Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[OH-].[Na+]>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:17])[CH3:18])=[O:15])[C:11]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: COC(=O)CCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 350 mg (0.85 mmol) of ester 19-1 in a 1:1:1 mixture of THF/MeOH/H2O was added 170 mg (4.25 mmol) of NaOH. After stirring overnight at room temperature, the reaction was quenched with 1M HCl and then extracted three times with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, and concentrated to provide 24-1 as a white solid. Data for 24-1: 1HNMR (500 MHz, d6-DMSO) δ 12.0 (s, 1H), 7.5-7.1 (m, 8H), 6.2 (s, 1H), 4.95 (m, 1H), 4.7 (m, 1H), 3.0 (m, 1H), 2.75 (s, 6H), 2.45 (m, 1H), 2.2 (m, 2H) ppm. HRMS (ES) calc'd M+H for C22H22F2N2O3: 401.1671. Found: 401.1695.
Reaction SMILES: [CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][C:9](O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.C1COCC1>[CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCC(=O)O)C1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CCCO)C1CCCC1
Yield: 59.2 %

Procedure:
A solution of 4-cyclopentylpentanoic acid (16 g; 94 mmol) in diethyl ether (30 ml) and THF (30 ml) was added within 20 minutes to lithium aluminum hydride (3.6 g; 94 mmol) and suspended in the same solvent (100 ml). After 2 hours at reflux, the reaction mixture was cooled with an ice-bath and quenched successively with water (4 ml), 15% sodium hydroxide (12 ml) and again water (4 ml). The white solid was filtered off, and the mixture diluted with MTBE (300 ml), washed with 1 N HCl (300 ml), sodium bicarbonate solution (300 ml) and brine (2×300 ml), dried (MgSO4), concentrated in vacuo, and distilled (59° C./0.075 torr) to give 8.7 g (59% yield) of 4-cyclopentylpentan-1-ol.
Reaction SMILES: [C:1](=[S:12])([S-:11])[S:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[K+].Cl[CH2:15][C:16]#[N:17]>>[C:1](=[S:11])([S:12][CH2:15][C:16]#[N:17])[S:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: S=C([S-])SCc1ccc(Cl)cc1
Reactant: N#CCCl
Agent: [K+]
Product: N#CCSC(=S)SCc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The reaction mixture from Example 1 containing potassium p-chlorobenzyl trithiocarbonate is stirred for 0.5 hours and 12.9 ml (200 mmol) of chloroacetonitrile is then added. The temperature of the reaction mixture is adjusted to 20° to 25° C. and stirring is continued for 2 hours. The yellow color from the aqueous layer transfers to the toluene layer and the toluene layer is then separated therefrom, washed with water, brine and dried with Na2SO4. The mixture is filtered and concentrated. The residue is taken up in ether-hexane, reduced in volume and crystallized in a freezer. Recrystallization of this material from ether-hexane gives 28.5 g of p-chlorobenzyl cyanomethyl trithiocarbonate, m.p. 41°-43° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[K+]>C(O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(OCc2ccccn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(OCc2ccccn2)cc1

Procedure:
A suspension of N-acetyl-4-(pyrid-2-ylmethoxy)aniline (116 g; 480 mmol), prepared as in step 1, in 1000 mL 95% ethanol and 130 mL 10M aqueous KOH was refluxed for 2 days. The reaction was concentrated and diluted with water. The mixture was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and concentrated to give 4-(pyrid-2-ylmethoxy)aniline as a brown oil.
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])=[O:5].[ClH:19].N([O-])=O.[Na+]>O>[Cl:19][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])=[O:5]
Reactant: Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(c1ccccc1Cl)c1ccccc1[N+](=O)[O-]

