Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl:59][C:60]1[CH:65]=[CH:64][C:63](I)=[CH:62][CH:61]=1>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:63]2[CH:64]=[CH:65][C:60]([Cl:59])=[CH:61][CH:62]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: Clc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Yield: 70 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-chloro-4-iodobenzene in 70% yield.
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OC(CCC(Cl)=O)=O)C.C(N(CC)[CH2:30][CH2:31][C:32](=[O:44])[CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=1)C.[K]>C1C=CC=CC=1.C(O)C.CCOCC>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([CH2:35][CH2:34][CH2:33][C:32](=[O:44])[CH2:31][CH2:30][C:2]([CH3:1])([C:8](=[O:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)CCC(=O)C(C)C(=O)OCC
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Agent: CCOC(=O)CCC(=O)Cl
Agent: [K]
Solvent: c1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CCC(=O)C(C)(CCC(=O)CCCc1cccc(OC)c1)C(=O)OCC
Temperature: 160 °C

Procedure:
Stir a mixture of diethyl 2-methyl-3-oxoadipate (2.3 g, b.p. 111°-112° C/0.2 mm), prepared from 2- methylacetoacetic ester and ethoxycarbonylpropionyl chloride by the method of Cardwell, J. Chem. Soc., 1949, 715, and the methiodide of 1-diethylamino-6-m-methoxyphenylhexan-3-one (4.6 g) in benzene (20 cc) in an ice bath and add a solution of potassium (0.4 g) in ethanol (10 cc) dropwise over one hour. After stirring for a further 4 hours add ether (50 cc) and evaporate the washed and dried ether extracts. Heat the residue at 160°C and 0.2 mm pressure to remove unchanged starting materials. The residual gum is diethyl 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methyl-3-oxoadipate (2.7 g); infrared absorption peaks at 5.78, 5.88, 6.25, 12.82, 14.49 μ.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[S:11][CH:12]=[C:13]([CH3:14])[C:9]=2[CH:8]=1)=[O:6])[CH3:3].[CH2:17]=O>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH2:2]([O:4][C:5]([C:7]1[CH:16]=[CH:15][C:10]2[S:11][C:12]([CH2:17][Cl:1])=[C:13]([CH3:14])[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: C=O
Reactant: CCOC(=O)c1ccc2scc(C)c2c1
Reactant: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2sc(CCl)c(C)c2c1
Reaction time: 8 h

Procedure:
Hydrogen chloride gas was passed for 30 minutes through a mixture of 3-methylbenzo[b]thiophene-5-carboxylic acid ethyl ester (5.50 g), anhydrous zinc chloride (1.25 g) and paraformaldehyde (1.50 g) in chloroform (50 ml). The resulting mixture was stirred for 8 hours and then the chloroform solution was decanted off from the gummy residue, washed well with water and dried (Na2SO4). Evaporation of the solvent gave crude 2-chloromethyl-3-methylbenzo[b]thiophene-5-carboxylic acid ethyl ester which was used directly in the next stage.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[CH:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.[I:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:10]([I:18])=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccccc1-c1cc2nccc(Cl)n2n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 7-chloro-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (I-1A-1c; 6.00 g, 22.7 mmol) in chloroform (23 ml) and methylene chloride (207 ml) cooled in an ice bath was added N-iodosuccinimide (7.67 g, 34.1 mmol), portionwise. The ice bath was removed and the reaction was stirred overnight at room temperature. After concentrating the red-brown reaction, in vacuo, an ethyl acetate solution of the residue was washed with saturated aqueous Na2S2O4 and brine. The solution was dried (MgSO4), concentrated, in vacuo, and the resulting solids repulped at room temperature from ethyl acetate (30 ml) to give product I-1A-1d as a solid (6.8 g, 77%): +APcI MS (M+1) 390.1; 1H NMR (400 MHz, CD2Cl2) δ 8.52 (d, J=4.6 Hz, 1H), 7.59–7.56 (m, 1H), 7.53–7.42 (m, 3H), 7.14 (d, J=4.6 Hz, 1H).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11](OC(C)(C)C)=O)[CH2:6]2)[CH2:4][CH2:3][NH:2]1.CCN(CC)CC.[CH3:25][C:26](OC(C)=O)=[O:27].C(OC(=O)[NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[S:46][CH:47]=[CH:48][CH:49]=2)=[CH:41][C:40]=1[NH:50][C:51]([C:53]1[CH:54]=[N:55]C(Cl)=[CH:57][CH:58]=1)=[O:52])(C)(C)C>CN(C=O)C>[C:26]([N:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[CH:57]=[CH:58][C:53]([C:51]([NH:50][C:40]4[CH:41]=[C:42]([C:45]5[S:46][CH:47]=[CH:48][CH:49]=5)[CH:43]=[CH:44][C:39]=4[NH2:38])=[O:52])=[CH:54][N:55]=3)[CH2:6]2)[CH2:1]1)(=[O:27])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCNC2)C1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC2(CCCN(c3ccc(C(=O)Nc4cc(-c5cccs5)ccc4N)cn3)C2)C1
Reaction time: 5 h

