Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:10]1[S:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=2)=[N:13][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-].[K+]>CO>[CH2:1]([C:10]1[S:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[N:13][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1nnc(-c2ccc(C(=O)OC)cc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCc1nnc(-c2ccc(C(=O)O)cc2)s1

Procedure:
2-Nonyl-5-(4-methoxycarbonylphenyl)-1,3,4-thiadiazole (0.02 moles, 7.4 g) is added to a solution of 0.2 moles (11.2 g) KOH in 400 mL methanol and heated for 2 hours at the boiling point. The solvent is distilled of in a rotary evaporator and the residue is dissolved in 200 mL of water and acidified with concentrated hydrochloric acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[C:16]([OH:18])=O)=[CH:4][CH:3]=1>S1(CCCC1)(=O)=O>[CH3:15][C:13]1[O:14][C:10]2[CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[C:16](=[O:18])[C:11]=2[N:12]=1
Reactant: Cc1ccc(CCc2oc(C)nc2C(=O)O)cc1
Solvent: O=S1(=O)CCCC1
Product: Cc1ccc2c(c1)C(=O)c1nc(C)oc1CC2
Temperature: 130 °C
Reaction time: 48 h

Procedure:
A mixture of the product from step (v) (21.5 g), polyphosphoric acid (120 g) and sulpholane (60 ml) was stirred at 130° C. for 2 days. The cooled mixture was poured onto ice/water and extracted with ethyl acetate. The extracts were washed with water, dried (MgSO4) and evaporated. Purification was by flash column chromatography eluting with 2% ethyl acetate in dichloromethane followed by recrystallisation from ethyl acetate.
Reaction SMILES: [CH2:1]([O:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].C#C.Cl.[Cl:34][CH:35](Cl)[CH3:36]>>[CH2:1]([O:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:19]=[CH:20][C:21]([C:22](=[O:23])[CH:36]=[CH:35][Cl:34])=[CH:25][CH:26]=2)[CH2:14][CH2:13]1)[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: CC(Cl)Cl
Reactant: COc1ccc(COC[C@H]2CC[C@H](c3ccc(C(=O)Cl)cc3)CC2)cc1
Agent: C#C
Agent: Cl
Agent: [Al+3]
Product: COc1ccc(COC[C@H]2CC[C@H](c3ccc(C(=O)C=CCl)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 16.3 g of p-[trans-4-(p-anisyloxymethyl)-cyclohexyl]benzoyl chloride in 50 ml of dichloroethane is cooled to 7° C. and treated portionwise under nitrogen within 5 minutes with 6.4 g of powdered aluminium chloride. A weak stream of acetylene gas is then conducted through the reaction mixture at 45° C. for 17 hours. The reaction mixture is subsequently poured into 100 ml of ice-water, treated with 50 ml of 3N hydrochloric acid and stirred for 10 minutes. The mixture is extracted with diethyl ether. The organic phase is washed in succession with water, with 5 percent potassium hydroxide solution and several times with water, then dried over magnesium sulphate and evaporated. The trans-4-(p-anisyloxymethyl)-1-[p-(3-chloroacryloyl)phenyl]cyclohexane obtained is purified by chromatography on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]1[C:13](O[C:16](=[O:17])[C:5]2=1)=[O:14].[N:18]1C=CC=C[CH:19]=1>>[O:17]=[C:16]1[C:5]2[C:4]3[CH:3]=[C:2]([Br:1])[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([CH3:12])[C:6]=2[C:13](=[O:14])[N:18]1[CH3:19]
Reactant: Cc1nc2ccc(Br)cc2c2c1C(=O)OC2=O
Reactant: c1ccncc1
Product: Cc1nc2ccc(Br)cc2c2c1C(=O)N(C)C2=O
Temperature: 25 °C

