Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:32][C:17]3=[CH:18][N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:20]2[CH:21]=[C:16]3[CH2:15][CH:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[O:32][C:17]3=[CH:18][N:19]=2)=[CH:23][CH:24]=1)(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (190 mg) and trifluoro acetic acid (0.40 mL) in dichloromethane (3 mL) is stirred at room temperature for 2 h. The reaction mixture is diluted with dichloromethane and washed with aqueous Na2CO3 solution. The aqueous phase is extracted dichloromethane and the combined organic phases are washed with water, dried over MgSO4, and concentrated in vacuo. LC (method 5): tR=0.62 min; Mass spectrum (ESI+): m/z=359 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:38][C:32]3[C:37]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(F)c4)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 498.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][O:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc([N+](=O)[O-])cc1Cl

Procedure:
A mixture of 2-chloro-4-nitrophenol (2.761 g), chloromethyl methyl ether (2.4 mL), acetone (16 mL) and potassium carbonate (3.1 g) was heated under reflux for 5 hours. The reaction mixture was poured in saturated saline solution, and the product was extracted with diethyl ether. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off, to provide crude 2-chloro-1-methoxy-methoxy-4-nitrobenzene (3.091 g).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]([F:34])([F:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>O>[F:15][C:16]([F:33])([F:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: FC(F)(F)CCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 60 °C

Procedure:
A mixture of ethyl 4-aminocinnamate, one equivalent of 15-(trifluoromethyl)pentadecyl bromide and one equivalent of anhydrous potassium carbonate in hexamethylphosporamide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperatures for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[C:20]([CH:23]=3)[CH:21]=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:32]([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[C:20]([C:21]#[CH:32])[CH:23]=3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
152 mg (0.79 mmol) dimethyl (1-diazo-2-oxo-propyl)-phosphate in 2 mL MeOH are added to a solution of 300 mg (0.66 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (Example 3.55b) and 183 mg (1.32 mmol) K2CO3 in 9 mL MeOH. The reaction solution is stirred for for 3 h at RT and diluted with 20 mL DCM. The organic phase is extracted twice with saturated NaHCO3 solution. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by HPLC-MS.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[S:6])[NH2:5].Cl[CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]1[S:6][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:19]([CH3:21])[N:5]=1
Reactant: NC(=S)c1c(F)cccc1F
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2c(F)cccc2F)nc1C
Reaction time: 0.5 h

