Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:16](=[O:18])[CH3:17])=[CH:4][N:3]=1
Reactant: Cc1nc(Cl)ncc1N
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cnc(Cl)nc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.36 g of 2-chloro-4-methylpyrimidin-5-ylamine was dissolved in 20 mL of dichloromethane, and under stirring on ice, 1.53 mL of pyridine, 2.7 mL of acetic anhydride and 1.16 g of 4-dimethylaminopyridine were added. After stirring at room temperature for 1 hour, water was added, extracted with ethyl acetate, and the resultant organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1), to afford 178 mg of the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:35])[N:4]([CH2:14][C:15]([NH:17][CH:18]([CH:32]([CH3:34])[CH3:33])[CH:19]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C:20]([F:23])([F:22])[F:21])=[O:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](O)=[O:46])=[CH:40][CH:39]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.CN(C)CCCC(N=C=NCC)CC.ON1C2C=CC=CC=2N=N1>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[Si:25]([O:24][CH:19]([C:20]([F:23])([F:21])[F:22])[CH:18]([NH:17][C:15](=[O:16])[CH2:14][N:4]1[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][C:41]2[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)[C:3]1=[O:35])[CH:32]([CH3:33])[CH3:34])([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CCN=C=NC(CC)CCCN(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CC(=O)Nc2ccc(-c3ccccc3)n(CC(=O)NC(C(C)C)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)c2=O)cc1
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To 2-(3-amino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.295 g) suspended in redistilled tetrahydrofuran (5 mL) was added 4-methoxyphenylacetic acid (0.97 g), followed by 1-hydroxybenzotriazole hydrate (0.156 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.123 g). The reaction was shown by TLC to be incomplete after overnight stirring; therefore, triethylamine (0.08 mL) and 4-dimethylaminopyridine (catalytic amount) were added to the mixture. After stirring 1 h, additional acid (0.098 g), 1-(3-dimethylaminopropylpropyl)-3-ethylcarbodiimide hydrochloride (0.123 g), triethylamine (0.08 mL), and 1-hydroxybenzotriazole (0.156 g) were added. Additional tetrahydrofuran (2 mL) was added to facilitate stirring. After stirring overnight TLC indicated little change in the reaction mixture which was diluted with ethyl acetate (50 mL); washed with water (twice), saturated aqueous sodium bicarbonate (three times) and brine; dried; and evaporated. Purification by chromatography, eluting with ethanol:ethyl acetate:dichloromethane (0.5:5:94.5) gave N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-[3-(4-methoxyphenyl)acetylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]acetamide (0.235 g); TLC (of crude reaction mixture): Rf =0.88, methanol:dichloromethane (4:96); MS: m/z=660(M+1).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@H:19]([F:40])[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:27]=[C:28]3[CH2:39][CH2:38][NH:37][CH2:36][C:29]3=[N:30][C:31]=2[NH:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]1.CO>C1COCC1>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@H:19]([F:40])[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:27]=[C:28]3[CH2:39][CH2:38][N:37]([C:5](=[O:7])[CH3:6])[CH2:36][C:29]3=[N:30][C:31]=2[NH:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21]1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Nc1nc2c(nc1N1CCC([C@@H](F)c3ccc(F)cc3F)CC1)CCNC2
Solvent: C1CCOC1
Solvent: CO
Solvent: O=CO
Product: CC(=O)N1CCc2nc(N3CCC([C@@H](F)c4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetic anhydride (14.1 μL, 0.149 mmol) and formic acid (38.1 μL, 0.994 mmol) were combined in THF (99 μL) and stirred at room temperature for 10 min. This solution was cooled to 0° C. and was added to a stirring solution of (R)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (41.7 mg, 0.099 mmol) in THF (895 μL) at 0° C. After 10 min, UPLC-MS showed conversion not to the formylated product, but to the acetylated product. The reaction mixture was treated with MeOH, concentrated under reduced pressure, taken up in MeOH, filtered, and purified by HPLC Method B to give the title compound, as a TFA salt, as a pale yellow solid (17.5 mg, 30.6%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.28 (m, 6H), 1.45 (d, J=12.7 Hz, 1H), 1.65 (m, 2H), 2.01 (m, 1H), 2.09 (m, 1H), 2.18 (s, 1.1H), 2.20 (s, 1.9H), 2.76 (m, 4H), 3.49 (m, 2H), 3.81 (t, J=6.1 Hz, 1.3H), 3.85 (t, J=5.9 Hz, 0.7H), 4.13 (m, 1H), 4.57 (s, 0.7H), 4.61 (s, 1.3H), 5.52 (m, 1H), 7.02 (m, 2H), 7.50 (m, 1H); ESI-MS m/z [M+H]+ 462.4.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[C:12]1[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:2][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: Nc1ncccc1Br
Reactant: CC(C)c1ccc(S)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(Sc2cccnc2N)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A mixture of 4-isopropylbenzenethiol (2.288 g), 3-bromopyridin-2-amine (2.0 g), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.669 g), tris(dibenzylideneacetone)dipalladium(0) (0.529 g) and DIEA (7.47 mL) in toluene (57.8 mL) was stirred overnight under a nitrogen atmosphere at 120° C. The reaction mixture was added to water, filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2508 mg) as a pale-yellow solid.
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:15]=[C:14]([C@H:16]2[C@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:20]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:19]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:18]([CH2:46][O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:17]2)[S:13][C:12]=1[Cl:55])(=O)C1C=CC=CC=1>C1COCC1.CO.O>[Cl:55][C:12]1[S:13][C:14]([C@H:16]2[C@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:20]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:19]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C@@H:18]([CH2:46][O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[O:17]2)=[CH:15][C:11]=1[CH2:10][OH:9]
Reactant: O=C(OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl)c1ccccc1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
To a solution of benzoate 36 (4.5 g, 5.80 mmol) in THF/MeOH/H2O (30 mL/10 mL/10 mL) was added LiOH monohydrate (0.73 g, 17.4 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours. The mixture was extracted with EtOAc/aq. saturated NH4Cl solution (100 mL/100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the title compound 37 (3.86 g, 99%), which was carried on to the next step without further purification.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[C:7]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)(=O)[CH3:8].[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)(=O)C.CC(N(C)C)=O>[N:13]1[CH:14]=[CH:15][C:10]([C:7]2[NH:16][C:17]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=2)=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccncc1
Reactant: Nc1cccnc1Cl
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: c1cnc2cc(-c3ccncc3)[nH]c2c1
Temperature: 140 °C
Reaction time: 10 h
Yield: 58.9 %

