Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1([C@@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1.Cl[C:19]1[C:24]([Cl:25])=[C:23]([CH2:26][CH3:27])[N:22]=[CH:21][N:20]=1>CN(C)C=O.O>[CH3:7][C:8]1([C@@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][C:19]3[C:24]([Cl:25])=[C:23]([CH2:26][CH3:27])[N:22]=[CH:21][N:20]=3)[CH2:13][CH2:12]2)[CH2:9][CH2:10]1
Reactant: CC1([C@H]2CC[C@@H](N)CC2)CC1
Reactant: CCc1ncnc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ncnc(N[C@H]2CC[C@@H](C3(C)CC3)CC2)c1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1.8 g (13.0 mmol) of K2CO3 were placed in 10 ml of dimethylformamide, 1.3 g (8.5 mmol) of cis-4-(1-methylcyclopropyl)cyclohexylamine and 1.5 g (8.5 mmol) of 4,5-dichloro-6-ethylpyrimidine were added, and the mixture was stirred at 80° C. for 4 hours. For working up, the cooled reaction solution was taken up in water. Extraction was carried out with ether, and the combined organic phases were washed with water, dried and concentrated. For purification, the mixture was chromatographed on silica gel with petroleum ether/ethyl acetate 3:1. 1.8 g (71.1% of theory) were obtained of a colorless oil.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[CH3:29][NH:30][CH2:31][CH2:32][OH:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:33][CH2:32][CH2:31][N:30]([CH3:29])[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[CH2:4]/[C:3](=[N:2]\[OH:1])/[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=2)=[CH:21][CH:20]=1
Reactant: Cc1cc(/C(C[C@H](c2ccc(C(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Reactant: CNCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(/C(C[C@H](c2ccc(C(=O)N(C)CCO)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 207, step 2, 4-[(R)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-benzoic acid (example 272) was coupled with 2-(methylamino)ethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a light yellow solid, MS (ESI+): m/z=432.4 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([NH:22][CH:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[N:19]=[C:18]([N:30]([CH3:37])[CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:17]=2)=[CH:11][C:10]=1Cl)C1C=CC=CC=1.C([O-])=O.[NH4+].C(Cl)Cl>O.CO.[Pd]>[CH:23]1([NH:22][C:20]2[N:19]=[C:18]([N:30]([CH3:37])[CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:17]=[C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[N:21]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CN(c1nc(Nc2ccc(OCc3ccccc3)c(Cl)c2)nc(NC2CCCCCC2)n1)C1CCNCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CN(c1nc(Nc2ccc(O)cc2)nc(NC2CCCCCC2)n1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
In a dry round bottomed flask was added 10% Pd/C (301.5 mg) and was wetted with 3-5 drops of water. Nitrogen was blown over the Pd/C for about 5 minutes, then methanol (10 mL) was added cautiously and nitrogen was blown on the mixture for another 5 minutes. Triazine E3 (251.8 mg, 0.50 mmol) dissolved in methanol (5 mL) was added followed by ammonium formate (381.5 mg, 6.0 mmol), and the reaction was stirred and heated reflux for about 1.5 hours. Methylene chloride was added and allowed to cool to room temperature. The mixture was filtered by vacuum through Celite with a methylene chloride rinsing and the filtrate was concentrated in vacuo. The material was purified by silica gel flash chromatography eluting with 90:9:1 by volume methylene chloride:methanol:ammonium hydroxide, and the collected fractions were dried over anhydrous magnesium sulfate, filtered and then concentrated in vacuo to give a light yellow solid (E4) (98 mg, 44%); mp 130° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 [KH2PO4(0.01 M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 3.2 min, 99.6% purity; MS (TOF ES+) m/z 412 (M+H, 100), 235.6 (87.2), 206.6 (16.1).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7](=[O:10])[CH:8]=[CH2:9].[CH3:11][CH:12]([CH3:15])[CH:13]=O>C1C=CC=CC=1>[CH3:11][C:12]1([CH3:15])[CH2:13][CH2:6][C:7](=[O:10])[CH:8]=[CH:9]1
Reactant: CC(C)C=O
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC1(C)C=CC(=O)CC1
Temperature: 25 °C

