Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:10]2[CH:11]=[C:12]([Br:16])[C:13]([OH:15])=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].O[CH2:18][C:19]1[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH:24]=1>>[C:1]([N:4]1[C:10]2[CH:11]=[C:12]([Br:16])[C:13]([O:15][CH2:18][C:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH:20]=3)=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCCc2cc(O)c(Br)cc21
Reactant: CN1CC=C(CO)CC1
Product: CC(=O)N1CCCCc2cc(OCC3=CCN(C)CC3)c(Br)cc21

Procedure:
The title compound was prepared from 1-acetyl-8-bromo-7-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine (D25) and 4-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D1) following the procedure of Description 2.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]2([OH:38])[CH2:37][CH2:36][CH2:35]2)[CH:33]=1)[C:28](O)=[O:29])#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]2([OH:38])[CH2:35][CH2:36][CH2:37]2)[CH:33]=1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:29])#[N:24]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: N#Cc1cc(C(=O)O)cc(C2(O)CCC2)c1
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(C3(O)CCC3)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the process described in Example 26, 80 mg (0.276 mmol) of the compound of Example 6A and 60 mg (0.276 mmol) of the compound of Example 73A gave 115 mg (82% of theory, 96% pure) of the title compound. In this case, the reaction time was 1 h. Final trituration of the product was carried out using a mixture of 10 ml of pentane and 2 ml of diisopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](C)[CH:6]=[CH:5][C:4]=1[S:10]([NH2:13])(=[O:12])=[O:11].[C:14]([O-:17])(O)=[O:15].[Na+].[O-][Mn](=O)(=O)=O.[K+]>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[S:10](=[O:12])(=[O:11])[NH2:13])[C:14]([OH:17])=[O:15]
Reactant: O=C([O-])O
Reactant: COc1cc(C)ccc1S(N)(=O)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)O)ccc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
2-Methoxy-4-methyl-benzenesulfonamide (201 mg, 1 mmol) was dissolved in H2O (10 mL). NaHCO3 (67 mg, 0.8 mmol) and KMnO4 (653 mg, 4.13 mmol) was added. The reaction mixture was stirred at reflux for 4 h. The reaction mixture was cooled to rt and filtered. the filtrate was acidified to pH=2 using conc. HCl. The precipitate was collected by filtration, washed with H2O affording the title compound as a white powder (117 mg).
Reaction SMILES: BrC1C(C)(C)OC2C=CSC=2C1O.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15].[H-].[Na+].[OH:28][CH:29]1[C:34]([CH3:36])([CH3:35])[O:33][C:32]2[CH:37]=[CH:38][S:39][C:31]=2[CH:30]1N1CCCC1=O.[K+].[Br-]>CN(C)C=O.O>[OH:28][CH:29]1[C:34]([CH3:36])([CH3:35])[O:33][C:32]2[CH:37]=[CH:38][S:39][C:31]=2[CH:30]1[NH:23][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:25][CH:24]=1
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Reactant: NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC1(C)Oc2ccsc2C(O)C1Br
Agent: [Br-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccsc2C(NC(=O)c2ccc([N+](=O)[O-])cc2)C1O

Procedure:
6-Bromo-7-hydroxy-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]-pyran (6.8 g, 25.8 mmol) and 4-nitrobenzamide (10.7 g, 64.5 mmol) were treated with sodium hydride 60% in oil (2.26 g, 56.8 mmol) in N,N-dimethylformamide (110 mL) using the procedure described for the preparation of 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran. The reaction mixture was poured into water and extracted into 10% isopropanol in dichloromethane. The solvent was evaporated in vacuo and the residue was purified by medium pressure chromatography using 2% methanol in dichloromethane as the eluant to give the product, 4.5 g (50%), as a pale yellow solid: mp 183°-186° C. dec; IR (KBr): 3398, 1664, 1644 and 1601 cm-1 ; MS: m/z 349 (MH+); 1H NMR (CDCl3): δ1.35(s, 3H), 1.50(s, 3H), 3.79(d, J=7.9 Hz, 1H), 4.26(bs, 1H, exchanges with D2O), 5.19(d, d, J=7.9 Hz, and J=7.0 Hz, 1H), 6.59(bd, J=7.0 Hz, 1H, shifts to 6.66 with D2O), 6.63(d, J=5.4 Hz, 1H), 7.18(d, J=5.4 Hz, 1H), 7.97(d, J=8.8 Hz, 2H) and 8.32(d, J=8.8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17]>>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccccc2Br)c1Br
Yield: 31 %

