Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH:19]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20]1.[C-:28]#[N:29].[K+]>CO.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:25]2[CH2:26][CH2:27][N:22]([CH:19]3[CH2:21][CH2:20]3)[CH2:23][CH2:24]2)([C:28]#[N:29])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 1-benzylpiperidin-4-one (26.42 mmol, 1.0 equiv.) and acetic acid (26.42 mmol, 1.0 equiv.) in methanol (10 ml) were added water (600 ml), N-cyclopropyl piperazine (29.06 mmol, 1.1 equiv.), and potassium cyanide (26.42 mmol, 1.0 equiv.). The resulting reaction mixture was stirred at room temperature for 1 h by which time a solid had separated. The solid was collected by filtration, washed with water and dried to obtain the desired product which was used in the next step without further purification. Yield: 53%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@@H:12](CC2CCCC2)[C:13](NC2C=CN(CCC(O)=O)N=2)=[O:14])C=CC=1S(C)(=O)=O.C(N(CC)CC)C.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1.[OH2:50]>C(Cl)Cl>[O:14]1[CH2:13][CH2:12][CH2:4][C@@H:3]1[CH2:2][O:46][S:45]([C:42]1[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=1)(=[O:50])=[O:47]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
In a round bottom flask was placed (R)-(tetrahydro-furan-2-yl)-methanol (prepared as in PCT WO 2003/095438 A1, Example 3, 4.65 g, 45.5 mmol), methylene chloride (100 mL) and triethylamine (8.4 mL, 60.6 mmol) and it was cooled to 0° C. To this cooled solution was then added a solution of p-toluenesulfonyl chloride (10.4 g, 54.6 mmol) in methylene chloride (30 mL) dropwise. Once the addition was complete the reaction was then warmed to 25° C. and stirred for 16 h. The reaction was then diluted with water (50 mL) and extracted with methylene chloride (3×30 mL). The combined organic extracts were then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (80 g column, 3% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded toluene-4-sulfonic acid tetrahydro-furan-2(R)-ylmethyl ester (8.37 g, 72%) as a clear colorless oil: [α]32589=−14.4° (c=0.72, methylene chloride); ES-HRMS m/e calcd for C12H16O4S (M+H)+ 257.0842, observed 257.0841; 1H NMR (300 MHz, CDCl3) δ ppm 1.95-2.08 (m, 1H, CH of CH2), 2.14-2.40 (m, 3H, CH2 and CH of CH2), 4.02-4.19 (m, 2H, OCH2), 4.29-4.49 (m, 3H, OCH and OCH2), 7.69 (d, J=8.0 Hz, 2H, Ar), 8.15 (d, J=8.0 Hz, 2H, Ar).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[CH3:12])=O.[NH4+:13].[OH-].[Na+].[CH:16]([OH:18])=O>>[CH3:12][C:6]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:13]=[CH:16][O:18][CH:2]=1
Reactant: Cc1cc(O)ccc1C(=O)CBr
Reactant: [NH4+]
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(O)ccc1-c1cocn1
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of 2-bromo-1-(4-hydroxy-2-methylphenyl)-1-ethanone (18 g, 78 mmol), ammonium fornate (17 g, 273 mmol) in formic acid (100 ml) was heated at reflux temperature for 3 hours. The mixture was cooled down to room temperature and made basic by addition of 50% NaOH aqueous solution at 0° C. The whole was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:5) to give title compound (1.8 g, 13% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C@@H:16]([NH2:21])[CH2:15]2>>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C@@H:16]([NH:21][C:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N:6]=1)=[O:10])[CH2:15]2
Reactant: N[C@@H]1Cc2ccc(Br)cc2C1
Reactant: O=C(O)c1ccc(O)cn1
Product: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(O)cn1

Procedure:
According to method C, 5-hydroxypyridine-2-carboxylic acid was reacted with (R)-5-bromo-indan-2-ylamine. This afforded the product with the molecular weight of 333.19 (C15H13BrN2O2); MS (ESI); 333 (M+H+).
Reaction SMILES: [Br:1]N1C(C)(C)C(=O)N(Br)C1=O.[Cl:12][C:13]1[C:18]([NH2:19])=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Br:1][C:15]1[C:16]([O:20][CH3:21])=[CH:17][C:18]([NH2:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(N)c(Cl)cc1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
1,3-Dibromo-5,5-dimethylhydantoin (commercially available, for example, from Aldrich) (9.1 g, 32 mmol) was added over 20 minutes to a stirred solution of 6-chloro-3-methoxyaniline (commercially available, for example, from Apollo Scientific) (10.0 g, 63 mmol) in ethyl acetate (150 ml) at −5° C. The resulting solution was stirred at −5° C. for 1 hour then washed with a solution of potassium carbonate (6 g, 43 mmol) in water (40 ml and then with water (20 ml). The resulting solution was concentrated under reduced pressure to give 4-bromo-2-chloro-5-methoxyaniline as a pale brown solid (14.3 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1Cl.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:9][CH3:10])[N:5]=[CH:6][C:7]=1[NH:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: CCn1ncc(Cl)c(Cl)c1=O
Reactant: COc1ccc(CCN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1ncc(NCCc2ccc(OC)cc2)c(Cl)c1=O
Reaction time: 8 h

