Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32]>>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:8]3[C:7]4[CH2:6][CH2:5][O:4][C:12]=4[CH:11]=[CH:10][N:9]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:32]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(Cl)cc1Cl

Procedure:
The title compound, white solid (92 mg, 73%), MS (ISP) m/z=503.2 [(M+H)+], mp 203.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 2,4-dichloro-benzoic acid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:10](O)[CH2:11][CH2:12][CH3:13].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:1]([N:3]([CH2:10][CH2:11][CH2:12][CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCNc1ccccc1
Reactant: CCCCO
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCCCN(CC)c1ccccc1
Yield: 69 %

Procedure:
182 parts of N-ethylaniline, 150 parts of n-butanol and 10 parts of triphenyl phosphite are heated for 20 hours at 230° C in a stirred autoclave. The autoclave is then let down and the water of reaction formed, unconverted ethylaniline and excess alcohol are distilled off. 183 parts of N-ethyl-N-butyl-aniline, corresponding to a yield of 69% of theory, distil at a boiling point of 88° - 91° C/5 mm Hg.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[O:11][C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:15]([C:12]1[O:11][C:10]([CH2:9][CH2:8][NH2:7])=[N:14][N:13]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1nnc(CCNC(=O)OC(C)(C)C)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nnc(CCN)o1

Procedure:
4.00 g (15.67 mmol) tert-butyl[2-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-ethyl]-carbamate and 20 ml trifluoroacetic acid are stirred in 200 ml dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is made basic and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([N:22]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)[CH:19]=[CH:20][CH:21]=1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)[CH:17]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: Nc1cccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)c1
Yield: 84.4 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and 1-(3-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:25]([C:38]#[N:39])[CH:24]=2)=[O:22])=[CH:6][CH:5]=1.B(Cl)(Cl)[Cl:41]>ClC(Cl)C>[ClH:41].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=3[C:11]=2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)=[C:25]([C:38]#[N:39])[CH:24]=2)=[O:22])=[CH:6][CH:5]=1
Reactant: ClB(Cl)Cl
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)c(C#N)c2)cc1
Agent: Cl
Solvent: CC(Cl)Cl
Product: N#Cc1cc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)ccc1OCCN1CCCCC1

Procedure:
The title compound was prepared by dissolving 1.6 g (3.04 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]3-cyanophenyl]methanone hydrochloride in 20 mL of dichloroethane. 2.1 mL of condensed BCl3 was added and sealed in a vessel at room temperature. The reaction was allowed to proceed for sixteen hours. The reaction was quenched by pouring onto ice. The crude product was collected in the organic layer and evaporated to a solid. The product was further purified by chromatography and the hydrochloride prepared as in Preparation 1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1F>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc(C(F)(F)F)ccc2Br)CC1
Temperature: 180 °C

Procedure:
A microwave vial was charged with 1-methylpiperazine (1.371 mL, 12.35 mmol) and 4-bromo-3-fluorobenzotrifluoride (1.000 mL, 4.12 mmol), and was heated under microwave irradiation at 180° C. for 90 minutes. The reaction was concentrated under a vacuum, and the solids were then filtered and washed with DCM (solids contained only minor amounts of product). The filtrate was then concentrated under a vacuum to yield 1-(2-bromo-5-(trifluoromethyl)phenyl)-4-methylpiperazine, mixed with starting bromide. Material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][OH:23])[CH2:10][C:11]([N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:10][C:11]([N:13]([CH3:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Yield: 100 %

