Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:21]2[C:22]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:9]=[C:10]([N:12](S(C)(=O)=O)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH2:35]([O:34][C:28]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=1[C:22]1[C:21]([C:8]2[CH:9]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)cc(N(S(C)(=O)=O)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1cc(C(=O)O)cc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)c1
Temperature: 50 °C

Procedure:
2-Benzyloxy-5-chloro-5″-dimethanesulfonylamino-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester was dissolved in ethanol (5 ml) and 1M sodium hydroxide (1 ml, 1 mmol) and left at room temperature for 5 hours then heated at 50° C. for 1 hour. The resulting solution was diluted with water, acidified with 1M hydrochloric acid and extracted with diethyl ether. The organic phase was dried (MgSO4), evaporated to dryness and triturated with diethyl ether/iso-hexane to yield the title compound as a white solid. (21 mg, 46%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](C(OC)=O)=[CH:3][N:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(Cl)Cl>C(OCC)C>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[N:2]1
Reactant: COC(=O)c1cnnc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: C1=NNc2ccccc2C1

Procedure:
A solution of 1.00 g of methyl cinnolin-4-carboxylate in 15 ml diethyl ether is added dropwise at 0° C. to a suspension of 222 mg of lithium aluminium hydride in 5 ml of diethyl ether. After 1.5 hours water is carefully added dropwise to the reaction mixture, this is stirred with methylene chloride and suction filtered through a glass fibre filter. The aqueous phase is extracted with methylene chloride and the combined organic phases are dried over magnesium sulphate and evaporated down. According to 1H-NMR a mixture of cinnoline and 1,4-dihydro-cinnoline compound is obtained as a yellow oil which is reacted further without any more purification.
Reaction SMILES: [CH3:1]C(S)C([O-])=O.COC(=O)C(Cl)=C.[OH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].IC>C[O-].[Na+]>[OH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].[CH3:1][O:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([OH:22])=[O:21]
Reactant: CC(S)C(=O)[O-]
Agent: C=C(Cl)C(=O)OC
Agent: COC(=O)c1sccc1O
Agent: C[O-]
Solvent: CI
Product: COc1ccsc1C(=O)O

Procedure:
Methyl 3-aminothiophene-2-carboxylate was Boc-protected and the resulting ester was saponified to yield 3-[(tert-butoxy)carbonylamino]-2-thiophene-carboxylic acid (11). Methyl 3-hydroxythiophene-2-carboxylate (12) was prepared by cyclization of methylthioglycolate and methyl-2-chloroacrylate in methanolic sodium methoxide (Huddleston et al., Synth. Commun. 1979, 9, 731). Alkylation of (12) with iodomethane and subsequent hydrolysis of the methyl ester yielded 3-methoxy-2-thiophenecarboxylic acid (13). 3-Fluorothiophene-2-carboxylic acid (14) was synthesized as described by Taylor et al. (Org. Prep. Proc. Int. 1997, 29, 221) (FIG. 3A, 3B, 3C). The remaining 3-substituted-thiophene-2-carboxylic acids were obtained from commercial sources.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:22][CH2:23][OH:24])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][O:24][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[Cl:27])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccccc1Cl
Reactant: CC(C)(C)c1ccc(CN(CCO)C(=O)c2cccc3cc[nH]c23)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(CCOc2ccccc2Cl)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a solution of 175 mg (0.5 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-(2-hydroxy-ethyl)-amide, 71 mg (0.55 mmol) of 2-chlorophenol and 144 mg (0.55 mmol) of triphenyl phosphine in 5 ml THF were added dropwise 88 μl (0.55 mmol) of azodicarboxylic acid diethyl ester at 0° C. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed twice with 2N aqueous NaOH solution, once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel, diethyl ether/heptane 1:1) to yield 160 mg (69%) product as a white solid. MS (ISP) 461.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19](F)[CH:18]=1>O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([S:4][CH:2]([CH3:3])[CH3:1])[CH:18]=1
Reactant: CC(C)S
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of propane-2-thiol (1.5 mL), potassium carbonate (3 g) and N,N-dimethylformamide (20 mL), 4-chloro-2-fluoronitrobenzene (2.5 g) was added and stirred at room temperature for 5 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 4-chloro-2-isopropylsulfanyl-1-nitrobenzene (3.30 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11][NH2:12])[CH3:8]>C1C=CC=CC=1>[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11][NH:12][C:2]1[S:3][CH:4]=[N:5][N:6]=1)[CH3:8]
Reactant: CCOC(CN)OCC
Reactant: Brc1nncs1
Solvent: c1ccccc1
Product: CCOC(CNc1nncs1)OCC
Yield: 79.8 %

