Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:19]([CH3:20])[CH3:18])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
5-Bromopyridine-2-carboxylic acid (20 g, 100 mmol, Frontier Scientific catalog# B1704) was stirred in methylene chloride (30 mL) and cooled to 0° C. 2.0 M Oxalyl chloride in methylene chloride (100 mL) was added slowly followed by DMF (0.8 mL). Vigorous degassing occurred. The mixture was stirred at 0° C. for 30 min and at rt overnight. The mixture was evaporated and redissolved in methylene chloride (130 mL). Dimethylamine hydrochloride (9.8 g, 120 mmol) was added and the mixture was cooled to 0° C. Triethylamine (56.1 mL, 400 mmol) was added slowly (over 5 minutes) which caused significant exotherm and precipitation of a brown/orange solid. The mixture was stirred at rt for 2 h. The mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes (0-60%) gave the desired compound, (22.0 g, 100%). LCMS calculated for C8H10BrN2O (M+H)+: m/z=229.0, 231.0. found: 228.9, 230.9.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][C:33]([F:38])([F:37])[CH2:32]1>>[ClH:28].[F:37][C:33]1([F:38])[CH2:34][CH2:35][CH2:36][N:31]([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:32]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: FC1(F)CCCN(CCCl)C1
Agent: Cl
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCN3CCCC(F)(F)C3)cc12

Procedure:
6-[2-(3,3-Difluoro-piperidin-1-yl)-ethoxy]-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 67% overall yield using the method described in example 127, starting from 6-Hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl-oxime (example 127B) and 1-(2-Chloro-ethyl)-3,3-difluoro-piperidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:21]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: C1CN(C2CNC2)CCO1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CN2CC(N3CCOCC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 65 h
Yield: 49.3 %

Procedure:
A mixture of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (235 mg, 0.82 mmol), 4-azetidin-3-ylmorpholine (122 mg, 0.86 mmol) and 4 Å powdered molecular sieves (300 mg) in DCE (8 mL) was stirred at room temperature for 3 h before the addition of sodium triacetoxyborohydride (346 mg, 1.63 mmol). The reaction mixture was stirred for 65 h then filtered through celite, washing with DCM. The organic phase was washed with brine and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) affording 2-Chloro-9-methyl-6-morpholin-4-yl-8-(3-morpholin-4-ylazetidin-1-ylmethyl)-9H-purine as a cream solid (165 mg, 49%). LCMS (Method A): RT 2.22 min [M+H]+ 408.2
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8]O)[O:4][C@H:3]1[N:10]1[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Na+].CNC=O.C(Br)(Br)(Br)Br>CO>[N:39]([CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@@H:2]([F:1])[C@@H:6]1[OH:7])=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CNC=O
Product: CCc1cn([C@@H]2O[C@H](CN=[N+]=[N-])[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
A mixture of 0.4 g of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil, 0.44 g of triphenylphosphine, 0.48 g of sodium azide and 6 ml of dry methylformamide was stirred at room temperature under nitrogen while 0.48 g of carbon tetrabromide was added portionwise. The mixture was stirred at room temperature under nitrogen for 20 hours. 3 ml of methanol were added, the mixture was stirred for 0.5 hour and then evaporated. The residue was stirred for 0.5 hour with 8 ml of 0.5M sodium hydroxide solution. The resulting suspension was filtered and the insoluble triphenylphosphine oxide was washed with water. The filtrate was acidified to pH 5 by the addition of hydrochloric acid and then extracted three times with 20 ml of ethyl acetate. The extracts were dried over magnesium sulfate, filtered and evaporated. The residual solid was washed on to a filter. with 10 ml of diethyl ether/petroleum ether (1:1) and then dried in vacuo to give 0.4 g of 1 -(5-azido-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil as a white solid of melting point 185°-188° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][NH:13][CH2:14][C:15]([OH:17])=O.[CH2:18]([C@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[CH:35][CH:34]=2)=[O:31])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([C@H:25]1[CH2:29][N:28]([C:15](=[O:17])[CH2:14][NH:13][CH2:12][C:4]2[N:3]([CH3:2])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:27]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[CH:35][CH:34]=2)=[O:31])[CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: Cn1c(CNCC(=O)O)cc2ccccc21
Agent: Cl
Product: Cn1c(CNCC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)cc2ccccc21
Yield: 30.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-((1-methyl-1H-indol-2-yl)methylamino)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 30, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-((1-methyl-1H-indol-2-yl)methylamino)acetyl)pyrrolidine-2-carboxamide (12.6 mg, 30.4%). 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.93 (m, 2H), 7.26 (m, 4H), 7.17 (m, 8H), 6.96 (m, 3H), 4.15 (m, 1H), 3.64 (m, 1H), 3.49 (m, 2H), 3.14 (m, 2H), 2.87 (s, 3H), 2.64 (m, 2H), 2.20 (m, 1H), 1.89 (m, 2H). MS (EI) for C35H34FN5O3: 592.7 (MH+).
