Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:22]([CH3:24])[CH3:23])[C:9](/[CH:18]=[CH:19]/[CH2:20][OH:21])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH3:27]I>CN(C)C=O>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:22]([CH3:24])[CH3:23])[C:9](/[CH:18]=[CH:19]/[CH2:20][O:21][CH3:27])=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1/C=C/CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC/C=C/c1c(C(C)C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 112.1 %

Procedure:
To a solution of (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-ol (30 mg) in N,N-dimethylformamide (1 mL) was added 60% sodium hydride in oil (3.8 mg) in an ice-water bath under nitrogen atmosphere. After 20 minutes, to the mixture was added methyl iodide (18.5 mg) at the temperature. After 15 minutes, the reaction mixture was stirred at ambient temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water three times and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=10-1) to give 7-chloro-4-(4-fluorophenyl)-2-isopropyl-3-[(1E)-3-methoxy-1-propenyl]pyrrolo[1,2-b]pyridazine as a brown oil (35 mg, 10.2%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([OH:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+:25].[K+]>CC(C)=O.O>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O-:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4].[K+:25]
Reactant: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)[O-]
Temperature: 25 °C
Yield: 163.7 %

Procedure:
The (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylic acid (4.83 g) prepared in Example 6 or 7 was dissolved in acetone (23 mL), and potassium carbonate (1.11 g) dissolved in water (4.5 mL) was slowly added. The solution was stirred at room temperature until the deposited inorganic salt was dissolved. While the solution was heated at 50° C. in a bath, acetone (100 mL) was dropped and a seed crystal was placed in the solution, and then the solution was stirred for 30 minutes. Acetone (94 mL) was again dropped, and the solution was stirred for 1 hour while the temperature was kept. While gradually cooled to room temperature, the solution was stirred overnight. The precipitated crystalline product was collected by filtration, washed with a mixture of 2% water-acetone (20 mL), dried in air to obtain white solid potassium (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (4.28 g, 81.7%). The NMR data of the solid product were the same as those in Example 11.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O[CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C:19](=[O:25])[CH2:18][CH2:17]4)[CH2:14][CH:13]=[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8]2.C(O)(=O)C.C(O)(=O)C.O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(CC(=O)C[C@@H]1C)=C[C@H]3C>>[C:1]([O:4][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C@@H:19]([OH:25])[CH2:18][CH2:17]4)[CH2:14][CH:13]=[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4CCCC[C@@]43CO)[C@@H]1CCC2=O
Agent: C[C@@H]1C=C2CC(=O)C[C@H](C)[C@]2(CO)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Product: CC(=O)OC[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
Substituting 19-hydroxy-5-androsten-17-one acetate for the 17β,19-dihydroxy-1α,7α-dimethyl-5-androsten-3-one diacetate above, results in the formation of 5-androstene-17β,19-diol 19-acetate.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1CCC(N=C=NC2CCCCC2)CC1.[CH3:31][C:32]([CH3:38])([CH2:36]O)[C:33]([OH:35])=[O:34].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][C:32]([CH3:38])([CH2:36][O:14][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:33]([OH:35])=[O:34]
Reactant: CC(C)(CO)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C(=O)O
Reaction time: 2 h

Procedure:
N-Boc-L-valine (10.8 g, 50 mmole), 4-dimethylaminopyridine (610 mg, 5 mmole) and DCC (6.18 g, 30 mmole) were dissolved in methylene chloride (100 ml). After stirring for 2 hour the mixture was filtered. To the filtrate were added 2,2-dimethyl-3-hydroxy-propionic acid (3.54 g, 30 mmole) and pyridine (10 ml). After 18 hr, the reaction mixture was filtered, and the filtrate was poured into sodium hydrogen carbonate aqueous solution, the organic phase was then washed with citric acid aqueous solution and water succesively. After evaporation the product was isolated with silica gel column chromatography to yield 4.4 g. This compound can be activated and esterified directly to a drug or further modified as described below.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:27]=[C:28]1[NH:32][C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:30][O:29]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:32]3[C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:30][O:29][C:28]3=[O:27])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2S(C)(=O)=O)CC1
Yield: 79.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using 4-(4-bromo-2-methanesulfonylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester (2.24 g) described in Preparation Example 168 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.11 g), the title compound (2.34 g) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[N:7]=1.[CH2:24]([NH2:35])[C:25]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=1>CN1CCCC1=O>[CH3:29][O:28][C:27]1[CH:26]=[C:25]([CH:34]=[CH:33][C:30]=1[O:31][CH3:32])[CH2:24][NH:35][C:2]1[N:3]=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[N:7]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Fc1ccccc1Cn1ccc2c(-c3ccco3)nc(Cl)nc21
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(-c3ccco3)c3ccn(Cc4ccccc4F)c3n2)cc1OC
Temperature: 100 °C
Yield: 88.4 %

