Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[ClH:22].[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:15][C:4]1[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=[C:2]([S:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1
Reactant: Sc1ccccc1
Reactant: Cc1csc(Nc2ncc(Br)cc2Sc2ccccc2Cl)n1
Product: Cc1csc(Nc2ncc(Sc3ccccc3)cc2Sc2ccccc2Cl)n1
Product: Cl

Procedure:
Prepared according to the method of Example 13 from N-(5-bromo-3-(2-chlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine (prepared according to Example 47) and benzenethiol. 1H NMR (d6-DMSO) δ 8.36 (bs, 1H), 7.57 (dd, 1H), 7.40-7.15 (m, 10H), 6.54 (s, 1H), 2.20 (s, 3H); Mass spectrum (esi) m/z=442.2 (M+H−HCl).
Reaction SMILES: ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:23]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@:36]([F:48])([CH3:47])[C@H:35](O)[O:34]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Br)(Br)(Br)[Br:51]>CCOC(C)=O>[C:23]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@:36]([F:48])([CH3:47])[C@@H:35]([Br:51])[O:34]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@@H]1Br
Temperature: -17 °C

Procedure:
Anhydrous dichloromethane (5.6 L) was charged into a reactor and cooled to −22° C. or below. Triphenylphosphine (205.4 g, 0.783 mol) was added to the cold solvent and the suspension was stirred to form a solution. The lactol (8, 209.4 g, 0.559 mol) in solid form was added to the cold solution and stirred for 15 mins. Carbon tetrabromide (278.2 g, 0.839 mol) was added portion-wise while maintaining the temperature of the solution between −22° C. to −20° C. under a flow of nitrogen gas (approx. 30 min). After finishing the addition of CBr4, the temperature was slowly raised to −17° C. over 20 mins. The reaction was judged to be >95% complete by TLC (Rfs 0.61 (α), 0.72 (β), 0.36 lactol; 20% EtOAc in hexanes). The reaction solution was immediately transferred to a vessel containing 230 g of flash chromatography grade silica gel (40-63 microns). The stirred mixture was immediately passed through a pad of silica gel (680 g) in a 2.5 L sintered glass Buchner funnel. The filtrate was concentrated under reduced pressure to about 800 mL and the ratio of α/β isomers of the crude product was 10:1 as determined by 1H-NMR. (CDCl3) δ=6.35, (s, α C1-H), 6.43, (d, β C1-H). The residue was purified by plug column chromatography using 2.1 kg of silica gel in a 6 L sintered glass Buchner funnel and eluted (via suction) with a stepwise gradient elution of 1%, 5%, 8% 12% EtOAc in hexane (ca 4 L each) to remove non-polar impurities followed by 12%, 25% EtOAc in hexane (6 L total) to elute the product. The product containing fractions were combined into two fractions, concentrated under reduced pressure, dried under vacuum (0.1 mmHg, ambient temp., 20 h) to colorless oils. Main fraction (197 g, 89% α/β=20:1). The alpha isomer crystallized from a small portion of the oil upon standing at 0° C. for several weeks to give large, thin plates, mp 59-61° C. The pure beta isomer crystallized from a mixture of alpha and beta product oil from an earlier less selective run to give needles, mp 77-79° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1)#[N:2].[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[N:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ncc(C#N)cc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
To a solution of 83 mg of (7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde and 80 mg of tert-butyl piperidin-4-yl-carbamate in 10 mL of chloroform, 24 μL of acetic acid was added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, 136 mg of sodium triacetoxyborohydride was added, and the mixture was stirred for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and an eluent of ethyl acetate:hexane=1:1 to obtain 76 mg of tert-butyl (1-(2-(7-cyano-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a brown solid.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[N+:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.S(Cl)([Cl:20])(=O)=O>ClC(Cl)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[Cl:20][C:9]1[CH:8]=[C:7]([CH:11]=[N+:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[NH:6][CH:10]=1
Reactant: C(c1ccc[nH]1)=[N+]1CCCC1
Reactant: O=S(=O)(Cl)Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(Cl)Cl
Product: Clc1c[nH]c(C=[N+]2CCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 215.4 g. (0.865 moles) of the product of Example IV in 4 liters of dichloroethane at 0° C. is added dropwise 116.8g. (0.865 moles) of freshly distilled sulfuryl chloride. After addition is complete (about 40 minutes), the reaction mixture is allowed to warm to ambient temperature and is stirred for about 4 hours, after which the solvent is evaporated to give a tan residue. Recrystallization of this residue from dichloroethane/ether gives 1-(4-chloropyrrol-2-ylmethylene) pyrrolidinium perchlorate; m.p. 122°-126° C.
Reaction SMILES: COC1C=CC=CC=1O[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[OH:8].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH3:6])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(O)COc2ccccc2OC)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: COc1ccc(C(C)=O)cc1
Temperature: 120 °C

