Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([CH3:14])([CH3:13])[N:5]2[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16].[N+:22]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])#[C-:23]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:23]=[N:22][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:7]1[C:6]([CH3:13])([CH3:14])[N:5]2[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Reactant: CC1(C)C(=O)Nc2ccc(F)cc2N1C(=O)N1CCCC1
Product: CC(C)(C)OC(=O)c1ncn2c1C(C)(C)N(C(=O)N1CCCC1)c1cc(F)ccc1-2

Procedure:
Following the general procedure for EXAMPLE 30 and making non-critical variation but starting with 6-fluoro-1,2,3,4-tetrahydro-3,3-dimethyl-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 32, 0.750 g) and t-butyl isocyanoacetate (0.436 g) are converted to the title compound. After crystallization from ethyl ether/hexane, mp 168.5°-169.5°; MS (m/z) at 414; IR (mineral oil) 1713, 1668, 1520, 1181 and 1155 cm-1 ; NMR (CDCl3) 1.63, 1.8, 1.92, 2.08, 2.95, 3.23, 3.58, 6.52, 6.71 and 7.92 δ.
Reaction SMILES: [Br-:1].[CH2:2]([N+:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[OH:23])([CH3:16])[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>O>[Br-:1].[C:24]([O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N+:14]([CH3:15])([CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCC[N+](C)(C)C1CCCCC1O
Agent: [Br-]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCC[N+](C)(C)C1CCCCC1OC(C)=O
Reaction time: 16 h

Procedure:
A mixture of 1.0 g of dodecyl(2-hydroxycyclohexyl)-dimethylammonium bromide prepared in Example 3, 5 ml of acetic anhydride and 5 ml of dry pyridine was allowed to stand at room temperature for about 16 hours. Twenty-five milliliters of water was added and the mixture allowed to stand for one hour. The solution was concentrated under reduced pressure at 50° using a rotary film evaporator. Two 20 ml portions of water were added successively to aid removal of pyridine, followed by absolute ethanol for final drying. The residue was 1.11 g of (2-acetoxycyclohexyl)(dimethyl)dodecylammonium bromide. The ir spectrum was consistent with the assigned structure and clearly showed esterification of the hydroxy group to have occurred.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:21])[NH:8][CH:7]=1)=[O:5])C.C(OC(=O)C=CC1C2C(=CC=CC=2)C=CC=1)C.CC(C)([O-])C.[K+].O>O1CCCC1>[OH:5][C:4]([C:6]1[C:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:21])[NH:8][CH:7]=1)=[O:3]
Reactant: CCOC(=O)c1c[nH]c(C)c1-c1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)C=Cc1cccc2ccccc12
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]cc(C(=O)O)c1-c1cccc2ccccc12
Yield: 66.1 %

Procedure:
3-ethoxycarbonyl-5-methyl-4-(naphthalen-1-yl)-1H-pyrrole 4.3 g(18.9 mmol) of 3-(naphthalen-1-yl)-acrylic acid ethylester prepared in Preparation 6-1) and 3.95 g(18.9 mmol) of α-methyltosylmethylisocyanide disclosed in A. M. van Leusen, et al., Tetrahedron Letter, 1975, 40, 3487 were dissolved in 100 ml of tetrahydrofuran. 2.55 g(22.7 mmol) of potassium t-butoxide dissolved in 100 ml of tetrahydrofuran was slowly added thereto, which was then refluxed for 30 minutes. To the reaction solution was added 100 ml of water to stop the reaction and the solvent was removed under reduced pressure. The residue was extracted with diethylether, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was subjected to silica gel column chromatography using a solvent mixture of ethyl acetate/n-hexane(1/3, v/v) as an eluent to give 3.50 g(12.5 mmol, Yield 66%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.CC(C)([O-])C.[K+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[C:11](=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC(O)c1cccc(F)c1)Nc1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCC(c2cccc(F)c2)N1c1ccc(OC(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Stir 4-(3-fluoro-phenyl)-N-(4-trifluoromethoxy-phenyl)-4-hydroxy-butyramide (2.45 g, 6.86 mmol) and p-toluenesulfonyl chloride (1.63 g, 8.60 mmol) in dry tetrahydrofuran (30 mL) under nitrogen. Cool to −40° C. and slowly add potassium t-butoxide (1M in tetrahydrofuran) (17.2 mL, 17.2 mmol). Allow to warm slowly to room temperature and stir for 2 hours. Add aqueous NH4Cl solution and extract with ethyl acetate, wash with brine and dry over anhydrous magnesium sulfate. Evaporate and purify on a silica gel column (dichloromethane-ethyl acetate) to give (±)-5-(3-fluoro-phenyl)-1-(4-trifluoromethoxy-phenyl)-pyrrolidin-2-one (1.9 g, 82% yield) MS (m/z): 340 (M+1). Instrumentation
Reaction SMILES: COC(=O)/C=C/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].CN1CCC(=O)CC1.CC(C1C=C([Br:47])C=CC=1O)=O>>[CH3:17][N:14]1[CH2:15][CH2:16][C:11]2([CH2:10][C:9](=[O:28])[C:8]3[C:25](=[CH:26][CH:27]=[C:6]([Br:47])[CH:7]=3)[O:24]2)[CH2:12][CH2:13]1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: CN1CCC(=O)CC1
Product: CN1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2

