Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8](Br)([CH3:10])[CH3:9].[Cl:14][C:15]1[C:20]([OH:21])=[CH:19][C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[C:17]([F:35])[CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][NH:6][C:7](=[O:12])[C:8]([O:21][C:20]1[CH:19]=[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:17]([F:35])=[CH:16][C:15]=1[Cl:14])([CH3:10])[CH3:9]
Reactant: COC(=O)CCNC(=O)C(C)(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)C(C)(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Yield: 63.8 %

Procedure:
3-(2-Bromo-2-methylpropionylamino)propionic acid methyl ester (224 mg) and 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-1H-pyrimidin-2,4-dione (250 mg) were dissolved in acetonitrile 5 ml. After addition of K2CO3 (204 mg), the reaction mixture was heated for 12 hours under reflux, cooled and diluted with ethyl acetate (50 mL). After washing with water (50 mL), thus obtained organic layer was dried with magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography to give the target compound (240 mg).
Reaction SMILES: S=[C:2]1[NH:6][C:5]2=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=[C:4]2[O:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc2oc(=S)[nH]c12
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2oc(Cl)nc12
Temperature: 95 °C
Yield: 100.3 %

Procedure:
A mixture of the thione from Step B (0.65 g, 3.11 mmol) and phosphorus pentachloride (0.65 g, 3.11 mmol) in phosphorus oxychloride (6 mL) was heated to 95° C. for 2.5 h. After cooling to room temperature, the reaction mixture was concentrated and dried on vacuum to give methyl 2-chlorobenzoxazole-4-carboxylate (0.66 g, quantitative) as a brown solid: 1H NMR (300 MHz, CDCl3) δ 8.05 (dd, J 8.1, 1.2 Hz, 1H), 7.72 (dd, J 8.1, 1.2 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 4.04 (s, 3H); MS (ESI+) m/z 212 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([O-])(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[K+].O=P(Cl)(Cl)[Cl:19]>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([Cl:19])(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(S(=O)(=O)[O-])sc2c(Cl)cccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Product: Cc1c(S(=O)(=O)Cl)sc2c(Cl)cccc12
Temperature: 60 °C
Yield: 61 %

Procedure:
A mixture of potassium 7-chloro-3-methylbenzothiophene-2-sulfonate (100 mg, 0.34 mmol) in POCl3 (5 mL) was heated at 60° C. over night. The POCl3 was evaporated and the crude product was purified on a small amount of silica using CH2Cl2 as eluent to give 58 mg of the title compound (61%).
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:4].C[Al](C)C.C(N(CC)CC)C.Cl.[NH2:40][C:41]1([C:44]#[N:45])[CH2:43][CH2:42]1>C(Cl)Cl.[Cl-].[Na+].O>[C:44]([C:41]1([NH:40][C:3]([C@H:5]2[CH2:9][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])(=[O:12])=[O:11])[CH2:7][C@@H:6]2[O:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:4])[CH2:43][CH2:42]1)#[N:45]
Reactant: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1Oc1ccc(Cl)cc1
Reactant: N#CC1(N)CC1
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@@H]2Oc2ccc(Cl)cc2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
To a solution of (1R,2R,4R) and (1S,2S,4S)-4-(2-chloro-benzenesulfonyl)-2-(4-chloro-phenoxy)-cyclopentanecarboxylic acid methyl ester (30 mg, 0.0699 mmol) in DCM (3 ml) was added trimethylaluminium (175 μl, 2M solution in toluene, 0.349 mmol), triethylamine (29.1 μl, 0.210 mmol) and 1-amino-1-cyclopropane-carbonitrile hydrochloride (21 mg, 0.1757 mmol) and the reaction mixture was stirred at 40° C. overnight. The mixture was then cooled to room temperature, diluted with brine and extracted 3 times with DCM. The combined organic layers were washed with water and brine, dried (Na2SO4) and evaporated. The remaining brown semisolid was purified by silica gel chromatography (DCM/MeOH 100:0-98:2) yielding a yellow solid (5 mg) that was triturated with ether to obtain the title compound (3 mg, 9%) as off-white solid. MS (EI): 477.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]([Cl:13])[C:3]=1[C:4]([OH:6])=[O:5].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([Cl:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cc(Cl)c(C(=O)O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1c(Cl)cc(O)cc1Cl
Temperature: -78 °C
Reaction time: 16 h

Procedure:
2,6-Dichloro-4-methoxy-benzoic acid (500 mg, 2.3 mmol) was taken up in CH2Cl2 and cooled to −78° C. BBr3 (6.9 ml of a 1 M solution in CH2Cl2) was added to the solution at −78° C. The solution was warmed to 25° C. and stirred at that temperature for 16 h. The solution was quenched with 3 N NaOH. The aqueous layer was extracted with CH2Cl2. The aqueous layer was cooled (0° C.) and acidified with conc. HCl (pH=1-2). The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4). Filtration and concentration gave the crude phenol which was used without further purification.
