Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH:13]1([CH2:16][OH:17])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>ClCCl>[CH:13]1([CH2:16][O:17][C:2]([N:37]2[CH2:38][CH2:39][N:34]([C:32]([O:31][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:33])[CH2:35][CH2:36]2)=[O:4])[CH2:15][CH2:14]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: OCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.3 g triphosgene and 2 g Cyclopropyl-methanol in 40 ml dichloromethane were added 9.1 ml DIPEA dropwise at 0° C. After 1 h, 5.1 g Piperazine-1-carboxylic acid tert-butyl ester and 4.5 ml DIPEA in 7 ml were added at 0° C. The reaction mixture was allowed to warm to RT and stirred for 16 h. Excess triphosgene was destroyed by adding a solution of 2 g NaOH in 120 ml water and stirring for 2 h. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with 1M aqueous hydrochloric acid, dried over MgSO4 and concentrated. The crude product thus obtained was purified was used in the next reaction step. Yield: 7.9 g.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([O:14][CH2:15][C:16]2[N:17]([CH3:28])[N:18]=[N:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:10][N:9]=1)=[O:7]>O.C1COCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[N:19]=[N:18][N:17]([CH3:28])[C:16]=2[CH2:15][O:14][C:11]2[N:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1cnc(OCc2c(-c3ccc(F)cc3)nnn2C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A solution of lithium hydroxide monohydrate (107 mg, 2.55 mmol) in water (3.2 mL) was added dropwise to a suspension of 5-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (438 mg, 1.27 mmol) in THF (1.8 mL). The reaction mixture was then stirred at room temperature for 1 h and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (403 mg, 96%) as a white solid. MS: m/e=328.1 [M−H]−.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30](=[O:37])[CH2:29][CH2:28][C:27]1=[O:38]>>[ClH:21].[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30](=[O:37])[CH2:29][CH2:28][C:27]3=[O:38])[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN3C(=O)CCC(=O)c4ccccc43)CC2)n1
Product: Cl

Procedure:
Analogously to Example 3b, reaction of 2-tert-butyl-4-cyclobutyl-6-piperazin-1-ylpyrimidine (1.97 mmol, 0.54 g) with 1-(4-chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione afforded 0.39 g of the title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:19])[CH2:8]/[CH:9]=[CH:10]/[C@H:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni].C(OCC)(=O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C@H:11]([CH3:18])[CH2:10][CH2:9][CH2:8][C@@H:7]([CH3:19])[CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:17]
Reactant: [H][H]
Reactant: CCOC(=O)C[C@@H](C)/C=C/C[C@@H](C)COC(C)(C)C
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](C)CCC[C@@H](C)COC(C)(C)C

Procedure:
A mixture of 1.104 g. (4.084 mmoles) of (3R,7R)-E-Ethyl 8-tert. butoxy-3,7-dimethyl-4-octenoate, a small amount of Raney nickel, and 30 ml. of ethyl acetate was stirred in an atmosphere of hydrogen, at room temperature, for 2 hours during which time approximately one equivalent ofhydrogen was taken up. The catalyst was filtered off and washed with ethyl acetate. Concentration of the combined filtrate and washes in vacuo followed by evaporative distillation afforded 1.045 g. (95%) of saturated ester (3S, 7R)-Ethyl 8-tert. butoxy-3,7-dimethyloctanoate as a colorless oil, b.p. 80°-83° C. (bath temperature) (0.15 mm Hg.).
Reaction SMILES: [C:1]([O:18][CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH3:27])[C:21]([CH3:29])([CH3:28])[CH2:20]1)(=[O:17])[CH2:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1)=[O:4].[H-].[Na+].[H][H].[CH2:34](Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1>[CH2:34]([C:2]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:1]([O:18][CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH3:27])[C:21]([CH3:29])([CH3:28])[CH2:20]1)=[O:17])[C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7]1)=[O:4])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN1C(C)(C)CC(OC(=O)CC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Reactant: [H][H]
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1C(C)(C)CC(OC(=O)C(Cc2ccccc2)(Cc2ccccc2)C(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Reaction time: 1 h

