Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:12]1([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[N:24]2[CH2:25][CH2:26][N:27]([C:6]([C:5]3[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=3[CH3:11])=[O:8])[CH2:28][CH2:29]2)[CH2:13][CH2:14]1
Reactant: c1cc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: Cc1cc(F)ncc1C(=O)O
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 103.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 6-fluoro-4-methylnicotinic acid (386 mg) and 1-(2,4-dicyclopropylphenyl)piperazine (650 mg), the title compound (980 mg) was obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:20]=3[F:19])=[O:23])[CH2:3][CH2:2]2)[N:12]=1
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4cccc(F)c4F)CC3)cccc2n1
Yield: 36 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2,3-difluorobenzoyl chloride (72.4 mg; 0.41 mmol) to obtain 27.6 mg. (36% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.54 (m, 1H), 7.34 (m, 3H), 7.11 (br s, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 5.93 (br s, 2H), 4.60 (br d, 1H), 3.50 (br s, 2H), 3.18 (m, 2H), 3.02 (m, 1H), 2.73 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:11][CH2:10][C@@H:9]1[CH:18]=O>[O-]S([O-])(=O)=O.[Cu+2].C(Cl)Cl>[O:8]1[C:12]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[O:11][CH2:10][C@@H:9]1/[CH:18]=[N:7]\[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6]
Reactant: O=C[C@H]1COC2(CCCCC2)O1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C\[C@H]1COC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.1 %

Procedure:
To a solution of (S)-2-methylpropane-2-sulfinamide (4.7 g, 39 mmol) and DCM (15 mL) at RT was added anhydrous CuSO4 (14 g, 85 mmol) followed by a solution of (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (6.0 g, 35 mmol) and DCM (20 mL). The reaction was stirred at RT for 3 d then filtered through CELITE, washed with DCM and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with hexane/EtOAc (9:1 to 7:1) to afford 4.7 g (49%) of (S,Z)—N—((S)-1,4-dioxaspiro[4.5]decan-2-ylmethylene)-2-methylpropane-2-sulfinamide (248).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:6]1.[OH-].[Na+].[ClH:33].S([O-])([O-])(=O)=O.[Mg+2]>C(O)C.ClCCl>[ClH:33].[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][N:7]3[CH2:8][CH2:9][CH:5]([CH2:4][C:3]([OH:30])=[O:2])[CH2:6]3)[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CC1CCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)CC1CCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The above ester (1.0 g, 2.5 mmol) was dissolved in ethanol (25 ml) and a 2 N aqueous sodium hydroxide solution (4.9 ml) was added. The mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo to give an oily residue. Dichloromethane (100 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution (1 ml) was added dropwise. The mixture was stirred vigorously for 15 minutes at approx. 10° C. Magnesium sulphate was added and the mixture was stirred at ambient temperature for 30 minutes and filtered. The solvent was evaporated in vacuo to give 0.9 g of the title compound as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][CH3:23])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:5][CH:4]=1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>>[CH2:22]([N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:24])=[CH:15][CH:16]=1)[C:31](=[O:34])[CH2:32][CH3:33])[CH3:23]
Reactant: CCNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Reactant: CCC(=O)Cl
Product: CCC(=O)N(CC)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-ethylaminomethyl-benzamide and propionyl chloride, the title compound was prepared as white solid (47% yield). MS: m/e=483(M+H+).
Reaction SMILES: [Cl:1][C:2]([SH:5])([Cl:4])[Cl:3].[F:6][C:7]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:8][OH:9].[OH-].[Na+]>C(Cl)Cl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:7]([CH2:8][O:9][S:5][C:2]([Cl:4])([Cl:3])[Cl:1])([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[F:6]
Reactant: O=[N+]([O-])C(F)(CO)[N+](=O)[O-]
Reactant: SC(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])C(F)(COSC(Cl)(Cl)Cl)[N+](=O)[O-]
Yield: 90.1 %