Procedure:
A mixture comprising 0.5 g of 4,5-dichloro-2-ethyl-3(2H)pyridazinone, 1.18 g of 4-methoxyphenylethylamine, 0.36 g of potassium carbonate, 18 ml of water and 6 ml of 1,4-dioxane, was refluxed under stirring for 8 hours. Then, 1,4-dioxane was distilled off under reduced pressure, and the residue thereby obtained was extracted with ethyl acetate. The extract was washed sequentially with dilute hydrochloric acid and water, and dried over sodium sulfate. Then, solvent was distilled off. The residue was purified by silica gel column chromatography by using benzene-ethyl acetate (1:1, v/v) as the developer, whereby 400 mg of the above identified compound was obtained as colorless crystals having a melting point of from 135° to 135.5° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19]([OH:21])=O)=[C:16]([C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[C:24]([CH3:32])[CH:23]=3)[C:15]=2[CH3:33])=[CH:10][CH:9]=1.[CH3:34][N:35]([CH:37]=O)[CH3:36].C(N(CC)CC)C.Cl.[CH3:47][NH:48][O:49][CH3:50]>ClCCl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([C:19]([N:48]([O:49][CH3:50])[CH3:47])=[O:21])=[C:16]([C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[N:29]=[CH:37][N:35]([CH3:34])[CH3:36])=[C:24]([CH3:32])[CH:23]=3)[C:15]=2[CH3:33])=[CH:10][CH:9]=1
Reactant: CNOC
Reactant: Cc1cc(-c2c(C(=O)O)sc(-c3ccc(Cl)cc3)c2C)ccc1S(N)(=O)=O
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.2 %

Procedure:
Oxalyl chloride (0.47 g, 0.32 ml, 3.7 mmol) was added drop wise to a solution of 5-(4-chlorophenyl)-4-methyl-3-(3-methyl-4-sulfamoylphenyl)thiophene-2-carboxylic acid (41d, 0.52 g, 1.23 mmol) in a mixture of dichloromethane (20 ml) and DMF (0.18 g, 0.19 ml, 2.46 mmol) at 0° C. The mixture was then allowed to warm to room temperature and stirred for 1.5 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was then dissolved in dry dichloromethane (20 ml) and cooled to 0° C. To the cooled solution so obtained was then added triethylamine (0.74 g, 1.03 ml, 7.39 mmol), which was then followed by addition of N,O-dimethylhydroxylamine hydrochloride (0.24 g, 2.46 mmol) under stirring. The reaction mixture was then stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then diluted with DCM (20 ml) and the mixture so obtained was washed with water (2×10 ml). The organic layer obtained was then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography over silica gel (100-200 mesh) using 0.8% methanol in DCM as an eluent to obtain the title compound (0.34 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Product: CC(=O)Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.004 mL (0.061 mMol) acetyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: O=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]#[N:8].[C:9]1([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][NH:24][C:25]=3[NH2:26])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:9]1([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][N:24]4[C:7]([NH2:8])=[C:3]5[CH2:4][S:5][CH2:6][C:2]5=[N:26][C:25]=34)=[CH:17][CH:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1[nH]ncc1-c1ccc(-c2ccccc2)nc1
Reactant: N#CC1CSCC1=O
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3c(-c4ccc(-c5ccccc5)nc4)cnn13)CSC2
Temperature: 115 °C

Procedure:
A mixture of 4-oxotetrahydrothiophene-3-carbonitrile (77.6 mg, 0.61 mmol) and 4-(6-phenylpyridin-3-yl)-1H-pyrazol-5-amine (144 mg, 0.61 mmol) in toluene (10 mL) was heated at 115° C. overnight. Concentration and purification with prep-LC provided 3-(6-phenylpyridin-3-yl)-5,7-dihydropyrazolo[1,5-a]thieno[3,4-d]pyrimidin-8-amine: LCMS tR=1.48 Min (5 min run, UV254mn), Mass calculated for, M+345.1, observed LC/MS m/z 346.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([CH2:25][CH3:26])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[N:13][OH:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)C=O>O>[CH2:33]([O:14][N:13]=[CH:12][CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[C:15]([CH2:25][CH3:26])=[CH:16][C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:23])[Cl:24])=[CH:18][C:3]=1[CH2:1][CH3:2])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=NO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
First, 0.27 g of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)-butyloxyacetaldehyde oxime, 0.10g of potassium carbonate, 0.16 g of benzyl bromide, and 10 ml of N,N-dimethylformamide were placed in a reaction vessel. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.21 g (yield, 56%) of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)-butyloxyacetaldehyde O-benzyloxime, nD22.5 1.5402.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][N:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:25]=[C:24]([CH:26]4[CH2:28][CH2:27]4)[N:23]([CH3:29])[C:22]=3[CH:30]=2)[C:14](=[O:31])[CH:13]=1>CC(N(C)C)=O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:12]2[CH:17]=[CH:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]4[N:25]=[C:24]([CH:26]5[CH2:28][CH2:27]5)[N:23]([CH3:29])[C:22]=4[CH:30]=3)[C:14](=[O:31])[CH:13]=2)[N:6]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Reactant: OCc1csc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Br)n4)cc3=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-bromo-1,3-thiazol-4-yl)methanol (169 mg) in DMA (5 ml) was added NaH (60% in oil, 34.9 mg) at 0° C. After being stirred at 0° C. for 30 min, 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one was added to the reaction mixture, and the mixture was stirred at 120° C. under N2 atmosphere for 30 min. The reaction mixture was quenched with water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (57.0 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])[N:6]=1.[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>>[NH2:1][C:2]1[NH:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:15]([NH:14][C:12]#[N:13])=[N:18][CH3:19])[N:6]=1
Reactant: CN=C(NC#N)SC
Reactant: NCCSCc1c[nH]c(N)n1
Product: CN=C(NC#N)NCCSCc1c[nH]c(N)n1