Procedure:
Into 12 mL dimethylacetamide are added 240 mg (2 mmoles) of anhydrous magnesium sulfate, 1.3 mL (12 mmoles) of 4-acetyl pyridine, 515 mg (4 mmoles) of 3-amino-2-chloropyridine and 0.3 mL of acetic acid. The resulting suspension is kept under argon. Then 1.1 g (5.2 mmoles) of potassium phosphate and 202 mg (0.4 mmole) of bis-(tri-t-butylphosphine) palladium are added to the reaction mixture which is then sealed in its reaction vessel and stirred at 140° C. for 10 hours. The reaction mixture is poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. The solid residue after concentration is purified by chromatography on silica gel (ethylacetate/methanol 9/1) to give 460 mg 2-pyridin-4-yl-1H-pyrrolo[3,2-b]pyridine as brown solid.
Reaction SMILES: [CH2:1]([Si:4]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])[CH:2]=[CH2:3].[C:14]([OH:20])(=[O:19])[CH2:15][CH2:16]C=C.ClCCl.CCCCCC>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.CCOCC>[CH:11]([Si:4]([CH:5]([CH3:6])[CH3:7])([CH:8]([CH3:10])[CH3:9])[CH2:1][CH:2]=[CH:3][CH2:16][CH2:15][C:14]([OH:20])=[O:19])([CH3:13])[CH3:12]
Reactant: C=CC[Si](C(C)C)(C(C)C)C(C)C
Reactant: C=CCCC(=O)O
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)[Si](CC=CCCC(=O)O)(C(C)C)C(C)C
Temperature: 40 °C
Yield: 95.4 %

