Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](O[C@H](C)[C@@H](NC1C=CC(C#N)=C(Cl)C=1C)C1OC(C2C=CC(O[Si](C(C)(C)C)(C)C)=CC=2)=NN=1)(C(C)(C)C)(C)C.[Si:42]([O:49][C:50]1[CH:83]=[CH:82][C:53]([C:54]([NH:56][NH:57][C:58](=[O:81])[C@H:59]([NH:70][C:71]2[CH:76]=[CH:75][C:74]([C:77]#[N:78])=[C:73]([Cl:79])[C:72]=2[CH3:80])[C@@H:60]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH3:61])=O)=[CH:52][C:51]=1[F:84])([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II>>[Si:63]([O:62][C@@H:60]([CH3:61])[C@@H:59]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([C:77]#[N:78])=[C:73]([Cl:79])[C:72]=1[CH3:80])[C:58]1[O:81][C:54]([C:53]2[CH:82]=[CH:83][C:50]([O:49][Si:42]([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:43])[CH3:44])=[C:51]([F:84])[CH:52]=2)=[N:56][N:57]=1)([C:66]([CH3:69])([CH3:67])[CH3:68])([CH3:65])[CH3:64]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(F)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](c2nnc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
Intermediate 29e was prepared by a procedure analogous to that used for the preparation of intermediate 10c by cyclization of 4-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-3-fluoro benzohydrazide (640 mg, 0.99 mmol) with PS-PPh3 (3.0 mmol/g, 661 mg, 1.98 mmol), I2 (502 mg, 1.98 mmol), and TEA (1.4 mL, 10 mmol). After column chromatography (25% EtOAc/hexanes) the title compound was isolated as a white solid (131 mg, 21%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.65 (m, 1H), 7.59 (m, 1H), 7.32 (d, J=8.6 Hz, 1H), 6.9 (t, J=8.3 Hz, 1H), 6.45 (d, J=8.8 Hz, 1H), 5.35 (d, J=8.6 Hz, 1H), 4.77 (dd, J=1.9, 8.7 Hz, 1H), 4.51 (m, 1H), 2.36 (s, 3H), 1.40 (d, J=6.1 Hz, 3H), 0.99 (s, 9H), 0.86 (s, 9H), 0.21 (s, 6H), 0.06 (s, 3H), −0.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([CH2:12][C:13]1[C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([O:38]CC)=[O:37])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[C:16]([CH:41]([CH3:43])[CH3:42])[O:15][N:14]=1)(=[O:11])=[O:10].O1CCCC1.CO.[OH-].[Na+]>ClCCl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([CH2:12][C:13]1[C:17]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([OH:38])=[O:37])[CH:30]=[CH:29]4)=[CH:24][CH:25]=2)=[C:16]([CH:41]([CH3:43])[CH3:42])[O:15][N:14]=1)(=[O:10])=[O:11]
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(CS(=O)(=O)c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1onc(CS(=O)(=O)c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 75 °C
Yield: 27.3 %

Procedure:
To a solution of ethyl 6-[4-({[3-{[(2,6-dichlorophenyl)sulfonyl]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (4 mg, 0.006 mmol) in 1:1 tetrahydrofuran:methanol (0.5 mL) was added 1 N sodium hydroxide (0.020 mL, 0.020 mmol). The solution was heated in a microwave reactor at 75° C. for approximately 10 minutes. Then the mixture was diluted with dichloromethane and 1 N hydrochloric (0.020 mL, 0.020 mmol) was added. The solution was washed with water, dried over magnesium sulfate and concentrated to afford 6-[4-({[3-{[(2,6-dichlorophenyl)sulfonyl]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (1 mg, 25%). 1H-NMR (400 MHz, CDCl3) δ 8.44 (d, J=8 Hz, 1H), 8.29 (d, J=8 Hz, 1H), 8.21 (d, J=8 Hz, 1H), 8.10-8.07 (m, 2H), 7.71 (d, J=8 Hz, 2H), 7.47-7.38 (m, 3H), 7.12 (d, J=8 Hz, 2H), 5.16 (s, 2H), 4.86 (s, 2H), 3.25 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). LRMS m/z 609 [M−H]−.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[C:31]2[CH:32]=[CH:33][C:34]([C:36](O)=[O:37])=[CH:35][C:30]=2[O:29][CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:36]([C:34]5[CH:33]=[CH:32][C:31]6[O:26][CH2:27][CH2:28][O:29][C:30]=6[CH:35]=5)=[O:37])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)c1ccc2c(c1)OCCO2

