Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[C:15]1([CH3:26])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[C:23](O)=[O:24]>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:23](=[O:24])/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH3:26])=[N:8]1
Reactant: Cc1ccccc1/C=C/C(=O)O
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: Cc1ccccc1/C=C/C(=O)Nc1ccn(CCCCC(C)(F)F)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-o-tolyl-acrylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=348.28.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:36])[CH2:12][CH:13]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:59][O:60][C:61](=[O:65])[CH2:62][CH2:63][NH2:64].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:59][O:60][C:61](=[O:65])[CH2:62][CH2:63][NH:64][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([C:14](=[O:15])[CH:13]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:29][CH:30]=2)[CH2:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)=[O:36])=[CH:17][CH:18]=1
Reactant: CC(C)(C)c1ccc(C(=O)CC(C(=O)c2ccc(C(=O)O)cc2)c2ccc(OC(F)(F)F)cc2)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ccc(C(=O)C(CC(=O)c2ccc(C(C)(C)C)cc2)c2ccc(OC(F)(F)F)cc2)cc1
Yield: 104.8 %

Procedure:
4-[4-(4-tert-Butylphenyl)-4-oxo-2-(4-trifluoromethoxyphenyl)butyryl]benzoic acid (10.4 g, 20.86 mmol) was dissolved in DMF (150 mL) and added EDAC (5.60 g, 29.20) and HOBt (4.23 g, 31.29 mmol). After ½ h a solution of beta-alanine methyl ester hydrochloride (4.37 g, 31.29 mmol) and DIPEA (5.36 mL, 31.29 mmol) in DMF (20 mL) was added to the above mixture and the reaction mixture was stirred night over. The reaction was concentrated to approximately 100 mL and diluted with water (200 mL) and extracted with ethyl acetate (200 mL). The water phase was extracted with additional ethyl acetate (75 mL). The combined organic phases were washed with hydrochloric acid (0.2 N, 3×150 mL), aqueous sodium chloride (50% saturation, 3×150 mL) and dried over magnesium sulphate. The dried organic phase was filtered and evaporated to dryness to afford 3-{4-[4-(4-tert-butylphenyl)-4-oxo-2-(4-trifluoromethoxyphenyl)butyryl]benzoylamino}propionic acid methyl ester (12.76 g).
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]1[C:13]2[C:12](=[O:14])[N:10]([CH3:11])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[CH:5]1.[Cl:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][CH:21]=1.O>C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([O:18][CH2:17][CH:2]([OH:1])[CH2:3][N:4]2[C:13]3[C:12](=[O:14])[N:10]([CH3:11])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=3[N:6]=[CH:5]2)=[O:27])=[CH:22][CH:21]=1
Reactant: Cn1c(=O)c2c(ncn2CC(O)CO)n(C)c1=O
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Cn1c(=O)c2c(ncn2CC(O)COC(=O)COc2ccc(Cl)cc2)n(C)c1=O
Yield: 79 %

