Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=CC=C[CH:2]=1.Cl.C([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2SC=1C(Cl)=O)CC.C(S(C1C=CC(N)=CC=1)(=O)=O)CCCCCC>CN(C)C=O>[CH3:11][NH:15][C:16]1[CH:2]=[N:1][CH:6]=[C:18]([NH:19][CH3:14])[CH:17]=1
Reactant: c1ccncc1
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Agent: CCCCCCCS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNc1cncc(NC)c1

Procedure:
In the mixture of 50 ml of pyridine and 5 ml of dimethylformamide was suspended 1.04 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonyl-chloridehydrochloride (described in Example 13). To the suspension was added 940 mg of 4-n-heptylsulfonylaniline obtained in Reference Example 7, and 45 mg of 3,5-dimethylaminopyridine, followed by stirring at 70° C. for 17 hours. The reaction mixture was concentrated and to the concentrate was added saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with chloroform. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous potassium carbonate. The solvent was removed under reduced pressure. The residue was dissolved in ethanol. To the mixture was added saturated hydrogenchloride diethylether solution, followed by stirring at room temperature. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol (10:1 by volume). To the resulting substance was added saturated hydrogenchloride diethylether solution. The solvent was removed under reduced pressure. The residue was recrystallized from methanol-diethylether to obtain 559 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].[CH2:14]=O.Cl>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:5]2[C:4]=1[CH2:14][O:7][C:6]2=[O:8]
Reactant: C=O
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: Cl
Product: COc1ccc2c(c1OC)COC2=O

Procedure:
3,4-dimethoxybenzoic-acid (5.0 g, 27 mmol) was added to Formalin (36 ml) saturated with hydrogen chloride gas, and stirred with bubbling hydrogen chloride gas at 65° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (16 ml), followed by neutralizing with dilute aqueous ammonia (concentrated aqueous ammonia:water=2:3). The precipitated crystals were collected by filtration, washed with water, followed by drying to give 4.0 g of 4,5-dimethoxyphthalide.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1>CN(C)C=O>[CH3:1][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccccc1CCN(CCCCC(=O)c1ccc2c(c1)CCN2C)C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 5 h
Yield: 33.5 %

Procedure:
Potassium carbonate (166 mg) and methyl iodide (170 mg) were added to a solution of tert-butyl 5-(2,3-dihydro-1H-indol-5-yl)-5-oxopentyl[2-(2-methoxyphenyl)ethyl]carbamate (362 mg) obtained in Reference Example 50 in dimethylformamide (2 ml), and the mixture was stirred at 60 to 70° C. for 5 hours. The solvent was evaporated under reduced pressure, water was added to the resulting residue, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluting solvent; hexane:ethyl acetate=1:1) to give the title compound as a pale yellow oil (125 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[C:12]([Br:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([OH:15])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:12]([Br:16])[N:11]([CH:17]([CH3:19])[CH3:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1nc(OCc2ccccc2)c(C=O)c1Br
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2c(OCc3ccccc3)nn(C(C)C)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Benzyloxy-5-bromo-4-formyl-1-isopropyl-1H-pyrazole (0.7 g) was dissolved in tetrahydrofuran (5 mL), and a solution of 4-methoxyphenylmagnesium bromide in tetrahydrofuran (0.5 mL/L, 4.3 mL) was added to the stirred solution. The mixture was stirred at room temperature for 1 hour. A small amount of a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran) to give the title compound (0.6 g).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[CH3:13][C:14]1[CH:25]=[CH:24][C:17]2[C:18](=O)[O:19]C(=O)[NH:21][C:16]=2[CH:15]=1>CCCCCC.O1CCCC1>[NH2:21][C:16]1[CH:15]=[C:14]([CH3:13])[CH:25]=[CH:24][C:17]=1[C:18](=[O:19])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: Cc1nnnn1C
Reactant: Cc1ccc2c(=O)oc(=O)[nH]c2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Cc2nnnn2C)c(N)c1
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexane (2.5M, 20 ml) was added slowly to a stirred solution of 1,5-dimethyltetrazole (4.9 g) in dry tetrahydrofuran (100 ml) at -5° to 0° under nitrogen. After stirring for 0.5 hour, 7-methyl-1H-3,1-benzoxazine-2,4-dione (2.6 g) was added and stirring continued for 1.5 hours at room temperature and for 3 hours at 40°. The solvent was evaporated under reduced pressure at 40°-50°, water (100 ml) was added to the residue, followed by 5N hydrochloric acid dropwise until neutral to Universal pH paper. The mixture was extracted with ethyl acetate (3×50 ml) and the combined extracts were washed with 10% aqueous potassium carbonate solution (50 ml), dried over anhydrous magnesium sulphate and then evaporated under reduced pressure at 50°. The residue was triturated with ether to give a solid product which was collected by filtration and recrystallised from ethyl acetate to give the novel compound 1-(2-amino-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 155°-6°.
Reaction SMILES: I[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[C:3]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[C:10]5[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]5)=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: OB(O)c1ccc(-c2ccc(Br)cc2)cc1
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: Cc1ccccc1
Product: Brc1ccc(-c2ccc(-c3c4ccccc4c(-c4ccccc4)c4ccccc34)cc2)cc1
Yield: 40.1 %