Procedure:
1 ml of concentrated sulphuric acid is added at room temperature to 81 ml of but-3-en-2-one and 88 ml of 2-methylpropionaldehyde in 450 ml of benzene, after which the reaction mixture is refluxed for 13 hours to remove the water by azeotropic entrainment. After cooling to room temperature, the reaction mixture is washed with saturated aqueous sodium bicarbonate solution and then with water. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. After distillation, 31.1 g of the expected compound are isolated; b.p.=78° C. (at a pressure of 22 mbar).
Reaction SMILES: [CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].C[N-]C.[Ti+4:13].[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[CH3:1][N-:2][CH3:3].[CH3:4][N-:5][CH3:6].[CH3:7][N-:8][CH3:9].[CH:14]1([Ti+3:13])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: [Ti+4]
Reactant: C1=Cc2ccccc2C1
Agent: C[N-]C
Solvent: Cc1ccccc1
Product: [Ti+3]C1C=Cc2ccccc21
Yield: 70 %

Procedure:
A 250 mL Schlenk flask is charged with toluene, 75 mL, and titanium tetrakis(dimethylamide), 2.35 g (10.48 mmole). The mixture is stirred magnetically throughout the procedure. Freshly degassed indene (nitrogen sparged) is added to the Schlenk flask at room temperature in excess, 2.44 mL (20.96 mmole). The mixture is refluxed at least 24 hours giving a blood red solution. All volatiles are removed under vacuum at room temperature leaving a deep red, oily residue. The residue is transferred in a minimum of hexane to a micro scale distillation apparatus and distilled under vacuum. A viscous red oil distills at 60° C. (0.025 mm Hg) which is identified by nuclear magnetic resonance (NMR) as indenyltitanium tris(dimethylamide). The yield is 70% by this method of preparation.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[Cl:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>CC(=O)CC>[C:9]([C:8]1[CH:17]=[CH:18][C:5]([O:4][CH2:3][CH2:2][O:1][C:29](=[O:30])[CH2:28][CH2:27][Cl:26])=[CH:6][CH:7]=1)(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCO)cc1
Reactant: O=C(Cl)CCCl
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCCl)OCCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
3.6 g (15 mmol) 4-(2-hydroxyethoxy)benzophenone and 1.8 g (18 mmol) triethyl amine were dissolved in 40 ml 2-butanone. The mixture was cooled to −10° C. and 2.3 g (18 mmol) 3-chloro-propionyl chloride was added drop wise while the temperature was kept below −5° C. The reaction was allowed to continue first at 0° C. for 30 minutes, followed by 16 hours at room temperature. The precipitated salts were removed by filtration and the solvent was removed under reduced pressure. The crude 3-chloro-propionic acid 2-(4-benzoylphenoxy)ethyl ester was purified by preparative column chromatography on a Prochrom LC80 column, using n.-hexane/ethyl acetate 70/30 as eluent at a flow rate of 50 ml/min and Kromasil 60A 10 micron as silica. 1.9 g (32%) of 3-chloro-propionic acid 2-(4-benzoylphenoxy)ethyl ester was isolated.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1.[CH3:12]OS(OC)(=O)=O.[H-].[Na+]>CN(C=O)C>[CH3:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C=O)c21
Temperature: 25 °C