Procedure:
A solution of 2-bromo-1,3,4-thiadiazole (3.14 g.) and aminoacetaldehyde diethyl acetal (5.1 g.) in benzene (75 ml) was refluxed for 20 hours. After cooling, the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give oil (6.3 g.). The oil was purified by column chromatography on silica gel (120 g.) using benzene and then ethyl acetate as developing solvent to give (1,3,4-thiadiazol-2-yl)aminoacetaldehyde diethyl acetal (3.3 g.), mp 108° to 112° C.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[O:10][C:11]2=[O:12])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=O)C.Cl.O>C(O)C>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[O:10][C:11]2=[O:12])=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: CCCCC1OC(=O)c2cc(NC(C)=O)c([N+](=O)[O-])cc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCC1OC(=O)c2cc(N)c([N+](=O)[O-])cc21
Reaction time: 8 h

Procedure:
To a suspension of 29.2 g of compound obtained in Step A in 25 ml of 95% ethanol there are added 15 ml of hydrochloric acid and 20 ml of water. The mixture is refluxed for 3 hours and put aside at room temperature overnight The solvents are removed under reduced pressure. The residue is treated with 5% NaOH; the solid is collected and washed with water, dried, and crystallised from ethanol giving the title compound.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[S:24][CH:23]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[Cl:34])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:23]1([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[Cl:34])[S:24][C@H:20]([CH2:19][OH:18])[CH2:21][CH2:22]1
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1

Procedure:
A solution of 11 (0.315 g, 0.62 mmol), acetic acid (30 μL, 0.63 mmol) and tetrabutylammonium fluoride (1 M in THF, 0.65 mL, 0.65 mmol) in 3 mL THF was stirred for 10 minutes under nitrogen. The solvent was removed in vacuo and the residue flash chromatographed with dichloromethane followed by 19:1 chloroform/methanol to give 0.164 g (98%) of the anomers. The anomers were separated by centrifugal chromatography with 19:1 chloroform/methanol: yield of β-anomer 10 mg; mp. 125°-128° C.; [α]D25 +2.5° (c=0.1 CH3OH); FAB MS 271 (M+H)+ ; 1H NMR (CDCl3) δ 9.0 (s, 1, H-2), 8.8 (s, 1, H-8), 6.3 (m, 1, 5'-OH), 3.8 (m, 1, 5'-H), 3.65 (m, 2, 4'-H, 5'-H), 2.6 (m, 1, 2'-H), 2.45 (m, 1, 2'-H), 2.2 (m, 1, 3'-H), 2.0 (m, 1, 3'-H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[C:18]2[CH:17]=[CH:16][C:15](=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)[C:13]=2[S:12][C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[C:18]2[CH:17]=[CH:16][C:15](=[O:19])[N:14]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([CH3:27])=[O:41])=[CH:24][CH:25]=3)[C:13]=2[S:12][C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(SC)cc2)c1Nc1ccccc1C#N
Solvent: ClCCl
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(S(C)=O)cc2)c1Nc1ccccc1C#N
Yield: 82 %