Procedure:
Wet Raney Ni 4200 was dried under vacuum and carefully weight (39 mg (dry weight), 6.8×10−4 mol, 150 mol %). 6 mL degassed heptane was added, followed by 2-(2-methoxyphenoxy)-1-(4-methoxyphenyl)ethan-1-ol (120 mg, 4.4×10−4 mol). The reaction was heated at 120° C. for 24 hours. The reaction was cooled, opened and 10 mg of NH4COOH was added. 50 mL of Et2O was used to transfer the crude to an erlenmeyer containing MgSO4. After drying the solution was filtered and concentrated. HNMR gave 38% conversion to 1-(4-methoxyphenyl)ethan-1-one, 38% of the β-O-4 bond was broken.
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C@@H:36]([CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1)[C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C:44]1[CH:49]=[CH:48][N:47]=[C:46]([N:50]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH2:52][CH2:51]2)[CH:45]=1)=[O:38].[CH:65]([N:68]([CH:71](C)C)CC)([CH3:67])[CH3:66]>CN(C=O)C.O>[CH:59]1([C@H:36]([NH:35][C:66](=[O:10])[C@@H:65]([NH:68][CH3:71])[CH3:67])[C:37]([N:39]2[CH2:43][CH2:42][CH2:41][C@H:40]2[C:44]2[CH:49]=[CH:48][N:47]=[C:46]([N:50]3[C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH2:52][CH2:51]3)[CH:45]=2)=[O:38])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1
Reactant: On1nnc2ccccc21
Reactant: N[C@H](C(=O)N1CCC[C@H]1c1ccnc(N2CCc3ccccc32)c1)C1CCCCC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(N2CCc3ccccc32)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of Boc-N-methyl-L-α-alanine (53 mg, 0.26 mmol), HOBt (39 mg, 0.29 mmol) and HBTU (108 mg, 0.29 mmol) in DMF (10 mL) is stirred at room temperature for 30 min. Then a solution of (S)-2-Amino-2-cyclohexyl-1-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-ethanone in DMF (10 mL) is added, followed by diisopropylethylamine (153 mg, 1.19 mmol). The mixture is stirs at room temperature for 2 h, then diluted with water and extracted with EtOAc. The combined organic layers are washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated down. The crude product is dissolved in dichloromethane (5 mL). TFA (5 mL) is added. The resulting mixture is stirred at room temperature for 1 h and concentrated down to give a crude product, which is purified by prep. reverse phase HPLC (Column: Waters Sunfire Prep C18 OBD 5 μM 30×100 mm; Gradient: AcCN/water with 0.1% TFA: 10%˜70%) to give (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide (72 mg, 42%) as a TFA salt. M/Z=490.2 [M+1].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].Cl>CO.O1CCCC1.O>[CH:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[C:10]([CH3:32])([CH3:33])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1)([CH3:31])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(OC(C)C)cc3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 63.7 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.30 g, 0.68 mmol) in methanol (2 mL) and tetrahydrofuran (15 mL), lithium hydroxide hydrate (0.28 g, 6.8 mmol) in water (1.0 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.18 g, 65%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C27H29NO3 (M+H)+: 416.5, observed: 416.1.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26]1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:31]([NH:30][C:27]4[CH:28]=[CH:29][S:25][CH:26]=4)=[O:32])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccsc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccsc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-thienyl isocyanate (0.152 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 50.0 mg (16.6%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Product: N#Cc1ccc(N2CCOCC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-bromo-3-(trifluoromethyl)-benzonitrile and morpholine (Fluka, Buchs, Switzerland), with a reaction temperature of 95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=1.CC(O)=O>CCOC(C)=O.O=[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:9])[F:10])[C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c(F)cccc2C(F)(F)F)CC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2c(F)cccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.7 %

