Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][CH2:13][C:14]([CH2:20][OH:21])([CH3:19])[C:15]([O:17][CH3:18])=[O:16].[CH3:22][O:23][CH:24](OC)[CH2:25][CH2:26]OC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:22][O:23][CH2:24][CH2:25][CH:26]1[O:21][CH2:20][C:14]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:13][O:12]1
Reactant: COC(=O)C(C)(CO)CO
Reactant: COCCC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCC1OCC(C)(C(=O)OC)CO1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
51 mg of 4-toluenesulphonic acid are added to a solution of 400 mg of methyl 3-hydroxyl-2-(hydroxymethyl)-2-methylpropanoate and 362 mg of 1,1,3-trimethoxypropane in toluene, and the mixture is stirred at 80° C. for 4 hours. After addition of saturated sodium bicarbonate solution, the organic phase is separated off and dried over sodium sulphate, and the solvent is removed under reduced pressure. The residue is filtered through silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gives 478 mg of methyl 2-(2-methoxyethyl)-5-methyl-1,3-dioxane-5-carboxylate as a mixture of two isomeric forms in a purity of about 38% (LCMS).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O-:24])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[Cl:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:34])=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 3-chlorobenzenesulfonamide. MS (ESI) m/z 509 [M+H]+, 507 [M−H]−, 1H-NMR (CDCl3)δ1.22 (3H, t, J=7.5 Hz), 2.68 (2H, q, J=7.5 Hz), 2.86 (2H, t, J=6.6 Hz), 3.47-3.56 (2H, m), 6.44 (1H, br), 7.23-7.28 (5H, m), 7.36 (2H, t, J=7.3 Hz), 7.45 (2H, t, J=8.1 Hz), 7.58 (2H, d, J=8.1 Hz), 7.73-7.78 (2H, m), 7.87 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][CH3:20])=[O:10].[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[NH2:22][C:21]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:9](=[O:10])[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19][CH3:20])[C:24](=[O:25])[CH:23]=1
Reactant: N#CCC(=O)O
Reactant: CSc1ccccc1CNC(=O)Nc1ccccc1C
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CSc1ccccc1Cn1c(=O)cc(N)n(-c2ccccc2C)c1=O
Temperature: 77.5 °C
Reaction time: 16 h

Procedure:
1-(2-Methylphenyl)-3-[2-(methylthio)benzyl]urea(23.47 g) and cyanoacetic acid (7.66 g) were ground together and acetic anhydride (23 ml) was added. The mixture was stirred and heated at 75-80° C. for 30 h. Toluene (20 ml) was then added and heating continued for a further 16 hours. The reaction was cooled and filtered. The filtrate was heated to boiling and treated with charcoal. The solid was removed by filtration and the filtrate evaporated in vacuo. The resulting oil was dissolved in dichloromethane (300 ml) and triethylamine (8.15 g) added. The mixture was stirred for 5 hours at room temperature and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and the product was recrystallised from ethyl acetate. Yield=2.60 g.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)(=[O:9])=[O:8].CCN(CC)CC.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:60][C:61]([F:71])([F:70])[C:62]1[CH:69]=[CH:68][C:65]([CH2:66][NH2:67])=[CH:64][CH:63]=1>C1COCC1>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:67][CH2:66][C:65]1[CH:64]=[CH:63][C:62]([C:61]([F:60])([F:70])[F:71])=[CH:69][CH:68]=1)=[O:15])(=[O:8])=[O:9]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cccc(C(=O)O)c2)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1cccc(S(=O)(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-{[(2,4-Dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}benzoic acid (Preparation 23, 90 mg, 0.207 mmol, 1 eq) THF (2 ml) was added Et3N (0.04 ml, 0.311 mmol, 1.5 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl, 52 mg, 0.27 mmol, 1.3 eq) and 1-hydroxybenzotriazole hydrate (HOBt, 28 mg, 0.207 mmol, 1 eq) at 0° C. and the reaction mixture stirred for 10 minutes before the addition of 4-(trifluoromethyl)benzylamine (0.032 ml, 0.228 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 18 hours. The mixture was extracted from water into DCM, dried over magnesium sulphate, filtered and evaporated in vacuo. The residue was dissolved in 4M HCl in dioxane (2 ml) and the reaction mixture stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration and washed with dioxane. The material was purified further by preparative HPLC to yield the title compound.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[C:31]([Cl:33])[CH:32]=1.C(N(CC)CC)C.Cl>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cc(Cl)cc(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 78 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 3,5-dichlorophenylisocyanate (0.19 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 18 h, 1 N aq. HCl (10 mL) was added and the solids were isolated by filtration and washed with water (40 mL). The solids were triturated in EtOAc (10 mL) for 18 h, then isolated by filtration, washed with EtOAc (40 mL) and dried in vacuo to give 1-(3,5-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.36 g, 78% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 9.14 min (96.29%); mp: 274-276° C.; 1H NMR (DMSO-d6) δ 1.86-2.12 (m, 1H, CHH), 2.24-2.47 (m, 1H, CHH), 2.60 (d, J=16.4 Hz, 1H, CHH), 2.77-3.05 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.38-4.56 (m, 3H, CHH, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 7.00 (t, J=5.9 Hz, 1H, NH), 7.08 (t, J=1.7 Hz, 1H, Ar), 7.44 (d, J=7.7 Hz, 1H, Ar), 7.48-7.59 (m, 3H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 9.08 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.83, 47.12, 51.58, 115.78, 120.16, 121.92, 122.94, 126.92, 130.35, 133.93, 142.39, 142.93, 144.43, 154.77, 167.92, 170.98, 172.85; LCMS: MH=461/463/465; Anal Calcd for C21H18N4O4Cl2: C, 54.68; H, 3.93; N, 12.15; Cl, 15.37. Found: C, 54.61; H, 3.78; N, 11.84; Cl, 15.10.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.CCO[C:42]([CH3:44])=O>>[C:3]1([CH2:8][CH2:9][C:42]2[CH:44]=[CH:16][C:17]([CH2:23][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[N:13]=[C:12]([N:14]4[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]4)[CH:11]=[CH:10][CH:9]=3)=[CH:18][CH:19]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(CCc4ccccc4)cc3)n2)c1C(F)(F)F
Reaction time: 2 h

