Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.C(C1CC(C(OCC)=O)=C(C)NC=1C)(OCC)=O.C1(C2C=CC3C(=CC=CC=3)N=2)C=CC=CC=1>C1C=CC=CC=1.P(O)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8]1
Reactant: c1ccc(-c2ccc3ccccc3n2)nc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=P(O)(Oc1ccccc1)Oc1ccccc1
Agent: c1ccc(-c2ccc3ccccc3n2)cc1
Solvent: c1ccccc1
Product: c1ccc(C2CCc3ccccc3N2)nc1
Temperature: 60 °C
Yield: 94 %

Procedure:
A suspension of 2-pyridin-2-ylquinoline (0.767 g, 3.72 mmol), 1,4-dihydro-3,5-dicarbethoxy-2,6-dimethylpyridine (2.17 g, 8.55 mmol), and diphenyl hydrogen phosphate (0.0093 g, 0.037 mmol) in benzene (18.6 mL) was heated at 60° C. for 10 h. The reaction mixture was treated with 2-phenylquinoline (0.305 g, 1.49 mmol) and heated at 60° C. for 3 h. The reaction mixture was then concentrated to a crude solid. Purification by flash column chromatography (100% hexanes to 50% ethyl acetate/hexanes [the ethyl acetate contained 5% methanol]) gave the desired product (0.735 g, 94%) as a racemic mixture. LCMS calculated for C14H15N2 (M+H)+: m/z=211.1. found: 211.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[O:16][C:17]=1[CH3:18])[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[O:16][C:17]=1[CH3:18]
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2cccnc2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1OCc1nc(-c2cccnc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of 3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzaldehyde (3.26 g) in tetrahydrofuran (50 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.38 g) at room temperature. After stirring the reaction mixture at room temperature for 30 min, water was added, and the precipitated crystals were collected by filtration to give {3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]phenyl}methanol as colorless crystals (3.00 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](CC#N)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:22]([OH:25])(=[O:24])[CH3:23]>O>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:23][C:22]([OH:25])=[O:24])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: N#CCc1ccc(C(=O)c2cccs2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc(C(=O)c2cccs2)cc1
Temperature: 0 °C

Procedure:
A mixture of 8.6 parts of 2-[p-(2-thenoyl)phenyl]acetonitrile, 18 parts of concentrated sulfuric acid, 10 parts of acetic acid and 10 parts of water is stirred and refluxed for one hour. The reaction mixture is cooled and poured onto 200 parts of ice-water. The product is extracted twice with 160 parts of ether. The combined extracts are washed with 100 parts of diluted sodium hydroxide solution and separated. The aqueous phase is acidified with concentrated hydrochloric acid solution, whereupon the product is separated as an oil. The latter is extracted with ether. The extract is dried and evaporated. The residue is triturated in petroleumether and the crude product is dissolved in chloroform. It is purified by column-chromatography, using a mixture of chloroform and 5% of methanol. The pure fractions are collected and the solvent is evaporated. The residue is triturated in petroleumether and the solid product is crystallized from acetonitrile at -20° C, yielding 2-[p-(2-thenoyl)phenyl]acetic acid; mp. 126°-129° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15].[CH3:19][C:20]([CH3:30])([CH2:26][C:27]#[C:28][CH3:29])[C:21](OCC)=[O:22].C(O)(=O)C>C1COCC1.O>[CH3:19][C:20]([CH3:30])([CH2:26][C:27]#[C:28][CH3:29])[C:21](=[O:22])[CH2:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15]
Reactant: COP(C)(=O)OC
Reactant: CC#CCC(C)(C)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC#CCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
Under argon atmosphere, a solution of n-butyllithium in hexane (1.64 N, 33 ml, 0.054 mol) was slowly added dropwise to a solution of dimethyl methylphosphonate (6.82 g, 0.055 mol) in anhydrous THF (100 ml) with stirring at -78° C., and the mixture was further stirred for 30 minutes. To the reaction mixture, there was added dropwise a solution of ethyl 2,2-dimethyl-4-hexynoate (3.7 g, 0.022 mol) in anhydrous THF (15 ml). The reaction mixture was stirred at -78° C. for 30 minutes and then at room temperature for one hour. Acetic acid (3.1 ml, 0.054 mol) and water (10 ml) were added to the reaction mixture. After concentration, water (20 ml) was added to the residue and the mixture was extracted with ethyl acetate (100 ml×2). The organic layers were combined, washed with water (20 ml) and with brine (20 ml), and dried over anhydrous sodium sulfate to concentrate. Vacuum distillation of the residue (b.p.=108°-110° C. at 0.15 mmHg) gave dimethyl 3,3-dimethyl-2-oxo-5-heptynylphosphonate (5.04 g, 0.020 mol, 93% yield). The structure was confirmed by the following data.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[N:22]=1)=[O:20]>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:27][C:23]2[N:22]=[C:21]([C:19]([OH:20])=[O:18])[CH:26]=[CH:25][CH:24]=2)=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: COC(=O)c1cccc(CBr)n1
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3[N+](=O)[O-])cc2)n1

