Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[NH:29][CH:28]=4)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH2:36])[CH2:9]1>C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[NH:29][CH:28]=4)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH:36][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3c[nH]c4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Temperature: -5 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
A solution of acryloyl chloride (0.522 mL, 1M in CH2Cl2, 0.52 mmol) was added dropwise to 4-(3-dimethylaminoazetidin-1-yl)-N-[4-(1H-indol-3-yl)pyrimidin-2-yl]-6-methoxy-benzene-1,3-diamine (Intermediate 166, 224 mg, 0.52 mmol) in CH2Cl2 (10 mL) and the mixture was then stirred at −5° C. for 1 h. The mixture was then diluted with CH2Cl2 (100 mL), and the resulting solution was washed with sat. NaHCO3 (25 mL), water (25 mL), and then sat. brine (25 mL) and then concentrated in vacuo. Purification by FCC, eluting with 0-30% CH3OH in CH2Cl2 gave the title compound (46 mg, 18%) as a beige solid; 1H NMR: 2.09 (6H, d), 3.09 (1H, s), 3.56 (2H, t), 3.85 (3H, s), 3.96 (2H, t), 5.68 (1H, dd), 6.20 (1H, dd), 6.26 (1H, s), 6.50 (1H, dd), 7.14 (2H, dt), 7.18 (1H, t), 7.40-7.46 (1H, m), 7.82 (1H, s), 7.90 (1H, s), 8.23 (1H, d), 8.31 (1H, d), 8.38 (1H, d), 9.34 (1H, s), 11.76 (1H, s); m/z: ES+ MH+ 484.
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:16][C@@H:15]([OH:17])[C@H:14](/[CH:18]=[CH:19]/[C@@H:20]([OH:28])[C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C([O:33]O)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].S([O-])([O-])(=O)=O.[Fe+2]>[Cl:1][C@@H:2]1[CH2:16][C@@H:15]([OH:17])[C@H:14]([CH:18]2[O:33][CH:19]2[C@@H:20]([OH:28])[C:21]([CH3:27])([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CC(C)(C)OO
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1O
Agent: [Fe+2]
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Product: CCCCC(C)(C)[C@H](O)C1OC1[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
4.7 mL of titanium(IV) isopropoxide are added dropwise to a solution of 6.52 g of methyl (5Z,13E)-(9R,11R,15R)-9-chloro-11,15-dihydroxy-16,16-dimethyl-5,13-prostadienoate in 33 mL of methylene chloride at −20° C. under nitrogen, and the mixture is stirred at −20° C. for 30 min. Six mL of tert-butyl hydroperoxide are then added to the reaction mixture. A solution of 10 g of iron sulphate and 20 g of citric acid in 100 mL of water is subsequently added, and the mixture is extracted 3× with methylene chloride. The combined organic phases are washed 1× with saturated sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. Chromatography on silica gel with methylene chloride/ethyl acetate (0-40%) results in 3.55 g of the epoxide as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:33])[C:7]=1[NH:8][C:9]([C:11]1[C:16]2[C:17]3[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][C:22]=3[O:23][C:15]=2[C:14]([O:31][CH3:32])=[CH:13][CH:12]=1)=[O:10].Cl>C(OCC)C.C(OCC)(=O)C>[ClH:1].[Cl:33][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[C:16]2[C:17]3[CH2:18][NH:19][CH2:20][CH2:21][C:22]=3[O:23][C:15]=2[C:14]([O:31][CH3:32])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3c(oc12)CCNC3
Reaction time: 8 h

Procedure:
To the suspension of N-(3,5-dichloropyridin-4-yl)-2-(tert-butyloxycarbonyl)-6-methoxy-1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine-9-carboxamide (from step 4) (600 mg) in dry diethyl ether (10 ml), ethyl acetate saturated with HCl (4 ml) was added and stirred overnight. Reaction mixture was concentrated and the residue obtained was stirred in dry diethyl ether and filtered. The solid obtained was further purified by refluxing in isopropanol overnight. Yield=400 mg
