Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][C@@H:15]([C:17]([F:20])([F:19])[F:18])[CH2:14][C@H:13]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[C:30]3[CH2:32][O:33][C:34]4[CH:61]=[C:60]5[C:37]([CH:38]=[CH:39][C:40]6[N:44]=[C:43]([C@@H:45]7[CH2:49][C@H:48]([CH2:50][O:51][CH3:52])[CH2:47][N:46]7[C:53](OC(C)(C)C)=[O:54])[NH:42][C:41]=65)=[CH:36][C:35]=4[C:29]3=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl.[CH3:63][O:64][C:65]([NH:67][C@H:68]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)C(O)=O)=[O:66].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>O1CCOCC1.CN(C=O)C.C(OCC)C>[CH3:63][O:64][C:65](=[O:66])[NH:67][C@H:68]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:53]([N:46]1[CH2:47][C@@H:48]([CH2:50][O:51][CH3:52])[CH2:49][C@H:45]1[C:43]1[NH:42][C:41]2[C:60]3[C:37]([CH:38]=[CH:39][C:40]=2[N:44]=1)=[CH:36][C:35]1[C:29]2[C:30]([CH2:32][O:33][C:34]=1[CH:61]=3)=[CH:31][C:26]([C:23]1[NH:22][C:21]([C@@H:13]3[CH2:14][C@H:15]([C:17]([F:18])([F:19])[F:20])[CH2:16][N:12]3[C:10](=[O:11])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:9])[CH3:8])=[N:25][CH:24]=1)=[CH:27][CH:28]=2)=[O:54]
Reactant: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4C[C@H](C(F)(F)F)CN4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]3)ccc2-5)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4C[C@H](C(F)(F)F)CN4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]3)ccc2-5)N(C(=O)[C@H](NC(=O)OC)c2ccccc2)C1
Reaction time: 1 h

Procedure:
tert-butyl(2S,4S)-2-(9-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-(trifluoromethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (<0.412 mmol, crude from previous step) was treated with 6 mL 4N HCl in dioxane at room temperature overnight and then at 50° C. for 1 hour. Diethyl ether (20 mL) was added and the precipitate of hydrochloride salt was collected by vacuum filtration. (126 mg, 0.16 mmol). This material was combined with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (34 mg, 0.16 mmol), COMU (70 mg, 0.16 mmol), and 1.6 mL of 10% DIPEA in DMF. After 1 hour at room temperature, the mixture was added dropwise into 25 mL saturated sodium bicarbonate, with stirring and the resulting precipitate was collected by vacuum filtration and washed with 2 mL water. The product was purified, then re-purified by reverse phase HPLC. (3.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][NH:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:20]([N:19]([CH3:18])[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH2:14]1)=[O:17])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCNC
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: CCCCN(C)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
300 mg (1.12 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N-methylbutan-1-amine to give after working up and purification 249 mg (66%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[NH3:13]>CC(O)C>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:13])[C:4]=2[CH:3]=1
Reactant: Clc1ncnc2ncc(Br)cc12
Reactant: N
Solvent: CC(C)O
Product: Nc1ncnc2ncc(Br)cc12

Procedure:
6-Bromo-4-chloropyrido[2,3-d]pyrimidine (1.0 g) and 4% NH3 in i-PrOH (25 mL) were stirred in a sealed tube at room temperature overnight. The pale brown heterogeneous slurry was concentrated, diluted with water and filtered. The brown solid thus collected was suction dried to obtain 6-bromopyrido[2,3-d]pyrimidin-4-amine (1.3 g, purity: 97%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (d, J=2.5 Hz, 1H), 9.01 (d, J=2.5 Hz, 1H), 8.52 (s, 1H), 8.31 (br s, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), pyrrolidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (25 ml) as the starting materials. After recrystallisation from ethanol, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-pyrrolidine (2.1 g), melting at 153° C., is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:5]=1.Cl[CH2:17][CH2:18][C:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:21])[CH3:20].O>CN1C(=O)N(C)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:21][C:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:20])[CH2:18][CH2:17][N:8]1[C:4]([CH3:3])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[N:7]1