Procedure:
A mixture of Example 78 (1.0 g, 2.17 mmol) and m-chloroperbenzoic acid (534 mg, 1 eq) in DCM (50 mL) was stirred at r.t. for 2 h. The mixture was diluted with DCM, washed with NaHCO3 aq, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (silica, 50% EtOAc in DCM) gave the title compound (850 mg, 82%). δH (CDCl3) 8.80 (1H, s), 8.12-7.70 (2H, m), 7.65-7.53 (3H, m), 7.50 (1H, t, J 7.4 Hz), 7.27 (1H, d, J 9.8 Hz), 7.17-7.09 (2H, m), 6.45 (1H, d, J 9.8 Hz), 4.28 (2H, q, J 7.1 Hz), 2.83 (3H, s), 1.30 (3H, t, J 7.1 Hz). LCMS (ES+) RT 3.16 minutes, 478 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:12]/[C:13](/[C:20]([F:23])([F:22])[F:21])=[CH:14]\[C:15](OCC)=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:15](=[O:16])[CH:14]=[C:13]([C:20]([F:23])([F:22])[F:21])[NH:12][C:10]2=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: COc1ccc(N=C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A stirred solution of 6.0 grams (0.0268 mole) of 4-methoxyphenyl isocyanate, 5.16 grams (0.028 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate, and 4.45 grams (0.032 mole) of potassium carbonate in 40 mL of N,N-dimethylformamide was heated to 140° C. where it stirred for one hour. After this time, the reaction mixture was poured into 100 mL of 10% aqueous hydrochloric acid. The resulting mixture was stirred for ten minutes and then extracted with three 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a black solid. This black solid was purified by flash chromatography, yielding 4.51 grams of 3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([CH3:20])[CH2:11][C@H:10]2[NH:12]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1>ClCCl>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:20])[CH2:11][CH:10]2[NH2:12])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@]1(C)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: CC1(c2ccc(Cl)cc2)CC1N
Yield: 141.4 %

Procedure:
HCl (4M in dioxan, 3.24 ml, 13 mmol) was added to a solution of racemic tert-butyl N-[(1R,2R)-2-(4-chlorophenyl)-2-methyl-cyclopropyl]carbamate (731 mg, 2.60 mmol) in dichloromethane (14 ml). After 16 hours at room temperature the solvent was evaporated and the light yellow solid was stirred with tBuOMe and filtered to give racemic (1R,2R)-2-(4-chlorophenyl)-2-methyl-cyclopropanamine hydrochloride (401 mg, 71%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C([Li])CCC.[CH3:17][C:18](=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)C>[S:4]1[CH:5]=[CH:6][C:2]([C:18]([OH:28])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:17])=[C:3]1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: Brc1ccsc1-c1cccs1
Reactant: CCCCCCCCCC(C)=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCCC(C)(O)c1ccsc1-c1cccs1
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
3-Bromo-2,2′-bithiophene (IIIa) (1.00 g, 4.08 mmol) in dry diethylether (35 mL) was added slowly to a solution of n-butyllithium (1.6 M in hexane, 2.50 mL, 4.0 mmol) in dry diethylether (35 mL) at −78° C. over 2 h under N2. The mixture was stirred for 15 minutes at the same temperature. Freshly distilled 2-undecanone (0.84 mL, 4.08 mmol) was added via a syringe to the mixture at −78° C., followed by stirring overnight at room temperature. The reaction was quenched with an aqueous NH4Cl-solution (2.5 M, 20 mL) and water (20 mL) at 0° C. The organic phase was separated and the aqueous phase was extracted with diethylether. The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure to give a crude oil. The oily residue was purified by column chromatography (eluent hexane/EtOAc 90:10) to afford the title compound (IIc) as a yellow oil (0.86 g, 64%). 1H-NMR (CDCl3): δ=7.35 (dd, J=1.2 Hz, J=5.2 Hz, 1H), 7.22 (d, J=5.4 Hz, 1H), 7.12 (dd, J=1.2 Hz, J=3.5 Hz, 1H), 7.04 (d, J=5.4 Hz, 1H), 7.01 (dd, J=3.5 Hz, J=5.2 Hz, 1H), 1.49 (s, 3H), 1.38-1.15 (m, 16H), 0.96-0.80 (m, 3H). 13C-NMR (CDCl3): δ=147.34, 136.12, 130.03, 129.50, 128.64, 127.76, 127.42, 125.40, 75.74, 44.52, 32.50, 30.99, 30.50, 30.29, 30.17, 29.94, 24.83, 23.32, 14.77.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[O:23])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[ClH:32].O1CCOCC1>ClCCl>[ClH:32].[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COCC(N)=N1
Temperature: 40 °C

