Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](F)(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>C(OCC)(=O)C>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][S:1](=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: CN(C)CCN
Solvent: CCOC(C)=O
Product: CN(C)CCNS(=O)(=O)c1ccc(N)cc1

Procedure:
5.26 g sulphanilic acid fluoride and 16.5 ml of N,N-dimethyl-ethylenediamine are stirred for 4 hours at 100° C., then dissolved in ethyl acetate and extracted three times with saline solution. The residue obtained by evaporation of the organic phase is crystallised from diethyl ether and dried at 60° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:19]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[N:6]([C:8]([CH:11]=[CH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[N:7]=1.C(N1CCCC(NC2C=C(N(CC3C=CC(OC)=CC=3)C3C=CC=CC=3)C3N(C(C#N)=CN=3)N=2)C1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].[C@H:82]1([NH2:89])[CH2:87][CH2:86][C@H:85]([NH2:88])[CH2:84][CH2:83]1>CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd].C1(C)C=CC=CC=1>[NH2:88][C@H:85]1[CH2:86][CH2:87][C@H:82]([NH:89][C:2]2[CH:3]=[C:4]([N:19]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]3[N:6]([C:8]([CH:11]=[CH:12][C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)=[CH:9][N:10]=3)[N:7]=2)[CH2:83][CH2:84]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C=Cc4ccncc4)cnc23)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1[c-]cccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2ccccc2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C=Cc4ccncc4)cnc23)cc1
Temperature: 85 °C

Procedure:
6-chloro-N-(4-methoxybenzyl)-N-phenyl-3-(2-(pyridin-4-yl)vinyl)imidazo[1,2-b]pyridazin-8-amine (75 mg, 0.16 mmol) from (1b), sodium tert-butoxide (22 mg, 0.22 mmol), trans-1,4-cyclohexanediamine (22 mg, 0.19 mmol) and acetato(2′-di-tert-butylphosphino-1,1′-biphenyl-2-yl)palladium (II) (7.4 mg, 0.01 mmole) were purged with argon for 15 min. then toluene (0.6 mL) was added via syringe. The contents were sonicated briefly and heated at 85° C. for 2 h. After cooling to room temperature, the mixture was partitioned between EtOAc (200 mL) and water (20 mL), and the organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by reverse phase preparative HPLC to provide N6-(trans-4-aminocyclohexyl)-N8-(4-methoxybenzyl)-N8-phenyl-3-(2-(pyridin-4-yl)vinyl)imidazo[1,2-b]pyridazine-6,8-diamine as a yellow solid (32 mg, 38%). LCMS[M+H]+ 546.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][C:18]#[N:19])[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]=[O:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2(CCC#N)CCCC[C:27]2=[O:32])C=CC=CC=1.C(OC=O)C>>[CH3:27][O:32][C:5]1[CH:6]=[C:1]([C:7]2([CH2:16][CH2:17][C:18]#[N:19])[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]=[O:14])[C:8]2=[O:15])[CH:2]=[CH:3][CH:4]=1
Reactant: N#CCCC1(c2ccccc2)CCCC(C=O)C1=O
Reactant: N#CCCC1(c2ccccc2)CCCCC1=O
Solvent: CCOC=O
Product: COc1cccc(C2(CCC#N)CCCC(C=O)C2=O)c1

