Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([NH:11]C(OCC2C=CC=CC=2)=O)[CH:9]2[CH2:22][CH2:23][CH:6]1[CH2:7][CH2:8]2)=[O:4].[ClH:24]>C(OCC)(=O)C.[Pd].C(OCC)C.O1CCOCC1>[ClH:24].[CH3:1][O:2][C:3]([C@H:5]1[C@@H:10]([NH2:11])[CH:9]2[CH2:22][CH2:23][CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)[C@@H]1C2CCC(CC2)[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C2CCC(CC2)[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2R,3S)-3-Benzyloxycarbonylamino-bicyclo[2.2.2]octane-2-carboxylic acid methyl ester (0.57 g, 1.79 mmol) was dissolved in ethyl acetate (20 mL). 10% Palladium on carbon (60 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil was dissolved in diethyl ether (6 mL) and added dropwise with vigorous stirring to a mixture of 4.0 M solution of hydrochloric acid in 1,4-dioxane (1.02 mL) and diethyl ether (10 mL). The desired product began to precipitate as a white solid. The mixture was stirred for 20 min. The precipitate was collected by vacuum filtration, washed with additional diethyl ether (5 mL). The solid was further dried in vacuo for 1 h to afford the desired product, (2R,3S)-3-amino-bicyclo[2,2,2]octane-2-carboxylic acid methyl ester hydrochloride (0.33 g, 1.50 mmol, 84%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.38 (2H, dd, J1=21.2 Hz, J2=13.6 Hz), 1.55-1.63 (5H, m), 1.76-1.89 (3H, m), 3.02 (1H, dd, J1=10.0 Hz, J2=2.4 Hz), 3.47 (1H, bs), 3.65 (3H, s), 7.97 (3H, s). LC-MS (ESI) calcd for C10H17NO2 (free amine) 183.25. found 184.2 [M+H+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][C:19]3=[O:24])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:25])[C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:34])[CH2:20][C:19]3=[O:24])=[CH:15][CH:16]=2)=[CH:5][C:4]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CN2CCNCC2=O)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)C(=O)C1

Procedure:
To 200 mg of the HCl salt of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide was added 55 mg of Paraformaldehyde and 185 mg of Sodium Triacetoxyborohydride in 1 mL of 2% AcOH in DMF. After completion, the reaction is extracted once with bicarbonate and brine in Ethyl Acetate, dried over Magnesium Sulfate, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-2-oxopiperazin-1-yl)methyl)benzamide. MS (Q1) 435.3 (M)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[O:20][C:21]([C:24](O)=[O:25])=[CH:22][N:23]=1>>[NH2:18][C:19]1[O:20][C:21]([C:24]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([Cl:2])[CH:4]=2)[CH3:16])=[O:25])=[CH:22][N:23]=1
Reactant: Nc1ncc(C(=O)O)o1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(Cl)c1
Agent: Cl
Product: CC(NC(=O)c1cnc(N)o1)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 47 %

Procedure:
The title compound is prepared in 47% yield (106 mg, clear colorless oil) from (+)-1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (182 mg, 0.63 mmol, Amine-5, single enantiomer) and 2-aminooxazole-5-carboxylic acid (80 mg, 0.63 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:15])[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)OCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)COc2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
In a 50 ml pear flask containing methyl 3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (32 mg, 0.16 mmol) were added methanol (3 ml) and 1.0 M sodium hydroxide (6 ml, 6 mmol) solution to give a suspension. This was stirred at room temperature for 1 hour. Then 2N hydrochloride solution (3.5 ml) was added to neutralize the excess base. The acidic mixture (pH ˜2) was then extracted with EtOAc twice, and the combined organic layers were dried over MgSO4, filtered and concentrated to give the desired 3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid (23 mg, 77% yield) as a white flakey oily solid that was used in the next step without further purification.
Reaction SMILES: [N+](C1C=C[C:7]([O:10][P:11]([CH3:23])(=[O:22])[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=CC=1)([O-])=O.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33]1C2C(=CC=C(O)C=2)N[N:34]=1.N12CCCN=C1CCCCC2.CO>ClCCl>[CH3:7][O:10][P:11]([CH3:23])(=[O:22])[O:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[NH:19][N:34]=[C:33]2[C:25]1[NH:24][C:32]2[C:27]([CH:26]=1)=[CH:28][CH:29]=[CH:30][CH:31]=2
Reactant: Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Reactant: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COP(C)(=O)Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1
Reaction time: 3 h
Yield: 26.3 %

