Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:9]1[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH:23]([CH2:10][C@@H:9]1[CH2:12][C@@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17])[CH2:14][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CNc1ccccc1
Yield: 81.6 %

Procedure:
(2S,4R)-2-Anilinomethyl-N-t-butoxycarbonyl-4-t-butyldimethylsiloxypyrrolidine (995 mg, yield: 82%) was prepared as a yellow oily substance, from (2S,4R)-N-t-butoxycarbonyl-4-t-butyldimethylsiloxyprolinal (990 mg, 3 mmol) and aniline (0.3 ml, 3.3 mmol), in the same manner as in Reference Example 95-2.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:20])=[N:11][CH:12]=[C:13]([C:15]([F:18])(F)F)[CH:14]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>CN(C)C=O>[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=2)=[N:11][CH:12]=[C:13]([CH2:15][F:18])[CH:14]=1
Reactant: CCOC(=O)C(N)c1ncc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(OC)c(OC)c1)c1ncc(CF)cc1Cl

Procedure:
Triethylamine (0.28 ml) was added to a solution of ethyl 2-(3-chloro-5trifluoromethyl-2-pyridyl)glycinate (1 g; prepared in a similar manner to the starting material for Example 3) in dimethylformamide (10 ml) with stirring followed by 3,4-dimethoxybenzoyl chloride (0.70 g), the mixture was stirred for 45 minutes and evaporated. The residue was extracted with ethyl acetate and the extracts worked up to give the title product, m.p. 40-3° C. (Compound 601)
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(C)cccc2Cl)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-n2nc(-c3c(C)cccc3Cl)[nH]c2=O)cc1OC
Yield: 46.1 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2-chloro-6-methylbenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (2.0 g), TFA (5 mL) and DCM (30 mL) to afford 0.700 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 2.31 (s, 3H), 3.78 (s, 3H), 3.84 (s, 3H), 7.40 (s, 1H), 7.49 (s, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.75 (s, 1H), 7.81 (d, J=8.7 Hz, 1H), 12.54 (s, 1H); MS (m/z): 373.95 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11](OC(C)C)=[O:12])=[CH:2]1.[BH4-].[Li+].Cl>C(O)(C)C.O>[OH:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CC(C)OC(=O)C(=O)c1c[nH]c2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)O
Solvent: O
Product: OCCc1c[nH]c2ccccc12
Reaction time: 5 h

Procedure:
To a stirred suspension of isopropyl 3-indolylglyoxylate (46.4 g.) in isopropanol (500 ml.), lithium borohydride (13.1 g.) was added in small portions. The resulting solution was heated to reflux and stirred for 5 hours then cooled and diluted with water (2 l.). The mixture was acidified with hydrochloric acid and the product extracted into dichloromethane. The extract was washed with sodium carbonate solution then with water and the solvent was evaporated under reduced pressure to give an oil which was crystallised from toluene (50 ml.). The crude product was a red-brown powder, yield 25.0 g. (78%). This was distilled at 0.5 - 1mm. pressure and the distillate crystallised from toluene (100 ml.), giving 3-(2-hydroxyethyl)indole as white crystals, mp. 57°-59°. Yield 20.7g(64.5%)
Reaction SMILES: NC1C=C(OC)C=CC=1[C:4](O)=[O:5].[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])=[O:23].[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1>>[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])=[O:23].[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]([C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[NH:13][C:4]([NH:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1)=[O:5])=[O:23]
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: Nc1nccs1
Agent: COc1ccc(C(=O)c2ccccc2OC)c(N)c1
Product: COc1ccc(C(=O)c2ccccc2OC)c(NC(=O)Nc2nccs2)c1
Yield: 68 %