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-methyl-N-phenylbenzenepropanamide (0.9 g) in CH2Cl2 (25 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (0.332 g), and methanesulfonyl chloride (0.365 g). After two hours the reaction mixture was washed with water (3×20 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (1.1 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([S:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH3:8].[OH-].[Na+].O>O1CCCC1>[CH2:7]([S:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCSc1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccc(CO)cc1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
The starting 4-(ethylthio)benzyl alcohol was prepared as follows. A mixture of lithium aluminum hydride (5.2 g) and tetrahydrofuran (250 mL) was cooled to 0° C. with stirring under N2 atmosphere. A solution of 4-(ethylthio)benzoic acid (25 g) in tetrahydrofuran (300 mL) was added at a rate so as to control H2 evolution. The reaction mixture was then allowed to warm to room temperature and stirred 15 hours. The mixture was cooled in ice and a solution of 15% aqueous sodium hydroxide solution was added, (6 mL) followed by water (21 mL). The mixture was stirred at ice temperature for 1 hour and for 2 hours at ambient temperature. The solution was decanted, diluted with diethyl ether and washed with saturated aqueous NaCl solution. The organic phase was dried over MgSO4, filtered through a celite pad and concentrated to give 4-(ethylthio)benzyl alcohol (20 g). This material was converted to the corresponding bromide as in Example 1 except that diethyl ether and hexane were used for the triturations rather than heptane and petroleum ether, respectively.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[O-]CC.[K+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20](C)[C:19]=1[CH3:25])([O-:17])=[O:16]>CCOCC>[CH3:25][C:19]1([CH2:2][C:1]([OH:8])=[O:7])[C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=[CH:21][CH2:20]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC1(CC(=O)O)CC=CC=C1[N+](=O)[O-]
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL of dry ether was added with stirring to 19 g of potassium ethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternately with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered off and the filtrate acidified with 6 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 1-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:35][C:5]2[C:6]3([CH2:16][CH2:15][N:14]([CH2:17][C:18]4[C:19]([C:30](OCC)=[O:31])=[N:20][N:21]([C:23]5[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=5)[CH:22]=4)[CH2:13][CH2:12]3)[O:7][CH2:8][C:9]([F:11])([F:10])[C:4]=2[CH:3]=1.[BH4-].[Li+]>O1CCCC1.C(O)C>[Cl:1][C:2]1[S:35][C:5]2[C:6]3([O:7][CH2:8][C:9]([F:11])([F:10])[C:4]=2[CH:3]=1)[CH2:12][CH2:13][N:14]([CH2:17][C:18]1[C:19]([CH2:30][OH:31])=[N:20][N:21]([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:22]=1)[CH2:15][CH2:16]3
Reactant: CCOC(=O)c1nn(-c2ncccc2Cl)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1nn(-c2ncccc2Cl)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
To a solution of ethyl 4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-1-(3-chloro-2-pyridyl)-1H-pyrazole-3-carboxylate (0.4 g, 0.73 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) is added lithium borohydride (1.80 mL, 2.0 M solution in tetrahydrofuran, 3.68 mmol) at 0° C. and stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude mixture is purified by column chromatography over silica gel eluting with dichloromethane/methanol (97:3) to yield 0.14 g (39%) of the title compound. MS (m/z): 500 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([C:13]([N:15]2[CH2:22][CH2:21][C@:20]3([CH3:26])[C:23]([CH3:25])([CH3:24])[C@H:16]2[CH2:17][C:18]2[C:30]([OH:31])=[CH:29][CH:28]=[CH:27][C:19]=23)=[O:14])[CH2:9][CH2:8]1)=[O:6].Cl.C(OCC)(=O)C>CO>[OH:31][C:30]1[C:18]2[CH2:17][C@@H:16]3[C:23]([CH3:25])([CH3:24])[C@:20]([CH3:26])([C:19]=2[CH:27]=[CH:28][CH:29]=1)[CH2:21][CH2:22][N:15]3[C:13]([C@@H:10]1[CH2:11][CH2:12][C@H:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]1)=[O:14]
Reactant: COC(=O)[C@H]1CC[C@@H](C(=O)N2CC[C@@]3(C)c4cccc(O)c4C[C@@H]2C3(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@H]1CC[C@@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 M aqueous NaOH solution (3.5 mL) is added to a solution of cis-4-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carbonyl]-cyclohexane carboxylic acid methyl ester (1.2 g) in methanol (20 mL). The resulting solution is stirred at room temperature overnight. Then, 4 M hydrochloric acid is added, the resulting mixture is extratced with ethyl acetate, and the combined extratcs are dried (Na2SO4). After removal of the solvent, the residue is triturated with a mixture of acetonitrile and ether.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)([O-:18])=[O:17]>C(Cl)Cl>[CH3:8][O:9][CH:10]1[CH2:15][CH2:14][N:13]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][C:21]=2[C:29]([F:30])([F:31])[F:32])(=[O:27])=[O:26])[CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(C(F)(F)F)c1
Reactant: COC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.0 g) and 4-methoxypiperidine (1.15 g) were added to a solution of 4-nitro-2-trifluoromethylbenzene sulphonyl chloride (2.89 g) in methylene chloride (40 ml). The mixture was stirred at 25°C. for 2 hours and then evaporated to dryness in vacuo. The residual oil was triturated with 1:1 aqueous isopropanol and the resulting solid was recrystallized from isopropanol to give 1-(4-methoxypiperidinosulphonyl)-4-nitro-2-trifluoromethyl-benzene, m.p. 141°-143°C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[C:25]([F:35])[CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[F:35][C:25]1[CH:24]=[C:23]([C:20]2([C:17]3[N:13]4[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]4=[N:19][N:18]=3)[CH2:21][CH2:22]2)[CH:28]=[CH:27][C:26]=1[C:29]1[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=1
Reactant: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2F)cn1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2F)cn1
Yield: 74.6 %

