Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:15])C=CC=CC=1.[CH3:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)=[CH:33][CH:32]=1)([CH3:30])C(O)=O>O1CCOCC1>[N:3]([C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:43][CH:44]=2)=[CH:33][CH:32]=1)([CH3:30])[CH3:25])=[C:6]=[O:15]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C(=O)O)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Solvent: C1COCCO1
Product: CC(C)(N=C=O)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 190.3 %

Procedure:
Triethylamine (2.90 ml, 20.8 mmol) and diphenylphosphorylazide (4.48 ml, 20.8 mmol) were added to a 1,4-dioxane solution (70 ml) of 2-methyl-2-[4-(4-trifluoromethylbenzyloxy)phenyl]propionic acid (7.03 g, 10.8 mmol) and heated at reflux. After 2 hours, the solvent was distilled off, and diethylether and water were added to the residue, followed by extraction with diethylether. The result was washed with water and a saturated sodium chloride aqueous solution and dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off to afford the title compound as a pale brown oil (6.89 g, 99%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]2[NH:11][C:12](=[O:20])[CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[CH:8]=1.[CH3:31]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:22]=[CH:21][C:10]2[N:11]([CH3:31])[C:12](=[O:20])[CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:14][C:9]=2[CH:8]=1
Reactant: CCOC(=O)C1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
60% Sodium hydride (1.0 g) was suspended in dimethylformamide (hereinafter abbreviated as DMF) (5 ml) and under ice-cooling, a DMF solution (5 ml) of ethyl 7-(2-chloro-4-trifluoromethylphenoxy)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylate (Compound 1) (0.8 g) was dropwise added thereto, followed by stirring for 10 minutes. Methyl iodide (0.4 g) was then added, the mixture was further stirred for 10 minutes, and to the reaction mixture was added water (20 ml) and the mixture was extracted twice with ethyl acetate (50 ml). The extract was washed with water and then saturated aqueous sodium chloride, and dried over magnesium sulfate. The solvent was then evaporated under a reduced pressure and the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=3/1) to give 0.4 g of the title compound (colorless oil).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[F:17].[CH:18]([O-])([O-])OC.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO.S(=O)(=O)(O)O>C(Cl)Cl>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:1]2[CH2:4][CH:3]([C:5]([O:7][CH3:18])=[O:6])[CH2:2]2)=[CH:11][C:10]=1[F:17]
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: COC([O-])[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Reaction time: 2 h

Procedure:
Azetidine-3-carboxylic acid (43 g, 421 mmol), 4-bromo-3-fluorobenzaldehyde (81.4 g, 401 mmol), methyl orthoformate (219 mL, 2005 mmol), and AcOH (34 mL, 601 mmol) were added to DCM (700 mL) at rt under an N2 atmosphere. The mixture was stirred for 15 min, at which point sodium triacetoxyborohydride (127 g, 601 mmol) was added portion-wise (exothermic). After 2 h, solvent swap with MeOH (257 g, 8019 mmol), and sulfuric acid (79 g, 802 mmol) was added slowly (exothermic). The mixture was heated at reflux for 18 h. Solvent was removed and the mixture was extracted using DCM and water. The organic layer was purified using a Biotage column (isopropanol/heptane), affording methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate as a clear oil. MS (ESI) m/z: Calculated: 301.0; Observed: 302.0 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[C:12]([Si:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)Cl)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1>CN(C)C=O.CN(C)C1C=CN=CC=1>[Si:16]([O:8][CH2:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1cccc(CO)c1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cccc([N+](=O)[O-])c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
A solution of 5 g (33 mmol) of 3-nitrobenzyl alcohol in 100 ml of dimethylformamide was treated with 10.8 g (40 mmol) of tert-butyldiphenylchlorosilane, 6.7 g (99 mmol) of imidazole and 100 mg (0.9 mmol) of 4-(dimethylamino)pyridine and the mixture stirred at ambient temperature for 4 hours. The solvent was evaporated and the residue partitioned between 100 ml of ethyl acetate and 100 ml of 2M aqueous hydrochloric acid. The organic phase was washed with a further 50 ml of 2M aqueous hydrochloric acid, dried over magnesium sulfate, filtered and evaporated to afford 12.9 g (100%) of 3-(tert-butyldiphenylsilyloxymethyl)nitrobenzene as a colorless oil. [Mass spectrum (ESI) MH+ =392].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([Cl:26])=[O:10])=[CH:4][CH:3]=1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]([C@H](C(=O)Cl)c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
19.5 g (73.13 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 860 ml of dichloromethane, and 0.5 ml of DMF was added. At −5° C. to −10° C. (ice/acetone cooling bath), 73 ml (146.26 mmol) of a 2 M solution of oxalyl chloride in dichloromethane were then slowly added dropwise, and the mixture was stirred at this temperature for 1 h. After the reaction had gone to completion, the reaction solution was concentrated under reduced pressure and the residue obtained was taken up in 200 ml of dichloromethane and then once more evaporated to dryness. This gave 20.1 g (70.5 mmol, 96% of theory) of the title compound as a colourless oil. The product obtained in this manner was used without further purification and without further spectroscopic characterization in subsequent reactions.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:11]=[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[C:16]([C:12]1[CH:13]=[CH:14][C:15]([C:5](=[O:7])[CH3:6])=[C:10]([Br:9])[CH:11]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cccc(Br)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.3 %