Reaction SMILES: Cl[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[C:9]1([S:15][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(=O)N1Sc1ccccc1
Reaction time: 1 h

Procedure:
To a partial solution of N-chlorosuccinimide (3.34 g, 25 mmol) in dry methylene chloride (30 mL), cooled in an ice bath and under an inert atmosphere, was added thiophenol (2.05 mL, 20 mmol) via syringe. After stirring for 1 hour, additional N-chlorosuccinimide (0.40 g, 3 mmol) was added. After 2.5 hours total, triethylamine (3.9 mL, 28 mmol) was added dropwise. Within 15 minutes the reaction mixture was diluted with methylene chloride, the solvent washed with dilute aq. HCl and the solvent then dried (Na2SO4), filtered through a pad of charcoal and evaporated. The residue was triturated with diethyl ether and the product collected by filtration to yield the title compound mp 115°-116° C. [lit. mp 115°-116° C., J. Org. Chem., 34, 51 (1969)]. This material was used as is.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Sn](CCCC)(CCCC)CCCC)[CH:16]=1>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>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[C:15]([CH3:14])[CH:20]=[CH:19][N:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccnc(-c2nc3ncccc3c(Cl)c2C)c1

Procedure:
Prepared according to procedure E and using 2,4-dichloro-3-methyl-1,8-naphthyridine (500 mg, 2.347 mmol), 4-methyl-2-(tributylstannyl)pyridine (897 mg, 2.347 mmol) and Pd(PPh3)4 (271 mg, 0.235 mmol). Purification by column chromatography (hexanes:EtOAc, from 1:0 to 1:2) gave 4-chloro-3-methyl-2-(4-methylpyridin-2-yl)-1,8-naphthyridine. Mass Spectrum (ESI) m/e=270.0 (M+1).
Reaction SMILES: C(N1[CH2:13][C@@H:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][C@H](C(OC)=O)[C@H]1C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:33]C(=C)C.C(N1C[C@@H](O)C[C@H](C(OC)=O)[C@H]1C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.S(=O)(=O)(O)O>>[C:15]([O:14][C:12]([CH3:11])([CH3:13])[CH3:33])([CH3:16])([CH3:17])[CH3:18]
Reactant: COC(=O)[C@H]1C[C@H](OC(C)(C)C)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: C=C(C)C
Agent: COC(=O)[C@H]1C[C@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)(C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
Part 1. 2-benzyl 3-methyl(2S, 3S, 5S)-1-benzyl-5-tert-butoxypiperidine-2,3-dicarboxylate: Isobutylene (2.96 mL, 0.0313 mol) was collected at −78 Celsius. To the cold isobutylene was added 2-benzyl 3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (0.60 g, 0.0016 mol) tetrahydrofuran (3.00 mL, 0.0370 mol), sulfuric acid (0.021 mL, 0.00039 mol). The reaction was sealed and allowed to warm up to rt and stirred at rt overnight. The mixture was cooled to −78 Celsius again. The seal was replaced with a septa connecting with a balloon. The reaction was then allowed to warm up to rt gradually to allow the evaporating of excess isobutylene. The residue was diluted with EtOAc, neutralized with aq. sodium hydroxide. The organic layers were washed with brine, dried. The residue was purified on silica gel, eluting with 0 to 30% EtOAc in hexane, to afford the tert-butyl ether (0.35 g, 51%). MS (ESI): (M+H)+=440.25.
