Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[CH3:26][O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>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.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3/[CH:9]=[C:8]([C:33]4[CH:34]=[CH:35][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:31][CH:32]=4)[C:12]([CH3:14])([CH3:13])[O:11]/3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)ccc43)OC2(C)C)cc1
Temperature: 80 °C

Procedure:
To 30 mL of 1,4-dioxane, was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (500 mg, 1.54 mmol), 4-methoxycarbonylphenylboronic acid (333 mg, 1.85 mmol), PdCl2(PPh3)2 (54 mg, 0.077 mmol), 1M Na2CO3 aqueous solution (6.2 mL, 6.2 mmol). The mixture was heated at 80° C. under N2 for 1 hour, cooled to room temperature and poured into 200 mL of water. The brown precipitates were filtered, washed with water and dried to give the crude product. Purification through silica gel column with 1-5% MeOH/CHCl3 led to methyl 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate as orange/red solid. Yield: 500 mg, 86%.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])NC3(CCCCC3)N2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](N=C=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]N=C=O.N12CCN(CC1)[CH2:31][CH2:30]2>C1C=CC=CC=1>[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:30][CH2:31][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:6][CH:15]=[O:16]
Reactant: O=C=NCCCCCCN=C=O
Reactant: C1CN2CCN1CC2
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCC=O
Reaction time: 0.5 h

Procedure:
5.5 Parts of 7.14-diazadispiro[5.1.5.2]pentadecan-15-one, 2.1 parts of hexamethylene diisocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 150 parts of dry benzene were refluxed for 48 hours. The solvent was removed in vacuo and the solid material stirred in 150 parts of water for 30 minutes. The solid was filtered and recrystallised from ethanol to give hexane-1',6'-bis[14-carbamoyl-7,14-diaza dispiro5.1.5.2]pentadecan-15-one] of melting point 164° to 165°C. This material gave the following elemental analysis by weight.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=O)=[N:9][CH:10]=1)([CH3:3])[CH3:2].[C:13]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.CCOC(C)=O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:10][N:9]=1)#[CH:13]
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1ccc(C=O)nc1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc(OC(C)C)cn1
Temperature: 25 °C

Procedure:
To 1.00 g (6.05 mmol) 5-isopropoxypicolinaldehyde in 20 mL methanol are added 1.67 g (12.1 mmol) K2CO3 followed by 1.4 g (7.26 mmol) dimethyl 1-diazo-2-oxopropylphosphonate. After stirring at r.t. over the weekend the reaction mixture is diluted with EtOAc and washed consecutively with NaHCO3 solution and water. The organic layer is dried with Na2SO4 and the solvent is removed in vacuo.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].C(N([CH2:13][CH3:14])CC)C.[CH:15]([O:17][CH:18](C#N)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>ClC(Cl)C.ClCCl>[CH2:18]([O:17][C:15]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:15]([O:17][CH2:18][C:14]1[CH:13]=[CH:21][CH:20]=[CH:19][CH:24]=1)=[O:16])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#CC(OC=O)c1ccccc1
Reactant: NCCNCCN
Reactant: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(NCCNCCNC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
4.87 g (47.2 mmol) of 1,4,7-triazaheptane as well as 5 ml of triethylamine are dissolved in 100 ml of dichloroethane. The solution of 15.22 g (94.4 mmol) of cyanobenzyl formate in 200 ml of dichloromethane is instilled in this solution within 3 hours. It is allowed to stir for 2 more days at room temperature, then evaporated to dryness in a vacuum, taken up in diethyl ether and washed with sodium bicarbonate solution. The ether solution is dried on sodium sulfate and evaporated to dryness in a vacuum. The residue is crystallized from a little ethanol. The title compound crystallizes into white needles.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].O>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:23](=[O:24])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:33][CH:34]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A solution of 2,4-dichloro-3-nitroquinoline (11.4 g, 47.1 mmol) in DMF (200 mL) was cooled to 0° C. Triethylamine (19.6 mL, 0.141 mol) and 1-(N-Boc-aminomethyl)-4-(aminomethyl)benzene (13.3 g, 56.5 mmol) were sequentially added, and the reaction was stirred for one hour and cooled again to 0° C. Water (300 mL) was added, and the mixture was stirred for 30 minutes at 0° C. and then extracted with dichloromethane. The dichloromethane fraction was concentrated under reduced pressure to provide 20 g of tert-butyl 4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}benzylcarbamate as a red oil.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:7]=1.N([O-])=O.[Na+].[Cl:18][C:19]([Cl:21])=[CH2:20].C(=O)([O-])O.[Na+].[ClH:27]>C(OCC)(=O)C.CCCCCC.CC(C)=O>[F:13][C:5]1[CH:4]=[CH:3][C:2]([CH2:20][C:19]([Cl:27])([Cl:21])[Cl:18])=[CH:7][C:6]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: CC(C(=O)O)c1cc(N)ccc1F
Reactant: C=C(Cl)Cl
Reactant: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C(=O)O)c1cc(CC(Cl)(Cl)Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 12 ml of 18% aqueous hydrochloric acid was dissolved 4 g of 2-(5-amino-2-fluorophenyl)propionic acid, and 4 ml of an aqueous solution of 1.1 g of sodium nitrite was added dropwise while maintaining the temperature between -15° C. and -10° C. The mixture was stirred for an hour, to which 40 ml of acetone, 8 g of 1,1-dichloroethylene, 1250 mg of sodium hydrogen carbonate and 400 mg of cupric chloride dihydrate were successively added. The mixture was gradually warmed up to room temperature and stirred overnight. The acetone layer was separated and the solvent was evaporated off. The residue was dissolved in ether, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated off and the residue obtained was subjected to silica gel column chromatography (eluent: n-hexane--ethyl acetate=20:1) to afford 3.9 g of 2-[2-fluoro-5-(2,2,2-trichloroethyl)phenyl]propionic acid as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Br[C:12]1C=CC=C2C=1N(C)C=C2.BrC1C=CC=C2C=1NC=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:12])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Cn1ccc2cccc(Br)c21
Agent: Brc1cccc2cc[nH]c12
Product: Cn1ccc2cc(Br)ccc21