Procedure:
27.0 g (0.1 mol) 7-(2,3-dihydroxypropyl)-theophylline and 18.6 g (0.1 mol) p-chlorophenoxyacetic acid were heated in 100 ml xylene for 8 hours in a water separator with the addition of 0.9 g p-toluenesulfonic acid. After cooling down, the xylene was decanted and the residue dissolved in hot isopropanol. After addition of a little water the monoester crystallized out slowly. The yield was 33.4 g (79% yield) of 1-(7-theophyllinyl)-2-hydroxy-3-propyl (p-chlorophenoxyacetate) with a melting point of 81°-83°C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])=[CH:14][C:13]=3[C:26]#[C:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.C(O)C>C(O)(=O)C.[C].[Pd]>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][C:22]([F:23])([F:24])[F:25])=[O:19])=[CH:14][C:13]=3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:11]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(C#CCCc2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(CCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
To a solution of N-cyclopropyl-1-(2-(4-phenylbut-1-yn-1-yl)-4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxamide (42.8 mg) obtained in Example 384 in acetic acid (7.0 ml)—ethanol (5.0 ml) was added palladium-carbon (20 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 days, and the insoluble material was filtered off. The solvent was evaporated, and the residue was purified by silica gel column (hexane/ethyl acetate=4/1 to 2/3). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (4.3 mg, 10%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][N:10]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]nc(I)c12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.0 g) obtained in Step C of Example 305 in DMF (10 mL) was added sodium hydride (60%, 130 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added trityl chloride (1.1 g) at room temperature, and the mixture was stirred for 15 hr. To the reaction mixture was added water, and the resulting solid was collected by filtration, and dried to give the title compound (1.7 g).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(OC(C)(C)C)=O.[ClH:22].N.CO>C(O)C>[ClH:22].[ClH:22].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCOc1cccnc1
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCO
Product: c1cncc(OCC[C@@H]2CCCN2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound from step 102b above (60 mg, 0.20 mmol) in 3 mL of ethanol at 0° C. was added saturated HCl in ethanol (10 mL), and the reaction mixture was stirred for 30 minutes at 0° C. The volatiles were removed under vacuum, and the residue was purified on a column of silica gel, eluting with methanol/methylene chloride (5:95). The product was treated with a saturated solution of HCl/EtOH and held under vacuum for 24 hours to afford a white solid. MS (DCI/NH3) m/e: 193 (M+H)+, 210 (M+NH4)+. 1H NMR (D2O, 300 MHz) δ: 1.69-1.86 (m, 1H), 1.91-2.20 (m, 3H), 2.26-2.43 (m, 2H), 3.28-3.47 (m, 2H), 3.70-3.85 (m, 1H), 4.27-4.45 (m, 2H), 7.82 (dd, J=8.5, 5.0 Hz, 1H), 7.98 (dd, J=9.0, 4.0 Hz, 1H), 8.35 (d, J=6.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H). Anal. Calc. for C11H16N2O.2.3 HCl: C, 47.84; H, 6.68; N, 10.14; Found C, 47.48; H, 6.92; N, 9.94. [α]25D =+41.62° (c=0.41, methanol).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[CH:35]=[CH:34][N:33]([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[N:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:40][C:39]2[CH:41]=[CH:42][C:36]([N:33]3[CH:34]=[CH:35][C:31]([CH3:30])=[N:32]3)=[CH:37][CH:38]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Cc1ccn(-c2ccc(N)cc2)n1
Product: Cc1ccn(-c2ccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)cc2)n1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(3-methyl-1H-pyrazol-1-yl)aniline in step 1. MS: 407.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]([C:21]1[CH:30]=[CH:29][C:24]([C:25](=[O:28])[CH2:26]Cl)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([CH2:26][C:25]([C:24]3[CH:29]=[CH:30][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=3)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)c1ccc(C(=O)CCl)cc1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Product: CC(C)(C)c1ccc(C(=O)CN2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 4-tert-butyl-phenacyl chloride (2 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[C:47]([O:51][C:52](=[O:74])[C@H:53]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[NH:54][C:55](=[O:64])[C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[CH:58][CH:57]=1)([CH3:50])([CH3:49])[CH3:48].C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>CN(C)C=O>[C:47]([O:51][C:52](=[O:74])[C@H:53]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[NH:54][C:55](=[O:64])[C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH:63][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:58][CH:57]=1)([CH3:49])([CH3:50])[CH3:48]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (210 mg), 4-(aminomethyl)benzoyl-glutamic acid di-t-butyl ester hydrochloride (144 mg), diethylphosphorocyanidate (75 mg) and triethylamine (93 mg) in dimethylformamide (10 ml) was stirred at room temperature for 30 minutes. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:2) to yield the title compound (328 mg, yield 99%) as a colorless wax-like substance.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH3:21])([CH3:18])[CH2:13]1.[CH2:22](I)C>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:19][O:20][CH2:21][CH3:22])([CH3:18])[CH2:13]1
Reactant: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Reactant: CCI
Product: CCOCC1(C)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared according to the procedure described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine except that ethyl iodide was used instead of methyl iodide.
Reaction SMILES: Br[C:2]1[C:3]2[NH:10][CH:9]=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[C:11]([Si](C)(C)C)#[CH:12]>>[C:11]([C:2]1[C:3]2[NH:10][CH:9]=[N:8][C:4]=2[CH:5]=[N:6][CH:7]=1)#[CH:12]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cncc2nc[nH]c12
Product: C#Cc1cncc2nc[nH]c12

