Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.C(=O)(O)[O-].[Na+].[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19](B(O)O)=[CH:18][N:17]=1>COCCOC.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][C:5]1[N:6]=[C:2]([C:19]2[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=2)[S:3][C:4]=1[CH3:8]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Cc1nc(I)sc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ncc(-c2nc(C)c(C)s2)c(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-iodo-4,5-dimethyl-1,3-thiazole (prepared in a similar manner to that described in JACS 123 (6), 1017-1022, (2001), 250 mg, 1.046 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (4.357 ml). Tetrakis(triphenylphosphine)palladium(0) (60.4 mg, 0.052 mmol) was added and the mixture was stirred at room temperature for 10 minutes. Sodium bicarbonate (4.183 ml, 4.18 mmol) and [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (385 mg, 2.091 mmol) were added and the resulting mixture was stirred at 85° C. for 2 hours. The mixture was allowed to cool to rt and left standing at rt over the week end. The mixture was diluted with DCM (5 mL), the aqueous phases was separated and extracted with DCM (2×5 mL). The organics were combined and dried over sodium sulphate to give a yellow solid that was purified by silica chromatography, eluting with DCM:MeOH from 100:0 to 95:5 to afford the title compound as a pale yellow solid (143 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][N:15]1[C:19]([CH3:20])=[C:18]([C:21]2[CH:22]=[C:23]([CH2:27]O)[CH:24]=[CH:25][CH:26]=2)[C:17]([CH3:29])=[N:16]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:14][N:15]1[C:19]([CH3:20])=[C:18]([C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[C:17]([CH3:29])=[N:16]1
Reactant: Cc1nn(C)c(C)c1-c1cccc(CO)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)nn(C)c3C)c2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.6 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (0.541 g, 3.00 mmol), [3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl]methanol (0.433 g, 2.00 mmol) and tributylphosphine (0.747 mL, 3.00 mmol) in toluene (30 mL) was stirred under ice-cooling, and 1,1′-(azodicarbonyl)dipiperidine (0.757 g, 3.00 mmol) was added by small portions. The mixture was allowed to warm to room temperature and the mixture was stirred for 22 hr. Hexane (15 mL) was added to the reaction mixture. The precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30%-70% ethyl acetate/hexane) to give the title compound (0.406 g, yield 54%) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])[CH3:2]
Reactant: CC(=O)c1cccc(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cccc(C#N)c1
Reaction time: 0.33 h

Procedure:
To a solution of 3-acetylbenzonitrile (1 equivalent) in methanol at room temperature was added sodium borohydride (approx. 1.67 equivalents), and the reaction was stirred for approximately 20 minutes. Aqueous work-up provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])(C)(C)C.I[CH2:20][CH2:21][CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([F:26])([F:25])[F:24].[Cl-].[NH4+]>O1CCCC1>[CH:11]([C@@H:4]1[C:3]([O:2][CH3:1])=[N:8][C@@H:7]([CH2:20][CH2:21][CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([F:25])([F:26])[F:24])[C:6]([O:9][CH3:10])=[N:5]1)([CH3:13])[CH3:12]
Reactant: FC(F)(F)C(CCI)c1ccccc1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1CCC(c1ccccc1)C(F)(F)F
Reaction time: 1 h

Procedure:
A solution of (R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (1.1 g) in tetrahydrofuran (25 ml) was cooled to −70° C., then tert.butyllithium (1.7 M in pentane, 3.88 ml) was added and the mixture was stirred for 1 hour. A solution of (3-iodo-1-trifluoromethyl-propyl)-benzene (1.98 g) in tetrahydrofuran (7 ml) was added slowly and the mixture was stirred overnight at −70° C. At room temperature saturated ammonium chloride solution was added and the mixture was extracted three times with ether. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, heptane/EtOAc=9:1 to yield a yellow liquid, (1.86 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[O:8])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: CCNCC
Reactant: O=C(O)c1ccc(Cl)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of 4-chloro-2-(trifluoromethyl)benzoic acid (18.1 g, 80 mmol) in 500 mL of methylene chloride was added oxalyl chloride (60 mL of a 2.0 M solution in methylene chloride, 120 mmol) followed by N,N-dimethylformamide (0.2 mL). The reaction was allowed to stir at ambient temperature for 18 h. The volatiles were removed in vacuo to afford the crude acid chloride intermediate. The residue was taken up in 500 mL of methylene chloride and then there was added diethylamine (16.5 mL, 160 mmol). The resulting solution was allowed to stir at ambient temperature for 2 h, and then the mixture was concentrated to an oil. The residue was purified (ISCO, 0-30% EtOAc/hexane, 45 min) to afford 11.4 g (51%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10](=[C:15](SC)SC)[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][C:23]=1[S:33]([NH2:36])(=[O:35])=[O:34]>O1CCOCC1>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]2[NH:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:24][C:23]=3[S:33](=[O:35])(=[O:34])[N:36]=2)[C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC(SC)=C1C(=O)C=CN(Cc2ccccc2)C1=O
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)ccn(Cc3ccccc3)c1=O)N2
Yield: 13.7 %

