Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.OS(O)(=O)=O.[OH-].[Na+].[CH:19]([OH:21])=[O:20]>>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[C:19]([OH:21])=[O:20])[CH2:9]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1C2CC3CC(C2)CC1C3
Reaction time: 1.5 h

Procedure:
hydroxyadamantane were dissolved in 30 mls of HCOOH 98-100 %, and this solution was added dropwise, while stirring vigorously, to 1.5 1. of H2SO4 96% cooled to 5°C. Stirring was then continued at the same temperature for 90 minutes and the mixture was finally poured out on ice. NaOH was added to the mixture until it has a pH of approximately 1 and the formed precipitate was extracted with diethyl ether. The extract was dried over Na2SO4 and the solvent was then evaporated. The cruse 2-adamantyl carboxylic acid was thus obtained, which was purified by two crystallizations from 70% ethanol. The purified acid had a melting point of 142-144°C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23]>>[C:22]([C@@H:21]([NH:20][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH:11]([CH3:16])[C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:19])[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[NH2:24]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CC(Oc1nc(C(=O)O)ccc1C1CC1)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OC(C)C(F)(F)F)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=388.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C(=O)Cl)c1

Procedure:
3,5-Dimethylbenzoic acid (25 g, 0.17 mol) and N,N-dimethylformamide (0.1 mL) were added to thionyl chloride (50 mL) at 0° C. The mixture was heated to reflux for 2 hours. The excess thionyl chloride was distilled off under reduced pressure and toluene (50 mL) was added to the residue. Toluene was distilled off under reduced pressure to obtain oily 3,5-dimethylbenzoyl chloride. A solution of propyleneimine (14 mL, 0.18 mol) in tetrahydrofuran (160 mL) was added to 1N aqueous sodium hydroxide (180 mL). To the solution was added dropwise 3,5-dimethylbenzoyl chloride at 0° C. After complete addition, the mixture was further stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off to obtain 31 g of the title compound (0.16 mol, yield 99%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:6]([OH:7])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:19][C:2]1([CH3:1])[CH:6]([O:7][C:27]([NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(O)C(C)(C)O1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC1(COCc2ccccc2)CC(OC(=O)Nc2ccccc2)C(C)(C)O1
Yield: 100 %

Procedure:
The alcohol of Example 3 (1 g) was dissolved in benzene (15 ml) and phenylisocyanate (600 mg) and a few drops of triethylamine were added. The mixture was refluxed for 20 hours. The solvent was then evaporated and the residue was taken up in ethyl acetate, washed with dilute hydrochloric acid and then with brine, dried over magnesium sulphate and evaporated down. The residue was purified on a silica column using 5% acetone in petrol as eluant. 1.4 g, corresponding to a 100% yield, of the desired product, as a viscous oil, were obtained. NMR showed the presence of both geometric isomers.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12]C>Br.C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1F
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)c(F)c1F
Temperature: 25 °C

Procedure:
A solution of 2,3-difluoro-4-nitroanisole (10 g) in 48% HBr (60 mL) and 30% HBr in acetic acid (30 mL) was stirred at 120° C. overnight. The mixture was cooled to room temperature and extracted with ethyl acetate (3×200 mL) and the combined extracts were washed with brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the product.
Reaction SMILES: [O-]CC.[Na+].[I:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].C(O)C.[C:19](OCC)(=[O:25])[C:20]([O:22]CC)=[O:21]>O>[I:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][C:19](=[O:25])[C:20]([OH:22])=[O:21]
Reactant: Cc1c(I)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)Cc1c(I)cccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Sodium ethoxide solution (35 ml, 44 mmol) in an ice-water bath was added dropwise with a solution of 1-iodo-2-methyl-3-nitro-benzene 74b in ethanol (35 ml, 40 mmol) under an argon atmosphere. Upon completion of the addition, the reaction mixture was stirred until substantial brown precipitates were formed, and added with diethyl oxalate (6 ml, 44 mmol) in one portion. The reaction mixture was refluxed at 100° C. in an oil bath for 0.5 hour, added with water (70 ml) and refluxed for another 1 hour. The reaction mixture was concentrated under reduced pressure to evaporate ethanol, washed with ethyl acetate (50 ml) under base condition, adjusted to pH 3 with hydrochloric acid (1M), and extracted with ethyl acetate (30 ml×3). The combined organic extracts were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 3-(2-iodo-6-nitro-phenyl)-2-oxo-propionic acid 74c (2.94 g) as a brown oil to be used directly in the next step.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[C:29](Cl)=[N:28][CH:27]=[CH:26][N:25]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:16][O:15][C:4]1[CH:3]=[C:2]([S:1][C:29]2[C:24]([Cl:23])=[N:25][CH:26]=[CH:27][N:28]=2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: Clc1nccnc1Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(S)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2nccnc2Cl)cc1OC
Yield: 33.3 %