Procedure:
To 350 ml of dry pyridine was added 14.7 g of the anhydride (ix) in a 3-neck flask with reflux condenser, drying tube, magnetic stirrer and a thermometer. The flask was cooled with an ice/H2O bath and dry reagent grade CH3NH2 was passed into the mixture. The flask was then allowed to warm up to room temperature and refluxed for 20 hours.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[CH:21](C1OC(C)=CC(=O)C=1OCC1C=CC=CC=1)C>>[CH3:1][O:2][CH:3]([C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(C)O)o1
Product: COC(C)c1oc(C)cc(=O)c1OCc1ccccc1
Yield: 97 %

Procedure:
In an analogous procedure in the preparation of 2-methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using 2-(1-hydroxyethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one (2.6 g, 10 mmol, 1 eq.) yielded the title compound as an orange oil (2.65 g, 97%). Further purification by column chromatography on silica gel (eluant: EtOAc) furnished the pure product as a bright yellow oil.
Reaction SMILES: [CH2:1]([C:8]([C:21]#[N:22])([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>O.C(O)C.O>[CH2:14]([C:8]([C:21]#[N:22])([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:11])=[O:10])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C#N)(Cc1ccccc1)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC(Cc1ccccc1)(Cc1ccccc1)C(=O)O
Yield: 100 %

Procedure:
Ethyl 2-benzyl-2-cyano-3-phenylpropionate (3.20 g, 11 mmol) was saponified at room temperature overnight with potassium hydroxide (6.17 g, 0.11 mol) in 10% water/ethanol. The mixture was diluted with water (200 mL) and extracted with hexane (2×50 mL). The aqueous layer was acidified with 1M phosphoric acid and extracted with methylene chloride (4×100 mL). The combined organic extracts were dried over magnesium sulfate and freed of solvent to afford 2-benzyl-2-cyano-3-phenylpropionic acid (2.94 g, 11 mmol) as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.34 (br s, 10 H), 3.24 (dd, J=13.5, 57 Hz); mass spectrum m/e 283 (M+NH4+).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH:24]=[O:25])=[CH:18][CH:17]=1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][CH2:24][OH:25])=[CH:18][CH:17]=1
Reactant: O=C/C=C/c1ccc(-c2ncccn2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: OCC=Cc1ccc(-c2ncccn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
DIBAL (1.0 M in THF, 18.0 mL) was added over 10 min to a −78° C. suspension of (2E)-3-[4-(2-pyrimidinyl)phenyl]-2-propenal (2.50 g, 11.89 mmol, prepared as described in Reference Example 2) in dichloromethane (100 mL). The resulting suspension was stirred for 30 min at −78° C., methanol (2 mL) was added cautiously, and stirring was continued for 5 min at −78° C. The mixture was poured into a mixture of 10% aq. citric acid (300 mL) and dichloromethane (200 mL) and allowed to stir for 1 h. The organic layer was separated, washed with sat. aq. NaHCO3 (200 mL) and brine (200 mL), dried (MgSO4), filtered through Celite, and concentrated. The resulting material was triturated with ether and dried in vacuo to provide 2.08 g (82%) of the title compound. MS 213 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](F)([F:12])[C:7](F)([F:14])[CH:6]=[CH:5]2>O1CCCC1.[OH-].[NH4+].ClCCl.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([F:14])[CH:6]=[CH:5]2
Reactant: FC1(F)C=Cc2cc(Br)ccc2C1(F)F
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc2cc(Br)ccc2c1F
Temperature: 25 °C

Procedure:
Zinc (341 mg, 5.22 mmol) was added to a stirred mixture of 6-bromo-1,1,2,2-tetrafluoro-1,2-dihydronaphthalene (730 mg, 2.60 mmol) in tetrahydrofuran and concentrated ammonium hydroxide (4 mL) at 0° C. The mixture was allowed to warm slowly to room temperature. After 6 hours the reaction was diluted with 35 mL of dichloromethane and extracted. The organic layer was washed with water (2×30 mL) dried and concentrated. The residue was purified by chromatography on silica gel eluting with pentane:hexane (1:1) to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].N1CCCCC1.CO>C(O)(=O)C.O>[CH:4]1[C:5](/[CH:6]=[C:14]2\[C:13]([NH:12][C:11]([S:10]\2)=[O:16])=[O:15])=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(O)cc1
Solvent: O
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C\c2ccc(O)cc2)S1

