Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](C3C=C(NC4C=CN=CN=4)C(=O)N(C)N=3)[C:16]=1[CH2:36][OH:37])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].Cl[C:39]1[CH:40]=[C:41]([NH:47][C:48]2[CH:52]=[CH:51][N:50]([CH:53]3[CH2:56][N:55]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:54]3)[N:49]=2)[C:42](=[O:46])[N:43]([CH3:45])[N:44]=1.C(OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N1CC2C(=CC=C(C(C)(C)C)C=2)C1=O)(=O)C>>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[C:16]([CH2:36][OH:37])=[C:17]([C:39]3[CH:40]=[C:41]([NH:47][C:48]4[CH:52]=[CH:51][N:50]([CH:53]5[CH2:56][N:55]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:54]5)[N:49]=4)[C:42](=[O:46])[N:43]([CH3:45])[N:44]=3)[CH:18]=[CH:19][CH:20]=1)[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(Cl)cc(Nc2ccn(C3CN(C(=O)OC(C)(C)C)C3)n2)c1=O
Reactant: Cn1nc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccncn2)c1=O
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Product: Cn1nc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccn(C3CN(C(=O)OC(C)(C)C)C3)n2)c1=O

Procedure:
Using the same general procedure as described for the preparation of 103, reaction of 105c (150 mg, 0.394 mmol) with 102f (201 mg, 0.433 mmol) afforded a crude product 105d which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:27][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC.Cl>O1CCCC1>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[CH3:27])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)c2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Yield: 56.8 %

Procedure:
To a solution of the compound (641 mg, 1.70 mmol) obtained in Example 178b in tetrahydrofuran (10 mL) was slowly added dropwise a solution (1.85 mL, 2.041 mmol) of 1.1M lithium hexamethyldisilazide in tetrahydrofuran under ice-cooling. The reaction mixture was stirred under ice-cooling for 5 min, iodomethane (0.16 mL, 2.55 mmol) was added dropwise at the same temperature, and the mixture was further stirred for 5 min. The reaction mixture was acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (378 mg, 57%) as a colorless oil.
Reaction SMILES: [C:1]1([N:7]2[C:24]([OH:25])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:1]1([N:7]2[C:24]([O:25][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)(C)Sc1ncnc2c(O)n(-c3ccccc3)nc12
Reactant: CCCCCCCCCCCCBr
Product: CCCCCCCCCCCCOc1c2ncnc(SC(C)(C)C(=O)OCC)c2nn1-c1ccccc1
Yield: 30 %

Procedure:
1 g of 2-phenyl-3-hydroxy-7-(1-ethoxycarbonyl-1-methyl-ethylthio)-pyrazolo[4,3-d]pyrimidine and 0.84 g of n-dodecyl bromide were reacted and treated in the same manner as in Example 31 to obtain the desired product.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22]>>[NH2:17][C:16]1[C:4]([C:2]#[N:3])=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:24]([NH:23][CH2:20][CH2:21][CH3:22])=[O:25]
Reactant: CCCN=C=O
Reactant: N#Cc1c(OC[C@@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CCCNC(=O)N1CCC[C@H]1COc1cccc(N)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 209a from (5)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 209b) and propyl isocyanate in 100% yield as a white solid. MS 303 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:12]=[C:11](I)[C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH3:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14](/[CH:15]=[CH:16]/[C:11]1[C:9](=[O:10])[NH:8][C:6](=[O:7])[N:5]([CH2:4][O:3][CH2:1][CH3:2])[CH:12]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=CC(=O)OCC
Reactant: CCOCn1cc(I)c(=O)[nH]c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCn1cc(/C=C/C(=O)OCC)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
Then, 1.184 g (4 mmol) of 1-(ethoxymethyl)-5-iodouracil, 870 μg (8 mmol) of ethyl acrylate, 45 mg of palladium acetate and 0.6 ml of triethylamine were dissolved in 40 ml of dimethylformamide, heated and stirred for 5 hours at 70° C. After the solvent was evaporated under reduced pressure, the residue was adsorbed on a silica gel column, eluted with a solution of dichloromethan/ethyl acetate (1:1 v/v) to recover the desired fraction, from which the solvent was evaporated under reduced pressure to obtain 798 mg of 5-(2-(E)-carboethoxyvinyl) -1-(ethoxymethyl)uracil as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@@H:11]([OH:24])[CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]([CH2:10][C@@H:11]([OH:24])[CH2:12][N:28]2[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C[C@H](O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 66.4 %

