Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:34][O:35][C:36](=[O:58])[C@@H:37]([NH:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][CH:52]=2)=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH:38]([CH3:40])[CH3:39]>N1C=CC=CC=1>[CH3:34][O:35][C:36](=[O:58])[C@@H:37]([NH:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:52]=[CH:53][C:54]([NH:57][C:20]([C:3]3[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[C:7]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=5)[C:6]=4[C:2]=3[CH3:1])=[O:21])=[CH:55][CH:56]=2)=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH:38]([CH3:40])[CH3:39]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: Cc1c(C(=O)O)oc2cccc(-c3cccc([N+](=O)[O-])c3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5cccc([N+](=O)[O-])c5)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To 100 mg (0.34 mmol) of 3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carboxylic acid was added 2 mL of oxalyl chloride and the resulting mixture was refluxed for 2 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 1 mL of dichloromethane and was added to a mixture of 183 mg (0.5 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were removed under vacuum. Column chromatography on silica gel gave 41 mg of (S)-3-methyl-2-(4′-{[3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-butyric acid methyl ester as white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1CN([P+]([O:28][N:29]2N=NC3C=CC=C[C:30]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:45]CN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:29]([O:28][CH3:45])[CH3:30])=[O:5]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc(F)c1Br
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(F)c1Br
Reaction time: 14 h
Yield: 75 %

Procedure:
2-Bromo-3-fluorobenzoic acid (9.27 g), 1-N,O-dimethylhydroxylamine hydrochloride (4.129 g, 42.33 mmol), and PyBOP (22.03 g, 1 eq., 42.33 mmol) were suspended in DCM (400 mL). DIEA was then added and the resulting solution was stirred at room temp. for 14 h (no SM left by TLC). The solution was then washed with water, IN aq HCl and aq sat. NaHCO3 in succession. The organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by ISCO (330 g SiO2, attached) to give 8.3 g (75%) of 2-bromo-3-fluoro-N-methoxy-N-methylbenzamide as a white solid. Rf˜0.5 (1:1 Hex:EtOAc); LC/MS ES+1: 261.99.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].[C:7]([C:9]1[C:10](F)=[CH:11][C:12]([NH:15][C:16]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[N:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:17])=[N:13][CH:14]=1)#[N:8]>CC(N(C)C)=O.CCOC(C)=O>[C:7]([C:9]1[C:10]([O:4][CH:2]([CH3:3])[CH3:1])=[CH:11][C:12]([NH:15][C:16]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]([O:31][CH3:32])[O:29][CH3:30])[N:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:17])=[N:13][CH:14]=1)#[N:8]
Reactant: CC(C)O
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(F)c(C#N)cn1)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(OC(C)C)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Propanol (16.2 mg, 0.269 mmol) was diluted in DMA (1 ml) under argon and treated with NaH (60% dispersion in mineral oil, 10.77 mg, 0.269 mmol). The reaction mixture was stirred for 30 min at room temperature. This mixture was added to a solution of N-(5-cyano-4-fluoropyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 33, 25 mg, 0.054 mmol) in DMA (1 ml). The reaction mixture was then stirred at room temperature for 1 h and the at 110° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with sat. aq. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated to give the title compound as a white solid. (UPLC-MS 3) tR 1.27 min; ESI-MS 412.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CC[O:22]CC1)C.C(Cl)(=O)C(C)(C)C.Br.C(N[C:36](=[O:40])[C@H:37]([CH3:39])[NH2:38])C>O1CCCC1.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:38][C@H:37]([C:36]([OH:40])=[O:22])[CH3:39])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN1CCOCC1
Reactant: CCNC(=O)[C@H](C)N
Agent: Br
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
7.5 g (0.034 mol) of N-benzyloxycarbonyl-L-alanine were dissolved in 50 ml of dry tetrahydrofuran and the solution was cooled to -5° C. 4.26 ml (0.034 mol) of N-ethylmorpholine and 4.14 ml (0.034 mol) of pivaloyl chloride were then added and the solution was stirred at -5° C. for 30 minutes. To this mixture was then added a solution of 7.0 g (0.034 mol) of L-alanine ethylamide hydrobromide in 50 ml of dimethylformamide followed by 8.5 ml (0.068 mol) of N-ethylmorpholine. The solution was stirred at -10° C. for 1 hour and then left to stand for 16 hours at room temperature. The solvents were removed by evaporation; the product crystallising on the addition of water. The yield of N-benzyloxycarbonyl-L-alanyl-L-alanine obtained was 9.05 g (83%); melting point 203°-205° C.; [α]D20 =-1.1° (c=1.02% in dimethylformamide; [α] 36520 =-9.2° (c=1.02% in dimethylformamide).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[CH3:21][C@H:22]1[CH2:27][NH:26][C@H:25]([CH3:28])[CH2:24][NH:23]1>>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:23]3[CH2:24][C@@H:25]([CH3:28])[N:26]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)[CH:4]=4)[CH2:27][C@@H:22]3[CH3:21])[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18].[ClH:1]
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3C[C@H](C)N(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)C[C@H]3C)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (123 mg) and trans-2,5-dimethylpiperazine (23 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a hydrochloride.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:9][C:10]1[C:18]2[O:17][N:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:14]=2[CH:13]=[CH:12][C:11]=1[O:26][CH2:27][C:28]#[N:29].O>C1COCC1>[Cl:9][C:10]1[C:18]2[O:17][N:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:14]=2[CH:13]=[CH:12][C:11]=1[O:26][CH2:27][C:28]1[NH:29][N:3]=[N:2][N:1]=1
Reactant: N#CCOc1ccc2c(-c3ccccc3F)noc2c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccccc1-c1noc2c(Cl)c(OCc3nnn[nH]3)ccc12