Procedure:
A stirred solution of 75 g. of 2-amino-2'- nitrobenzophenone in 700 ml. of hot concentrated hydrochloric acid is cooled to 0° and a solution of 21.5 g. of sodium nitrite in 50 ml. of water is added in the course of 3 hours. The temperature of the suspension is kept at 2-7° during the addition. The resulting clear solution is poured into a stirred solution of 37 g. of cuprous chloride in 350 ml. of hydrochloric acid 1:1. The solid which has formed after a few minutes is filtered off, washed with water and recrystallized from ethanol. Crystals of 2-chloro-2'-nitrobenzophenone melting at 76-79° are obtained.
Reaction SMILES: [CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=O)[O:4][CH3:5])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>>[CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:10]=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(=[S:29])[O:4][CH3:5])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCP(=O)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CCP(=S)(OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate (4.7 mmol) and phosphorus pentasulfide (1.2 mmol) is heated to 150°-160° under nitrogen for 3-4 hours. After cooling, the residue is purified by preparative thin-layer chromatography (on silica gel, eluting with 20% ethyl acetate/hexane) to give O-methyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinothioate.
Reaction SMILES: [Br:1][C:2]([Br:22])=[C:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.O.NN.[ClH:26]>CO>[ClH:26].[C:16]1([C:3](=[C:2]([Br:1])[Br:22])[CH2:4][NH2:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(=C(Br)Br)c1ccccc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: NCC(=C(Br)Br)c1ccccc1

Procedure:
Treatment of 1,1-dibromo-2-phenyl-3-phthalimidopropene (421 mg) with hydrazine hydrate (55 mg) and methanol (6 ml) followed by 50% aqueous hydrochloric acid as described in Example 19 D gives 2-phenyl-3,3-dibromoallylamine hydrochloride (175 mg): colorless needles; m.p. 243°-244°;
Reaction SMILES: [Na].[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[NH2:3].C(O[CH2:13][CH2:14][C:15]#[N:16])C>C(O)C>[NH2:16][C:15]1[CH2:14][CH2:13][N:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[N:3]=1
Reactant: NNc1ccccn1
Reactant: CCOCCC#N
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccccn2)CC1

Procedure:
A 0.58 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 14.0 g. of 2-hydrazinopyridine is added followed by 12.7 g. of betaethoxypropionitrile. The reaction mixture is refluxed on a steam bath for 16 hours, then the solvent is removed in vacuo. Water is added and the solid collected by filtration. The solid is recrystallized twice from acetone to give 5.55 g. of the product of the Example as tan colored crystals, m.p. 168.5°-171° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:18]3[N:19]=[CH:20][NH:21][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:31]([O:33][CH2:34]Cl)[CH3:32]>O1CCCC1.C(OCC)C>[C:23]1([CH2:22][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[C:18]3[N:19]=[CH:20][N:21]([CH2:34][O:33][CH2:31][CH3:32])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3c3[nH]cnc23)cc1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of N,N-bis(phenylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2 g, 5.49 mmole) in tetrahydrofuran (10 mL) was added to a suspension of sodium hydride (0.21 g, 6.58 mmole) in tetrahydrofuran (25 mL). After 30 minutes chloromethyl ethyl ether (0.61 mL, 6.58 mmole) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water, dried over magnesium sulfate, and then concentrated under vacuum to provide crude product as a brown oil. The oil was purified by column chromatography (silica gel eluting with 20-30% ethyl acetate in hexanes v/v) to provide 1.77 g of N,N-bis(phenylmethyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white/tan solid.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCBr
Product: CCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (273 mg, 1.08 mmol) and 1-bromododecane (671 mg, 2.69 mmol), alcohol 31 was obtained as a colorless oil (195 mg, 43% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[Br:20][C:12]1[S:11][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:14][CH:13]=1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)NCc1nccs1
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ncc(Br)s1

Procedure:
A solution (2 L) of 1.33 kg of 2-t-butoxycarbonylaminomethylthiazole in ethyl acetate was added to an aqueous solution (20 L) of 8.6 kg of sodium acetate, and the mixture was stirred. Bromine (1.35 L) was added dropwise to this solution (internal temperature: 19 to 24° C.) over a period of 3.5 hr, and the mixture was stirred at an internal temperature of 25.5±5° C. for 14 hr. Sodium sulfite pentahydrate (180 g) was added thereto, the mixture was then extracted with 3 L of ethyl acetate, and the organic layer was washed with 1 L of water and 1.53 L of a 6 M aqueous sodium hydroxide solution. The aqueous layer was then extracted with 3 L of ethyl acetate. The organic layers were combined, were dried over anhydrous magnesium sulfate, and were filtered. The solvent was removed from the filtrate by evaporation under the reduced pressure, followed by substitution concentration twice with 2 L of ethanol to give 944 g of 5-bromo-2-t-butoxycarbonylaminomethylthiazole.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41]2[CH:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41]2[CH:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cc(C)on5)cc4F)c3s2)nc1
Reaction time: 18 h
Yield: 43.4 %