Procedure:
A mixture of tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate (200 mg, 0.833 mmol), NEt3 (0.200 mL, 1.44 mmol) and Ac2O (0.100 mL, 1.06 mmol) in 1 mL of DMF was stirred for 5 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. The mixture was treated with 1:1 TFA/CH2Cl2, stirred for 1 h and concentrated. The oily residue was azeotroped with methanol and placed under high vacuum overnight. The resulting thick residue was then dissolved in 2 mL of DMSO containing tert-butyl[2-{[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]carbamate (100 mg, 0.233 mmol), treated with NEt3 (0.50 mL) and stirred at 90° C. for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. Finally, the residue was dissolved in 1:1 TFA/CH2Cl2, stirred for 1 h and concentrated. Reverse-phase chromatography (10-100% MeCN/water with 0.05% TFA) followed by TFA removal by EtOAc/saturated extraction and drying (Na2SO4) gave the title compound: 1H NMR (600 MHz, CD3OD): δ 8.69 and 8.71 (2s, 1H), 8.05 and 8.07 (2d, J=9.1 Hz, 1H), 7.47 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.23 (d, J=5.0 Hz, 1H), 7.20 (d, J=3.5 Hz, 1H), 7.01 (dd, J=5.0, 3.5 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.82 (dd, J=9.1, 6.2 Hz, 1H), 3.75 (m, 2H), 3.65 (m, 1H), 3.52 (m, 3H), 3.03 and 3.19 (2d, J=12.3 Hz, 1H), 2.00 and 2.04 (2s, 3H), 1.6-1.9 (m, 6H); MS (ESI+): cal'd [M+H]+ 476.2, obs'd 476.2.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[N:25][CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:18][C@@H:17](C(C)=C)[CH2:16][CH2:15][C:14]=2[CH3:22])=[CH:9][CH:8]=1)=[O:5].[CH:27]([OH:30])([CH3:29])[CH3:28].[OH2:31]>O=[Os](=O)(=O)=O>[OH:31][CH2:28][C@@:27]([C@@H:17]1[CH2:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:23]=[CH:24][N:25]=[CH:26][C:2]=3[CH3:1])=[CH:8][CH:9]=2)=[C:14]([CH3:22])[CH2:15][CH2:16]1)([OH:30])[CH3:29]
Reactant: CC(C)O
Reactant: C=C(C)[C@H]1CCC(C)=C(c2ccc(NC(=O)c3ccncc3C)cc2)C1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Product: CC1=C(c2ccc(NC(=O)c3ccncc3C)cc2)C[C@@H]([C@@](C)(O)CO)CC1
Reaction time: 18 h

Procedure:
A solution of Compound 3 (133 mg, 0.383 mmol) in 2:1 isopropylalcohol and water was stirred at room temperature. N-morpholine oxide (40 mg, 1 eq.) was added followed by a solution of OsO4 (3 mol %). The reaction was stirred for 18 hours, quenched with water and extracted with methylene chloride.
Reaction SMILES: [CH3:1][N:2]1[C:19]([OH:20])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])[C:4]2=[N:3]1.C1(C)C=CC(S(O[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=O)=O)=CC=1>>[CH3:1][N:2]1[C:19]([O:20][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])[C:4]2=[N:3]1
Reactant: CCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCOC(=O)CSc1ncnc2c(O)n(C)nc12
Product: CCCCCCCCCCCCCCCCOc1c2ncnc(SCC(=O)OCCCC)c2nn1C
Yield: 75 %