Procedure:
1′-Methyl-6-bromo-spiro[chromane-2,4′-piperidine]-4-one was synthesized according to the procedure for the preparation of Intermediate 1, Step A, using N-methyl-4-piperidone (1.13 g, 10 mmol), and 2-hydroxy-5-bromoacetophenone to give an orange solid (2.29 g).
Reaction SMILES: C[Si](C)(C(C)(C)C)O[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]1[CH2:32][C:31]2[C@H:26]([CH2:27][CH2:28][C:29](=[O:33])[CH:30]=2)[C@@H:25]2[C@@H:16]1[C@H:17]1[C@@:21]([CH2:23][CH2:24]2)([CH3:22])[C:20](=[O:34])[CH2:19][CH2:18]1.[C:40]([OH:43])(=[O:42])[CH3:41].O.C(OC(=O)C)(=O)C>O1CCCC1.C(OCC)C.N1C=CC=CC=1>[C:40]([O:43][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]1[CH2:32][C:31]2[C@H:26]([CH2:27][CH2:28][C:29](=[O:33])[CH:30]=2)[C@@H:25]2[C@@H:16]1[C@H:17]1[C@@:21]([CH2:23][CH2:24]2)([CH3:22])[C:20](=[O:34])[CH2:19][CH2:18]1)(=[O:42])[CH3:41]
Reactant: CC(=O)O
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCCCCCCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
28.3 g of 7α-[11-(dimethyl-tert-butylsilyloxy)-undecyl]-4-estrene-3,17-dione is stirred in 141 ml of tetrahydrofuran with 156 ml of glacial acetic acid and 78 ml of water for 2 hours at 50°. Then the mixture is concentrated to dryness under vacuum. The crude 7α-(11-hydroxyundecyl)-4-estrene-3,17-dione obtained in this way is agitated with 140 ml of pyridine and 70 ml of acetic anhydride for 15 hours at 25°. For working up the mixture, the latter is cooled to 0°, combined diluted with diethyl ether, washed with sodium bicarbonate and sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with dichloromethane/ethyl acetate, yielding 22.4 g of 7α-(11-acetoxyundecyl)-4-estrene-3,17-dione, [α]D =62.4°, as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[N:14]([C:23](=[O:40])[CH2:24][NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][C:36]([O:38]C)=[O:37])[CH:30]=3)=[O:27])[CH:13]([C:41](=[O:47])[NH:42]CC(C)C)[CH2:12]2)(=[O:10])=O)=[CH:4][CH:3]=1.[OH-:48].[K+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[N:14]([C:23](=[O:40])[CH2:24][NH:25][C:26](=[O:27])[NH:28][C:29]3[CH:30]=[C:31]([CH2:35][C:36]([OH:38])=[O:37])[CH:32]=[CH:33][CH:34]=3)[C:13]([C:41](=[O:47])[NH2:42])([CH2:15][CH:16]([CH3:21])[CH3:17])[CH2:12]2)(=[O:10])=[O:48])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(S(=O)(=O)c3ccc(Cl)cc3)C2c2ccccc2F)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CC1(C(N)=O)CC(S(=O)(=O)c2ccc(Cl)cc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 100.6 %