Procedure:
2-Bromo-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2-bromobenzenesulfonyl chloride according to the procedures described in Example 5. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 84°-86° C., yield 31%.
Reaction SMILES: [F:1][C@H:2]1[CH2:39][C@@:17]2([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:40])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:8][C:9]=1[CH2:10][CH2:11]2.O1CCCC1.O.[BH4-].[Na+]>CO.C(OCC)(=O)C>[F:1][C@H:2]1[CH2:39][C@@:17]2([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28][CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:40])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:8][C:9]=1[CH2:10][CH2:11]2
Reactant: O=C1CC[C@H]2[C@@H]3CCc4cc(OC5CCCCO5)ccc4[C@H]3[C@@H](F)C[C@]12CCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O[C@H]1CC[C@H]2[C@@H]3CCc4cc(OC5CCCCO5)ccc4[C@H]3[C@@H](F)C[C@]12CCCCCCCCCCSCCCC(F)(F)C(F)(F)F
Reaction time: 0.75 h
Yield: 81.6 %

Procedure:
2.2 g of 11β-fluoro-[9-(4,4,5,5,5-pentafluoropentylthio)-nonyl]-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-triene-17-one in a mixture of 45 ml of methanol, 7 ml of tetrahydrofuran and 4.5 ml of water is mixed in portions with 450 mg of sodium borohydride at 0° C. After 45 minutes, it is diluted with ethyl acetate, washed with water, dried and concentrated by evaporation. Chromatography of the crude product on silica gel with a hexane-ethyl acetate gradient yields 1.8 g of 11β-fluoro-[9-(4,4,5,5,5-pentafluoropentylthio)-nonyl]-3-(tetrahydropyran-2-yloxy)-estra-1,3,5(10)-trien-17β-ol as an oil.
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][C:4]([N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]4([C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:10]=3[CH:9]=2)=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Br:52]N1C(=O)CCC1=O>C(OCC)(=O)C>[C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:2]=[CH:3][C:4]([N:7]([C:33]2[CH:34]=[CH:35][C:36]([Br:52])=[CH:37][CH:38]=2)[C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[C:27]5[C:32]4=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:10]=3[CH:9]=2)=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc(N(c3ccccc3)c3ccc4c(c3)C3(c5ccccc5-c5ccccc53)c3ccccc3-4)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc3c(c2)C2(c4ccccc4-c4ccccc42)c2ccccc2-3)cc1
Reaction time: 25 h
Yield: 84.3 %

Procedure:
To a 100 mL three-neck flask were added 3.0 g (5.4 mmol) of N-(1,1′-biphenyl-4-yl)-N-phenyl-9,9′-spirobi[9H-fluoren]-2-amine, 20 mL of toluene, and 40 mL of ethyl acetate. To the solution was added 0.93 g (5.2 mmol) of N-bromosuccinimide (abbreviation: NBS), and the mixture was stirred for 25 hours. After the stirring, the mixture was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, and then the organic layer was dried over magnesium sulfate. This mixture was separated by gravity filtration, and the filtrate was concentrated to give a solid. This solid was purified by silica gel column chromatography. In the column chromatography, hexane and then toluene:hexane=1:5 were used as developing solvents. The resulting fraction was concentrated to give a solid. The obtained solid was recrystallized from ethyl acetate/hexane to give 2.8 g of a white solid in a yield of 83%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-])=O.[N+](C1C=CC=C2C=1C(C(=O)C1C=CC=CC=1)=NN2)([O-])=O>>[NH2:11][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([OH:10])=[N:2]2)=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Oc1n[nH]c2ccccc12
Agent: O=C(c1ccccc1)c1n[nH]c2cccc([N+](=O)[O-])c12
Product: Nc1ccc(C(=O)n2nc(O)c3ccccc32)cc1