Procedure:
A mixture of 4-hydroxy benzaldehyde, 36 (3 g, 24.6 mmol), 2,4-thiazolidinedione, 37 (2.9 g, 24.8 mmol), piperidine (2.5 mL) and methanol (100 mL) was refluxed for 18 h. The reaction mixture was poured into water and acidified with acetic acid to give 38, which was recrystallised from methanol. Yield 4.7 g (86%); mp 296-298° C.; MS (FAB) 222 (M++1); IR (KBr) 3404, 3123, 1723, 1678; 1H NMR (200 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.46 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:18][N:17]=2)=[CH:10][CH:9]=1)(=O)=O.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:15]#[C:14][C:11]3[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][NH:34][CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:9][CH:10]=3)=[N:17][CH:18]=2)=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)OCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Reactant: NC1CCCC1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(CCNC4CCCC4)cc3)nc2)cc1

Procedure:
The product was prepared analogously to Example 1.1g from 60 mg (0.15 mmol) of 2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]phenyl}ethyl methanesulfonate and 0.03 mL (0.30 mmol) of cyclopentylamine (6 hours at 50° C., potassium carbonate as base). Yield: 20 mg (34% of theoretical); C26H25ClN2 (M=400.943); calc.: molpeak (M+H)+:401/403 (Cl); found: molpeak (M+H)+:401/403 (Cl); HPLC-MS: 5.0 minutes (method H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2([CH2:11][C:12]([C:27]([F:30])([F:29])[F:28])([OH:26])[CH:13]=[N:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][C:19]([CH3:25])=[N:20]4)[CH2:10][CH2:9]2)[CH:7]=1.[BH4-].[Na+]>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2([CH2:11][C:12]([C:27]([F:28])([F:29])[F:30])([OH:26])[CH2:13][NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][C:19]([CH3:25])=[N:20]4)[CH2:9][CH2:10]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(C=Nc2cccc3nc(C)ccc23)C(F)(F)F)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)cc1C1(CC(O)(CNc2cccc3nc(C)ccc23)C(F)(F)F)CC1

Procedure:
870 mg (1.95 mmol) of 3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-methylquinolin-5-ylimino)-2-(trifluoromethyl)propan-2-ol is reacted analogously to Example 37 with 96 mg (2.53 mmol) of sodium borohydride in 6.0 ml of methanol and 3.0 ml of tetrahydrofuran. After recrystallization from hexane and ethyl acetate, 790 mg (90% of theory) of the product is obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][N:10]1[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]1=[O:22])[CH2:6]2.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[O:22]=[C:11]1[N:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH:7]3[CH:3]([CH:2]3[NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:4]2)[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: N#Cc1ccc2c(c1)N(CCN1CC3C(N)C3C1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc2c(c1)N(CCN1CC3C(C1)C3NCc1ccc3c(n1)NC(=O)CO3)C(=O)CO2
Yield: 6 %

Procedure:
4-[2-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 93), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 6% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][OH:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CN(CCO)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COCCN(CC(=O)OCC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of ethyl N-(tert-butoxycarbonyl)-N-(2-hydroxyethyl)glycinate (1.2 g) in THF (17 mL) was added ethyl bromoacetate (0.8 ml) under ice-cooling, and the mixture was stirred for 5 min. To this solution was added sodium hydride (288 mg), and the mixture was stirred under ice-cooling for 5 min, and at room temperature for 60 min. The reaction mixture was ice-cooled again, ice water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (788 mg).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[C:10]([Cl:15])[C:9]2[C:4](=[CH:5][C:6]([F:16])=[CH:7][CH:8]=2)[N:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Sn](CCCC)(CCCC)CCCC)[CH:19]=1>C1(C)C=CC=CC=1>[Cl:15][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:16])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:20]2[CH:19]=[C:18]([CH3:17])[CH:23]=[CH:22][N:21]=2)[C:11]=1[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)c1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)ccc3c(Cl)c2C(C)C)c1