Procedure:
A solution of the product of Example 426B (0.028 g, 0.092 mmol) and the product of Example 425D (0.025 g, 0.092 mmol) in 1,4-dioxane was heated at 100° C. for 40 minutes. The solvent was removed under a stream of with warm nitrogen and the residue was triturated with water and ethyl acetate. The precipitate in the organic layer was filtered and dried to yield the title compound (0.006 g, 12%). MS (ESI−) m/z 473 (M−H)−. 1H NMR (500 MHz, DMSO-D6) δ 3.06 (s, 3 H) 5.21 (s, 2 H) 6.38 (d, J=4.88 Hz, 1 H) 7.34 (m, 5 H) 7.55 (m, 3 H) 8.18 (d, J=3.05 Hz, 1 H) 10.25 (s, 1 H) 13.87 (s, 1 H) 14.05 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C@@H:6]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH2:7][N+:8]([O-])=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O>O1CCCC1>[NH2:8][CH2:7][C@H:6]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[OH:17])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1
Reactant: O=C1CCCC[C@H]1[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H](c1ccc(Cl)cc1)[C@@H]1CCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.55 g (16.1 mmol) of (-)-(2S)-[(R)-4-chloro-α-(nitromethyl)benzyl]cyclohexanone [prepared according to Helv. Chim. Acta 65, 1637 (1982)] in 80 ml of dry tetrahydrofuran is added dropwise at room temperature while stirring to a suspension of 1.5 g (40.4 mmol) of lithium aluminium hydride in 50 ml of dry tetrahydrofuran under argon. The reaction mixture is stirred at room temperature overnight, treated with 20 ml of tetrahydrofuran/water (1:1), the separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The residue is dissolved in ether, the ethereal phase is extracted with 1N hydrochlorid acid, the acidic phase is made alkaline with 3N sodium hydroxide solution and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated. There is obtained (+)-(1S)-cis-2-[(R)-α-(aminomethyl)-4-chlorobenzyl]cyclohexanol in the form of a yellow oil ([α]D20 =+14.7°, c=0.6 in chloroform), which is processed as such.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]COC)=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:17]([CH2:21][C:22]#[CH:23])[C:18](=O)[CH3:19])(C)(=O)=O>C(O)C>[OH:8][C:7]1[C:2]2[N:3]([C:17]([CH2:21][C:22]#[CH:23])=[C:18]([CH3:19])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Reactant: COCOc1cccnc1N
Solvent: CCO
Product: C#CCc1c(C)nc2c(O)cccn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.3 %

Procedure:
A solution of 2-amino-3-methoxymethoxypyridine (7.5 g) and 3-mesyloxy-5-hexyn-2-one (10.18 g) in ethanol (150 ml) was refluxed for 46.5 hours and then evaporated in vacuo. To the residue was added 20% sulfuric acid (75 ml) and the mixture was stirred for 5 hours at room temperature. The mixture was made alkaline with sodium bicarbonate and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (30 g) with chloroform and then a mixture of chloroform and methanol (30:1 to 20:1) as eluents. The eluates were evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 8-hydroxy-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (1.93 g).
Reaction SMILES: [C:1]1([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:20].O>C(OCC)C>[Br:20][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OC(c1ccccc1)c1cccc2ccccc12
Solvent: O
Solvent: CCOCC
Product: BrC(c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.5 %