Procedure:
A The process is performed as in Example 1A, but starting with 3.35 g of (2 RS,4 SR,5RS)-4-(4-chlorophenyl)sulphonyl-5-(2-fluorophenyl)-2-isobutylcarbamoyl-1-{2-[3-(3-methoxycarbonylmethylphenyl)ureido]acetyl}-pyrrolidine and 0.36 g of potassium hydroxide in a mixture of 60 cm3 of methanol and 20 cm3 of distilled water. After treatment, 1.65 g of 3-(3-{2-[4-(4-chlorophenyl)sulphonyl-5-(2-fluorophenyl)-2-isobutyl carbamoyl-1-pyrrolidinyl]-2-oxoethyl}ureido)phenylacetic acid are obtained [Rf=0.45; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 373 K, δ in ppm): 0.94 (d, J=6.5 Hz, 6H: C(CH3)2); 1.85 (mt, 1H: CH); from 2.30 to 2.55 and 2.84 (2 mts, 1H each: CH2 at 3); 3.06 (mt, 2H: NCH2); 3.50 (s, 2H: ArCH2COO); 3.67 and 3.88 (broad d and d respectively, J=17 Hz, 1H each:COCH2N); 4.08 (mt, 1H: H4); 4.78 (t, J=8 Hz, 1H: H2); 5.68 (d, J=3 Hz, 1H: H5); 6.12 (residual t:NHCO); 6.85 (broad d, J=7.5 Hz, 1H: aromatic H (H4 : ortho to the CH2)); from 6.95 to 7.30 (mt, 6H: aromatic H); 7.69 (broad d, J=8.5 Hz, 2H: H of the aromatic at 4 (H ortho to the Cl)); 7.96 (broad d, J=8.5 Hz, 2H: H aromatic at 4 (H meta to the Cl)); 8.20 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6)); 8.40 (residual s: CONHAr)].
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1.CS(O[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O>CN(C=O)C>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]2)[C:6](=[O:10])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: CN1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
A 60% dispersion of sodium hydride (84.55 mg, 2.114 mmol) was added to a stirred solution of 4-methylpiperazin-2-one (241.3 mg, 2.114 mmol) in DMF (10 mL) and the reaction stirred at ambient temperature for 30 minutes. Tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (477 mg, 1.626 mmol) in DMF (5 mL) was added dropwise and the reaction stirred at ambient temperature for a further 92 hours then at 50° C. for a further 20 hours. The reaction was cooled to ambient temperature, quenched by the addition of water and the mixture extracted with EtOAc (×3). The combined organic extracts were washed with brine (×3), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give tert-butyl 4-((4-methyl-2-oxopiperazin-1-yl)methyl)piperidine-1-carboxylate product as a colourless oil (99 mg, 20% Yield). MS (ES+) 312.2.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O)(=O)=O.O[CH2:15][CH2:16][N:17]([CH3:30])[S:18]([C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29])(=[O:20])=[O:19].[OH:31][CH2:32][CH2:33][SH:34].[Na].N>CN(C)C=O>[OH:31][CH2:32][CH2:33][S:34][CH2:15][CH2:16][N:17]([CH3:30])[S:18]([C:21]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=1[CH3:29])(=[O:20])=[O:19]
Reactant: OCCS
Reactant: Cc1cc(C)c(S(=O)(=O)N(C)CCO)c(C)c1
Agent: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Agent: N
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N(C)CCSCCO)c(C)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
17.6 g (0.04 mole) N-(2-hydroxyethyl)-N-methylmesitylenesulphonamide mesitylenesulphonate were added to a mixture of 7.8 g (0.1 mole) 2-hydroxyethanethiol, 2.3 g (0.1 mole) sodium and 200 ml ammonia, and then 50 ml dimethylformamide were added, the reaction vessel being cooled in an acetone-CO2 bath. The cooling bath was removed and the mixture was stirred at about 20° C. overnight. Water and diethyl ether was added and the aqueous phase was extracted with diethyl ether. The combined ether phases were washed with brine and dried with Na2SO4. Removal of the solvent in vacuum gave 12.3 g of an oil, which was used as such without further purification. NMR showed that it was the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1.I[CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:30][CH3:31])=[CH:24][N:23]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(O)cn2)c1
Reactant: CCI
Product: CCOc1ccc(-c2cc(NC(=O)c3ccc(C(F)(F)F)nc3C)ccc2Cl)nc1