Procedure:
A flame dried round-bottomed flask was charged with allyltriisopropylsilane (0.722 mL, 3 mmol, 3 eq), 4-pentenoic acid (0.102 mL, 1 mmol, 1 eq) and dichloromethane (3 nmL). Hoveyda-Grubbs' catalyst (5 mol %, 31 mg) was subsequently added as a solid and the reaction was heated to reflux (40° C.) and left to stir under an atmosphere of argon. After 3 days the reaction was concentrated under reduced pressure to give a dark brown oil. Column chromatography (100% hexane to remove remaining silane, then hexane:ether, 75:25) gave 6-(triisopropylsilyl)-hex-4-enoic acid as a colourless oil (258 mg, 95% yield). For major isomer E: 1H NMR (400 MHz, CDCl3) δ 1.04-1.06 (m, 21H, Si(i−Pr)3), 1.54-1.56 (d, 2H, CH2Si(i−Pr)3, J=8.0 Hz), 2.29-2.35 (m, 2H, HOOCCH2CH2), 2.37-2.42 (m, 2H, HOOCCH2), 5.28-5.35 (m, 1H, CH2CHCH), 5.52-5.60 (m, 1H, CH2CHCH); 13C NMR (100 MHz, CDCl3) δ 11.0 (Si(CH(CH3)2)3), 15.3 (CH2Si(i−Pr)3), 18.7 (Si(CH(CH3)2)3), 27.8 (HOOCCH2CH2), 34.3 (HOOCCH2CH2), 125.9 (CH2CHCH), 129.0 (CH2CHCH), 179.5 (HOOC). For minor isomer Z: 1H NMR (400 MHz, CDCl3) δ 1.04-1.06 (m, 21H, Si(i−Pr)3), 1.62-1.64 (d, 2H, CH2Si(i−Pr)3, J=8.0 Hz), 2.29-2.35 (m, 2H, HOOCCH2CH2), 2.37-2.42 (m, 2H, HOOCCH2), 5.38-5.50 (m, 1H, CH2CHCH), 5.63-5.75 (m, 1H, CH2CHCH); 13C NMR (100 MHz, CDCl3) δ 10.9 (CH2Si(i−Pr)3), 11.1 (Si(CH(CH3)2)3), 18.7 (Si(CH(CH3)2)3), 24.7 (HOOCCH2CH2), 30.9 (HOOCCH2CH2), 124.6 (CH2CHCH), 128.2 (CH2CHCH), 176.9 (HOOC); IR (v, cm−1) 2867 (COO—H), 1713 (HOC═O), 660 (C—Si); HRMS required for C15H30O2Si [M−H]−: 269.1937, found 269.1937.
Reaction SMILES: [C:1]1([C:7]([C@H:9]2[O:14][CH2:13][CH2:12][N:11]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([SiH](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.B(F)(F)F.CCOCC.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]1([C@H:7]([C@H:9]2[O:14][CH2:13][CH2:12][N:11]([C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH2:10]2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@H](C(=O)c2ccccc2)C1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@H](c1ccccc1)N1CCO[C@H]([C@H](O)c2ccccc2)C1
Temperature: 25 °C

Procedure:
To a stirred solution of 48a (0.08 g, 0.26 mmol) and triphenylsilane (0.34 g, 1.31 mmol) in dichloromethane (4 ml) cooled to 0° C. was added boron trifluoride etherate (0.09 g, 0.66 mmol) followed by trifluoroacetic acid (0.36 ml, 63 mmol). The reaction mixture was allowed to warm to room temperature and diluted after three hours with dichloromethane (20 ml) and neutralised with aqueous sodium bicarbonate. The organic phase was dried over magnesium sulphate, filtered and evaporated to give the required product. This was purified as its hydrochloric acid salt crystallising from isopropanol and diethyl ether (0.05 g, 69%%); MW 297.4; C19H23NO2; 1H NMR (CDCl3) on free base 7.08-7.29 (10H, m), 4.78 (1H, d), 3.90-4.00 (1H, m), 3.57-3.68 (2H, m), 3.33 (1H, q), 2.53-2.64 (1H, m), 2.37-2.47 (1H, m), 2.09-2.26 (2H, m), 1.29 (3H, d). m/z [M+H]+ 298.
Reaction SMILES: IC1SC(NC(=O)C)=NC=1C.C([C:14]1[S:18][C:17]([C:19]2[S:23][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:21][C:20]=2[CH3:28])=[CH:16][CH:15]=1)=O.C([Sn](CCCC)(CCCC)C1SC=CC=1)CCC>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:28][C:20]1[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=1[C:17]1[S:18][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C=O)s2)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)Nc1nc(C)c(I)s1
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2cccs2)s1
Temperature: 100 °C