Procedure:
205 g of bis-(1,2,2,6,6-pentamethyl-4-piperidinyl) malonate, prepared according to known methods, are heated with 12 g of sodium hydride in 500 ml of absolute toluene for 6 hours under reflux. After this time the evolution of hydrogen has ceased and virtually no particles of sodium hydride can be detected in the reaction mixture. The mixture is cooled to 50°, 63 g of benzyl chloride are added dropwise in about 30 minutes and the mixture is then stirred for 1 hour under reflux. It is then again cooled to about 50°, a further 12 g of sodium hydride are added and the mixture is heated under reflux until the evolution of hydrogen has completely ceased (about 6 hours). It is then again cooled to 50°, 63 g of benzyl chloride are added dropwise in about 30 minutes and the mixture is then stirred for 3 hours under reflux. The reaction solution is washed with three times 200 ml of water, dried over sodium sulphate and evaporated. Crystallisation of the residue from hexane gives bis-(1,2,2,6,6-pentamethyl-4-piperidinyl) dibenzylmalonate (compound 7) which has a melting point of 121°-122°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11]Cl.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCOc1ccccc1Br
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccccc3Br)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-bromo-2-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, 1H, J=1.6, 7.9 Hz), 7.48 (s, 1H), 7.32 (m, 1H), 7.28–7.22 (m, 3H), 7.17 (s, 1H), 6.98 (d, 1H, J=7.7 Hz), 6.93 (dd, 1H, J=1.4, 8.4 Hz), 6.82 (dt, 1H, J=7.6, 1.4 Hz), 4.11 (t, 2H, J=6.3 Hz), 3.07 (d, 2H, J=11.3 Hz), 2.61 (t, 2H, J=6.9 Hz), 2.50 (m, 3H), 2.07 (m, 1H), 1.8–1.75 (m, 5H), 1.25 (d, 6H, J=6.7 Hz); Anal. Calcd for C24H31BrN2O2.HCl+0.2 CHCl3: C, 55.9; H, 6.24; N, 5.39. Found: C, 55.8; H, 6.23; N, 5.47; ESMS m/e: 459.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][CH:5]([OH:8])[CH2:6][N:7]=1.S(Cl)(Cl)=O.[C:13](O)(=[O:15])[CH3:14]>>[CH3:1][C:2]1[NH:7][CH2:6][CH:5]([O:8][C:13](=[O:15])[CH3:14])[CH2:4][N:3]=1
Reactant: CC(=O)O
Reactant: CC1=NCC(O)CN1
Solvent: O=S(Cl)Cl
Product: CC(=O)OC1CN=C(C)NC1

Procedure:
2-Methyl-5-hydroxy-1,4,5,6-tetrahydropyrimidine (JOC 1966, 31, 3838; 1.5 g, 13.3 mmol) was dissolved in glacial acetic acid (100 ml) with stirring, and thionyl chloride (1 ml, 13.1 mmol) was added dropwise. The resulting solution was refluxed 19 hours, then evaporated to dryness in vacuo. The residue was taken up in water (5 ml), the pH adjusted to 9 (sat. Na2CO3), extracted with chloroform and the organics discarded. The aqueous layer was then adjusted to pH 12 (sat. NaOH) and extracted with chloroform. The chloroform was dried (MgSO4) and evaporated in vacuo to 575 mg (28%) white crystals, mp 141°-146° C. 400 MHz nmr confirmed the product calculated: C 53.82, H 7.75, N 17.94; found: C 53.9, H 7.73, N 17.77.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[S:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(O)=O.[N:17]([O-])=[O:18].[Na+]>O>[CH3:1][C:2]1[C:12]2[S:11][CH2:10][CH2:9][CH2:8][N:7]([N:17]=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1cccc2c1SCCCN2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2c1SCCCN2N=O
Temperature: 23 °C

