Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[H-].[Na+].[CH3:14]I>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:14])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
4-Bromo-2-nitrophenol (1.00 g, 4.59 mmol) was added in small portions to a suspension of sodium hydride (400 mg, 9.17 mmol) in dimethylformamide (12 ml) at room temperature under argon atmosphere, then the mixture was stirred at room temperature for 30 minutes. A solution of methyl iodide (1.30 g, 9.174 mmol) in dimethylformamide (4 ml) was added to this mixture, and stirred at room temperature for 6 hours. The reaction mixture was diluted with water and extracted with diisopropyl ether. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (658 mg, 61.8%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH2:48][C:49]([OH:51])=O)[CH:42]=1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:49](=[O:51])[CH2:48][O:47][C:43]1[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=1)[CH2:19][CH2:18]2
Reactant: O=C(O)COc1cccnc1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)COc3cccnc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using 3-pyridyloxyacetic acid as the reacting carboxylic acid. LCMS: m/e 665.6 (M+H)+, 4.37 min (method 3).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:21]([CH3:23])[CH3:22])[C@@H:13]([OH:20])[CH2:14][C:15](OCC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O)(=O)=O.[C:40]([SiH:44]([CH3:46])[CH3:45])([CH3:43])([CH3:42])[CH3:41].O>O1CCCC1>[Si:44]([O:20][C@H:13]1[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]1[CH:21]([CH3:22])[CH3:23])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:46])[CH3:45]
Reactant: C[SiH](C)C(C)(C)C
Reactant: CCOC(=O)C[C@H](O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution (10 mL) of ethyl (3S,4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxy-5-methylhexanoate (700 mg) in tetrahydrofuran were added 2,6-lutidine (0.504 mL) and tert-butyldimethylsilane trifluoromethanesulfonate (0.596 mL), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the residue in tetrahydrofuran (5 mL)-ethanol (1 mL) was added lithium borohydride (94 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution (10 mL) of the residue in tetrahydrofuran were added triethylamine (0.602 mL) and methanesulfonyl chloride (0.25 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), potassium tert-butoxide (363 mg) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with 0.1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→5:1) to give the title compound (yield: 441 mg) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[O:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[I-].ClCC[S+](C)C.O>C(O)(C)(C)C>[O:7]=[C:8]1[C:9]2([CH2:2][CH2:1]2)[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)CCCl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C2(CC2)C1
Reaction time: 1 h
Yield: 20.3 %