Procedure:
Into a 100 mL three-neck flask were put 2.8 g (7.2 mmol) of 9-iodo-10-phenylanthracene and 1.5 g (7.2 mmol) of 4′-bromobiphenyl-4-boronic acid. The air in the flask was replaced with nitrogen. To the mixture were added 40 mL of toluene and 10 mL (2.0 mol/L) of an aqueous solution of sodium carbonate. This mixture was stirred to be degassed while the pressure was being reduced. After the degassing, 120 mg (0.10 mmol) of tetrakis(triphenylphosphine)palladium(0) was added to the mixture. This mixture was stirred at 90° C. for 4 hours. After the stirring, about 50 mL of toluene was added to this mixture. The mixture was subjected to suction filtration through alumina, celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The solid obtained by condensation of the obtained filtrate was purified by high-performance liquid chromatography (a mobile phase: chloroform) to give a light yellow solid. The obtained solid was recrystallized with a mixed solution of chloroform and hexane to give 1.4 g of a light yellow powdered solid, which was the object of the synthesis, in a yield of 40%. A synthesis scheme of Step 1 is shown in (b-1) given below.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]2.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42])[C:34](Cl)=[O:35]>ClCCl>[Cl:30][C:31]1[CH:32]=[C:33]([C:34]([O:1][NH:2][C:3](=[NH:22])[C:4]2[C:5]([CH3:21])=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:8][CH2:7]3)=[O:35])[CH:37]=[CH:38][C:39]=1[O:40][CH:41]([CH3:43])[CH3:42]
Reactant: Cc1c(C(=N)NO)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C(=N)NOC(=O)c2ccc(OC(C)C)c(Cl)c2)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of 1,1-dimethylethyl 6-[(hydroxyamino)(imino)methyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 17; 435 mg; 1.42 mmol) in dichloromethane (10 ml) was added triethylamine (0.30 ml; 2.14 mmol) followed by 3-chloro-4-[(1-methylethyl)oxy]benzoyl chloride (Preparation 8; 365 mg; 1.57 mmol) in dichloromethane (5 ml). After 30 min, the reaction was concentrated, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with a gradient of 10-50% ethyl acetate in cyclohexane gave the title compound as a white foam (413 mg).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=O)C.CN(C)C=O.[BH4-].[Na+].BrC1[CH:30]=[CH:29][CH:28]=[CH:27]N=1>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:30]=[CH:29][CH:28]=[CH:27][N:13]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: Brc1ccccn1
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2ccccn2)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 5.85 g. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 20 ml. dimethylformamide is cooled, under nitrogen, to about 0° C. and 1.14 g. of sodium borohydride is added. The exothermic reaction is controlled to less than about 30° C., then the mixture is stirred for one hour at 20°-30° C. 6 Ml. of 2-bromopyridine is added and the mixture warmed slowly to about 110° C. and kept at that temperature for 1 hour. The mixture is cooled, diluted with water, and filtered. The crude product is recrystallized from aqueous methanol, yielding 1-amino-2-nitro-4-(pyrid-2-ylthio)benzene.
Reaction SMILES: Cl[C:2]1[NH:3][S:4](=[O:13])(=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CO>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[NH:3][S:4](=[O:13])(=[O:12])[C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=S1(=O)NC(Cl)=Nc2ccccc21
Solvent: CO
Product: CN1CCN(C2=Nc3ccccc3S(=O)(=O)N2)CC1
Yield: 72.2 %