Procedure:
Methylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester is prepared according to procedure F using 150 mg of methylphosphonic acid bis-(4-nitrophenyl) ester, 4 ml of dichloromethane, 100 mg of 3-(1H-indol-2-yl)-1H-indazol-5-ol, 67 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene and 4 ml of dichloromethane. After stirring for 3 hours, a solution of 100 μl of methanol in 2 ml of dichloromethane is added dropwise. The reaction medium is stirred for approximately 16 hours and then concentrated to dryness under reduced pressure. The oil obtained is purified on a 5 g Interchim flash cartridge of silica with a particle size of 15-35 μ. Eluent: 30% of ethyl acetate in cyclohexane, then with 80% of ethyl acetate in methanol. The solvents are evaporated off under reduced pressure and the product obtained is crystallized from ethyl acetate. 36 mg of methylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester methyl ester are obtained in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8]C(OCC)=O)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[CH2:17][O:16]1.I[Si](C)(C)C.Cl>C(Cl)(Cl)Cl>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:14][N:15]2[C:19](=[O:20])[C:18]([CH3:21])([CH3:22])[CH2:17][O:16]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)Nc1ccc(CN2OCC(C)(C)C2=O)c(Cl)c1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 8.4 grams (0.026 mole) of 2-[2-chloro-4-(ethoxycarbonylamino)phenyl]methyl-4,4-dimethyl-3-isoxazolidinone in 100 ml of chloroform, under an argon atmosphere and at ambient temperature, was carefully added dropwise 6.0 grams (0.03 mole) of iodotrimethylsilane. Upon completion of addition the reaction mixture was warmed to 60° C. where it stirred for 16 hours. Five ml of methanolic 2N hydrochloric acid was added to the reaction mixture. The solution was stirred for 10 minutes, then concentrated under reduced pressure to a residual solid. The solid was triturated in 25 ml of water. The water/solid mixture was neutralized with aqueous saturated sodium bicarbonate solution. The solid was collected by filtration to give 2-(4-amino-2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone; m.p. 106°-108° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6]/[C:7](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CO>[CH3:6]/[C:7](=[CH:17]\[C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: CC(/C=C/C(=O)OC(C)(C)C)=C\c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: CC(/C=C/C(=O)OC(C)(C)C)=C\c1ccc(N)cc1
Reaction time: 1.17 h
Yield: 85 %

Procedure:
Tin(ii) chloride dihydrate (11.5 g, 51 mmol) was added to a stirred solution of tert-butyl (E,E)-4-methyl-5-(4-nitrophenyl)penta-2,4-dienoate (3.67 g, 12.7 mmol) in methanol (75 ml). The mixture was stirred and heated at reflux and the reaction monitored by HPLC. After 70 min, 4% starting material remained and there were two new products comprising 90 and 6% respectively. The cool mixture was concentrated in vacuo, water (75 ml) was added to the residue and then 2N NaOH solution until at pH 11. Ethyl acetate (150 ml) was added and the mixture filtered through Celite. The EtOAc layer was washed with 5% NaCl solution, dried over MgSO4 and concentrated in vacuo. The residual oil was stirred in diisopropyl ether (20 ml) for 10 min, insoluble by-products removed by filtration and the filtrate concentrated in vacuo to give 2.8 g (86%) of a yellow solid, mp 99-101° C.
Reaction SMILES: FC(F)(F)S(O[CH2:7][CH2:8][N:9]([CH2:22][CH2:23]OS(C(F)(F)F)(=O)=O)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])(=O)=O.Cl.[NH2:35][C:36]1([C:39]([O:41][CH3:42])=[O:40])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([N:9]1[CH2:8][CH2:7][N:35]([C:36]2([C:39]([O:41][CH3:42])=[O:40])[CH2:38][CH2:37]2)[CH2:23][CH2:22]1)(=[O:11])=[O:12])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCOS(=O)(=O)C(F)(F)F)CCOS(=O)(=O)C(F)(F)F
Reactant: COC(=O)C1(N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)CC1
Temperature: 60 °C