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16](CC3C=CC(OC)=CC=3OC)[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][C:8]=2[C:33]#[N:34])=[C:4]([C:37]2[N:38]([CH3:42])[N:39]=[CH:40][CH:41]=2)[CH:3]=1.[CH3:43][O:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[CH:49][CH:50]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.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:33]([C:8]1[CH:9]=[C:10]([S:13]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:14])=[O:15])[CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:35]=[CH:36][C:2]([C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([O:44][CH3:43])[CH:50]=2)=[CH:3][C:4]=1[C:37]1[N:38]([CH3:42])[N:39]=[CH:40][CH:41]=1)#[N:34]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(Oc3ccc(Br)cc3-c3ccnn3C)c(C#N)c2)c(OC)c1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2ccc(Oc3ccc(S(=O)(=O)Nc4nccs4)cc3C#N)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 4-[4-bromo-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-3-cyano-N-(2,4-dimethoxy-benzyl)-N-thiazol-2-yl-benzenesulfonamide (Preparation 88, 98.5 mg, 0.148 mmol), 3-methoxyphenylboronic acid (48 mg, 0.32 mmol), and potassium carbonate (62.5 mg, 0.452 mmol) in toluene (3 mL) was added tetrakistriphenylphosphinepalladium (0) (22.5 mg, 0.0195 mmol) and the mixture was sparged two times with argon. The reaction mixture was heated at reflux for 4.5 hours. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with saturated sodium chloride solution, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by automated flash column chromatography using a 0-100% EtOAc/hexanes gradient to yield a clear oil. This oil was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (1 mL, 10 mmol). After stirring for 1 hour, the reaction mixture was concentrated in vacuo and purified by automated flash column chromatography (0%-5% methanol in dichloromethane gradient elution) to yield the title compound (49 mg, 61%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:51][CH3:52])[C@H:4]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C@@H:33]3[CH2:37][CH2:36][CH2:35][NH:34]3)=[O:32])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=[O:13])=[O:6])[CH3:2].[CH3:53][O:54][C:55]([NH:57][C@@H:58]([C:62]([CH3:65])([CH3:64])[CH3:63])[C:59](O)=[O:60])=[O:56]>>[CH3:53][O:54][C:55]([NH:57][C@H:58]([C:59]([N:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C@@H:8]3[CH2:9][CH2:10][CH2:11][N:7]3[C:5](=[O:6])[C@H:4]([N:3]([CH2:1][CH3:2])[CH2:51][CH3:52])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:20][CH:19]=2)[C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)=[CH:25][CH:26]=1)=[O:32])=[O:60])[C:62]([CH3:63])([CH3:64])[CH3:65])=[O:56]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Product: CCN(CC)[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)(C)C)cc2)c2ccc(F)cc2)cc1)c1ccccc1
Yield: 59 %

Procedure:
The product from Example 81A (0.042 g, 0.060 mmol) and (S)-2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid (0.013 g, 0.066 mmol) were processed as in Example 81A to give 0.031 g (59%) of the title compound as an off-white solid. 1H NMR (500 MHz, DMSO-D6) δ ppm 0.88 (t, J=7.10 Hz, 6 H) 0.95 (s, 9 H) 1.76-1.89 (m, 4 H) 1.93-2.00 (m, 2 H) 2.02-2.10 (m, 1 H) 2.10-2.18 (m, 1 H) 2.40-2.47 (m, 2 H) 2.56-2.65 (m, 2 H) 3.52 (s, 3 H) 3.61 (dd, J=17.24, 7.48 Hz, 2 H) 3.73-3.80 (m, 2 H) 4.20 (d, J=9.00 Hz, 1 H) 4.37 (dd, J=7.93, 4.27 Hz, 1 H) 4.42 (dd, J=7.78, 5.19 Hz, 1 H) 4.54 (s, 4 H) 4.66 (s, 1 H) 6.63 (dd, J=9.31, 4.43 Hz, 2 H) 6.90 (t, J=8.85 Hz, 2 H) 7.07 (d, J=8.85 Hz, 1 H) 7.17 (dd, J=8.47, 3.89 Hz, 4 H) 7.26 (t, J=7.17 Hz, 1 H) 7.32 (t, J=7.40 Hz, 2 H) 7.39 (d, J=7.17 Hz, 2 H) 7.50 (dd, J=8.39, 6.10 Hz, 4 H) 9.95 (s, 1 H) 9.99 (s, 1 H); MS ESI+ m/z 876.5.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4]O.[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>>[CH2:1]([N:11]1[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: OCCCCO
