Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:29][CH2:30][S:31][CH3:32])[NH:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]2[NH:20][C:19](=[O:21])[CH2:18][CH2:17]2)=[O:15])=[CH:9][C:8]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C1COCC1>[NH:20]1[CH:16]([C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:33])=[O:2])[CH2:29][CH2:30][S:31][CH3:32])=[O:28])=[C:8]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:9]=2)=[O:15])[CH2:17][CH2:18][C:19]1=[O:21]
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)C2CCC(=O)N2)cc1-c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccc(NC(=O)C2CCC(=O)N2)cc1-c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
LiOH monohydrate (29 mg, 0.69 mmol) was dissolved in 1 mL H2O and added to a solution of [4-(2-pyrrolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester, prepared as in Example 202A, (108 mg, 0.23 mmol) in 3 mL of THF and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was evaporated and 2 mL of 1N HCl was added to the aqueous residue. The resulting precipitate was filtered and dried under vacuum to give [4-(2-pyrrolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methionine (96 mg, 91%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[N:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[C:28]([O:27][CH3:26])=[N:36][CH:35]=[CH:34][CH:33]=4)=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: COc1ncccc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccnc4OC)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-methoxynicotinic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].[CH:23]([S:26](Cl)(=[O:28])=[O:27])([CH3:25])[CH3:24]>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][S:26]([CH:23]([CH3:25])[CH3:24])(=[O:28])=[O:27])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CNS(=O)(=O)C(C)C

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl)amide (precursor 5c) and isopropylsulfonyl chloride, according to the general working procedure followed by purification by flash chromatography 16 mg of 2′-(isopropylsulfonylaminomethyl)biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained as an oil. MS (ES+): m/e=403 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](O)=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:46]([NH:53][CH3:54])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](=[O:44])[N:53]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH3:54])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CNCc1ccccc1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)N(C)Cc4ccccc4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 50.0 mg of (2S,4R,5R)-2-carboxymethyl-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 9b) reacted with benzyl methyl amine to afford the title compound as a yellow oil. Rf=0.11 (EtOAc-heptane 1:1); Rt=5.47.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c2cc(Br)cnc21
Temperature: -40 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a 500 ml 3-neck flask, 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (32 g, 99.1 mmol) and DMF (300 ml) were added. The solution was cooled to −40° C. under nitrogen and sodium hydride (2.8 g, 118.9 mmol) was added in 2 batches. The mixture was stirred at −40° C. for 1 hour. Then SEM-Cl (21 ml, 118.9 mmol) in DMF (50 ml) was added drop wise and the resulting mixture was allowed to stir at −40° C. for another 2 hours. The reaction was quenched with saturated NH4Cl (40 ml) and worked up with ethyl acetate, brine, dried with Na2SO4, concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (32.8 g, 73% yield). NMR (500 MHz, DMSO-d6) δ 0.06 (s, 9H), 0.91 (m, 2H), 3.62 (m, 2H), 5.70 (s, 2H), 8.04 (m, 1H), 8.11 (s, 1H), 8.51 (m, 1H). MS: m/z 455.9 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][CH2:17][CH2:18]Br>C1CCCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:18][CH2:17][O:16][CH3:15])[CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC=CCC1
Reactant: COCCBr
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COCCN(C(=O)OC(C)(C)C)C1CC=CCC1
Yield: 31 %

Procedure:
Cyclohex-3-enyl-carbamic acid tert-butyl ester (Kampferer, P.; Vasella, A. Helvetica Chimica Acta 2004, 87, 2764-2789) (3 g, 15.2 mmol) and 2-bromoethyl methyl ether (1.43 ml, 15.2 mmol) were treated overnight to the method of Example 7 Step A. After work up and chromatography of the reaction mixture (silica, cyclohexane/ethyl acetate=7/1) the title compound (Rf=0.33, 1.2 g, 31% yield) was obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[NH:14][CH:15]=O.CSC.O>O1CCCC1.B.Cl>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[NH:14][CH3:15]
Reactant: CC(C)Cn1c(N)c(NC=O)c(=O)[nH]c1=S
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: CNc1c(N)n(CC(C)C)c(=S)[nH]c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.6 %

