Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:33]([N:36]([CH2:49][CH2:50]Br)[S:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N+:46]([O-:48])=[O:47])(=[O:39])=[O:38])[CH:34]=[CH2:35]>CC(N(C)C)=O>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([N:15]([CH2:50][CH2:49][N:36]([CH2:33][CH:34]=[CH2:35])[S:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[N+:46]([O-:48])=[O:47])(=[O:38])=[O:39])[S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([I:14])[CH:12]=2)[O:7][C:6]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:4]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Reactant: C=CCN(CCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C=CCN(CCN(c1nc2oc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1I)S(C)(=O)=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
2-(4-Fluoro-phenyl)-5-iodo-6-methanesulfonylamino-furo[2,3-b]pyridine-3-carboxylic acid methylamide (150 mg, 0.31 mmol) is dissolved in DMA (4 mL) and Cs2CO3 (110 mg, 0.34 mmol) and N-Allyl-N-(2-bromo-ethyl)-2-nitro-benzenesulfonamide (214 mg, 0.61 mmol) is added and the mixture is placed in the microwave for 30 min at 150° C. The mixture is then filtered and the solid is washed with EtOAc (30 mL). The organic is washed with H2O (10 mL) then Brine (20 mL) and then dried over Na2SO4 then concentrated to dryness. HPLC (CH3CN/H2O/0.1% TFA) provides 6-({2-[Allyl-(2-nitro-benzenesulfonyl)-amino]-ethyl}-methanesulfonyl-amino)-2-(4-fluoro-phenyl)-5-iodo-furo[2,3-b]pyridine-3-carboxylic acid methylamide (45 mg, 19%). MS-ES [M+H]+=758.3.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([O:10][CH2:11][CH2:12][OH:13])([CH3:9])[CH3:8].[Cl:14][C:15]1[CH:23]=[CH:22][C:21](F)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].Cl>CN1C(=O)CCC1.O>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:13][CH2:12][CH2:11][O:10][CH:7]([CH3:9])[CH3:8])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cc(F)ccc1Cl
Reactant: CC(C)OCCO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)OCCOc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon atmosphere, potassium tert-butoxide (168 mg) was added to a solution of 2-isopropoxyethanol (172 μL) in NMP (1.5 mL). The mixture was stirred at room temperature for 10 minutes, 2-chloro-5-fluorobenzoic acid (87 mg) was added, and it was then stirred at 130° C. for 4 hours. The reaction mixture was cooled on ice bath, water was added, and it was then acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was separated, washed with brine, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude 2-chloro-5-[2-(propan-2-yloxy)ethoxy]benzoic acid. This was dissolved in DMF (2 mL), HATU (61 mg), N,N-diisopropylethylamine (29 μL) and 6-amino-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (50 mg) were added in this order, and it was stirred at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-2-methylphenyl)-6-[({2-chloro-5-[2-(propan-2-yl oxy)ethoxy]phenyl}carbonyl)amino]-2-(methoxymethyl)-1H-benz imidazole-4-carboxamide (41 mg) as white powder. This was dissolved in ethyl acetate (2 mL), and treated with 4N hydrogen chloride/ethyl acetate (1.2 Eq). The precipitate was collected by filtration, and dried to obtain the titled compound (28 mg) as white powder.