Procedure:
(R)-2-Chloro-1-[2-hydroxy-3-(4-methylbenzene-sulfonyloxy)propyl]-4-nitroimidazole prepared in Example 8 (16.86 g, 44.86 mmol) and tert-butyl piperazine-1-carboxylate (8.36 g, 44.89 mmol) were dissolved in acetonitrile (100 ml). To the solution, triethylamine (6.3 ml, 45.2 mmol) was added followed by stirring under reflux for 6 hours. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. To the residue, water (100 ml) was added and extracted with ethyl acetate (100 ml) twice. The organic phases were combined, washed with water (100 ml) and a saturated saline solution (100 ml) in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=40/1) and then recrystallized from ethyl acetate/n-hexane to afford tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxypropyl]piperazine-1-carboxylate (11.61 g, yield 66%) as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:28]
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1Cl
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2cccc(Cl)c2Cl)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2,3-dichloro-phenyl)-acrylic acid.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][O:15][CH2:16][CH:9]1[CH2:10][N:11]([S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:12]2)C1C=CC=CC=1.[H][H]>CCO.CO.[Pd]>[C:20]1([S:17]([N:11]2[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][O:15][CH2:16]3)[CH2:12]2)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=S(=O)(c1ccccc1)N1CC2COCC(C1)N2
Yield: 89 %

Procedure:
To a solution of 112e (3.0 g, 8.37 mmol) in EtOH (100 ml) was added Pd/C (0.5 g) in MeOH (30 ml). The reaction mixture was hydrogenated at atmospheric hydrogen at 50° C. for overnight. Then, the catalyst was filtered off, washed with ethanol, and the solvent was evaporated to give 112f as a colorless solid (2.0 g, 90%) MS: [M+H]+: 268
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12](=[N:14][OH:15])[NH2:13])=[CH:10][CH:11]=1)=[O:4].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O>[OH:15][NH:14][C:12]([C:9]1[N:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[NH:13]
Reactant: C1COCCN1
Reactant: NC(=NO)c1ccc(NC(=O)CCl)cn1
Solvent: O
Product: N=C(NO)c1ccc(NC(=O)CN2CCOCC2)cn1

Procedure:
Compound of example 4 (0.10 g, 0.44 mmol) was stirred in morpholine (1 mL) at 25 ° C. for 2 hours. The reaction mixture was then diluted with water and extracted with chloroform (2×50 mL), followed by extraction with ethyl acetate (2×50 mL). Both organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product obtained was purified using column chromatography (silica gel, 1% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=3)[CH:17]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CCN(C(C)C)C(C)C.[CH3:36][C:37]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[C:38]=1[C:39](O)=[O:40]>CS(C)=O>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][CH2:18][C:16]2[CH:17]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH:2]([NH:1][C:39](=[O:40])[C:38]4[C:42]([CH3:47])=[CH:43][C:44]([CH3:46])=[CH:45][C:37]=4[CH3:36])[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=3)[O:14][CH:15]=2)[CH:25]=1
Reactant: Cc1ccnc(NCc2coc(-c3ccc(CC(N)C(=O)O)cc3)c2)c1
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccnc(NCc2coc(-c3ccc(CC(NC(=O)c4c(C)cc(C)cc4C)C(=O)O)cc3)c2)c1
Reaction time: 12 h