Procedure:
To a solution of the compound prepared in Example 344 (50 g) in ethanol (250 mL) was added ethyl 2-chloroacetoacetate (42 mL) at room temperature. The mixture was heated to reflux for 12 hours, cooled and concentrated. The residue was stirred with hexane (250 mL) for 30 minutes, filtered and then washed with hexane (50 mL). The solid was dried to obtain the title compound (48.6 g) having the following physical data.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([OH:12])[O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.CCN(CC)CC>CS(C)=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:20][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]([OH:12])[O:7][C:8]3=[O:11])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: O=C1OC(O)c2ccc(I)cc21
Reactant: C=Cc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(C=Cc2ccc3c(c2)C(=O)OC3O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1.38 g (5 mmol) of 6-iodo-3-hydroxyisobenzofuranone, 0.74 g (5.5 mmol) of p-methoxystyrene, 0.83 ml (5.5 mmol) Et3N, 0.01 g of Pd (OAc)2 and 1 ml of DMSO was prepared in a 10 ml flask. The flask was surmounted with a reflux condenser and the solution was heated to 95° (oil bath) with stirring under N2 for 1 hour. The dark solution was allowed to cool to RT and poured onto 75 ml of ice/H2O with stirring. After standing overnight, the solid which had formed was collected, washed well with cold H2O and air dried. It was then heated with 50 ml of 95% EtOH, charcoaled and filtered. The reddish filtrate was cooled in ice and deposited 100 mg of reddish-brown solid which was found to be impurity and was discarded. The filtrate was evaporated at reduced pressure and the residual orange-yellow solid was triturated with 25 ml of Et2O and filtered to afford 860 mg (60.9%) of the desired coupling product as a yellow solid; homogeneous by TLC--used as is for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I.O>CN(C=O)C>[CH3:15][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:10]=2)[C:6]([CH:11]=[O:12])=[CH:7]1
Reactant: Cc1ccc2c(C=O)c[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(C=O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of the known 6-methyl-1H-indole-3-carboxaldehyde (5 g, 31 mm) in DMF (100 mL) was cooled to 0° C. and treated with NaH (38 mm), and stirred at 0° C. for 3 hours. After treatment with CH3I (2.35 mL, 38 mm), the mixture was allowed to warm to room temperature overnight. The mixture was poured into H2O(500 mL) and extracted with ethylacetate (EtOAc) (200 mL×3). The combined organic layers were dried over MgSO4, filtered and evaporated. Purification by flash column chromatography afforded 1,6-dimethyl-1H-indole-3-carboxaldehyde (5.2 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:22][CH2:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)CCl)ccc1-c1cnco1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1D (500 mg, 2.63 mmol) and triethylamine (370 μL, 2.89 mmol) in dichloromethane (13.0 mL), was added chloroacetyl chloride (0.23 mL, 2.89 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. and then at RT for 4 h. The mixture was diluted with dichloromathane, washed with water, brine, and dried over Na2SO4. The mixture was filtered through celite and concentrated in vacuo to give 2A as a yellow solid. LC/MS: ret. timeA=3.123 min., MS (M+H)+=267.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([C:25]3[C:24]([CH3:34])=[CH:23][C:22]([CH:19]4[CH2:20][CH2:21]4)=[CH:27][N:26]=3)[CH2:29][CH2:30]2)=[O:8])=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Yield: 63.1 %

Procedure:
Using methyl 4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (1 g) described in Preparation Example 239 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (0.65 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 166, the title compound (0.98 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(O)c1ccncc1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccncc3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and isonicotinic acid as brown solid (36%). MS 409 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]([C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:19]#[N:20])[CH:22]=3)=[O:33])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Reactant: N#Cc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C#N)c3)n2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-cyano-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.70 min; [M+H]+=417.70.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:16][C:17]([N:19]1[C@H:23]([CH:24]([OH:33])[C:25]2[N:26]3[CH:32]=[N:31][CH:30]=[C:27]3[S:28][CH:29]=2)[CH2:22][C@@H:21]([OH:34])[CH2:20]1)=[O:18])[CH:14]=[CH2:15].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:13]([O:16][C:17]([N:19]1[C@H:23]([CH:24]([OH:33])[C:25]2[N:26]3[CH:32]=[N:31][CH:30]=[C:27]3[S:28][CH:29]=2)[CH2:22][C@@H:21]([O:34][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:20]1)=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(O)c1csc2cncn12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(O)c1csc2cncn12
Reaction time: 0.5 h

Procedure:
Triethylamine (0.25 ml) and 0.12 ml of methanesulfonyl chloride are successively added to a solution of 457 mg of crude (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidine (stereoisomer A) in 12 ml of dry THF in an argon atmosphere at 3° C., and the mixture is stirred in this state for 30 min. A 5% aqueous sodium hydrogencarbonate solution (30 ml) is added thereto, and the mixture is extracted with 100 ml of ethyl acetate. The organic layer is washed with saturated saline, dried over magnesium sulfate, and filtered, and the solvent is removed by evaporation under reduced pressure to give a slightly cloudy orange brown oil. This oil is purified by flash column chromatography on silica gel (ethyl acetate:methanol=92:8) to give 344 mg of crude (3R,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]-3-methanesulfonyloxypyrrolidine (stereoisomer A) as a milky white amorphous material.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([Cl:12])[N:3]=1.[OH-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=[O:35])C>C1COCC1>[Cl:12][C:4]1[NH:3][C:2](=[O:35])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=c1[nH]c(Cl)nc2ccccc12
Yield: 86 %