Reaction SMILES: C1(C#CC2CC3(CCN(C(OC(C)(C)C)=O)CC3)ON=2)C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]#[C:34][CH:35]=[N:36][OH:37])[CH:30]=[CH:31][CH:32]=1.[CH2:38]=[C:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[Cl:26][C:27]1[CH:28]=[C:29]([C:33]#[C:34][C:35]2[CH2:38][C:39]3([CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[O:37][N:36]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: ON=CC#Cc1cccc(Cl)c1
Reactant: C=C1CCOCC1
Agent: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Product: Clc1cccc(C#CC2=NOC3(CCOCC3)C2)c1

Procedure:
The title compound was prepared following the procedure described for Compound 1b, using Compound 31e instead of Compound 1a and 4-methylenetetrahydropyran (Tetrahedron, 46(7), 2411-2424, 1990) instead of tert-butyl 4-methylenepiperidine-1-carboxylate. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP1 ®TM-Biotage; gradient Petroleum Ether-EtOAc from 10:1 to 8:2) to give the title compound as a yellowish solid. Yield: 23.7%.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Br:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9](O)=[O:10].N1C=CC=CC=1>ClCCl>[Br:7][CH:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([Cl:4])=[O:10]
Reactant: CC(C)CC(Br)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CC(Br)C(=O)Cl
Reaction time: 20 h

Procedure:
A solution of sodium nitrite (31.55 g) in water (70 ml) was added dropwise to a stirred solution of D-leucine (20 g) in 47% aqueous hydrobromic acid (140 ml)/water (211 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours, then diluted with diethyl ether (600 ml). The organic layer was separated and washed with aqueous sodium metabisulphite (200 ml), dried over sodium sulphate, filtered and the solvent removed under reduced pressure to give 2-bromo-4-methyl-pentanoic acid as a yellow oil (27.6 g) [1H NMR (CDCl3): δ0.93 (d, 3H), 0.98 (d, 3H), 1.75-1.85 (m, 1H), 1.91-1.95 (m, 2H), 4.30 (t, 1H)]. Oxalyl chloride (9.56 ml) was added dropwise to a stirred solution of the 2-bromo-4-methylpentanoic acid (10.7 g) and pyridine (0.1 ml) in dichloromethane (60 ml). The reaction mixture was stirred for 20 hours and the solvent was removed under reduced pressure to give 2-bromo-4-methylpentanoyl chloride (12 g) [1H NMR (CDCl3); δ0.95 (d, 3H), 1.01 (d, 3H), 1.80-2.07 (m, 3H), 4.52 (t, 1H)]. A solution of this 2-bromo-4-methylpentanoyl chloride (12 g) in dichloromethane (40 ml) was added dropwise to a stirred solution of 2,6-dimethoxy-4-methylphenol (9.41 g) and triethylamine (15.6 ml) in dichloromethane (20 ml). The reaction mixture was stirred for 20 hours and was then chromatographed on silica gel, eluting with dichloromethane, to give the title compound as a viscous yellow oil (14.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:31][CH3:32])=[CH:5][C:6]2[N:12](CC)[C:11](=[O:15])[CH:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:23])[N:9]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:7]=2[CH:30]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:31][CH3:32])=[CH:5][C:6]2[NH:12][C:11](=[O:15])[CH:10]([C:16]3[CH:17]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][NH:23][C:39](=[O:41])[CH3:40])[N:9]=[C:8]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:7]=2[CH:30]=1
Reactant: CCN1C(=O)C(Cc2ccccc2N)N=C(c2ccccc2)c2cc(OC)c(OC)cc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(c1ccccc1)=NC(c1ccccc1CNC(C)=O)C(=O)N2
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 40 mg (0.09 mmol) of 7,8-dimethoxy-1-ethyl-3-(2-aminobenzyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one IIca, add 18.4 mg (0.23 mmol) of pyridine in 4 ml of CH2Cl2, 11.5 mg (0.11 mmol) of acetic anhydride dropwise. Stir for 24 hours. Evaporate to dryness and purify by silica chromatography (AcOEt then AcOEt 5/CH2Cl2 4/EtOH 1). Yield: 70%. M: 144–145° C. 1H-NMR (CDCl3, 300 MHz): d 0.89–0.96 (m, 3H, CH3), 2.01 (s, 1H, COCH3), 3.36–3.45 (m, 2H, CHCH2), 3.61 (s, 3H, OCH3), 3.73–3.84 (m, 2H, CHCH2+1HNCH2), 3.91 (s, 3H, OCH3), 6.60 (s, 1H Ar), 7.07–7.61 (m, 10H Ar). Mass: (M+H)+=472.23.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([CH3:22])[CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Reactant: Cc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(CCN2CCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)c1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.5 g--see Preparation 8), 3-methylphenethylbromide (0.36 g--see J. Ind. Chem. Sac., 40, 327, (1963)) , anhydrous potassium carbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 4 hours. On cooling to room temperature, water (60 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield, 0.17 g.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@H:26]([C:33]([OH:35])=O)[CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30].[NH2:53][C@H:54]([C:67]([O:69][CH2:70][CH:71]=[CH2:72])=[O:68])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:58][CH:57]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:25]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42]2[C:41]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:37])[C@H:26]([C:33]([NH:53][C@H:54]([C:67]([O:69][CH2:70][CH:71]=[CH2:72])=[O:68])[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:60][CH:61]=1)=[O:35])[CH2:27][O:28][C:29]([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C=CCOC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 94.2 %

Procedure:
According to the general procedure for HBTU promoted coupling, 18.26 g Fmoc-Ser(tBu), 16.95 g HBTU, 11.95 g H-Tyr(tBu)-OAllyl and 26.10 ml DIPEA were reacted in a CYTOS® Lab System in anhydrous DMF at 45° C. and at a total flow rate of 32 ml/min at residence time of 1 min to yield 26.09 g crude material (yield based on HPLC: 96%) which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([C:22](O)=[O:23])[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)C1CCC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCC4)cc23)CC1