Procedure:
A vial was charged with the title compound from Example 1 Step B (36.0 mg, 0.095 mmol), cesium carbonate (62.2 mg, 0.191 mmol), and 4-chloromethyl dibenzyl (33.0 mg, 0.143 mmol). DMF (0.5 mL) was added, and the resulting suspension was stirred vigorously. After 2 h, the reaction mixture was diluted with EtOAc and washed with brine. The organic phase was separated and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 572.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.98 (dd, J=7.5, 1.5 Hz, 1H), 7.86 (t, J=7.5 Hz, 1H), 7.53 (d, J=7.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.29-7.26 (m, 4H), 7.22-7.17 (m, 5H), 7.11 (t, J=7.5 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 5.13 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.93 (app s, 4H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+]([O-])=O)=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[NH:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2C(C(NCCOC3C=CC=CC=3)=C([N+]([O-])=O)C=[N:39]2)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH2:39])=[C:12]2[NH:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Reactant: CNc1ccnc2ccc(OCc3ccccc3)c([N+](=O)[O-])c12
Product: CNc1c(N)cnc2ccc(OCc3ccccc3)cc12

Procedure:
The general method described in Part B of Example 46 was followed using N-(6-benzyloxy-5-nitroquinolin-4-yl)-N-methylamine (11.36 g, 36.7 mmol) in lieu of (7-benzyloxy-3-nitroquinolin-4-yl)-(2-phenoxyethyl)amine. 6-Benzyloxy-N4-methylquinoline-3,4-diamine (7.91 g) was obtained as a dark yellow oil and used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40](=[O:46])[NH:41][S:42](Cl)(=[O:44])=[O:43])([CH3:38])([CH3:37])[CH3:36]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:42]([NH:41][C:40](=[O:46])[O:39][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:43])=[O:44])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)NS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, t-butyl(chlorosulfonyl)carbamate In this connection, the method for the synthesis of t-butyl(chlorosulfonyl)carbamate is described in Tetrahedron, 49(1), 65 (1993).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:10])=[NH:9].C[O:12][CH:13]=[C:14]([C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15](OC)=O.C(N(CC)CC)C>CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:10]=[C:13]([OH:12])[C:14]([C:19]#[C:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][N:9]=1
Reactant: N=C(N)c1ccccn1
Reactant: COC=C(C#C[Si](C)(C)C)C(=O)OC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(-c2ccccn2)nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of compound 37-b (15 g, 71 mmol), compound 37-h (12.2 g, 77.8 mmol), triethylamine (21.4 g, 212 mmol) in methanol (200 mL) was stirred overnight at room temperature. The residue obtained from removal of the solvent was purified by flash chromatography (DCM) to afford compound 37-i (7.5 g, 39%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.668-8.649 (m, 1H), 8.428-8.395 (m, 1H), 8.257 (s, 1H), 7.937-7.880 (m, 1H), 7.517-7.471 (m, 1H), 0.285 (s, 9H). LC-MS (ESI): 270 [M+H]+
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[NH:16]([C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1)[C:17]([CH3:19])=[O:18].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:23]2[CH:24]=[CH:25][C:20]([NH:16][C:17]([CH3:19])=[O:18])=[CH:21][CH:22]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(OC(=O)CCC2CCN(C(=N)N)CC2)cc1
Yield: 47.9 %

