Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.B(OB=O)=O.[Cl:21][C:22]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:23]=1[CH:24]=O.B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[Cl:21][C:22]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:23]=1/[CH:24]=[CH:13]/[C:12](=[O:14])[CH2:11][C:10](=[O:15])/[CH:9]=[CH:8]/[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: CC(=O)CC(=O)C=Cc1ccc(O)cc1
Reactant: O=Cc1ccc(O)cc1Cl
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: O=BOB=O
Solvent: O
Solvent: CCCCN
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1ccc(O)cc1Cl
Reaction time: 1 h
Yield: 45.3 %

Procedure:
6-(4-Hydroxyphenyl)hex-5-ene-2,4-dione (17.5 mg, 85 μmol) and boron trioxide (11 mg, 0.16 mmol) was placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring mixture at 80° C. was added a solution of 2-chloro-4-hydroxybenzaldehyde (17 mg, 0.11 mmol) and tri-n-butyl borate (25 μL, 93 μmol, sequentially. After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The reaction mixture was treated with a 1:1 solution (1 mL) of 1N HCl and brine at room temperature, and was stirred at 50° C. for 5 min to 1 h (if necessary, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound (13.2 mg, 45%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]([CH2:24][CH:25](OC)OC)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH:25]=[CH:24][N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:13](=[O:14])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN(Cc1ccc(F)cc1)C(=O)CNC(=O)OCc1ccccc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CN(C(=O)OCc2ccccc2)C=CN1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of N2-benzyloxycarbonyl-N1-(2,2-dimethoxyethyl)-N1-(4-fluorobenzyl)glycinamide (61.5 g, 152 mmol) and p-toluenesulfonic acid monohydrate (3 g) in toluene (450 mL) was stirred at 75° C. for 5 days. Each day an additional 3 g of toluenesulfonic acids was added. The resultant reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue dissolved in dichloromethane. The organic solution was washed successively with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. To the residual solid was subjected to column chromatography on silica gel eluting with dichloromethane and then 5% ethyl acetate in dichloromethane. Appropriate fractions were collected and concentrated under vacuum. Residual ethyl acetate and dichloromethane was removed by co-evaporation with toluene for 3 time for subsequent hydrogenation. The residue was triturated with hexane, and filtered to provide the cyclization product as an off-white solid.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:15]=[CH:16]\[CH:17]=[CH:18]\[CH:19]([OH:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])C.[OH-].[Na+]>CO>[OH:28][CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:18]=[CH:17]/[CH:16]=[CH:15]\[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3]
Reactant: CCCCCCCCC(O)/C=C/C=C\c1ccccc1OCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/C=C\c1ccccc1OCCCC(=O)O
Yield: 98.5 %