Procedure:
N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide, Intermediate 1 (2 g; 7.09 mmol; 1 eq.) and Pd(dppf)Cl2 (0.52 g; 0.71 mmol; 0.10 eq.) are dissolved in DMF (35 ml). 2-(Tributylstannyl)thiophene (2.68 ml; 8.44 mmol; 1.19 eq.) is added. The reaction mixture is flushed with argon and heated at 100° C. for 1 h30. Solvents are evaporated and the crude mixture is dissolved in EtOAc (100 ml), washed with water (3×100 ml). The aqueous phase are combined and extracted with EtOAc (2×50 ml). Combined organic phases is washed with brine and dried over MgSO4. After evaporation of the solvents, the crude product is purified by preparative HPLC, affording Compound (6) as white-off powder (1.24 g; 73.5%). 1H NMR (DMSO-d6) δ 2.16 (s, 3H), 2.42 (s, 3H), 7.15 (dd, J=3.8, 5.3 Hz, 1H), 7.20 (dd, J=1.1, 3.8 Hz, 1H), 7.60 (dd, J=1.1, 5.3 Hz, 1H), 12.19 (s, 1H). M−(ESI): 237.01; M+(ESI): 239.01. HPLC, Rt: 3.01 min (purity: 98.7%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][S:5][C:6]=1[NH2:7].C(N(CC)CC)C.[CH2:16]1[CH:23]2[C:19]3([C:25](Cl)=[O:26])[CH2:20][CH:21]([CH2:24][CH:17]1[CH2:18]3)[CH2:22]2>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][S:5][C:6]=1[NH:7][C:25]([C:19]12[CH2:20][CH:21]3[CH2:24][CH:17]([CH2:16][CH:23]1[CH2:22]3)[CH2:18]2)=[O:26]
Reactant: O=C(Cl)C12CC3CC(CC1C3)C2
Reactant: Cc1nsc(N)c1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nsc(NC(=O)C23CC4CC(CC2C4)C3)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of 4-bromo-3-methylisothiazol-5-amine (prepared as described in J. Chem. Soc. 1963, p 2032) (1.93 g, 10.1 mmol) in tetrahydrofuran (25 mL) with triethylamine (1.7 mL, 12.2 mmol) at 0° C. was added slowly a solution of Example 4A (1.9 g, 10.3 mmol) in tetrahydrofuran (15 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was evaporated to dryness, partitioned between H2O/ethyl acetate and the aqueous extracted again (2×) with ethyl acetate. The organics were combined, dried (MgSO4), filtered and solvent evaporated. Flash chromatography over silica gel eluting with 15% ethyl acetate/hexane provided 0.3 g of the title compound plus 1.8 g of diacylated compound. The latter was heated to reflux in methanol for 3 h, cooled, solvent evaporated and flash chromatographed over silica gel eluting with 20% ethyl acetate/hexane to provide an additional 0.99 g of the title compound. 1H NMR (300 MHz, CDCl3) δ 1.63-1.76 (m, 4H), 1.87-1.98 (m, 4H), 2.10-2.15 (m, 2H), 2.45 (s, 3H), 2.81 (t, 1H), 8.23 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Li+].[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31]([O-])=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C([O-])c1ncoc1-c1ccncc1
Agent: [Li+]
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccncc3)cn2)o1

Procedure:
Following general procedure Z3 followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-pyridin-4-yl-oxazole-4-carboxylic acid lithium salt. LC-MS-conditions 02: tR=0.70 min; [M+H]+=378.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:8][S:7](=O)(=O)[C:6]=2[CH:18]=1.O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.[H][H]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)=[CH:8][S:7][C:6]=2[CH:18]=1
Reactant: O=S1(=O)C=C(N2CCNCC2)c2ccc(Cl)cc21
Reactant: [H][H]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc2c(N3CCNCC3)csc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 111.3 %