Reactant: Cc1ccc(-c2n[nH]c(C)n2)cc1
Reactant: CC(C)(CCCl)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(C)n(CCC(C)(C)NC(=O)OC(C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.35 g (34 mmol, 60%) sodium hydride are added at 0° C. to a solution of 4.87 g (28 mmol) 5-methyl-3-p-tolyl-[1,2,4]triazole in 40 mL of DMPU. The reaction mixture is heated to ambient temperature and then stirred for one hour. 9.35 g (42 mmol) tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate and 1.87 g (5 mmol) tetrabutylammonium iodide are added and the mixture is stirred overnight at ambient temperature and then for 2 hours at 80° C. The mixture is combined with water and ethyl acetate, the aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are washed with water and sodium chloride solution, dried with sodium sulphate and evaporated down. The residue is purified by column chromatography (silica gel; petroleum ether/ethyl acetate=1:1). Oil. Yield: 2.97 g (30%); mass spectroscopy [M+H]+=359.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:36]1([C:42]2([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([N:45]1[CH2:46][CH2:47][C:42]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43][CH2:44]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCOC(=O)C1(C2CCCCC2)CCNCC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To 3.22 g (10.9 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-propionic acid dissolved in 20 mL of DMF are added 2.29 g (12.0 mmol) of EDC, 1.62 g (12.0 mmol) of HOBt, 2.62 g (10.9 mmol) of ethyl 4-cyclohexylpiperidine-4-carboxylate (cf. preparation 3-1-2) and 4.6 mL (32.7 mmol) of triethylamine. After stirring for 2 hours 30 minutes, the reaction is stopped by adding aqueous 1N sodium hydroxide solution and the organic products are extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and evaporated. The crude product obtained is chromatographed on silica gel (eluent: 7/3 heptane/EtOAc). 3.70 g of ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionyl]-4-cyclohexyl-piperidine-4-carboxylate in the form of a white powder are obtained in a yield of 66%.
Reaction SMILES: [C:1]([C:4]1[C:14]([OH:15])=[CH:13][C:12]2[CH:11]3[CH2:16][CH:7]([CH2:8][N:9]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:10]3)[C:6]=2[CH:5]=1)(=O)[CH3:2].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>CO.O>[F:20][C:18]([F:21])([F:19])[C:17]([N:9]1[CH2:10][CH:11]2[CH2:16][CH:7]([C:6]3[CH:5]=[C:4]([C:1](=[N:24][OH:25])[CH3:2])[C:14]([OH:15])=[CH:13][C:12]=32)[CH2:8]1)=[O:22]
Reactant: CC(=O)c1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cc2c(cc1O)C1CC2CN(C(=O)C(F)(F)F)C1
Yield: 89.1 %

Procedure:
1-(4-Acetyl-5-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (190 mg, 0.605 mmol), hydroxylamine HCl (99 mg, 1.21 mmol) and sodium acetate (118 mg, 1.21 mmol) were combined in methanol (4 mL) and H2O (1 mL) and warmed to 65° C. for 18 hours. The mixture was cooled, diluted with H2O and extracted with ethyl acetate which was dried (Na2SO4), filtered and concentrated to provide a yellow oil (177 mg, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)/[C:6]([CH3:24])=[C:5]2[CH2:25][C:26]([OH:28])=O.C(Cl)(=O)C([Cl:32])=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)/[C:6]([CH3:24])=[C:5]2[CH2:25][C:26]([Cl:32])=[O:28]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(/C=C2/C(C)=C(CC(=O)Cl)c3cc(F)ccc32)cc(OC)c1OC

Procedure:
(Z)-5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 35 ml) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:5]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:6]3[C:10](=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]=2[CH:13]=1)[CH2:9][CH2:8][CH2:7]3.C([Li])CCC.Cl[Si:32]([CH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:49]=[CH:48][C:47]([C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:46][CH:45]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[C:36]1[CH:54]([CH3:56])[CH3:55])([CH3:34])[CH3:33].[Cl-].[NH4+]>C(OCC)C.C1COCC1.CCCCCC.[Cu](C#N)C#N>[CH3:33][Si:32]([CH3:34])([CH:7]1[C:6]2[C:10](=[C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:12]3[CH2:13][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:9][CH2:8]1)[CH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:45]=[CH:46][C:47]([C:50]([CH3:51])([CH3:52])[CH3:53])=[CH:48][CH:49]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[C:36]1[CH:54]([CH3:55])[CH3:56]