Procedure:
A mixture of 2.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 1.29 g of p-acetaminophenol was dissolved in 20 ml of dry pyridine. To the solution was added with stirring and ice-cooling 1.75 g of dicyclohexylcarbodiimide, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered to give crystals which were then washed with ethyl acetate and further with ether and dried. The crystals were refluxed with 600 ml of dichloromethane, and the resulting mixture was filtered to give an insoluble substance. The substance was washed with dichloromethane and recrystallized from methanol-ethyl acetate to obtain 1.5 g (yield: 48.4%) of p-acetaminophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 258° to 261° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27](I)[S:28][C:21]=12)[NH2:15]>>[F:11][C:12]1[CH:13]=[C:14]([NH2:15])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27]([C:10]#[C:9][CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[S:28][C:21]=12
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN1CCN(C)CC1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 50 °C
Yield: 77.6 %

Procedure:
Prepared from 1-methyl-4-(prop-2-ynyl)piperazine (26.8 mg, 0.194 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was purified by preparative TLC eluting with 5% MeOH (containing 7N NH3) in CH2Cl2. The product was obtained as a waxy solid (40 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6 Hz, 1H), 7.58 (s, 1H), 7.03 (m, 1H), 6.53 (m, 3H), 3.86 (br s, 2H), 3.61 (s, 2H), 2.5-2.8 (m, 8H), 2.37 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12]/[CH:13]=[C:14](/[CH2:16][CH2:17]/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20])\[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:25][C:24]([CH3:26])=[CH:23][CH2:22][CH2:21]/[C:19](/[CH3:20])=[CH:18]/[CH2:17][CH2:16]/[C:14](/[CH3:15])=[CH:13]/[CH:12]=[O:11]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 102.1 %

Procedure:
To a stirred solution of 2.5 ml (28.7 mmol) of distilled oxalyl chloride in 50 ml of dry CH2Cl2 at -60° C. was added 4.2 ml (58.5 mmol) of DMSO in 10 ml of CH2Cl2 over 6 minutes between -60° C. and -55° C. with much gas evolution. After 7 minutes at -60° C., a solution of 5.0 g (22.50 mmol) of E,E-farnesol in 14 ml of CH2Cl2 was added over 15 minutes to give a thick white suspension. After 20 minutes at -65° C., 19 ml (136 mmol) of triethylamine was added over 7 minutes and 5 minutes later the cold bath was removed and the reaction was allowed to warm to room temperature over 50 minutes. The mixture was diluted with 400 ml of ether, washed with two 50 ml portions each of water and brine, dried over MgSO4, and evaporated. The residue was taken up in ether, filtered to remove some insoluble solid, and evaporated to provide 5.06 g (100%) of crude E,E-farnesal, contaminated with a trace of the 2Z-isomer.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:17])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CO[C:20]1[CH2:21][CH2:22][CH2:23][N:24]=1>CO.C(O)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH:17][C:20]1[CH2:21][CH2:22][CH2:23][N:24]=1)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC1=NCCC1
Reactant: NC(Cc1cccnc1)c1cccc(Cl)c1Cl
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(C(Cc2cccnc2)NC2=NCCC2)c1Cl
Temperature: 70 °C
Yield: 49.7 %