Procedure:
Reaction of 1H-indazol-3-ol with p-nitrobenzoyl chloride and subsequent catalytic reduction of the nitrobenzoyl indazol derivative according to the general procedure B above afforded the desired amine as a colorless solid in 49.1% overall yield; m.p. 233°-235° C.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]([CH2:11][CH2:12][C:13](O)=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21].P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:28]>O1CCCC1>[OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]([CH2:11][CH2:12][C:13]([NH2:28])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)O)CC2=O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCc1c(O)ccc2c1OC(C)(CCC(N)=O)CC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title product of Example 3, (1.0 g, 3.4 mmole) in 50 ml of dry tetrahydrofuran cooled to 0° was added 2.1 g (10.2 mmole) of phosphorus pentachloride. After the mixture was stirred for 30 minutes, approximately 2 ml of liquid ammonia was added, and the solution was warmed to room temperature and stirred for an additional 30 minutes. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed successively with saturated sodium bicarbonate solution, water, and brine, dried over MgSO4, filtered, and concentrated to dryness. The crude product, mp. 108°-115°, was not purified further. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:10]([NH:24][C:25](=[O:36])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1CCCC1.C(O)(=[O:50])C>CN(C=O)C.O>[Si:1]([O:8][C@H:9]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C@H:10]([NH:24][C:25](=[O:36])[O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH2:11][CH2:12][C:13](=[O:50])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)N[C@H](CCC#Cc2ccc([N+](=O)[O-])cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Reactant: CC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: O
Product: COc1ccc(COC(=O)N[C@H](CCC(=O)Cc2ccc([N+](=O)[O-])cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of nitrophenyl acetylene (from Step F, 41 g, 65.5 mmol) in DMF (40 ml) was added pyrrolidine (14 mL, 196.5 mmol) and the resulting mixture heated at 80° C. for 3 h. The mixture was cooled to room temperature and a 10% solution of acetic acid in water (110 ml) was added, and the resulting solution stirred at room temperature for another 3 h. The mixture was poured into water (300 ml) and extracted with EtOAc (3×250 ml); combined EtOAc layers were washed with water (2×250 ml), sat. NaCl (100 ml), dried over MgSO4, filtered and evaporated. The residue was purified by Horizon Flash 75 eluting with a gradient rising from 100% Hexanes to 50% EtOAc in Hexanes to give 34 g (81%) as a dark orange oil. 1H NMR (500 MHz, CDCl3): 8.17-8.14 (m, 2H), 7.32-7.23 (m, 9H), 6.87 (d, J=8.4 Hz, 2H), 4.96 (d, J=12.2 Hz, 1H), 4.90 (d, J=12.1 Hz, 1H), 4.72 (d, J=3 Hz, 1H), 4.16-4.13 (m, 1H), 3.81 (s, 3H), 3.71-3.77 (m, 2H), 2.65-2.52 (m, 2H), 1.97-1.92 (m, 1H), 1.72-1.60 (m, 1H), 0.93 (s, 9H), 0.05 (s, 3H), −0.13 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH2:11][CH2:12][O:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.ClCCl>O>[CH3:14][O:13][CH2:12][CH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:10]=1
Reactant: COCCc1nc(Cl)c2nc[nH]c2n1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O
Product: COCCc1nc(N2CCOCC2)c2nc[nH]c2n1
Temperature: 25 °C
Yield: 75 %

Procedure:
6-Chloro-2-(2-methoxy-ethyl)-9H-purine (0.5 g, 2.4 mmol, synthesized by following the procedure reported by Crespo and al.(Journal of Medicinal Chemistry, 1998, Vol. 41, No. 21, p. 4024) was heated in morpholine (1 mL, 5 eq) at 150° C. for 15 minutes. Reaction mixture was cooled to room temperature and distributed between dichloromethane and water. Organic layer was washed 2 times with water, then with brine, dried over MgSO4 and 2-(2-methoxy-ethyl)6-morpholin-4-yl-9H-purine (0.46 g, 75%) was isolated by column chromatography.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][N:24]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@@H](N5CCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 30A for the product of Example 1E and substituting 2-methoxypyrimidine-5-boronic acid for pyrimidine-5-boronic acid. 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (s, 2H) 8.04 (d, J=8.90 Hz, 1H) 7.98 (d, J=1.23 Hz, 1H) 7.58 (dd, J=8.44, 1.99 Hz, 1H) 4.08 (s, 3H) 3.60-3.72 (m, 1H) 3.04-3.14 (m, 1H) 2.65-2.78 (m, 2H) 2.51-2.63 (m, 4H) 2.38-2.51 (m, 2H) 1.84 (s, 4H). MS: (M+H)+=367.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC(C)C)=O.[CH:30]1([CH2:33][N:34]2[CH2:38][CH2:37][CH:36]([CH2:39][NH2:40])[CH2:35]2)[CH2:32][CH2:31]1>O.C(N(CC)CC)C>[CH:30]1([CH2:33][N:34]2[CH2:38][CH2:37][CH:36]([CH2:39][NH:40][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=3[O:2][CH3:1])[CH2:35]2)[CH2:31][CH2:32]1
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Reactant: NCC1CCN(CC2CC2)C1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(S(N)(=O)=O)cc(C(=O)NCC2CCN(CC3CC3)C2)c1OC

