Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].[CH2:7]([S:11](Cl)(=[O:13])=[O:12])[CH2:8][CH2:9][CH3:10]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:5][C:2]([NH:1][S:11]([CH2:7][CH2:8][CH2:9][CH3:10])(=[O:13])=[O:12])([CH3:6])[C:3]#[N:4]
Reactant: CC(C)(N)C#N
Reactant: CCCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)(=O)NC(C)(C)C#N
Temperature: 25 °C
Yield: 39.2 %

Procedure:
To a stirred mixture of 8.4 g (0.1 mole) 2-amino-2-methyl-propionitrile and 12.2 g (0.1 mole) 4-dimethylaminopyridine in 125 ml chloroform, 15.7 g (0.1 mole) 1-butanesulfonyl chloride in 25 ml chloroform were added dropwise over 20 minutes, with evolution of heat and separation of solids. The reaction mixture was refluxed 2.5 hours. After cooling to room temperature, the reaction mixture was washed with 25 ml concentrated hydrochloric acid which had been diluted with 25 ml water. The layers were phase separated. The organic layer was washed twice with 50 ml ice water, dried over magnesium sulfate and stripped to give 8.0 g of the above-identified product, as a dark red oil.
Reaction SMILES: C(N[C:9]1[CH2:17][CH2:16][CH2:15][CH2:14][C:10]=1[C:11]([NH2:13])=[O:12])C1C=CC=CC=1.[SH2:18]>C(O)(=O)C>[OH:12][C:11]1[C:10]2[CH2:14][CH2:15][CH2:16][CH2:17][C:9]=2[S:18][N:13]=1
Reactant: S
Reactant: NC(=O)C1=C(NCc2ccccc2)CCCC1
Solvent: CC(=O)O
Product: Oc1nsc2c1CCCC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-benzylamino-3,4,5,6-tetrahydrobenzamide 21a (15 g) in glacial acetic acid (100 mL) was added excess hydrogen sulfide at 80° C. for 4 h. The reaction mixture was evaporated and ether was added to the residue which afforded crystallisation. The crystals were dissolved in ethyl acetate (30 mL) and a solution of bromine (8.3 mL) in ethyl acetate (30 mL) was dropwise added at room temperature. The mixture was stirred for 20 h at room temperature and evaporated. Column chromatography on silica gel (eluent: ethyl acetate-ethanol 1:1 containing 1% glacial acetic acid) gave the title compound (3.3 g): mp 157-158° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(=[O:35])[O:34][C:32](=[O:33])[CH2:31][O:30][CH2:29]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([C:32](=[O:33])[CH2:31][O:30][CH2:29][C:28]([OH:35])=[O:34])[CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(=O)O1
Reactant: O=C(NCCNCCNC(=O)OCc1ccccc1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)COCC(=O)N(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
37.14 g (100 mmol) of the bis(benzyloxycarbonylaminoethyl)-amine described in Example 1a is dissolved in DMF, mixed in an ice bath with 17.4 g (150 mmol) of diglycolic anhydride (Janssen Chimica) and 21 ml (150 mmol) of triethylamine and then stirred overnight at room temperature. The solution is concentrated by evaporation in a vacuum, the residue is taken up in ethyl acetate and shaken out with diluted hydrochloric acid. The organic phase is dried with sodium sulfate and after filtration from drying agent, it is crystallized by adding hexane.