Procedure:
Following the procedure set forth in Example 1 there was prepared 2-phenyl-2-(2-cyanoethyl)-6-formylcyclohexanone from 2-phenyl-2-(2-cyanoethyl)cyclohexanone and ethylformate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.C([O-])([O-])=O.[Cs+].[Cs+].BrC1C=CC(S(O[C@@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]2)(=O)=O)=CC=1>CN1C(=O)CCC1.O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:14][C@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: COc1ccc2nc(Cl)c(O)nc2c1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3nc2Cl)CN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
A solution (0.35M) of the product of step 2 in NMP was treated with Cs2CO3 (1.5 eq) and 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.1 eq). The resulting mixture was stirred at 50° C. for 18 hours, then a further portion (0.1 eq) of 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate was added. After stirring for 2 hours, the mixture was cooled and diluted with H2O and EtOAc. The organic phases were washed with aqueous HCl (1 N), saturated aqueous NaHCO3 and brine. The dried organic phase was concentrated to a residue that was purified by flash-chromatography (0-60% EtOAc/petroleum ether) to give the title compound (35% for two steps) as a solid. MS (ES−) m/z 438 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11](Br)=[C:10]([C:14]([NH2:16])=[O:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:19]3[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=3[Cl:17])=[C:10]([C:14]([NH2:16])=[O:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NC(=O)c1cc(-c2ccnc(N)n2)[nH]c1Br
Reactant: N#Cc1ccc(Cl)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(Cl)c(-c2[nH]c(-c3ccnc(N)n3)cc2C(N)=O)c1
Temperature: 25 °C
Yield: 12.7 %

Procedure:
5-(2-Aminopyrimidin-4-yl)-2-bromo-1H-pyrrole-3-carboxamide (prepared according to WO2007/110344, 0.1 g, 0.35 mmol), 2-chloro-5-cyanophenylboronic acid (127 mg, 0.7 mmol), Na2CO3 (111 mg, 1.05 mmol), and PdCl2(dppf) (28 mg, 0.035 mmol) in DME (2.5 mL) and water (1 mL) were heated at 80° C. for 12 h, under argon. After cooling to room temperature, the precipitate was filtered and the filtrate was evaporated under reduced pressure. The crude material was purified by preparative HPLC (Method 1) to afford the title compound (15 mg, 13%).
Reaction SMILES: ClC1C=C(C=CC=1F)C1C(C2C=CC3C(=CC=C(C4N(C5CCCCC5)C5C=CC(C(O)=O)=CC=5N=4)C=3)N=2)=CC(OC)=CC=1.C[O:46][C:47]([C:49]1[CH:82]=[CH:81][C:52]2[N:53]([CH:75]3[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]3)[C:54]([C:56]3[CH:57]=[C:58]4[C:63](=[CH:64][CH:65]=3)[N:62]=[C:61]([C:66]3[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[CH:68][C:67]=3Br)[CH:60]=[CH:59]4)=[N:55][C:51]=2[CH:50]=1)=[O:48].[N+:83]([C:86]1[CH:91]=[CH:90][C:89](B(O)O)=[CH:88][CH:87]=1)([O-:85])=[O:84]>>[CH:75]1([N:53]2[C:52]3[CH:81]=[CH:82][C:49]([C:47]([OH:46])=[O:48])=[CH:50][C:51]=3[N:55]=[C:54]2[C:56]2[CH:57]=[C:58]3[C:63](=[CH:64][CH:65]=2)[N:62]=[C:61]([C:66]2[C:67]([C:89]4[CH:90]=[CH:91][C:86]([N+:83]([O-:85])=[O:84])=[CH:87][CH:88]=4)=[CH:68][CH:69]=[C:70]([O:72][CH3:73])[CH:71]=2)[CH:60]=[CH:59]3)[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80]1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 14.3 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-nitrophenylboronic acid (62 mg, 0.2625 mmol) to produce the title compound (15 mg, 14% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:3]1.N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:3]1)(=[O:36])=[O:35]
Reactant: O=C1NCCN1C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methyl pyrrolidine (1.60 g), pyridine (0.43 ml) and N,N-dimethylaminopyridine (0.54 g) in dichloromethane (20 ml) was added methanesulfonyl chloride (0.37 ml) under ice-cooling and the mixture was stirred under the same condition for 1 hour and then allowed to stand at ambient temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.90 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:16]=1[CH2:17][N:18]=[N+]=[N-])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:14][C:15]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:16]=1[CH2:17][NH2:18])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCc1cc(C(F)(F)F)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 81.9 %