Procedure:
(2-Amino-4-methoxy-phenyl)-(2-methoxy-phenyl)-methanone (720 mg, 28%) was prepared from 2-amino-4-methoxy-benzoic acid (1.67 g, 0.1 mol) following the general procedure S. N-[2-(2-Methoxy-benzoyl)-5-methoxy-phenyl]-N′-(thiazol-2-yl)urea (131 mg, 68%) was prepared from (2-amino-4-methoxy-phenyl)-(2-methoxy-phenyl)-methanone (129 mg, 0.5 mmol) and 2-aminothiazole (0.060 g, 0.6 mmol) following the general procedure D.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>C(#N)C>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1CCN1CCOCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.100 g, 0.303 mmol), cesium carbonate (0.296 g, 0.909 mmol) and 4-(2-chloroethyl)morpholine (0.059 g, 0.394 mmol) were suspended in acetonitrile (4 mL). The reaction was stirred at 60° C. overnight. H2O (25 mL) was added and the resulting precipitate was collected by filtration. The solid was subjected to chromatography (silica gel, ethyl acetate with 10% methanol) afforded an off-white solid (0.040 g, 30%). 1H NMR (400 MHz, CDCl3) δ 7.55 (app q, J=7.92 Hz, 1H), 6.93 (app t, J=8.39 Hz, 1H), 6.84 (app t, J=9.40 Hz, 1H), 5.95 (s, 1H), 5.18 (s, 2H), 4.16 (app t, J=6.78 Hz, 2H), 3.68 (s, 4H), 2.65 (app t, J=6.38 Hz, 2H), 2.54 (s, 4H), 2.43 (s, 3H). ES-HRMS m/z 443.0743 (M+H C19H21BrF2N2O3 requires 443.0776).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:22][CH:21]2[CH2:23][CH:14]1[CH:15]1[CH:20]2[CH:19]2[CH2:24][CH:16]1[CH:17]=[CH:18]2>>[CH:15]12[CH:16]3[CH2:24][CH:19]([CH:18]=[CH:17]3)[CH:20]1[CH:21]1[CH2:23][CH:14]2[CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:1]2([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:22]1
Reactant: ClCCCCCC1CC2CC1C1C3C=CC(C3)C21
Reactant: O=C1CCCC1
Product: OC1(CCCCCC2CC3CC2C2C4C=CC(C4)C32)CCCC1
Yield: 82 %

Procedure:
1-{5-(8-Tetracyclo[4.4.0.12,5.17,10]dodecen-3-yl)pentyl}-cyclopentanol (yield: 82%) was obtained in the same manner as in Synthesis Example 1, except that cyclopentanone and 1-chloro-5-(8-tetracyclo[4.4.0.12,5.17,10] dodecen-3-yl)pentane were used in place of acetone and 1-chloro-4-(5-norbornen-2-yl)butane, respectively.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.B(OC)(OC)[O:19]C.OO>O1CCCC1>[CH3:10][N:6]1[CH2:7][CH2:8][O:9][C:4]2[CH:3]=[C:2]([OH:19])[CH:12]=[CH:11][C:5]1=2
Reactant: CN1CCOc2cc(Br)ccc21
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCOc2cc(O)ccc21
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 89.2 %