Reaction SMILES: [Br:1][CH2:2][C:3](C1NCCS1)=[O:4].[CH:10]1([CH:13](Cl)[C:14]([NH2:16])=O)[CH2:12]C1>>[Br:1][CH2:2][C:3]([N:16]1[CH2:12][CH2:10][CH2:13][CH2:14]1)=[O:4]
Reactant: O=C(CBr)C1NCCS1
Reactant: NC(=O)C(Cl)C1CC1
Product: O=C(CBr)N1CCCC1

Procedure:
In a manner similar to that described above, bromoacetylthiazolidine, cyclopropylchloroacetamide were prepared. ##STR10##
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][C:9]1[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=1.[CH:23]([O:25][CH3:26])=O.Cl>CN(C=O)C.O>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][C:9]1[C:14](/[C:15](=[CH:23]\[O:25][CH3:26])/[C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COC=O
Reactant: COC(=O)Cc1cccnc1Oc1cccc(CO)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a stirred suspension of sodium hydride (1.056 g, 50% dispersion in oil, pre-washed with petroleum ether) in dry DMF (15 ml) at 0°-5° C. was added dropwise over 5 minutes a solution containing methyl 2-(3-hydroxymethylphenoxy)pyridin-3-ylacetate (2.0 g) and methyl formate (9 ml) in DMF (effervescence). After the addition was complete, the reaction mixture was allowed to warm to room temperature. After stirring for a further 3 hours, the reaction mixture was carefully poured into water, neutralised with 2N hydrochloric acid and then extracted thoroughly with ether (×6). The combined ether layers were dried, filtered and evaporated to afford a crude residue which was used without further purification. The residue was dissolved in DMF (10 ml) and then treated with potassium carbonate (0.60 g) and dimethyl sulphate (0.64 g). Standard work-up and chromatography on silica gel (eluent petroleum ether-ether, 1:1) afforded (E)-methyl 2-[2-(3-hydroxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.35 g, 15 %); mass spectrum m/e 315 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:14][CH3:15].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:36][CH3:37])[C:20]([Cl:38])=[CH:19][N:18]=1.Cl.COCCO>O1CCOCC1>[Cl:38][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][C:25]=2[O:36][CH3:37])=[N:22][C:17]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:14][CH3:15])=[N:18][CH:19]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(=O)N2
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2OC)CCCC(=O)N3)ncc1Cl
Temperature: 25 °C

Procedure:
Combined 7-Amino-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (110 mg, 0.00053 mol) Isopropyl alcohol, (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (170 mg, 0.00048 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (200 uL) and 2-Methoxyethanol (5.3 mL, 0.067 mol) in a Radley tube, heat to 110° C. for about 4.5 h. Cool to RT and a solid came out of solution, stirred over night Filtration was followed by washing with 2-methoxyethanol to give a yellow powder. The powder was treated with saturated aq. bicarb, sonicated to break up solids and stirred for 1 h. The yellow solid was filtered and dried overnight. Isolated C as a yellow solid (131.16 mgs, 52%); MP: 248-249° C.; 1H-NMR (dmso, 400 MHz) δ 9.60 (s, 1H), 9.38 (br s, 1H), 9.15 (br s, 1H), 8.32 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.70 (s, 1H), 6.53-6.48 (m, 2H), 3.80-3.78 (m, 4H), 3.77 (s, 3H), 3.70 (s, 3H), 3.25-3.19 (m, 6H), 2.70-2.68 (m 2H), 2.14-2.10 (m, 2H); LC/MS: 525.36 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH2:23]OS(C(F)(F)F)(=O)=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[N:9]([CH2:16][C:17]3([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Reactant: CC1(COS(=O)(=O)C(F)(F)F)CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(CN2C(=O)SC(=Cc3ccc(O)cc3)C2=O)CCCCC1
Yield: 42 %

Procedure:
A solution of compound vii (0.5 mmol), compound iii (0.6 mmol) and K2CO3 (0.65 mmol) were stirred in DMF (3 mL) at 80° C. for 4 hr, poured into water, extracted with ethyl acetate (3×10 mL), dried and concentrated. The residue was purified by chromatography, affording compound 9 in 42% yield. 1H NMR (300 MHz, CDCl3) δ 0.94 (s, 3H), 1.14-1.86 (m, 10H), 3.63 (s, 2H), 5.69 (s, 1H), 6.94 (d, J=8.40 Hz, 2H), 7.43 (d, J=8.40 Hz, 2H), 7.83 (s, 1H); HRMS exact mass of (M+Na)+, 354.1140 amu; observed mass of (M+Na)+, 354.1141 amu.