Procedure:
LAH (136 mg, 3.58 mmol) was added to a solution of 2-benzyloxy-5-trifluoromethyl-benzylazide (1.1 g, 3.58 mmol) at 0° C. After 1 hour, the reaction was quenched by the sequential addition of water (136 μL), 15% NaOH (136 μL), and water (400 μL), the mixture was diluted with dichloromethane and dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (3% methanol/dichloromethane) to afford 825 mg (82%) of the title compound as a colorless oil. MS 282 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.6-7.3 (m, 7H); 6.92 (d, 1H, J=9.1 Hz); 5.18 (s, 2H); 3.9 (s, 2H); 2.65 (bs, 2H).
Reaction SMILES: [CH2:1]1[C@@H:6](N)[C@H:5](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H:4](O)[C@H:3](O[C@H]2O[C@H](CN)[C@@H](O)C[C@H]2N)[C@H:2]1N.[Cl:33][C:34](OC(=O)C1C=CC=CC=1)=[O:35].C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl.N1C=CC=CC=1>[C:34]([Cl:33])(=[O:35])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)C[C@@H]1O
Reactant: O=C(Cl)OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Cl)c1ccccc1

Procedure:
When the requisite 5-O-thioformyl intermediate is prepared by reacting tobramycin with an excess of benzoyl chloroformate and potassium carbonate in aqueous methanol in a manner similar to that described in Preparation 1A(1) followed by reaction of the thereby formed 1,3,2',6',3"-penta-N-benzyloxycarbonyltobramycin with benzoyl chloride in pryidine in the manner of Preparation 1C(1) thence reaction of the resulting 1,3,2',6',3"-penta-N-benzyloxycarbonyl-4',2",4",6"-tetra-O-benzoyltobramycin with N,N-dimethyl-α-chloroformimidinium chloride in methylene chloride in pyridine followed by treatment with dry hydrogen sulfide in a manner similar to that described in Preparation 1D(1) whereby is obtained 1,3,2',6',3"-penta-N-benzloxycarbonyl-5-O-thioformyl-4',2",4",6"-tetra-O-benzoyltobramycin.
Reaction SMILES: [CH2:1]([N:5]([CH2:51][CH2:52][CH2:53][CH3:54])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:16][C:15]=2[C:30]([N:32]2[C@H:41]([CH2:42][O:43][Si](C(C)(C)C)(C)C)[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CCCC)C(C1C=C(C)N(C2C=CC(N(S(C3C=CC=CC=3)(=O)=O)S(C3C=CC=CC=3)(=O)=O)=CC=2C(N2[C@H](CO[Si](C(C)(C)C)(C)C)CC3C(=CC=CC=3)C2)=O)N=1)=O)CCC.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH2:51]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:22])=[O:23])=[CH:16][C:15]=2[C:30]([N:32]2[CH:41]([CH2:42][OH:43])[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33]2)=[O:31])[N:9]=1)=[O:7])[CH2:52][CH2:53][CH3:54]
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(NS(=O)(=O)c3ccccc3)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Agent: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(N(S(=O)(=O)c3ccccc3)S(=O)(=O)c3ccccc3)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)n1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc(NS(=O)(=O)c3ccccc3)cc2C(=O)N2Cc3ccccc3CC2CO)n1