Procedure:
To a −78° C. solution of 7-bromo-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (90%, 10.40 g, 41.0 mmol) in tetrahydrofuran (70 mL) under nitrogen was slowly added n-butyllithium solution (1.4 M in hexanes, 32 mL, 45 mmol) and the resulting suspension was stirred at −78° C. for 35 min. Trimethyl borate (6.0 mL, 54 mmol) was then added dropwise and the clear solution was stirred at −78° C. for 25 min and at ambient temperature for 16 h. The reaction was cooled to 0° C. and aqueous hydrogen peroxide (8.2 mL, 35%, 95 mmol) was slowly added. The resulting mixture was stirred at 0° C. for 10 min and at ambient temperature for 5 h. The insoluble material was removed by filtration and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was taken up into ethyl acetate (100 mL) and was acidified with hydrochloric acid (100 mL, 1 M). The layers were separated and the organic solution was extracted with water (2×50 mL). The combined aqueous solution was neutralized to pH ˜6-7 with 5 M sodium hydroxide and extracted with ethyl acetate (3×100 mL). This organic solution was washed with brine (200 mL) and dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (2:1) to afford 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol (6.04 g, 89%) as a light brown solid: mp 84-87° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ6.59 (d, J=9.0 Hz, 1H), 6.40-6.28 (m, 2H), 5.42 (br s, 1H), 4.30 (dd, J=4.2, 4.2 Hz, 2H), 3.19-3.09 (m, 2H), 2.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ149.1, 145.6, 130.5, 114.7, 108.0, 104.1, 65.3, 49.8, 40.1; MS (ES+) m/z 166.1 (M+1).
Reaction SMILES: [NH2:1][N:2]([CH:10]([CH3:12])[CH3:11])C(=O)OC(C)(C)C.O/[CH:14]=[C:15]1\[C:16](=O)[C:17]2[C:22]([O:23][C:24]3\1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:26][CH2:25]3)=[CH:21][CH:20]=[CH:19][CH:18]=2.C(O)(C(F)(F)F)=O>ClCCl>[CH:10]([N:2]1[C:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[O:23][C:24]3([CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:31])[CH2:26][CH2:25]3)[C:15]=2[CH:14]=[N:1]1)([CH3:12])[CH3:11]
Reactant: CC(C)N(N)C(=O)OC(C)(C)C
Reactant: O=C1/C(=C\O)C2(CCN(C(=O)OCc3ccccc3)CC2)Oc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncc2c1-c1ccccc1OC21CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of tert-butyl N-amino-N-isopropyl-carbamate (530.4 mg, 3.0 mmol), (Z)-benzyl 3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (1.10 g, 2.9 mmol) and TFA (223.4 μL, 2.9 mmol) in dichloromethane (10 mL) was stirred 2 h. The reaction was concentrated to ⅓ volume, then TFA (˜1.5 mL) was added. The mixture was stirred for 30 min, then concentrated, neutralized with excess Et3N, re-concentrated, and purified by column chromatography (0-60% EtOAc/hexanes) to give benzyl 1-isopropyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (1.1 g, 91%) as a pale yellow oil. ESI-MS m/z calc. 417.2. found 418.3 (M+1)+; Retention time: 2.07 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C:24]([F:27])([F:25])[F:26])[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: FC(F)(F)c1ccncc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cnccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (604 mg, 4.2 mmol) was dissolved in anhydrous DMF (30 mL), and then potassium carbonate (1.76 g, 12.8 mmol) and 3-(bromomethyl)-4-(trifluoromethyl)pyridine (5.5 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 12% DCM/MeOH to afford 6-methyl-2-({[4-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)pyrimidin-4-ol (349 mg, 21% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.22 (s, 3H), 4.59 (s, 2H), 6.07 (bs, 1H), 7.75 (d, J=5.3 Hz, 1H), 8.76 (d, J=5.1 Hz, 1H), 9.02 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([OH:9])[CH:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]([CH3:10])[C:4](=[O:9])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Br)cc(Cl)n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(Cl)cc(Br)cc1=O
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 4-bromo-6-chloropyridin-2-ol (1.0 equiv.) in DMF (0.16 M) was added potassium carbonate (2.0 equiv.) and iodomethane (1.2 equiv.) at room temperature. The solution was stirred for 2 hours, then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate two more times, the organic phase was washed with brine, dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and heptanes (0-50% ethyl acetate). The pure fractions were concentrated to yield 4-bromo-6-chloro-1-methylpyridin-2(1H)-one in 38% yield. LCMS (m/z) (M+H)=221.9/223.9, Rt=0.64 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]2([CH3:20])[NH:16][C:15](=S)[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10](=[O:19])(=[O:18])[CH2:9]2)[CH:7]=1.[NH3:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]2([CH3:20])[N:16]=[C:15]([NH2:22])[C:11]3([CH2:14][CH2:13][CH2:12]3)[S:10](=[O:19])(=[O:18])[CH2:9]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CCC2)C(=S)N1
Reactant: N
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CCC2)C(N)=N1
Temperature: 60 °C
Reaction time: 40 h
Yield: 55.6 %

Procedure:
A mixture of (R)-7-(5-bromo-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]nonan-9-thione (1.05 g, 2.68 mmol, Eq: 1.00) and ammonia (7 N in MeOH) (19.1 ml, 134 mmol, Eq: 50) was stirred in a sealed tube for 40 hours at 60° C. Extracted with ethyl acetate and sat. NaHCO3-sol., dried the organic layer over Na2SO4, filtered and evaporated. The residue was chromatographed on 20 g silica gel with ethyl acetate to give (R)-7-(5-bromo-2-fluoro-phenyl)-7-methyl-5,5-dioxo-5λ6-thia-8-aza-spiro[3.5]non-8-en-9-ylamine (560 mg, 1.49 mmol, 55.8% yield) as a white solid. MS (ISP): m/z=375.0 [M+H]+ and 377.4 [M+2+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[C:30]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([N:39]3[CH2:40][CH2:41][N:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:37][CH2:38]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(N3CCN(c4ccccc4)CC3)n2)cc1
Yield: 73 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (40 mg, 73% yield.) MS/ES+: m/z=476.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][OH:35])=[NH:33])=[CH:30][N:29]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:35][N:34]=[C:32]([C:31]4[CH:36]=[CH:37][C:28]([NH2:27])=[N:29][CH:30]=4)[N:33]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5cccc(C(F)(F)F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.31) (188 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a yellow solid (22 mg, 9%). MS (ISP) 492.1 [(M+H)+]; mp 264° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH:26][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:16]
Reactant: NCc1cccc(Cl)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1cccc(Cl)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 3-chloro benzylamine (45 mg, 0.32 mmol). The title compound was obtained as a solid (66 mg, 50% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.41 (1H, m), 8.98 (2H, m), 8.47 (1H, s), 7.34 (3H, m), 7.24 (1H, m), 4.39 (2H, m). MS m/z: 471.98, 473.99 [M+H]+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:3]2[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]3/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/3)[CH2:5][CH2:4]2)=[C:23]([C:29]([F:30])([F:31])[F:32])[CH:22]=1
Reactant: O=Cc1ccc(Cl)cc1C(F)(F)F
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(Cl)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (1.00 g) in DMF (15.5 mL) were added 4-chloro-2-(trifluoromethyl)benzaldehyde (1.10 g) and triethylamine (1.95 mL). The reaction mixture was stirred at room temperature for 1.5 hr, and sodium triacetoxyborohydride (2.28 g) was added. The reaction mixture was stirred at room temperature for 1 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.04 g).
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[Br:20])=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[Br:20][C:14]1[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:13]=1[NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)Nc1cc(Br)ccc1Br)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(Br)ccc1Br
Temperature: 62.5 °C
Yield: 68.3 %