Reaction SMILES: Cl.[C:2]([O:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1)(=[O:4])[CH3:3].N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20].O>ClCCl>[C:2]([O:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:19](=[O:21])[CH3:20])[S:10][CH:11]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(=O)OCc1csc(N)n1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(COC(C)=O)cs1
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
To a mixture of (2-amino-1,3-thiazol-4-yl)methyl acetate hydrochloride (56 g) and pyridine (45 g) in dichloromethane (560 ml) was added acetyl chloride (23 g) over a period of 30 minutes at 5° C., and the reaction mixture was stirred for 10 minutes at the same temperature. The reaction mixture was poured into water (500 ml) and extracted with chloroform (1 L). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residual solid was collected by filtration with isopropyl ether to give (2-(acetylamino)-1,3-thiazol-4-yl)methyl acetate (47 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:19](=[CH:20][CH:21]=1)[C:7]1([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)[CH2:6][CH2:5]2>CO.Cl.CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:19](=[CH:20][CH:21]=1)[C:7]1([CH2:11][CH2:10][NH:9][CH2:8]1)[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCC2(CCc3cc(Cl)ccc32)C1
Agent: Cl
Solvent: CO
Product: Clc1ccc2c(c1)CCC21CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of tert-butyl 5-chloro-2,3-dihydrospiro[indene-1,3′-pyrrolidine]-1′-carboxylate (Prep9, 900 mg, 2.93 mol) in methanol (10 ml), HCl/CH3OH (10 ml, 3M in methanol) was added and stirred overnight at room temperature. The solvent was evaporated in vacuo to give the title compound (500 mg, y=82%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:11][C:12]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:13]=1[CH:14]=[CH:15][N+:16]([O-])=O.[NH4+].[OH-]>C1COCC1.O>[Cl:11][C:12]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:13]=1[CH2:14][CH2:15][NH2:16]
Reactant: COc1ccc(C=C[N+](=O)[O-])c(Cl)c1OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCN)c(Cl)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
28.8 g of LiAlH4 was dispersed in 920 ml of THF in a nitrogen stream. A solution of 100 g of AlCl3 in 1220 ml of THF was added dropwise to the dispersion under cooling at 0° C. After the completion of the addition, the mixture was stirred for 1 hour and a solution of 92 g of 2-chloro-3,4-dimethoxy-β-nitrostyrene obtained in Step 3 in 1440 ml of THF was added dropwise thereto. After the mixture was stirred at room temperature overnight, 122 ml of water was carefully added dropwise thereto under cooling with ice and then 122 ml of concentrated NH4OH was added dropwise thereto. The mixture was stirred for 1 hour and crystals thus precipitated were separated by filtration and the mother liquor was concentrated under reduced pressure. 300 ml of ethyl acetate and a 10% NaOH aqueous solution were added to the residue to conduct extraction. After washing with water followed by dehydration over MgSO4 and concentration to dryness under reduced pressure, 2-(2-chloro-3,4-dimethoxyphenyl)ethylamine (63.9 g, 79%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[OH2:9]>O1CCCC1>[N:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:9])=[CH:4][CH:5]=1
Reactant: O
Reactant: N#Cc1ccncc1
Solvent: C1CCOC1
Product: NC(=O)c1ccncc1
Yield: 91.4 %

Procedure:
(0.0051 g, 0.0119 mmol) of the platinum complex, prepared as in Example 1, was stirred with 4-cyanopyridine (2.0 g, 0.019 mol) and 0.75 ml (0.042 mol) of water and 10 ml tetrahydrofuran and the mixture heated under reflux for 4 hours. After cooling the liquids were removed using a rotary evaporator to give pyridine 4-carboxamide (2.12 g) corresponding to 90% yield.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11].[H-].[Na+].I[CH3:15]>CN(C=O)C>[F:11][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[I:1])[N:8]([CH3:15])[CH:7]=[CH:6]2
Reactant: Fc1cc2cc[nH]c2cc1I
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)c(I)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To a solution of 6-iodo-5-fluoro-1H-indole (0.495 g, 1.890 mmol) in dry DMF (7.0 mL) was added sodium hydride (55% suspension in oil) (0.124 g, 2.840 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, and then iodomethane (0.15 mL, 2.47 mmol) was added. The mixture was stirred for 1 hour at room temperature, and then quenched with ice and extracted with EtOAc (50 mL). The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EtOAc-hexane, 1:9) to afford 5-fluoro-6-iodo-1-methyl-1H-indole as a colorless solid (0.50 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([CH2:14][CH:13]([CH2:15][C:16](O)=[O:17])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.Cl.Cl.[NH2:36][CH:37]1[CH2:43][CH:42]2[N:44]([CH3:45])[CH:39]([CH2:40][CH2:41]2)[CH2:38]1>ClCCl.O>[CH3:45][N:44]1[CH:39]2[CH2:40][CH2:41][CH:42]1[CH2:43][CH:37]([NH:36][C:16](=[O:17])[CH2:15][CH:13]1[CH2:12][C:11]3([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][CH2:19]3)[CH2:14]1)[CH2:38]2
Reactant: CN1C2CCC1CC(N)C2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(CC(=O)O)C2
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN1C2CCC1CC(NC(=O)CC1CC3(CCN(C(=O)OC(C)(C)C)CC3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
1.7 g of [7-(tert-butoxycarbonyl)-7-azaspiro[3.5]non-2-yl]acetic acid was dissolved in 50 ml of dichloromethane. After adding 0.9 ml of triethylamine, the resulting mixture was ice-cooled. After adding 0.95 ml of ethyl chloroformate, the resulting mixture was stirred at room temperature for 30 minutes. Then 1.9 g of 3-amino-8-methyl-8-azabicyclo[3.2.1]octane dihydrochloride and 2.5 ml of triethylamine were added thereto and the resulting mixture was stirred at room temperature for 6 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 N sodium hydroxide and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained crystals were washed with ether to thereby give 1.25 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9][C:8]([CH2:24][CH3:25])([CH3:23])[C:7]=2[N:6]=1)=[O:4].[H-].[Na+].I[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9][C:8]([CH2:24][CH3:25])([CH3:23])[C:7]=2[N:6]=1)=[O:4]
Reactant: CCC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)OC)nc21
Reactant: CC(C)CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(C)CC(c2ccc(F)c(Cl)c2)N(CCC(C)C)c2ccc(C(=O)OC)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a 0° C. solution of 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid methyl ester (200 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL) was added a 60% dispersion of sodium hydride in mineral oil (44 mg, 1.1 mmol) portionwise. The mixture was stirred at 0° C. for 30 min and then 1-iodo-3-methyl-butane (327 mg, 1.6 mmol) was added to above mixture dropwise at 0° C. The mixture was stirred at 0° C. for 3 hours and then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish residue was purified by ISCO combi-flash chromatography (gradient elution, 0-5% ethyl acetate/hexane) to afford 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid methyl ester (160 mg, 67.5%) as a yellow oil. MS (ESI+) [(M+H)+] 433.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=O)[CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[CH:10]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([N:67]2[CH2:66][CH2:65][N:64]([C:47](=[O:46])[CH2:48][NH:49][C:50]([C:52]3[CH:57]=[CH:56][C:55]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[CH:54][CH:53]=3)=[O:51])[CH2:69][CH2:68]2)=[O:19])[CH2:11][CH2:12]1