Procedure:
6-(2′-Nitro-biphenyl-4-yloxymethyl)-pyridine-2-carboxylic acid was prepared using general procedure B from 4-hydroxy-2′-nitrobiphenyl (available from TCI America. Portland, Oreg.) and 6-bromomethyl-pyridine-2-carboxylic acid methyl ester (Intermediate 2). Yield: 62 mg. Mass spectrum (ES) MH+=351.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[NH:14]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:15]([C:31]([OH:33])=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(#N)C>[CH2:24]([O:23][C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:14][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:31]([O:33][CH2:2][C:1]#[N:4])=[O:32])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCC#N
Reaction time: 13 h
Yield: 101.9 %

Procedure:
N,N-Diisopropylethylamine (81 μL, 0.463 mmol) and subsequently bromoacetonitrile (147 μL, 2.103 mmol) were added to a solution of Boc-Lys(Z)-OH (Compound tk44) (160 mg, 0.421 mmol) in acetonitrile (0.6 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 13 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 6-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk45) (180 mg, quant.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9](O)[CH2:10][OH:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1
Reactant: OCCO
Reactant: O=Cc1cc(Br)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1csc(C2OCCO2)c1
Reaction time: 1.5 h

Procedure:
4-Bromo-thiophene-2-carbaldehyde (9.24 g, 48.4 mmol), ethane-1,2-diol (13.5 mL, 242 mmol), toluene-4-sulfonic acid monohydrate (416 mg, 2.42 mmol) were dissolved in toluene (100 mL), and the solution was stirred for 1.5 hours under reflux. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (11.8 g, quantitatively) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21](CC2C=CC(OC)=CC=2)[C:22](=[O:24])[CH3:23])[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:34]1([NH2:41])[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1.O>CN1C(=O)CCC1>[C:22]([NH:21][C:4]1[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=[C:2]([NH:40][C@H:37]2[CH2:38][CH2:39][C@H:34]([NH2:41])[CH2:35][CH2:36]2)[CH:3]=1)(=[O:24])[CH3:23]
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(CN(C(C)=O)c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1cc(N[C@H]2CC[C@H](N)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 6-chloro-N-(3-fluoropyridin-4-yl)-8-(N-(4-methoxybenzyl)acetamido)imidazo[1,2-b]pyridazine-3-carboxamide 19B (30 mg, 0.064 mmol) and trans-cyclohexane-1,4-diamine (14.61 mg, 0.128 mmol) in NMP (0.5 mL) was heated at 70° C. for 2.5 h, and then cooled to room temperature. Water was added. The mixture was extracted with EtOAc for three times, the combined extracts were washed with H2O and brine, and then concentrated. The resulting residue was treated with MeOH. The solid was filtered off, and the filtrate was purified by preparative HPLC. The desired fraction was concentrated to dryness and then dissolved in TFA (1 mL). The solution was stirred at 70° C. for 6 h and then concentrated. The residue was treated with MeOH/DCM, and concentrated again to give a solid, which was triturated with ether. The solid was collected by filtration, rinsed with ether, and dried under vacuum to give 19C (7.3 mg, 21%) as an off white solid. [M+H]=427. HPLC Peak Rt=2.018 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:34]=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][Mg]Br.[NH4+].[Cl-].CCOCC>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:26][Si:27]([CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:30][CH3:31])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:34]([OH:35])[CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC[Si](CC)(CC)OC(c1ccc2c(c1)cc(C=O)n2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)cc(C(C)O)n2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 105.7 %