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[CH:2]1.Cl[C:10]([C:12]1[CH:13]=[C:14]([CH:18]([CH3:21])[C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:10]([C:12]1[CH:13]=[C:14]([CH:18]([CH3:21])[C:19]#[N:20])[CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Reactant: c1cc2ccsc2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C#N)c1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
A mixture of thieno[2,3-b]thiophene (23.8 g) and 2-(3-chloroformyl-phenyl)propionitrile (29.6 g) is added dropwise to a suspension of anhydrous aluminium chloride (50 g) in methylene chloride (425 cc). After 16 hours at 25° C., the reaction mixture is heated under reflux for 40 minutes and then, after cooling, distilled water (600 cc) and 12 N hydrochloric acid (50 cc) are added. The organic phase is decanted and the aqueous phase is extracted twice with methylene chloride (total 200 cc). The combined methylene chloride solutions are washed three times with distilled water (total 1500 cc), and then stirred with 5 N aqueous sodium hydroxide solution (50 cc) for 2 hours at 25° C. The organic phase is decanted, washed four times with distilled water (total 2000 cc) and dried over anhydrous sodium sulphate, decolourizing charcoal (5 g) is added, and the organic phase is filtered and evaporated. The residue obtained (43.6 g) is chromatographed on a column (4.8 cm diameter, 47 cm height) containing silica gel (410 g). Elution is carried out with methylene chloride (total 1500 cc). The first fraction (500 cc) is discarded, whilst the two following fractions are combined and concentrated to dryness. 2-{3-(Thieno[2,3-b]thien-2-yl)carbonylphenyl}propionitrile (16.9 g) is obtained in the form of an oil. Rf=0.60 (silica gel chromatographic plate; solvent: methylene chloride).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 21 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 21% of theory, C34H41N7O5 (627.8) Rf value: 0.60 (silica gel; dichloromethane/methanol=9:1) ##EQU77##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:13]2[CH:26]=[CH:25][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[O:11][CH:12]=1.C1CN2C(=NCCC2)NC1.Br[C:38]1([CH2:47][CH2:48][O:49][CH3:50])[C:43](=[O:44])[NH:42][C:41](=[O:45])[NH:40][C:39]1=[O:46]>C(#N)C>[CH3:50][O:49][CH2:48][CH2:47][C:38]1([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]3[CH:15]=[CH:14][C:13]([C:10]4[O:11][CH:12]=[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=4)=[CH:26][CH:25]=3)=[CH:19][CH:20]=2)[C:39](=[O:46])[NH:40][C:41](=[O:45])[NH:42][C:43]1=[O:44]
Reactant: Oc1ccc(Oc2ccc(-c3nc(-c4ccccc4F)co3)cc2)cc1
Reactant: COCCC1(Br)C(=O)NC(=O)NC1=O
Agent: C1CN=C2NCCCN2C1
Solvent: CC#N
Product: COCCC1(Oc2ccc(Oc3ccc(-c4nc(-c5ccccc5F)co4)cc3)cc2)C(=O)NC(=O)NC1=O
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
4-[4-(4-(2-fluorophenyl)-oxazol-2-yl)-phenoxy]-phenol (142 mg, 0.41 mmol), and 1,5,7-triazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (Fluka) (473 mg @ 2.6 meq/g, 1.23 meq) in acetonitrile were shaken for 30 minutes. 5-Bromo-5-(2-methoxy-ethyl)-pyrimidine-2,4,6-trione (163 mg, 0.62 mmol) (from Preparation 3b) was then added and shaking continued for 3 days. The reaction was quenched with 20% acetic acid in methanol and after 15 minutes filtered. The filtrate was concentrated and the crude product chromatographed yielding 145 mg of 5-(2-methoxy-ethyl)-5-{4-[4-(4-(2-fluorophenyl)-oxazol-2-yl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-trione as a white solid. LC-MS (m/z, APCI): 533 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:9][NH:10][C:11](=[O:14])[CH2:12][Cl:13])[CH2:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][CH:2]([CH2:9][NH:10][C:11](=[O:14])[CH2:12][Cl:13])[CH2:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7]
Reactant: O=C(CCl)NCC(O)CNC(=O)CCl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCl)NCC(CNC(=O)CCl)OC1CCCCO1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a suspension of 2-hydroxy-N,N'-1,3-propanediyl-bis(2-chloroacetamide) (12.16 g; 0.050 mol) and 3,4-dihydro-2H-pyran (6.31 g; 0.075 mol) in 350 ml of CH2Cl2, 1.25 g of pyridinium p-toluenesulfonate (PPTS) (0.005 mol ) are added in portions under stirring at a temperature of 5° C. After 30 minutes, temperature raises up to 20°-25° C. and the stirring is continued during 72 h; the solution is washed with 20% aqueous NaCl (2×100 ml), dried over Na2SO4 and concentrated to dryness under vacuum. The residue solidifies in n-hexane, and then after filtration, is crystallized from EtOH (115 ml) to obtain 14.1 g of 2-[(tetrahydro-2H-pyran-2-yl)oxy]-N,N'-1,3-propanediyl-bis(2-chloroacetamide).