Procedure:
To compound 148 (0.27 g, 0.42 mmol) in dichloromethane (75 mL) was added TFA (3 mL). The solution was stirred for 18 h then concentrated. The residue was partitioned between dichloromethane and 1M NaOH, and filtered to remove insolubles. The organic phase was collected, washed with 1M NaOH, brine, dried (anhydrous MgSO4), filtered, and concentrated. The residue was triturated with ether to afford title compound 149 (0.10 g, 45% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.67 (s, 1H), 9.23 (s, 1H), 8.56 (d, J=1.4 Hz, 1H), 8.51 (d, J=5.3 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.88 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=12.9, 2.3 Hz, 1H), 7.46 (t, J=9.0 Hz, 1H), 7.29-7.26 (m, 1H), 6.65 (d, J=5.5 Hz, 1H), 6.55 (s, 1H), 3.77 (s, 2H), 3.40 (t, J=5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J=5.7 Hz, 2H), 2.36 (s, 3H). MS (m/z): 549.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=O>>[Cl:21][C:22]1[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)[N:16]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3Cl)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 2-chloro-3-(trifluoromethyl)benzoic acid: MS (APCl): m/z 471 (M+1).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[C:15]([C:20]3[C:21](F)=[N:22][CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:28][CH:27]=4)[CH:25]=3)[CH:14]=2)[N:10]=[N:9]1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[NH:8]1[CH:12]=[C:11]([C:13]2[N:18]=[CH:17][C:16]3[NH:19][C:21]4[N:22]=[CH:23][C:24]([C:26]5[CH:31]=[CH:30][C:29]([CH2:32][N:33]6[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]6)=[CH:28][CH:27]=5)=[CH:25][C:20]=4[C:15]=3[CH:14]=2)[N:10]=[N:9]1
Reactant: Nc1cnc(-c2cn(Cc3ccccc3)nn2)cc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: c1cc(-c2cnc3[nH]c4cnc(-c5c[nH]nn5)cc4c3c2)ccc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.3 %

Procedure:
To a solution of 6′-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4′]bipyridinyl-3′-ylamine (80 mg, 0.16 mmol) in anhydrous tetrahydrofuran (2 mL) was added sodium bis(trimethylsilyl)amide (1N solution in THF, 0.46 mL, 0.46 mmol) under a flow of nitrogen and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then evaporated in vacuo to afford a residue that was purified by preparative HPLC (20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min) to afford the title compound as an orange solid (10 mg, 10%). 1H NMR (DMSO-D6, 500 MHz): 12.33 (s, 1H), 9.12 (s, 1H), 8.95 (s, 1H), 8.94 (d, J=2.2 Hz, 1H), 8.88 (s, 1H), 8.31 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 3.49 (s, 2H), 2.36 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H), triazole NH not observed. LCMS (Method D): RT=6.68 min, M+H+=410.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]#[C:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:12]2=[O:25])=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].CO>ClCCl>[OH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]#[C:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:12]1=[O:25]
Reactant: O=C(O[C@@H]1CCN(CC#CCN2CCCC2)C1=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C1[C@H](O)CCN1CC#CCN1CCCC1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 1.6 g of (R)-3-[(4-Nitrobenzoyl)oxy]-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone, 1.6 g of potassium carbonate and 60 ml of methanol was stirred for 2 hours, diluted with dichloromethane and filtered. The filtrate was concentrated to dryness. The residue was chromatographed (alumina) to give 0.8 g of the desired product as an off white solid; mp 81°-85° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:14][N:13]=[N:12][C:11]=1[C:15]([NH2:17])=[O:16])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1SN=NC=1C(N)=O)C.C(NC1SN=NC=1C(N)=O)CCCCC>>[CH2:1]([NH:9][C:10]1[S:14][N:13]=[N:12][C:11]=1[C:15]([NH2:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1nnsc1NC(=O)c1ccccc1
Agent: CCCCCCNc1snnc1C(N)=O
Agent: CCNc1snnc1C(N)=O
Product: NC(=O)c1nnsc1NCc1ccccc1