Procedure:
50 mg of (11) as 2HCl salt and 1201l of DIPEA were dissolved in 1 ml of DMSO. 29 mg of the OAT ester of 2,4,6-trimethylbenzoic acid were added. The solution was stirred for 12 h and the product was purified by HPLC to give 10.8 mg of (12) as TFA salt.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:34][CH2:35]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f58) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.C1C(=O)N([I:19])C(=O)C1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([C:9]([I:19])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1cc(Br)c2nccn2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Clc1cc(Br)c2ncc(I)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.2 g, 5.16 mmol) in chloroform (30 mL) were added NIS (1.161 g, 5.16 mmol) and TFA (0.795 mL, 10.32 mmol). The reaction mixture was stirred at room temperature for 2 h and quenched with NaHCO3. The organic layers were washed with brine and dried over Na2SO4. The crude product was purified by BIOTAGE® (100% CH2Cl2) to give the product (1.4 g, 76%). 1H NMR (400 MHz, CDCl3) δ ppm 7.91 (1H, s), 7.46 (1H, s); LC/MS: Rt=2.44 min. LC/MS (Condition A): 357.80/359.80/361.80.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].C(O)(=O)C.[O-:18][C:19]#[N:20].[K+]>O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([NH:10][C:19]([NH2:20])=[O:18])[CH:11]=[CH:12][CH:13]=1
Reactant: COCCCOc1cccc(N)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COCCCOc1cccc(NC(N)=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a flask containing 3-(3-methoxypropoxy)aniline (11A) (2.00 g, 11.04 mmol) was charged a 100 mL solution of 80% glacial acetic acid and 20% water. This mixture was chilled to 0° C. A solution of potassium cyanate (1.34 g, 16.56 mmol) in 5 mL of water was slowly added portion-wise to the reaction mixture. The reaction was then stirred for about 1 hour at RT. The glacial acetic acid was then removed under reduced pressure. The resulting white solid residue was then rinsed with copious amounts of water then dried under vacuum to give title compound 11B (1.70 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86-1.95 (m, 2H) 3.24 (s, 3H) 3.46 (t, J=6.32 Hz, 2H) 3.94 (t, J=6.32 Hz, 2H) 5.82 (br. s., 2H) 6.45 (dd, J=8.08, 2.27 Hz, 1H) 6.81 (d, J=7.33 Hz, 1H) 7.00-7.17 (m, 2H) 8.49 (s, 1H). ESI-MS: m/z 225.3 (M+H)+.
Reaction SMILES: CC(C)(O)[C:3]#[N:4].[OH:7][C@:8]12[CH2:25][CH2:24][C@@:22]3([CH3:23])[C@@H:18]([CH2:19][CH2:20][C:21]3=[O:26])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:28])[CH2:10][CH2:11][C:12](=[O:27])[CH:13]=1.[C-]#N.[K+]>CO>[CH3:23][C@@:22]12[C:21]([OH:26])([C:3]#[N:4])[CH2:20][CH2:19][C@H:18]1[C@@H:17]1[CH2:16][CH2:15][C:14]3[C@@:9]([CH3:28])([C:8]1([OH:7])[CH2:25][CH2:24]2)[CH2:10][CH2:11][C:12](=[O:27])[CH:13]=3
Reactant: CC(C)(O)C#N
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(O)(C#N)[C@@]3(C)CCC12O
Reaction time: 2 h

