Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:18]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][O:40][C:41](=[O:45])[CH2:42][CH2:43][NH2:44].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][O:40][C:41](=[O:45])[CH2:42][CH2:43][NH:44][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([CH:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:31][CH:30]=1
Reactant: COC(=O)CCN
Reactant: CC(C)CC(Nc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a mixture of 4-[1-(4′-tert-butyl-biphenyl-4-ylamino)-3-methyl-butyl]-benzoic acid (310 mg, 0.75 mmol) in methylene chloride (7 mL) are added triethyl amine (0.31 mL, 2.24 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (156 mg, 1.12 mmol) and EDCI (431 mg, 2.24 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, and eluted with hexanes using a gradient from 0-100% ethyl acetate to provide 230 mg of the titled compound as a white solid. 1H-NMR.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([N:34]3[CH2:45][CH2:44][C:43]4[C:42]5[CH2:41][C:40]([CH3:47])([CH3:46])[CH2:39][C:38]=5[S:37][C:36]=4[C:35]3=[O:48])[C:31]=2[CH:32]=[O:33])=[CH:3]1.[BH4-].[Na+].[CH3:51][OH:52]>>[OH:33][CH2:32][C:31]1([CH:51]=[O:52])[C:30]([N:34]2[CH2:45][CH2:44][C:43]3[C:42]4[CH2:41][C:40]([CH3:46])([CH3:47])[CH2:39][C:38]=4[S:37][C:36]=3[C:35]2=[O:48])=[CH:29][N:28]=[CH:27][CH:26]1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:20][CH2:21]3)=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2cncc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: Cn1cc(C2C=NC=C(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)C2(C=O)CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a solution of 106j (130 mg, 0.20 mmol) in methanol (5 mL) at 0° C. was added sodium borohydride (22 mg, 0.6 mmol) and stirred for 30 minutes. Then the reaction mixture was quenched with water (1.0 mL) and concentrated. The residue was purified by reverse-phase prep-HPLC to afford 106 (60 mg, 45%) as a yellow solid. LCMS: [M+H]+ 668. 1H NMR (500 MHz, DMSO) δ 8.58 (d, J=2.0, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 7.87 (d, J=2.5, 1H), 7.38-7.36 (m, 2H), 7.24-7.22 (m, 1H), 5.15 (t, J=5.0, 1H), 4.56-4.42 (m, 6H), 4.08-4.04 (m, 2H), 3.60 (s, 3H), 3.43-3.42 (m, 1H), 3.07-2.94 (m, 6H), 2.55-2.53 (m, 4H), 2.39-2.38 (m, 4H), 1.23 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[Cl:13]Cl.Cl>>[Cl:13][C:9]([CH3:10])([CH3:11])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:12]
Reactant: ClCl
Reactant: CC(C)C(=O)c1ccc(Cl)cc1
Agent: Cl
Product: CC(C)(Cl)C(=O)c1ccc(Cl)cc1

Procedure:
182.7 g (1.0 mol) of 1-(4-chlorophenyl)-2-methylpropan-1-one are warmed to 40° and chlorinated with 71 g (1.0 mol) of chlorine gas at 40°-65° in the course of 5 hours. The dissolved HCl gas is then driven off by blowing with nitrogen. The liquid crude product is then reacted further.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[NH:13][C:14](=[O:16])[CH3:15])([O-:3])=[O:2].[OH2:17]>CC(O)=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:17])=[CH:6][C:5]=1[NH:13][C:14](=[O:16])[CH3:15])([O-:3])=[O:2]
Reactant: O
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Temperature: 17.5 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of CrO3 (26.5 g) in a mixture of 15 ml of H2O and 235 ml of AcOH was prepared by sonicating the suspension for 45 min. The resulting solution was added dropwise to a cooled solution of N-(6-nitro-indan-5-yl)-acetamide (22 g, 0.1 mol) in Ac20 (2.5 L) while maintaining the temperature between 15-20° C. After the addition was completed, the mixture was stirred at 25° C. overnight, poured into 10 L of water, and stirred for 1 h. The solution was then extracted with two 2-L portions of CH2Cl2. The organic layers were combined, and concentrated to 500 ml, washed with two 50-ml portions of 10% NaOH followed by water, and then dried (Na2SO4). The solvent was removed, leaving a yellow powder (16 g, 75%), which was used for next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6](=[O:18])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([CH3:11])[C:9]=1[CH3:10].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[OH:2][CH2:3][CH2:4][C:5]1[C:6](=[O:18])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([CH3:11])[C:9]=1[CH3:10]
Reactant: COC(=O)Cc1c(C)n(C)n(-c2ccccc2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(CCO)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a cooled (0° C.) solution of (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-acetic acid methyl ester (122 mg, 0.479 mmol) in ethanol (5 mL) were added CaCl2.2H2O (68.9 mg, 0.469 mmol) and sodium borohydride (37.4 mg, 0.937 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 4-(2-hydroxy-ethyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one (33.7 mg, 31% yield). LCMS 233.3 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1)[CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[F:24][C:19]1[CH:18]=[C:17]([N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=2)=[O:34])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1)c1ccc(F)c(F)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccc(F)c(F)c2)c2ccccc2)c1
Yield: 10.2 %