Procedure:
To a solution of 9-methyl-2,3,4,5-tetrahydro-1,5-benzothiazepine (500 mg, 2.6 mmol) and AcOH (2 mL) cooled to ˜9° C. was added a solution of NaNO2 (212 mg, 3.1 mmol) and water (1 mL) dropwise over 4 min (internal temperature<12° C.). The cooling bath was removed and the reaction was maintained at 23° C. for 2 h. It was diluted with H2O (50 mL). 9-methyl-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine was obtained (470 mg, 87%) as a yellow solid after it was collected by vacuum filtration and air-dried at 23° C.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:13][C:7]1[C:8]([F:9])=[C:2]([F:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(F)c(F)c1Cl
Reaction time: 48 h

Procedure:
2-Chloro-3,4-difluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell et al. (Mitchell, R. H. et al., J. Org. Chem. 44:4733 (1979)). To a solution of 4,5-difluoro-2-nitroaniline (500 mg, 2.87 mmol) in DMF (16 mL) under N2 was added N-chlorosuccinimide (401 mg, 3.00 mmol) in DMF. The reaction was allowed to stir 48 h. The solution was then poured into 75 mL H2O. the cloudy orange suspension which formed was then extracted with 4×25 mL of methylene chloride. The combined organic extracts were washed with 5×20 mL of H2O and 25 mL sat'd NaCl solution. The organic phase was dried (MgSO4) and the drying agent removed by vacuum filtration. The solvent was rotary evaporated to yield a yellow orange oil which crystallized on standing. 1H NMR showed this solid to be mixture of chlorinated product and starting material. The mixture was separated by flash chromatography (silica gel, 3:1 hexanes:ethyl acetate) to yield 162 mg of a yellow crystalline solid (27%). 1H NMR (CDCl3) δ6.60 (br s, 2H, NH2), 8.00 (m, 1H, H-5). There was 17% starting material contamination by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH:14]=O)[CH:10]=[CH:11][C:5]=2[CH:4]=1.[NH2:21][CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:21][CH:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC=O)C=C2
Reactant: NC1CCc2ccccc2C1
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNC1CCc3ccccc3C1)CC2

Procedure:
Here, 3-[7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-propionaldehyde (1.5 g, 0.0054 mol) and 2-amino-1,2,3,4-tetrahydronaphthalene (0.8 g, 0.0054 mol) are hydrogenated in ethanol (150 ml) in the presence of 10% palladium/charcoal (0.5 g) for 15 hours under pressure (5 bar) at 60° C. The catalyst is removed by suction filtering, the filtrate is concentrated in vacuo and the residue is purified over silica gel by column chromatography with methylene chloride and increasing amounts of ethanol (up to 4%). The clean fractions are concentrated by evaporation and the hydrochloride is precipitated from acetone. Yield: 1.35 g. Mp: 229°-230° C.
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+:4].[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)[CH3:6]>C(O)=O>[CH:1]([NH:4][CH:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6])=[O:3]
Reactant: [NH4+]
Reactant: CC(=O)c1ccccc1
Reactant: O=C[O-]
Solvent: O=CO
Product: CC(NC=O)c1ccccc1
Reaction time: 3 h

Procedure:
In the same manner as in Example 1 except that a mixture of formic acid, ammonium formate and acetophenone was heated with stirring at 160° C. for 6 hours in place of the concurrent addition of acetophenone and formic acid to ammonium formate for 3 hours and keeping the mass after the addition stirred for 3 hours, the reaction and post treatment were carried out to obtain 112 g of crude N-formyl-1-phenylethylamine; the purity: 82.7%
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[CH:41]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[Cl:46][C:42]1[CH:41]=[C:40]([CH:45]=[CH:44][CH:43]=1)[CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: Clc1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cc2cccc(Cl)c2)cc1O

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-chlorophenyl)methyl]pyridazine (Intermediate 48) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[OH:22])[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:21]([O:22][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[C:12]([Cl:11])[CH:13]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc(Br)cc2C=O)c(Cl)c1