Procedure:
Acetone cyanohydrin (1.37 ml) is added to a mixture of 9α-hydroxyandrost-4-ene-3,17-dione (0, U.S. Pat. No. 3,065,146, 3.024 g) in methanol (10 ml). The mixture is stirred at about 35°-39° for about 2 hr, then at about 4°-54° for 1.25 hr. 0.1 ml of a potassium cyanide solution (1 g in 2.0 ml of water) is added and the mixture stirred at about 50°-55° for 30 min and then allowed to stand at 20°-25° overnight. The solids are collected, washed well with methanol and dried under reduced pressure at about 55° for 3 hr to give the title compound, NMR (CDCl3 /DMSO-d6 ; 10/1) 5.8, 2.4, 1.3 and 1.0 δ.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:4]=1.N1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31]>C(Cl)Cl>[C:19]([C:5]1[CH:4]=[C:3]([NH:2][C:30](=[O:31])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])[N:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][NH:14][C:15]3=[O:18])=[CH:10][CH:9]=2)[N:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=O)NCC3)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3c(c2)C(=O)NCC3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 7-(5-amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-2H-isoquinolin-1-one hydrochloride (0.5 g, 1.76 mmol) in CH2Cl2 (25 mL) were added pyridine (0.22 mL) and trichloroethyl chloroformate (0.27 mL) at 0° C. and the mixture was stirred overnight at RT. LCMS showed the reaction was incomplete. Pyridine (0.25 mL) and TROC-Cl (0.25 mL) were added and then the mixture stirred at RT for 2 hours. The reaction mixture was diluted with CH2Cl2, the organic layer was washed with 3M HCl and brine, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in EtOAc and hexane was added. The solid was filtered to obtain 2,2,2-trichloroethyl 3-tert-butyl-1-(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-ylcarbamate (0.46 g, 57% yield). MS (ESI) m/z: 458.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[C:15]([O:21][C@H:22]([CH3:27])[CH2:23][N:24]([CH3:26])[CH3:25])[C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[C:15]([O:21][C@H:22]([CH3:27])[CH2:23][N+:24]([O-:33])([CH3:26])[CH3:25])[C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2
Reactant: C[C@H](CN(C)C)Oc1nc(Nc2cc3cccc(Cl)c3cn2)cnc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: C[C@H](C[N+](C)(C)[O-])Oc1nc(Nc2cc3cccc(Cl)c3cn2)cnc1C#N
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
(R)-5-(8-Chloroisoquinolin-3-ylamino)-3-(1-(dimethylamino)propan-2-yloxy)pyrazine-2-carbonitrile (30 mg, 0.078 mmol) was dissolved in DCM (1 mL) and cooled to −10° C. 3-Chloroperoxybenzoic acid (77% wt., 12 mg, 0.086 mmol) dissolved in DCM (1 mL) was added dropwise to the solution. The reaction mixture was stirred at −10° C. for 15 minutes, and was then warmed to room temperature. The reaction mixture was diluted with water, the layers partitioned and the aqueous phase extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated to dryness. The residue was dissolved in methanol and absorbed on to an SPE (TsOH) cartridge. The cartridge was washed with methanol and the compound eluted with 2 M and 7 M ammonia in methanol. Preparative HPLC afforded the title compound (23 mg, 0.057 mmol, 73%). 1H NMR (d6-DMSO, 400 MHz) δ 9.25 (s, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.73-7.71 (m, 1H), 7.57-7.56 (m, 1H), 6.10-6.07 (m, 1H), 4.16-4.10 (m, 1H), 3.77 (br d, 1H, J=14 Hz), 3.43 (s, 3H), 3.28 (s, 3H), 1.44 (d, 3H, J=6.6 Hz). LC-MS (2) Rt=2.20 min; m/z (ESI+) 399 & 401 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:28][C:29]1[CH:30]=[C:31]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=[C:33]([F:36])[C:34]=1[F:35]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:37]([C:31]1[CH:30]=[C:29]([F:28])[C:34]([F:35])=[C:33]([F:36])[CH:32]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)c(F)c1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)c(F)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (2.8 g, 13 mmol) in tetrahydrofuran (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 15.6 mL, 15.6 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was then cooled to −78° C. and 3,4,5-trifluorobenzene-1-sulfonyl chloride (3.0 g, 13.0 mmol) was added. The mixture was stirred at −78° C. for 0.5 h, warmed to 0° C. and 4,5-trifluorobenzene-1-sulfonyl chloride (0.6 g, 2.6 mmol) was added. The mixture was allowed to warm to ambient temperature, stirred for 20 h, diluted with ethyl acetate (200 mL), washed with saturated aqueous ammonium chloride (200 mL) and brine (200 mL), dried over sodium sulphate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane to afford N-(2,4-dimethoxybenzyl)-3,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a beige solid in 53% yield (3.1 g): 1H NMR (300 MHz, CDCl3) δ8.24-8.18 (m, 1H), 7.37-7.28 (m, 2H), 7.26-7.22 (m, 1H), 7.07 (d, J=8.1 Hz, 1H), 6.39-6.32 (m, 1H), 6.29-6.24 (m, 1H), 5.27 (s, 2H), 3.75 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.Cl.[F:29][CH:30]1[CH2:33][NH:32][CH2:31]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[F:29][CH:30]1[CH2:33][N:32]([C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:27])[CH2:31]1
Reactant: FC1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), 3-fluoroazetidine hydrochloride (30.8 mg, 276 mmol), diisopropylethylamine (241 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 3 hours at 70° C. under nitrogen atmosphere in a closed vessel and then over the weekend at room temperature. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording 4-(3-fluoroazetidine-1-carbonyl)-1-methyl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (111 mg, 93.3%) as an insoluble white solid. mp.: 259-262° C. MS: m/z=420.2 (M+H+).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:13]2([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.[B:21](OCCCC)([O:27]CCCC)[O:22]CCCC.Cl>C1COCC1.O>[C:18]([C:13]1([C:9]2[CH:8]=[C:7]([B:21]([OH:27])[OH:22])[CH:12]=[CH:11][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1)([OH:20])=[O:19]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: O=C(O)C1(c2cccc(Br)c2)CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2cccc(B(O)O)c2)CCCC1
Reaction time: 0.75 h

Procedure:
A solution of n-butyl lithium (2.5 M in hexanes, 5 mL, 12.48 mmol) in THF (30 mL) is chilled to −78° C., and a solution of 1-(3-bromo-phenyl)-cyclopentanecarboxylic acid [1.05 g, 3.9 mmol] in THF (10 mL) is added dropwise via syringe. The solution is stirred at temperature for 45 minutes and treated with tributyl borate (3.2 mL, 11.7 mmol). The reaction mixture is allowed to stir for 2.5 hours and then diluted with water (60 mL), acidified with 3M HCl and extracted twice with EtOAc (50 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 3-(1-carboxy-cyclopentyl)-phenylboronic acid as a solid, which is used without further purification.