Procedure:
A mixture of tert-butyl 4-(2-fluoro-6-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (21, 0.479 g, 1.41 mmol) and PtO2 (0.095 g, 0.42 mmol) in EtOAc (15 mL) and HOAc (82 μL, 1.4 mmol) stirred at ambient temperature for 72 h under an atmosphere of H2 (1 atm). The mixture was diluted with EtOAc (50 mL) and filtered over Celite. The filtrate was concentrated and the residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 24 g Redisep column, 0% to 15% EtOAc in hexanes) to provide tert-butyl 4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carboxylate (22) as a white solid (0.219 g, 45%): 1H NMR (300 MHz, DMSO-d6) δ 7.62-7.48 (m, 3H), 4.15-3.94 (m, 1H), 3.10-2.94 (m, 2H), 2.93-2.67 (m, 2H), 2.00-1.79 (m, 2H), 1.67-1.55 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[F:8][C:9]1([F:55])[CH2:14][CH2:13][CH:12]([C:15]2[C:24]3[CH:23]([OH:25])[CH2:22][C:21]([CH3:27])([CH3:26])[CH2:20][C:19]=3[N:18]=[C:17]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]4[N:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][N:35]=4)[CH2:30][CH2:29]3)[C:16]=2[CH:43]([F:54])[C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)[CH2:11][CH2:10]1>>[F:55][C:9]1([F:8])[CH2:10][CH2:11][CH:12]([C:15]2[C:24]3[CH:23]([OH:25])[CH2:22][C:21]([CH3:27])([CH3:26])[CH2:20][C:19]=3[N:18]=[C:17]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]4[N:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:42])[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:36][N:35]=4)[CH2:32][CH2:33]3)[C:16]=2[CH:43]([F:54])[C:44]2[CH:45]=[CH:46][C:47]([C:50]([F:51])([F:53])[F:52])=[CH:48][CH:49]=2)[CH2:13][CH2:14]1
Reactant: CNCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)N(C)Cc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 51 were performed except for using isopropylsulfonyl chloride instead of methanesulfonyl chloride, and from 64 mg (94 μmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1-{5-[(methylamino)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 58, 14 mg of the title compound was obtained as a white solid (yield: 19%).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.[CH2:53]=[CH:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=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:55]1(/[CH:54]=[CH:53]/[C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: C=Cc1ccccc1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(/C=C/c3ccccc3)cc2s1
Yield: 62 %

Procedure:
A mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, Pd(PPh3)2Cl2, dppp, triethylamine, styrene, and two crystals of BHT in anhydrous DMF was reacted according to the procedure of Example 225 to give the desired compound 0.201 g (62%). LC/MS 324.2 (M+1); LC retention time 2.87 min.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([O:15][CH3:16])[CH2:13][S:14][C@H:9]12)=[S:6])#[N:2].CO.C(OCC)(=O)CCCCC.[K].[K+:35].[Br-]>CCOCC>[K+:35].[C:1]([CH2:3][CH2:4][C:5]([NH:7][CH:8]1[C:20](=[O:21])[N:10]2[C:11]([C:17]([O-:19])=[O:18])=[C:12]([O:15][CH3:16])[CH2:13][S:14][C@H:9]12)=[S:6])#[N:2]
Reactant: COC1=C(C(=O)O)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1
Agent: [Br-]
Agent: [K+]
Agent: [K]
Solvent: CCCCCC(=O)OCC
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C(=O)[O-])N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1