Procedure:
A solution of the compound (377 mg, 0.71 mmol) obtained in Example 82-1) and 4 M hydrochloric acid (1,4-dioxane solution, 3 mL) in methanol (6 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, a 5 M aqueous sodium hydroxide solution (10 mL) was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=20:80) to obtain the title compound (219 mg, 75%) as a colorless solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:15])[NH2:14]>C(N(CC)CC)C.CO>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:14][N:13]([CH3:15])[CH3:12])[CH:7]=1
Reactant: CN(C)N
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)Nc1cc(F)ccc1[N+](=O)[O-]
Yield: 48.8 %

Procedure:
10 g (0.0628 mol) of 2,4-difluoronitrobenzene was stirred for 4 days with 4.36 g (0.0728 mol) of N,N-dimethylhydrazine in 7.08 g of triethylamine and 100 ml methanol. The mixture was concentrated and the resulting solid dissolved in methylene chloride, washed with water and brine, dried with MgSO4 and concentrated to yield an orange solid. The solid was triturated in 95% ethanol/water, filtered and dried to give 6.1 g 4-fluoro-2-(2,2-dimethylhydrazino) nitrobenzene, m.p. 67°-71° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([OH:6])[CH3:5].ClCCl.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCC(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A solution of 1-methoxy-2-propanol in dichloromethane (2.3 g, 25.5 mmol) (25 ml) and pyridine (5 ml) was cooled to between −5 and 0° C. 4-Methylbenzenesulfonyl chloride (5.35 g, 28.1 mmol) was added dropwise and the mixture was stirred at 0° C. for 15 minutes. The mixture was then stirred at room temperature for 18 hours. Ice was added and the mixture was stirred for 1 hour. The organic phase was separated, washed with 10% aqueous sulfuric acid (4×) and water (1×), and then dried (MgSO4) and filtered. The filtrate was purified by column chromatography on silica gel eluting with dichloromethane. The solution obtained was dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound as a colorless oil, 4.3 g, 69% yield.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[Na].C(OCC)(=O)C>CN(C)C=O>[OH:1][C:3]1([CH2:2][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2ccnc2)CC1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 87.9 %

Procedure:
4.25 g of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate was dissolved in 30 ml dimethylformamide, 5.38 g of sodium imidazole was added thereto, and the mixture was stirred at 60° C. for 3 hr and 40 min. After cooling, ethyl acetate was added to the reaction solution, and it was washed with water for 3 times and then with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated and subjected to silica gel column chromatography to give 4.93 g of tert-butyl 4-hydroxy-4-(1H-1-imidazolylmethyl)-1-piperidinecarboxylate.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N+:19]([O-:21])=[O:20])=[C:7]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH:24]=2)[N:6]=1)(=O)=O.[OH:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:38]#[N:39].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:44]([O:43][C:42]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[O:34][C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([N+:19]([O-:21])=[O:20])=[C:7]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH:24]=2)[N:6]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: CN(C)C(=O)c1cccc(Oc2nc(S(C)(=O)=O)nc(NCc3ccccc3)c2[N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN(C)C(=O)c1cccc(Oc2nc(Oc3cc(C#N)ccc3OCc3ccccc3)nc(NCc3ccccc3)c2[N+](=O)[O-])c1

