in 1 mL of CH2Cl2, 1.5 mL of TFA was added and the solution was stirred for 1 h at rt. It was concentrated and washed with ether to afford the title compound as white solid; Mass Spectrum: m/e=256 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].CO>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]2[NH:8][CH:7]=[C:6]([C:15](=[O:17])[CH3:16])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Clc1ccc2cc[nH]c2n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2nc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-7-azaindole (1 g, 6.55 mmol) was added to a suspension of AlCl3 (4.37 g, 32.8 mmol) in CH2Cl2 (150 mL) under nitrogen atmosphere. The mixture was stirred at RT for 30 min, and acetyl chloride (2.34 mL, 32.8 mmol) was added dropwise. The resulting mixture was further stirred at RT for 2 h. After completion, MeOH (40 mL) was added cautiously and volatils were removed under reduced pressure. The residue was diluted in CH2Cl2 and neutralized by addition of a saturated aqueous solution of NaHCO3. The layers were separated and the organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified twice by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 95-5). TLC, Rf (CH2Cl2/MeOH 9:1)=0.5; MS (UPLC/MS): 195.1/197.1 [M+H]+, 193.1/195.1 [M−H]−; tR (HPLC conditions f): 1.54 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].C([Li])(CC)C.[P:16](Cl)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[CH3:6][O:5][P:4]([CH:3]([P:16](=[O:17])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH:2]([CH3:10])[CH3:1])(=[O:9])[O:7][CH3:8]
Reactant: COP(=O)(CC(C)C)OC
Reactant: CCOP(=O)(Cl)OCC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C(C)C)P(=O)(OC)OC
Reaction time: 0.5 h

Procedure:
To a solution of 2--methylpropylphosphonic acid, dimethyl ester (2.20 g, 14.47 mmol) in anhydrous THF (200 ml) is added sec-butyllithium (20.04 ml, 26.05 mmol, 1.3M in cyclohexane) at 0° C. Following the addition, stirring is continued for an additional 30 minutes. This solution is then slowly added to a solution of diethyl chlorophosphate (2.50 9, 14.47 mmol) in anhydrous THF (100 ml) at room temperature. After stirring the reaction overnight, the mixture is quenched by the addition of a saturated aqueous solution of sodium bicarbonate and then extracted with methylene chloride. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography with 30% acetone in hexanes on silica gel.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].[C:17](#[N:19])[CH3:18]>>[OH:13][CH:12]([C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:10]=1)[CH2:18][C:17]#[N:19]
Reactant: CC#N
Reactant: O=Cc1cccc(OCC2CCCCO2)c1
Product: N#CCC(O)c1cccc(OCC2CCCCO2)c1