Yield: 96.3 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 15.0 mg (0.10 mMol) cyclobutanecarboxylic acid, 15.0 mg (96%) of the title compound were recovered.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](Cl)=[N:33]1)=O)(C)(C)C.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:34]4[C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[NH:32][N:33]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CC(C)(C)OC(=O)n1nc(Cl)c2ccccc21
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4n[nH]c5ccccc45)cc3CC[C@@H]12
Yield: 41.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol) , 1-(t-butoxycarbonyl)-3-chloroindazole (116 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 60 mg (16%) of the title compound as an oil. FDMS: m/e=377.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:14])=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5](N(OC)C)=[O:6].[CH3:15][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[C:3]([Cl:14])=[C:4]([C:5](=[O:6])[CH3:15])[CH:11]=[CH:12][CH:13]=1
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cccc(Br)c1Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(Br)c1Cl
Reaction time: 8 h

Procedure:
To a solution of 3-bromo-2-chloro-N-methoxy-N-methylbenzamide (0.71 mmol) in 7 mL THF was added a solution of MeMgBr (4.31 mmol, 3M solution in Et2O) at 0° C. The cooling bath was removed after 1 h and stirring was continued at RT overnight. The reaction was quenched with water and sat. aq. NH4Cl solution under cooling. The mixture was extracted with EtOAc (3×), the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (85/15) gives the desired compound as colorless oil;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][NH:16][CH2:17][C:18]1[NH:22][C:21]2[C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=1>C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([S:11]([N:16]([CH2:17][C:18]2[NH:22][C:21]3[C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=[CH:26][C:20]=3[N:19]=2)[CH3:15])(=[O:13])=[O:12])=[C:4]([CH3:10])[CH:5]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CNCc1nc2cccc(C(=O)OC)c2[nH]1
Solvent: ClCCl
Product: COC(=O)c1cccc2nc(CN(C)S(=O)(=O)c3c(C)cc(OC)cc3C)[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
A solution of 2,6-dimethyl-4-methoxybenzenesulfonyl chloride (12.54 mmol, 1.0 eq.) in methylene chloride (12 ml) was added to a cooled solution (0° C.) of methyl 2-((methylamino)methyl)-1H-benzo[d]imidazole-7-carboxylate (12.54 mmol, 1.0 eq.) and TEA (2.5 eq.) in abs. methylene chloride (60 ml). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with methylene chloride and washed successively with water and sat. NaCl solution. The organic phase was dried over Na2SO4 and the solvent was evaporated off in vacuo to obtain the crude product, which led to the desired product by purification by column chromatography (silica gel). Yield: 46%
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[C:22]([F:25])=[N:23][CH:24]=1.C([O-])(=O)C.[K+].O>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:22]([F:25])=[N:23][CH:24]=1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: OB(O)c1cc(Cl)cnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(Cl)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.500 g, 1.979 mmol) and 5-chloro-2-fluoropyridin-3-ylboronic acid (1.388 g, 7.91 mmol) (Combi-Blocks, Inc., San Diego, Calif.) in THF (25 ml) were added to a 100 mL round-bottomed flask. Potassium acetate (0.583 g, 5.94 mmol) was added to the mixture, followed by water (1 mL). The mixture was evacuated, then backfilled with Nitrogen gas. Then bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.050 g) (Aldrich, St. Louis, Mo.) was added into the mixture. The mixture was evacuated, then backfilled with nitrogen gas. The flask was fitted with a reflux condenser, then placed into a pre-heated (90° C.) oil bath and allowed to stir under inert atmosphere for 2 h. The progress of the reaction was monitored by LCMS, which showed mostly desired product. The reaction mixture was allowed to cool to room temperature, diluted with water (10 mL) and extracted with CH2Cl2 (3×25 mL). The organic extracts were washed with satd aqueous Na2CO3 (1×20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (120 g), eluting with a gradient of 1% to 40% EtOAc in CH2Cl2, to give 6-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.502 g, 1.443 mmol, 73.0% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.37-8.45 (m, 1H); 8.27-8.33 (m, 2H); 5.79-5.92 (m, 1H); 4.14-4.26 (m, 1H); 3.74-3.91 (m, 1H); 2.89 (s, 3H); 1.96-2.25 (m, 3H); 1.63-1.91 (m, 3H). m/z (ESI, +ve) 348 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.[Cl-].[Na+]>CCCCCC.O1CCCC1>[C:19]1([CH2:29][CH2:30][C:31]([N:14]2[C@@H:13]([CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:17][O:16][C:15]2=[O:18])=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)CCc1cccc2ccccc12
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(CCc1cccc2ccccc12)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
14.8 mmole of butyllithium in hexane were added dropwise to a solution of 2.63 g (14.8 mmole) of (S)-(-)-4-benzyl-2-oxazolidinone dissolved in 50 ml of anhydrous tetrahydrofuran at -78° C. under an atmosphere of nitrogen. The mixture was stirred for 30 minutes at this temperature, and then 2.95 g (13.5 mmole) of 1-naphthylpropionyl chloride in 15 ml of anhydrous tetrahydrofuran were slowly added dropwise at the same temperature=the mixture was then stirred for 3 hours. At the end of this time, a saturated aqueous solution of sodium chloride was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then freed from the solvent by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: a 1: 4 by volume mixture of ethyl acetate and hexane), to afford 4.65 g (96%) of the title compound as a white amorphous substance.