Procedure:
A solution of (5-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (44.4 mg, 0.1 mmol) in dichloromethane was treated with 4M HCl in dioxane (40 eq). The mixture was warmed to 40° C. for 10 h and then evaporated under reduced pressure to yield the title compound (hydrochloride salt) in the form of a colourless solid. 1H-NMR (500 MHz, DMSO-d6): 10.70 (s, 1H), 10.62 (s, 1H), 9.14 (s, 1H), 8.87 (d, 1H), 8.52 (s, 1H), 8.34 (dd, 1H), 8.11 (d, 1H), 7.96 (m, 2H), 7.43 (t, 1H), 7.21 (d, 1H), 4.59 (s, 2H), 3.88 (m, 2H), 1.65 (s, 3H); MS: 389 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1.[BH4-].[Na+].C(OCC)(=O)C>CO>[CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]([C:15]4[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][CH:22]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1
Reactant: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3ccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CO)cc4)nc3ccn12
Reaction time: 0.17 h

Procedure:
To a solution of 4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzaldehyde (5-2, 0.317 g, 0.870 mmol) in methanol (5 mL) was added sodium borohydride (0.033 g, 0.870 mmol) at 0° C. After 10 minutes, the reaction mixture was poured into ethyl acetate, and the organic layer was washed with a saturated solution of sodium bicarbonate, water, then brine, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. Purification by reverse phase chromatography (Waters Sunfire MSC18, 1% acetonitrile/0.1% trifluoroacetic acid/water→95% acetonitrile/0.1% trifluoroacetic acid/water) gave the title compounds as a solid. HRMS (M+H+): calculated=367.1554, observed=367.1547.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>>[C:1]1([O:11][CH2:12][C:13]([Cl:18])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)COc1cccc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)COc1cccc2ccccc12

Procedure:
10 g of naphthoxy-acetic acid and 60 ml of thionyl chloride were refluxed for 2 hours and after evaporating to dryness under reduced pressure, several distillations with benzene were carried out to obtain 11.16 g of the expected product which was used as is for Step B.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11])[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C=CCCCCCC
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Product: CCCCCC=CCON1C(C)(C)CC(O)CC1(C)C
Temperature: 100 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
A mixture of 20.0 g (0.12 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 164.0 g (1.04 mol) of 1-octene is heated under a nitrogen atmosphere at 100° C. for 24 hours, and then for an additional 24 hours at 115° C. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, and the filtrate is washed with 10% (w/v) ascorbic acid (2×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous magnesium sulfate and the volatiles removed in vacuo. The residue is chromatographed to give 14.4 g (83% yield) of the title compound as an amber oil.
Reaction SMILES: [CH3:1][O:2][P:3]([O-:6])[O:4][CH3:5].[H-].[Na+].[O:9]([CH2:16][CH2:17][CH2:18]Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][O:2][P:3]([CH2:18][CH2:17][CH2:16][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:6])[O:4][CH3:5]
Reactant: COP([O-])OC
Reactant: BrCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COP(=O)(CCCOc1ccccc1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
Dimethylphosphite (5.0 g, 45 mmol) was cautiously added to a suspension of NaH (60% dispersion, 2.0 g, 50 mmol) in DMF (45 mL) at 0°. After 2 h, 3-phenoxy propylbromide (10.75 g, 50 mmol) was added, and the mixture stirred at rt for 48 h. The solvent was removed under reduced pressure, the residue dissolved in water (100 mL), extracted with Et2O, and the combined extracts washed with water, brine and dried (MgSO4). The solution was concentrated at reduced pressure to give 10.28 g of crude product. A portion of the crude material (5 g) was distilled to afford 52 (3.4 g, 63%) as a colourless oil. 13C NMR (CDCl3) δ 21.4 (d, J=141.8 Hz), 22.7 (d, J=4.5 Hz), 52.5 (d, J=6.8 Hz), 67.2 (d, J=15 Hz), 114.6, 121.0, 129.6, 158.8. ESMS 245 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=[C:7]([NH:17][C:18](=[O:29])[NH:19][C:20]2[S:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[N:6]=1.[H-].[Na+].[CH3:34][O:35][CH2:36]Br.O>CN(C)C=O>[CH3:34][O:35][CH2:36][N:17]([C:7]1[N:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:30])[F:31])[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=1)[C:18](=[O:29])[NH:19][C:20]1[S:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: O=C(Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)Nc1ccc(C(F)(F)F)s1
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(C(=O)Nc1ccc(C(F)(F)F)s1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reaction time: 2.5 h