Procedure:
5-Bromo-1-methylindole was prepared from 5-bromoindole as described for the preparation of 7-bromo-1-methylindole from 7-bromoindole. Purification by chromatography using EtOAc:petroleum ether 1:10
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1([CH3:13])[NH:12][CH2:11][CH2:10][O:9]1.C(N(CC)CC)C.[C:21](Cl)(=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O>[CH3:7][C:8]1([CH3:13])[N:12]([C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:11][CH2:10][O:9]1
Reactant: CCCCCCC(=O)Cl
Reactant: CC1(C)NCCO1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCC(=O)N1CCOC1(C)C

Procedure:
Sixteen and one-half (16.5 ml.) milliliters of a benzene solution containing 4.6 g. of 2,2-dimethyl oxazolidine was added to 50 ml. of benzene and 4.1 g. of triethylamine. To this mixture 6 g. of n-heptanoyl chloride was added dropwise with stirring and cooling in an ice bath. The mixture was poured into water and the benzene layer extracted, dried over magnesium sulfate and the benzene removed under vacuum. Yield was 7.5 g. of an oil, nD30 =1.4598.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([OH:5])=O.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CCNCC
Product: CCN(CC)C(=O)C(C)=CCCC(C)=CCCC(C)=CCCC(C)=O

Procedure:
Starting materials: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and diethylamine.
Reaction SMILES: [C:1]([C:3]1[C:4]2[NH:11][CH:10]=[N:9][C:5]=2[CH:6]=[N:7][CH:8]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=1)=[O:17]>>[NH:11]1[C:4]2[C:3]([C:1]#[C:2][C:38]3[CH:37]=[C:15]([CH:14]=[CH:13][C:39]=3[CH3:40])[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=3)=[O:17])=[CH:8][N:7]=[CH:6][C:5]=2[N:9]=[CH:10]1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cncc2nc[nH]c12
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cncc2nc[nH]c12