Procedure:
Aluminum chloride (8.0 g, 60 mmol) was stirred in CH2Cl2 (200 mL), and acetyl chloride (8.5 mL, 120 mmol) was slowly added, producing a homogeneous solution. A solution of 3-bromo tert-butyl benzene (11 g, 50 mmol) in CH2Cl2 (20 mL) was slowly added, and the reaction was stirred at room temperature 16 h. After being diluted with CH2Cl2, the reaction was washed with water, saturated aqueous NaHCO3, and water. The organic solution was dried over Na2SO4 and concentrated under vacuum. Purification by silica gel chromatography (0%-50% CH2Cl2-hexanes) afforded 1-(4-tert-butyl-2-bromophenyl)ethanone (3.1 g, 24% yield) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=1.8 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.37 (dd, J=8.1, 1.8 Hz, 1H), 2.63 (s, 3H), 1.32 (s, 9H) ppm.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH:9]([CH:44]([F:46])[F:45])[CH2:10][C:11]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:12]=1[CH2:13][NH:14][C:15](=[O:38])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:37])[C@H:22]([NH:29]C(OC(C)(C)C)=O)[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[NH2:29][C@H:22]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([NH:14][CH2:13][C:12]1[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:11]=1[CH2:10][CH:9]([NH2:8])[CH:44]([F:46])[F:45])=[O:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CC(N)C(F)F)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(Cc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](N)C1CCCCC1)C(F)F