Procedure:
To a solution of 1H-indole-7-carboxaldehyde (20.0 g, 137 mmol) and dimethylsulfate (19.1 g, 151 mmol) in DMF (400 mL) at 0° C. was added a 60% dispersion of NaH in mineral oil (6.60 g, 165 mmol). The reaction was stirred and allowed to warm to room temperature over 30 minutes. The reaction was quenched with H2O, diluted with EtOAc (1 L) and H2O. The two layers were separated and the aqueous layer was extracted with EtOAc (250 mL). The combined organic layers were washed with H2O (3×500 mL), brine, saturated aq LiCl, and brine. The solution was dried (MgSO4), filtered and concentrated to afford the title compound as an off white solid of sufficient quality to use directly in the next step. Flash chromatography (80% hexane/EtOAc) can be used to afford the title compound pure, as a white solid. 1H NMR (400 MHz, DMSO-d6) 10.39 (s, 1H), 7.91 (d, J=7 Hz, 1H), 7.75 (d, J=7 Hz, 1H), 7.42 (d, J=3 Hz, 1H), 7.21 (dd, J=7, 7 Hz, 1H), 6.60 (d, J=3 Hz, 1H), 4.08 (s, 3H). MS (electrospray, m/z) 160 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])C1C=CC=CC=1.C(OC(OC)=O)(OC)=O>CO.[Pd]>[CH3:1][O:8][C:9]([NH:11][C@@H:12]([C@@H:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H]1CCCOC1
Agent: [Pd]
Agent: COC(=O)OC(=O)OC
Solvent: CO
Product: COC(=O)N[C@H](C(=O)OC)[C@@H]1CCCOC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
10% Pd/C (69.3 mg, 0.065 mmol) was added to a solution of (S)-methyl 2-(benzyloxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (200 mg, 0.651 mmol) and dimethyl dicarbonate [4525-33-1] (0.104 mL, 0.976 mmol) in MeOH (10 mL). The reaction mixture was vacuum flushed with N2, followed by Hz, and then the reaction was stirred under H2 (55 psi) at rt for 5 h. The reaction mixture was filtered through CELITE®/silica pad and the filtrate was concentrated to a colorless oil. The crude oil was purified by flash silica chromatography (loading solvent: DCM, eluted with 30% EtOAc in hexanes) to yield product (S)-methyl 2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (132 mg) as colorless oil. LC-MS retention time 0.92 min; m/z 231.97 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2)(=[O:23])=[O:22]>>[C:16]([O:15][C:13]([N:11]1[CH2:12][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:29]3[C:30]4[C:26](=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:32][CH:31]=4)[CH:27]=[CH:28]3)=[CH:3][CH:4]=2)[CH2:10]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(Cl)nc2)C1
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)nc2)C1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 3-((6-chloropyridin-3-yl)oxy)azetidine-1-carboxylate (intermediate-9) and 5-(methylsulfonyl)-1H-indole (intermediate-21).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:28]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: COc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 61.1 %

Procedure:
4.16 g of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 2.5 g of 4-methoxyisoindoline, 6.4 g of DBU, and 28 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 3.64 g of the target compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([N:24]([C:30]3[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=3)[C:35]([O:37][CH3:38])=[O:36])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 70 °C
Reaction time: 72 h
Yield: 83.3 %

Procedure:
A mixture of 55.0 g (123 mmol) of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide, 36.7 g (184 mmol) of methyl 5-fluoro-2-nitrobenzoate, and 39.1 g (369 mmol) of sodium carbonate in 400 mL of DMF was heated to 70° C. with vigorous stirring. After 72 hours LCMS indicated nearly complete reaction. The mixture was cooled to RT, diluted with 300 mL of EtOAc, and filtered through a bed of celite to remove solids. The filter cake was washed with EtOAc until the filtrate ran colorless which gave a total filtrate volume of 1.2 L. The filtrate was transferred to a separatory funnel, partitioned with 1.4 L of 5% aqueous NaCl, and the phases separated. The aqueous solution was extracted with two additional 300 mL portions of EtOAc. The combined EtOAc solutions were washed with 95% aqueous NaCl (2×), saturated aqueous NaCl (1×), dried over sodium sulfate and concentrated to approximately 200 mL by rotary evaporation. At this point a solid began to crystallize. The suspension was diluted with 200 mL of DCM and the suspension stirred overnight. The suspension was then cooled in an ice water bath for 2 hours and the solid collected by vacuum filtration. The filter cake was washed twice with cold 1:1 EtOAc/DCM, suction air dried for 30 minutes and then dried in vacuo overnight to afford 59.6 g (83%) of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (q, J=4.42 Hz, 1H) 8.13 (d, J=9.07 Hz, 1H) 8.08 (s, 1H) 7.93-8.01 (m, 2H) 7.57 (d, J=2.63 Hz, 1H) 7.53 (dd, J=9.07, 2.73 Hz, 1H) 7.38-7.46 (m, 2H) 7.29 (s, 1H) 3.83 (s, 3H) 3.60 (s, 3H) 2.85 (d, J=4.59 Hz, 3H) 1.87-2.04 (m, 1H) 0.87 (m, 2H) 0.73 (m, 1H) 0.46 (m, 1H). LCMS (ESI): 582 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=3[F:30])[N:17]=[CH:16][N:15]=2)=[O:12])[CH2:7][CH2:6]1)[CH3:3]>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:18]2[CH:19]=[C:14]([NH:13][C:11]([N:8]3[CH2:7][CH2:6][CH:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH2:10][CH2:9]3)=[O:12])[N:15]=[CH:16][N:17]=2)=[C:22]([F:30])[CH:23]=1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reaction time: 8 h
Yield: 93.5 %

