Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.[C:38]1([C:44]2[S:45][CH:46]=[C:47]([C:49]([N:51]3[CH2:56][C:55]4([CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)[O:54][CH2:53][CH2:52]3)=[O:50])[N:48]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:59]2[CH2:60][CH2:61][C:55]3([O:54][CH2:53][CH2:52][N:51]([C:49]([C:47]4[N:48]=[C:44]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[S:45][CH:46]=4)=[O:50])[CH2:56]3)[CH2:57][CH2:58]2)=[CH:10][CH:11]=1)[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36]
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)c2csc(-c4ccccc4)n2)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.619 g) in MeCN (3 mL) was added dropwise to a solution of (2-phenylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 112, step b) (0.274 g) and triethylamine (0.22 mL) in MeCN (7.3 mL) at RT under argon. The resulting mixture was stirred at 80° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine and water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-70% EtOAc in petroleum ether (40-60° C.) to give the subtitled compound as a yellow solid. Yield 0.42 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[C:18]1(=[O:28])[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>O1CCCC1.C(Cl)Cl>[Cl:17][C:4]1[CH:3]=[C:2]([NH:1][C:18]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=[O:28])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(NC(=O)c3ccccc3C(=O)O)cc2Cl)C1=O
Yield: 10.3 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1, Step C, using 3.0 grams (0.012 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 1.8 grams (0.012 mole) of phthalic anhydride in 125 mL of tetrahydrofuran. The reaction mixture was dissolved in 200 mL of methylene chloride and washed with four 50 mL portions of an aqueous 10% hydrochloric acid solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a semi-solid residue. The residue was stirred and heated in ethyl acetate-heptane. The resultant solid was collected by filtration and was recrystallized from acetate/hexane to yield 0.5 gram of 2-[[2-chloro-4-[(2-carboxyphenyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 172° C., dec.
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1([N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.O.O.[C:28]([O-])(=[O:30])C.[Na+]>CC(C)=O>[C:19]1([N:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH:28]=[O:30])=[CH:15][CH:14]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)[O-]
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 73 %

Procedure:
30 mL of dimethylformaldehyde (DMF) was put into a 250 mL flask, cooled to 0° C. and 3.8 mL of POCl3 was slowly added thereto. Then, 10 g of triphenylamine was added to the resultant mixture and heated to 70° C. for 5 hours. The reaction container was cooled to room temperature and then a reactant solution was poured into ice water. Subsequently, 40 g of sodium acetate trihydrate was put for neutralization and then an organic layer was separated with methylenechloride. The obtained organic layer was dried using magnesium sulfate and methylenechloride was removed under reduced pressure, yielding a product. The product was recrystallized using methanol and a light yellow solid was finally obtained, yielding 73% of a desired product. Data of NMR spectra confirmed that the product had the same structure as 4-(diphenylamino)benzaldehyde, that is, the compound (1) in the reaction scheme 2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[CH2:23]([N:31]1[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CN(CCc2ccccc2)CCN1
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccc5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 38.2 %

Procedure:
tert-Butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (370 mg, 1.01 mmol) and 4-phenethylpiperazin-2-one (197 mg, 0.965 mmol) were reacted according to Example 2 (step f) to provide the title compound (180 mg, 39%) as a yellow powder: 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=8.4 Hz, 1H), 7.35-7.28 (m, 2H), 7.27-7.18 (m, 4H), 6.99-6.97 (dd, J=8.3, 1.8 Hz, 1H), 4.61 (br s, 2H), 3.74 (br s, 4H), 3.60 (s, 3H), 3.45 (br s, 2H), 2.91 (br s, 4H), 2.74 (br s, 4H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].IC.[CH2:23](C(C)=O)[CH3:24]>O>[CH2:23]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]#[N:14])=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:24]