Reactant: CC1=Cc2c(c(-c3ccccc3)c3c(c2-c2ccccc2)CCC3)C1
Reactant: CC(C)C1=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc2C1[Si](C)(C)Cl
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=Cc2c(c(-c3ccccc3)c3c(c2-c2ccccc2)C([Si](C)(C)C2C(C(C)C)=Cc4c(-c5ccc(C(C)(C)C)cc5)cccc42)CC3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To 11.4 g (35.3 mmol) of 6-methyl-4,8-diphenyl-1,2,3,5-tetrahydro-s-indacene (5c) and 100 mg of copper cyanide (I) in 300 ml of diethylether plus 20 ml of THF was added dropwise at −70° C. 16 ml (40 mmol) of 2.5 M of n-butyllithium in n-hexane. The solution was slowly warmed to room temperature and stirred for 3 hrs at room temperature (yellow brown suspension). Then to the suspension was added at −70° C. 13.4 g (35 mmol) of chloro-(2-i-propyl-4-(4-t-butylphenyl)-indenyl)-dimethylsilane and the solution was warmed to room temperature and stirred over the weekend. The resulting brown slurry solution was poured into an aqueous ammonium chloride solution and the organic layer was washed with brine, dried over sodium sulfate and the solvents were evaporated. The crude product was purified by column chromatography to get 17.0 g of amorphous solid (yield: 64%).
Reaction SMILES: [C:1]([S:4][CH:5]([C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=1)[CH2:6][C:7]([NH:9][C@H:10]([C:14]([OH:16])=[O:15])C(C)C)=[O:8])(=[O:3])[CH3:2].F[C:29]1[CH:30]=[C:31]([CH:46]=[CH:47][C:48]=1OC)[C:32](CCC(N[C@H](C(O)=O)C(C)C)=O)=O>>[C:1]([S:4][CH:5]([C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=1)[CH2:6][C:7]([NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH2:32][C:31]1[CH:46]=[CH:47][CH:48]=[CH:29][CH:30]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)CCC(=O)N[C@H](C(=O)O)C(C)C)cc1F
Reactant: COc1ccc(C(=O)C(CC(=O)N[C@H](C(=O)O)C(C)C)SC(C)=O)cc1F
Product: COc1ccc(C(=O)C(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)SC(C)=O)cc1F

Procedure:
By substituting N-[3-(3-fluoro-4-methoxybenzoyl)propionyl]-L-phenylalanine (prepared as described for the L-valine derivative of Example 21), m.p. 140°-146° C. for N-[3-(3-fluoro-4-methoxybenzoyl)propionyl-L-valine in the procedure of Example 21, one can obtain a glass which can be chromatographed over silica gel with hexane-ethyl acetate (4:1) containing 2% acetic acid to obtain N-[3-acetylthio-3-(3-fluoro-4-methoxybenzoyl)propionyl]-L-phenylalanine as a glass.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:36]1([O:41][C:42]2[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=2[O:50][CH3:51])[CH:45]=O)[CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[CH:36]1([O:41][C:42]2[CH:43]=[C:44](/[CH:45]=[CH:5]/[C:4]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:3]=3[Cl:2])[CH:47]=[CH:48][C:49]=2[O:50][CH3:51])[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Clc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(/C=C/c2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A stirred suspension of 2,6-dichlorobenzyltriphenylphosphonium bromide (2.5 g) in dry tetrahydrofuran (30 mL) is treated dropwise with a solution of potassium t-butoxide (0.56 g) in dry tetrahydrofuran (32 mL) at 0° C. After stirring at this temperature for 1 hour, it is treated with a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (1.1 g) in dry tetrahydrofuran (15 mL). The reaction mixture is stirred from 0° C. to 5° C. for 1 hour and 30 minutes, and then allowed to warm to room temperature. After stirring overnight, the mixture is concentrated and the resulting residue is treated with ethyl acetate (200 mL). The resulting organic solution is filtered. The filtrate is concentrated and the resulting residue is subjected to flash chromatography, eluting with dichloromethane, to give trans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethene (1.16 g), m.p. 47°-49° C. [Elemental analysis: C,66.4; H,5.6; Cl,19.4%, calculated: C,66.1; H,5.55; Cl19.5%].