Procedure:
To a solution of 6.45 g of methyl 4-mercapto-5-nitro-o-anisate in N,N-dimethylformamide (100 ml) were added 4.4 g of potassium carbonate and 4.75 g of 2,3-dichloropyrazine. Then the mixture was allowed to react at 80° C. for 2 hours. After adding ethyl acetate, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 3.14 g of the title compound as a brown solid.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])C.[CH2:33]([OH:37])[CH:34]([CH3:36])[CH3:35].Cl.O1CCOCC1>>[CH2:33]([O:37][C:4](=[O:3])[C@H:5]([OH:31])[CH2:6][N:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:22][CH:23]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH:34]([CH3:36])[CH3:35]
Reactant: CCOC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Reactant: CC(C)CO
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)COC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.9 %

Procedure:
(R)-3-[N-(3′-Chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-propionic acid ethyl ester (1.5 g, 3.3 mmol) was dissolved in isobutyl alcohol (20 mL, 200 mmol) and 4 M HCl in dioxane (10 mL, 40 mmol) was added. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated, dissolved in water/MeCNe/MeOH, and purified (Interchim C18 reverse phase chromatography column, 25-75% MeCN in water for 22 minutes). The clean fractions were combined and lyophilized to yield the title compound (948 mg; purity 99%). MS m/z [M+H]+ calc'd for C24H26ClN3O6, 488.15. found 488.4.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:33]1([C:39]([O:41][CH3:42])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:30])(=[O:31])[NH2:29])=[CH:24][CH:23]=3)=[CH:14][CH:13]=2)=[O:32])[CH:4]=1)[N:36]1[CH2:37][CH2:38][N:33]([C:39]([O:41][CH3:42])=[O:40])[CH2:34][CH2:35]1
Reactant: COC(=O)N1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccc(S(N)(=O)=O)cc3)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)Nc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 5.3 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide following procedure C and using 1 equivalent of methyl piperazine-1-carboxylate as secondary amine and 1 equivalent of DIEA as base. The product was purified by preparative HPLC.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([O:26][C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([O:26][C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:3]4[CH2:4][CH2:5][CH:6]([N:9]5[C:17]6[C:12](=[N:13][CH:14]=[CH:15][CH:16]=6)[NH:11][C:10]5=[O:18])[CH2:7][CH2:8]4)[CH:21]=3)=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 mg (0.34 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 100 mg (0.34 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.86 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down and the precipitate was suction filtered and dried i. vac.
Reaction SMILES: [C:1](=[O:26])([O:7][C:8]1[N:12]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=2)[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:1](=[O:26])([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])[O:7][C:8]1[N:12]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(I)cc2)nn1-c1ncccn1
Reactant: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ncccn1
Yield: 95 %