Procedure:
6.6 g of 2,3-dimethoxy-5-sulphamoyl benzoic acid, 50 ml of acetone, 10 ml of water and 3.6 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The solution is cooled to 0°-+5° C. and 3.6 g of isobutyl chloroformate is poured in drop by drop. It is reacted for 30 minutes with the same temperature maintained, after which 4.8 g of 1-cyclopropylmethyl-3-aminomethyl-pyrrolidine is added drop by drop. The reaction medium is agitated for 1 hour at room temperature, whereupon 50 ml of water is added and the acetone evaporated under vacuum. A further 50 ml of water is added and the solution is made alkaline with 5 ml of ammonia (density=0.91). An oil is precipitated. The suspension is extracted 3 times with 50 ml of methylene chloride. The organic phase is dried over magnesium sulphate, filtered, then evaporated under vacuum. The residue is dissolved in boiling ethyl acetate. It crystallises hot. The crystals are cooled, filtered and dried in an oven at 50° C.
Reaction SMILES: [C:1](/[C:3](=[C:9](/[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)\SC)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(N(CC)C(C)C)(C)C.Cl.[CH:32]([NH2:34])=[NH:33]>C(O)C>[NH2:34]/[CH:32]=[N:33]/[C:9](/[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[C:3](\[C:1]#[N:2])/[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: N=CN
Reactant: CCOC(=O)/C(C#N)=C(\NCc1ccc(OC)cc1)SC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)/C(C#N)=C(/N=C/N)NCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
(E)-Ethyl 2-cyano-3-((4-methoxybenzyl)amino)-3-(methylthio)acrylate was dissolved in 65 mL ethanol. N,N-Diisopropylethylamine (13 mL, 74.44 mmol) and formamidine hydrochloride (2.12 g, 26.33 mmol) were added and the reaction mixture was stirred at room temperature for 48 h. The solvent was concentrated and the residue was directly purified using SP1® Purification System (0% to 10%, dichloromethane-methanol) to give 0.96 g (25% yield) of the title compound as a yellow oil. Purity 85%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[C:74]([CH2:75][NH:76][C:77](=[O:83])[O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[N:73][N:72]=[N:71]1>C(Cl)Cl.CN(C=O)C>[C:79]([O:78][C:77]([NH:76][CH2:75][C:74]1[N:70]([CH2:69][C@@H:65]2[C@H:64]([NH:63][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:16]3[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[S:19][CH:20]=3)[C:67](=[O:68])[NH:66]2)[N:71]=[N:72][N:73]=1)=[O:83])([CH3:82])([CH3:80])[CH3:81]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCc1nnnn1C[C@H]1NC(=O)[C@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1nnnn1C[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
Prepared in an analogous manner to example 4, step 3 using (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (214 mg, 0.498 mmol), DIPEA (953 μL, 5.46 mmol) and HATU (830 mg, 2.18 mmol) in DCM:DMF (5:1, 3.6 mL) at 0° C. followed by a solution of tert-butyl ((1-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-1H-tetrazol-5-yl)methyl)carbamate (123 mg, 0.415 mmol) in DCM:DMF (4.3:1, 3.7 mL). After stirring at rt for 1 h it was subjected to an identical workup then purified via silica gel chromatography (Acetone-DCM), affording the title compound (174 mg, 59%) as a light purple solid. LCMS: Rt=1.03 min, m/z=709.2 (M+1) Method 2m_acidic.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:32]2[N:36]([CH:37]([F:39])[F:38])[C:35]3[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=3[N:33]=2)[C:24]=1[C:25]([O:27]C(C)(C)C)=[O:26])=[O:18]>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:32]2[N:36]([CH:37]([F:38])[F:39])[C:35]3[CH:40]=[CH:41][CH:42]=[CH:43][C:34]=3[N:33]=2)[C:24]=1[C:25]([OH:27])=[O:26])=[O:18]
Reactant: CC(C)(C)OC(=O)c1c(-c2nc3ccccc3n2C(F)F)csc1NC(=O)c1cc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1scc(-c2nc3ccccc3n2C(F)F)c1C(=O)O)c1cc2ccccc2o1
Reaction time: 6 h
Yield: 88.9 %