Procedure:
To a solution of 32.3 g (138 mmol) of 7 in 150 mL of dry diethyl ether, 24.8 g (8.62 mL, 91.6 mmol) of PBr3 was added at −10° C. The resulting mixture was stirred for 12 hr at room temperature and then added to 450 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 2×150 mL of water. The combined organic extracts were washed with aqueous NaHCO3, dried over Na2SO4, and then evaporated to dryness. This procedure gave 37.7 g (92%) of 8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][CH3:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=S)=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]2[N:22]([CH3:23])[C:21]3[CH:20]=[CH:19][C:4]([O:5][C:6]4[CH:11]=[CH:10][N:9]=[C:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=4)=[CH:3][C:2]=3[N:1]=2)=[CH:27][CH:26]=1
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Reactant: S=C=Nc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(Br)cc2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Temperature: 50 °C

Procedure:
A solution of the diamine from step 6 (1 eq) and 4-bromophenyl isothiocyanate (1 eq) in anhydrous tetrahydrofuran under nitrogen was stirred at 20° C. for 2-3 hours or when determined to be complete by HPLC. The solution was treated with 3 equivalents of 1-ethyl-(3-dimethylaminopropyl)carbodiimide HCl. The stirred solution was heated to 50° C. under nitrogen for 2-3 hrs or until the reaction is determined to be complete by HPLC. The reaction was evaporated under reduced pressure and then diluted with ethyl acetate and water. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and later evaporated under reduced pressure. The crude material was purified by reverse high-pressure liquid chromatography to afford the product as a brown powder after lyophlization. MS: MH+=495.
Reaction SMILES: COC1C=CC2N=C(C3C=CC(F)=NC=3)OC=2C=1.[CH3:19][N:20]([CH3:29])[C:21]1[N:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][N:22]=1.[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][C:32]=1O>>[CH3:19][N:20]([CH3:29])[C:21]1[N:22]=[CH:23][C:24]([C:27]2[O:28][C:32]3[CH:33]=[C:34]([C:35]([O:37][CH3:38])=[O:36])[CH:39]=[CH:40][C:31]=3[N:30]=2)=[CH:25][N:26]=1
Reactant: CN(C)c1ncc(C=O)cn1
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: COc1ccc2nc(-c3ccc(F)nc3)oc2c1
Product: COC(=O)c1ccc2nc(-c3cnc(N(C)C)nc3)oc2c1
Yield: 72.3 %

Procedure:
The synthesis was performed according to the procedure described for 5-(6-methoxy-1,3-benzoxazol-2-yl)-2-fluoropyridine starting with 180 mg of 2-dimethylamino-pyrimidine-5-carbaldehyde and 200 mg of methyl 4-amino-3-hydroxybenzoate to give 256.8 mg of the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:13]Br>Br>[BrH:13].[Br:13][C:10]1[CH:9]=[N:8][C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: BrBr
Agent: Br
Product: Brc1ccc(N2CCNCC2)nc1
Temperature: 115 °C