Procedure:
Under the conditions of example 9, a solution of 60 mg of 4-[2-[(1Z,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl]-phenoxy]-butyric acid ethyl ester in 5 ml of methanol and 2 ml of 0.5 n sodium hydroxide solution is saponified, worked up and chromatographed on silica gel with n-hexane/ethyl acetate=98/2. 55 mg of the title compound is obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[N:6][CH:7]=1
Reactant: OCc1ccc(Cl)cn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: ClCc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a stirring solution of (5-chloropyridin-2-yl)methanol (840 mg, 5.8 mmol) in dichloromethane (10 mL) at 0° C. under argon was added thionyl chloride (0.64 mL, 8.77 mmol), followed by 4 drops of DMF (white precipitate formed). The reaction mixture was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to a white solid. The solid thus obtained was cooled in an ice bath before EtOAc (20 mL) and water (20 mL) and then 10% aqueous Na2CO3 solution (20 mL) were added. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated to obtain 840 mg of the title compound as a light brown gum. HPLC/MS: retention time=2.392 min, [M+H]+=162.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[I:20]I>CS(C)=O>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-(tert-butyldimethylsilyloxy)-1H-indazole (5.3 g, 0.02 mol) in DMSO (50 mL) at 0° C., was added KOH (3.36 g, 0.06 mol) followed by iodine (10.2 g, 0.04 mol) portionwise. The mixture was stirred at room temperature for additional 10 minutes, then the reaction was quenched with 10% Na2S2O3 and diluted with water. The mixture was filtered and the filter cake was washed with water and dried to give 5-(tert-butyldimethylsilyloxy)-3-iodo-1H-indazole. The crude solid was used in the next step without purification. MS: (M+H)+=375.
Reaction SMILES: Cl.[CH2:2]([C:9]1[S:13][C:12]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:27]([C@@H:29]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][N:31]([C@H:40]([CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[O:42])[CH2:30]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:2]([C:9]1[S:13][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:27][C@@H:29]3[C@@H:33]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:32][N:31]([C@H:40]([CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]4)[C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)=[O:42])[CH2:30]3)[CH2:16][CH2:15]2)=[N:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(Cc2cnc(C3CCNCC3)s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4ncc(Cc5ccccc5)s4)CC3)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
To a solution of 24 mg of 4-(5-benzyl-thiazol-2-yl) -piperidine hydrochloride (from Step C) in 3 ml DCE was added 8 mg of triethylamine. After 20 minutes, 35 mg of α-(R)-(3-(R)-Formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (prepared above as Aldehyde 5) was added, followed by 31 mg of sodium triacetoxyborohydride. The reaction was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography with 10% EtOAc in hexane followed by 50% EtOAc in hexane to give 44 mg of the title compound.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7])[CH3:2].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[CH3:2][O:1][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-methoxylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH3:22])=[CH:4][CH:3]=1.[CH:25](O)=[O:26]>C1(C)C=CC=CC=1>[CH:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH3:22])=[CH:23][CH:24]=1)=[O:26]
Reactant: COc1cc2c(cc1OC)C(C)N(CCc1ccc(N)cc1)CC2
Reactant: O=CO
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(C)N(CCc1ccc(NC=O)cc1)CC2
Yield: 100 %

Procedure:
To a stirred solution of N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline (18.5 g, 0.056 m) in toluene (200 ml) under nitrogen was added 97% formic acid (25 ml) and the mixture heated to reflux, collecting the toluene insoluble material in a Dean-Stark tube. After 25 ml had been collected (ca 1 hr) the mixture was cooled and analyzed by TLC to insure completion. The mixture was poured into 500 ml H2O and basified to pH 11 with 10% NaOH, then extracted with CHCl3 (3×250 ml) and the combined extracts dried over MgSO4. Evaporation of the solvent gave N-(4-formamidophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as an oil, 20.0 g (100% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][C:10]1[N:15]=[C:14]([C:16](OC)=[O:17])[CH:13]=[C:12]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:11]=1.[BH4-].[Na+].C(O)C>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][O:9][C:10]1[N:15]=[C:14]([CH:16]=[O:17])[CH:13]=[C:12]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:11]=1
Reactant: COC(=O)c1cc(N2CCOCC2)nc(OCCc2ccccn2)n1
Agent: [Mn+4]
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1cc(N2CCOCC2)nc(OCCc2ccccn2)n1
Yield: 40.6 %