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with methyl 3-chloro-4-hydroxybenzoate (4 g, 21 mmol)(Lancaster) and K2CO3 in N,N-dimethylacetamide to give 4-(4-bromo-2-formyl-phenoxy)-3-chloro-benzoic acid methyl ester as an off white solid (Yield 3.7 g, 50%).
Reaction SMILES: [F-:1].[K+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCCCCCCCCC.Cl[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N+:35]([O-:37])=[O:36]>>[F:1][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N+:35]([O-:37])=[O:36].[N+:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=1)([O-:37])=[O:36]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [F-]
Agent: CCCCCCCCCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1ccccc1F
Temperature: 145 °C
Reaction time: 24 h
Yield: 0.4 %

Procedure:
Potassium fluoride (69.6 g; 1.2 mole) and undecyltributylammonium bromide (25.2 g; 0.06 mole) were added to molten 2-chloronitrobenzene (157.5 g; 1.0 mole). After stirring at 145° C. for 24 hours and a similar work-up to Example 1, 2-fluoronitrobenzene was obtained in 84.6% yield, together with 0.4% nitrobenzene.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:24]([O-:26])=[O:25])=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:5]([C:10]2[N:14]=[C:13]([CH3:15])[O:12][N:11]=2)=[CH:6][C:7]=1[O:8]C.C(OCC)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>N1C=CC=CC=1>[OH:1][C:2]1[C:3]([N+:24]([O-:26])=[O:25])=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:5]([C:10]2[N:14]=[C:13]([CH3:15])[O:12][N:11]=2)=[CH:6][C:7]=1[OH:8]
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1nc(-c2cc(O)c(O)c([N+](=O)[O-])c2C(=O)c2ccccc2)no1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
To a mixture of [3-hydroxy-4-methoxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone (reference example 22-1) (377 mg) and ethyl acetate (10.6 mL) were added aluminum chloride (361 mg) and pyridine (0.387 mL). The mixture was refluxed for 2.5 hours. After cooling to room temperature, 1 mol/L hydrochloric acid was added to the mixture. The separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane:methylene chloride=4:1 to give the title compound (317 mg) as an amorphous.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[N:13]([C:27](=[O:28])[NH:26][CH2:24][CH3:25])[N:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CSc1ccc2c(c1)C(c1ccc(NC(C)=O)cc1)=NNC2C
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)N1N=C(c2ccc(NC(C)=O)cc2)c2cc(SC)ccc2C1C
Yield: 50 %

Procedure:
To a solution of dihydrophthalazine 8 in chloroform was added ethyl isocyanate (3 eq) at room temperature. The resulting solution was stirred at such temperature for a few days until there is no starting material left from TLC. The solvent was removed under reduced pressure. Purification of the crude product by using a silica gel gave the desired products 9 (Yield: 50%). 1HNMR (CDCl3): 7.70−7.55 (m, 5H), 7.35 (dd, J=4.3 Hz, 1H), 7.19 (m, 2H), 6.53 (br, 1H), 5.73 (q, J=13.2 Hz, 1H), 3.42 (m, 2H), 2.40 (s, 3H), 2.25 (s, 3H), 1.22 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:20](O)[C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=1[F:29])[CH2:10][C:11]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=1[F:29])[CH2:10][C:11]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OC1CCCCC1)C(O)c1cc(F)c(F)cc1F
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OC1CCCCC1)Cc1cc(F)c(F)cc1F
Yield: 79 %