Procedure:
A solution of potassium tert-butoxide (3.26 g, 27.6 mmol) in tert-butanol (40 mL) was treated with tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol), causing the reaction to turn bright orange. The mixture was stirred for 1 h, then treated with (2-chloroethyl)dimethylsulfonium iodide (5.70 g, 22.59 mmol), added in three portions at 10 minute intervals. This addition caused the color of the reaction to gradually fade to pale yellow. The mixture was stirred for 2 hours, then diluted with tert-butanol (10 mL), treated with potassium tert-butoxide (2.96 g, 25.09 mmol), and stirred overnight at room temperature. The reaction was poured into water (100 mL) and extracted 3× with 100 mL ethyl acetate. The combined organic phases were washed with water and brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was purified over a 5×15 cm silica gel column, eluting with ethyl acetate/hexanes (10%-15%-20%-25% EtOAc, 1 L at each concentration), to yield the title compound (1.15 g, 5.10 mmol, 20.34% yield) as a colorless oil.
Reaction SMILES: C([N-:3]C=O)=O.[Na+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[Cl:18])=[O:10]>C(#N)C>[ClH:17].[NH2:3][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[Cl:18])=[O:10]
Reactant: O=C[N-]C=O
Reactant: O=C(CBr)c1cccc(Cl)c1Cl
Agent: [Na+]
Solvent: CC#N
Product: Cl
Product: NCC(=O)c1cccc(Cl)c1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
At RT, 411 mg (4.33 mmol) of sodium diformylamide were added to 1.0 g (3.73 mmol) of 2-bromo-1-(2,3-dichlorophenyl)ethanone [for the preparation, see for example U.S. Pat. No. 5,831,132] in 4 ml of acetonitrile, and the mixture was stirred at RT overnight. The mixture was then heated to 70° C. and filtered whilst still warm. The solid that remained was washed with 2 ml of hot acetonitrile. The combined filtrates were freed from the solvent on a rotary evaporator. 10 ml of a 5% strength ethanolic hydrogen chloride solution were added to the dark-brown oily residue, and the mixture was stirred at RT overnight. The volatile components were removed on a rotary evaporator and the yellow solid that remained was stirred in 20 ml of boiling diethyl ether. After cooling to RT, the solid was isolated by filtration, washed with diethyl ether and dried under high vacuum. This gave 410 mg (46% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH2:25][O:26]C2CCCCO2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH2:25][OH:26])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCOC4CCCCO4)nc3N21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To the solution of 0.16 g (0.36 mmol) (4R,9aR)-4-methyl-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxymethyl]-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 3 ml methanol was added 0.136 g (0.71 mmol) para-toluenesulphonic acid. After 30 min, the solvent was removed on a rotary evaporator and the residue was chromatographed on silica gel (0.032–0.063 mm) with dichloromethane:methanol:ammonia (19:1:0.1) as eluant to afford the desired compound as a light yellow oil (71.6%).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:5])[F:4])=[CH:8][CH:9]=1)[CH3:14])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OC(F)(F)C(F)F)cc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)C(F)F)cc1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (0.95 g, a white solid) from 1-(4-(1,1,2,2-tetrafluoroethoxy)phenyl)ethanone (0.82 g, 3.46 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH:3](C)C.[C:8]([O:23]C)(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=O>>[CH3:1][CH:2]([CH3:3])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([OH:23])=[O:22]
Reactant: CC(C)CC(=O)O
Reactant: COC(=O)CCCCCCCCCCC(=O)O
Product: CC(C)CCCCCCCCCCCC(=O)O

Procedure:
13-methyltetradecanoic acid is synthesized electrolytically from isovaleric acid and methyl hydrogen dodecanedioate in methanolic solution, based on Kolbe electrolysis.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].C(Cl)Cl.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>O>[CH3:22][S:23]([O:11][C@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[NH:1][S:23]([CH3:22])(=[O:25])=[O:24])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(1R,2S)-1-amino-2-indanol (300 mg, 2.01 mmol) is in suspended 10 mL DCM, combined with triethylamine (1.68 mL, 12.1 mmol) and cooled to 0° C. Then methanesulphonic acid chloride (467 μL, 6.03 mmol) is added dropwise and the reaction mixture is left to warm up to RT. The reaction mixture is stirred for 1 h at RT and once the reaction is complete it is mixed with water and extracted with DCM. The organic phase is dried on MgSO4, filtered, the filtrate is evaporated down and the crude product B-1a (HPLC-MS: tRet.=1.03 min; MS (m-H)−=304) is used in the subsequent reactions without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CN1CCCC1=O>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: Clc1ccnc2ccc(Br)cc12
Solvent: CN1CCCC1=O
Product: Brc1ccc2nccc(N3CCCCC3)c2c1
Temperature: 150 °C
Yield: 100.4 %

Procedure:
To a solution of 4-choro-6-bromoquinoline (726 mg, 3 mmol) in 3 mL of 1-methyl-2-pyrrolidinone was added piperidine (510 mg, 6 mmol). The reaction was heated to 150° C. for 5 h. The solvents were removed in vacuo at 100° C. and the residue dissolved in methylene chloride and washed with water. The methylene chloride was dried with sodium sulfate and concentrated. The residue was triturated with hexane and the solid filtered off to give 6-bromo-4-(1-piperidinyl) quinoline (877 mg, 73%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:25][CH3:26])=[C:5]([C:11]([CH2:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH3:2]>C1COCC1.O>[CH2:1]([C:3]1[C:4]([O:25][CH3:26])=[C:5]([C:11]([CH2:14][S:15]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(CC)c1OC
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(CS(=O)(=O)c2ccc(F)cc2)c(C(=O)O)c1OC
Yield: 19.9 %