Procedure:
Preparation of alcohol derivative used to prepare Compounds 1-4: To a solution of 2-[2-(pyridin-2-yl)-ethoxy]-4-(methoxycarbonyl)-6-(morpholin-4-yl)-pyrimidine (0.81 g, 2.35 mmol) in ethanol sodium borohydride (4 eq, 0.36 g) was added in portions and the reaction mixture was refluxed for 3 hours. Solvent was removed, the reaction mixture distributed between ethyl acetate and water, organic solution washed with brine, dried and concentrated to give crude alcohol. The above alcohol (0.64 g, 2 mmol) was heated in toluene at 85° C. with manganese dioxide, (10 eq, 1.75 g) for 4 hours to give 2-[2-(pyridin-2-yl)-ethoxy]-4-formyl-6-(morpholin-4-yl)-pyrimidine (0.3 g, 48%) which was isolated by column chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]CN(C)C(=O)[O-])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CSc1ccccc1C(C)(C)C)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccccc1S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a well stirred solution of the carbamate (30.0 g, 0.127 mol) dissolved in 500 ml of methanol was added a solution of sodium hydroxide (15.2 g, 0.38 mol) in methanol (100 ml). The resulting mixture was stirred at room temperature for 30 min followed by gentle reflux (1.5 h) to completion (TLC). Usual work-up followed by flash chromatography yielded 2-tert-butylbenzenethiol (18.0 g, 86% yield) as a pale yellow liquid.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:18][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:18][O:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: CCOC(=O)c1sc(-c2ccncc2)nc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 4-hydroxy-2-(4-pyridyl)-thiazole-5-carboxylate (0.5 gm, 2.0 mmol) in 30% methanol in benzene (30 mL) was added (trimethylsilyl)diazomethane (2.0M solution in hexanes) (1.0 mL, 2.0 mmol). After stirring for 30 minutes at room temperature, an additional 1.0 mL of (trimethylsilyl)diazomethane was added. The mixture was stirred overnight at room temperature and evaporated. The title compound was purified by flash chromatography eluting with 20% acetone in hexane; yield 206 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6](=[O:23])[C:5]2([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])[NH:24][C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26].[H][H]>CCO.C1COCC1.[Ni]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])([NH:24][C:25]([N:27]([CH2:28][CH3:29])[CH2:30][CH3:31])=[O:26])[C:6]2=[O:23])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: CCN(CC)C(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(Cl)cc21
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(CC)C(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(N)cc2)c2ccc(Cl)cc21

Procedure:
7.6 g of the compound obtained in EXAMPLE 12 in 100 ml of EtOH and 50 ml of THF are reduced with hydrogen under a pressure of 50 bar for 6 hours at RT, in the presence of 2 g of Raney nickel. The mixture is filtered on C elite and the filtrate is evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=3.2 g. M.p.=210° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19]OC(C)(C)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]=[CH2:19])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=CCCCc1ccc(-c2ccc(Br)cc2)nc1
Reactant: COC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=CCCCc1ccc(-c2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 6.64 g of methyltriphenylphosphonium bromide in 80 ml of t-butyl methyl ether in a sulphonation flask fitted with a mechanical stirrer is treated while gassing with argon at -10° C. within 3 minutes with 2.12 g of solid potassium t-butylate. The mixture is stirred at room temperature for a further 1 hour, then treated at 0° C. within 5 minutes with a solution of 3.61 g of 4-[2-(p-bromophenyl)- -5-pyridyl]butyraldehyde in 20 ml of t-butyl methyl ether and stirred at room temperature for a further 15 hours. The reaction mixture is subsequently partitioned three times in diethyl ether/water. The organic extracts are washed twice with water, dried over magnesium sulphate, filtered and evaporated. The residue is taken up in ethyl acetate and then the mixture is diluted with petroleum ether and filtered. Evaporation of the filtrate and purification of the residue by chromatography on silica gel gives 2-(p-bromophenyl)-5-(4-pentenyl)pyridine.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH:10]=[CH:9]1>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: C=CCN(CC=C)C(=O)/C=C\C(=O)O

Procedure:
The reaction of equimolar amounts of diallylamine with maleic anhydride in toluene at temperatures below 40° C. gives a quantitative conversion to the N,N-diallylmaleamic acid (I). ##STR14##
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[C:31]([OH:33])=[O:32])=[C:4]([F:36])[CH:3]=1.Cl.[F:38][C:39]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:38][C:39]1([F:45])[CH2:44][CH2:43][N:42]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]3[C:31]([OH:33])=[O:32])=[C:4]([F:36])[CH:3]=2)[CH2:41][CH2:40]1
Reactant: FC1(F)CCNCC1
Reactant: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4F)c3c2)nc1
Agent: Cl
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CCC(F)(F)CC5)cc4F)c3c2)nc1