Procedure:
To a solution of 3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (1) (150 mg, 0.31 mmol) in anhydrous dimethyl formamide (DMF, 1.5 mL) at ambient temperature was added NaH (6.6 mg, 0.28 mmol, 60% dispersion in mineral oil). After stirring 20 minutes a solution of bromomethyl methyl ether (35 mg, 0.28 mmol) in anhydrous DMF (0.5 mL) was added. After 2.5 h the reaction was judged complete by TLC analysis. To the reaction was carefully added H2O (2 mL). The reaction was extracted with EtOAc (10 mL). The EtOAc solution was washed with H2O (3×7 mL) followed by brine (7 mL). The organics were dried (Na2SO4), filtered and evaporated to give crude product. The crude material was purified by silica gel chromatography (0 to 8% EtOAc in pet ether) to afford 3-(methoxymethyl)-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (4) as an off white solid (18 mg, 11%), mp 118-119° C.; 1H NMR (400 MHz, Acetone-d6) δ 11.84 (s, 1H), 7.41-7.28 (m, 1H), 6.66 (dd, J=4.1, 0.9 Hz, 1H), 6.18 (s, 1H), 5.54 (s, 2H), 5.02 (q, J=8.6 Hz, 4H), 3.27 (s, 3H); ESIMS m/z 527 ([M−H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(F)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl)amino]pyrimidine and 4-fluorobenzyl bromide
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:23])[CH3:2].C1(=O)CCCCC1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:21][CH3:22])[CH2:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:23])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CC[C@@H]2O
Agent: CC(C)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Solvent: O
Product: CC[C@]12CC[C@@H]3C4=C(CC(OC)=CC4)C(C)C[C@H]3[C@@H]1CCC2=O
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
Dissolve dl-13-ethyl-3-methoxy-6-methylgona-2,5(10)-dien-17β-ol (5.5 g) in toluene (200 ml) containing cyclohexanone (70 ml) and treat with aluminum isopropoxide (4.0 g) in toluene (50 ml). Reflux under nitrogen for 2.5 hours, then add water (10 ml) followed by anhydrous sodium sulfate (5 g). Stir the suspension for 0.5 hour, filter, and wash the filter cake with benzene. Remove the solvents and concentrate the residue at 100° under vacuum (.02 mm). Triturate the crystalline residue with ice-cold methanol to obtain dl-13β-ethyl-6-methyl-3-methoxygona-2,5(10)-dien-17-one (3.6 g), m.p. 118°-125°; infrared absorption peaks (potassium bromide) at 5.78 μ, 5.90 μ, 6.00 μ, no selective ultraviolet absorption above 220 mμ.