Procedure:
Perchloromethylmercaptan (5.6 g, 0.03 mol) and 2-fluoro-2,2-dinitroethanol (5.0 g, 0.033 mol) in 30 ml of methylene chloride was combined with 0.3 g of tetrabutyl ammonium chloride in 20 ml of water and the vigorously stirred mixture was cooled in an ice-salt bath. A solution obtained by diluting 2.6 g of 50 percent aqueous sodium hydroxide with 3 ml of water was added dropwise keeping the temperature at 0° C. Separation of the methylene chloride layer and removal of the solvent gave 8.2 g of an oil which was extracted with 2×40 ml of hexane. The combined extracts were passed through a silica gel 60 pad and the pad was washed with benzene. Removal of solvent gave 5.9 g (65 percent) of an oil which was essentially pure by TLC and GLC analysis; H-NMR (CDCl3): δ 5.37 (d); mass spectrum (C.I.): m/e 304, 302, 267, 269.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:26]\[C@H:27]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28]3)/[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[BH4-].[Na+].O>C(O)C.C(Cl)(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[C:6](/[C:16](=[CH:26]\[C@H:27]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28]3)/[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: Cn1ccc(NC(=O)/C(=C/[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cn1ccc(NC(=O)/C(=C/[C@H]2CCC(O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)n1
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
To a suspension of (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(1-methyl-1H-pyrazol-3-yl)-3-[(1S)-3-oxocyclopentyl]acrylamide (140 mg) in ethanol (2 mL) was added sodium borohydride (12 mg) at 0° C., followed by stirring for 15 minutes. The reaction mixture was diluted with chloroform and the reaction was stopped with water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to obtain (2E)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1S)-3-hydroxycyclopentyl]-N-(1-methyl-1H-pyrazol-3-yl)acrylamide (140 mg) as a colorless amorphous substance.
Reaction SMILES: [CH2:1]([C:7]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12]2[S:13][CH2:14][CH2:15][C:11]=2[C:10]2[C:16](O)=[CH:17][C:18](C)=[CH:19][C:9]=2[O:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BrH:28].[N:29]1([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>>[BrH:28].[CH2:22]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:12]2[S:13][CH2:14][CH2:15][C:11]=2[C:10]2[C:16]([O:38][C:37](=[O:39])[CH2:36][CH2:35][CH2:34][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:17][CH:18]=[CH:19][C:9]=2[O:8]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCC1(CCCCCC)Oc2cc(C)cc(O)c2C2=C1SCC2
Reactant: O=C(O)CCCN1CCCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCC1(CCCCCC)Oc2cccc(OC(=O)CCCN3CCCC3)c2C2=C1SCC2

Procedure:
By reacting 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c][1]benzopyran with n-hexyl magnesium bromide, using the procedure described in Example 8, there is obtained 4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-7-methyl-4H-thieno[2,3-c][1]benzopyran. The benzopyran is then reacted with γ-pyrrolidinobutyric acid, hydrobromide salt and dicyclohexylcarbodiimide according to the method of Example 10 to yield the desired ester.
Reaction SMILES: C(N[C:10]([N:12]([CH2:21][C:22]1[NH:26][C:25]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:24][C:23]=1[Cl:31])[C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH2:20])=[O:19])=[S:11])(=O)C1C=CC=CC=1>N>[CH2:27]([C:25]1[NH:26][C:22]([CH2:21][N:12]2[C:13]3[N:14]=[CH:15][NH:16][C:17]=3[C:18](=[O:19])[NH:20][C:10]2=[S:11])=[C:23]([Cl:31])[N:24]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1nc(Cl)c(CN(C(=S)NC(=O)c2ccccc2)c2nc[nH]c2C(N)=O)[nH]1
Agent: N
Product: CCCCc1nc(Cl)c(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)[nH]1
Temperature: 80 °C
Yield: 13.6 %