Procedure:
The title compound was prepared in the same manner as in Example C-1, except that an equimolar amount of each of 3-(4-iodophenyl)-1-(pyrimidin-2-yl)-1H-pyrazol-5-yl tert-butyl carbonate (25) prepared in Example B-6 and phenylboronic acid (manufactured by Aldrich) was used in place of Compound 21 prepared in Example B-2 and phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.[Cu](I)I>[Cl:1][C:2]1[C:7]([C:23]#[C:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: C#Cc1ccccc1
Reactant: Clc1ncncc1I
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1ncncc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2.1 g of 4-chloro-5-iodopyrimidine, 10 mL of triethylamine, 1.2 mL phenylacetylene, 80 mg copper iodide and 160 mg of dichlorobis(triphenylphosphine was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane and evaporated in vacuo. The residue was redissolved in a few mL of dichloromethane, 10 mL of triethylamine added and the mixture heated at reflux for one hour. The heterogeneous mixture was evaporated in vacuo and the residue obtained was partitioned between water and dichloromethane. A gelatinous precipitate which formed on shaking the two layers was filtered off, enabling separation of the two layers. The organic extracts were dried over sodium sulfate, filtrated and evaporated in vacuo to yield 2.5 g of a dark brown syrup. The syrup was purified by column chromatography on silica gel, twice, eluting with hexanes, 1:1 hexanes/dichloromethane, dichloromethane and finally ethyl acetate. Like fractions from dichloromethane elution were pooled, obtaining 350 mg of the product, 5-phenylethynyl-4-chloropyrimidine as an oil which solidified to white rosettes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCCO
Reactant: Cc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(-c2[nH]c(-c3ccc(OCCCN(C)C)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-Hydroxyphenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 3-dimethylaminopropanol, triphenyl-phosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(3-dimethylamino-propyloxy)phenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C(Cl)=O.C[N:21](C=O)C.[NH4+].[OH-]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:21])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 88 %

Procedure:
To 5-Fluoro-2-nitro-benzoic acid (3 g, 16,2 mmol) in 200 mL of methylene chloride was added oxalyl chloride (2.26 g, 17.8 mmol) and a drop of DMF. After stirring for 2 h, the solution was poured into concentrated NH4OH. The partial solution was poured into water, extracted with Ethyl acetate, dried (Na2SO4) and concentrated to give 5-Fluoro-2-nitro-benzamide (2.61 g, 88% yield) used without purification. LCMS m/e 185.1(M+H) 183.2 (M−H), HPLC tr=2,9 min (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:44])=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([Cl:44])=[O:32])=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: Cc1ncnc(N2CCOc3ccc(-c4ccc(C(=O)O)cc4)cc3C2)c1Cc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ncnc(N2CCOc3ccc(-c4ccc(C(=O)Cl)cc4)cc3C2)c1Cc1ccc(F)cc1

Procedure:
To a solution of 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoic acid (0.50 g, 1.07 mmol) and DMF (20 μL) in chloroform (15 mL) was added drop wise oxalyl chloride (0.35 mL, 4.0 mmol). The reaction mixture was refluxed for 15 min, and then concentrated to give 4-(4-{5-[(4-fluorophenyl)-methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoyl chloride as an oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]2)=[O:13])=[CH:6][CH:5]=1.CO.[CH2:25](Cl)Cl>CS(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:25][C@H:11]2[C:12]([N:14]2[CH2:15][CH2:16][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][CH2:19]2)=[O:13])=[CH:6][CH:5]=1
Reactant: ClCCl
Reactant: CC(C)N1CCN(C(=O)/C=C/c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)N1CCN(C(=O)[C@@H]2C[C@H]2c2ccc(F)cc2)CC1
Reaction time: 0.05 h
Yield: 57 %