Reactant: CCCCN
Product: CCCCN1CCCC1
Yield: 96 %

Procedure:
11.7 kg of butane-1,4-diol were reacted with 7.3 kg of n-butylamine similarly to Example 1. N-(n-butyl)-pyrrolidine was obtained in 96% yield.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:40]=[C:41]([Br:43])[CH:42]=1)[CH2:12][N:13]([CH:37]1[CH2:39][CH2:38]1)[C:14]([C@H:16]1[C@H:21]([C:22]2[CH:27]=[CH:26][N:25]([CH3:28])[C:24](=[O:29])[CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl>[C:1]([C:9]1[CH:10]=[C:11]([CH:40]=[C:41]([Br:43])[CH:42]=1)[CH2:12][N:13]([CH:37]1[CH2:39][CH2:38]1)[C:14]([C@H:16]1[C@H:21]([C:22]2[CH:27]=[CH:26][N:25]([CH3:28])[C:24](=[O:29])[CH:23]=2)[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N(Cc2cc(Br)cc(C(=O)c3ccccc3)c2)C2CC2)cc1=O
Agent: Cl
Solvent: ClCCl
Product: Cn1ccc([C@@H]2CCNC[C@H]2C(=O)N(Cc2cc(Br)cc(C(=O)c3ccccc3)c2)C2CC2)cc1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a CH2Cl2 solution (0.1 M) of trans-tert-butyl 3-{[(3-benzoyl-5-bromobenzyl)(cyclopropyl)amino]carbonyl}-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)piperidine-1-carboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 45 min. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 93:7 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound. MS (ESI+, M+H): 548.
Reaction SMILES: O[C:2]1[C:3]2[CH:16]=[N:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:4]=2[C:5](=[O:13])[N:6]([CH3:12])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH3:49][C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][C:55]=1[CH3:56].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O1CCOCC1.O.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.CCOC(C)=O>[CH3:49][C:50]1[CH:51]=[C:52]([C:2]2[C:3]3[CH:16]=[N:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:4]=3[C:5](=[O:13])[N:6]([CH3:12])[C:7]=2[C:8]([O:10][CH3:11])=[O:9])[CH:53]=[CH:54][C:55]=1[CH3:56]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: COC(=O)c1c(O)c2cnn(Cc3ccc(OC)cc3)c2c(=O)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccc(C)c(C)c2)c2cnn(Cc3ccc(OC)cc3)c2c(=O)n1C
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a solution of methyl 4-hydroxy-1-(4-methoxybenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-5-carboxylate (585 mg, 1.7 mmol) in dichloromethane (15 mL) was added TEA (0.48 mL, 3.4 mmol) and the mixture was cooled to 0° C. and triflic anhydride (0.32 mL, 1.87 mmol) was added dropwise. After 1 h the mixture was washed with saturated sodium bicarbonate/water and brine. The organic phase was dried over sodium sulfate and concentrated. To a solution of crude triflate in 1,4-dioxane (14 mL) was added (3,4-dimethylphenyl)boronic acid (0.33 g, 2.2 mmol), Palladium tetrakis (0.19 g, 0.17 mmol) and a solution of sodium carbonate (0.54 g, 5.05 mmol) in water (3.5 mL) and the mixture was heated to 70° C. under nitrogen atmosphere for 1 h. EtOAc and water was added and the mixture was washed with saturated sodium bicarbonate/water. The organic phase was dried over sodium sulfate, concentrated and purified on silica using EtOAc/hexanes 0-30% to provide the title compound (645 mg, 84%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (s, 