Procedure:
To a stirred suspension of 10.7 g of 3-chloro-2H-1,2,4-benzothiadiazine 1,1-dioxide in 100 ml of methanol is added 9.9 g of 1-methylpiperazine and the mixture is heated under reflux for 2 hours. After cooling, the crystalline precipitate is collected by suction filtration and recrystallized from a mixture of dimethylformamide and water to give 10.0 g of the desired product, m.p. 265°-267° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH2:15][CH3:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:8]2[N:9]=[C:20]1[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[S:17][CH2:14][CH2:15][CH3:16]
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCCSc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Yield: 13 %

Procedure:
A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (0.96 g), 2-propylsulfanylbenzoic acid (1.08 g), WSC (0.78 g), and pyridine (10 ml) was stirred with heating at 120° C. for 1.5 hours. To the reaction mixture, HOBt (0.74 g) was added, and stirred with heating for 1.5 hours. WSC (0.38 g) was added thereto, and stirred with heating for further 2 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.23 g of 3-methyl-2-(2-propylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 7).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Cl[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH:23]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2cccc3c2oc2ccccc23)c1
Yield: 90.6 %

Procedure:
4-dibenzofuranboronic acid (5.0 g, 23.6 mmol), 2-chloro-4-methylpyridine (2.6 g, 20 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (0.36 g, 0.8 mmol), and potassium phosphate (11.4 g, 50 mmol) were mixed in 100 mL of toluene and 10 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, Pd2(dba)3 was added (0.18 g, 0.2 mmol) and the mixture was heated to reflux under nitrogen for 8 h. The mixture was cooled and the organic layer was separated. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with dichloromethane. 4.7 g of desired product was obtained after purification.
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH3:29][CH:30]([CH3:35])[CH2:31][CH2:32]C=O>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:32][CH2:31][CH:30]([CH3:35])[CH3:29])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CC(C)CCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)ccc1c2CCC(C)C

Procedure:
The product of Example 84 is treated with 4-methylpentanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[NH:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.CN(C=O)C>CS(C)=O>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=2)=[CH:6]3)[CH:32]=[CH:31][CH:30]=[CH:29]1
Reactant: c1cc[nH]c1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(Cn4cccc4)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester prepared in Preparation 41 and pyrrole were reacted according to the same procedure as Preparation 92 except that DMF was used as the solvent instead of DMSO to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:3]=1.[C:17]([O:21][C:22]([CH2:24][CH2:25][CH2:26][S:27]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39](F)(F)F)[CH:38]=1)[C:33](O)=[O:34])(=[O:29])=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CCCCCCC.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:23])[CH2:24][CH2:25][CH2:26][S:27]([C:30]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:32]([C:33](=[O:34])[N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH3:9])[CH:31]=1)(=[O:29])=[O:28])([CH3:18])([CH3:19])[CH3:20]
Reactant: CNc1nnc(Cl)cc1-c1ccccc1C
Reactant: CC(C)(C)OC(=O)CCCS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1cc(C(=O)N(C)c2nnc(Cl)cc2-c2ccccc2C)cc(S(=O)(=O)CCCC(=O)OC(C)(C)C)c1
Yield: 14 %