Procedure:
A mixture of (S)—N,N-dibutyl-1-(2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(phenylsulfonamido)phenyl)-5-methyl-1H-pyrazole-3-carboxamide and (S)—N,N-dibutyl-1-(2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(N-(phenylsulfonyl)phenylsulfonamido)phenyl)-5-methyl-1H-pyrazole-3-carboxamide (0.21 g, 0.272 mmol) in THF (2.1 mL) was treated with 3N HCl (0.62 mL) at RT for 10 min. The reaction mixture was diluted with water (20 mL), the pH was adjusted to about 8 using aq. NaHCO3 solution and extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as a hygroscopic solid, 0.025 g (14%). Rf=0.38 (5% MeOH in DCM); 1H NMR (400 MHz, DMSO-d6): δ 10.85-10.70 (m, 1H, D2O exchangeable), 7.78-6.60 (m, 12H), 6.50-6.20 (m, 1H), 5.00-3.60 (m, 4H), 3.60-2.40 (m, 8H), 2.25-2.00 (m, 3H), 1.60-0.50 (m, 14H); LC-MS: m/z 658.4 (M+H), HPLC: 95.08% (RT=9.403 min., method I).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]4[N:30](COCC[Si](C)(C)C)[C:29]5[C:28](=[O:39])[N:27]([CH2:40][CH2:41][CH3:42])[C:26](=[O:43])[N:25]([CH2:44][CH2:45][CH3:46])[C:24]=5[N:23]=4)[CH:19]=[N:18]3)[CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>C(O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]4[NH:30][C:29]5[C:28](=[O:39])[N:27]([CH2:40][CH2:41][CH3:42])[C:26](=[O:43])[N:25]([CH2:44][CH2:45][CH3:46])[C:24]=5[N:23]=4)[CH:19]=[N:18]3)[CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC4CC(=O)N(c5ccc(C(C)C)cc5)C4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC4CC(=O)N(c5ccc(C(C)C)cc5)C4)c3)nc2n(CCC)c1=O
Temperature: 85 °C
Yield: 59.6 %

Procedure:
A mixture of 8-{1-[1-(4-Isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione obtained in step 5 (0.1 g, 0.23 mmol), 2 N HCl (3 ml), ethanol (2 ml) were heated at 85° C. for 3 hours. The mixture was cooled to 10-15° C. The solid obtained was filtered and washed with water (1 ml), diethyl ether (1 ml) to obtain 8-{1-[1-(4-isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (0.071 g, 76%) as a white solid.
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=[O:15].Br[C:18]1[CH:19]=[C:20]([CH:39]=[CH:40][CH:41]=1)[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=2[O:37][CH3:38])=[CH:25][CH:24]=1>[Cu]I>[F:36][C:32]1[C:33]([F:35])=[CH:34][C:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:20]3[CH:19]=[C:18]([N:9]4[CH2:13][CH2:12][CH2:11][C@H:10]4[C:14]([OH:16])=[O:15])[CH:41]=[CH:40][CH:39]=3)=[CH:28][CH:27]=2)=[C:30]([O:37][CH3:38])[CH:31]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(Br)c2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N3CCC[C@H]3C(=O)O)c2)cc1
Temperature: 100 °C

Procedure:
To a vial containing copper(I) iodide (10 mg, 0.050 mmol), sodium iodide (30 mg, 0.2 mmol), cesium carbonate (114 mg, 0.35 mmol) and (S)-pyrrolidine-2-carboxylic acid (14 mg, 0.12 mmol) was added an aliquot of a stock solution of 4′-(3-bromo-benzyloxy)-4,5-difluoro-2-methoxy-biphenyl (1 ml of 0.1M in DMSO). The vial was sealed and heated to 100° C. for 15 hr. The reaction was filtered through Celite and purified by HPLC with increasing concentration of acetonitrile in water with 0.1% trifluoroacetic acid, yielding the product, (S)-1-[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenyl]-pyrrolidine-2-carboxylic acid as an off white solid (11 mg, 25%). LC-MS (ES) calculated for C25H23F2NO4, 439.16; found m/z 440 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[OH-].[Na+].Cl[C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[CH3:1][C:2]1[N:3]=[N:4][N:5]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:6]=1
Reactant: Cc1nnn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 20 °C
Reaction time: 72 h
Yield: 37.4 %