Procedure:
A solution of 2-chloro-7-(2-fluorobenzyl)4(2-furyl)-7H-pyrrolo[2,3-d]pyrimidine (254 mg, 0.78 mmol) in N-methylpyrrolidone (2 mL) was treated with veratrylamine (0.25 mL, 1.66 mmol), heated to 100° C. for 16 h and purified by chromatography (Heptane:EtOAc, 4:1) to give the title compound (316 mg, 88%) as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14][O:15][CH3:16].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:16][O:15][CH2:14][CH2:13][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cccc([N+](=O)[O-])c1N

Procedure:
A solution of 5 g 2-Amino-3-nitro-phenol, 4.5 g 1-Bromo-2-methoxy-ethane, 4.4 g K2CO3 in 50 mL DMF were heated to 60° C. for 16 h. Then 50 mL of water were added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over MgSO4, and the solvents were removed under reduced pressure. The remaining product was pure enough for the next reaction step. Yield: 5.8 g.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:12]>>[CH:1]1([C:7]([Cl:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C1CCCCC1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
The mixture of cyclohexylcarboxylic acid (40 g) and SOCl2 (60 mL) was heated at 30° C. for 30 min and then at 50° C. for 3-5 hrs. The volatile materials were removed in vacuum and the residue was used for the next reaction without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=1)[C:9](=[O:11])[CH3:10].[CH2:34]([I:36])[CH3:35]>>[I-:36].[C:9]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=1[CH2:34][CH3:35])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: CCCCCCCCCCCCCCOc1ccc(CN(Cc2ccccn2)C(C)=O)cc1
Reactant: CCI
Product: CCCCCCCCCCCCCCOc1ccc(CN(Cc2cccc[n+]2CC)C(C)=O)cc1
Product: [I-]

Procedure:
The title compound is prepared by the procedure of Example 28 using 0.500 g of product from Example 69 and 4.42 ml of ethyl iodide. The residue is recrystallized from methanol to give 0.554 g of the desired product as yellow crystals.
Reaction SMILES: [Mg].[CH3:2]I.[CH2:4]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]1C(OCC)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C(O[CH2:31][CH3:32])C>O1CCCC1.O.C(OCC)(=O)C>[CH2:4]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:31]([CH3:32])=[CH2:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOCC
Reactant: CCOC(=O)c1cc2cc(OC)ccc2n1Cc1ccccc1
Reactant: CI
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)c1cc2cc(OC)ccc2n1Cc1ccccc1
Yield: 79 %

Procedure:
8.95 g of magnesium was suspended in 160 ml of anhydrous diethyl ether. To the suspension was dropwise added 52.3 g of methyl iodide in 1 hour with stirring under refluxing. The resulting mixture was refluxed for 1 hour. Thereto was dropwise added a solution of 38 g of 1-benzyl-2-ethoxycarbonyl-5-methoxyindole dissolved in 110 ml of anhydrous tetrahydrofuran in 40 minutes at room temperature. The resulting mixture was refluxed for 1 hour and then cooled with ice cooling. Thereto was added 400 ml of ethyl acetate and to the resulting mixture was dropwise added 300 ml of water in 1 minute with stirring at 0° C. The resulting mixture was adjusted to pH 7.0 with diluted hydrochloric acid. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 190 ml of methylene chloride. To the solution was added 29.8 g of triethylamine, and to the resulting mixture was dropwise added 16.9 g of methanesulfonyl chloride in 20 minutes with stirring at 0° C. The resulting mixture was stirred for 20 minutes at room temeprature. The reaction mixture was washed with 1N hydrochloric acid, an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from acetonitrile to obtain 26.8 g (yield: 79%) of 1-benzyl-2-isopropenyl-5-methoxyindole as light yellow crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH2:14][C:15]1([NH2:19])[CH2:18][O:17][CH2:16]1.[S:20]1(=[O:32])(=[O:31])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][NH:23][CH2:22][CH2:21]1>>[NH2:19][C:15]1([CH2:14][NH:13][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:23]3[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:20](=[O:32])(=[O:31])[CH2:21][CH2:22]3)[N:11]=2)[CH2:18][O:17][CH2:16]1
Reactant: NCC1(N)COC1
Reactant: O=S1(=O)CCNCc2ccccc21
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: NC1(CNc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccccc23)COC1