Reactant: CCn1cc(C#N)c2ccc(O)cc21
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCOc1ccc2c(C#N)cn(CC)c2c1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone is added anhydrous K2CO3 (71 mg, 0.52 mmol) and iodomethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are dried and concentrated. Flash chromatography (CH2Cl2) gives 94 mg (100% S) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C)C=O>[Si:13]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: C#CCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCCCO[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a solution of 5-hexyne-1-ol (4.81 g, 49.0 mmol) in N,N-dimethylformamide (100 ml) were added imidazole (4.0 g, 59.0 mmol) and t-butyldimethylsilylchloride (8.12 g, 54.0 mmol) at 0° C., which was then stirred at the same temperature for 3 hour After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane:ethyl acetate=10:1) to give the title compound (10.0 g, yield: 99%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH3:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([Sn](CCCC)(CCCC)CCCC)[N:53]=1>CN(C=O)C.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:54]2[CH:55]=[CH:56][CH:57]=[C:52]([CH3:51])[N:53]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)n1
Yield: 98.1 %

Procedure:
A solution containing the product from Example 23I (0.113 g, 0.160 mmol) in DMF (1.5 mL) was treated with LiCl (0.068 g, 1.60 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.034 g, 0.048 mmol), and the product from Example 68A (0.367 g, 0.961 mmol), heated at 110° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-50% ethyl acetate in dichloromethane to give the title compound (0.102 g, 98% yield).
Reaction SMILES: [H-].[Na+].C(O)(=O)C(O)=O.[CH3:9][N:10]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]2[CH:22]=[CH:21][C:20](C(F)(F)F)=[CH:19][CH:18]=2)[C@H:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:11]1.[Cl:33]C1C=C(F)C=CC=1.[Na+].[Cl-:42]>CN(C=O)C.CCOCC>[ClH:33].[Cl:42][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C@@H:13]1[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][C@H:12]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: [Cl-]
Reactant: Fc1cccc(Cl)c1
Reactant: CN1CC[C@@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CC[C@@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.9 g of sodium hydride, 12.07 g of 1-methyl-3-phenyl-4-piperidinol (mixture of isomers of Example 1) and 70 ml. of dry DMF is heated at approximately 100° C. for 1 hour, under nitrogen, then cooled to room temperature. A solution of 16.45 g of 3-chlorofluorobenzene in 40 ml of DMF is added all at once, and the mixture is stirred for 18 hours at room temperature, then heated slowly so that after 4 hours the pot temperature is 68° C. After stirring for about 48 hours at room temperature, another 0.76 g of sodium hydride is added, and the mixture is again heated slowly to approximately 70° C. After 2 hours the mixture is cooled and treated with saturated aqueous NaCl solution, then poured into a mixture of saturated aqueous NaCl solution and ether. The phases are separated and the aqueous phase is extracted with ether. The combined ether extracts are washed with water, saturated aqueous NaCl solution, and concentrated in vacuo. The residue is partitioned between dichloromethane and water. The phases are separated, the aqueous phase is extracted with more dichloromethane, and the combined dichloromethane phases are extracted with 2 N HCl solution, then washed successively with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution, and dried over anhydrous Na2SO4. Concentration is vacuo affords an oil which is a mixture of product isomers. This mixture is chromatographed on silica gel, using acetone as the initial solvent. The trans product is eluted with 25% methanol/acetone as solvent. The fractions containing the trans isomer are combined and concentrated in vacuo to an oil. This oil is taken up in ether, dried over anhydrous Na2SO4, filtered, and treated dropwise with HCl-saturated ether solution. The ether and excess HCl are removed in vacuo and the resulting gummy solid is triturated with fresh ether until completely solid. This solid is filtered, washed with ether and dried to afford a crude salt, mp s 211.5°, 213°-214.5° C. Recrystallization from acetone affords needles of trans-4-(3-chlorophenoxy)-1-methyl-3-phenylpiperidine hydrochloride having the same melting point.