Procedure:
TFA (0.65 mL) was added to a stirred solution of N-[2-(2-amino-3,3-difluoropropyl)-5-chlorobenzyl]-1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-prolinamide (0.080 g, 0.14 mmol) in CH2Cl2 (0.7 mL). After 1 h the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was partitioned between EtOAc and 1M HCl. The aqueous layer was evaporated in vacuo to give the HCl salt of the title compound as an off white solid; MS m/z=471.5.
Reaction SMILES: C(OC([N:8]1[C:20]2[CH2:19][CH:18]([C:21]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])([F:26])[C:22](=[O:25])[NH:23][CH3:24])[CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=2)=O)(C)(C)C.[H-].[Na+].Br[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[C:30]1([S:27]([C:21]([CH:18]2[CH2:17][CH2:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=4)[NH:8][C:20]=3[CH2:19]2)([F:26])[C:22]([N:23]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:24])=[O:25])(=[O:28])=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CNC(=O)C(F)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
60 mg (0.112 mmol) of (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester (from example 59.1) in 3 mL of THF were treated with 7 mg (0.168 mmol, 1.5 eq) of NaH (55% in oil) at 0° C. over 40 min. 38 mg (0.224 mmol, 2eq) of bromomethly-benzene were added and the reaction mixture was stirred over night at RT. The solvent was evaporated, the residue was dissolved in 3 mL of CH2Cl2, 1 mL of TFA was added, and the reaction mixture was stirred over night at RT. Evaporation of the solvent and purification of the residue by preparative HPLC (C18 column) yielded 35 mg (60%) of (RS,SR)-2-benzenesulfonyl-N-benzyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide as a white solid, MS: 525 (MH+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[N:7]=NN(O)[C:4]2=[CH:3][CH:2]=1.O.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22]([OH:24])=O)[CH3:21])=[O:18])([CH3:15])([CH3:14])[CH3:13].[C:25]1([C@H:31]2[CH2:35][N:34]([S:36]([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[N:44]([C:48](=[O:56])C3C=CC(N)=CC=3)[CH2:43][CH2:42]4)(=[O:38])=[O:37])[C:33](=[O:57])[NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:25]1([C@H:31]2[CH2:35][N:34]([S:36]([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[N:44]([C:48](=[O:56])[C:4]3[CH:3]=[CH:2][C:1]([C:22](=[O:24])[CH:20]([NH:19][C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:18])[CH3:21])=[CH:6][C:5]=3[NH2:7])[CH2:43][CH2:42]4)(=[O:38])=[O:37])[C:33](=[O:57])[NH:32]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: On1nnc2ccccc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(C(=O)N2CCc3cc(S(=O)(=O)N4C[C@H](c5ccccc5)NC4=O)ccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)C(=O)c1ccc(C(=O)N2CCc3cc(S(=O)(=O)N4C[C@H](c5ccccc5)NC4=O)ccc32)c(N)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
To a solution of 1,3-dicyclohexylcarboimide (483 mg, 2.15 mmol) and 1-hydroxybenzotriazolehydrate (291 mg 2.15 mmol) in 10 m of tetrahydrofuran were added N-(t-butoxycarbonyl)-L-alanine (352 mg, 1.86 mmol) and 4-dimethylaminopyridine (50 mg, 0.41 mmol) in order. The reaction mixture was stirred at room temperature for 5 min. Then, (S)-(+)-4-phenyl-1-[N-(4-aminobenzoyl)-indoline-5 -sulfonyl]-4,5-dihydro-2-imidazolone (200 mg, 0.41 mmol) prepared in Example 65 was added thereto and the whole mixture was stirred at room temperature for 24 hours. After stirring, the reaction mixture was filtered. The filtrate was diluted with ethylacetate, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The crude product thus obtained was purified by silica gel column chromatography (eluent: ethylacetate/hexane=2/1, v/v) to provide 260 mg (Yield: 96%) of (S)-(+)-4-phenyl-1-[N-{4-(2-t-butoxycarbonylaminopropanoyl)-aminobenzoyl}indoline-5-sulfonyl]-4,5-dihydro-2-imidazolone.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:33])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:31][CH3:32])=[C:17]([CH2:20][N:21]([CH2:29][CH3:30])[C:22]4([C:26]([NH2:28])=[O:27])[CH2:25][NH:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:34][N:35]([CH3:42])[C:36](=[O:41])[CH2:37][C:38]([CH3:40])=O>>[Cl:2][C:3]1[C:4]([F:33])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:31][CH3:32])=[C:17]([CH2:20][N:21]([CH2:29][CH3:30])[C:22]4([C:26]([NH2:28])=[O:27])[CH2:25][N:24]([CH:38]([CH3:40])[CH2:37][C:36]([N:35]([CH3:42])[CH3:34])=[O:41])[CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)CC(=O)N(C)C
Reactant: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(N)=O)CNC1
Agent: Cl
Product: CCN(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)C1(C(N)=O)CN(C(C)CC(=O)N(C)C)C1
Yield: 50 %

Procedure:
3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(ethyl)amino]azetidine-3-carboxamide hydrochloride salt Example 75 was coupled with N,N-dimethylacetoacetamide using the same methodology as for the equivalent step in Example 76 to give the title product (58 mg, 50%) as a white powder; 1H NMR Spectrum: (CDCl3) 1.05 (d, 3H), 2.22 (m, 1H), 2.41 (s, 3H), 2.45 (m, 1H), 2.92 (s, 3H), 2.98 (m, 1H), 3.03 (s, 3H), 3.31 (m, 2H), 3.61 (m, 2H), 3.96 (s, 2H), 3.98 (s, 3H), 5.33 (brs, 1H), 7.17 (m, 2H), 7.24 (s, 1H), 7.51 (brs, 1H), 7.87 (brs, 1H), 7.99 (s, 1H), 8.44 (m, 1H), 8.72 (s, 1H); Mass Spectrum: (M+H)+ 558.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][S:4][C:3]1=[N:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:9].[I:17][CH3:18]>CC(C)=O>[IH:17].[CH3:1][N:2]1[CH2:6][CH2:5][S:4][C:3]1=[N:7][C:8]([S:9][CH3:18])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN1CCSC1=NC(=S)Nc1ccccc1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=Nc1ccccc1)N=C1SCCN1C
Product: I
Temperature: 25 °C