Procedure:
The title compound was prepared in a manner analogous to that in Example 152 substituting racemic cis-2-{1-(4-bromo-2-fluorobenzyl)-6-[(5-methylpyridin-2-yl)methoxy]-1H-benzimidazol-2-yl}cyclohexanecarboxylic acid and 4,4-difluoropiperidine hydrochloride. MS (ESI): mass calcd. for C33H35F3N4O3, 592.27; m/z found, 593.3 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 7.65 (d, J=8.3, 1H), 7.55 (d, J=8.6, 1H), 7.46 (d, J=8.0, 1H), 7.03-6.98 (m, 2H), 6.85-6.76 (m, 2H), 6.67 (dd, J=8.6, 2.3, 1H), 5.47 (d, J=16.7, 1H), 5.41 (d, J=16.7, 1H), 5.12 (s, 2H), 3.64-3.53 (m, 1H), 3.41-3.35 (m, 4H), 2.91-2.81 (m, 1H), 2.35 (s, 4H), 2.34-2.29 (m, 1H), 2.11-1.95 (m, 5H), 1.86-1.72 (m, 4H), 1.56-1.49 (m, 1H), 1.49-1.41 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]=2)[CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1F.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cl-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:27]2[CH:26]=[CH:25][C:24]([S:29]([N:32]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=3[O:47][CH3:48])[C:33]3[S:37][N:36]=[CH:35][N:34]=3)(=[O:30])=[O:31])=[CH:23][C:22]=2[Cl:21])=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH:12]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc(Cl)ccc2O)cn1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(Cl)c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3-c3cnn(C(=O)OC(C)(C)C)c3)c(Cl)c2)c(OC)c1
Yield: 49.8 %

Procedure:
tert-butyl 4-(5-chloro-2-hydroxyphenyl)-1H-pyrazole-1-carboxylate (Preparation 205, 99.6 mg, 0.338 mmol), 3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 653, 153 mg, 0.345 mmol) and potassium carbonate (59.8 mg, 0.433 mmol) were stirred in dimethylsulphoxide (5 ml) at room temperature for 16 hours. The mixture was diluted with saturated aqueous sodium chloride solution (40 ml) and extracted with ethyl acetate (3×40 ml). The combined organics were dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give the crude product which was purified by column chromatography using the ISCO® (using a gradient of 0-40% v/v ethyl acetate in heptane, 12 g SiO2) to give the title compound as a white solid (121 mg)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.O1CCCC1.[OH-].[Na+]>O.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2n[nH]cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Yield: 44.6 %

Procedure:
147 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-(2-pyridyl)imidazo[1,2-a]pyridine obtained in Example 22, 1.8 mL of 5 N hydrochloric acid, 4 ml tetrahydrofuran and 4 mL methanol were stirred overnight at room temperature. The reaction solution was cooled and then basified with 5 N aqueous sodium hydroxide, followed by adding ethyl acetate and water to separate an organic layer. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was evaporated, the residue was triturated with dichloromethane, and the crystals were separated by filtration. This product was dried under vacuum to give 39 mg of the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH:25]1(O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:17]=2)=[O:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: OC1CCCC1
Reactant: CCCCN1CCN(CCNC(=O)c2n[nH]c3ccccc23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCN1CCN(CCNC(=O)c2nn(C3CCCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71 %

Procedure:
To a solution of N-[2-(4-n-butyl-1-piperazinyl)-ethyl]-1H-indazole-3-carboxamide (0.42 g) obtained in Example 10 in THF (10 ml) were successively added cyclopentanol (0.16 g), triphenylphosphine (0.41 g) and diethyl azodicarboxylate (0.36 g) under ice-cooling, and then the mixture was stirred at room temperature for 22 hours. The residue obtained by concentration of the reaction solution was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:1-chloroform:methanol:aqueous ammonia=10:1:0.05) to give a fraction (0.47 g) containing the title compound. This fraction was separated by thin-layer chromatography on silica gel (chloroform:methanol:aqueous ammonia=10:1:0.1) to give the title compound (0.36 g) as a pale yellow oily substance. Yield=71%.