Procedure:
To a solution of 1-benzoyl-3-(2,5-dibromo-phenyl)-thiourea II (3.90 g, 11.8 mmol) in THF (80 mL) was added NaOH solution (1.13 g in 20 mL H2O) at room temperature. The reaction mixture was then heated up to 60-65° C. overnight. After completion of the reaction (TLC monitoring) THF was distilled off followed by addition of water, and extracted with ethyl acetate (2×50 mL). The combined organic layers were combined and dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude residue was washed with mixture of hexane and diethyl ether (95:5) and dried under high vacuum to obtain the desired product as pale-yellow solid (2.5 g, 86%). 1H NMR (DMSO-d6, 400 MHz): δ 7.35 (dd, J=8.80 and 2.80 Hz, 1H), 7.48 (br s, 1H), 7.60 (d, J=8.40 Hz, 1H), 7.87 (d, J=2.40 Hz, 1H), 8.0 (br s, 1H) and 9.33 (br s, 1H). MS: 308.98 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[C:7]([NH:15][CH:16]=[N:17][OH:18])=[C:8]([C:11]([O:13]C)=O)[S:9][CH:10]=1.O>O1CCCC1.N1C=CC=CC=1.CN1CCCC1=O>[C:1]([O:18][N:17]1[C:11](=[O:13])[C:8]2[S:9][CH:10]=[C:6]([Br:5])[C:7]=2[N:15]=[CH:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1scc(Br)c1NC=NO
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(=O)On1cnc2c(Br)csc2c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of acetyl chloride (0.234 g) in dry tetrahydrofuran (3 ml) was added a solution of the product from Example 4 (0.741 g) in pyridine (0.237 g) and N-methylpyrrolidone (5 ml) at room temperature. The solution was stirred at room temperature for 3 days and then poured into water (15 ml). The resulting precipitate was filtered, washed with water and dried to give title product, m.p. 159-162° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:8]([CH3:26])=[N:9][C:10]2[N:11]([N:23]=[CH:24][CH:25]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])=[O:6].O>CO>[CH3:3][O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:22])[F:20])[N:11]2[N:23]=[CH:24][CH:25]=[C:10]2[NH:9][C:8]=1[CH3:26])=[O:6]
Reactant: COC(=O)c1c(C)nc2ccnn2c1-c1ccccc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1=C(C)Nc2ccnn2C1c1ccccc1C(F)(F)F
Temperature: 60 °C

Procedure:
16 mg of sodium borohydride is added gradually to a solution of 17 mg of 6-methoxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)pyrazolo[1,5-a]pyrimidine in 1 ml of methanol with stirring and heating at 60° C. The reaction mixture is poured into water, extracted with ethyl acetate and dried. The solvent is removed and the residue is recrystallized from methanol to give 6-methoxycarbonyl-5-methyl-7-(2-trifluoromethylphenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine, melting at 209°-210° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.CCOC(C)=O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:9])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(N(C)c2ccc(O)cc2)c2ccccc2n1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 60 °C

Procedure:
(4-Hydroxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine (468 mg, 1.41 mmol) and K2CO3 were dissolved in DMF (10 mL). Methyl bromoacetate (0.67 mL, 7.08 mmol) was added and the reaction was heated at 60° C. for 2 h. The mixture was cooled and diluted with EtOAc. The organics were washed with water (2×) and dried over MgSO4. The title compound was purified by preparative RPLC. 1H NMR (DMSO-d6) δ 7.64 (d, 1H), 7.59 (t, 1H), 7.20 (d, 2H), 7.05 (t, 1H), 7.0-6.9 (m, 3H), 4.85 (s, 2H), 3.71 (s, 3H), 3.50 (s, 3H), 2.58 (s, 3H); LC-MS (ESI+; 338 ([M+H]+)).