Procedure:
To a solution of0.11 g (0.21 mmol) of 1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indole-2-carbaldehyde in 3 mL of THF were added 0.14 mL (0.42 mmol) of methyl magnesium bromide dropwise at 0° C. under an argon stream. The mixture was stirred at RT for 1.5 h and poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 0.118 g (quantitative) of crude 1-[1-benzyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-1H-indol-2-yl]-ethanol, which was dissolved in 2 mL of THF and treated with 0.43 mL (0.43 mmol) of a 1M TBAF-solution in THF, stirred for one hour and then poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to yield 0.066 g (74%) of 2-[1-benzyl-2-(1-hydroxy-ethyl)-1H-indol-5-yl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, yellow solid, MS: 418 (M−H)−.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=3)[CH2:31][CH2:32]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)c(OC)nc1C
Yield: 68 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][NH:32][CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:16][CH2:15]1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([N:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][C:26]([C:24]4[CH:25]=[C:20]([N:17]5[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]5)[N:21]=[C:22]([NH2:36])[N:23]=4)=[CH:27][CH:28]=3)[CH2:33]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3ccc(Cl)nc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from (6-chloropyridin-3-yl)acetic acid (Matrix Scientific, Cat. #023734) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=478.2/480.1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][O:34][C:33]([CH3:38])([CH3:37])[CH2:32]1>>[CH3:37][C:33]1([CH3:38])[CH2:32][CH:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:20]2[C:19]([O:23][CH3:24])=[N:18][C:17]3[C:21]2=[N:22][C:14]([O:13][C@H:9]([CH3:8])[CH2:10][CH2:11][CH3:12])=[N:15][C:16]=3[NH2:25])[CH2:36][CH2:35][O:34]1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CC1(C)CC(CCCCBr)CCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCOC(C)(C)C3)c2n1

Procedure:
Prepared similarly to Intermediate 223 from 2-{[(R) —-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)-2,2-dimethyltetrahydro-2H-pyran but conducting the alkylation over 1 hour at 60° C.
Reaction SMILES: C(#N)C.C(N(CC)C(C)C)(C)C.[CH3:13][C:14]1[C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:22])[O:16][N:15]=1.Cl[CH2:24][N:25]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][C:31]([O:40][CH3:41])=[CH:32][C:33]=2[CH:37]([CH3:39])[CH3:38])[S:26]1(=[O:28])=[O:27]>C(OCC)(=O)C>[CH3:13][C:14]1[C:18]([C:19]([O:21][CH2:24][N:25]2[C:35](=[O:36])[C:34]3[C:29](=[CH:30][C:31]([O:40][CH3:41])=[CH:32][C:33]=3[CH:37]([CH3:39])[CH3:38])[S:26]2(=[O:27])=[O:28])=[O:20])=[C:17]([CH3:22])[O:16][N:15]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1c(C)noc1C)C2=O
Reaction time: 0.08 h
Yield: 10 %