Procedure:
3.35 g NaN3 and 2.25 g of AlCl3 are stirred in 50 ml THF at reflux for 0.5 hour. A solution of 5 g {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetonitrile, of Example 50, in 50 ml THF is added and the reaction mixture is stirred at reflux for about 120 hours. To the reaction mixture is added water and the solvent is removed. The residue is treated with dilute HCl and extracted with CHCl3. Upon attempted extraction of the chloroform solution with 15% NaOH a precipitate forms which is filtered, dissolved in hot water and acidified to afford 7-chloro-3-(2-fluorophenyl)-6-{[5-tetrazolylmethyl]oxy}-1,2-benzisoxazole, mp 198°-200° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[Mn]([O-])(=O)(=O)=[O:15].[K+].[OH-:20].[Na+]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:20])=[CH:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cc1ccc(-c2cnn(C)c2)cc1
Reactant: [OH-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: Cn1cc(-c2ccc(C(=O)O)cc2)cn1

Procedure:
A mixture of 1-methyl-4-(4-methylphenyl)-1H-pyrazole (1.70 g), potassium permanganate (9.70 g), and 1 N sodium hydroxide (100 ml) was refluxed for 18 hours. The suspension was filtered through diatomaceous earth and cooled. The aqueous solution was extracted with dichloromethane which was discarded. The aqueous solution was acidified to pH 5.5. The resultant precipitate was difficult to filter and was thus extracted with dichloromethane. After evaporation of the solvent, the resulting solid was recrystallized from acetone to yield the title compound (0.60 g), m.p. 274-275° C.; MS m/z: 202 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2I)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Cl:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(OC(C)C)OC(C)C)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:13]=2[NH:12][C:4]2[C:5]([CH3:11])=[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=2)[NH:9][CH:8]=[CH:7]3)[C:19]#[N:20])=[CH:28][CH:27]=1
Reactant: CC(C)OB(OC(C)C)c1ccc(OCCCl)cc1
Reactant: Cc1c(Nc2c(I)cncc2C#N)cc(Cl)c2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCCl)cc2)cc(Cl)c2[nH]ccc12
Temperature: 80 °C
Yield: 84.8 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile (534 mg, 1.3 mmol) in DME (30 mL) was added diisopropyl 4-(2-chloroethoxy)phenylboronate (754 mg, 2.6 mmol), sodium carbonate solution (2.7 mL of 2M solution, 5.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (150 mg, 0.15 mmol) under nitrogen atmosphere and the reaction mixture was heated at 80° C. for 6 h and cooled to room temperature. Ethyl acetate was added and the organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane) to give 5-[4-(2-chloroethoxy)phenyl]-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile as a yellow solid (482 mg, 84%). HPLC retention time: 10.7 min.(g) and MS: 437.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:19][C:18](=[O:20])[C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:21])[F:22])=[CH:17][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cccn1CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 35 °C
Reaction time: 18 h