Procedure:
N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.05 mmol) was used in Procedure L with excess iodoethane. Purified by silica gel chromatography (0-100% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-ethoxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.64 (50% ethyl acetate/hexanes); MS (Q1) 436 (M)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:34][C:35]1[C:43]2[C:42]([N:44]3[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]3)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][CH:36]=1>C(Cl)Cl>[CH3:34][C:35]1[C:43]2[C:38]([NH:39][CH:40]=[N:41][C:42]=2[N:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH2:46][CH2:45]2)=[N:37][CH:36]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Reactant: O=C(O)c1ccccn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccn4)CC3)c1-2
Reaction time: 0.17 h

Procedure:
To a mixture of 2-pyridine carboxylic acid (41.4 mg, 0.336 mmol), EDC (68.7 mg, 0.359 mmol), HOBt (54.9 mg, 0.359 mmol) and DIPEA (0.098 mL, 0.560 mmol) in DCM (1 mL), prestirred for 10 minutes, was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (60 mg) and the mixture stirred for 18 hours. The mixture was partitioned between DCM (4 mL) and aqueous sodium bicarbonate (4 mL) and the aqueous phase extracted with further DCM (4 mL). The combined organic fractions were concentrated in vacuo and purified by MDAP. The solvent was then removed in vacuo from the product-containing fractions, to afford E21 (34 mg), 1H NMR (d6-DMSO) δ 11.52 (1H, s), 8.69 (1H, d), 8.65 (1H, d), 8.21 (1H, s), 8.06 (1H, d), 8.00 (1H, t), 7.61 (1H, t), 7.06 (1H, s), 4.08 (1H, m), 4.00 (2H, d), 3.05 (2H, t), 2.37 (3H, s), 2.0-1.7 (4H, m), MS(ES+) 337 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([F:31])[C:15]=2[N:16]2[CH2:21][CH2:20][CH:19]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[O:23])[CH2:18][CH2:17]2)=[O:8])=[C:5]([NH2:32])[NH:4][N:3]=1.C(O)(=O)C.C(N(C(C)C)[CH:41]=[C:42]([F:45])[CH:43]=O)(C)C>CC(O)C.O.C(O)C>[NH2:32][C:5]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([F:31])[C:15]=2[N:16]2[CH2:17][CH2:18][CH:19]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[O:23])[CH2:20][CH2:21]2)=[O:8])=[C:2]2[N:1]=[CH:41][C:42]([F:45])=[CH:43][N:3]2[N:4]=1
Reactant: CC(C)N(C=C(F)C=O)C(C)C
Reactant: CN1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)c3c(N)n[nH]c3N)CC2)CC1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: CN1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)c3c(N)nn4cc(F)cnc34)CC2)CC1
Temperature: 25 °C

Procedure:
To a suspension of 3,5-diamino-N-[5-fluoro-4-[4-(4-methylpiperazine-1-carbonyl)-1-piperidyl]-3-pyridyl]-1H-pyrazole-4-carboxamide 9a (106 mg, 1.19 mmol) in IPA/water (1:1, 1 mL) and acetic acid (71.46 mg, 67.67 μL, 0.1078 mmol) was added 3-(diisopropylamino)-2-fluoro-prop-2-enal (41.21 mg, 0.2379 mmol). The reaction mixture was heated under reflux for 6 h and was then allowed to cool to room temperature overnight. IPA was removed in vacuo, and the resulting aqueous solution was partitioned between DCM and 2M sodium carbonate solution. The organic layer was washed with 1:1 brine/water, dried (MgSO4) filtered and concentrated in vacuo to leave a yellow solid which was stirred as a suspension in ethanol (0.5 mL) for 2 h. The solid was collected by filtration to give the desired compound I-G-4 (63 mg, 53%).
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][C:17](OCC)=[O:18])[CH:9]=1.Cl>CN(C)C=O>[CH:17]([CH:16]([CH2:15][CH2:14][C:10]1[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:18]
Reactant: CCOC=O
Reactant: CCOC(=O)CCCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C=O)CCc1cccnc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A suspension of 2.53 g. of sodium hydride in 35 ml. of anhydrous dimethyl formamide was prepared. The suspension was cooled to about 0° C. with stirring. Next, a mixture of 9.56 g. of ethyl formate and 19 g. of ethyl 4-(3-pyridyl)butyrate were added. The consequent reaction mixture was stirred at about 0° C. for 1 additional hour and then at room temperature for about 3 days. The reaction mixture was acidified with 2N aqueous hydrochloric acid and the acidic aqueous solution evaporated to a very small volume in vacuo. The acidity of the solution was adjusted to pH=6 by the addition of solid potassium carbonate. The neutral aqueous layer was then extracted with ether. The ether layer was separated and dried. Evaporation of the ether yielded 16.4 g. of ethyl 2-formyl-4-(3-pyridyl)butyrate (formed in the above reaction) as an orange oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](O)[C:2]=1[OH:12].C1([OH:23])C2CC=CCC=2C=CC=1.ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(OCC)C>[O:12]1[CH:2]2[CH:3]1[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:23])[C:10]=1[CH2:1]2
Reactant: Oc1cccc2c1CC=CC2
Reactant: Oc1cc2ccccc2cc1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Oc1cccc2c1CC1OC1C2