Procedure:
The title compound, white solid (28 mg, 69.5%), MS (ISP) m/z=493.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][N:7]=[C:6]2[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]=[C:28]=[S:29])[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][N:7]=[C:6]2[N:14]1[CH2:15][CH2:16][N:17]([C:28](=[S:29])[NH:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19]1
Reactant: COc1cc2c(N3CCNCC3)ncnc2cc1C
Reactant: S=C=NCc1cccnc1
Product: COc1cc2c(N3CCN(C(=S)NCc4cccnc4)CC3)ncnc2cc1C
Yield: 36 %

Procedure:
Substantially the same procedure as in Example 1 was repeated, except that 6-methoxy-7-methyl-4-(1-piperazinyl)quinazoline was used in place of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline, and the corresponding 3-picolyl isothiocyanate was used in place of phenyl isocyanate, to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][OH:14])[CH2:9][CH2:8]1)=[O:5].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.C(OCC)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(N[C@H]1CC[C@H](CO)CC1)c1cc(C(F)(F)F)ccc1Cl
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of trans-2-chloro-N-(4-hydroxymethyl-cyclohexyl)-5-trifluoromethyl-benzamide (step 2) (24 g, 71.5 mmol) in DCM (72 mL) under N2 supply at RT, is added triethylamine (29.7 mL, 214 mmol) followed by DMSO (24 mL), giving an almost homogenous solution. The mixture is cooled to 0° C. (ice/salt bath), and to this is added dropwise a solution/suspension of sulfur trioxide-pyridine complex (34.1 g, 214 mmol) in DMSO (30 mL): DCM (20 mL) over a period of ˜90 min. The mixture is stirred at 0-5° C. over a 1 h period then allowed to warm to RT over 2 h. The mixture is cooled to 0° C. in an ice bath and is quenched by the addition of 1 M HCl (aq) (40 mL) dropwise over 30 min. The mixture is then diluted with water (60 mL) and DCM (150 mL). 2 M HCl is added to give pH ˜1-2. The organic phase is separated, washed again with 2 M HCl (100 mL), followed by sat. NaHCO3 (100 mL). The organic layer is diluted with EtOAc (800 mL) and is vigourously stirred at RT. The mixture is then filtered removing some insoluble material in the process. The now clear two phase mixture is separated, the organic (EtOAc) layer is dried over over MgSO4 and is filtered and concentrated to give an off white solid. The crude solid is suspended in diethylether (500 mL) and is triturated, removing some brown/yellow colour. The solid is allowed to settle, and the liquors are decanted off. The solid is then triturated in iso-hexane (300 mL), using the same procedure twice, then the solid is transferred to a small flask in iso-hexane slurry and is dried in vacuo to give an off-white solid; [MH+334]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([C:32]#[CH:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH2:41][O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45].O>CN(C)C=O>[C:43]([O:42][CH2:41][O:30][C:29](=[O:31])[CH2:28][C@@H:27]([C:32]#[CH:33])[NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])/[CH:15]=[CH:14]/[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH2:19]1)=[O:25])(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#C[C@H](CC(=O)OCOC(=O)C(C)(C)C)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C
Yield: 59.3 %

Procedure:
To a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine (0.5 g) in dimethylformamide (5 ml) was added K2CO3 (75 mg) under stirring at 0° C., stirred for 15 minutes, and pivalic acid iodomethyl ester (0.61 g) in dimethylformamide (3 ml) was added to the mixture. After stirring at room temperature for 1 hour, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over MgSO41 and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with CHCl3:MeOH=(98:2) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine pivaloyloxymethyl ester as a colorless oil (0.37 g, 59.3%).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1[CH:31]=[C:32]([CH:38]=[CH:39][CH:40]=1)/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:35](=[O:36])/[CH:34]=[CH:33]/[C:32]4[CH:38]=[CH:39][CH:40]=[C:30]([F:29])[CH:31]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1cccc(F)c1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2cccc(F)c2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J (0.50 mmol), trans-3-fluorocinnamic acid, by the method of Example 1, step K, giving the title compound as a white solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H35FN4O2: 503 (M+H). Found: 503
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)(OC(C)(C)C)=O.C(Cl)[Cl:23]>C(O)(C(F)(F)F)=O.Cl>[ClH:23].[ClH:23].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2ncccc2o1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2cc([C@@H]3CCCN3)oc2c1
Temperature: 25 °C

Procedure:
A 980 mg sample of 2-(1-BOC-2-(S)-pyrrolidinyl)furo[3,2-b]pyridine, from Example 1d above, was dissolved in a solution of TFA in CH2Cl2 at 0° C. and stirred under N2 while warming to room temperature. The reaction mixture was diluted with 1 N HCl, and the aqueous layer was separated. The aqueous solution was adjusted to pH 10 with K2CO3, and the mixture was extracted with CH2Cl2. The solution was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel and treated with HCl in Et2O as described in Example 1e to obtain 280 mg of title compound: 1H NMR (CDCl3, 300 MHz) δ 2.17-2.52 (m, 3H), 2.65 (m, 1H), 3.57 (dt, 2H, J=1.5, 7.5 Hz), 5.15 (t, 1H, J=8 Hz), 7.44 (s, 1H), 7.84 (dd, 1H, J=6, 8.5 Hz), 8.5 (dt, 1H, J=1, 8.5 Hz), 8.70 (dd, 1H, J=1, 6 Hz). MS m/z: 189 (M+H)+, 206 (M+NH4)+ ; Anal. Calcd for C11H12N2O.2.0 HCl: C, 50.59; H, 5.40; N, 10.73. Found: C, 50.52; H, 5.26; N, 10.50.
Reaction SMILES: C([N:8]([CH2:16][C:17]1[CH:43]=[CH:42][C:20]([C:21]([NH:23][C@@H:24]([CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[CH:39][CH:38]=[CH:37]3)[C:25]([OH:27])=[O:26])=[O:22])=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(OC(C)(C)C)=O.Cl.O1CCOCC1>CO>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@@H:24]([CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[CH:39][CH:38]=[CH:37]3)[C:25]([OH:27])=[O:26])=[O:22])=[CH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)N[C@@H](CCCNc2cccc3cccnc23)C(=O)O)cc1)Cc1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(N[C@@H](CCCNc1cccc2cccnc12)C(=O)O)c1ccc(CNCc2ccccn2)cc1
Reaction time: 2.5 h

Procedure:
The compound obtained in Example 53-3 (19.0 mg) was dissolved in methanol (0.19 ml) and 4 mol/l hydrochloric acid/dioxane (0.19 ml) was added. After 2.5 hours, the reaction solution was concentrated and azeotropically distilled with methanol. The residue was purified by silica gel column chromatography (1 g, chloroform/methanol/water=7/3/0.5). The obtained title compound was dissolved in methanol. Activated carbon (4 mg) was added to the solution, followed by filtration and concentration. After the addition of 1 mol/l hydrochloric acid and a small amount of methanol, the residue was concentrated and dried under reduced pressure to obtain hydrochloride of the title compound (17.9 mg) as a yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]C(=O)C)=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2].[OH-].[K+].O.Cl>CO>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:9][C:8]([OH:15])=[CH:7][C:6]=1[C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