Procedure:
The title compound can be synthesized from 7-ethynyl-1H-imidazo[4,5-c]pyridine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 1. 7-ethynyl-1H-imidazo[4,5-c]pyridine is prepared from 7-bromo-1H-imidazo[4,5-c]pyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH:44]1([C:50]([NH:8][C@@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:51])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and cyclohexanoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:12])[C:7]=1[NH:8][CH:9]([CH3:11])[CH3:10].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl>C1(C)C(C)=CC=CC=1>[Cl:12][C:6]1[C:7]([NH:8][CH:9]([CH3:11])[CH3:10])=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:3]=[N:4][CH:5]=1
Reactant: CC(C)Nc1c(Cl)cnnc1Cl
Reactant: C1CNCCN1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CC(C)Nc1c(Cl)cnnc1N1CCNCC1

Procedure:
A mixture of 3,5-dichloro-4-(1-methylethyl)aminopyridazine (PREPARATION 31, 1.77 g) and piperazine (2.96 g) in xylene (18 ml) is refluxed for 40 hr. The mixture is cooled and then treated with concentrated hydrochloric acid (8 ml). After further cooling, a precipitate forms and the organic liquid is separated. The aqueous phase is diluted with an excess of a solution of aqueous sodium hydroxide (10%) and then is extracted with chloroform (3×). The combined organic extracts are washed with water, then saline, dried over sodium sulfate, and concentrated to an oil. The crude product is flash chromatographed on silica gel eluting with methanol. The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.20, 3.04, 3.18, 4.46, 4.73 and 8.50δ; CMR (CDCl3) 24.0, 44.3, 45.9, 50.2, 118.2, 135.8, 148.3 and 155.4δ.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Cl:23][C:24]1[CH:25]=[C:26]([O:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])[CH:27]=[C:28]([Cl:36])[C:29]=1[CH2:30]OS(C)(=O)=O>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([O:37][S:38]([C:41]([F:43])([F:44])[F:42])(=[O:40])=[O:39])[CH:27]=[C:28]([Cl:36])[C:29]=1[CH2:30][CH:10]1[CH2:11][CH2:12][N:8]([CH:5]2[CH2:4][CH2:3][C:2]([F:1])([F:14])[CH2:7][CH2:6]2)[C:9]1=[O:13]
Reactant: CS(=O)(=O)OCc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: O=C1CCCN1C1CCC(F)(F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCC(F)(F)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one (447 mg, 2.2 mmol) in 22 mL dry THF, add 1.76 mL of 2M LDA (1.2 eq.) in THF dropwise at −78° C. Then, add 1.24 g of trifluoro-methanesulfonic acid 3,5-dichloro-4-methanesulfonyloxymethyl-phenyl ester (1.4 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NH4Cl and extract with CH2Cl2. Wash the organic layer with water, then brine, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 376 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][S:4](=[O:8])[N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].I([O-])(=O)(=O)=[O:17].[Na+].Cl>C(#N)C.O>[CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][S:4](=[O:17])(=[O:8])[N:3]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: CC1OS(=O)N(C(=O)OC(C)(C)C)C1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1OS(=O)(=O)N(C(=O)OC(C)(C)C)C1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
tert-Butyl 4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (4.7 g, 20.0 mmol) is dissolved in acetonitrile (50 mL) and H2O (30 mL) is added. The reaction mixture is cooled to 0° C. and sodium periodate (6.4 g, 30.0 mmol) is added. After 5 min, the pH of the mixture is adjusted to 7-8 by addition of saturated Na2HPO4 solution. Then the solution of RuCl3 (42 mg, 0.2 mmol) in H2O (0.5 mL) is added. The pH of the reaction mixture is kept between 6 and 9 by addition of Na2HPO4 solution. After stirring for 2 h, H2O (100 mL) is added and the pH is adjusted to 6 by addition of 2M HCl solution. The mixture is extracted with EtOAc and the organic layer is separated, washed with NaHCO3 and brine. The aqueous layers are back extracted once with EtOAc. Then all organic layers are combined, dried (MgSO4) and concentrated. Purification by flash column chromatography using a gradient elution of 5-80% ethyl acetate/hexanes affords the title compound (4.48 g, 89%).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]([NH:9][C@H:10]([C:15]([O:17]C(C)(C)C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]([S:4][CH2:5][CH:6]([CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(CCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)O
Yield: 73 %