Procedure:
Addition of acetonitrile to 3-((tetrahydro-2H-pyran-2-yl)methoxy)benzaldehyde gave 3-hydroxy-3-(3-((tetrahydro-2H-pyran-2-yl)methoxy)phenyl)propanenitrile as a yellow oil. Yield (1.1 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.26-7.31 (m, 1H), 6.93-6.99 (m, 2H), 6.87-6.92 (m, 1H), 4.97-5.03 (m, 1H), 3.68-4.01 (m, 4H), 3.47-3.55 (m, 1H), 2.75 (d, J=6.4, 2H), 1.90-1.93 (m, 1H), 1.43-1.71 (m, 5H).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[CH:11]=[CH:12][N:13]([CH:16]([CH3:18])[CH3:17])[C:14]=2[CH:15]=1.[OH-].[Na+].CN([CH:28]=[O:29])C>O>[Br:6][C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[C:11]([CH:28]=[O:29])=[CH:12][N:13]([CH:16]([CH3:18])[CH3:17])[C:14]=2[CH:15]=1
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)cc2c1c(C=O)cn2C(C)C
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
To a stirred solution of DMF (1.04 lit) POCl3 (40.3 g, 263 mmol) was added at 0° C. and stirred for 20 min. Then methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate (65 g, 219.5 mmol) in DMF (260 mL) was added to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 3 h. Diluted the reaction mixture with cold water and adjusted PH-8 using with 2N NaOH solution, extracted with ethylacetate (4×1 lit). The organic layer washed with cold water, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford desired product methyl 6-bromo-3-formyl-1-isopropyl-1H-indole-4-carboxylate (65 g, 91.3%). 1H NMR (CD Cl3,400 MHz): δ 1.588 (d, 6H, J=6.8 Hz), 3.994 (s, 3H), 4.634-4.701 (m, 1H), 7.760 (d, 1H, J=1.6 Hz), 7.958 (d, 1H, J=1.6 Hz), 8.122 (s, 1H), 10.446 (s, 1H). LC-MS (ES+) m/z=324.02 (M+H)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:27].CO>C1COCC1>[CH2:3]([O:10][C:11]([N:13]([C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[CH3:27])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)OCc1ccccc1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
Sodium hydride (60% oil dispersion, 0.32 g) was added to a stirred solution of tert-butyl (S)-3-benzyloxycarbonylaminopyrrolidine-1-carboxylate (prepared according to Cheng et al, WO2007 142585, 1.73 g) in THF (20 mL) and the mixture was stirred for 15 minutes. Iodomethane (1.85 g) was added and the mixture was stirred at room temperature for 1 hour. Methanol was carefully added to destroy the excess sodium hydride then ethyl acetate and water were added and the organic layer was washed with brine, dried (Na2SO4), filtered. The filtrate was concentrated in vacuo to give tert-butyl (S)-3-(N-benzyloxycarbonyl-N-methylamino)pyrrolidine-1-carboxylate (1.66 g) as a pale coloured oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:16](OC=C)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([O:15][C@@H:13]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:12][N:11]=1)[CH3:14])(=[O:18])[CH3:17]
Reactant: CC(O)c1cc(-c2cccc(Cl)c2)on1
Reactant: C=COC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)c1cc(-c2cccc(Cl)c2)on1
Yield: 39.5 %

Procedure:
1-[5-(3-chlorophenyl)isoxazol-3-yl]ethanol (106.5 g, 476 mmol) and Novozyme 435® (13 g) are taken up under Ar in dry toluene (1.5 L). After addition of vinyl acetate (66 mL, 716 mmol) the reaction was run at r.t. over night, followed by filtration over celite and washing with DCM. The solvent was evaporated in vacuo and the crude product was subjected to column chromatography on silica using dichloromethane/methanol=20:1, to give the title compound (50 g, 47%). 1H NMR: 7.76 (m, 1H), 7.65 (m, 1H), 7.41 (m, 2H), 6.54 (s, 1H), 6.07 (q, 1H), 2.13 (s, 3H), 1.66 (d, 3H). LC-MS (M++1)=266.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[CH2:20]([NH2:23])[CH2:21][CH3:22]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([NH:23][CH2:20][CH2:21][CH3:22])=[O:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2]
Reactant: CCCN
Reactant: CCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCCNC(=O)CN(CC)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-ethylglycine and propylamine: 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8.8 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.77 (dd, J=8.8, 2.4 Hz, 1H), 5.99 (bs, 1H), 3.96 (s, 2H), 3.54 (q, J=7.1 Hz, 2H), 3.47 (q, J=7.0 Hz, 2H), 1.46 (m, 2H), 1.25 (t, J=7.1 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]1OCC(CCCCC)CO1)[C:5]([OH:7])=[O:6].FC1C=C(Br)C=CC=1C.[Mg].C(=O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: CCCCCC1COC(c2ccc(C(=O)O)cc2F)OC1
Agent: Cc1ccc(Br)cc1F
Agent: O=C=O
Agent: [Mg]
Product: Cc1ccc(C(=O)O)cc1F