1H), 7.4 (d, 2H), 7.2 (d, 1H), 7.14 (s, 1H), 7.08 (d, 1H), 6.85 (d, 2H), 5.92 (s, 2H), 3.8 (s, 3H), 3.64 (s, 3H), 3.6 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H); ES-LCMS: 432.24 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:16]2[N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:13]([CH2:26][CH2:27][O:28][CH3:29])[C:12]=2[C:11]([O:30][CH3:31])=[CH:10][C:9]=1[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)[OH:33].C(N(CC)CC)C>ClCCl.CS(C)=O>[Br:7][C:8]1[C:16]2[N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=3)[N:13]([CH2:26][CH2:27][O:28][CH3:29])[C:12]=2[C:11]([O:30][CH3:31])=[CH:10][C:9]=1[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)=[O:33]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C(O)c3cccc(OC)c3)cc(OC)c21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C(=O)c3cccc(OC)c3)cc(OC)c21
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 0.16 ml oxalylchloride in 4 ml dichloromethane, 0.27 ml DMSO (in 0.8 ml dichloromethane is slowly added at −60° C. This mixture is stirred under argon at −60° C. for 0.5 h. Then 250 mg (0.463 mmol) [4-Bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-(3-methoxy-phenyl)-methanol (in 2 ml dichloromethane) are added and stirring is continued at −60° C. for 1 h. 1 ml triethylamine is added and the reaction mixture is allowed to warm to room temperature, poured on water and extracted (3×) with dichloromethane. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 179 mg of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[C:14]([CH:22]([CH3:24])[CH3:23])[CH:13]=1)=[O:11].Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH3:25])[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([CH:18]([CH3:19])[CH3:20])[C:15]([S:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=2)(=[O:34])=[O:33])=[C:14]([CH:22]([CH3:23])[CH3:24])[CH:13]=1)=[O:11]
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2cc(C(C)C)c(S(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (0.300 g, 0.639 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.197g, 0.831 mmol). Purification on Dynamax C18 (90% CH3CN/H2O) gave 0.20 g (47%) of the tide compound as a yellow solid, mp 90-95° C. 1H NMR (DMSO-d6) δ1.06 (d, 12 H), 1.85 (s, 3 H), 2.19 (s, 3 H), 3.07 (septet, 2 H), 3.91 (s, 2 H), 7.14-7.16 (m, 2 H), 7.29 (dt, 1 H), 7.44 (d, 1 H), 7.47-7.52 (m, 4 H), 8.05 (d, 1 H) (KBr) 3400, 2950, 1690, 1380 and 1190 cm31 1. mass spectrum (−EST) rnz 667/669 (M−H). Anal. Calcd. for C33H33BrO8S: C, 59.19; H, 4.97; N, 0.00. Found: C, 58.82; H, 5.13; N, 0.13.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][N:7](CC2C=CC=CC=2)[CH2:8][CH2:9][CH:10]=1.[Cl:18][CH:19]([O:21][C:22](Cl)=[O:23])[CH3:20]>ClCCCl>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH2:6][N:7]([C:22]([O:21][CH:19]([Cl:18])[CH3:20])=[O:23])[CH2:8][CH2:9][CH:10]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CON=CC1=CCCN(Cc2ccccc2)C1
Solvent: ClCCCl
Product: CON=CC1=CCCN(C(=O)OC(C)Cl)C1
Yield: 140 %

Procedure:
A solution of 13.2 g of 1-benzyl-1,2,5,6-tetrahydropyridin-3-carboxaldehyde-O-methyloxime in 120 cm3 of anhydrous 1,2-dichloroethane is cooled to 0° C., 11.7 g of alpha-chloroethyl-chloroformate is added and the whole is heated to reflux for 2 hours. After cooling, the insoluble matter is filtered off. The filtrate is evaporated to dryness, and the residue is taken up with anhydrous ether, diluted and filtered. The filtrate is evaporated and 19.8 g of product is obtained which is used immediately for the following reaction.