Procedure:
A solution of 1.15 g (9.19 mmol) 1H-pyrrole-2-carboxylic acid methyl ester and 2.70 g (10.1 mmol) 2-bromo-(1-(4-trifluoromethyl-phenyl)-ethanone in 20 ml acetonitrile is treated with 3.30 g (10.1 mmol) cesium carbonate. The resulting suspension is stirred at 35° C. for 18 hours. The reaction mixture is filtered and the filtrate is evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 1-[2-oxo-2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester as yellow oil; HPLC/MS 2.52 (A), [M+H] 312.
Reaction SMILES: [BrH:1].[C:2]1([P:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]=1[CH2:32]O)[C:25]([O:27][CH3:28])=[O:26]>C(#N)C>[Br-:1].[OH:21][C:22]1[CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:29]=[CH:30][C:31]=1[CH2:32][P+:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Br
Reactant: COC(=O)c1ccc(CO)c(O)c1
Solvent: CC#N
Product: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(O)c1
Product: [Br-]

Procedure:
A suspension of triphenylphosphine hydrobromide (11.9 g, 34.7 mmol) and methyl 3-hydroxy-4-hydroxymethylbenzoate (6 g, 35 mmol) in acetonitrile (65 ml, was heated at reflux for 1.5 h. The solvent was removed on a rotary evaporator under vacuum and the resulting solid was diluted in ethyl ether (30 ml). The product was isolated by filtration. Its properties were as follows:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([Cl:27])[C:20]=1[N:28]=[C:29]=[S:30]>>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:29](=[S:30])[NH:28][C:20]1[C:21]([Cl:27])=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[Cl:18]
Reactant: COc1cc(Cl)c(N=C=S)c(Cl)c1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(Cl)cc(OC)cc2Cl)c1NCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.8 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (500 mg, 1.93 mmol) and 1,3-dichloro-2-isothiocyanato-5-methoxybenzene (678 mg, 2.90 mmol) was stirred at room temperature for 1 day and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown oil (255 mg, 0.517 mmol, 27%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8]([O:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH:17]=[O:16])=[CH:19][CH:20]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: O=Cc1ccc(CO)cc1
Product: COc1ccc(C(=O)OCc2ccc(C=O)cc2)cc1C(C)(C)C

Procedure:
In a manner similar to Example 1(d), by reaction of 7.6 g (34 mmol) of 3-tert-butyl-4-methoxybenzoyl chloride with 4.6 g (34 mmol) of 4-hydroxymethylbenzaldehyde, 5.6 g (51%) of the expected aldehyde, melting point 75°-6° C., are obtained.
Reaction SMILES: CC1=C(C)[C:4]([O:6]C1=O)=[O:5].[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])C1C=CC=CC=1.C(=O)=O.C=C>ClCCl.[Hg].C(O)(C)C>[CH3:23][C:18]12[C:10](=[O:17])[O:6][C:4](=[O:5])[C:21]1([CH3:22])[CH2:20][CH2:19]2
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CC1=C(C)C(=O)OC1=O
Agent: C=C
Agent: O=C=O
Agent: [Hg]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC12CCC1(C)C(=O)OC2=O
Yield: 1201.2 %