Procedure:
4-{[4-(Dimethylaminomethyl)piperidin-1-yl]carbonylamino}-6-(2-fluoro-4-nitrophenoxy)pyrimidine (136 mg) was dissolved in tetrahydrofuran (15 ml). After adding 20% palladium hydroxide-carbon (100 mg), the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated under reduced pressure, and the resultant residue was dried under reduced pressure to provide the title compound (118 mg, 94%) as a colorless oil.
Reaction SMILES: [I-:1].[Na+].I.Cl[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1>CC(C)=O>[I:1][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1
Reactant: [I-]
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: I
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(I)nc1
Reaction time: 0.08 h

Procedure:
A mixture of 15.962 g ((0.106 mol) of sodium iodide in 51 g (30 ml, 40 mmol) of hydriodic acid were stirred for 5 minutes. To the mixture was added 17.184 g (0.109 mol) of 6-chloro-nicotinic acid and the resulting mixture refluxed at 100°-130° C. for 40 hours. The dark brown mixture was then taken up in 300 ml of acetone and stirred to dissolve the excess NaI. The product was collected by suction filtration, rinsed with 100 mL in 1N NaHSO3 and dried to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:12])=[C:6]([C:10]#[N:11])[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH3:13][N:14]([CH3:25])[CH:15](N(C)C)C(=O)C(C)(C)C>>[CH3:13][N:14]([CH3:25])[CH:15]=[CH:2][C:1]([C:4]1[C:5]([CH3:12])=[C:6]([C:10]#[N:11])[NH:7][C:8]=1[CH3:9])=[O:3]
Reactant: CN(C)C(C(=O)C(C)(C)C)N(C)C
Reactant: CC(=O)c1c(C)[nH]c(C#N)c1C
Product: Cc1[nH]c(C#N)c(C)c1C(=O)C=CN(C)C
Temperature: 75 °C
Yield: 65 %

Procedure:
4-Acetyl-3,5-dimethyl-1H-pyrrole-2-carbonitrile (1.38 g, 8.51 mmol) was suspended in 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one (1.3 mL) and heated at 75° C. for 42 h. The reaction mixture was evaporated to dryness and the residue was purified by SiO2 chromatography (heptane/EtOAc) to afford the title compound (1.2 g, 65%) as a pale tan solid. 1H-NMR (DMSO-d6) δ: 2.21 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.32 (s, 6H, CH3), 5.22 (d, 1H, J=12.4 Hz, CH), 7.47 (d 1H, J=12.4 Hz, CH), 11.96 (br. s, 1H, NH).
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15][CH3:16])=[N:9][C:8]=1[CH3:17])C.Cl.NO.[OH-].[Na+].C(O)(=O)C>O1CCOCC1.O>[CH2:13]([C:11]1[C:10]([O:15][CH3:16])=[N:9][C:8]([CH3:17])=[C:7]([C:6]2[O:18][N:2]=[CH:4][N:5]=2)[CH:12]=1)[CH3:14]
Reactant: CCc1cc(C(=O)N=CN(C)C)c(C)nc1OC
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(-c2ncno2)c(C)nc1OC
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 56 %