Procedure:
N-(6-Amino-1-isobutyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-formamide (0.25 g, 1.0 mmol) was suspended in dry tetrahydrofuran (5 mL) and borane.dimethylsulphide complex (1M in dichloromethane, 2.5 mL, 2.5 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 2.5 h. To the resulting clear yellow solution was added a few drops of 2M hydrochloric acid to eliminate unreacted borane. Water was added and the resulting aqueous solution was extracted with dichloromethane (3×15 mL). The combined organic phase was washed with brine and dried over Na2SO4. The solvent was evaporated off under reduced pressure yielding the title compound (0.12 g, 54% yield). This material was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([NH:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:13]=1)(=[O:26])=[O:25]
Reactant: Nc1cccc(COCCC2CC2)n1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCCC2CC2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(2-cyclopropyl-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.117 g) as a light yellow gum (0.088 g). MS (ESI−): 413.1 ([M−H]−).
Reaction SMILES: C(#N)C.BrC(F)COCC(F)Br.[CH3:13][C:14]1[CH:15]=[C:16]([O:21][C:22](F)([F:27])[C:23]([F:26])([F:25])Br)[CH:17]=[CH:18][C:19]=1[CH3:20]>[Zn].O.CCCCCC>[F:27][C:22]([O:21][C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([CH3:13])[CH:15]=1)=[C:23]([F:25])[F:26]
Reactant: Cc1ccc(OC(F)(F)C(F)(F)Br)cc1C
Agent: FC(Br)COCC(F)Br
Agent: [Zn]
Solvent: CCCCCC
Solvent: CC#N
Solvent: O
Product: Cc1ccc(OC(F)=C(F)F)cc1C
Temperature: 50 °C
Yield: 87 %

Procedure:
Acetonitrile (200 mL) and zinc (50 g, 0.765 mol) are transferred to an oven-dried two liter three-necked Morton flask fitted with a mechanical stirrer, reflux condenser, and thermocouple. The mixture is stirred and heated to 50° C. by means of a heating mantle and temperature controller. The mixture is assayed for water (700 ppm) and the temperature is increased to 65° C. The bromofluoroethyl ether, 3,4-dimethyl-l-(2-bromotetrafluoroethoxy)benzene (187.04 g, 0.621 mole) is added over a period of thirty minutes to the stirring mixture. The temperature of the mixture is then increased to 77° C. and the mixture is stirred overnight. Gas chromatographic analysis of the mixture shows no remaining starting material. The mixture is transferred to a 2 L round-bottomed flask using hexane and water to rinse out the reaction vessel. The solvents (water, hexane and acetonitrile) are then removed by rotary evaporation at 65° C. and 100 mm Hg (13.33 kPa). Under these conditions a small amount of the product is carried over with the solvent. The pressure is then reduced to about 2 mm Hg (0.26 kPa) which causes the product, monomer, 3,4-dimethylphenyl perfluorovinyl ether, to distill over as a clear liquid. Yield 108 g (87 percent yield, purity 94 percent).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:34]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:35]=1[C:36]#[N:37].C([O-])([O-])=O.[Na+].[Na+]>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>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:34]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Reactant: Cc1cccc(OCCCO)c1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(OCCCO)c1N(C)C(=O)c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2C#N)c1
Temperature: 95 °C
Yield: 79.5 %

Procedure:
A mixture of 4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (206 mg, 0.45 mmol), 2-bromo-5-(trifluoromethyl)-benzonitrile (75 mg, 0.3 mmol), Pd(PPh3)4 (34.7 mg, 0.03 mmol), Na2CO3 (190.8 mg, 1.8 mmol) in dioxane/water (9/1, 1.5 mL), was heated at 95° C. for approximately 16 hrs after degassing of the solvent with a stream of nitrogen. The reaction was allowed to cool to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was further washed with brine and dried with MgSO4. The filtrate was evaporated and the residue purified by preparative TLC [eluent: 40% acetone in hexane] to afford 4-chloro-3-(2-cyano-4-trifluoromethyl-phenyl)-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide 10-1 (120 mg). MS [M+H]+: 502.9; tR=8.15 min. (method 2)
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=3)[N:7]([CH3:18])[C:6]=2[CH:19]=1.[CH3:20][O-:21].[Na+].CO>CS(C)=O>[CH3:20][O:21][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=3)[N:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: C[O-]
Reactant: COc1cncc(-c2nc3ccc(F)cc3n2C)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1cncc(-c2nc3ccc(OC)cc3n2C)c1
Temperature: 165 °C