Procedure:
2.96 gms. of 3-fluoro-4-(5-pentyl-1,3-dioxan-2-yl)-benzoic acid (prepared from 2-fluoro-4-bromotoluene by reaction with magnesium according to Grignard and reaction with carbon dioxide giving 3-fluoro-4-methyl-benzoic acid, esterification thereof with ethanol/sulfuric acid giving ethyl 3-fluoro-4-methyl-benzoate, bromination by bromine or N-bromo-succinimide giving ethyl 3-fluoro-4-bromomethylbenzoate, oxidation by dilute nitric acid giving 3-fluoro-terephthalic aldehydic acid and ketalization thereof with 2-pentyl-propane-1,3-diol) and 2.0 gms. of SOCl2 are boiled for 1 hour, then evaporated and the crude acid chloride thus obtained is dissolved in 20 ml of toluene and then 1.5 ml of pyridine and 1.10 gms. of 4-cyano-phenol are added and then boiled for two hours. After separation the organic phase is washed with water, dried over sodium sulfate and evaporated leaving behind 4-cyanophenyl 3-fluoro-4-(5-pentyl-1,3-dioxan-2-yl)-benzoate.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:6][N:5]=[C:4]2[NH:18][CH:19]=[CH:20][C:3]=12.[NH2:21][CH:22]1[CH:29]2[CH2:30][C:25]3([C:32]([NH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:33])[CH2:26][CH:27]([CH2:31][CH:23]1[CH2:24]3)[CH2:28]2.C(N(CC)CC)C.C(OCC)(=O)C>CN1CCCC1=O.O>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][NH:34][C:32]([C:25]12[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:31][CH:23]([CH:22]3[NH:21][C:2]3[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]4[NH:18][CH:19]=[CH:20][C:3]=34)[CH2:24]1)[CH2:26]2)=[O:33])[CH3:40]
Reactant: O=C(OCc1ccccc1)c1cnc2[nH]ccc2c1Cl
Reactant: CCOC(=O)CNC(=O)C12CC3CC(C1)C(N)C(C3)C2
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CNC(=O)C12CC3CC(C1)C(Nc1c(C(=O)O)cnc4[nH]ccc14)C(C3)C2
Temperature: 180 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
Benzyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (55 mg), ethyl {[(4-amino-1-adamantyl) carbonyl]amino}acetate (54 mg) and triethylamine (80 μl) were dissolved in N-methyl-2-pyrrolidone (0.55 ml) and stirred at 180° C. for 1 hour using a microwave reaction system. To the reaction solution were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate), the obtained compound was dissolved in dioxane (1.1 ml) and methanol (1.1 ml), 10% palladium on carbon (50% wet) was added, and catalytic reduction was performed for 4 hours at ambient temperature at 1 atm. Methanol, dioxane, and 1M hydrochloric acid were added, and the precipitated solid was dissolved and filtered to remove the catalyst. The filtrate was concentrated under reduced pressure to obtain 4-({5-[(2-ethoxy-2-oxoethyl)carbamoyl]adamantan-2-yl}amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (18 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cccc(F)c4)c3c2)C(c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,4-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3-fluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=493 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11]Cl)[N:5]=1)([CH3:3])[CH3:2].C([O-])(=[O:15])C.[Na+].[OH-].[Na+].Cl>O>[CH:1]([C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11][OH:15])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(C)c1nc(O)cc(CCl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1nc(O)cc(CO)n1
Reaction time: 72 h

Procedure:
9.33 gm of 2-isopropyl-4-hydroxy-6-chloromethyl-pyrimidine (0.0495 mole) and 13.60 gm of sodium acetate (having 3 molecules water of crystallization, 0.10 mole) were heated in 200 ml of water under reflux (atmospheric pressure). At the 5, 24 and 48 hours periods in the reaction, the reaction was interrupted and the pH of the reaction mixture was adjusted to 7 with 1N sodium hydroxide solution. After 72 hours overall duration, the reaction was discontinued. (Throughout this reaction period the pH was always between 5 and 8.) 50 ml of 1N hydrochloric acid were added. Over a 5 hour period, acetic acid and water were distilled off, with the lost water continuously being replaced. The distillation residue was brought to a pH of 5 and was evaporated until dry. The dry residue subsequently was extracted with methylene chloride in a Soxhlet extractor (separation of NaCl and sodium acetate). After distillation off of the methylene chloride, the 2-isopropyl-4-hydroxy-6-hydroxymethyl-pyrimidine was obtained. The yield of the product was 93.72 percent and the product has a purity of 97.9 percent. The melting point of the product was 186.2° to 186.5°C.