Procedure:
Alternatively, the 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-(substituted-amino)propoxy]-2,3-naphthalenediol isomer XXVII can be prepared from a 5,8-dihydro-1-naphthol of the structure ##STR34## prepared as described hereinbefore, by mixing a cooled solution (temperature less than about 30° C.) of 5,8-dihydro-1-naphthol in ethyl acetate with m-chloroperbenzoic acid and mixing the resulting slurry with a mixture of ethyl ether and aqueous sodium bicarbonate, to form 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol ##STR35## and reacting the 5,6,7,8-tetrahydro-6,7-epoxy-1-naphthol in tetrahydrofuran with aqueous perchloric acid at a temperature within the range of from about 0° to about 60° C., to form trans-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol XXV which can be converted to the 2,3-trans-1,2,3,4-tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol XXVI which in turn can be converted to the 2,3-trans-1,2,3,4-tetrahydro-5-[2-hydroxy-3-substituted amino)propoxy]-2,3-naphthalenediol XXVII in a manner similar to that described hereinbefore.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:25][CH:24]([OH:26])[CH2:23]4)[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(C)=[O:39]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][C:24]([OH:39])([OH:26])[CH2:25]4)[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC(O)C3)ccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC(O)(O)C3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(4-chlorobenzyl)-6-[(3-hydroxy-1-azetidinyl)methyl]-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 75 in dry DMSO (3 mL) containing triethylamine (0.35 mL) is treated with pyridine-sulfar trioxide complex (0.25 gm). The reaction mixture is stirred at room temperature for 2 hrs. The reaction mixture is diluted with ethyl acetate and washed with water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is purified by recrysrallization from acetonitrile to afford 0.06 gm of the title compound as a tan solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[Br-].[Br-].[Br-].[Al+3].[C:11]([O:14][C@@H:15]1[C@@:33]2([CH3:34])[C:19](=[CH:20][CH2:21][C@@H:22]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:23]3[CH2:24][CH2:25]/[C:26]/2=[CH:27]/[CH3:28])[CH2:18][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:16]1)(=[O:13])[CH3:12]>C(Cl)Cl>[CH3:6][O:5][C:1](=[O:4])[CH:2]=[CH:3][C@H:27]([C:26]1[C@:29]2([CH3:35])[C@H:23]([C@H:22]3[C@H:32]([CH2:31][CH2:30]2)[C@:33]2([CH3:34])[C:19]([CH2:18][C@@H:17]([O:36][C:37](=[O:39])[CH3:38])[CH2:16][C@@H:15]2[O:14][C:11](=[O:13])[CH3:12])=[CH:20][CH2:21]3)[CH2:24][CH:25]=1)[CH3:28]
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: C#CC(=O)OC
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: COC(=O)C=C[C@@H](C)C1=CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 0.13 ml (1.5 mmol) of methyl propiolate in 10 ml of dry methylene chloride (over 4 A molecular sieves) under a nitrogen atmosphere was added 0.954 g (3.5 mmol) of aluminum tribromide. Immediately thereafter was added 398 mg (1 mmol) of Z-pregna-5,17(20)-diene-1α,3β-diol diacetate dissolved in 10 ml dry methylene chloride. The orange-colored solution was stirred for 15 min. A 2-ml sample was quenched with 5 ml of 10% aqueous potassium sodium tartrate salts. Analysis of the organic phase showed 20% of 1α,3β-diacetyloxychola-5,16,22-trien-24-oic acid methyl ester had formed (GC analysis).