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:6]=[N:7]2.[NH2:16][CH2:17][C:18]([NH:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)=[O:19].C(N(CC)CC)C>COCCOCCOC.O>[F:13][C:12]([F:15])([F:14])[C:5]1[CH:6]=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:16][CH2:17][C:18]([NH:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)=[O:19])[N:11]=[CH:10][CH:9]=2
Reactant: FC(F)(F)c1cnc2ccnc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Solvent: COCCOCCOC
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2nccc3ncc(C(F)(F)F)cc23)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Into a 10 mL round-bottom flask, was placed a solution of 5-chloro-3-(trifluoromethyl)-1,6-naphthyridine (as prepared in the previous step, 23.3 mg, 0.10 mmol, 1.00 equiv) in diglyme (3 mL), tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (prepared as described in Example 1, Step E) (27 mg, 0.12 mmol, 1.20 equiv) and triethylamine (30 mg, 0.30 mmol, 3.00 equiv). The reaction mixture was stirred overnight at 120° C. The resulting mixture was diluted with 20 mL of H2O. The resulting solution was extracted with 3×20 mL of dichloromethane. The combined organic layers dried (Na2SO4) and concentrated under vacuum. The title compound was obtained as a gray solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH3:22].[NH4+].[Cl-]>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH3:22]
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)=O)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 95.6 %

Procedure:
To a solution of 4′-hydroxy-3′-nitroacetophenone (1.0 g, 5.5 mmol) in anhydrous DMF (20 mL) was added anhydrous K2CO3 (3.0 g, 22 mmol) and then bromoethane (0.49 mL, 6.6 mmol). After heating at 80° C. for 20 h, the reaction mixture was cooled, combined with satd aqueous NH4Cl (50 mL) and extracted with Et2O (2×100 mL). The combined organic layers were washed with water (3×50 mL), 1 N NaOH (50 mL) and then brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (1.1 g, 96%) as a light brown solid, which was used without further purification. 1H-NMR (CDCl3): δ 8.41 (1H, d), 8.15 (1H, dd), 7.14 (1H, d), 4.28 (2H, q), 2.61 (3H, s), 1.52 (3H, t).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C([Li])CCC.[C:14]12([C:24](Cl)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>C1COCC1.CCCCCC>[C:14]12([C:24]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:25])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: OCc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(OCc1cccnc1)C12CC3CC(CC(C3)C1)C2
Yield: 77.8 %

Procedure:
The method followed that described in Example 1, but using 3-pyridylcarbinol (240 mg, 2.2 mmol) in THF (10 ml), n-butyllithium (2.5 M; 0.84 ml, 2.1 mmol) in hexane, and 1-adamantanecarbonyl chloride (397 mg, 2.0 mmol) in THF (2 ml). Chromatography, on elution with petrol-ether-triethylamine 200:50:1, gave the title compound (422 mg, 78%) as an oil. IR νmax 1728 cm-1 ; 1H-NMR (CDCl3) δ1.71 and 1.91 (12H, 2s, adamantyl CH2), 2.02 (3H, s, adamantyl CH), 5.11 (2H, s, OCH2), 7.30 (1H, m, Py 5-H), 7.66 (1H, m, Py 4-H), 8.56 (1H, m. Py 6-H), 8.61 (1H, m, Py 2-H). Anal. Calcd: C, 75.24; H, 7.80; N, 5.16. Found: C, 75.09; H, 7.84; N, 5.03%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:11]([C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: c1ccc2ccccc2c1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)c1ccc2ccccc2c1
Yield: 41.2 %

Procedure:
Naphthalene (0.128 g), acryloyl chloride (0.11 g), and aluminium chloride (0.15 g) were treated in the same manner as described in Example 1 to obtain the title compound (75 mg).