Procedure:
2-Methyl-3-hydroxy-7-n-butoxycarbonylmethylthiopyrazolo[4,3-d]pyrimidine and n-hexadecyl p-toluenesulfonate were reacted and treated in the same manner as in Synthesis 2 of Example 1 to obtain the desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.O>CS(C)=O>[Cl:1][C:2]1[C:11]([C:12]([C:14]2[C:15]([O:22][CH3:23])=[CH:16][CH:17]=[CH:18][C:19]=2[O:20][CH3:21])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(OC)c1C(O)c1cc2ccccc2nc1Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(OC)c1C(=O)c1cc2ccccc2nc1Cl
Temperature: 25 °C

Procedure:
(2-Chloroquinolin-3-yl)(2,6-dimethoxyphenyl)methanol (0.5 g, 1.5 mmol) and triethylamine (0.84 mL, 6.1 mmol) were dissolved in dimethyl sulfoxide (20 mL) and mixed with a solution of sulfur trioxide-pyridine complex (0.72 g, 4.55 mol) in dimethyl sulfoxide (5 mL) under nitrogen. The batch was stirred at room temperature until the reaction was complete (TLC monitoring). After adding water, the mixture was stirred for 1 hour at room temperature. The precipitated product was filtered with suction, washed with water and dried in a vacuum drying cabinet (20 mbar, 50° C.). Yield: 0.45 g (1.37 mmol, 91%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@H:16]([CH2:38][C:39]3[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[C:41]([CH3:47])[CH:40]=3)[C:17]([N:19]3[CH2:24][CH2:23][CH:22]([CH:25]4[CH2:30][CH2:29][N:28](CC5C=CC=CC=5)[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[O:18])=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@H:16]([CH2:38][C:39]3[CH:40]=[C:41]([CH3:47])[C:42]([OH:46])=[C:43]([CH3:45])[CH:44]=3)[C:17]([N:19]3[CH2:20][CH2:21][CH:22]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH2:23][CH2:24]3)=[O:18])=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCC(C3CCN(Cc4ccccc4)CC3)CC2)cc(C)c1O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCC(C3CCNCC3)CC2)cc(C)c1O

Procedure:
A solution of 51 mg (0.07 mmol) (R)-2-(1′-benzyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate (Example 2.7) in 10 mL MeOH was combined with 5 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen pressure until the reaction came to an end. The catalyst was removed by suction filtering and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11]CC)=O.[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH2:20])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH:20][C:9](=[O:11])[CH2:8][N:3]1[C:4](=[O:7])[CH2:5][CH2:6][CH:2]1[CH3:1])[CH3:16]
Reactant: CC(C)N(CCN)C(C)C
Reactant: CCOC(=O)CN1C(=O)CCC1C
Product: CC1CCC(=O)N1CC(=O)NCCN(C(C)C)C(C)C

Procedure:
From 9.2 g. of ethyl 2-methyl-5-oxo-1-pyrrolidineacetate and 8.7 g. of 2-(diisopropylamino)ethylamine, following the procedure of Example 9, there is obtained N-[2-[Bis(1-methylethyl)amino]ethyl]-2-methyl-5-oxo-1-pyrrolidineacetamide; m.p. 73°-74° C. after recrystallization from hexane.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[CH:29]([CH:31]([NH:40][C:41]([CH:43]([NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:44][CH:45]([CH3:47])[CH3:46])=[O:42])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O>C1COCC1.O.C(OCC)(=O)C>[CH3:46][CH:45]([CH3:47])[CH2:44][CH:43]([NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:41](=[O:42])[NH:40][CH:31]([CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH:29]=[C:2]([CH3:4])[CH3:3]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(C=O)CCc1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)=CC(CCc1ccccc1)NC(=O)C(CC(C)C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 16.7 %