Procedure:
The Stille coupled product was prepared according to Procedure E using 2,4-dichloro-7-fluoro-3-isopropylquinoline (0.3 g, 1.162 mmol), 4-methyl-2-(tributylstannyl)pyridine (0.489 g, 1.28 mmol) and palladium tetrakistriphenylphosphine (0.134 g, 0.12 mmol) in toluene (2.3 mL) at 100° C. for 6.5 days to give 4-chloro-7-fluoro-3-isopropyl-2-(4-methylpyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=315.1 (M+1).
Reaction SMILES: [Na].[CH2:2]([NH:4][C:5]1[CH:10]=[C:9]([C:11](=[N:13]O)[CH3:12])[CH:8]=[CH:7][N:6]=1)[CH3:3].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[O-]CC.[K+].[S-:30][C:31]#[N:32].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)C.C(O)C>[CH2:2]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[N:13]=[C:31]([SH:30])[NH:32][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[CH3:3]
Reactant: N#C[S-]
Reactant: CCNc1cc(C(C)=NO)ccn1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCNc1cc(-c2c[nH]c(S)n2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 20 ml. of absolute ethanol containing 240 mg. of dissolved sodium was added 1.79 g. (10 mmoles) of 1-(2-ethylamino-4-pyridyl)-1-ethanone oxime, and the mixture stirred until homogeneous (~5 minutes). p-Toluenesulfonyl chloride (2.04 g., 10.7 mmole) was added and the mixture stirred at room temperature under nitrogen for 1 hour. the mixture was added to a solution of potassium ethoxide (prepared by dissolving 430 mg. of potassium in 20 ml. of absolute ethanol) and the resulting mixture allowed to stir at room temperature for 0.5 hour. The resulting gelatinous suspension was diluted with 100 ml. of diethyl ether and stirred at room temperature for 30 minutes. The reaction was filtered through celite and the filtrate was concentrated. The residue was dissolved in 100 ml. of ether and any remaining solids filtered. The ether solution was extracted with 2 N hydrochloric acid (4×15 ml.) and the combined acid extracts concentrated to give a yellow solid. The residue was dissolved in 30 ml. of water containing 1.94 g. (20 mmoles) of potassium thiocyanate and the solution heated on a steam bath for 2 hours. After cooling, the mixture was made basic with sodium sodium carbonate and the precipitate filtered, washed with water and dried, 1.27 g. (58%), m.p. >260° C.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Mn+2:13].C(=O)([O-])[O-]>O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Mn+2:13]
Reactant: O=C(O)/C=C\C(=O)O
Agent: [Mn+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
An aqueous solution composed of 40 g water, 11.6 g maleic acid, and 11.5 g manganese carbonate is prepared. The carbonate slowly reacts and dissolves to give manganese maleate derivative solution. This manganese maleate solution is used as a monomer source in a polymerization such as that described in Example 8, wherein equimolar amounts of maleate and vinyl acetate were used. After that, a hydrolysis is performed using the procedures described in Example 14. The reaction proceeded as follows:
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.FC(F)(F)C([O-])=O.C([O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][NH2+:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1)(=O)C.C(O)C(N)(CO)CO>C1COCC1>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:44][CH2:43]3)=[CH:38][CH:37]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CC(=O)Oc1ccc(NC(=O)c2ccc(N3CC[NH2+]CC3)cc2)cc1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)COC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
2 eq of isobutyl-chloroformate and 3.5 eq of Et3N were added to a solution of 4-[4-({[4-(acetyloxy)phenyl]amino}carbonyl)phenyl]piperazin-1-ium trifluoroacetate in dry THF (0.05 M) and the solution was allowed to stir at RT for 3 h under N2. PS-trisamine resin (excess) was added and the reaction mixture was stirred for 16 h. The resin and a white precipitate were filtered off. Excess aqueous NaOH (1 M) was added to the organic solution and the reaction mixture was stirred for 2 h. The organic solvent was removed in vacuo and aqueous HCl (1 M) was added until precipitation of a white solid that was filtered off, washed and dried in vacuo to afford the title compound (90%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH:14][S:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:27])[F:28])[CH:18]=3)(=[O:25])=[O:24])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(COCCC2CC2)n1
Product: O=S(=O)(Nc1cccc(COCCC2CC2)n1)c1cccc(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(2-cyclopropyl-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 3-(trifluormethyl)-benzenesulfonyl chloride (0.11 g) as a light yellow gum (0.106 g). MS (ESI−): 399.2 ([M−H]−).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:12]1
Reactant: N#Cc1cccnc1F
Reactant: CN1CCCC(O)C1
Product: CN1CCCC(Oc2ncccc2C#N)C1