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([C:66]3[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=3)=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=2)[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2cccc(Cl)c2)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2cccc(Cl)c2)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(3-chlorophenyl)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 82% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(3-chlorophenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z=449.40 [M-16]+. 1H NMR (MeOD) δ: 7.93 (d, J=2.0 Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.47-7.52 (m, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.38-7.44 (m, 3H), 7.30 (d, J=1.5 Hz, 1H), 7.23 (dd, J=7.2, 1.4 Hz, 1H), 4.08-4.17 (m, 1H), 3.72 (d, J=10.8 Hz, 1H), 3.67 (d, J=10.8 Hz, 1H), 1.98-2.09 (m, 1.75-1.84 (m, 2H), 1.51 (s, 3H), 1.03-1.23 (m, 4H), 0.90-1.02 (m, 1H), 0.85 (s, 9H)
Reaction SMILES: [I:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:19]=[CH:18][N:17](C(OC(C)(C)C)=O)[N:16]=4)=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[OH-].[Na+]>O1CCCC1.C(O)C.Cl>[I:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:19]=[CH:18][NH:17][N:16]=4)=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ccc(-c3nc4ccc(I)cc4o3)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Ic1ccc2nc(-c3ccc(-c4cc[nH]n4)cc3)oc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
Subsequently, tert-butyl 3-[4-(6-iodo-1,3-benzoxazol-2-yl)phenyl]-1H-1-pyrazolecarboxylate (49 mg) was dissolved in a mixture of tetrahydrofuran (2 mL) and ethanol (2 mL), and 6N hydrochloric acid (500 μL) was added to the solution, followed by stirring at 80° C. for 2 hours. The reaction mixture was alkalified with 1N sodium hydroxide, followed by stirring at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, followed by drying. The thus-obtained white solid was recovered through filtration, and washed sequentially with water and ethanol, followed by drying under reduced pressure, to thereby yield the title compound (26 mg).
Reaction SMILES: [Na:1].N1C(N)=C2C(N(C([C@@H]([C@H](CO)OCP(O)(O)=O)O)=O)C=N2)=NC=1.[N:25]1([C:33]([C@@H:35]([C@H:37]([CH2:50][OH:51])[O:38][CH2:39][P:40]([O:46]C(C)C)([O:42]C(C)C)=[O:41])[OH:36])=[O:34])[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]1=[O:27]>>[Na:1].[N:25]1([C:33]([C@@H:35]([C@H:37]([CH2:50][OH:51])[O:38][CH2:39][P:40]([OH:42])([OH:46])=[O:41])[OH:36])=[O:34])[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]1=[O:27]
Reactant: CC(C)OP(=O)(CO[C@@H](CO)[C@@H](O)C(=O)n1ccc(N)nc1=O)OC(C)C
Agent: Nc1ncnc2c1ncn2C(=O)[C@H](O)[C@H](CO)OCP(=O)(O)O
Agent: [Na]
Product: Nc1ccn(C(=O)[C@H](O)[C@H](CO)OCP(=O)(O)O)c(=O)n1
Yield: 43 %

Procedure:
This compound was prepared as described for 3a, using 18 (150 mg, 0.38 mmol) as a starting material. Compound 3d (58 mg, 0.16 mmol) was obtained as a colorless solid, in 43% yield, which was characterized as follows:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].Cl[S:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[O:15]=[C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:16])[N:6]1[O:5][CH2:4][CH2:3][NH:2][S:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])(=[O:19])=[O:20]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: NCCON1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a mixture of 2-(2-aminoethoxy)-1H-isoindole-1,3(2H)-dione hydrochloride 75 (0.53 g, 2.19 mmol, EP 16744522 A1, 2006), tert-butyl (chlorosulfonyl)carbamate 76 (0.71 g, 3.28 mmol, WO 2006/84281 A1) in DCM (10 mL) was added triethylamine (0.92 mL, 6.57 mmol) slowly at 0° C. The resulting mixture was stirred at room temperature for 7 h and concentrated to provide a residue which was subjected to chromatography to give 77 (0.63 g, 74° A) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][N:10]=[C:9]2[CH2:14]Cl)=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:3]=1.[CH3:24][NH:25][CH3:26]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][N:10]=[C:9]2[CH2:14][N:25]([CH3:26])[CH3:24])=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:3]=1
Reactant: Cc1nnc(CCl)n1-c1ccc(Br)cc1C(=O)c1ccccn1
Reactant: CNC
Solvent: CCO
Product: Cc1nnc(CN(C)C)n1-c1ccc(Br)cc1C(=O)c1ccccn1

Procedure:
A mixture of 0.25 g of 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-chloromethyl-5-methyl-4H-1,2,4-triazole, 10 ml. of ethanol and 0.5 ml. of dimethylamine is refluxed for 1.5 hours. After evaporation of the solvent, the residue is diluted with water and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate, followed by evaporation of the solvent to give 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-dimethylaminomethyl-5-methyl-4H-1,2,4-triazole as colorless crystals. Recrystallization from a mixture of acetone and n-hexane gives colorless prisms, melting at 127° to 128° C.