Procedure:
The procedure is analogous to that described in Example 1, but 3.8 g of 2-(2-amino-N-phenylacetamido)-N-(3,4-difluorophenyl)-N-methylacetamide and 1.4 g of 3-methylphenyl isocyanate are used as the starting material. The crude product obtained is purified by chromatography on 80 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: ethyl acetate/cyclohexane (75-25 by volume)], collecting 20 cm3 fractions. Fractions 3 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from a cyclohexane/ethyl acetate mixture (50-50 by volume), 0.5 g of N-(3,4-difluorophenyl)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 163° C is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:34])[NH:29]3)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22]
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 300 mg (0.93 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 149 mg (0.93 mmol) of 5-aminoquinolin-2(1H)-one and 0.27 ml of titanium tert-butoxide are reacted to give 5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one. 210 mg of chromatographically purified imine (silica gel, hexane/ethyl acetate 0-80%) are cyclized in the same way as in Example 130 at −30° C. with 3.6 ml (3.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-100%) yields 203 mg of desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:15]=1C(O)=O>>[OH:10][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:1]([C:20]3[CH:19]=[CH:15][C:14]([OH:13])=[CH:22][C:21]=3[OH:23])[O:2][C:3]=2[CH:9]=1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: COc1ccc(N)c(OC)c1
Product: Oc1ccc(-c2nc3ccc(O)cc3o2)c(O)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,4-dimethoxyaniline, and 2,4-dimethoxybenzoic acid and was obtained as a white solid, m.p. 293–296° C.; MS m/e 242 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH2:30]1[C@@H:35]2[CH2:36][CH2:37][CH2:38][N:34]2[CH2:33][C@H:32]([CH2:39]O)[O:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:39][C@@H:32]5[O:31][CH2:30][C@@H:35]6[CH2:36][CH2:37][CH2:38][N:34]6[CH2:33]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: OC[C@H]1CN2CCC[C@H]2CO1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@H]1CN2CCC[C@H]2CO1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and [(3R,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl]methanol (prepared as described in WO 2004/006846) following General Procedure J.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C([O-])([O-])=O.[K+].[K+].[CH2:18]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCNCCCCCC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 86 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (1.59 g, 10 mmol) in DMSO (15 mL) were added K2CO3 (3.04 g, 22 mmol) and di-n-hexylamine (2.04 g, 11 mmol). The mixture was heated at 90° C. overnight, then cooled to rt, diluted with water (50 mL) and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=10:1) to give the title compound as pale yellow oil (2.79 g, 86%).
Reaction SMILES: N1C=CN=C1.[NH2:6][C@H:7]([C:11]([OH:13])=[O:12])[CH2:8][CH2:9][OH:10].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C=O)C>[NH2:6][CH:7]([CH2:8][CH2:9][O:10][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@@H](CCO)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC(N)C(=O)O
Reaction time: 0.25 h

Procedure:
Imidazole (20.4 g, 300 mmol) is added to a solution of homoserine (11.9 g, 100 mmol) in DMF (100 mL) and the solution is stirred 15 minutes then cooled to 0° C. tert-Butyldimethylsilyl chloride (13.7 g, 91 mmol) added and the mixture is stirred for ten minutes at 0° C. the for 4 hours at room temperature. The reaction mixture is poured into water (3 L) and the resulting solid is collected by filtration. The isolated product is dried and used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]([CH3:21])([CH3:20])[C:16]([F:19])([F:18])[F:17])[CH:9]=1.CS(O[CH2:27][C@@H:28]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:29])(=O)=O.O>CN(C)C=O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:29][C@@H:28]([NH:30][C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH3:27])=[C:10]([C:15]([CH3:21])([CH3:20])[C:16]([F:17])([F:18])[F:19])[CH:9]=1
Reactant: CC(C)(c1cc(Cl)ccc1O)C(F)(F)F
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1ccc(Cl)cc1C(C)(C)C(F)(F)F)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Cesium carbonate (2.05 g, 6.28 mmol) was added to a solution of 4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenol (C48) (500 mg, 2.10 mmol) in N,N-dimethylformamide (5 mL). (2S)-2-[(tert-Butoxycarbonyl)amino]propyl methanesulfonate (P12) (0.53 g, 2.1 mmol) was added, and the reaction mixture was heated to 60° C. After 30 minutes, additional P12 (0.53 g, 2.1 mmol) was added, and heating was continued for 18 hours. Water (100 mL) was added, and the mixture was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 15% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 625 mg, 1.58 mmol, 75%.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[N:10]=[C:9]([CH3:14])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C([N:17]([CH2:20][CH3:21])[CH2:18]C)C.CC1CN1>C(Cl)Cl>[CH2:12]([N:11]1[C:3]2[C:2]([N:17]3[CH2:18][CH:20]3[CH3:21])=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[C:9]([CH3:14])=[N:10]1)[CH3:13]
Reactant: CCN(CC)CC
Reactant: CCn1nc(C)c2nc(C)nc(Cl)c21
Agent: CC1CN1
Solvent: ClCCl
Product: CCn1nc(C)c2nc(C)nc(N3CC3C)c21
Reaction time: 20 h