Procedure:
To 1-(2,3-dichlorophenyl)-2-(pyridin-3-yl)ethanamine (258 mg, 0.97 mmol) in methanol (5 mL) was added 5-methoxy-3,4-dihydro-2H-pyrrole (96 mg, 0.97 mmol) followed by acetic acid (2 drops). The mixture was heated at 70° C. for 16 hours. The mixture was cooled to room temperature and methanol was removed. Purification by chromatography on silica gel (5% 7N NH3 in MeOH/CH2Cl2) gave N-(1-(2,3-dichlorophenyl)-2-(pyridin-3-yl)ethyl)-3,4-dihydro-2H-pyrrol-5-amine (161 mg, 50%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-:12].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:3](=[O:12])[NH:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: [OH-]
Reactant: Fc1nc(F)c(Cl)c(Cl)c1Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(F)c(Cl)c(Cl)c1Cl
Reaction time: 2 h

Procedure:
A solution of 3,4,5-trichlorodifluoropyridine (21.8 g.) in dioxan (220 ml.) was refluxed with a solution of sodium hydroxide (8 g.) in water (40 ml.). After 2 hours a further 8 g. of sodium hydroxide in water (40 ml.) was added (4 molar equivalents of sodium hydroxide in toto). After a further 2 hours, water was added to produce a homogeneous solution which was acidified to precipitate the product (17.6 g., m.p. 170°-4°). After initial purification by charcoal and silica gel column, crystallisation from benzene gave 3,4,5-trichloro-6-fluoro-2-pyridone, m.p. 172°-6°(11.8 g.), having a pale yellow colour. After vacuum sublimation at 100°-120°, the white microcrystals melted at 173°-4° (10.65 g/.).
Reaction SMILES: [CH:1]1([N:6]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15]C(O)=O)=[CH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]1(N[C@H]2CC[C@H](C(C)C)CC2)CCCC1.C([O:45][C:46](=[O:56])[CH2:47]CSC1SC(N)=NC=1)C>>[CH:1]1([N:6]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][CH2:47][C:46]([OH:56])=[O:45])=[CH:12][N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CC(C)[C@H]1CC[C@H](NC2CCCC2)CC1
Product: CC(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclopentyl-(trans-4-isopropyl-cyclohexyl)-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=O.[CH3:14][N:15]([CH3:19])[C:16]([NH2:18])=[S:17]>C(O)(C)C.CCOC(C)=O>[CH3:14][N:15]([CH3:19])[C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[N:18]=1
Reactant: CN(C)C(N)=S
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CN(C)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Yield: 64.7 %

Procedure:
A solution of 2-bromo-4′-nitroacetophenone (4.42 g, 18.1 mmol), N,N,-dimethylthiourea (3.77 g, 36.2 mmol) in isopropanol (60 mL) was heated at reflux for 45 min. The cooled reaction mixture was diluted with EtOAc. The solution was washed with saturated aqueous NaHCO3, H2O and brine, dried (MgSO4) and concentrated under reduced pressure to give N,N-dimethyl-4-(4-nitrophenyl)-2-thiazolamine (2.92 g, 65% yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ8.24 (d, J=8.8 Hz, 2H), 8.11 (d, J=8.8 Hz, 2H), 7.56 (s, 1H), 3.11 (s, 6H); MS (FAB) m/z 250 (MH)+.
Reaction SMILES: C([N:8]1[CH2:39][CH2:38][C:11]2[N:12]=[C:13]([C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[N:14]=[C:15]([O:16][CH3:17])[C:10]=2[CH2:9]1)C1C=CC=CC=1.[H][H]>O.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:17][O:16][C:15]1[C:10]2[CH2:9][NH:8][CH2:39][CH2:38][C:11]=2[N:12]=[C:13]([C:18]2[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[N:21][N:22]3[S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[N:14]=1
Reactant: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(Cc1ccccc1)CC2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1nc(-c2c(C)ccc3c2cnn3S(=O)(=O)c2ccc(C)cc2)nc2c1CNCC2

Procedure:
A mixture of 6-benzyl-4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.85 g, 3.43 mmol) and Pd(OH)2 on carbon (wet) (10%, 0.722 g, 1.03 mmol) in water (7.5 mL) and acetic acid (0.59 mL) was stirred under 1 atm of hydrogen at room temperature for 2.5 h. The reaction mixture was filtered through Celite® and the solids were washed with EtOAc. The combined filtrates were washed with saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH (10% NH4OH)/DCM) to provide 4-methoxy-2-(5-methyl-1-tosyl-1H-indazol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 450.1 (M+H)+.