Reaction SMILES: [C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:20][OH:21]>O>[C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([O:21][CH3:20])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C(=O)c2ccccc2)n1

Procedure:
60 grams of 2-benzoyl-3-nitro-6-chloropyridine were added in portions to a solution of 10 grams of sodium metal in 500 ml. of methanol at 50° C. with stirring, whereby the temperature gradually increased. Then the mixture was heated under reflux for four hours and subsequently treated with two liters of water. The precipitated crystals were filtered off with suction after one hour and recrystallized from methanol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1c(O)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1c(O)cccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.7 %

Procedure:
To a cold (0° C.) solution of 2-fluoro-6-hydroxybenzoic acid (5.00 g, 32.029 mmol) in dimethyl formamide (200 mL) were added N,O-dimethylhydroxylamine hydro-chloride (6.25 g, 64.057 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.82 g, 48.043 mmol), 1-hydroxybenzotriazole (5.19 g, 38.435 mmol), and triethylamine (8.93 mL, 64.057 mmol). The mixture was stirred at room temperature for 15 hrs. The reaction mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (ethyl acetate/hexane=2/1) to give 2-fluoro-6-hydroxy-N-methoxy-N-methylbenzamide as an orange solid (4.320 g, yield; 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.[OH2:19]>C(Cl)Cl.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:19])[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ncc2C1
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(Cl)ncc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of NaIO4 (9.56 g, 44.7 mmol) and RuCl3 (927 mg, 4.47 mmol) in water (50 mL), DCM (50 mL) and MeCN (2 mL) was added a solution of tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (4.0 g, 14.9 mmol) in DCM (25 mL). This reaction was stirred at room temperature for 2 h. At completion, the reaction was and was quenched with isopropanol (10 mL), filtered over celite and the filter cake was washed with DCM (20 mL). The filtrate was partitioned in a separatory funnel and the layers were separated. The organic layer was extracted with DCM (2×20 mL) and the combined organics were dried over Na2SO4, then filtered and concentrated. The residue was purified by flash chromatography over silica gel (20-50% EtOAc/hexane eluent) to give tert-butyl 6-chloro-1-oxo-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (3.0 g, 71% yield) as a yellow crystalline solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.92 (s, 1H), 7.47 (s, 1H), 4.03 (t, J=6.3 Hz, 2H), 3.09 (t, J=6.1 Hz, 2H), 1.54-1.62 (m, 9H); MS (EI) m/z=283.7 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:9]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1CCCCCN1c1ccc(F)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1CCCCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A solution of 1-(4-fluorophenyl)azepan-2-one (1.1 g, 5.3 mmol) was dissolved in THF (5 mL) and was added into LDA (11 mmol) at −78° C. and stirred for 5 minutes. Benzyl chloroformate (1.6 ml, 11 mmol) was added at −78° C. and the reaction warmed to ambient temperature. The solution was poured into ice and diluted with EtOAc (100 mL). The organic layer washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography (50% EtOAc in hexane) to afford the product (1 g, 55% yield) as brown oil.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(OCC)(=O)C>[OH:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)CC(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)CC(O)C(=O)OCc1ccccc1

Procedure:
2-Hydroxy-4-methylpentanoic acid is reacted with benzyl bromide in ethyl acetate in the presence of triethylamine, to give benzyl 2-hydroxy-4-methylpentanoate.