Procedure:
A solution comprised of isopropyltriphenylphosphonium iodide (13.02 g, 30.1 mmol) in TBF (80 mL) was cooled to −78° C. and then n-butyllithium (12.44 mL, 2.5M in hexane) was added. The mixture was stirred for 5 minutes, heated to room temperature and stirred for an additional 25 minutes. Benzyl 1-(1-formyl-3-phenylpropylcarbamoyl)-3-methylbutylcarbamate (4.12 g, 10.04 mmol), prepared as in the procedure set forth in Synthesis, 1983, pp 676-678, was dissolved in THF (40mL) and the solution was added dropwise. The mixture was stirred for 18 hours at room temperature and then diluted with water (5 mL) and ethyl acetate (250 mL). The organic layer was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried (MgSO4) and concentrated to dryness in vacuo. Product was purified from the residue by column chromatography using 20% ethyl acetate/hexane to provide benzyl 3-methyl-1-(3-methyl-1-phenethylbut-2-enylcarbamoyl)butylcarbamate (0.75 g, 1.68 mmol) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]#[N:25])[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Reactant: N#Cc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1cccnc1N1CCC(S(=O)(=O)c2cccc(Cl)c2)CC1
Yield: 66.2 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-3-cyanopyridine (108 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (91 mg), a yellow solid, in 62% yield.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:24])[CH:20]([CH3:23])[CH2:21][CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH3:24][N:19]([CH:20]([CH3:23])[CH2:21][CH3:22])[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CCC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C)N(C)c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 8-benzyl-N-methyl-N-(1-methylpropyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (0.64 g) in methanol (20 mL) was added 20% Pd(OH)2/C (0.13 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (20 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (540 and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (0.44 g, 82%) as a pale-yellow powder.
Reaction SMILES: [C:1]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:23][CH2:24]I>CC#N>[C:1]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:23][CH3:24])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccsc1C(=O)c1ccncc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccsc1C(=O)c1ccncc1
Temperature: 30 °C
Reaction time: 48 h
Yield: 85.5 %

Procedure:
To a solution of 2-isonicotinoylthiophene-3-carboxylic acid (2.2 g, 9.4 mmol) from example 2.1 and Cs2CO3 (6.2 g, 18.9 mmol) in CH3CN (500 mL) was added CH3CH2I (2.9 g, 18.9 mmol) dropwise. The mixture was stirred at 30° C. for 48 h. The mixture was filtered and concentrated to give the title compound (2.1 g, 85.5% yield) as yellow oil. LC-MS (Method A): m/z 340 (M+H)+, Rt: 0.81 min.
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.ClCCl.[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][N+:21]([O-])=C(C)[CH:19]=1>CCCCCC>[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][N:21]=[C:7]([CH2:6][OH:11])[CH:19]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c[n+]([O-])c(C)cc1Br
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cnc(CO)cc1Br
Reaction time: 0.33 h
Yield: 83.3 %