Procedure:
4-{[(Benzoylamino)carbonothioyl][(2-butyl-4-chloro-1H-imidazol-5-yl)methyl]amino}-1H-imidazole-5-carboxamide (0.17 g, 0.37 mmol, obtained from Example 7(b)) was dissolved in ammonia (7 N in methanol, 3 mL) and the mixture was heated at 80° C. for 1 h. The mixture was concentrated and purified by preparative HPLC, obtaining the title compound (0.017 g, 14%) as a solid.
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3]([NH2:5])=[O:4].C(=O)=O.[NH2:13][C:14]([NH:16][C:17]([NH2:19])=[NH:18])=[NH:15]>CO>[NH2:18][C:17]1[N:16]=[C:14]([NH2:13])[N:15]=[C:1]([CH2:2][C:3](=[O:4])[NH2:5])[N:19]=1
Reactant: CCOC(=O)CC(N)=O
Reactant: N=C(N)NC(=N)N
Agent: O=C=O
Solvent: CO
Product: NC(=O)Cc1nc(N)nc(N)n1
Temperature: 15 °C
Reaction time: 0.58 h

Procedure:
Ethyl malonamate (34.7 g, 0.26 mole) and methanol (100 ml) were placed in a flash equipped with a dropping funnel, a stirrer, and a soda lime trap (to exclude CO2). The flask was cooled to about 15° C. in an ice-water bath. Freshly prepared biguanide (26.3 g, 0.26 mole, in 250 ml methanol) was added, with stirring, over 35 min at 15°-20° C. A white precipitate began to form within 8-9 min. The mixture was allowed to stir overnight at room temperature. It was then cooled to 15° C., and the white precipitate was filtered, washed with cold water to remove sodium sulfate, and finally washed with cold methanol. A crude yield of 32.7 g (76%) was obtained. A pure sample recrystallized from water had a mp of 295°-96° C. (dec.) when placed in a preheated bath at 295° C. Anal. calcd. for C5H8N6O: C, 36.59; H, 4.91; N, 48.76. Found: C, 36.73; H, 5.08; N, 48.51.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)C#N.C[CH2:11][N:12](CC)CC>[Pd].CCO>[NH2:1][C:2]1[CH:3]=[C:4]([NH:12][CH3:11])[CH:7]=[CH:8][N:9]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccnc(N)c1
Agent: [Pd]
Solvent: CCO
Product: CNc1ccnc(N)c1
Reaction time: 12 h

Procedure:
To a mixture of 2-aminoisonicotinonitrile (0.043 mol) and Pd/C (10%, 6.00 g) was added Et3N (40.0 mL) and EtOH (160.0 mL) in a parr bottle and hydrogenated at 50 psi for 12 h. Crude mixture was filtered through Celite®, concentrated under vacuo and dried under high vacuum to yield compound.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:9]([CH2:10][Cl:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[NH3:12]>O.CO>[ClH:11].[ClH:1].[CH3:2][O:3][C:4]1[C:9]([CH2:10][NH2:12])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: N
Reactant: COc1ncccc1CCl
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ncccc1CN
Temperature: 35 °C
Reaction time: 1 h

Procedure:
15.1 g of 2-methoxy-3-picolyl chloride hydrochloride (77.76 mmol) were slowly added dropwise to a mixture of 600 ml of 30% strength ammonia solution in water and 250 ml of methanol at 35° C. while continuously passing in gaseous ammonia. After the solution had been stirred at 35° C. for 1 h it was concentrated under reduced pressure in a rotary evaporator, the residue was made alkaline with 20% strength NaOH solution (water phases were kept small) and extracted several times with DCM, and the org. phases were dried over magnesium sulfate and concentrated under reduced pressure in a rotary evaporator. The residue was taken up in ether and, after addition of ethereal hydrochloric acid, filtration with suction and washing of the precipitate with ether, 11.0 g (67%) of 2-methoxy-3-picolylamine.2HCl were obtained as white crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH:30]=O>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH2:30][C:29]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Product: COc1ccc(CN2CCc3c(-c4ccc(Cl)cc4)nn(Cc4ccccc4)c3CC2)cc1OC