Procedure:
A solution of 81.5 g of 2-piperazinylpyridine [J. Org. Chem., 18, 1484 (1953)] in 250 g of 48% hydrobromic acid is heated at 70° C. With stirring, 80 g of liquid bromine is added dropwise. The mixture is heated at 115° C. for 1 hour. The mixture is cooled and the product 3-bromo-6-piperazinylpyridine hydrobromide is isolated by filtration. The salt is treated with excess dilute sodium hydroxide and extracted into toluene. The 3-bromo-6-piperazinylpyridine crystallizes as the solvent is removed in vacuo and is recrystallized from toluene-petroleum ether; mp 70°-73° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[C:29]([OH:32])(=[S:31])[CH3:30]>>[C:26]([C:24]1[N:25]=[C:21]([C:19]([NH:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([S:31][C:29](=[O:32])[CH3:30])([CH3:15])[CH3:16])=[CH:13][C:8]=2[C:5]2[CH2:6][CH2:7][C:2]([CH3:28])([CH3:1])[CH2:3][CH:4]=2)=[O:20])[NH:22][CH:23]=1)#[N:27]
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CC(O)=S
Product: CC(=O)SC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d)) and thioacetic acid using the conditions described in Example 70. 1H-NMR (CDCl3; 400 MHz): δ 9.73 (s, 1H), 8.29 (d, 1H, J=8.6 Hz), 7.74 (s, 1H), 7.49-7.47 (m, 1H), 7.35 (d, 1H, J=2.2 Hz), 5.79 (m, 1H), 2.32-2.28 (m, 2H), 2.20 (s, 3H), 2.11 (m, 2H), 1.86 (s, 6H), 1.59 (t, 2H, J=6.2 Hz), 1.11 (s, 6H).
Reaction SMILES: BrBr.[C:3]([NH:11][C:12]1[CH:17]=[C:16]([CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=O)[CH:15]=[CH:14][N:13]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:29][C:30]([NH2:32])=[S:31].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)(=O)C>[NH2:32][C:30]1[S:31][C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:17]=2)=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:29]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)cc1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(N)sc2-c2ccnc(NC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
Bromine (0.11 mL, 2.1 mmol) was added to a solution of 2-(2-benzoylamino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (0.72 g, 2.1 mmol) in acetic acid (20 mL) at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was dissolved in acetonitrile (20 mL), to the solution were added thiourea (0.17 g, 2.2 mmol) and triethylamine (0.35 mL, 2.5 mmol) and the mixture was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate (200 mL) was added and the resulting solid was filtered and washed with water. The resulting crude crystals were collected by filtration and washed with water. The crude crystals were recrystallized from ethanol to obtain 0.17 g (0.43 mmol, yield 21%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(N(C(C)C)C(C)C)C.[CH3:44][O:45][CH2:46]Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][C:30]([CH3:33])([CH3:34])[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:44][O:45][CH3:46])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COCCl
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCO[C@H]1CC[C@H](N(c2cc(C3=CCC(C)(C)CC3)sc2C(=O)OC)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (406 mg, 0.83 mmol), i-Pr2EtN (218 μL, 1.25 mmol) and DMAP (15 mg, 0.12 mmol) in dry CH2Cl2 (20 mL) was added chloromethyl methyl ether (95 μL, 1.25 mmol), and the mixture was stirred at room temperature overnight. Then the mixture was diluted with CH2Cl2, washed with brine, organic fraction was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with 0-30% EtOAc in hexanes to give 286 mg (65%) of 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([O:16]CC3C=CC=CC=3)=[O:15])=[O:11])=[CH:8][C:7]=2[CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][C:7]=2[CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH2:3][CH2:2]1
Reactant: O=C(COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)COC(=O)c1ccc(OCC2CC2)c(CN2CCOCC2)c1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-(morpholinomethyl)-benzoate (4.55 g, 10.35 mmol) was dissolved in MeOH (50 ml), then Pd/C 5% (1.10 g, 0.340 mmol) was added. The solution was shaken under hydrogen atmosphere at 60 psi on a Parr apparatus for 1 hour. The catalyst was filtered off and the solvent removed under vacuum to give 3.18 g of the desired compound (yield 88%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[N:8][C:7](O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:7]1[N:8]=[N:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=1
Reactant: Oc1ccc(C2CC2)nn1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(C2CC2)nn1
Yield: 89 %

Procedure:
A mixture of 6-cyclopropylpyridazin-3-ol (182 mg, 1.3 mmol) in POCl3 (15 mL) was refluxed for 1 hour, and concentrated. The residue was treated with ethyl acetate (60 mL) and sat. NaHCO3 aqueous solution (10 mL) at 0° C. The organic layer was dried over Na2SO4 and concentrated to afford 3-chloro-6-cyclopropylpyridazine (185 mg, 89%). 1H NMR (400 MHz, CD3OD): δ1.11 (m, 2H), 1.20 (m, 2H), 2.25 (m, 1H), 7.52 (d, 1H), 7.67 (d, 1H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:29])=O>>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([Cl:29])=[O:23])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Decyloxypyrimidine-2-yl)benzoic acid (1.50 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-decyloxypyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].O>CN(C)C=O>[C:23]([CH2:22][CH2:21][S:20][C:18](=[S:19])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)([OH:25])=[O:24]
Reactant: O=C(O)CCS
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(N=C=S)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCSC(=S)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of 27.2 g of 4-(4-nitrophenyloxy)-phenylisothiocyanate (m.p. 124°-125° C) and 10 ml of 3-mercaptopropionic acid in 250 ml of anhydrous dimethyl formamide is stirred at room temperature. When the reaction is complete, the solution is poured, with stirring, into 250 ml of water. The resultant fine precipitate is collected by filtration, washed with water and dried under reduced pressure to yield the N-[4-(4-nitro-phenyloxy)-phenyl]-dithiocarbamic acid-(2-carboxyethyl)-ester with a melting point of 146° C.