Reactant: O=C(O)c1ccccc1OCC1CC1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2OCC2CC2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
DIPEA (149.8 mg, 1.16 mmol) was added to the stirred solution of 2-Cyclopropylmethoxy-benzoic acid (59.4 mg, 0.31 mmol) in DMF (3 mL), HOBt (45.9 mg, 0.34 mmol) and EDCI.HCl (148.1 mg, 0.77 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 40 mg (26.0% yield) of biphenyl-4-carboxylic acid {2-[4-(2-cyclopropylmethoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 92.64%. 1H NMR: (DMSO) δ 8.64 (t, 1H), 7.96 (d, 2H), 7.8-7.7 (q, 3H), 7.54-7.46 (t, 2H), 7.44-7.32 (m, 2H), 7.2 (d, 1H), 7.1-6.94 (m, 2H), 4.2 (d, 2H), 3.9 (d, 1H), 3.7-3.4 (m, 6H), 3.25-3.0 (m, 2H), 1.2 (s, 2H), 0.6 (d, 2H), 0.3 (s, 2H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[O:22])[CH2:11]1)=[O:7])(C)(C)C.[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37](C(O)=O)=[C:36]([O:44][CH3:45])[CH:35]=1>>[NH2:33][C:34]1[C:42]([Cl:43])=[CH:41][C:37]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH3:32])[CH:24]=3)=[O:22])[CH2:11]2)=[O:7])=[C:36]([O:44][CH3:45])[CH:35]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: Cn1cc(C(=O)NCCCCCN2CCC(CNC(=O)OC(C)(C)C)C2)c2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNC(=O)c2cn(C)c3ccccc23)C1

Procedure:
N-(5-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentyl)-1-methyl-1 H-indole-3-carboxamide (0.89 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.42 g) to give N-(5-(3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)pentyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)CCCCCCCN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 8-aminooctanoic acid, methyl ester hydrochloride in the presence of diisopropylethylamine as more fully described in Example 11 of European Patent Application 136,883 to give (±)-8-[[2-[(acetylthio)methyl]-1-oxo-3phenylpropyl]amino]octanoic acid, methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:26][C:27]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1)[CH2:23][CH2:24][CH3:25]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3([O:26][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCCOC1=CCCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCCCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCCC1
Yield: 38.5 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1-n-butoxycyclooctene (1.3 g, 5.56 mmol) in the same manner as the example 20 to give the compound 32 (203 mg, 38%). Rf 0.70 (Al2O3 hexane-EtOAc 4:1) PMR (CDCl3 -0.1% d5 -Py): δH0.88 (3 H, t, J 7.2 Hz, CH3), 1.23 (6 H, d, J 6.9 Hz, (CH3)2CH), 1.25-1.80 (14 H, m, --CH2 --), 2.99 (2 H, t, J 5.7 Hz, CH2 -Im), 3.05 (2 H, t, J 6.6 Hz, CH2 -Im), 3.10 (1 H, s, J 6.9 Hz, (CH3)2CH), 3.51 (3 H, s, NCH3), 3.67 (2 H, t, J 6 Hz, OCH2), 6.82 (2 H, d, J 1.8 Hz, arom-H), 7.12 (1 H, t-like, arom-H) Elementary analysis (for C27H40N2O2Cl2S) Calcd.: C, 61.47% H, 7.64% N, 5.31% S, 6.08% Cl, 13.44% Found: C, 61.58% H, 7.71% N, 5.36% S, 6.16% Cl, 13.18%