Procedure:
Acetonitrile (3 ml), followed by N,N-diisopropylethylamine (0.26 ml, 1.5 mmol) were added to 3,5-dimethylisoxazole-4-carboxylic acid (0.21 g, 1.5 mmol). The mixture was stirred for 5 minutes, then 2-chloromethyl-4-isopropyl-6-methoxysaccharin (0.30 g, 1 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate (75 ml) and washed with saturated NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative layer chromatography eluting with CH2Cl2 (100%) to afford 0.041 g (10%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl 3,5-dimethylisoxazole-4-carboxylate as a white solid, m.p. 136.8°-139.1° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:11][C@H:8]([O:9][CH3:10])[C@H:7](OS(C(F)(F)F)(=O)=O)[C@H:6]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[CH2:21]([O:20][C@H:6]1[C@H:5]2[CH2:4][NH:1][C@@H:7]1[C@H:8]([O:11]2)[O:9][CH3:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CO[C@H]1O[C@H](CN=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1OS(=O)(=O)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CO[C@H]1O[C@@H]2CN[C@H]1[C@H]2OCc1ccccc1
Yield: 95.1 %

Procedure:
Methyl 5-azido-3-O-benzyl-5-deoxy-2-O-trifluoromethanesulphonyl-α-D-xylofuranoside (12α) (1.60 g, 3.89 mmol) was dissolved in ethyl acetate (30 ml) and stirred under hydrogen at room temperature with 5% palladium on charcoal (200 mg) for four hours. The solution was filtered through celite, concentrated, and purified by flash chromatography (10% ethanol in dichloromethane) to yield methyl 3-O-Benzyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside (870 mg, 95%) as a pale brown oil, which rapidly darkened, Rf 0.3 (10% ethanol in dichloromethane); νmax (film) 3420 (NH), 2940, 1450, 1245, 1170, 1025 and 640 cm-1 ; 1H NMR δ 3.14, 3.37 (2H, 2×d, H-5,5', J5,5' 15.0 Hz); 3.79 (1H, s, H-2); 4.29, 4.40 (2H, 2×bs, H-3, H-4); 4.52, 4.70 (2H, 2 x d, CH2Ph, JH,H' 12.4 Hz); 5.88 (1H, s, H-1); 6.23 (1H, bs, NH); 7.30-7.42 (5H, m, H-Ph). 13C NMR δ 49.47 (t, C-5); 55.56 (q, CH3); 59.88 (d, C-2); 72.85 (t, CH2Ph); 74.03, 78.32 (2d, C-3, C-4); 103.38 (d, C-1); 128.19, 128.37, 128.67 (3d, HC-Ph); 136.64 (s, C-Ph). m/z: 236 (M+H+, 100%), 68 (30%), 91 (15%). Methyl 5-azido-3-O-benzyl-5-deoxy-2-O-trifluoromethanesulphonyl-β-D-xylofuranoside (12) (1.57 g, 3.82 mmol) under the same conditions gave methyl 3-O-benzyl-2,5-dideoxy-2,5-imino-β-D-lyxofuranoside (829 mg, 92.5%) after chromatography, as a rapidly darkening oil, Rf 0.4 (10% ethanol in dichloromethane); νmax (film) 3400 (NH), 2910, 1450, 1255, 1115, 1030 and 640 cm-1 ; 1H NMR δ 3.46 (3H, s, CH3); 3.48 (2H, m, H-5); 4.21, (1H, s, H-2); 4.28 (2H, bs, H-3, H-4); 4.55, 4.76 (2H, 2×d, CH2Ph, JH,H' 12.0 Hz); 5.06 (1H, d, H-1, J1,2 1.9 Hz); 6.29 (1H, bs, NH); 7.33-7.38 (5H, m, H-Ph). 13C NMR δ 49.94 (t, C-5); 55.92 (q, CH3); 60.50 (d, C-2); 72.58 (t, CH2Ph); 76.27, 78.84 (2×d, C-3, C-4); 100.50 (d, C-1); 128.34, 128.64, (2×d, HC-Ph); 136.37 (s, C-Ph). m/z: 236 (M+H+, 100%), 68 (40%), 91 (20%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH:17]1[C:13]2=[N:14][CH:15]=[CH:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[C:12]2[CH:19]=[CH:18]1
Reactant: O=[N+]([O-])c1ccc(Nc2ccnc3[nH]ccc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Nc2ccnc3[nH]ccc23)cc1