Procedure:
Potassium trimethylsilanoate (0.257 g) was added to a solution of ethyl 3-ethyl-6-(4-fluorobenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 23, 0.076 g) in dry THF (10 ml). The resultant mixture was stirred at room temperature for 3 days. The mixture was diluted with water and washed with ethyl acetate. The aqueous layer was acidified by careful addition of concentrated hydrochloric acid and then extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.1% formic acid with a gradient of 50-80% to give 3-ethyl-6-(4-fluorobenzenesulphonyl-methyl)-2-methoxybenzoic acid (0.014 g) as a white solid.
Reaction SMILES: [CH3:1]N(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:43])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:36])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][O:33][CH3:34])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:35].C([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[S:52]([NH2:55])(=[O:54])=[O:53])=O.O>COCCOC>[CH3:9][O:10][C:11](=[O:43])/[C:12](/[NH:13][C:14](=[O:36])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][O:33][CH3:34])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:35])=[CH:1]/[C:50]1[CH:51]=[CH:46][C:47]([S:52]([NH2:55])(=[O:53])=[O:54])=[CH:48][CH:49]=1
Reactant: COCOc1cccc(CNC(=O)c2ccc(C(=O)NC(C(=O)OC)P(=O)(OC)OC)c(Cl)c2)c1
Reactant: NS(=O)(=O)c1ccccc1C=O
Reactant: CN(C)C(=N)N(C)C
Solvent: COCCOC
Solvent: O
Product: COCOc1cccc(CNC(=O)c2ccc(C(=O)N/C(=C\c3ccc(S(N)(=O)=O)cc3)C(=O)OC)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1,1,3,3-Tetramethylguanidine (0.046 g, 0.40 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-methoxymethoxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 142; 0.047 g, 0.10 mmol) and 4-15 formylbenzenesulfonamide (lit.: Van Es, T.; Staskun, B. Organic Syntheses 1971, 51, 20-23; 0.019 g, 0.10 mmol) in DME (4 mL). The solution was stirred at room temperature for 20 h and then was poured into water (25 mL). The aqueous layer was extracted with ethyl acetate and the organic layers were dried (Na2SO4), filtered and evaporated to give crude (Z)-3-(4-aminosulfonylphenyl)-2-[[2-chloro-4-[[(3-methoxymethoxybenzyl)amino]carbonyl]benzoyl]amino]propenoic acid methyl ester. A solution of tetrahydrofuran/methanol/water (3:1:1; 4 mL) was added, followed by lithium hydroxide monohydrate (7 mg, 0.17 mmol). The mixture was stirred at room temperature for 24 h, neutralized with 1N hydrochloric acid solution and extracted with ethyl acetate.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[C:33](B(O)O)=[CH:32][CH:31]=[N:30]1>C(O)C.C1(C)C=CC=CC=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>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: OB(O)c1ccn[nH]1
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: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccn[nH]3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
1-Methylethyl((cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol) was dissolved in ethanol (1 mL) and Toluene (1 mL), mixed with potassium carbonate (74.9 mg, 0.542 mmol), 1H-pyrazol-5-ylboronic acid (36.4 mg, 0.325 mmol, available from Frontier Scientific) followed by tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) and refluxed under nitrogen at 90° C. After 21 hours a sample of tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) was added to the reaction which was left to stir under nitrogen at the same temperature. Another sample of 1H-pyrazol-5-ylboronic acid (36.4 mg, 0.325 mmol) was added after 171 hours total reaction time and heating and stirring continued. Another sample of 1H-pyrazol-5-ylboronic acid (36.4 mg, 0.325 mmol) was added to the mixture after 345 hours. After 391 hours total reaction time the reaction was partitioned between distilled water (40 mL) and EtOAc (40 mL). The organic and aqueous layers were run off and the latter was extracted twice more using EtOAc (2×40 mL). Organic fractions were combined, washed (brine (80 mL), dried (sodium sulfate), filtered and evaporated to dryness to give a clear, colourless solid (110 mg). This was purified on a 12+M Biotage silica column, eluting with 0 to 100% EtOAc in cyclohexane. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (6 mg).
Reaction SMILES: [N:1]1[CH:6]=[C:5](B(O)O)[CH:4]=[N:3][CH:2]=1.[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19](Br)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>>[N:10]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)=[N:20][CH:21]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: OB(O)c1cncnc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1cn(Cc2ccc(-c3cncnc3)nc2)cn1