The 1,4-diacetoxy-2,6-di-tert-butylbenzene obtained in Example 11 was dissolved in 60 mL of methanol and the solution was cooled to 20° C.; after adding 3.30 g (50.1 mmol) of potassium hydroxide, the mixture was stirred for 1.5 hours. The mixture was cooled to 10˜15° C. and then 30 mL of water and 12.5 mL of 6 N hydrochloric acid were gradually added. The solution was cooled to 5° C. and stirred for 0.5 hours. The crystal was centrifuged, washed with 10 mL of a methanol/water mixed solvent (methanol/water=1/1) and dried with a through-flow dryer (parallel flow) overnight at 50° C. to give 10.97 g of 4-acetoxy-3,5-di-tert-butylphenol (91.4% in yield from the 2,6-di-tert-butyl-1,4-benzoquinone of Example 10).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[NH:12][C:13]([CH:17]=[O:18])=[C:14]([I:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH3:34][O:33][C:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([CH2:20][N:12]2[C:13]([CH:17]=[O:18])=[C:14]([I:16])[N:15]=[C:11]2[CH2:7][CH2:8][CH2:9][CH3:10])=[CH:22][CH:23]=1)=[O:32]
Reactant: CCCCc1nc(I)c(C=O)[nH]1
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc(I)c(C=O)n1Cc1ccc(C(=O)OC)c2ccccc12
Temperature: 70 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
A suspension of 29.53 g (0.214 mol) of powdered potassium carbonate, 60.00 g (0.214 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde and 65.68 g (0.235 mol) of methyl 4-bromomethylnaphthalene-1-carboxylate (E. A. Dixon, A. Fischer, and F. P. Robinson, Can. J. Chem. 59, 2629 (1981)) in 600 mL of dimethylformamide was stirred for 5 hours under argon at 70° C. An additional 6.56 g (0.0235 mol) of the bromomethyl ester was added and the suspension was stirred an additional 15 hours at 70° C. The reaction mixture was poured into water and the resulting solid was collected by filtration, washed with water, and triturated several times with 250 mL of boiling methanol to give 86.8 g (85%) of a solid; mp 177.5°-179° C.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[NH2:2].[C:5]1([NH:11][C:12]([N:14]2[CH2:18][CH2:17]N[C:15]2=[O:19])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C[Si](C)(C)Cl.C(Cl)(Cl)=O>>[C:5]1([NH:11][C:12]([N:14]2[CH2:18][CH2:17][N:2]([C:1]([Cl:4])=[O:3])[C:15]2=[O:19])=[O:13])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1NCCN1C(=O)Nc1ccccc1
Reactant: NC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(Cl)Cl
Product: O=C(Cl)N1CCN(C(=O)Nc2ccccc2)C1=O

Procedure:
This carbamic acid chloride was produced as described in Example 1 B from 15.0 parts by weight of N-phenylaminocarbonyl-imidazolid-2-one, 15.8 parts by weight of trimethylchlorosilane and 7.2 parts by weight of phosgene. Recrystallization from acetone/pentane.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:13][C:14]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>C(N(CC)CC)C>[C:1]([NH:13][C:14]1[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.55 mL of benzoyl chloride was added to 10 mL of a methylene chloride solution containing 1.0 g of methyl 2-amino-4-bromobenzoate and 0.73 mL of triethylamine while ice-cooled and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 0.9 g of methyl 2-(benzamido)-4-bromobenzoate as while solid.