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:4]=1[C:5](OC)=[O:6].[NH3:16]>CN(C)C=O.C(OCC)(=O)C>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:3]2[C:4]=1[C:5](=[O:6])[NH:16][CH2:2]2)([O-:15])=[O:14]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NCc2cccc([N+](=O)[O-])c21

Procedure:
1.5 g (5.473 mmol) methyl 2-bromomethyl-6-nitro-benzoate are dissolved in 20 ml N,N-dimethylformamide and combined with 15 ml of methanolic ammonia (7 mmol/ml). After 20 h at 25° C. the mixture is diluted with 100 ml of ethyl acetate and extracted 3 times with saturated sodium hydrogen carbonate solution. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31].[H-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][N:36]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:42][O:41][C:38]1[CH:37]=[N:36][C:35]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[N:40][CH:39]=1
Reactant: COc1cnc(Cl)nc1
Reactant: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCOc2ncc(OC)cn2)c1Oc1ccccc1OC
Temperature: 75 °C
Yield: 55.2 %

Procedure:
Ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (89 mg) was dissolved in THF (6 ml). Sodium hydride (40 mg) and 2-chloro-5-methoxy-pyrimidine (92 mg) were added and the mixture was heated to 75° C. for 46 h, then poured onto water, acidified with solid citric acid and the precipitate was filtered off. The crude material was purified by crystallization from methanol to give ethanesulfonic acid [6-[2-(5-methoxy-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (61 mg) as a white powder. LC-MS: tR: 3.87, [M−H]+: 554.02.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:30]>>[OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]3[O:25][N:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]=3)[CH2:9]2)=[O:7])[CH2:3]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: NC(=NO)c1ccccc1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccc3)no2)C1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 42.3 mg (0.295 mmol) of N′-hydroxybenzenecarboximidamide (95% pure) were reacted according to the General Method 1. Yield: 48 mg (36% of theory).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: NCCCCCCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=C(O)CCCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
11-Aminoundecanoic acid (4.02 g, 0.02 mol) was treated with 4-chlorobenzenesulphonyl chloride (4.22 g, 0.02 mol) as described in Example 4 to give the title compound which was recrystallised from 2-propanol/ether (1.8 g, m.p. 128°-9° C.).