Reaction SMILES: CC(C)=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:16][C@H:17]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:23]3[CH2:24][C:25]([CH3:39])=[C:26]2C(=O)C)[CH2:18]1.Cl.NO.C(NC1C=CC(S(Cl)(=O)=O)=CC=1)(=O)C.N1C=CC=CC=1.C(NC1[C@]2(CC[C@H]3[C@@H](CC=C4[C@]3(C)CC[C@H](C)C4)[C@@H]2CC=1C)C)(=O)C>C(O)C.O1CCCC1.Cl.N1C=CC=CC=1>[CH3:16][C@H:17]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:23]3[CH2:24][C@H:25]([CH3:39])[C:26]2=[O:3])[CH2:18]1
Reactant: CC(=O)C1=C(C)C[C@H]2[C@@H]3CC=C4C[C@@H](C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)=O
Agent: CC(=O)NC1=C(C)C[C@H]2[C@@H]3CC=C4C[C@@H](C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCO
Solvent: c1ccncc1
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](C)C[C@@H]32)C1

Procedure:
To a solution of 16β-methyl-3β-hydroxy-5,16-pregnadien-20-one was added toluene, ethylene glycol, and p-toluene-sulfonic acid. The resulting solution was refluxed overnight forming the 20-ketal. The procedure for this ketalization step is described in JACS, 76, 5674 (1954). Tosyl chloride in pyridine was added to the above product to form the 3β-tosylate derivative. The 3β-tosylate was refluxed overnight with 10% NaI/acetone to form the 3β-iodo-16-methyl-5,16-pregnadien-20-one-ethylene ketal. This product was methylated with lithium dimethylcuprate in ether and tetrahydrofuran at -78° C. under a nitrogen atmosphere to form the 3β,16-dimethyl-5,16-pregnadien-20-one ethylene ketal. This product was deketalized by refluxing in the presence of acetone/p-toluenesulfonic acid. The resulting 3β,16-dimethyl,5,16-pregnadien-20-one was converted to the C-20-oxime by refluxing in ethanol and pyridine with an excess of hydroxylamine hydrochloride. This product was subjected to a Beckmann rearrangement in the presence of p-acetamidobenzenesulfonyl chloride/pyridine according to the procedure by Rosenkranz, et al. in J. Org. Chem., 21, 520-522 (1956). The product, 17-acetamido-3β,16-dimethyl-5,16-androstadiene was refluxed in tetrahydrofuran/hydrochloric acid solution. 3β,16β-dimethyl-5-androst-en-17-one was formed, separated and purified by normal phase HPLC using a 1 in.×25 cm silica gel preparative column at a flow rate of 30 ml/min and using ethyl acetate/hexane (in a gradient ranging from 0 to 20%) as the eluent. The product was recrystallized from methanol and characterized by NMR and IR. Colorless crystals were isolated: 3β,16β-dimethyl-5-androsten-17-one m.p. 86.5°-88.5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([C:19]([CH3:21])=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1>C(O)C.[Pt](=O)=O>[NH2:1][CH2:2][C:3]1[C:4]([F:22])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: C=C(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)c1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethenyl)benzonitrile (0.067 g, 0.212 mmol) dissolved in ethanol (10 mL) was treated with platinum(IV) oxide (0.050 g, 0.220 mmol) under hydrogen (1 atm) at 25° C. for 4 h. LC-MS indicates ˜90% conversion but multiple impurities are present. The reaction mixture was filtered through Celite and concentrated to give crude 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(1-methylethyl)benzonitrile as an amber oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:8]=[C:7]([O:30][C@@H:31]([C@@H:33]3[CH2:37][C:36](=[O:38])[NH:35][CH2:34]3)[CH3:32])[C:6]=12.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>>[CH3:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)=[CH:13][CH:12]=3)[N:8]=[C:7]([O:30][C@@H:31]([C@H:33]3[CH2:34][NH:35][C:36](=[O:38])[CH2:37]3)[CH3:32])[C:6]=12.[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40]
Reactant: Cc1cnn2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc(O[C@H](C)[C@H]3CNC(=O)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn2cc(-c3ccc(N4CCNCC4)cc3)nc(O[C@H](C)[C@H]3CNC(=O)C3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl 4-(4-(3-methyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazin-6-yl)phenyl)piperazine-1-carboxylate (20.2 mg, 0.04 mmol) 5.55 was dissolved in TFA (1.5 mL, 20 mmol) and mixture stirred at room temperature. After 2 hours, reaction mixture was concentrated and azeotroped with toluene to yield (R)-4-((R)-1-((3-methyl-6-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.56 as a trifluoroacetic acid salt (21 mg).