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:7]=[CH:6][S:5][C:4]1=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:9]#[N:10].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C.O>O1CCCC1.ClCCl>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([O:1][N:2]=[C:3]3[CH:7]=[CH:6][S:5][C:4]3=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[C:9]#[N:10])(=[O:37])=[O:36])=[CH:31][CH:30]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccccc1C(C#N)=C1SC=CC1=NO
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2ccc(S(=O)(=O)ON=C3C=CSC3=C(C#N)c3ccccc3C)cc2)cc1
Reaction time: 1 h
Yield: 79 %

Procedure:
In 490 g of tetrahydrofuran were dissolved 45 g (0.19 mol) of (3-(hydroxy)imino-3H-thiophen-2-ylidene)-(2-methylphenyl)-acetonitrile in Synthesis Example 14 and 61.8 g (0.19 mol) of 4-(4′-methylphenylsulfonyloxy)benzenesulfonyl chloride in Synthesis Example 7. To the solution cooled, 20.6 g (0.20 mol) of triethylamine was added dropwise such that the temperature might not exceed 10° C. The solution was allowed to ripen for 1 hour at room temperature, after which 150 g of water and 500 g of dichloromethane were added. The organic layer was separated, and washed with 150 g of water three times. The organic layer was concentrated in vacuum to 130 g. Methanol was added to the concentrate for recrystallization, followed by filtration and drying. There was obtained 83 g of yellow crystals. The crystals were purified by silica gel column chromatography (eluent, dichloromethane). The elute was concentrated, followed by recrystallization from methanol, filtration and drying. There was obtained 77 g of yellow crystals (yield 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[C-:18]#[N:19].[Na+]>CN(C)C=O.O>[C:18]([CH2:11][C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([OH:10])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)#[N:19]
Reactant: [C-]#N
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
To 2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (6.7 g) in dimethylformamide (198 ml) at 60° C. was added dropwise over 25 minutes, a solution of sodium cyanide (2.84 g) in water (49 ml). Heating at 60° C. was continued for five hours. The reaction mixture was then cooled, poured into water (900 ml), and extracted with ethyl acetate (3×150 ml). The combined organic extracts were washed with saturated aqueous brine, dried (Na2SO4) and evaporated to dryness to give a pale yellow solid (6.1 g) which was triturated with ethyl ether. The residual solid was recrystallized from ethyl ether/methanol to give the title compound, 4.13 g (56%), m.p. 217°-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[C:8]1[O:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[N:12]=1.[CH2:21]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[C:8]1[O:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:21][CH3:22])=[CH:25][CH:26]=3)=[CH:15][CH:14]=2)[N:12]=1
Reactant: Clc1cncc(Cl)c1C1=NC(c2ccc(I)cc2)CO1
Reactant: CCOc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: Cl
Product: CCOc1ccc(-c2ccc(C3COC(c4c(Cl)cncc4Cl)=N3)cc2)cc1

Procedure:
A solution of 2-(3,5-dichloro-4-pyridinyl)-4-(4-iodophenyl)oxazoline (0.2 g, 0.48 mmol), p-ethoxybenzeneboronic acid (0.095 g, 0.57 mmol), sodium carbonate (0.076 g, 0.72 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.025 g) and tri-o-tolylphosphine (0.020 g) was heated at reflux for 12 h under an atmosphere of nitrogen. After cooling, 1N HCl (15 mL) was added and the mixture was extracted with diethyl ether (3×30 mL). The combined ether layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (eluant, ether/hexane—1:1) to give the product as an off-white solid: mp 121-122° C.