Procedure:
The title compound was prepared in analogy to Example 57-1 in Scheme 23 by using 2,4-dichloroquinazoline, 3-(aminomethyl)oxetan-3-amine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 7.98-7.93 (m, 1 H), 7.91-7.88 (m, 2 H), 7.64-7.60 (m, 1 H), 7.57-7.51 (m, 1 H), 7.48-7.41 (m, 2 H), 7.15-7.11 (m, 1 H), 5.24 (s, 2 H), 4.67-4.54 (m, 6 H), 4.09 (s, 2 H), 3.55-3.50 (m, 2 H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:38])=[C:23]([NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:27])[CH:24]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:38])=[C:23]([NH:25][C:26]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[N:34]=[CH:33][CH:32]=[CH:31]4)=[O:27])[CH:24]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1NC(=O)c1ccc2ncccc2c1
Yield: 49.5 %

Procedure:
Triethylamine (0.28 ml) was added to a stirred mixture of 4-chlorobenzoyl chloride (0.29 g), N-(5-amino-2-methylphenyl)quinoline-6-carboxamide (0.28 g) and methylene chloride (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with water and with methylene chloride. There was thus obtained the title compound as a solid (0.208 g); NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 7.24 (d, 1H), 7.52-7.62 (m, 4H), 7.87 (s, 1H), 7.98 (d, 2H), 8.12 (d 1H) 8.46 (d, 1H), 8.52 (d, 1H), 8.65 (s, 1H) 9.00 (s, 1H), 10.15 (s, 1H) 10.31 (s, 1H); Mass Spectrum: M+H+ 416.
Reaction SMILES: C[O:2][C:3](=[O:25])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([CH3:23])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:24])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[Cl:24][C:14]1[CH:13]=[C:12](/[C:4](=[CH:5]\[CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)/[C:3]([OH:25])=[O:2])[CH:17]=[CH:16][C:15]=1[N:18]1[C:22]([CH3:23])=[N:21][N:20]=[N:19]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCCC2)C(=O)O)cc1Cl
Temperature: 47.5 °C
Yield: 100.9 %

Procedure:
A solution of (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid methyl ester (209 mg, 0.58 mmol) in ethanol (3 mL) was treated with a 1N aqueous sodium hydroxide solution (1.2 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo to remove ethanol, and the residue was diluted with water (10 mL) and extracted with diethyl ether (1×30 mL) to remove any neutral impurities. The aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting acid was extracted into ethyl acetate (2×20 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-2-[3chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid (203 mg, 99%) as a brown solid: FAB-HRMS m/e calcd for C17H19ClN4O2 (M+H)+ 347.1275, found 347.1283.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@@H:13]1[CH2:41][N:16]2[C@H:17]([CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@H:15]2[CH2:14]1.C(N(CC)CC)C.O>ClCCl>[CH:28]([C@H:17]1[N:16]2[CH2:41][C@@H:13]([NH:12][C:2]([O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:3])[CH2:14][C@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H](N)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H](NC(=O)OCc3ccccc3)CN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of benzyl chloroformate (58 μl) in dichloromethane (0.5 ml) was added dropwise to an ice-cooled solution of tert-butyl (4R,7S,8aS)-7-amino-4-benzhydrylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate and triethylamine (96 μl) in dichloromethane (2 ml), and the whole was stirred for 2 hours at the same temperature. The mixture was poured into water and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected to give tert-butyl (4R,7S,8aS)-4-benzhydryl-7-[(benzyloxycarbonyl)amino]hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (190 mg) as a syrup.
Reaction SMILES: [CH2:1]([CH:8]1[NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[S:37](Cl)(=[O:39])=[O:38])[CH:30]=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([CH:8]1[N:15]([S:37]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:36]=2[N:27]=[CH:28][CH:29]=[CH:30]3)(=[O:38])=[O:39])[CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2CCCc3ccccc3CN2)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2CCCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 301 (crude 1.58 mmol), Et3N (0.33 mL, 2.4 mmol) and DMAP (39 mg, 0.32 mmol) in DCM (25 mL), quinoline-8-sulfonyl chloride (538 mg, 2.37 mmol) in DCM (5 mL) was added dropwise at 0° C. After addition was complete, the solution was left to stir at rt overnight. The mixture was washed with water (2×30 mL) and brine. The organic layer was combined, dried over Na2SO4, concentrated in vacuo. MeOH (10 mL) was added to the residue and the precipitation was filtered to give the desired product (60 mg, 81% over three steps). 1H NMR (500 MHz, CDCl3) δ: 9.07 (m, 1H), 8.51 (d, 1H), 8.13 (d, 1H), 7.93 (d, 1H), 7.57 (t, 1H), 7.44 (m, 1H), 7.29 (d, 1H), 7.12 (m, 2H), 6.98 (m, 1H), 6.90 (m, 3H), 6.59 (d, 2H), 5.76 (d, 1H), 5.53 (d, 1H), 4.34 (m, 1H), 3.61 (m, 1H), 2.59 (m, 1H), 2.27 (t, 1H), 2.07 (m, 1H), 1.88 (m, 1H), 1.60 (m, 1H), 1.34 (m, 1H), 1.24 (m, 1H). MS (ESI+) m/z: 443 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(Cl)[Cl:11]>>[Cl:11][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCl
Reactant: Cc1ncccc1CO
Product: Cc1ncccc1CCl