Procedure:
The title compound was prepared in analogy to example 1, from (6-chloro-4-o-tolyl-pyridazin-3-yl)-methyl-amine (example 4, intermediate a) and 3-(3-tert-butoxycarbonyl-propane-1-sulfonyl)-5-trifluoromethyl-benzoic acid after a reaction time of 18 hours and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Another purification step using preparative HPLC (Gemini NX column) with a gradient of methanol:water with 0.05% formic acid (80:20 to 98:2) yielded the desired compound as a colorless solid (14%). MS (ESI+): m/z=541.090 ([M+H]+).
Reaction SMILES: [O:1]([CH:8]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:27](I)[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[O:1]([C:8]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH2:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOP(=O)(OCC)C(Oc1ccccc1)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(CC)(Oc1ccccc1)P(=O)(OCC)OCC
Reaction time: 0.75 h

Procedure:
Tetraethyl (phenoxymethylene)-bisphosphonate (1.14 g) was added to a suspension of 55% sodium hydride (0.15 g) in dimethylformamide (10 ml). After 45 minutes at room temperature, ethyl iodide (0.49 ml) was added, and the mixture was left overnight at room temperature, diluted with ethyl acetate and washed with 40% aqueous calcium chloride. The organic phase was dried and evaporated to leave an oil which was purified by chromatography on silica gel. The title compound was isolated as a colourless oil.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][Cl:20])[C:12]=2[N+:21]([O-])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C.[Pd]>[C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][Cl:20])[C:12]=2[NH2:21])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2ccccc2)cccc1OCCCl
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1c(CS(=O)(=O)c2ccccc2)cccc1OCCCl
Temperature: 60 °C

Procedure:
A mixture of 1-benzenesulfonylmethyl-3-(2-chloro-ethoxy)-2-nitrobenzene (0.57 g, 1.6 mmoles) in ethanol (10 mL) was stirred under nitrogen in a round bottom flask at 60° C. 10% Pd/C was added, and the temperature was increased to 80° C. Hydrazine hydrate (1.5 mL) was added dropwise and the mixture was stirred at reflux for 3 hours. Reaction mixture was filtered off through Celite, and the solution was washed with H2O (3×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.5 g, 1.53 mmoles).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]([C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17](B(O)O)[CH:18]=1)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1ccc(Br)nc1
Reactant: COc1ccc(C(C)(C)C)cc1B(O)O
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(C)(C)C)cc1-c1ccc(C)cn1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 2-bromo-5-methylpyridine [purchased from TCI] (0.827 g, 4.81 mmol), (5-(tert-butyl)-2-methoxyphenyl)boronic acid [Intermediate 5] (1.2 g, 5.77 mmol) and potassium carbonate (0.997 g, 7.21 mmol) in dimethoxyethane (15 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (277.8 mg, 0.24 mmol) was added and the reaction mixture heated to 80° C. in a sealed vial for 22 hours. The cooled reaction mixture was partitioned between ethyl acetate (80 mL) and 1 M aqueous sodium hydroxide solution (80 mL), the organic phase separated, washed with water (80 mL) and saturated brine (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow syrup. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 35% ethyl acetate in hexanes to give 2-(5-(tert-butyl)-2-methoxyphenyl)-5-methylpyridine (1.216 g, 99% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:20])=[C:18](Br)[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([CH:21]3[CH2:23][CH2:22]3)[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1Br)OCCN(Cc1ccccc1)C2
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc2c(c1C1CC1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
A mixture of 4-benzyl-9-bromo-8-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine (500 mg, 1.49 mmol), cyclopropylboronic acid (153 mg, 1.78 mmol), potassium carbonate (617 mg, 4.46 mmol), dioxane (3 ml) and water (3 ml) was deaerated with argon gas, and bis(triphenylphosphine)palladium(2) dichloride (52.2 mg, 0.0744 mmol) was added. The mixture was stirred under an argon atmosphere for 3 hr at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (408 mg, 92.1%) as an oil.