Procedure:
36 mg of 10% palladium-on-carbon are added to a solution of 170 mg (0.67 mmol) of N-(4-nitrophenyl)-1H-pyrrolo[2,3-b]pyridine-4-amine in 6 ml of ethanol, and the suspension is stirred in a hydrogen atmosphere at atmospheric pressure overnight. The suspension is filtered through Celite and the Celite is washed with ethanol. Concentration under reduced pressure gives the target product.
Reaction SMILES: [Cl-].[F:2][C:3]([Zn+])([F:5])[F:4].Br[C:8]1[CH:12]=[C:11]([CH:13]([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[NH:10][C:9]=1[CH:29]([O:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33]>>[F:39][C:30]([F:38])([C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH:29]([C:9]1[NH:10][C:11]([CH:13]([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])=[CH:12][C:8]=1[C:3]([F:5])([F:4])[F:2])[O:40][Si:41]([CH3:42])([CH3:43])[CH3:44]
Reactant: FC(F)(F)[Zn+]
Reactant: C[Si](C)(C)OC(c1cc(Br)c(C(O[Si](C)(C)C)C(F)(F)C(F)(F)C(F)(F)F)[nH]1)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Cl-]
Product: C[Si](C)(C)OC(c1cc(C(F)(F)F)c(C(O[Si](C)(C)C)C(F)(F)C(F)(F)C(F)(F)F)[nH]1)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
Trifluoromethylzinc chloride is reacted with 3-bromo-2,5-bis(2,2,3,3,4,4,4-heptafluoro-1-trimethylsilyloxybutyl)pyrrole utilizing reaction and purification conditions described in Example 22.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([NH:16]C(=O)C)=[N:13][C:12]=2[CH3:20])[CH:8]=[C:7]([CH3:21])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:20])[CH:8]=[C:7]([CH3:21])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(C)nc(C(C)(C)C)n2)s1
Agent: Cl
Product: Cc1cc(-c2sc(N)nc2C)nc(C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 1.2, but using N-[5-(2-tert-butyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-acetamide in place of N-[5-(2-tert-butyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-acetamide and using 2 N HCl. The reaction mixture is stirred 16 h at RT and then 3 h at 90° C. ESI-MS [M+H]+263.1.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18]N(C)C)=[CH:12][CH:11]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3].ClCC[CH2:28][N:29]([CH3:31])[CH3:30]>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:14][CH:15]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3]
Reactant: CN(C)CCCCl
Reactant: CN(C)CCOc1ccc(-c2cc(NC(N)=O)c(C(N)=O)s2)cc1
Product: CN(C)CCCOc1ccc(-c2cc(NC(N)=O)c(C(N)=O)s2)cc1

Procedure:
Prepared by the method of Example 9(b) using the product of Example 10 (a) and N-(3-chloropropyl)dimethylamine.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH3:15])[C:6]=1[CH3:26].CO.[OH-].[Li+]>C1COCC1>[CH3:25][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[C:6]2[CH3:26])[CH3:15])=[CH:17][CH:18]=1)(=[O:23])=[O:24]
Reactant: COC(=O)Cc1c(C)n(C(C)c2ccc(S(C)(=O)=O)cc2)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1C(C)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {1-[1-(4-methanesulfonyl-phenyl)-ethyl]-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-acetic acid methyl ester (Enantiomer A) (22 mg, 0.05 mmol) in THF (0.5 ml) and methanol (0.5 ml) is treated with 2M lithium hydroxide (0.2 ml) and stirred at room temperature for 30 minutes. The solvent is removed in vacuo and the crude is dissolved in water (10 ml) and acidified to pH1 using concentrated HCl. The mixture is then extracted with ethyl acetate (2×10 ml) and the organic portions are washed with brine, dried (MgS04) and concentrated in vacuo to yield the titled product as a colourless glassy solid. (MH+373) The enantiomer of the titled compound (Enantiomer 2) is prepared analogously using the procedure described above by replacing Enantiomer A with Enantiomer B. (MH+373)