Procedure:
Under an atmosphere of argon, trifluoroacetic acid (0.75 mL) was added to a stirred solution of 43 (33 mg, 65 μmol) in dichloromethane (0.75 mL) at room temperature. The reaction was stirred for 6 hours then concentrated under reduced pressure. Flash chromatography (silica, 5% methanol in dichloromethane) provided 44 (26.2 mg, 90%) as a solid: 1H NMR (500 MHz, d6-DMSO) δ 13.70 (bs, 1H), 12.46 (s, 1H), 7.92 (s, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.81-7.72, (m, 3H), 7.65-7.54 (m, 2H), 7.44-7.38 (m, 4H); LRESIMS m/z 454 [M+H]+, calcd. for C22H13F2N3O4S1 454.1.
Reaction SMILES: [CH3:1][Zn]Cl.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[C:25](Br)=[CH:24][N:23]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[C:25]([CH3:1])=[CH:24][N:23]([S:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Zn]Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Yield: 95.6 %

Procedure:
MeZnCl (2.0M in THF, 720 uL, 1.4 mmol) was added to a stirred solution 4-(7-Benzenesulfonyl-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.48 mmol) and tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.12 mmol) in THF (10 mL) at room temperature under N2. The solution was stirred and heated at reflux for 2 hours, cooled to room temperature, quenched with saturated aqueous NH4Cl, extracted into EtOAc (2×100 mL), dried over Na2SO4 and concentrated in vacuo. The product was purified on a Biotage (silica, 40% EtOAc/hexanes) to give 4-(7-Benzenesulfonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (210 mg, 94%.) LCMS (APCI+) m/z 458 [M+H]+; Rt: 3.73. 1H NMR (CDCl3, 400 MHz) δ 8.49 (1H, s), 8.18 (2H, d, J 8.2 Hz), 7.59 (1H, t, J 6.9 Hz), 7.50 (2H, t, J 7.8 Hz), 7.34 (1H, s), 3.59-3.54 (4H, m), 3.48-3.44 (4H, m), 2.35 (3H, s), 1.48 (9H, s.)
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C([O:6][C:7]([NH:9][N:10]([CH2:13][CH3:14])[C:11]#[N:12])=O)C>C(O)(=O)C>[CH2:13]([N:10]1[C:11]([S:3][CH2:1][CH3:2])=[N:12][C:7]([OH:6])=[N:9]1)[CH3:14]
Reactant: CCOC(=O)NN(C#N)CC
Reactant: CCS
Solvent: CC(=O)O
Product: CCSc1nc(O)nn1CC
Yield: 75.1 %

Procedure:
To an ethanolic solution of sodium ethylate produced from 4.6 g of sodium and 100 ml of absolute ethanol there is firstly added dropwise 14.9 g of ethyl mercaptan and subsequently 31.4 g of 2-ethyl-2-cyanohydrazinecarboxylic acid ethyl ester is added dropwise. There is formed a crystalline precipitate, which is refluxed for 3 hours. The cooled suspension is freed, after the addition of 12 g of glacial acetic acid, by filtration from the precipitated sodium acetate, and the filtrate is concentrated in vacuo to dryness. 200 ml of chloroform is added to the residue and filtration is performed. The filtrate is again concentrated to dryness. The residue is recrystallised with cyclohexane. There is obtained 26 g (75% of theory) of 1-ethyl-5-ethylthio-3-hydroxy-1,2,4-triazole, m.p. 65°-68° C.