Procedure:
A suspension of 17.0 g (0.067 mole) of N-(3-methyl-2-thiazolidinylidene)-N'-phenylthiourea and 11.1 g (0.078 mole) of iodomethane in 350 ml of acetone is refluxed for one hour. The solution is cooled at room temperature overnight (about 16 hours) and solids are filtered off, 25.1 g (95.2%), m.p. 159.5°-161.5° C. Recrystallization from methanol-ether (1:1) gives pure methyl N-(3-methyl-2-thiazolidinylidene)-N'-phenylcarbamimidothioate hydroiodide; m.p. 163.5°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:21][N:22]1[C:26]([CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:25]([C:33](O)=[O:34])[C:24](=[O:36])[N:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:33]([C:25]4[C:24](=[O:36])[N:23]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:22]([CH3:21])[C:26]=4[CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:34])=[N:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Oc3ccc(N)nc3)ccnc2c1
Reactant: Cn1c(CN2CCCC2)c(C(=O)O)c(=O)n1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(CN5CCCC5)n(C)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Temperature: 25 °C
Yield: 8 %

Procedure:
5-(7-methoxy-quinolin-4-yloxy)pyridin-2-amine (549 mg, 2.05 mmol) and 1-methyl-3-oxo-2-phenyl-5-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1H-pyrazole-4-carboxylic acid (696 mg, 2.31 mmol) were suspended in dichlormethane (10 ml) and N-ethyl-N-isopropylpropan-2-amine (0.70 ml, 4.0 mmol), DMF (0.5 ml) and more dichlormethane (5 ml) were added. Finally, HATU (1.004 g, 2.641 mmol) was added, and the reaction was stirred under nitrogen at room temperature. After stirring for 2.5 weeks, the reaction was filtered and the solid was washed with DCM and MeOH. The filtrate was concentrated and purified on silica gel (˜3 inches, dichlormethane, MeOH, 2 N ammonia in MeOH) to give the desired N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-1-methyl-3-oxo-2-phenyl-5-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1H-pyrazole-4-carboxamide (90.6 mg, 0.165 mmol, 8%). MS (ESI pos. ion) m/z: 551 (MH+). Calc'd exact mass for C31H30N6O4: 550. 1H NMR (400 MHz, CDCl3): 11.44 (s, 1H), 8.61 (d, J=6.0 Hz, 1H), 8.38 (d, J=9.2 Hz, 1H), 8.30-8.21 (m, 2H), 7.62-7.37 (m, 7H), 7.24 (d, J=8.0 Hz, 1H), 6.43 (d, J=6.4 Hz, 1H), 4.35 (s, 2H), 3.98 (s, 3H), 3.57 (s, 3H), 2.73 (s, 4H), 1.84 (s, 4H).
Reaction SMILES: C([NH:4][C:5]1C=CC=[CH:7][C:6]=1S(Cl)(=O)=O)(=O)C.[OH-].[Na+].S(Cl)(Cl)(=O)=O.C([NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)(=O)C>O.O1CCCC1>[S:32]([NH2:4])(=[O:34])([C:29]1[CH:30]=[CH:31][C:26]([NH2:25])=[CH:27][CH:28]=1)=[O:33].[CH2:5]([NH2:4])[CH:6]=[CH2:7]
Reactant: CC(=O)Nc1ccccc1S(=O)(=O)Cl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=S(=O)(Cl)Cl
Product: C=CCN
Product: Nc1ccc(S(N)(=O)=O)cc1