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][C@:5]1([NH2:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1.[CH3:19][NH:20][C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=S>>[CH3:19][N:20]1[C:3](=[O:18])[CH2:4][C@@:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[CH2:7][CH2:6]2)[N:17]=[C:21]1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29]
Reactant: COC(=O)C[C@@]1(N)CCc2ccc([N+](=O)[O-])cc21
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Product: CN1C(=O)C[C@]2(CCc3ccc([N+](=O)[O-])cc32)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from ((S)-1-amino-6-nitro-indan-1-yl)-acetic acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product tert-butyl [(1S)-1′-methyl-6-nitro-6′-oxo-2,3,5′,6′-tetrahydro-1′H-spiro[indene-1,4′-pyrimidin]-2′-yl]carbamate was obtained as pale brown solid. MS (ESI): m/z=373.1 [M−H]−.
Reaction SMILES: [NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.OO.CN(C=[O:39])C>CO.C(O)(=O)C.[Pd]>[NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:15][CH2:16][S:17]([CH3:18])=[O:39])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: [Pd]
Agent: OO
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)CC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 5 h

Procedure:
In a mixed solvent comprising 10 ml of MeOH and 5 ml of acetic acid is dissolved 2.2 g of BOC-Tyr-(D)-Met-Gly-OH, followed by adding 0.6 ml of 30% aqueous hydrogen peroxide solution, and the mixture is stirred at roomtemperature for 5 hours. Following the addition of a small amount of palladium black, the mixture is stirred. The catalyst is filtered out, andthe solvent is distilled off, whereby the precipitated crystals are collected by filtration. Thus obtained is 2.1 g of the desired product, m.p. 185° C. (decomposed), Rf1 =0.20, [α]D21 +1.8° (c=0.5, DMF)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([O:46][CH2:47][CH3:48])=[C:28]([C:30]2[NH:35][C:34](=[O:36])[C:33]3=[C:37]([CH3:45])[N:38]=[C:39]([CH:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[N:32]3[N:31]=2)[CH:29]=1)=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH2:47]([O:46][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([CH:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[O:22])=[CH:29][C:28]=1[C:30]1[NH:35][C:34](=[O:36])[C:33]2=[C:37]([CH3:45])[N:38]=[C:39]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[N:32]2[N:31]=1)[CH3:48]
Reactant: CCOc1ccc(NC(=O)C2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(NC(=O)C2CNCCN2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
132 mg (0.198 mmol) of the compound from example 48 are treated with 5 ml of trifluoroacetic acid for 90 minutes the solution is then concentrated dichloromethane and 10% strength NaHCO3 solution are added to the residue and the organic phase is dried and concentrated under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1.[CH3:28][O-:29].[Na+]>CO>[CH3:28][O:29][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2nc(OC)c(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2-Chloro-6-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example ε(100 mg, 0.25 mMol) was added to freshly prepared sodium methoxide (0.27 mMol) in methanol and stirred at room temperature for 22 hours and then at 75° C. for 4 hours. The reaction solution was concentrated and the product was purified by silica gel chromatography to give a white solid. Anal. Calc'd. for C21H18N2O4S (394.45): C, 63.95; H, 4.60; N, 7.10. Found: C, 63.80; H, 4.71; N, 6.94.