Reaction SMILES: O[C@@H:2]([CH3:28])[CH2:3][C:4]1[C:5]([C:13](=[N:23][NH:24][C:25](=[O:27])[CH3:26])[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:25]([N:24]1[C@H:2]([CH3:28])[CH2:3][C:4]2[CH:12]=[C:8]3[O:9][CH2:10][O:11][C:7]3=[CH:6][C:5]=2[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[N:23]1)(=[O:27])[CH3:26]
Reactant: CC(=O)NN=C(c1ccc([N+](=O)[O-])cc1)c1cc2c(cc1C[C@H](C)O)OCO2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C[C@H]1C)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
1.05 grams (S)-Acetic acid [[6-[2-[hydroxy]propyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methylene]hydrazide and 0.78 grams triphenylphosphine in 70 mL tetrahydrofuran were cooled to 0° C. 0.57 grams diethyl azodicarboxylate in 5 mL tetrahydro-furan was added dropwise over 15 min. The resulting mixture was stirred for 2 h then warmed to room temperature for 2 h. The mixture was transferred to a separatory funnel and the solution was washed with 1N HCl, water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was eluted through a silica gel column (1:1 ethyl acetate:hexane). Fractions containing the desired compound were concentrated to a yellow oil which solidified on standing. The yellow crystalline material was slurried in 30 mL of CH2Cl2 and hexane (3:7) at 0° C. The precipitate was removed by filtration and the filtrate was concentrated to a yellow foam. The residue was suspended in 10 mL ethanol which was warmed to reflux then slowly cooled to room temperature. The precipitate was collected by filtration and dried in a vacuum oven at 60° C. to give 0.51 grams (50%) of the subtitled product (100% ee) which was 98.3% pure by HPLC potency assay.
Reaction SMILES: [P](I)(I)(I)I.[Cl:6][C:7]1[CH:8]=[C:9]([S:14][C:15]2[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([CH3:23])[C:16]=2[CH:24](O)[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:10]=[C:11]([Cl:13])[CH:12]=1.S(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Cl:13][C:11]1[CH:10]=[C:9]([S:14][C:15]2[N:19]([CH:20]([CH3:21])[CH3:22])[N:18]=[C:17]([CH3:23])[C:16]=2[CH2:24][C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[CH:8]=[C:7]([Cl:6])[CH:12]=1
Reactant: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccncc1
Agent: I[P](I)(I)I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccncc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A solution of 466 mg of phosphorus tetraiodide in 15 mL of benzene was heated at 80° C. for 15 minutes. To this solution was added dropwise a solution of 400 mg of 4-[[5-(3,5-dichloro-phenylsulfanyl)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-hydroxy-methyl]-pyridine in 10 mL of benzene. The mixture was then heated at 80° C. for 1 hour then allowed to cool to room temperature. Then 8 mL of 10% aqueous sodium bisulphite solution was added and the biphasic mixture stirred for 1 hour. The aqueous phase was extracted three times with 30 mL of ethyl acetate and combined extracts were washed with brine, dried, filtered and evaporated to give a yellow residue which was purified by flash chromatography on silica gel using ethyl acetate/hexane (1:1 then 2:1) for the elution to give 238 mg of 4-[5-(3,5-dichloro-phenylsulfanyl)-1-isopropyl-3-methyl-1H-pyrazol-4-ylmethyl]-pyridine as a white solid. Mass spectrum (ES) m/z 392 [M+H]+, 433 [M+H+MeCN]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>O>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(Cl)s1
Yield: 57.5 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5-chloro-2-thiophenecarboxylic acid (9.5 g), N,N'-carbonyldiimidazole (9.5 g) and 2-amino-7-chloro-1,8-naphthyridine (8 g). The product obtained by precipitation in water is purified by recrystallization in propanol (700 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-5-chloro-2-thiophenecarboxamide (8.3 g), m.p. 275° C., is thereby obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[SH:7].[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1>>[Cl:8][C:9]1[N:14]=[C:13]([S:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Sc1ncccn1
Reactant: Clc1ccnc(Cl)n1
Product: Clc1nccc(Sc2ncccn2)n1
Yield: 93.4 %

Procedure:
In a procedure analogous to Example 3, reaction of pyrimidine-2-thiol (415 mg, 3.70 mmol) and 2,4-dichloropyrimidine (500 mg, 3.36 mmol) furnished the product (705 mg, 93%).