Procedure:
Poly(allylamine sulfanilamide) is synthesized from poly(allylamine) and acetamidobenzenesulfonyl chloride by a variation of a method developed by Dawson, Gless & Wingard, Jr. [98 JACS 5996 (1970)] for the synthesis of polysulfanilamide. 1.66 g of poly(allylamine) which contained 17.6 mmol of amine groups were dissolved in 14 ml of water. 1.5 ml of 8 N NaOH were added to bring the pH to 10. 7 ml of tetrahydrofuran (THF) were added to promote co-solubility of the polymer and sulfonyl chloride during reaction. 1.51 g of p-acetamidobenzenesulfonyl chloride was added to the stirred solution, and 8 N NaOH was added as required to maintain the pH between 9 and 10. After 5 min. a further 1.51 g of the p-acetamidobenzenesulfonyl chloride was added, along with 7 ml of THF. This procedure was repeated a third time. The solution separated into two phases, a lower water-rich phase, and an upper THF-rich phase containing poly(p-acetamido-N-propylbenzene-sulfonamide). The polymer was precipitated from the THF with ethanol, washed with ethanol, and dried. Recovery was 73% of the theoretical weight of the polymer. The polymer was dissolved in 30 ml of 1 N HCl and heated at reflux for 6 h. to produce the poly(allylamine sulfanilamide).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][OH:24])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:25][C:26](=[O:28])[CH3:27])[CH2:6]1)(=[O:3])[CH3:2].[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.O>N1C=CC=CC=1>[C:29]1([CH3:39])[CH:34]=[CH:33][C:32]([S:35]([O:24][CH2:23][C@@:20]23[C@@H:19]4[C@H:10]([C@H:11]5[C@@:15]([CH2:17][CH2:18]4)([CH3:16])[C@@H:14]([O:25][C:26](=[O:28])[CH3:27])[CH2:13][CH2:12]5)[CH2:9][CH:8]=[C:7]2[CH2:6][C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:22][CH2:21]3)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)O[C@H]1CC[C@@]2(CO)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1CC[C@@]2(COS(=O)(=O)c3ccc(C)cc3)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Reaction time: 96 h

Procedure:
To a solution of 3β,17β-diacetoxy-19-hydroxyandrost-5-ene (14.4g) in pyridine (370ml) at 25° is added p-toluenesulfonyl chloride (38.1g) and the solution is left at 25° for 4 days. Water is then added, and the mixture is extracted with ethyl acetate, and the organic extract is washed successively with water, 5% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate and water, and then dried (Na2SO4) and evaporated in vacuo. The residue is crystallized from methylene chloride-hexane to give the compound of this Example (11), mp. 135°-137°; mass spectrum m/e 484, 372, 312.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=O)[NH:12][CH2:13][C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:22](O[C@H]1CC[C@H](C2N3C=CN=C(Cl)C3=CN=2)CC1)(=O)C>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:22])[C:14]3=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Reactant: CC(=O)O[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Product: CC(=O)O[C@H]1CC[C@H](c2ncc3c(C)nccn32)CC1

Procedure:
(Trans)-4-((3-chloropyrazin-2-yl)methylcarbamoyl)cyclohexyl acetate (2.8 g) was transformed into (trans)-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (2.2 g) using the procedure described in example 1 step 1b using a reaction temperature of 60° C. for 16 hours. Reaction of the latter compound (2.6 g) yielded (trans)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (1.6 g) using the procedure described in example 2 step 2d.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1
Reactant: CC(=O)NC(C)c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NC(C)c1ccc(CCl)cc1

Procedure:
A solution of N-(1-(4-formylphenyl)ethyl)acetamide (0.32 g) and sodium borohydride (63 mg) in ethanol (10 ml) was stirred at room temperature for 1 hr. Thereto was added 2N hydrochloric acid (1 ml) to stop the reaction, and the reaction mixture was poured into ice water (100 ml) and extracted with ethyl acetate. The extract was washed successively with saturated sodium hydrogencarbonate solution (500 ml) and saturated brine (500 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=2:5, later 1:4) to give N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) as a colorless oil. A solution of the obtained N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) and thionyl chloride (0.050 ml) in chloroform (5 ml) was stirred at 60° C. for 1 hr. This was diluted with ethyl acetate (100 ml) and poured into a saturated sodium hydrogencarbonate solution (100 ml) to separate the organic layer. The aqueous layer was extracted with ethyl acetate (100 ml) and combined with the organic layer obtained earlier. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate alone) to give N-(1-(4-chloromethylphenyl)ethyl)acetamide (92 mg) as yellow crystals.