Procedure:
To a vigorously stirring mixture of NaH (300 mg, 12.5 mmol) in DMSO (30 mL) at ambient temperature under an argon (g) atmosphere was added (CH3)3S(I)O (2.50 g, 11.4 mmol) in small portions over 1 min. Following complete addition, the reaction was stirred for 50 min before the rapid dropwise addition of DMSO (10 mL) solution of 10A (1.57 g, 5.68 mmol). After ca. 50 h the reaction was quenched with H2O (80 mL) and extracted into EtOAc (75 mL). The phases were separated and the aq. phase was further extracted with EtOAc (2×70 mL). The combined organics were washed with H2O (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting gum was subjected to flash chromatography (SiO2—40 g; gradient elution: 1% MeOH/DCM for 3 min then 1%-5% MeOH/DCM over 20 min at 40 mL/min) to afford 947 mg 10B (57% yield). m/z (ES+) M+1=291.3; HPLC tR=1.52 min. 1H NMR (500 MHz, CDCl3) δ 7.07 (dd, J=8.7, 5.3 Hz, 2H), 6.96 (t, J=8.7 Hz, 2H), 3.63 (dd, J=14.5, 5.0 Hz, 4H), 2.71 (ddd, J=13.0, 6.7, 6.6 Hz, 1H), 2.57-2.44 (m, 4H), 1.90 (ddd, J=8.3, 5.4, 4.3 Hz, 1H), 1.68-1.56 (m, 2H), 1.21 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 1.04 (d, J=6.4 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH2:7][CH2:6][CH2:5][C:4]=1[NH:8][C:9]([NH:11]C(=O)C1C=CC=CC=1)=[O:10])#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[CH2:7][CH2:6][CH2:5][C:4]=2[NH:8][C:9](=[O:10])[N:11]=1
Reactant: N#CC1=C(NC(=O)NC(=O)c2ccccc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(=O)[nH]c2c1CCC2
Temperature: 25 °C
Yield: 67.5 %

Procedure:
A solution of N-(2-cyanocyclopent-1-enylcarbamoyl)benzamide (example 75a) (500 mg, 1.96 mmol) and NaOH (2 N, 2.7 mL) in EtOH (20 mL) was stirred at 100° C. under nitrogen for 2 hours. After cooling to room temperature, the clear reaction solution was filtered and the filtrate was carefully neutralized with 10% AcOH with vigorous stirring at 0° C. The resultant precipitate was collected by filtration, washed with warm water and then 20% EtOH in water to give the final product 4-amino-6,7-dihydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (200 mg, 68%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ10.57 (brs, 1H), 6.93 (brs, 1H), 6.65 (brs, 1H), 2.56 (t, J=7.2 Hz, 2H), 2.43 (t, J=7.6 Hz, 2H) 1.96-1.89 (m, 2H). MS 152 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:29])[CH2:27][CH:26]([OH:28])[CH2:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:24][CH2:25][CH:26]([OH:28])[CH2:27][C:22]3([CH3:29])[CH3:21])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)CC(O)CCN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(O)CCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2,2-dimethylpiperidin-4-ol (937681-12-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=396.6 [MH+].
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[Li][CH3:24]>C1COCC1.C(Cl)Cl>[CH3:24][C@@:14]1([OH:22])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13]1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [Li]C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
A solution of 17β-methoxy-5α-androstan-3-one (101 mg, 0.33 mmol) in dry THF (20 mL) was treated with MeLi (1 mL, 1.5M in THF, 1.5 mmol) at -75° C. After stirring the mixture at -78° C. for 0.5 hr, the mixture was quenched with NH4Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-methyl-3α-hydroxy-17β-methoxy-5α-androstane (35 mg); mp 151-154° C.; TLC Rf (hexane:acetone 7:3)=0.43; and then 3α-methyl-30-hydroxy-17β-methoxy-5α-androstane (30 mg) as a colorless solid; TLC Rf (hexane:acetone 7:3)=0.27.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:2]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[C:12]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:1]2[CH:5]=[N:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:2]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cc1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
Ethyl (1H-1,2,4-triazol-3-yl)acetate (2.83 g) was dissolved in DMF (40 ml). To the solution were added triphenyl methyl chloride (5.08 g) and triethylamine (2.55 ml). The mixture was stirred for 3 hours at 25° C. The reaction mixture was added to ice-water (150 ml), which was subjected to extraction with ethyl ether (100 ml). The organic layer was washed twice with water (150 ml), which was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: silica gel, 150 g, developing solvent: ethyl acetate-hexane, 1:1) to afford the title compound (2.56 g) as a crystalline product, m.p.117-119° C.