Procedure:
5-Benzoylamino-[1,2,3]thiadiazole-4-carboxylic acid amide; 5-Ethylamino-[1,2,3]thiadiazole-4-carboxylic acid amide; 5-Hexylamino-[1,2,3]thiadiazole-4-carboxylic acid amide;
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]2)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[O:1]([C:8]1[N:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]2)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)C=Cc2ccc(Oc3ccccc3)nc2)CCN1
Agent: [Pd]
Solvent: CO
Product: O=C1CN(C(=O)CCc2ccc(Oc3ccccc3)nc2)CCN1
Reaction time: 12 h

Procedure:
10 mg of 5% palladium on carbon were added to a solution of 142 mg (0.4 mmol) of 4-[3-(6-phenoxy-pyridin-3-yl)-acryloyl]-piperazin-2-one in 15 ml of methanol, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 12 h. The mixture was filtered and evaporated. The product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 87 mg.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:20])[C:13]([OH:19])=[CH:14][N:15]2[CH3:18])=[CH:10][CH:9]=1)#[N:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:19][C:13]1[C:12](=[O:20])[C:11]2[C:16](=[CH:17][C:8]([C:6]#[N:7])=[CH:9][CH:10]=2)[N:15]([CH3:18])[CH:14]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2ccc(C#N)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccc(C#N)cc21

Procedure:
Methanesulphonyl chloride (1.0 ml) was added to a stirred suspension of 7-cyano-3-hydroxy-1-methyl-4quinolone (0.4 g) and triethylamine (2.0 ml) in dry dichloromethane (200 ml) at 0 to 5° and the resultant solution stirred for 2 hours. The solution was washed with water (2×50 ml), dried over magnesium sulphate and the solvent removed by distillation. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (40:1) followed by trituration with diethyl ether (10 ml) to give the novel compound 7-cyano-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 268°.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[C:21]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[CH3:28]>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:30][CH2:31]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(C)ccc2C)CC1
Yield: 72 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2,5-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([C:41]2[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=2)=[O:40])=[CH:35][CH:34]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)([C:41]3[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cn1cncc1C(=O)c1ccc(F)cc1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(F)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.07 mL, 0.175 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (75.8 mg, 0.177 mmol, Intermediate 16) in dry THF (3 mL) in a dry ice-acetone bath. After 1 minute, a solution of (4-fluorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (37.8 mg, 0.185 mmol, Intermediate 29: step b) in dry THF (0.6 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-50% EtOAc-Hexanes) to provide the title compound as a clear foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (d, J=2.1 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.57-7.50 (m, 3H), 7.35 (d, J=8.6 Hz, 2H), 7.34-7.29 (m, 2H), 7.25 (s, 1H), 7.04-6.96 (m, 2H), 6.45-6.40 (m, 1H), 6.30 (s, 1H), 4.30 (s, 2H), 4.08 (s, 3H), 3.34 (s, 3H); MS m/e 554.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]([S:15][CH2:16][C:17]([OH:19])=[O:18])[N:3]=1.[CH:20]1(N=C=NC2CCCCC2)[CH2:25]CCC[CH2:21]1.C(O)C=C.CC#N>CN(C=O)C.CN(C)C1C=CN=CC=1.C(O)(C(F)(F)F)=O>[CH2:25]([O:18][C:17](=[O:19])[CH2:16][S:15][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=1)[CH:20]=[CH2:21]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Nc1nc(SCC(=O)O)ncc1Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: C=CCO
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)CSc1ncc(Cc2ccccc2)c(N)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(4-Amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid (0.25 mmol, 69 mg), dicyclohexylcarbodiimide (0.3 mmol, 62 mg) and allyl alcohol (0.3 mmol, 18 mg) were dissolved in 1 ml of DMF, and a catalytic amount of 4-dimethylaminopyridine (approx. 1–3 mg) was added. After shaking the mixture for 24 h at r.t., the title compound, MS: m/e=316.2 (M+H+), was obtained from the reaction mixture by HPLC chromatography (YMC CombiPrep C18 column 50×20 mm, solvent gradient 10–95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).