Procedure:
To a solution of the title compound from Example 1 Step C (0.010 g, 0.038 mmol) in dimethylsulfoxide (0.2 mL) was added a solution of sodium methoxide in methanol (25 wt %, 0.018 mL, 0.078 mmol). The reaction was heated at 165° C. for 1 hour, then cooled to room temperature and purified by flash chromatography (50% ethyl acetate in hexanes, then 100% ethyl acetate) to provide the title compound: LCMS m/z 270.25 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.55 (d, 1.5 Hz, 1 H), 8.43 J=2.7 Hz, 1H), 7.72 (d, J=8.8 Hz, 1 H), 7.66 (dd, J=2.5, 1.8 Hz, 1 H), 6.98 (dd, J=8.8, 2.3 Hz, 1 H), 6.86 (d, J=2.3 Hz, 1 H), 3.95 (s, 3 H), 3.92 (s, 3 H), 3.88 (s, 3 H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH2:4]1.[Sn].[OH-].[Na+]>Br.C(Cl)Cl>[CH3:27][N:2]([CH3:1])[C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:4][CH2:5][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:8]1
Reactant: CCCc1c(C2=CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCc1c(C2CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Reaction time: 1 h

Procedure:
Ex. 44 (1,057 mg, 2.948 mmol) was dissolved in hydrogen bromide/glacial acetic acid (33% HBr, 70 ml). Tin powder (5.250 g, 44.2 mmol) was then added to the mixture in portions at room temperature in the course of 1 h and the mixture was stirred for a further 1 h. The mixture was then diluted with methylene chloride (250 ml). 3 N sodium hydroxide solution (750 ml) was added, while cooling. The mixture was stirred at room temperature for 20 min. After separation of the phases, the aqueous phase was extracted with methylene chloride (3×20 ml). The combined organic extracts were dried over Na2SO4 and then concentrated (976 mg of beige-coloured solid). After separation of this mixture by chromatography [silica gel 60 (100 g); ethyl acetate/methanol 10:1 (550 ml), ethyl acetate/methanol 20:3 (575 ml), ethyl acetate/methanol 5:1 (1,200 ml), ethyl acetate/methanol 3:1 (400 ml)] N,N-dimethyl-1-phenyl-4-(3-propyl-1H-indol-2-yl)cyclohexanamine (less polar diastereoisomer) (318 mg, 30%, m.p.: 177-181° C.) and the more polar diastereoisomer (267 mg, 25%, m.p.: 211-215° C.) were obtained as white and, respectively, beige-coloured solids.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][C@H:23]([CH3:26])[CH2:24][OH:25]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][C@H:23]([CH3:26])[CH2:24][OH:25])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: C[C@@H](N)CO
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 2 step a), using the product of example 4 step b) and (R)-(−)-2-amino-1-propanol.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[CH:11]#[N:12].OP(O)(O)=O>COC(=O)[O-].C[N+](C)(C)C>[O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([C:4]1([CH3:10])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1)#[N:12]
Reactant: C#N
Agent: COC(=O)[O-]
Agent: C[N+](C)(C)C
Agent: O=P(O)(O)O
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: CC1(C)CC(=O)CC(C)(C#N)C1
Yield: 128.3 %

Procedure:
In reaction apparatus equipped with a stirrer, condenser, thermometer and dripping funnel there are placed 622 g (4.5 mol) of isophorone and 4.47 g (30 mmol) of tetramethylammonium methylcarbonate. Over a period of 60 min there are added, at 120° C., 288.3 g of a mixture of isophorone and hydrocyanic acid (3 mol of HCN, 1.5mol Of isophorone). When all of said mixture has been added, the HCN concentration is 20 ppm. 3.5g of 85% strength H3PO4 are then added and the mixture is distilled at 0.1 mbar. There are obtained 426.6g of isophorone (99% based on converted isophorone) and 476.8 g of 3-cyano-3,5,5-trimethylcyclohexanone (96.2% based on HCN used).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19](Cl)(=[O:21])=[O:20])=[N:17][CH:18]=1)([CH3:12])[CH3:11]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:18][N:17]=2)(=[O:20])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Product: COc1ccc(NS(=O)(=O)c2ccc(C(C)C)cn2)cn1

Procedure:
prepared by reaction of 6-methoxy-pyridin-3-ylamine with 5-isopropyl-pyridine-2-sulfonyl chloride
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][C:9]=1Br)=[O:4].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:9]2[CH:8]=[CH:7][O:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1occc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1occc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 69.7 %