Procedure:
Synthesized using pyrimid-5-ylboronic acid (155 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 121 mg, 0.51 mmol, 81%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.23 (s, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.12 (t, J=1.3 Hz, 1H), 7.57 (dd, J=8.2, 2.5 Hz, 1H), 7.67 (s, 1H), 7.74 (dd, J=8.2, 0.9 Hz, 1H), 8.62 (m, 1H), 9.23 (s, 1H), 9.29 (s, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 119.0, 120.5, 130.1, 131.6, 131.8, 136.1, 137.3, 149.2, 152.1, 155.0, 158.8; MS (ESI): m/z=238.10 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(#N)C.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH2:30].[H][H]>[C].[Pd].O>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[NH2:17]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NCc1ccccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC#N
Solvent: O
Product: Nc1cc(-c2nc3ccccc3o2)ccc1NCc1ccccn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.9 %

Procedure:
2-(4-Fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (500 mg, 1.9 mmol) was added to an acetonitrile (5 mL) suspension containing 2-picolylamine (520 mg, 4.8 mmol), and this was heated to reflux for 2.5 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a tetrahydrofuran solution (7 mL) of the crystals obtained was added 10% palladium-carbon (100 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 14 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (480 mg, 78% yield) as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].[CH:21]([S:24]C(C)C)([CH3:23])[CH3:22].O>O1CCCC1>[CH:21]([S:24][C:5]1[CH:4]=[C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])[O:7][C:6]=1[C:8]([OH:10])=[O:9])([CH3:23])[CH3:22]
Reactant: C[Si](C)(C)c1ccc(C(=O)O)o1
Reactant: CC(C)SC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Sc1cc([Si](C)(C)C)oc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 25.01 g (136.0 mmol) of 5-trimethylsilyl-2-furancarboxylic acid (Carpenter, A. J. and Chadwick, D. J., Tetrahedron Lett., 26, 1777 (1985)) in 50 mL of dry tetrahydrofuran is added over 10 minutes to a -76° C. solution of freshly generated lithium diisopropylamide (328.0 mmol, 2.41 equiv) in dry tetrahydrofuran (175 mL) under nitrogen atmosphere and the resulting mixture is stirred at -76° to 65° C. for 1.5 hours. The reaction is recooled to -76° C. and treated with 23.58 g (151.0 mmol, 1.11 equiv) of diisopropyl sulfide in 25 mL of tetrahydrofuran and the resulting mixture is stirred for 4 hours while slowly warming to room temperature. The reaction is poured onto 1.5 L of water and the aqueous mixture is extracted with diethyl ether (200 mL, 3x), treated with 400 g of ice, and acidified with concentrated hydrochloric acid. The resulting precipitate is collected by vacuum filtration and recrystallized from diethyl ether/cyclohexane to give 18.22 g (35.14 g theo., 52%) of analytically pure 3-isopropylthio-5-trimethylsilyl-2-furancarboxylic acid as a tan solid; mp 181°-183° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])(=[O:4])=[O:3].[C:14](Cl)(Cl)=[O:15]>>[N:11]([C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([O:12][CH3:13])[CH:7]=1)=[C:14]=[O:15]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(N)ccc1S(C)(=O)=O
Product: COc1cc(N=C=O)ccc1S(C)(=O)=O

Procedure:
4-Isocyanato-1-methanesulfonyl-2-methoxy-benzene was prepared by reaction of 4-methanesulfonyl-3-methoxy-phenylamine with phosgene following the procedure of step 6 of Example 3.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH:28]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[C:34]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:35])=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Reactant: O=C(O)C1CCCCC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2C(=O)C2CCCCC2)CC1

Procedure:
L52. (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was coupled with cyclohexane carboxylic acid in analogy to experiment A1 to give (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as an amorphous pale yellow solid. MS: 498.3 [M+H]+.