Procedure:
A solution of N,N-bis-(2-trifluoromethanesulfonyloxyethyl)-2-nitrobenzenesulfonamide (1.83 g, 3.30 mmol) from Example 16B and methyl 1-aminocyclopropane-1-carboxylate HCl (0.50 g, 3.30 mmol) in anhydrous acetonitrile (10 mL) was treated with sodium carbonate (1.40 g, 13.2 mmol) and heated overnight at 60° C. (J. A. Kozlowski, et al., Bioorg. Med. Chem. Lett. 12: 791-794, 2002). Reaction diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 3:1 hexane:ethyl acetate to afford the title compound. MS(ESI) m/z 370 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.C(C1C=CC=CN=1)(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:57][CH2:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([O:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[Cl:74])[CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.O>[Cl:74][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=1[O:67][CH:64]1[CH2:63][CH2:62][N:61]([C:59](=[O:60])[CH2:58][NH:57][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=3)[NH:21][N:20]=2)=[O:24])[CH2:66][CH2:65]1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: O=C(O)c1cc(-c2ccccn2)[nH]n1
Agent: CC(=O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccccn2)[nH]n1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
DIPEA (287 mg, 2.2 mmol) was added to a stirred solution of 5-pyridin-2-yl-1H-pyrazole-3-carboxylic acid hydrochloride (100 mg, 0.44 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from 2-acetylpyridine) in DMF (2 mL) followed by HOBt (63 mg, 0.46 mmol) and EDCI.HCl (89 mg, 0.46 mmol). After 2 minutes 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (135 mg, 0.44 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by filtering through 60-120 silica gel column and filtrate collected was concentrated under reduced pressure to afford 145 mg (74.3% Yield) of 5-pyridin-2-yl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 440, 90%. 1H NMR (300 MHz, DMSO-d6): δ 13.9 (s, 1H), 8.6 (d, 1H), 8.1 (bs, 1H), 7.84 (m, 2H), 7.24 (m, 5H), 6.94 (m, 2H), 4.75 (m, 1H), 4.15 (d, 2H), 3.6 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(CBr)ccc1Cl
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a stirred solution of 2-chloro-5-methyl-benzoic acid (25 g) in chloroform (500 ml) at 50° C. was added N-bromosuccinimide (27.40 g). The flask was purged with nitrogen and azobisisobutyronitrile (0.10 g) added in one portion. The solution was heated at reflux for 1 h. Further azobisisobutyronitrile (0.10 g) was added and the mixture heated a further 3 h. The solution was concentrated in vacuo, redissolved in diethyl ether and filtered to remove insoluble succinimide. The ether solution was washed with 2N aqueos hydrochloric acid solution followed by brine then dried over magnesium sulphate. The solution was concentrated to a volume of 150 ml then diluted with isohexane. After further partial concentration crystallization started. The mixture was allowed to stand in an ice-bath for 1 h. The resulting crystals were filtered, washed with isohexane and dried in vacuo to give the subtitle compound (17 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5]>C1CCCCC1>[Cl:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][O:5][C:3]([CH3:6])([CH3:4])[CH3:2]
Reactant: CC(C)(CO)CCl
Solvent: C1CCCCC1
Product: CC(C)(CCl)COC(C)(C)C
Yield: 78.06 %