Procedure:
2-Fluoro-nicotinonitrile was reacted with 1-methyl-piperidin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 218 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16](=[O:27])[NH:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]#[CH:25])[C:19]1=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:28]([O:32][C:33](=[O:42])[NH:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][C:36]=1I)([CH3:31])([CH3:30])[CH3:29].C1CCN2C(=NCCC2)CC1>CN(C=O)C.C(OCC)(=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.[Cu]I>[C:28]([O:32][C:33]([N:34]1[C:35]2[CH:40]=[CH:39][N:38]=[CH:37][C:36]=2[CH:25]=[C:24]1[CH2:23][N:20]1[CH2:21][CH2:22][C@H:18]([NH:17][C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:27])[C:19]1=[O:26])=[O:42])([CH3:31])([CH3:29])[CH3:30]
Reactant: C#CCN1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(CN2CC[C@H](NC(=O)OCc3ccccc3)C2=O)cc2cnccc21
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
Pd(PPh3)2Cl2 (0.49 g, 0.70 mmol), CuI (0.08 g, 0.42 mmol) followed by triethylamine (7.8 mL, 56.0 mmol) is added to a solution of (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid benzyl ester (3.81 g, 13.9 mmol) and (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester (4.48 g, 14.0 mmol) in DMF (50 mL) at room temperature. The mixture is heated to 100° C. and stirred for 1.5 h. The reaction mixture is then cooled to 50° C. and DBU (4.2 mL, 28.1 mmol) is added. After 30 min the solution is cooled to room temperature, diluted with ethyl acetate and washed with saturated ammonium chloride, water and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness in vacuo. The resulting solid is purified by column chromatography eluting with a gradient of 2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2 to give the product (4.79 g, 10.3 mmol) as a white solid.
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH:9]([CH3:11])[CH3:10])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.ClCCl>[C:12]([O:7][CH2:6]/[CH:5]=[CH:4]/[C:3](/[CH2:1][CH3:2])=[CH:8]/[CH:9]([CH3:10])[CH3:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(/C=C/CO)=C\C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(/C=C/COC(C)=O)=C\C(C)C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a solution of (E,E)-4-ethyl-6-methyl-2,4-heptadien-1-ol (23.8 g) in pyridine (61.4 g) at 0° C. was added dropwise acetic anhydride (50.9 g). After two hours, the reaction mixture was diluted with dichloromethane. The solution was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (3% ethyl acetate-hexane) to give (E,E)-1-acetoxy-4-ethyl-6-methyl-2,4-heptadiene (24.11 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:17][CH:18]=2)=[O:23])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Yield: 63.5 %

Procedure:
Reaction of 4-aminobenzophenone (102 mg, 0.52 mmol) in THF (6 mL) with 4-biphenylcarbonyl chloride (143 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave biphenyl-4-carboxylic acid (4-benzoyl-phenyl)-amide (125 mg, 0.33 mmol, 63% yield) as a yellow powder after purification by crystallisation in DCM/EtOAc.