Procedure:
The title compound can be synthesized from 7-ethynyl-1H-imidazo[4,5-c]pyridine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 1. 7-ethynyl-1H-imidazo[4,5-c]pyridine is prepared from 7-bromo-1H-imidazo[4,5-c]pyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:15][CH2:16][CH2:17][C:18]1[O:19][CH:20]=[CH:21][CH:22]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ICCCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCc2ccco2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a mixture of 1.16 g of 1-tert-butoxycarbonylpiperazine, 1.47 g of 2-(3-iodopropyl)furan and 20 ml of N,N-dimethylformamide was added 0.86 g of anhydrous potassium carbonate, and the mixture was stirred overnight at room temperature. To the reaction solution was added 300 ml of ethyl acetate, the solution was washed successively with water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography and eluted with ethyl acetate to give 1.5 g of oily 1-tert-butoxycarbonyl-4-[3-(2-furyl)propyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][OH:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.CN1CCCN(C)C1=O>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH:15]=[O:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: OCc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CN1CCCN(C)C1=O
Product: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
With ice-cooling, 1.9 g of manganese dioxide (85%) are added to a suspension of 715 mg (2.6 mmol) of 4-(3-chloroanilino)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidine in 170 ml of methylene chloride and the mixture is stirred at RT for 20 h. 20 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) are then added to the reaction mixture, and it is stirred for 1 h and then filtered through Hyflo. The filtration residue is again stirred (1 h) in 50 ml of methylene chloride/DMPU (1:1) and again filtered. The two filtrates are combined, evaporated and taken up in ethyl acetate/THF and water. The aqueous phases are extracted twice with ethyl acetate; the organic phases are washed 4 times with water and brine, dried (MgSO4) and evaporated down to a residual volume of ≈20 ml. Addition of diethyl ether and filtration yields 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=10.1; TLC-Rf=0.24 (CH2Cl2/methanol [10:1]).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][N:18]([S:26]([C:29]1[CH:34]=[C:33]([C:35](=[NH:37])[NH2:36])[CH:32]=[CH:31][C:30]=1[OH:38])(=[O:28])=[O:27])[CH2:19][C:20]1[N:21]=[C:22]([CH3:25])[S:23][CH:24]=1)C.[OH-].[Na+]>C(O)C>[C:35]([C:33]1[CH:32]=[CH:31][C:30]([OH:38])=[C:29]([S:26]([N:18]([CH2:19][C:20]2[N:21]=[C:22]([CH3:25])[S:23][CH:24]=2)[CH2:17][CH2:16][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:14])[CH3:15])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:39])=[O:3])(=[O:27])=[O:28])[CH:34]=1)(=[NH:36])[NH2:37]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCN(Cc1csc(C)n1)S(=O)(=O)c1cc(C(=N)N)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(CN(CCc2ccc(C(C)C)cc2OCC(=O)O)S(=O)(=O)c2cc(C(=N)N)ccc2O)cs1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a stirred solution of 100 mg of ethyl[2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazol-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetate in 0.8 mL of ethanol was added 0.183 mL of 2 mol/L sodium hydroxide solution under ice-cooling. After being stirred at the same temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure. To the stirred solution of the residue in a mixture of 0.8 mL of acetonitrile and 0.8 mL of water was added 0.174 mL of 1 mol/L hydrochloric acid under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. To the mixture was added additional 0.174 mL of 1 mol/L hydrochloric acid under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. The precipitate was collected by filtration, and washed with water to give 74 mg of [2-[2-[(5-carbamimidoyl-2-hydroxybenzenesulfonyl)-(2-methyl-1,3-thiazole-4-ylmethyl)amino]ethyl]-5-isopropylphenoxy]acetic acid.
Reaction SMILES: [SH:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].N1CCOCC1.[CH2:13]([NH:16][C:17](=[O:24])[C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH2:15]>C(OCOCC)C>[CH2:13]([NH:16][C:17]([CH:18]1[C:3]([OH:5])([CH3:4])[CH:2]([CH3:6])[S:1][CH:19]1[Si:20]([CH3:21])([CH3:22])[CH3:23])=[O:24])[CH:14]=[CH2:15]
Reactant: C=CCNC(=O)C#C[Si](C)(C)C
Reactant: CC(=O)C(C)S
Solvent: C1COCCN1
Solvent: CCOCOCC
Product: C=CCNC(=O)C1C([Si](C)(C)C)SC(C)C1(C)O
Reaction time: 4 h
Yield: 81.8 %

Procedure:
A solution of 3-mercapto-2-butanone (2.1 g, 0.020 mol) and morpholine (1.5 g, 0.017 mol) in diethoxymethane (20 mL) was heated to reflux and treated with N-allyl-3-trimethylsilylpropiolic amide (3.04 g, 0.017 mol). The mixture is heated at reflux under a nitrogen atmosphere overnight. An additional portion of the 3-mercapto-2-butanone (0.7 g, 0.0067 mol) was added, and heating was continued for 4 hours more. A final portion of the 3-mercapto-2-butanone (0.7 g, 0.0067 mol) was added, heating was continued for 4 hours at reflux, then the mixture was cooled and evaporated under reduced pressure. The residue was extracted with two 40 mL portions of hot heptane, filtered, and allowed to cool (ice/salt bath). The resulting solid precipitate was collected by filtration and dried to give 4.0 g of 4-hydroxy-4,5-dimethyl-2-trimethylsilanyl-dihydrothiophene-3-carboxylic acid allylamide (84% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:40]2[NH:44][NH:43][C:42](=[O:45])[CH2:41]2)[CH:35]=[CH:36][C:37]=1[O:38][CH3:39].[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH2:56][CH2:57][N:58]([CH2:60][CH2:61][CH2:62]O)[CH3:59])[CH:51]=[CH:52][C:53]=1[O:54][CH3:55]>O1CCCC1.C1(C)C=CC=CC=1.CN(C)C=O>[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH2:56][CH2:57][N:58]([CH2:60][CH2:61][CH2:62][O:45][C:42]2[CH:41]=[C:40]([C:34]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[CH:33]=3)[NH:44][N:43]=2)[CH3:59])[CH:51]=[CH:52][C:53]=1[O:54][CH3:55]
Reactant: COc1ccc(C2CC(=O)NN2)cc1OC
Reactant: COc1ccc(CCN(C)CCCO)cc1OC
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCOc2cc(-c3ccc(OC)c(OC)c3)[nH]n2)cc1OC
Temperature: 20 °C
Reaction time: 48 h
Yield: 50.6 %