Procedure:
Under an argon atmosphere, trifluoroacetic anhydride (20.6 ml, 0.146 mol) was added to a dichloromethane solution (100 ml) solution of 4-bromo-2,5-dimethylpyridine 1-oxide (9.8 g, 48.5 mmol) under ice cooling. The resulting mixture was stirred for 20 minutes and then, stirred at room temperature for 7.5 hours. The reaction mixture was concentrated under reduced pressure. To a dichloromethane solution (50 ml) of the residue was added a saturated aqueous solution (100 ml) of sodium bicarbonate. The resulting mixture was stirred for 14 hours. The reaction mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure to give the title compound (8.17 g, 40.4 mmol, 83%) as a yellow powder.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)[C:11]([OH:13])=[O:12].[NH2:16][C:17]1[CH:46]=[CH:45][C:20]2[NH:21][C:22]([C:27]3[C:28](=[O:44])[C:29]([CH2:41][CH2:42][CH3:43])([CH2:38][CH2:39][CH3:40])[C:30]4[C:35]([C:36]=3[OH:37])=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:23][S:24](=[O:26])(=[O:25])[C:19]=2[CH:18]=1.C(N(CC)CC)C>ClCCl.Cl>[OH:37][C:36]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH3:43])[C:28](=[O:44])[C:27]=1[C:22]1[NH:21][C:20]2[CH:45]=[CH:46][C:17]([NH:16][S:24]([NH:23][C:11](=[O:12])[O:13][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:26])=[O:25])=[CH:18][C:19]=2[S:24](=[O:26])(=[O:25])[N:23]=1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A solution of chlorosulfonyl isocyante (25 mL, 0.281 mmol) in dichloromethane, was treated with benzyl alcohol (29 μL, 0.281 mmol) dropwise at room temp, stirred for 30 min, treated with a solution of example 71 (103 mg, 0.234 mmol) and triethylamine (130 μL, 0.936 mmol) in 3 mL of dichloromethane, stirred for 2 h, diluted with 10 mL of dichloromethane and 10 mL of 1N HCl. The organic phase was dried over Na2SO4, concentrated, and purified by silica gel chromatography with a gradient of methanol in dichloromethane (0-3%) to afford the desired product (26 mg, 17% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.59 (m, 2H) 0.68 (m, 6H) 0.91 (m, 2H) 2.01 (m, 2H) 2.18 (m, 2H) 5.11 (s, 2H) 7.50 (m, 11H) 8.17 (d, J=7.72 Hz, 1H) 10.04 (s, 1H) 11.10 (s, 1H) 12.13 (s, 1H) 13.74 (d, J=21.69 Hz, 1H); (ESI+) m/z 653 (M+H)+ (ESI+) m/z 670 (M+NH4)+ (ESI+) m/z 675 (M+Na)+ (ESI+) m/z 1327 (2M+Na)+ (ESI−) m/z 1303 (2M−H)− (ESI−) m/z 651 (M−H)−
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)[CH2:6]1.[N+:30]([O-:33])([O-])=[O:31].CC1([C:41]([NH2:43])=[NH2+:42])C=C(C)N=N1>C(O)C>[N+:30]([O:29][C@@:11]12[C@H:10]3[C@@H:19]([C@:20]4([CH3:23])[C@H:7]([CH2:8][CH2:9]3)[CH2:6][C@@H:5]([O:4][CH2:3][CH2:2][NH:1][C:41]([NH2:43])=[NH:42])[CH2:22][CH2:21]4)[CH2:18][CH2:17][C@:15]1([CH3:16])[C@@H:14]([C:24]1[CH:28]=[CH:27][O:26][CH:25]=1)[CH2:13][CH2:12]2)([O-:33])=[O:31]
Reactant: O=[N+]([O-])[O-]
Reactant: CC1=CC(C)(C(N)=[NH2+])N=N1
Reactant: C[C@]12CC[C@H](OCCN)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Solvent: CCO
Product: C[C@]12CC[C@H](OCCNC(=N)N)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O[N+](=O)[O-]

Procedure:
To a solution of 0.17 g of 3β-(2-aminoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-aa) in 12 ml of absolute ethanol 0.090 g of 3,5-dimethyl-1-pyrazolylformamidinium nitrate were added and the mixture was kept at reflux for 7 hrs; the ethanol was concentrated under reduced pressure and 0.18 g of the title compound (1-al) crystallized as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CO>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Fc1cccc(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cccc(F)c3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a mixture of 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (4.2 mg, 0.016 mmol)described in Manufacturing Example 5-1-1 and methanol (0.4 mL) was added 1 N aqueous sodium hydroxide solution (16 μL, 0.016 mmol), which was then concentrated under a reduced pressure. To a mixture of the residue and N,N-dimethylformamide (0.5 mL) was added 3-fluorobenzyl bromide (2.3 μL, 0.019 mmol), which was stirred for 1 hour at room temperature. The reaction mixture was purified directly by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (4.3 mg, 55%) as a trifluoroacetic acid salt.
Reaction SMILES: O[CH2:2][N:3]([CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:4](=[O:7])[O:5][CH3:6].B(F)(F)F.O(CC)CC>C(Cl)Cl>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]2[S:10][CH2:9][CH2:8][N:3]([C:4]([O:5][CH3:6])=[O:7])[CH2:2][C:16]=2[CH:15]=1
Reactant: COC(=O)N(CO)CCSc1ccc(OC)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)N1CCSc2ccc(OC)cc2C1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A solution of compound 9 (20.0 mg) in 10 mL CH2Cl2 was treated with 1.1 eq. of BF3—OEt2 under Ar. The mixture was stirred overnight and washed with 1N HCl and sat. NaHCO3 Removal of the solvent gave the crude product and TLC analysis showed one major spot. The crude product was further purified on SiO2 column to provide the title compound (16 mg). The structure was confirmed by NMR and TLC comparison with authentic sample prepared by the reaction of 7-MeO-2,3,4,5-tetrahydro-1,4-benzothiazepine with methyl chloroformate.