Procedure:
The title compound was prepared (12 mg) from 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.1 mmol) using 3,4-dimethoxy-benzaldehyde (0.2 mmol) in place of formaldehyde. MS (ESI): exact mass calculated for C29H30ClN3O2, 487.20. found, m/z 488.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.44-7.43 (m, 2H), 7.30-7.29 (m, 2H), 7.25-7.22 (m, 2H), 7.20-7.18 (m, 1H), 7.03-7.02 (m, 2H), 6.86 (d, J=1.7 Hz, 1H), 6.76-6.71 (m, 2H), 5.25 (s, 2H), 3.79 (s, 6H), 3.63 (s, 2H), 2.72 (s, 4H), 2.68-2.66 (m, 4H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([OH:21])=O)(=[O:13])=[O:12].C(Cl)(=O)C([Cl:25])=O>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([Cl:25])=[O:21])(=[O:13])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1
Solvent: c1ccccc1
Product: O=C(Cl)[C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
15.6 g of (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carboxylic acid [Chem, Ber., 35, 3783 (1902)] are dissolved in 120 ml of anhydrous benzene, and 17.5 ml of oxalyl dichloride are added dropwise thereto under stirring. The mixture is allowed to stand at 40° to 50° C. overnight. Then, the mixture is condensed to dryness under reduced pressure, and the residue is recrystallized from a mixture of n-hexane and benzene. 14.3 g of (S)-1-(2-naphthylsulfonyl)pyrrolidine-2-carbonyl chloride are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[CH2:12][CH3:13].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][CH3:13])=[O:5]
Reactant: O=C(O)c1ccccc1Br
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
2-Bromobenzoic acid (2.005 g, 9.47 mmol, 1.0 eq.) was combined with iodoethane (1.60 ml, 19.9 mmol, 2.0 eq.)and sodium bicarbonate (1.68 g, 19.9 mmol, 2.0 eq.) in dimethylformamide (10 ml, 1M) and stirred at room temperature for a total of 4 days. The reaction was then diluted with water (20 ml) and extracted with ether:hexane (1:1, 3×20 ml). The combined organic extracts were washed with aqueous 10% sodium hydrogen sulfite (20 ml), water (20 ml), and aqueous saturated sodium chloride (20 ml). Next, the organic extracts were dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on silica gel (50 g) eluting with ether:hexane (1:6) to furnish the title C compound (2.17 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Yield: 78.9 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (0.109 g, 0.361 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.100 g, 0.361 mmol) and DIPEA (0.126 mL, 0.723 mmol) were combined in THF (3 mL) and treated with HATU (0.151 g, 0.397 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in EtOAc, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 20 to 60% EtOAc/hexanes to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (0.16 g, 0.285 mmol, 79% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.79 (t, J=5.63 Hz, 1H), 8.00 (s, 1H), 7.80 (s, 1H), 7.37-7.54 (m, 3H), 7.25 (s, 1H), 6.75 (dd, J=17.67, 11.08 Hz, 1H), 6.05 (d, J=17.67 Hz, 1H), 5.51 (s, 2H), 5.44 (d, J=10.99 Hz, 1H), 4.50 (d, J=5.59 Hz, 2H), 3.40 (t, J=8.10 Hz, 2H), 0.76 (t, J=8.06 Hz, 2H), −0.07 (s, 9H). LC-MS (ES−) m/z 559.13, 561.19 [M−1]. LC-MS (ES+) m/z 561.14, 563.12 [M+H].
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[OH-].[K+].[N:10](=[C:12]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]1[CH:32]=[CH:31][C:16]([CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])=[CH:15][CH:14]=1)[NH2:11]>C(O)C.C1COCC1.[Hg]=O>[N+:10](=[C:12]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]1[CH:14]=[CH:15][C:16]([CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])=[CH:31][CH:32]=1)=[N-:11]
Reactant: NN=C(c1ccccc1)c1ccc(COCCNC(=O)Nc2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: O=[Hg]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: [N-]=[N+]=C(c1ccccc1)c1ccc(COCCNC(=O)Nc2ccccc2)cc1
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a vigorously stirred mixture of yellow mercury oxide (0.18 g, 0.8 mmol), sodium sulfate (0.14 g, 1 mmol) and sat. KOH in ethanol (1 ml) was added a solution of (XII) (0.27 g, 0.7 mmol) in THF (10 ml). The mixture was stirred for 16 h. in the dark, then filtered through a pad of celite. The filtrate was collected and concentrated in vacuo to yield (XIII) (0.27 g, 100%) as a dark red solid; m.p. 111-115° C., decolurises at 136° C.; δ H (CDCl3, 200 MHz) 3.43 (m, 2H, CH2CH2NH), 3.69 (m, 2H, CH2CH2O), 4.49 (s, 2H, ArCH2O), 5.80 (bs, 1H, CH2NHC(O)), 7.02 (m, 1H, 4″-H), 7.41-7.44 (m, 13H, Ar—H), 7.44 (s, 1H, ArNHC(O)) ppm; δC (CDCl3, 400 MHz) 40.3 (CH2NH), 62.4 (CH2CH2O), 68.0 (ArCH2O), 120.3 (4″-C), 123.2 (4′-C), 125.0, 125.8, 126.5, 126.7 (2-, 2′-, 2″-, 6-, 6′-, 6″-C), 128.9, 129.1, 129.2, 129.3 (1-, 1′-, 3-, 3′-, 3″-, 5-, 5′-, 5″-C), 135.0, 138.9 (4-, 1″-C), 156.5 (NHC(O)NH) ppm; υmax 3344 (N—Hstr), 2042 (R2C═N═N), 1658 ((R(H)N)2C═Ostr) cm−1; m/z 445 [M+MeCN+NH4]+ (100%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([O:29]C)=[O:28])=[CH:20][C:19]=2[CH:31]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=2[CH:31]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1CCCOc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1ccccc1CCCOc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 58.8 %