Procedure:
In a low temperature exposure unit equipped with a 125 W mercury lamp in a cooled immersion bath, stirrer and gas inlet pipe, 15 g (0.12 mole) of dimethyl maleic anhydride and 1 g (0.0054 mole) of benzophenone are dissolved in 300 ml of dichloromethane, and the solution is cooled by means of an external cooling bath with a mixture of isopropanol and dry ice to -60° to -70° C. Ethylene gas is then introduced over 1 hour and the reaction mixture is subsequently irradiated at the above temperature for 12 hours while introducing a weak flow of ethylene. The solvent is then evaporated off and the crude product is recrystallised from dichloromethane/n-hexane, affording 10 g of 1,2-dimethylcyclobutane-1,2-dicarboxylic anhydride (54% of theory) in the form of white crystals with a melting point of 84°-86° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([OH:23])=O)=[C:6]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:9][C:8]=3[C:7]=12.O1C=C[N:26]=C1Cl>O1CCCC1.CN(C)C=O>[CH3:1][S:2][C:3]1[S:4][C:5]([C:21]([NH2:26])=[O:23])=[C:6]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:9][C:8]=3[C:7]=12
Reactant: Clc1ncco1
Reactant: CSc1sc(C(=O)O)c2c1-c1sc(-c3ccccc3)cc1CC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1sc(C(N)=O)c2c1-c1sc(-c3ccccc3)cc1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
4,5-Dihydro-8-methylthio-2-phenylbenzo[2,1-c:3,4-b']dithiophene-6-carboxylic acid (0.50 g) was dissolved in tetrahydrofuran (10 ml); oxazolyl chloride (0.15 ml) and then N,N-dimethylformamide (one drop) were added. After the mixture was stirred at room temperature for 2 hours, it was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml); concentrated aqueous ammonia (5 ml) was added. After the reaction mixture was stirred at room temperature for one hour, it was poured over water and extracted with chloroform-methanol. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-8-methylthio-2-phenylbenzo[2,1-c:3,4-b']dithiophene-6-carboxamide (0.28 g, 56%), which was recrystallized from ethanol. Melting point 192-193° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]C(N)=O)=[C:11]([O:20][CH3:21])[C:10]=1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[N:25]1C(=O)CCC1=O.[OH-].[K+].[CH2:34]([OH:36])C>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:25])=[C:11]([O:20][CH2:21][O:36][CH3:34])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(CCC(N)=O)ccc(OCc2ccccc2)c1OC
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCOc1cc(OCc2ccccc2)ccc1CCN
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a solution of 28.42 g of 3-(4-benzyloxy-2-methoxy-methoxyphenyl)propionamide and 40.4 mL of 1,8-diazabicyclo-[5.4.0]-7-undecene in 895 mL of methanol was added 16.04 g of N-bromosuccinimide at 65° C. After the mixture was stirred at 65° C. for 15 minutes, to the reaction mixture was added additional 16.04 g of N-bromosuccinimide at 65° C. After being stirred at 65° C. for 15 minutes, the resulted mixture was concentrated under reduced pressure to remove the solvent. To the residue were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give oily product. To a solution of this residue in 242 mL of ethanol was added 67.6 mL of 8 mol/L aqueous potassium hydroxide solution, and the mixture was refluxed for 15 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. To the residue were added 500 mL of ethyl acetate, 50 mL of toluene, and 300 mL of water, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel (eluent: hexane-ethyl acetate) to give 80.0 g of 2-(4-benzyloxy-2-methoxymethoxy-phenyl)ethylamine as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (2-nitro-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example C10) (7.35 g, 19.75 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light orange solid (6.75 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.[OH:20]O>C(O)(=O)C.N>[NH2:1][C:2]1[N+:3]([O-:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:16])[F:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-c2ccc(N)nn2)ccc1OC(F)F
Reactant: OO
Agent: N
Solvent: CC(=O)O
Product: COc1cc(-c2ccc(N)[n+]([O-])n2)ccc1OC(F)F
Temperature: 0 °C
Yield: 85.4 %

Procedure:
20.0 g (74.8 mmol) of 3-amino-6-(4-difluoromethoxy-3-methoxyphenyl)pyridazine are dissolved in 100 ml of glacial acetic acid and, while stirring, 30.6 ml (300 mmol) of 30% strength hydrogen peroxide are added, and the mixture is stirred at 80° C. for 2.5 h. The reaction solution is diluted with 1 kg of ice and 200 ml of concentrated ammonia solution, and the precipitate which has formed is collected on a suction funnel, washed first with water and then with ethanol and petroleum ether (b.p. 40°-70° C.) and dried at 75° C. in vacuo. 18.1 g (85.4%) of the title compound of m.p. 214° C. are obtained.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C@@H:17]2[CH2:21][O:20][CH2:19][C@H:18]2[OH:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].Cl[CH2:24][C:25]([OH:27])=[O:26].[K].Cl>C(O)(C)(C)C>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][C@@H:17]2[CH2:21][O:20][CH2:19][C@H:18]2[O:22][CH2:24][C:25]([OH:27])=[O:26])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2O)cc(C(C)(C)C)c1O
Reactant: O=C(O)CCl
Agent: Cl
Agent: [K]
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2OCC(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
The compound of Example 2 (3.6 g, 0.011 mole) and chloroacetic acid (2.04 g, 0.022 mole) were added to t-butyl alcohol (40 ml) to which had been added potassium (1.39 g, 0.033 mole) and the reaction mixture was refluxed for 36 hours. The reaction mixture was cooled to room temperature, and 1N hydrochloric acid (50 ml) was added slowly. The reaction mixture was extracted twice with 100 ml of diethyl ether. The combined diethyl ether extracts were