Procedure:
To a solution of 5-methyl-1H-tetrazole (1.513 g, 18.00 mmol), tetrabutylammonium bromide (0.029 g, 0.090 mmol) and sodium hydroxide (18.90 mL, 18.90 mmol) in dichloromethane (DCM) (25 mL) stirred under nitrogen at room temperature, was added (chloromethanetriyl)tribenzene (5.02 g, 18 mmol). The reaction mixture was stirred at 20° C. for 72 hours. The reaction was quenched with water, then partitioned between dichloromethane (10 mL) and water (25 mL). The organic phase was separated (hydrophobic frit) and the aqueous phase re-extracted (stirred for 5 min) with additional DCM (10 mL), then separated with a hydrophobic frit. The combined organic fractions were washed with water (2×25 mL), 5% aqueous sodium bicarbonate (10 mL) and brine (10 mL). The organic phase was evaporated in vacuo to give a white solid. Recrystallisation from hot ethyl acetate (8 mL/g) provided the product as a white solid (2.2 g). LCMS RT 1.35 mins.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15][CH3:16])[S:14][C:10]=3[CH:9]=2)[CH:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[CH:18]=[CH:17][C:11]3[N:12]=[C:13]([S:15]([CH3:16])=[O:24])[S:14][C:10]=3[CH:9]=2)[CH:6]=1
Reactant: CSc1nc2ccc(Cn3cnc(Br)c3)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc(Br)c3)cc2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 121.6 %

Procedure:
To a stirred mixture of 6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (105 mg, 0.3 mmol) from Step 5 of this Example in CH2Cl2 (15 mL) at 0° C. was added 70-75% 3-chloroperoxybenzoic acid (91 mg, 0.4 mmol). After the mixture was stirred at 0° C. for 2 h, saturated aq NaHCO3 (10 mL) was added. The mixture was stirred for 10 min and the CH2Cl2 layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (130 mg) as a white foam. The material was used in the next step without further purification. LCMS (ESI) m/z 356 and 358 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:17]1[N:18]([CH3:35])[C:19](=[O:34])[C:20]([CH3:33])=[CH:21][C:22]=1[NH:23][S:24]([C:27]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28]1)(=[O:26])=[O:25])C(=O)OC(C)(C)C.Cl.O1CCOCC1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:17]1[N:18]([CH3:35])[C:19](=[O:34])[C:20]([CH3:33])=[CH:21][C:22]=1[NH:23][S:24]([C:27]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28]1)(=[O:26])=[O:25]
Reactant: Cc1cc(NS(=O)(=O)C2(CCO)CC2)c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)n(C)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)C2(CCO)CC2)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
To a solution of tert-butyl (2-fluoro-4-iodophenyl)[3-({[1-(2-hydroxyethyl)cyclopropyl]sulfonyl}amino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-2-yl]carbamate (324 mg, 0.521 mmol) in dry THF under a nitrogen atmosphere was added a solution of HCl in dioxane (30 eq, 3.80 ml, 15.640 mmol). The mixture was stirred at room temperature for 18 hours, after which again a solution of HCl in dioxane (8 eq, 1.01 ml, 4.055 mmol) was added and stirred for another 18 hours. The mixture was partitioned between ethyl acetate and aq. NaOH (2 N) and the aqueouse layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated in vacuo. The crude material was purified by flash chromatography to afford the title compound (172 mg, 65%).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[OH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]2[CH2:26][C@@H:25]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][N:23]2[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=2)=[O:33])=O)[C:16]1=[O:45].CO>O1CCCC1.C(OCC)(=O)C>[OH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][N:17]([CH2:20][C@@H:22]2[CH2:26][C@@H:25]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][N:23]2[C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=2)=[O:33])[C:16]1=[O:45]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCN(CCO)C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
To a suspension of sodium borohydride (0.71 g) in tetrahydrofuran (25 ml) was added dropwise boron trifluoride etherate (11.8 ml) under ice-cooling and stirred at the same temperature for 10 minutes. To the mixture was added a solution of (2S,4R)-2-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]carbonyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.73 g) in tetrahydrofuran (50 ml) and the mixture was stirred at ambient temperature overnight. To the reaction mixture was added dropwise methanol (60 ml) under ice-cooling and evaporated in vacuo. The resulting residue was dissolved in methanol (30 ml) and conc. hydrochloric acid (1 ml) and stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]methyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.70 g).