Procedure:
The higher RfTLC fraction product of N-(2-acetylthiomethyl-4-phenylbutanoyl)-(L)-leucine, t-butyl ester (1.90 g, 4.5 mmole) was dissolved in 5 mL of trifluoroacetic acid (TFA) and 420 mg anisole at 0° C. for 18 h. No starting material was observed by TLC. The TFA was azeotroped off under reduced pressure with benzene. The product was suspended in hexane and filtered to remove the anisole. Recovered 1.2 g of N-(2-acetylthiomethyl-4-phenylbutanoyl)-(L)-leucine (73% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:10]([O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])=[C:26]([Cl:38])[CH:25]=1>>[ClH:2].[C:28]([C:27]1[CH:36]=[CH:37][C:24]([NH:23][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:10]([O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:25][C:26]=1[Cl:38])(=[O:29])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: Nc1ccc(C(=O)c2ccccc2)c(Cl)c1
Agent: Cl
Product: COCCOc1cc2ncnc(Nc3ccc(C(=O)c4ccccc4)c(Cl)c3)c2cc1OCCOC
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6,7-di-(2-methoxyethoxy)quinazoline hydrochloride was reacted with 4-amino-2-chlorobenzophenone to give 4-(4-benzoyl-3-chloroanilino)-6,7-di-(2-methoxyethoxy)quinazoline hydrochloride salt in 32% yield, m.p. 242°-244° C.;
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[N:7][N:8]=1.[CH2:18]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21]>O1CCCC1>[CH2:18]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[N:7][N:8]=2)=[O:34])=[CH:36][CH:37]=1)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21]
Reactant: CCN(CC)CCCSc1nnc(N)s1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCCSc1nnc(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.3 %

Procedure:
Sodium hydride (0.4 g) and 2-amino-5-diethylaminopropylthio-1,3,4-thiadiazole (1.5 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.8 g) and carbonyldlimidazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 3.1 g of the aimed compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:10]([Cl:11])=[C:9]([C:12]([OH:14])=O)[S:8][N:7]=1>CN(C)C=O>[Cl:5][C:6]1[C:10]([Cl:11])=[C:9]([C:12]([Cl:3])=[O:14])[S:8][N:7]=1
Reactant: O=C(O)c1snc(Cl)c1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1snc(Cl)c1Cl
Temperature: 25 °C
Yield: 125.1 %

Procedure:
At room temperature, 146 g (1.23 mol) of thionyl chloride are added dropwise with stirring over a period of 5 minutes to 8.92 g (0.045 mol) of 3,4-dichloro-isothiazole-5-carboxylic acid. Four drops of dimethylformamide are then added and the reaction mixture is heated under reflux for one hour. The reaction mixture is subsequently cooled to room temperature and concentrated under reduced pressure. In this manner, 12.19 g of 3,4-dichloro-isothiazole-5-carbonyl chloride are obtained in the form of an orange oil.
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=O)(C)(C)C.[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH2:27])=[CH:25][C:20]=2[O:19][CH2:18]1>>[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][NH:27][C:10]([C@@H:9]3[CH2:13][C:14](=[O:16])[CH2:15][NH:8]3)=[O:12])=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Product: O=C1CN[C@H](C(=O)NCc2ccc3c(c2)OCO3)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-oxoproline, and 1,3-benzodioxol-5-ylmethylamine the title compound was obtai-ned in 71% purity by LC/MS. MS(ESI+): m/z=263.0.