Procedure:
To a mixture of 6-chloro-3-piperazinyl-benzo[b]thiophene-1,1-dioxide (6.0 g) and tetrahydrofuran (THF) (30 mL) under a nitrogen atmosphere was added a solution of D1BAL-H (diisobutylaluminum hydride) (0.084 mol) in toluene (84 mL) dropwise with ice bath cooling. The reaction mixture was stirred at 0° C. for 2 hours then overnight at room temperature. To the yellow solution was added, with vigorous stirring, water (5 ml) at a rate to control hydrogen evolution. Then 5NNaOH (5 mL) was added with rapid stirring. The resulting precipitate was filtered off and washed with dichloromethane and ether. The filtrate was concentrated in vacuo. The residue was taken up in dichloromethane (150 mL), washed with water (75 mnl) and brine (100 ml), dried over sodium sulfate and concentrated in vacuo to yield 5.93 g of a viscous gummy material which was triturated with ether. The ether fraction was concentrated in vacuo to yield 2.75 g of residue which was chromatographed (silica gel, 50% MeOH/CH2 Cl2) to yield 1.53 g product as a clear oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([C:2]2[N:3]=[C:4]3[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]3[C:6](=[O:8])[CH:7]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2

Procedure:
A mixture of 1 g of (S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one and of 15 ml of morpholine is heated at 80° C. After one and a half hours of heating and after verification by LC/MS, the reaction is complete. After cooling, the reaction mixture is concentrated under reduced pressure. 10 ml of cold water and 100 ml of ethyl acetate are added to the residue obtained. The resulting organic phase is separated and then dried over magnesium sulphate, filtered, and concentrated under reduced pressure so as to give 1.2 g of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([O:20]CCCO)[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9][N:8]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30](F)[CH:29]=2)[CH:7]=1)=[O:5])[CH3:2].C(OC(C1C2NC3C=C(O)C=CC=3C=2C(C)(C)C[N:44]([C:59](=[O:67])[C:60]2C=CC(F)=CC=2)C=1)=O)C.C(N(C(C)C)CC)(C)C.BrCCCO>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([O:20][CH2:60][C:59](=[O:67])[NH2:44])[CH:17]=[CH:18][C:19]=3[C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9][N:8]([C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2c1[nH]c1cc(OCCCO)ccc21
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(O)ccc21
Agent: OCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OCC(N)=O)ccc21
Temperature: 75 °C
Reaction time: 10 h

Procedure:
To prepare 3-(3,4-difluoro-benzoyl)-1,1-dimethyl-8-(3-hydroxy-propoxy)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester, a mixture of 3-(4-fluorobenzoyl)-8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]-indole-5-carboxylic acid ethyl ester (46 mg, 0.11 mmol), diisopropylethylamine (0.5 mL), and 3-bromo-1-propanol (1.4 mL) in dry acetonitrile (1 mL) was stirred at 75° C. for 10 hours. The solvent was removed in vacuo, and the residue was purified by preparative reverse-phase HPLC, which was then acylated in the manner described in Example 2A. 1HNMR (CDCl3): δ 10.51 (1H, s), 7.86 (1H, s), 7.82 (1H, d), 7.66-7.59 (2H, m), 7.15-7.09 (2H, m), 6.87 (1H, d), 6.74 (1H, m), 4.27-4.15 (4H, m), 4.09 (2H, brs), 3.90 (2H, m), 2.11-2.05 (2H, m), 1.60 (6H, s), 1.26-1.21 (3H, m). MS (ES): 481 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25]([CH2:27][C:28](Cl)=[O:29])#[N:26].O>C(#N)C>[C:25]([CH2:27][C:28]([NH:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][CH:3]=1)=[O:29])#[N:26]
Reactant: N#CCC(=O)Cl
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: N#CCC(=O)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 79.7 %

Procedure:
22.5 g (0.076 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole and 8 g (0.1 mol) of pyridine are taken in 200 ml of acetonitrile, and 13.2 g (0.128 mol) of cyanoacetyl chloride are added dropwise at 20°-25° C., while stirring and cooling. The reaction mixture is stirred at room temperature for a further two hours and then poured into water. After extraction with methylene chloride and drying of the organic phase over sodium sulphate, the solvent is distilled off in vacuo. The crystalline residue is stirred with a mixture of ligroin and diisopropyl ether and filtered off with suction. 22 g (80% of theory) of 5-cyanoacetylamino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 169°-175° C. are obtained.