Procedure:
In a round bottom flask under a nitrogen atmosphere a mixture of N-dimethylaminomethylene-5-ethyl-6-methoxy-2-methylnicotinamide (synthesized on 1.13 mmol scale) of Step 2, Example 16, hydroxylamine hydrochloride (103 mg, 1.48 mmol) and sodium hydroxide (59.4 mg, 1.48 mmol) and glacial acetic acid (1.7 mL) is treated with water (0.85 mL) and 1,4-dioxane (1.24 mL). The resulting dark mixture is stirred at 90° C. for 45 min. The reaction mixture is evaporated and the residue is partitioned between water and dichloromethane. The mixture is treated with excess solid sodium bicarbonate, the dichloromethane layer is separated and the aqueous layer is extracted with 2 further portions of dichloromethane. The combined organic layer is dried over magnesium sulfate and evaporated. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined and the solvent evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(1,2,4-oxadiazol-5-yl)pyridine as a white solid (138 mg, 56% yield, 2 steps). NMR (CDCl3, δ ppm): 8.45 (1H, s), 8.05 (1H, s), 4.02 (3H, s), 2.82 (3H, s), 2.62 (2H, q), 1.23 (3H, t).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[C:48]2[C:43](=[CH:44][N:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1>>[CH3:1][N:2]([CH3:38])[CH:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[N:15][C:14]([C:40]4[C:48]5[C:43](=[CH:44][N:45]=[CH:46][CH:47]=5)[NH:42][CH:41]=4)=[N:13][C:12]=3[CH:11]=2)[CH2:7][CH2:8]1
Reactant: Brc1c[nH]c2cnccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Product: CN(C)C1CCN(Cc2cc3nc(-c4c[nH]c5cnccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure G for Stille coupling, N,N-dimethyl-1-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine and 3-bromo-1H-pyrrolo[2,3-c]pyridine were reacted to give 216. LCMS m/z: 478.6 (MH+)
Reaction SMILES: B.C1COCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[Cl:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)=[O:31]>C1COCC1>[Cl:28][CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[OH:31]
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Product: O[C@@H](CCl)c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
To a solution consisting of BH3.THF (1 M, 150 mL) and (R)-(+)-2-methyl-CBS-oxazaborolidine (1 M in THF) (2.14 mL) was added a second solution consisting of 2-chloro-4′-fluoro-acetophenone (37.0 g, 214 mmol) and THF (100 ml) over 1 h at rt. The resultant colorless reaction mixture was stirred for 45 min and then quenched with MeOH (75 mL). The solvent was removed in vacuo leaving the title compound as pale yellow oil, which was used without further purification (37 g, 100%)
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[CH2-]C(C)=O.[C:9]([OH:18])(=[O:17])[CH:10]([CH:12]([C:14]([OH:16])=[O:15])O)O.CC(C)([O-])C.[K+].Cl.O1CCOCC1>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:4])[O:16][C:14](=[O:15])/[C:12](=[CH:10]/[C:9]([OH:18])=[O:17])/[O:3]1
Reactant: [CH2-]C(C)=O
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC1(C)OC(=O)/C(=C/C(=O)O)O1
Temperature: -40 °C

Procedure:
A solution of tartaric acid bis(acetonide) prepared as in Example 1 (1.84 g, 8.0 mmol) in anhydrous tetrahydrofuran (15 mL) was cooled to −40° C. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (8.0 mL, 8 mmol) was added by syringe over the course of 5 min. The mixture was stirred an additional 20 min. at −40° C. after which 4 M HCl in dioxane (3.0 mL, 12 mmol) was added and the reaction was allowed to warm. Ethyl acetate (75 mL) and 1 N HCl (25 mL) were added. The organic layer was separated and washed with water (25 mL). Removal of volatiles on the rotary evaporator afforded the crude product (1.37 g, 99%). This material contained ca. 5% of a side-product presumed to be the E-stereoisomer and characterized by an NMR singlet at δ 5.48 as well as ca. 10% of recovered bis(acetonide) starting material. A 0.63 g sample of this material was crystallized from hot ethyl acetate to afford Z-2,2-dimethyl-5-carboxymethylene-1,3-dioxolan-4-one as fine white needles (0.37 g).