Reaction SMILES: [C:1](Cl)(C)=O.[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)([O-:7])=[O:6]>CO>[CH3:1][O:16][C:15](=[O:17])[CH2:14][CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:19][CH:18]=1
Reactant: O=C(O)CCOc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CCOc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
Neat AcCl (0.27 mL; 3.8 mmol) was added to a suspension of 3-(4-nitro-phenoxy)-propionic acid (1.591 g; 7.53 mmol) in dry MeOH (8.0 mL). A soln formed followed by a ppt. After sitting at 4° C. overnight, product was collected by filtration as a white microcrystalline solid (1.316 g; 78%). The mother liquor contained pure product by HPLC. LC-MS 226 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]([CH3:17])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:19]=2[Cl:18])[C:9]2[S:10][C:11]([CH3:17])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1sc(Nc2ccc(Cl)cc2)nc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1sc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.0 g (7.4 mmol) 2-(4-Chloro-phenylamino)-5-methyl-thiazole-4-carboxylic acid, 1.56 ml (11.1 mmol) 2,4-Dichlorobenzoyl chloride and 3.09 ml (22.3 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 2 h. After removal of all volatiles the resulting yellow foam was used without further purification in the consecutive step. MS (m/e): 441.0 (MH+, 100%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH2:31][C:30]#[CH:29])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C#CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
To a solution of 200 mg (0.59 mmol) of 3-[4-chloro-2-fluoro-5-(hydroxy)phenyl]-1-methyl-6- (trifluoromethyl)-2,4 (1H,3H) -pyrimidinedione in 3 mL of acetonitrile was added 162 mg of potassium carbonate (1.18 mmol) and 131 mL (1.18 mmol) of an 80% solution of propargyl bromide in toluene. It was warmed under reflux for 2 h. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give colorless oil which was flash chromatographed over silica gel, eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 204 mg of title compound as a white foam: 1H-NMR (CDCl3, 200 MHz) ppm 7.35 (d, 1H), 7.0 (d, 1H), 6.4 (s, 1H), 4.78 (d, 2H), 3.58 (s, 3H), 2.6 (d, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[C:4]=2[C:5]([OH:8])=[N:6][CH:7]=1.[C:20]([Cu])#[N:21].Cl>CN(C=O)C.CN1C(=O)CCC1>[OH:8][C:5]1[C:4]2[C:9]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=3[S:11][C:3]=2[C:2]([C:20]#[N:21])=[CH:7][N:6]=1
Reactant: Oc1ncc(Br)c2sc3cc(C(F)(F)F)ccc3c12
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(O)c2c1sc1cc(C(F)(F)F)ccc12
Temperature: 150 °C

Procedure:
A solution of 4-bromo-7-(trifluoromethyl)[1]benzothieno[3,2-c]pyridin-1-ol in a 4:1 mixture of DMF/NMP (0.9 M) in the presence of CuCN (2.5 equiv) was heated in a microwave reactor at 150° C. for 25 min. The reaction was poured into 0.1 N HCl and the title product filtered as a solid.