Procedure:
A solution of 3 g (11 mmol) of the dichloroquinazoline (1A) in 50 mL THF was stirred with 30 mL of 40% aqueous KOH and 3 mL of 40% aqueous tetrabutylammonium hydroxide for 3 days. The layers were allowed to separate and the upper layer was concentrated to give a white solid. This was treated with dilute acetic acid and the solid was collected and washed with water, then dried at 65° C. in vacuo to afford 2.4 g (86%) of the 2-chloroquinazolin-4-one (1). Mp 251–251.7° C.; MS (ES+) m/z 255 (M+H)+. Anal. (C11H11ClN2O3) Calcd.: C, 51.88; H, 4.35; N, 11.00. Found: C, 51.94; H, 4.34; N, 10.95.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:23]1([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:21][O:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:33][CH:34]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(OCCN4CCOCC4)cc3)nc12

Procedure:
[8-(2-methoxy-5-triflouromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.5 mmol), and 4-(morpholin-4-yl-ethoxy)-phenylamine (0.130 g, 0.58 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.19 g, 81%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.8 Hz, 1H), 7.96 (s, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.55 (d, J=5.7 Hz, 1H), 7.51-7.46 (m, 2H), 7.12 (d, J=7.9 Hz, 1H), 6.94-6.89 (m, 1H), 6.77 (d, J=6.8 Hz, 1H) 6.71 (s, 1H) 6.65 (d, J=7.9 Hz, 1H), 4.15-4.03 (m, 2H), 3.89 (s, 3H), 3.78-3.71 (m, 4H), 2.86-2.76 (m, 2H), 2.64-2.56 (m, 4H). MS=514 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[Cu][C:14]#[N:15].CN(C=O)C>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5]([C:14]#[N:15])=[CH:6][N:7]=1
Reactant: N#C[Cu]
Reactant: CNC(=O)c1nc(Br)cnc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(C#N)cnc1N
Temperature: 25 °C
Yield: 32.4 %

Procedure:
3-Amino-6-bromo-N-methylpyrazine-2-carboxamide (2.0 g, 8.7 mmol) and copper (I) cyanide (3.9 g, 43.5 mmol) were taken into DMF (20 mL) and the mixture was heated to reflux for two hours. The mixture was allowed to cool to room temperature then diluted with ethyl acetate (250 mL). The insoluble residue was removed by filtration and the filtrate partitioned with water. The organic layer was separated and washed with water (2×) then brine and dried over anhydrous magnesium sulfate. Filtration and concentration afforded 3-amino-6-cyano-N-methylpyrazine-2-carboxamide (500 mg, 33% yield) as a white solid: 1H NMR (400 MHz, d6-DMSO): 8.84 (br m, 1H), 8.67 (br s, 1H), 8.65 (s, 1H), 2.77 (d, 3H).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:5][OH:6])[CH2:2][CH3:3].C[O:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:14]([O:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCC(=O)OC
Reactant: CCCCCC(CO)CCC
Product: CCCCCCCC(=O)OCC(CCC)CCCCC
Temperature: 60 °C
Reaction time: 48 h

Procedure:
500 g 2-propylheptanol, 500 g octanoic acid methyl ester and 50 g Novozym 435 (Novo, Denmark: immobilized lipase—lipase B—from Candida antarctica) were heated under nitrogen for 5 h to 45° C. The temperature was then increased to 60° C. and vacuum (20 mbar) was applied. After 48 h under these conditions, the reaction was terminated. After the enzyme had been filtered off, the product accumulated as a colorless oil. Less than 1% of the educts could be detected by GC.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:2]=1.C(=O)([O-])O.[Na+:26]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O-:15])=[O:14])[CH:2]=1.[Na+:26]
Reactant: O=C(O)CCCC/C=C(\c1ccccc1)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C([O-])CCCC/C=C(\c1ccccc1)c1cccnc1
Yield: 55.7 %