Procedure:
In accordance with the method described in Example 6, except that 43.14 g (3S)-cyclohexyl 3-(tert-butoxycarbonylamino)-4-hydroxy-4-(2,4,5-trifluorophenyl)butyrate and an equal amount of anhydrous ethanol were used to replace (3S)-3-(tert-butoxycarbonylamino)-4-hydroxy-4-(2,4,5-trifluorophenyl)n-butyl ester and methanol respectively, 32.82 g (R)-cyclohexyl 3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyrate (yield: 79%) was obtained using the same method.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2nc(N)sc2c1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
2-Amino-6-nitrobenzothiazole (500 mg, 2.56 mmol) was dissolved in methanol (20 mL) and 10% palladium on carbon (50 mg) was added as a slurry in methanol (1 mL). The atmosphere was replaced with hydrogen and the suspension was stirred overnight. The catalyst was removed by suction filtration and the solvent evaporated to afford 2,6-diaminobenzothiazole (420 mg, 99%) as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[NH4+].[Cl-]>CO.O.[Zn]>[NH2:14][C:9]1[CH:10]=[N:11][N:12]([CH3:13])[C:8]=1[N:6]1[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH:2]([CH3:1])[CH2:7]1
Reactant: CC1CN(c2c([N+](=O)[O-])cnn2C)CCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CC1CN(c2c(N)cnn2C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 142.9 %

Procedure:
To a solution of tert-butyl (±)-2-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazine-1-carboxylate (500 mg, 1.54 mmol) in MeOH (20 mL) and H2O (5 mL) was added zinc (845 mg, 13 mmol) and NH4Cl (1.4 g, 26 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and filtered through Celite. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography PE/EtOAc (10/1˜1/10) as eluting solvents to give tert-butyl (±)-4-(4-amino-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (650 mg, ˜100%) as red solid. 1H NMR (500 MHz, CD3OD) δ (ppm): 7.22 (s, 1H), 4.35-4.33 (m, 1H), 4.12-4.11 (m, 1H), 3.94 (s, 3H), 3.43-3.46 (m, 1H), 3.25-3.30 (m, 2H), 3.01-3.00 (m, 1H), 2.89-2.87 (d, J=12 Hz, 1H), 1.49 (s, 9H), 1.34-1.36 (d, J=5.6 Hz, 3H); MS (ESI) m/z=296 (M+H+).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:10][OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+]>ClCCl>[S:23]([O:11][CH2:10][CH2:9][C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:7]=1)(=[O:25])(=[O:24])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccc(N2CCCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(N2CCCC2)c1
Reaction time: 8 h

Procedure:
3-Pyrrolidinophenethyl alcohol was dissolved in dichloromethane (20 ml). Triethylamine (3.7 ml, 26.7 ml) and methanesulfonyl chloride (1.9 ml, 24.5 mmol) were added to the obtained solution at 0° C., and they were stirred overnight. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (7:3), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain 3-pyrrolidinophenethyl mesylate in the form of a white solid (5.13 g, 87%).
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]=[C:14](/[CH:16]=[CH:17]/[C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:23](=[O:36])[CH:22]=[CH:21]4)[O:13][N:12]=2)=[CH:6][C:5]=1[CH3:37].[N+](=[CH2:41])=[N-]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]=[C:14]([C@@H:16]3[CH2:41][C@H:17]3[C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:23](=[O:36])[CH:22]=[CH:21]4)[O:13][N:12]=2)=[CH:6][C:5]=1[CH3:37]
Reactant: C=[N+]=[N-]
Reactant: Cc1cc(Nc2noc(/C=C/c3ccc4c(ccc(=O)n4COCC[Si](C)(C)C)c3)n2)ccc1OC(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: Cc1cc(Nc2noc([C@@H]3C[C@H]3c3ccc4c(ccc(=O)n4COCC[Si](C)(C)C)c3)n2)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of (E)-6-(2-(3-((4-(difluoromethoxy)-3-methylphenyl)amino)-1,2,4-oxadiazol-5-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (65 mg, 0.120 mmol) in diethylether (20 mL) were added palladium (II) acetate (2.70 mg, 0.012 mmol) and a diazomethane solution [prepared from N-nitroso-N-methylurea (62.0 mg, 0.601 mmol) and KOH (33.7 mg, 0.61 mmol)]. The reaction was stirred at room temperature overnight, The reaction mixture was filtered through celite and concentrated to give trans-6-(2-(3-((4-(difluoromethoxy)-3-methylphenyl)amino)-1,2,4-oxadiazol-5-yl)cyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)quinolin-2(1H)-one (45 mg, 67%). LCMS, RT 2.25 min; LCMS (ES-API), m/z 555.