Procedure:
A solution of 4.2 g (0.02 mol) of 7-chloro-3,5-dimethyl-1-ethyl-1H-pyrazolo[4,3-d]pyrimidine (Ex. 16), 3 ml of triethylamine and 5 ml of 2-methylaziridine in 100 ml of methylene dichloride is allowed to stand at room temperature 20 hours. The solution is washed with saturated sodium bicarbonate solution, dried (MgSO4), and evaporated in vacuo to give 4 g of 1-ethyl-3,5-dimethyl-7-(2-methylaziridinyl)pyrazolo[4,3-d]pyrimidine as an oil, characterized by IR and NMR. The aziridine (4 g, 0.017 mol) in 40 ml of acetone is refluxed 1.5 hours with 3 g (0.02 mol) of sodium iodide. The solution is evaporated in vacuo. The residue is partitioned in 100 ml of methylene dichloride and 30 ml of 20% sodium carbonate solution. The organic layer is separated, dried over magnesium sulfate, and the solvent is evaporated in vacuo to give 2.8 g (71%) of the title compound, mp 145°-147° C. from ethyl acetate-pet ether.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([S:27]([NH2:30])(=[O:29])=[O:28])[CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([NH:30][S:27]([CH:24]2[CH2:26][CH2:25]2)(=[O:29])=[O:28])=[O:21])=[CH:22][CH:23]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NS(=O)(=O)C2CC2)cn1
Yield: 56 %

Procedure:
As described for example 233, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (128 mg, 0.41 mmol) was converted, using cyclopropanesulfonic acid amide instead of butane-1-sulfonic acid amide, to the title compound (96 mg, 56%) which was obtained as an off white solid. MS: m/e=412.1 [M−H]−.
Reaction SMILES: [C:1]([CH:6]([C:18]([OH:20])=O)[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])([O:3][CH2:4][CH3:5])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:27][C:28]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:29]=1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>C(Cl)Cl.CN(C)C=O>[C:30]([C:29]1[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=1[NH:27][C:18](=[O:20])[CH:6]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)Nc1cc(Cl)ccc1C(=O)c1ccccc1

Procedure:
A suspension of 45.0 g. of 2-carbethoxy-N-(benzyloxycarbonyl)glycine in 120 ml. of dry methylene chloride, cooled to -20° C., is treated portionwise with 30 g. of phosphorus pentachloride and stirred for 30 minutes at -20° C. to -10° C. To the now clear solution, there is added at the same temperature a solution of 27.7 g. of 2-amino-4-chlorobenzophenone and 1 ml. of dimethylformamide in 120 ml. of dry methylene chloride. The mixture is concentrated under reduced pressure at 40°-45° C. The residue is partitioned between methylene chloride and 10% aqueous soda solution and the methylene chloride phase is dried over sodium sulfate and evaporated to dryness. There is obtained a reddish-colored resin of crude 2'-benzoyl-2-[(benzyloxycarbonyl)amino]-2-carbethoxy-5'-chloroacetanilide, which is then immediately reacted with 130 ml. of a 33% solution of hydrobromic acid in glacial acetic acid. After stirring at room temperature for 90 minutes, the obtained solution is concentrated at 45° C. and the oily residue partitioned between water and ether. The aqueous solution is made weakly alkaline with solid sodium bicarbonate while cooling with ice. The separated base is extracted with methylene chloride and the extracts are dried over sodium sulfate and evaporated to dryness. The resulting oil is dissolved in a mixture of 180 ml. of toluene and 180 ml. of glacial acetic acid and heated at 80° C. for 90 minutes. The solution is concentrated to an oil and is crystallized from ether so that there is obtained 8-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ethyl ester, having a melting point of 214°-217° C. (decomposition). Recrystallization from acetonitrile does not increase the melting point.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8](F)(F)[C:9]([F:18])=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CCCCC>[F:18]/[C:9](=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])/[C:8]([O:7][CH3:6])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCC=C(F)C(F)(F)OC
Solvent: CCCCC
Product: CCCCCCC/C=C(\F)C(=O)OC
Temperature: 20 °C
Reaction time: 40 h
Yield: 54.5 %