Procedure:
3-Bromofuran-2-carboxylic acid methyl ester (2.0 g, 9.8 mmol, 1.0 eq.), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (3.1 g, 10 mmol, 1.0 eq.), THF (100 mL) and Na2CO3 (20 mL, 40 mmol, 4.0 eq.) were combined. The mixture was degassed and purged with nitrogen (3×). PdCl2(PPh3)2 (0.2 g, 0.3 mmol, 0.03 eq.) was added, and the mixture was again degassed and purged with nitrogen (3×), then heated at 80° C. overnight. The mixture was then cooled and the layers were separated. The THF layer was diluted with EtOAc (100 mL), washed with saturated aqueous NaCl (50 mL) and dried over Na2SO4. The material was filtered and applied onto a silica gel column and purified by chromatography with PE/EtOAc (50:1 to 10:1) to yield 4-(2-methoxycarbonylfuran-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (2.1 g) as a white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C.OS(O)(=O)=O.[CH2:27](O)[CH3:28]>>[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:10]=1[C:11]([O:13][CH2:27][CH3:28])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C(F)(F)F)ccc1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)-5-(trifluoromethyl)benzoic acid (7.21 mmol, 2.2 g), H2SO4 (36 mmol, 1.92 ml) in ethanol (25 ml) was stirred at 100° C. for 16 hours. The solvent was evaporated, water was added, pH was taken to 6 and extracted with CHCl3. The crude mixture was purified by chromatography over SiO2 eluting with DCM/MeOH mixtures and affording 0.69 g (yield 41%) of the expected product.
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[CH:12]([Mg]Br)=[CH2:13].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:25][C@@H:26]1[C@@H:32]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[Cl:43])[O:31][C@H:28]([O:29][CH3:30])[C:27]1=[O:44]>C1COCC1>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:25][C@@H:26]1[C@@H:32]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[Cl:43])[O:31][C@H:28]([O:29][CH3:30])[C@:27]1([CH:12]=[CH2:13])[OH:44]
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Reactant: C=C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@]1(O)[C@@H](OC)O[C@H](COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Temperature: 160 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
Cerium chloride heptahydrate (50 g, 134.2 mmol) was finely crushed in a pre-heated mortar and transferred to a round-bottom flask equipped with a mechanical stirrer. The flask was heated under high vacuum overnight at 160° C. The vacuum was released under argon and the flask was cooled to room temperature. Anhydrous THF (300 mL) was cannulated into the flask. The resulting suspension was stirred at room temperature for 4 h and then cooled to −78° C. Vinylmagnesium bromide (1M in THF, 120 mL, 120 mmol) was added and stirring continued at −78° C. for 2 h. To this suspension was added a solution of 3,5-bis-O-(2,4-dichlorophenylmethyl)-1-O-methyl-α-D-erythro-pentofuranose-2-ulose (14 g, 30 mmol) [from Example 2, Step B] in anhydrous THF (100 mL), dropwise with constant stirring. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with saturated ammonium chloride solution and allowed to come to room temperature. The mixture was filtered through a celite pad and the residue washed with Et2O (2×500 mL). The organic layer was separated and the aqueous layer extracted with Et2O (2×200 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to a viscous yellow oil. The oil was purified by flash chromatography (SiO2, 10% EtOAc in hexanes). The title compound (6.7 g, 13.2 mmol) was obtained as a pale yellow oil.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])(=[O:3])[CH3:2].[O:14]=O.[OH-].[Na+:17]>O.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:17]
Reactant: O=O
Reactant: CC(=O)NCCOCCOCCO
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NCCOCCOCC(=O)[O-]
Temperature: 70 °C
Yield: 94 %

Procedure:
95.5 g of 8-acetylamino-3,6-dioxa-1-octanol were dissolved in 405 g of water, and 2.90 g of Pd/C (10% by weight) were added. The solution was heated to 70° C. and, while stirring vigorously, about 17 ml/min O2 were passed continously through the solution under atmospheric pressure for 14 h. Throughout the reaction, the pH was kept at 10 by continuously metering in a total of 105 g of 20% by weight aqueous NaOH. The remaining solution was then extracted with ethyl acetate in a perforator for 3 days. The aqueous phase was then distilled to dryness to leave 106 g (corresponding to 94% of theory) of sodium 8-acetylamino-3,6-dioxaoctanoate as viscous oil.