Procedure:
(E)-7-(3-pyridyl)-7-phenyl-6-heptenoic acid (Ia-4) (500 mg) and sodium hydrogen carbonate (160 mg) were added to water (5 ml) to make a homogeneous solution. The solution was concentrated under reduced pressure. The concentrate was pulverized by the use of ethanol-isopropylether to obtain sodium (E)-7-(3-pyridyl)-7-phenyl-6-heptenoate (Ii-76, 300 mg). The physico-chemical properties and other data of the product are shown in Table 6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:20][C:17]1[CH:18]=[CH:19][C:10]2[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[CH2:14][C:13](=[O:15])[NH:12][C:11]=2[CH:16]=1
Reactant: O=C1CC(c2cccc(Br)c2)=Nc2ccc([N+](=O)[O-])cc2N1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)CC(c1cccc(Br)c1)=N2
Temperature: 90 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
To a stirred solution of compound 3 (0.1 g, 0.27 mmol) in EtOH:H2O (10 mL, 6:3) was added Fe-powder (0.076 g, 1.39 mmol) followed by NH4Cl (0.037 g, 0.70 mmol) at RT. The resulting reaction mixture was heated to 90° C. and stirred for 1 h; progress of the reaction was monitored by TLC. The reaction mixture was then cooled to RT; the reaction mixture was filtered and the obtained filtrate was concentrated under reduced pressure. The residue was diluted with water (10 mL) and then extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 4 (35 mg, 38%) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.32 (bs, 1H), 8.15-8.13 (m, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 6.32 (s, 1H), 5.48 (bs, 2H), 3.42 (s, 2H). Mass: m/z 331 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[CH2:14][OH:15])=[C:4](F)[CH:3]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[CH2:14][O:15][C:4]=2[CH:3]=1
Reactant: OCc1cnccc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)OCc1cnccc1-2
Yield: 60.5 %

Procedure:
To a cooled solution of (4-(4-chloro-2-fluorophenyl)pyridin-3-yl)methanol (2.89 g, 12.14 mmol) in THF (10 mL) at 0° C. was added a sodium hydride (1.94 g, 48.6 mmol) suspension in THF (10 mL) and the resultant mixture was stirred at 0° C. for 40 min. The reaction was quenched by addition of cold water (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic extracts were dried with sodium sulfate and concentrated under reduced pressure. The residue so obtained was purified by column chromatography (50% ethyl acetate in pet ether) to afford 8-chloro-5H-chromeno[3,4-c]pyridine (1.6 g, 7.35 mmol, 61% yield) as a white solid. 1H NMR (400 MHz, MeOD) δ 8.54 (d, J=5.60 Hz, 1H), 8.43 (s, 1H), 7.89 (d, J=8.40 Hz, 1H), 7.76 (d, J=5.60 Hz, 1H), 7.14 (dd, J=2.40, 8.40 Hz, 1H), 7.07 (d, J=2.00 Hz, 1H), 5.24 (s, 2H); LCMS (ESI) m/e 218 [(M±H)+, calcd for C12H9ClNO 218.0].
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.N1C(C)=CC=CC=1C.O([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Si:28]([O:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: O=C(O)[C@H]1CC[C@H](CO)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of trans-4-(1-hydroxymethyl)-cyclohexanecarboxylic acid (1.00 g, 6.32 mmol) and 2,6-lutidine (2.95 mL, 25.29 mmol) in DCM (61 mL) was added drop wise tert-butyldimethylsilyl triflate (4.36 mL, 18.96 mmol). The reaction mixture was stirred at RT for 1.5 hours. The reaction mixture was quenched with water and the organic phase removed. The aqueous phase was extracted with further DCM (×2). The combined organic extracts were combined and washed with brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was dissolved in THF (30 mL) and methanol (90 mL) and 10% aqueous potassium carbonate (30 mL) added. The reaction mixture was stirred at RT for 2 hours. The solvent was evaporated at reduced pressure and the residue partitioned between water and ether. The organic phase was discarded. The aqueous phase was washed with further ether (×2). The pH of the aqueous extract was adjusted to 5 and extracted with ethyl acetate (×3). The combined ethyl acetate extracts were washed with brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title compound (1.59 g, 93%).