Procedure:
To a stirring solution of crude (2-methylpyridin-3-yl)methanol in 20 mL of CH2Cl2 was added 2.2 mL of SO2Cl2. After 17 h the solution was concentrated and CH2Cl2 and saturated NaHCO3 were added. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1% MeOH/CHCl3) provided 1.18 g of 3-(chloromethyl)-2-methylpyridine as yellow-orange oil.
Reaction SMILES: CO[CH:3]([O:11]C)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[OH-].[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O>[C:15]([NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:11])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(OC)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
1.06 g of 3-aminobenzaldehyde dimethyl acetal was dissolved in a mixture of 5 ml of toluene and 10 ml of water containing 0.8 g of sodium hydroxide, and 5 ml of a toluene solution of 1.3 g of benzoyl chloride was added. The mixture was stirred at room temperature for 2 hours. The organic layer was separated, and evaporated under reduced pressure. The residue was dissolved in a mixture of 10 ml of methanol and 10 ml of 10% hydrochloric acid, and heated at 90° C. for 30 minutes. Water (20 ml) was added to the reaction mixture to allow it to cool. There was obtained 1.16 g (yield 87.3%) of 3-benzoylaminobenzaldehyde as colorless needles having a melting point of 122° to 123° C.
Reaction SMILES: [ClH:1].[O:2]([CH2:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[NH2:3].[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([OH:19])=[O:18])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O>[ClH:1].[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:3][O:2][CH2:4][C:5]2[NH:6][CH:7]=[CH:8][N:9]=2)[C:17]([OH:19])=[O:18])[N:15]=1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Reactant: NOCc1ncc[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1nc(C(=NOCc2ncc[nH]2)C(=O)O)cs1
Reaction time: 12 h

Procedure:
2 g of 2-[(aminoxy)methyl]-1H-imidazolehydrochloride (1:2) from example 1(b) and 2.24 g 2-amino-thiazol-4-glyoxylic acid are suspended with stirring in 50 ml H2O. The pH is adjusted with potassium carbonate to 6 and stirring is continued for 12 hours. The pH is then adjusted to 6.4 with hydrochloric acid. After 2 hours 0.8 of crystalline 2-amino-α-[(1H-imidazol-2-yl-methoxy)imino]-4-thiazole acetic acid hydrochloride (1:2) is filtered off with a melting point of 158°-160° C. (dec.).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]2[CH3:26])=O)=[N:14][CH:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CO>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:18]([C@@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][N:21]3[CH3:26])=[N:17][N:16]=2)[CH:15]=1
Reactant: CN1CCCC[C@H]1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCCC[C@H]1c1nnc2ccc(F)cn12
Reaction time: 1.5 h
Yield: 41.9 %

Procedure:
Hexachloroethane (505 mg, 2.14 mmol) was added portionwise over 5 min at RT to a stirred mixture of Intermediate 120a (270 mg, 1.07 mmol), triethylamine (595 μL, 4.28 mmol) and triphenylphosphine (560 mg, 2.14 mmol) in THF (10 mL). The reaction mixture was stirred for 1.5 h and then diluted with methanol and loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-8% [2M NH3 in MeOH] in EtOAc to give the title compound (105 mg, 42%). 1H NMR (400 MHz, CDCl3): 1.34-1.51 (1H, m), 1.62-1.92 (5H, m), 2.00 (3H, s), 2.20 (1H, td, J=11.4, 3.7 Hz), 3.06 (1H, m), 3.87 (1H, dd, J=10.9, 3.3 Hz), 7.18 (1H, ddd, J=9.8, 7.6, 2.3 Hz), 7.71 (1H, ddd, J=9.9, 5.0, 0.7 Hz), 8.75-7.79 (1H, m).