Procedure:
B.P.=169.0°-174.0° C. GC assay=2.98% cyclohexane, 16.79% 3-chloro-2,2-dimethyl-1-propanol, 78.06% desired product, and 1.17% unknowns.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:12]=[N:11][N:10]=1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>C(#N)C>[CH3:28][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39]([NH:8][C:9]1[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:12]=[N:11][N:10]=1)=[O:40])[CH3:27]
Reactant: CCCCCCCCCCCCn1nnnc1N
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCn1nnnc1NC(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 23.7 %

Procedure:
Triethylamine (2.50 mL, 18.0 mmol) was added to a slurry of 5-amino-1-dodecyltetrazole (4.56 g, 18.0 mmol) in acetonitrile (150 mL). The mixture was heated to reflux and upon dissolution of the solid, 2,6-diisopropylphenyl isocyanate (3.90 mL, 18.1 mmol) was added in one portion. The solution was refluxed for 18 hours and allowed to cool. The resultant precipitate was filtered and the filtrate concentrated in vacuo and partitioned between ethyl acetate and water (1:1). The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and columned on silica gel, eluting with 10% then 15% ethyl acetate in hexanes to give an oil which solidified on standing to give the title compound as a white solid (1.95 g, 24%), m.p. 80-88° C.
Reaction SMILES: [OH-].[K+].[C:3]([OH:6])(=[S:5])[CH3:4].Br[CH2:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]>O.CC(C)=O>[C:3]([S:5][CH2:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])(=[O:6])[CH3:4]
Reactant: CC(O)=S
Reactant: O=C(CBr)OCCOc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)SCC(=O)OCCOc1ccccc1
Yield: 98.1 %

Procedure:
The solution of potassium hydroxide (6.6g) in water (20 ml) was added under ice cooling to thioacetic acid (7.6g) and then the solution of β-phenoxyethyl bromoacetate (25.9g) in acetone (30ml) was added and treated for 6 hours at room temperature. Extracted twice with 200 ml of ethylether and the ether layer was washed with water, dried, and concentrated, giving colourless crystals (24.9g) which was then recrystallized from n-hexane. Thus colourless crystals (20.8g), m.p. 56.0°-57.0° C., of β-phenoxyethyl S-acetylthioglycolate was obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([O:11][CH2:12][C:13]([N:15]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]1[NH:25][C:26]([C:28]1[NH:32][C:31]2[C:33]([Cl:37])=[C:34]([Cl:36])[S:35][C:30]=2[CH:29]=1)=[O:27])=[O:14])(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([O:11][CH2:12][C:13]([N:15]([CH2:38][C:39]([OH:41])=[O:40])[C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]1[NH:25][C:26]([C:28]1[NH:32][C:31]2[C:33]([Cl:37])=[C:34]([Cl:36])[S:35][C:30]=2[CH:29]=1)=[O:27])=[O:14])(=[O:10])[CH3:9]
Reactant: CC(=O)OCC(=O)N(CC(=O)OC(C)(C)C)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC(=O)N(CC(=O)O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
TFA (3 mL) was added to a solution of 1,1-dimethylethyl [[(acetyloxy)acetyl]((1R,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)amino]acetate (Method 20, 130 mg, 0.25 mmol) in DCM (10 mL) and the reaction was stirred at ambient temperature for 2 h. The volatiles were removed by evaporation under reduced pressure to afford the title compound (130 mg, 99%) as a white solid.
Reaction SMILES: COC1C=CC2NC3C(C)=C4C=CN=CC4=C(C)C=3C=2C=1.C(I)CCC.[CH3:27][O:28][C:29]1[CH:41]=[CH:40][C:39]2[N:38]([CH2:42]CCC)[C:37]3[C:36]([CH3:46])=[C:35]4[CH:47]=[CH:48][N:49]=[CH:50][C:34]4=[C:33]([CH3:51])[C:32]=3[C:31]=2[CH:30]=1>>[CH3:27][O:28][C:29]1[CH:41]=[CH:40][C:39]2[N:38]([CH3:42])[C:37]3[C:36]([CH3:46])=[C:35]4[CH:47]=[CH:48][N:49]=[CH:50][C:34]4=[C:33]([CH3:51])[C:32]=3[C:31]=2[CH:30]=1
Reactant: CCCCn1c2ccc(OC)cc2c2c(C)c3cnccc3c(C)c21
Agent: COc1ccc2[nH]c3c(C)c4ccncc4c(C)c3c2c1
Solvent: CCCCI
Product: COc1ccc2c(c1)c1c(C)c3cnccc3c(C)c1n2C