Procedure:
1.31 g of triphenylphosphine were dissolved in 15 ml of tetrahydrofuran. 1.6 ml of a solution of 0.8 ml of ethyl azodicarboxylate in 0.8 ml of toluene were added dropwise to the solution at a temperature of 5° C. After 5 minutes a solution of 1.1 g of 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one in 10 ml of dimethylformamide was added dropwise. After 20 minutes a solution of 1.26 g of 3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylamino]-propanol in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was subsequently stirred at 20° C. for 48 hours. The reaction mixture was then evaporated to dryness. The resulting crude product was purified by flash chromatography in accordance with the method described in Example 1E). 1.14 g of the title compound were obtained as an oily base. This base was converted as described in Example 1E), to the hydrochloride having a melting point of from 189° to 192° C.
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:19][N:20]([CH3:22])/[CH:21]=[C:8](\[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)/[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(CC(=O)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(/C(=C\N(C)C)C(=O)c2ccccc2)cc1

Procedure:
A solution of 1-phenyl-2-p-tolylethanone (2 g, 9.5 mmol) and dimethylformamide dimethylacetal (4.5 g, 38.1 mmol) in DMF (30 ml) was heated at 75° C. for 24 hours. Solvents were removed under high vacuum to obtain the title compound as a yellow oil, which was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[F:11][C:12]1[CH:24]=[C:23](F)[C:22]([F:26])=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:23]2[C:22]([F:26])=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[C:12]([F:11])[CH:24]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(O)cc1Cl
Reactant: CC(C)(C)OC(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ncc(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A mixture of 5-chloro-6-methoxypyridin-3-ol (Preparation 77, 100 mg, 0.627 mmol), tert-butyl 2,4,5-trifluorobenzoate (Preparation 6, 147 mg, 0.633 mmol), and potassium carbonate (260 mg, 1.88 mmol) in DMSO (5 ml) was stirred overnight at 25° C. under a nitrogen atmosphere. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The combined organics were washed with aqueous sodium hydroxide solution (1.0 M, 30 mL), brine (2×40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography eluting with 5% EtOAc in heptane to afford the title compound as a white solid (65 mg, 28%):
Reaction SMILES: C[O:2][C:3](=O)[C:4]([F:11])([F:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[BH4-].[Na+].Cl.[CH3:16]O>O>[CH3:16][O:9][C:7](=[O:8])[CH2:6][CH2:5][C:4]([F:11])([F:10])[CH2:3][OH:2]
Reactant: CO
Reactant: COC(=O)C(F)(F)CCC(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCC(F)(F)CO
Reaction time: 2 h

Procedure:
To a solution of 2 g of 2,2-difluoroglutaric acid 1-methyl ester in 20 ml of methanol is added at 25° 250 mg of sodium borohydride and the mixture allowed to remain at 25° for 2 hrs. The solution is diluted with water and acidified to pH 1 with 1N HCl and the methanol removed in vacuo. The residual suspension is extracted with methylene chloride and the extract dried with sodium sulfate and evaporated to dryness in vacuo. The residual oil is treated with ethereal diazomethane until the yellow color persists and the ether is removed in vacuo. There remains behind the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[OH:16][C:17]([C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[C:50](O)[CH:49]=[CH:48]2)([C:21]1[N:22]=[CH:23][N:24]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=1)[CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1.O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:50]1[CH:49]=[CH:48][C:47]2[C:52](=[CH:53][CH:54]=[C:45]([C:17]([OH:16])([C:21]3[N:22]=[CH:23][N:24]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:25]=3)[CH:18]([CH3:19])[CH3:20])[CH:46]=2)[CH:51]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride (9.1 mL) was added dropwise to a solution of 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthol (27.0 g) in pyridine (200 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C., diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate=1:1). Crystallization from diisopropyl ether gave the titled compound (29.6 g) as a colorless powder.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[N:5]1C=CC=CC=1.[Br:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14]C=1>C(Cl)Cl>[CH3:3][O:2][N:4]=[CH:17][C:15]1[S:16][C:12]([Br:11])=[N:5][CH:14]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: CON
Reactant: c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CON=Cc1cnc(Br)s1
Reaction time: 18 h

Procedure:
Methoxylamine HCl (1 equivalent) is added portionwise to a stirred pyridine (1 equivalent) solution of 5-bromo-2-thiophene carboxaldehyde (1 equivalent) (CAS 4701-17-1). After 18 hours, reaction is diluted with CH2Cl2 and washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude mixture is purified by silica gel column chromatography (gradient: 0-20% EtOAc/hexanes) to give title intermediate that is confirmed by NMR.