Reaction SMILES: [O:1]1[C:5]2=[N:6][C:7]3[C:13](=O)[O:12][C:10](=[O:11])[C:8]=3[CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH2:15][C:16]([CH3:23])([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18].CCOCC>C1COCC1>[CH:20]([C:16]1([CH3:23])[C:17](=[O:18])[NH:19][C:13]([C:7]2[N:6]=[C:5]3[O:1][CH:2]=[CH:3][C:4]3=[CH:9][C:8]=2[C:10]([OH:12])=[O:11])=[N:15]1)([CH3:22])[CH3:21]
Reactant: O=C1OC(=O)c2nc3occc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
Furo[2,3-b]pryidine-5,6-Dicarboxylic anhydride (2.50 g, 0.013 mol) is suspended in 40 mLs anhydrous THF and (+)-2-amino-2,3-dimethylbutyramide (1.72 g, 0.013 mol) is added. The mixture is stirred under N2 at room temperature for 16 hours. The solution is poured into 150 mLs anhydrous ether, and the resulting solid is collected in 88.6% crude yield. The unpurified adduct is converted to the indicated product in the manner described in Example 38 for the racemic mixture. The (+)-isomer is recrystallized from absolute ethanol, and is isolated in 27.0% yield from the adduct, mp 244°-245° C. [α]D25 =44.5°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[N:10]([C:11]([S:17][CH3:18])=[N:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].B(F)(F)F.CCOCC.C(#N)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]([C:19](=[O:21])[CH3:20])=[C:15]3[N:10]([C:11]([S:17][CH3:18])=[N:12][CH:13]=[CH:14]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc2cc(-c3ccc(F)cc3)nn12
Reactant: CC(=O)OC(C)=O
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CSc1nccc2c(C(C)=O)c(-c3ccc(F)cc3)nn12
Temperature: 90 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidine (150 mg, 0.58 mmol) in toluene (10 mL) was added acetic anhydride (0.065 mL, 0.69 mmol), followed by boron trifluoride diethyl etherate (0.080 ml, 0.64 mmol). An additional 10 mL of toluene was added and the mixture heated to 90° C. Acetonitrile (10 mL) was added to the reaction and the mixture heated at 70° C. for additional 16 hours. Additional acetic anhydride (0.11 mL, 1.1 mmol) and boron trifluoride diethyl etherate (0.15 ml, 1.2 mmol) were added dropwise to the reaction mixture at 90° C. The reaction was stirred for 1 hour, cooled to room temperature, stirred for 16 hours, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered, concentrated, and the residue purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to yield 110 mg (63%) of 1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]ethanone. 1H NMR (CDCl3): δ 8.13 (d, 1H), 7.98 (d, 1H), 7.65 (dd, 2H), 7.27 (m, 2H), 2.77 (s, 3H), 2.23 (s, 3H). MS m/z 302 (M+1).
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[C:21]([O-:24])([O-])=O.[K+].[K+]>C(O)C>[OH:12][CH:11]([CH2:13][N:16]1[CH2:17][CH2:18][CH:13]([C:11](=[O:12])[C:10]2[CH:9]=[CH:8][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:20][CH:19]=2)[CH2:14][CH2:15]1)[CH2:10][O:24][C:21]1[CH:19]=[CH:20][C:7]([NH:6][S:3]([CH3:2])(=[O:5])=[O:4])=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(OCC(O)CN2CCC(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Reaction time: 24 h
Yield: 155.8 %

Procedure:
A stirred solution of 4-[4-methylsulfonylaminobenzoyl)piperidine hydrochloride (2.25 g, 7.06 mmol), 2-[(4-(methylsulfonyamino)phenoxy)-methyl]oxirane (U.S. Pat. No. 4,994,459, 1.73 g, 7.06 mmol) and K2CO3 (0.98 g, 7.06 mmol) in ethanol (40 mL) was heated at 90° C. for 24 hours and then at 25° C. for an additional 24 hours. The mixture was concentrated and the residue was partitioned between aqueous 10% NaHCO3 and 4:1 CH2Cl2 /isopropanol. The organic phase was dried and concentrated to afford 2.89 g (78%) of the title compound. A portion (1.60 g) was purified by HPLC (15% CH3OH/EtOAc) to give 0.92 g of product as a white solid: mp 179°-183° C. (dec); 1H NMR (DMSO-d6): δ 10.20 (brs, 1H), 9.33 (brs, 1H), 7.94 (d, J=8.72 Hz, 2H), 7.26 (d, J=8.92 Hz, 2H), 7.13 (d, J=9.13 Hz, 2H), 6.91 (d, J=8.92 Hz, 2H), 4.83 (m,1H), 3.93 (m, 2H), 3.85 (m, 1H), 3.09 (s, 3H), 2.96 (m, 2H), 2.87 (s, 3H), 2.45 (m, 2H), 2.20 (m, 2H), 1.75-1.50 (m, 4H); IR (KBr): 3420, 3300, 3250, 2910, 1675, 1610 cm-1 ; MS (m/z) 526 (MH+, 25%), 217 (40), 91 (100).