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:12]=2[CH:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH2:2]([N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]=2[CH:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccc3c2ccn3Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: c1ccc(Cn2ccc3c(C4CCNCC4)nccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
15 ml of a 2.9N ethanolic HCl solution are added to a solution of 0.9 g of the compound obtained in Step 3 in 15 ml of ethanol. The reaction mixture is stirred for 24 hours at ambient temperature and then concentrated in vacuo, enabling the expected product to be isolated in dihydrochloride form. The dihydrochloride is converted into a free base by extraction in dichloromethane in the presence of water that has previously been adjusted to a basic pH by 20% sodium hydroxide solution.
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:21](Cl)(=[O:23])=[O:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[NH3:25]>>[CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:21](=[O:23])(=[O:22])[NH2:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: N
Reactant: C=CCSc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1Oc1ccccc1
Product: C=CCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
3-Allylthio-5-chlorosulfonyl-4-phenoxybenzoic acid (1 g) is dissolved in cooled concentrated aqueous ammonia (20 ml) while stirring. After 1 hour the reaction mixture is heated on a steam bath for 5 minutes, cooled, and 3-allylthio-4-phenoxy-5-sulfamylbenzoic acid precipitated by addition of 4 N hydrochloric acid. After collection by filtration, recrystallisation from aqueous ethanol, and drying, the compound is obtained with a melting point of 218°-219°C.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]#[N:13])[N:9]=[CH:8]1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:16][C:8]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])[CH:11]=[C:10]([C:12]#[N:13])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCn1cnc(C#N)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1Br
Temperature: 60 °C
Yield: 77.9 %

Procedure:
To a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.70 g, 3.1 mmol) (as prepared in the previous step) in CCl4 (10 mL) was added N-bromosuccinimide (NBS) (0.61 g, 3.4 mmol) and azobis(isobutyronitrile) (AIBN) (cat), and the mixture was heated at 60° C. for 4 h. The reaction was diluted with EtOAc (30 mL), washed with NaHCO3 (2×30 mL), brine (30 mL), the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.73 g (77%) of a yellow solid. Mass spectrum (CI (CH4), m/z) Calcd. for C10H16BrN3OSi, 302.0/304.0 (M+H), found 302.1/304.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](/[N:19]=[N:20]/[C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:23][CH:22]=2)[S:5][C:6]=1[CH:7]=[C:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O1CCCC1>[CH2:28]([N:27]([CH2:30][CH3:31])[C:24]1[CH:25]=[CH:26][C:21](/[N:20]=[N:19]/[C:4]2[S:5][C:6]([CH:7]=[C:8]3[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:18])=[C:2]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[N:3]=2)=[CH:22][CH:23]=1)[CH3:29]
Reactant: CCN(CC)c1ccc(/N=N/c2nc(Cl)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(/N=N/c2nc(N3CCN(C)CC3)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.00 g (2.20 mmol) 2-[(4-chloro-2-{(E)-[4-(diethylamino)phenyl]diazenyl}-1,3-thiazol-5-yl)methylene]-1H-indene-1,3(2H)-dione and 0.30 g (2.70 mmol) 1-methylpiperazine were dissolved in 40 ml tetrahydrofurane (THF) and heated under stirring for 5 hours when thin layer chromatography (TLC) analysis indicated complete consumption of the starting material. After cooling to room temperature the formed precipitate was filtered off, washed with THF and dried in vacuum at 40° C. to obtain a dark green powder.