Procedure:
from 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole and butyl iodide, there can be prepared 9-methoxy-5,11-dimethyl-6-butyl-6H-pyrido[4,3-b]carbazole
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17]CC)=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:21].C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:21]
Reactant: CCOC(=O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Yield: 91.3 %

Procedure:
Six hundred mg (1.83 mmol) of ethyl 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylate obtained in Example 15 was added to a mixed solvent of ethanol and water (1:1), then 2 ml of 2 N aqueous solution of sodium hydroxide was added thereto, and the mixture was heated to reflux for two hours. When the reaction was completed, ethanol was evaporated therefrom, the residual aqueous solution was adjusted to pH nearly 7.0 with 1 N aqueous solution of acetic acid and, after stirring for a while, crystals separated out therefrom were collected by filtration, successively washed with ethanol, acetone and ether and air dried to give 501 mg (91.4 percent) of the title compound, melting point 318° C. (decomposition). Elementary analysis calculated as C12H7FClNO3S: C 48.09, H 2.35, N. 4.67; Found: C 48.28, H 2.14, N 4.37.
Reaction SMILES: O.[OH-].[Li+].[C:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO.O>[C:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccccc3)nc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(c2ccc(-c3ccccc3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide, monohydrate (0.016 g, 0.37 mmol) was added to ethyl 1-(6-phenylpyridin-3-yl)cyclopropanecarboxylate (50.0 mg, 0.19 mmol) in methanol (1.5 mL) and water (0.5 mL). The mixture was stirred at room temperature for overnight, then was adjusted to be acidic (pH=5) with 1N HCl aqueous solution, and then was concentrated to give a crude product which was directly used in the reaction of the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[N:24][C:23]=3[CH2:34][CH:35](OC)OC)=[O:21])=[CH:15][C:14]=2[O:40][CH3:41])[CH2:9]1)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:35]=[CH:34][C:23]4[N:24]=[C:25]([C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=5)[S:26][C:22]=4[C:20]3=[O:21])=[CH:15][C:14]=2[O:40][CH3:41])[CH2:9]1
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CC(OC)OC)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Temperature: 95 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
Dissolve 3-(4-{[2-(4-chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (18.9 g, 31.28 mmol) and p-toluenesulfonic acid monohydrate (19.7 g, 103.56 mmol) in dry toluene (460 mL) and stir mechanically at 95° C. overnight. Cool the reaction mixture and add 1 N NaOH. Stir the mixture vigorously at room temperature for one hour. Extract the aqueous layer with CH2Cl2 (2×700 mL). Combine the organic portions, wash with brine (700 mL), dry over MgSO4, and filter. Concentrate the filtrate in vacuo to give 13.0 g (85%) of the title compound. ES/MS m/z (35Cl) 440.0 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.[CH3:21][N:22]([CH3:32])[C:23]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>>[CH3:21][N:22]([CH3:32])[C:23]([NH:25][CH:26]1[CH2:27][CH2:28][N:29]([C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:20][CH:19]=2)[CH2:30][CH2:31]1)=[O:24]
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CN(C)C(=O)NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: CN(C)C(=O)NC1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 61.5 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (200 mg, 0.76 mmol) obtained in Step 6 of Example 1, 1,1-dimethyl-3-(piperidin-4-yl)urea (0.20 ml, 1.14 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 1.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (204 mg, 1.06 mmol) and N-methylmorpholine (0.18 mL, 1.66 mmol) in a similar manner to Example 5, was crystallized from ethyl acetate to obtain Compound 132 (195 mg, 62%).