Procedure:
To a mixture of 3 g 75% sulfuric acid and 15 mL of n-pentane at 20° C. in a round-bottom 50 mL flask was added the crude 1-methoxy-1,1,2-trifluoro-2-decene (1.2 g). The resulting mixture was stirred for 40 hours at 20° C. The reaction mixture was poured into a large excess of ice-water and the liquid extracted twice with diethyl ether. The ether layers were combined, washed with water and brine, then dried over anhydrous magnesium sulfate. Evaporation of solvent gave a yellow oil which was chromatographed on silica gel (5% ethyl acetate in hexanes) to give 0.59 g (64.5%) of methyl (Z)-2-fluoro-2-decenoate as a clear liquid: 1H-NMR (300 MHz, CDCl3): δ 0.86(3H, t), 1.24(1OH), 2.22(2H, dq,J=2,8 Hz), 3.80(3H, s), 6.10(1H, dt, J=8, 33Hz). Mass spectrum: m/e=202 (M+ ). 19F-NMR (CDCl3): φ 131.8(d, J=33.0).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[C:7]([F:32])=[C:8]([CH:29]=[CH:30][CH:31]=1)[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=2)[N:13]=[CH:12][N:11]=1>ClCCl>[Cl:5][C:6]1[C:7]([F:32])=[C:8]([CH:29]=[CH:30][CH:31]=1)[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([C:3](=[O:4])[NH:2][CH3:1])[CH2:23][CH2:22]3)[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCC(Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
Methylisocyanate (20.4 μl, 0.33 mmol) was added dropwise to a mixture of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (120 mg, 0.3 mmol) in dichloromethane (5 ml) at room temperature. The mixture was stirred at room temperature for 4 hours. After evaporation of the solvents under vacuum, the residue was purified by chromatography on silica gel (eluant: 2% 7N methanolic ammonia in dichloromethane) to give the title compound as a white solid (100 mg, 72%).
Reaction SMILES: [Se](=O)=[O:2].[Cl:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1>O1CCOCC1.O>[Cl:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH:15]=[O:2])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: Cc1ccnc2cc(Cl)ccc12
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccnc2cc(Cl)ccc12
Temperature: 85 °C
Reaction time: 6 h
Yield: 74.7 %

Procedure:
Selenium dioxide (4.52g; 40.3mmol) in a mixture of 25ml of dioxane and 6ml of water was added in a dropwise fashion to 7-chlorolepidine (6; 6.50g; 36.6mmol) in 25ml of dioxane to 65 °-75° C. The temperature was raised to 85° C. and maintained there with stirring for 6 hours. After cooling, the mixture was filtered through Celite™ and concentrated. The crude material was purified on a flash column, eluting with 10% ethyl acetate/hexane to obtain 5.24g (74%) of aldehyde 7 as a yellow solid. 1H NMR (CDCl3): δ7.68 (d, 1H); 7.79 (d, 1H); 8.19 (d, 1H); 9.01 (dd, 1H); 9.21 (m, 1H); 10.45 (s, 1H). IR (KBr): 1702, 1499, 1216, 1041, 900, 653 cm-1.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[N:8]1[N:12]2[CH2:13][CH2:14][CH2:15][NH:16][C:11]2=[C:10]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:9]=1>C(O)=O>[CH:1]([N:16]1[CH2:15][CH2:14][CH2:13][N:12]2[N:8]=[CH:9][C:10]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:11]12)=[O:3]
Reactant: O=C(O)CCc1cnn2c1NCCC2
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN1CCCn2ncc(CCC(=O)O)c21
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To formic acid (50 ml) was added acetic anhydride (60 ml), and the mixture was stirred at 40° C. for 2 hours. The resulting mixture was added to the above oily product [3-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionic acid] and the mixture was stirred at room temperature for 15 hours. After evaporation of the solvent in vacuo, to the residue was added water. The mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and concentrated in vacuo. The residue was dissolved in methanol, and the insoluble materials were removed by filtration. The filtrate was concentrated in vacuo to give 3-(4-formyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)propionic acid (23 g) as an oil.