Procedure:
In a similar manner, 2-methylsulfonyl-4-benzylamino-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine was treated with 3-hydroxy-4-benzyloxybenzonitrile in the presence of cesium carbonate to afford 2-(2-benzyloxy-5-cyanophenoxy)-4-benzylamino-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (P).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH:18](OC)[O:19]C)[CH:15]=[CH:14][C:13]=2[N+:23]([O-:25])=[O:24])=[N:8][C:7]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)=[O:5])[CH3:2].Cl>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=2[N+:23]([O-:25])=[O:24])=[N:8][C:7]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Nc2cc(C(OC)OC)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Yield: 978.4 %

Procedure:
A mixture of 3.4 g (0.71 mmole) of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid ethyl ester (VI.41a), 80 mL of acetonitrile and 20 mL of 1M hydrochloric acid was heated 60 degrees for 30 minutes. The mixture was concentrated under reduced pressure, 200 mL of water was added and the pH was adjusted to 9 by the addition of 15% sodium hydroxide solution. The precipitate was collected by filtration to give 3.0 g of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid ethyl ester (VI.41b) as a white solid.
Reaction SMILES: C(OCOC([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([F:16])=[CH:11][C:10]=1[B:17]1[O:21][C:20]([CH3:23])([CH3:22])C(C)(C)[O:18]1)(C)C)C.Cl>C1COCC1>[F:16][C:12]1[C:13]([CH3:15])=[CH:14][C:9]2[C:20]([CH3:22])([CH3:23])[O:21][B:17]([OH:18])[C:10]=2[CH:11]=1
Reactant: CCOCOC(C)(C)c1cc(C)c(F)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc2c(cc1F)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of 2-(2-(2-(ethoxymethoxy)propan-2-yl)-5-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.35 g, 6.68 mmol) in THF (67 mL) was added 6 N HCl (67 mL). The reaction mixture was stirred at room temperature overnight, and extracted with DCM (200 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with PE-EA (from 10:1 to 3:1) to give 6-fluoro-3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (835 mg, 64%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.189 (d, J=8.0 Hz, 1H), 6.995 (d, J=6.5 Hz, 1H), 5.950 (s, 1H), 2.266 (s, 3H), 1.472 (s, 6H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]=[O:25])=[CH:19][CH:18]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(CCO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(CC=O)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
[4-(2-Hydroxyethyl)benzyl]-(2-phenylethyl)carbamic acid tert-butyl ester (238 mg) in dichloromethane (10 mL) was treated with Dess-Martin periodinane (341 mg) and stirred for 1 hour. The reaction mixture was added to a mixture of ethyl acetate (10 mL), saturated aqueous sodium thiosulphate solution (10 mL) and saturated aqueous sodium bicarbonate (10 mL), and the mixture was stirred vigorously for 10 minutes. The phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organics were washed with water, dried (magnesium sulfate) and evaporated to give the subtitle compound as an oil (232 mg).
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH3:5].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(OCC)C>ClCCl>[CH2:1]([O:6][CH:7]1[C:18](=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOCCCC=CCCC=CCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCOC1CCC=CCCC=CCCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
8.8 g of diatomaceous earth and a solution of 5.39 g of 12-pentyloxy-4,8-dodecadien-1-ol in 50 ml of dichloromethane were charged into a 250 ml flask. 8.8 g of PCC were then added in small portions and the mixture was stirred for 2 h at room temperature. Ethyl ether was added to the reaction mixture to precipitate the chromium salts, and the mixture was then filtered on SiO2, concentrated and distilled in a bulb-to-bulb apparatus. 4 g of 12-pentyloxy-4,8-cyclododecadien-1-one were obtained.