Procedure:
To methyl 7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (832 mg) dissolved in THF-methanol (15-7.5 ml) was added a 2 M aqueous solution of potassium carbonate (1.5 ml), and the resulting mixture was stirred at 60° C. for 20 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the precipitated crystals were washed with ethyl acetate to obtain 7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (474 mg) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)(Cl)Cl>[CH3:11][O:10][C:8]([C:3]1[C:2]([CH3:1])=[N+:7]([O-:17])[CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1nccnc1C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ncc[n+]([O-])c1C
Temperature: 70 °C

Procedure:
In a 1-L flask, the methyl 3-methylpyrazine-2-carboxylate (step 1, 16.08 g, 106 mmol) was suspended in CHCl3 (300 mL). 3-chlorobenzoperoxoic acid (Aldrich, 24.62 g, 143 mmol) was added. The reaction mixture was heated to 70° C. for 16 h. The reaction mixture was quenched with saturated NaHCO3 (200 mL). The layers were separated, and the aqueous layer was further extracted with DCM (2×100 mL). The combined organic layers were dried over MgSO4, and the filtrate was concentrated to afford the title compound. MS m/z=169 (M+H).
Reaction SMILES: CN(C)C1N=CC([C:9]2[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]3[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:19]3)=[N:13][C:14]=2[CH2:15][CH3:16])=C(C)C=1.[Cl:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1B(O)O>>[Cl:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][C:42]=1[C:9]1[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Reactant: COc1ccc(B(O)O)c(Cl)c1
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate but substituting 2-chloro-4-methoxy phenyl boronic acid and making non-critical variations provided the title compound as a oil: 1H NMR (DMSO-d6) δ) 1.04, 1.16, 2.38, 2.68, 3.34, 3.40, 3.54, 3.70, 3.82, 4.18, 4.62, 5.10, 5.95, 6.98, 7.10, 7.26, 7.38; IR (diffuse reflectance) 2971, 2934, 2350 (w), 2338 (w), 2063 (w), 1949 (w), 1710 (s), 1568, 1482 (s), 1419 (s), 1397 (s), 1348, 1287, 1228, 1096, cm−1 HRMS (FAB) calcd for C29H35ClN4O4+H 539.2425. found 539.2436. Anal. Calcd for C29H35ClN4O4: C, 64.61; H, 6.54; N, 10.39; Cl, 6.58. Found: C, 64.30; H, 6.56; N, 10.26.