Procedure:
7-Cyanomethylthioacetamido-3-methoxy-3-cephem-4-carboxylic acid (35 mg.) is dissolved in 1 ml. of methanol and 50 μ l of 2.5 M potassium 2-ethyl hexanoate is added. Addition of ether causes precipitation of a very hygroscopic solid. All solvent is removed in vacuo from the mixture and the residue is solidified by the addition of acetonitrile. The desired potassium salt is collected by filtration and dried yielding 19 mg; NMR (DMSO d6 δ) 3.43 (m, CH2),3.52 (s, NCCH2SCH2CO--) 3.76 (s,OCH3), 4.10 (d, J=4Hz, H6), 5.30 (q, J=4, 9.5 Hz, H7), 9.03 (d, J=9.5 Hz,NH); νmax (KBr) 3575, 3270, 2240, 1750, 1630, 1595, 1540 cm-1.
Reaction SMILES: [C:1]1([C:7]2[CH:23]=[CH:22][C:10]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[O:19][CH:20]=[CH:21][C:15]=4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[CH3:24][N:25]([CH2:27][C:20]1[O:19][C:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:23][CH:22]=3)[CH2:14][C:15]=2[CH:21]=1)[CH3:26]
Reactant: CNC
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2occc2C1
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1ccc(-c3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.120 g (0.396 mmol) of 5-(4-phenylbenzoyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.054 ml (0.59 mmol) of 50% aqueous dimethylamine and 0.048 ml (0.59 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1 to 25/1) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.C([O:25][CH:26]=[C:27]([C:33](OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C.C[O-].[Na+]>C(O)C>[CH2:31]([O:30][C:28]([C:27]1[CH:33]=[N:1][C:2]2[N:3]([N:4]=[CH:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)=[CH:9][CH:8]=2)[C:26]=1[OH:25])=[O:29])[CH3:32]
Reactant: Nc1n[nH]cc1-c1ccc(Cc2ccc3c(c2)OCO3)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(-c3ccc(Cc4ccc5c(c4)OCO5)cc3)cnn2c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-amino-4-[4-(3,4-methylenedioxyphenylmethyl) phenyl]pyrazole (1.5 g) in ethanol (10 ml) was added diethyl ethoxymethylenemalonate (2.07 ml), and the mixture was heated and refluxed for 12 hours. To the mixture was added sodium methoxide (829 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 day. The solvent was distilled away under reduced pressure, and thereto was added water (50 ml) under ice-cooling. The mixture was adjusted to acid with 10% hydrochloric acid, and the precipitate was separated by filtraltion, washed with water to give the title compound (2.1 g) at a quantitative yield.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.N.Cl[CH2:13][C:14]([N:16]([C:18]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)[CH3:17])=[O:15]>C(O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:18]2[N:16]([CH3:17])[C:14](=[O:15])[CH2:13][N:2]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]=2[CH:28]=1
Reactant: CN(C(=O)CCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: N
Solvent: CCO
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of ethanol (600 ml) and hexamethylenetetramine (39.1 g., 0.279 mol) was stirred and saturated with ammonia. With ammonia bubbling into the mixture it was slowly heated to reflux. Over a period of 41/2 hours, 2-(2-chloro-N-methylacetamido)-5-chlorobenzophenone (40 g., 0.124 mol) was added in increments yielding ##STR6## which was not isolated. Refluxing was continued for 2 hours longer. The reaction mixture was then distilled to dryness in vacuo at 50° C. The residue was stirred with toluene (250 ml), heated to reflux and heated with two increments of para-toluene sulfonic acid. Reflux was continued for one hour. After cooling to 70° C., the toluene was washed with hot water to remove soluble salts and distilled to dryness in vacuo. The residue was dissolved in hot ethanol (111 mol) and the solution cooled at -10° C. for one hour. The crystalline 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one obtained was isolated and weighed 29 g., melting point 129° to 131° C. Concentration of the mother liquor by ca. 50% gave a second crop weighing 2.0 g. melting at 127° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[CH3:23])[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[C:13]=2[CH3:22])[C:6]=1[CH3:23])[CH3:2]
Reactant: Cn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1C
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1C

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-methyl-benzoic acid ethyl ester and 4-bromo-1-methylpyrazole.