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]2[CH2:18][CH2:17][N:16](CCC3C=NC=CC=3)[CH2:15][CH2:14]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.N1C=CC=C(CCCl)C=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[O:48][CH3:49])[CH2:42][CH2:43]Cl>>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH2:42][CH2:43][N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=3)[CH2:14][CH2:15]2)[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]
Reactant: CS(=O)(=O)Nc1ccc(SC2CCN(CCc3cccnc3)CC2)cc1
Reactant: COc1ccc(CCCl)cc1OC
Agent: Cl
Agent: ClCCc1cccnc1
Product: COc1ccc(CCN2CCC(Sc3ccc(NS(C)(=O)=O)cc3)CC2)cc1OC

Procedure:
The same procedure as that of Example 1 (1) to (8) was repeated except that 2-(3-pyridyl)ethyl chloride hydrochloride was replaced with 3,4-dimethoxyphenethyl chloride to prepare the intended compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([CH3:28])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(OCC)C>[CH3:28][C:20]1[CH:19]=[C:18]([C@H:10]2[CH2:9][C@@H:8]([C:6]3[O:7][NH:32][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])[CH:23]=[CH:22][C:21]=1[C:24]([F:27])([F:26])[F:25]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)c(C)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)c(C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (1.4 g, 3.37 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. NaOH (0.135 g, 3.37 mmol) dissolved in water (2 mL) was added during 10 min and the resulting colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.223 g, 3.37 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 30 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M HCl and the mixture continued to stir at 80° C. for 20 min. The mixture was dissolved between diethyl ether and water. The phases were separated and the organic phase was dried over Na2SO4, filtered through celite and the solvent removed. Purified by preparative HPLC. Gradient eluation using acetonitrile-acidic buffer, started 40-60 and ended 55-45. Cis-methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.37 g, 29%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.80-1.87 (m, 1H), 2.07-2.28 (m, 2H), 2.31-2.38 (m, 1H), 2.41 (s, 3H), 3.03-3.10 (m, 1H), 3.35-3.43 (m, 1H), 3.66 (s, 3H), 4.13-4.19 (m, 1H), 5.09 (t, 1H), 5.52 (s, 1H), 7.02-7.06 (m, 2H), 7.49 (d, 1H). MS m/z 385 (M+H)+
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[C:3]([OH:5])=[O:4].[CH3:14]O>>[ClH:13].[CH3:14][O:4][C:3](=[O:5])[C@@H:2]([NH2:1])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13]
Reactant: CO
Reactant: N[C@@H](Cc1ccccc1Cl)C(=O)O
Product: COC(=O)[C@@H](N)Cc1ccccc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2(S)-Amino-3-(2-chlorophenyl)propionic acid (1 g, commercially available) was dissolved in methanol (10 mL) and HCl gas was bubbled through the solution for 5 min. The reaction mixture was stirred at room temperature for 3 h and the solvent was evaporated using the rotavap to get 2(S)-amino-3-(2-chlorophenyl)propionic acid methyl ester hydrochloride (1.2 g).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2].[C:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)(=[O:27])[CH3:26].C>N1C=CC=CC=1.C1C=CC=CC=1.CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:18][CH2:17][CH:16]([NH:19][S:35]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[CH:34][CH:33]=4)(=[O:37])=[O:36])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N)C3)c(F)c21
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NS(=O)(=O)c4ccc(NC(C)=O)cc4)C3)c(F)c21
Reaction time: 1 h
Yield: 32.7 %

Procedure:
2.80 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-3-quinolinecarboxylic acid (see REFERENCE SYNTHESIS EXAMPLE hereinafter) is suspended in 100 ml of pyridine. To this is slowly added 3.88 g of 4-acetamidobenzenesulfonyl chloride in 20 ml of benzene. The mixture is stirred for 1 hour under ice-cooling and then overnight at room temperature. After evaporating off the solvent from the reaction mixture, the residue is added water and then adjusted to pH 12 with 2N sodium hydroxide solution. Any undissolved matter, if present, is filtered off. The filtrate is adjusted to pH 7 with acetic acid. The precipitated crystals are collected by filtration and washed. The crystals are then suspended in 100 ml of water. The suspension is adjusted to pH 4 with acetic acid, stirred and then filtered to recover the crystals, which are then thoroughly washed with water. The crude crystals thus obtained are dissolved in dimethylformamide (DMF), treated with activated charcoal, and recrystallized from DMF-methanol to give 1.45 g of the titled compound.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:23]=[C:22]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH:21]=[CH:20][C:15]=3[C:16]([O:18]C)=[O:17])[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>C1COCC1.C(O)C(O)C.O>[C:1]1([C:7]2([C:14]3[CH:23]=[C:22]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[CH:21]=[CH:20][C:15]=3[C:16]([OH:18])=[O:17])[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(O)CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Temperature: 110 °C
Reaction time: 18 h
Yield: 76.3 %

Procedure:
To a solution of 2b (67.0 mg, 0.14 mmol) in THF (3 mL) and 1,2-propanediol (3 mL) was added aqueous potassium hydroxide (0.40 mL of a 8 M solution in water, 3.20 mmol). The mixture was stirred at 110° C. for 18 h and then cooled to room temperature. The reaction mixture was diluted with water, acidified with 1 N hydrochloric acid and extracted three times with EtOAc. The combined organic extracts were washed with water, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; dichloromethane/methanol/concentrated aqueous ammonium hydroxide (85:15:1) gave a solid (48.0 mg) that was triturated with ether/hexane to provide 2c as a solid (38 mg), m.p. 205-210° C. (dec.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]([F:28])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH2:22][CH2:23][CH2:24][NH2:25])[N:16]=1.CCO>C(N(CC)CC)C>[F:28][C:10]([F:9])([F:27])[CH2:11][N:12]=[C:13]([NH2:26])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH2:22][CH2:23][CH2:24][NH:25][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[N:16]=1
Reactant: O=C(Cl)c1ccco1
Reactant: NCCCSc1nccc(NC(N)=NCC(F)(F)F)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NCC(F)(F)F)Nc1ccnc(SCCCNC(=O)c2ccco2)n1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
2-Furoyl chloride (145 mg.) was added to a mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropylthio)pyrimidine (308 mg.), EtOH (10 ml.) and triethylamine (0.5 ml.), the mixture left at room temperature for 2 hours and then evaporated to dryness. The residue was dissolved in N aqueous HCl and the solution washed with EtOAc. The aqueous phase was basified with 10N aqueous NaOH and then extracted with EtOAc, and the extract was dried amd evaporated to dryness. The residue was recrystallised from EtOAc to give N-[3-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimidin-2-yl-thio)propyl]-2-furamide (300 mg.), m.p. 127°-129°.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]1(=[O:24])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]21[CH2:23][CH2:22][CH2:21][CH2:20]2>S(=O)(=O)(O)O>[N+:6]([C:17]1[CH:18]=[C:19]2[C:14]([CH2:13][CH2:12][C:11]3([CH2:23][CH2:22][CH2:21][CH2:20]3)[C:10]2=[O:24])=[CH:15][CH:16]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2CCC12CCCC2
Agent: O=S(=O)(O)O
Product: O=C1c2cc([N+](=O)[O-])ccc2CCC12CCCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
41.1.14 ml of a sulphuric acid/nitric acid 65% 1:1 mixture was slowly added dropwise to a solution of 20 g of 3'4'-dihydro-spiro[cyclopentane-1,2'(1'H)-naphthalen]-1'-one in 60 ml of sulphuric acid. After stirring for 2 hrs. at RT the mixture was poured on to 200 g of ice, extracted with ether, washed with a saturated aqueous NaHCO3 solution and with water, dried on Na2SO4, filtered, concentrated and chromatographed over silica gel with cyclohexane/ethyl acetate 9:1. Yield: 12.7 g (52%). A sample was recrystallized from hot isopropyl ether and gave 7'-nitro-3'4'-dihydro-spiro[cyclopentane-1,2'(1'H)-naphthalen]-1'-one as white crystals; m.p. 69°-70° C.