Procedure:
By the procedure of Example 3(a), 2-amino-4-[(2-aminoethyl)thiomethyl]imidazole is reacted with N-cyano-N',S-dimethylisothiourea to give the title compound. EXAMPLE 24
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:18])C(=O)C1>C(#N)C>[I:18][C:8]1[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:10][CH:9]=1
Reactant: Cc1cccc2nccn12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1cccc2ncc(I)n12
Reaction time: 18 h

Procedure:
To 5-methyl-imidazo[1,2-a]pyridine (0.51 g, 3.0 mmol) in ACN (1 ml) at RT is added NIS (0.73 g, 3.3 mmol) and stirring continued for 18 h. The mixture is poured onto water. The precipitate is collected, washed with water and dried. Yield: 0.78 g (92%). HPLC-MS: M+H=259; tR=1.04 min (METHOD—1).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH:4]([CH2:21]Cl)[CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH2:19][CH3:20])=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=2)[CH2:8][CH2:7][NH:6]1>C(O)C.CCOCC>[ClH:2].[Cl:2][CH2:3][CH:4]1[CH:5]2[C:14]3[C:9]([CH2:8][CH2:7][N:6]2[CH2:21]1)=[CH:10][C:11]([O:18][CH2:19][CH3:20])=[C:12]([O:15][CH2:16][CH3:17])[CH:13]=3
Reactant: CCOc1cc2c(cc1OCC)C(C(CCl)CCl)NCC2
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOc1cc2c(cc1OCC)C1C(CCl)CN1CC2
Yield: 75 %

Procedure:
Following the procedure described in Example 2 but using 1-[bis(chloromethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride as a starting material, the aimed compound is obtained with a melting point of 130° to 131° C. (ethanol/ether).
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.[NH:31]1[CH2:36][CH2:35]C[CH2:33][CH2:32]1.C(NCC)C>>[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:31]([CH2:36][CH3:35])[CH2:32][CH3:33])=[C:7]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)[CH:6]=1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Reactant: C1CCNCC1
Solvent: CCNCC
Product: CCN(CC)CCCCC(=O)c1cc(Cl)c(N)cc1OCc1cc(OC)cc(OC)c1

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with diethylamine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-diethylaminopentan-1-one, m.p. 105°-107° C.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28](OCC2C=CC=CC=2)=O)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([C:8]1[N:9]=[C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH3:28])[S:11][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(-c3nc(Cc4ccccc4)cs3)cc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(-c3nc(Cc4ccccc4)cs3)cc12
Yield: 71 %

Procedure:
(R)-5-(4-Benzyl-1,3-thiazol-2-yl)-3-(N-benzyloxycarbonylpyrrolidin-2-yl-methyl)-1 H-indole was used. Chromatography using 5% triethylamine in ethyl acetate afforded the title compound (71%) as a white solid: top, 146.0°-148.0° C.; 13C NMR (CDCl3) 67 169.8, 157.1, 139.3, 137.3, 129.2, 128.5, 128.0, 126.4, 125.7, 123.2, 121.2, 117.6, 114.8, 113.2, 111.5, 66.6, 57.5, 40.8, 38.1, 31.4, 29.6, 21.9; LRMS (m/z, relative intensity) 387 (M+, 4), 303 (34), 155 (30), 147 (17), 115 (18), 85 (63), 84 (100), 83 (57); [α]25 =+68° (CHCl3, c=1.0). Anal. calcd. for C24H25N3S·1/4H2O: C, 73.54; H, 6.56; N, 10.72. Found: C, 73.50; H, 6.53; N, 10.57.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: OCc1ccc(OC(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccc(OC(F)(F)F)cc1

Procedure:
The above alcohol was oxidised using the conditions of Swern (oxalyl chloride, 2.05 ml; dimethyl sulphoxide, 3.33 ml and triethylamine, 14.8 ml) in dichloromethane to give 4-trifluoromethoxy benzaldehyde (4 g). NMR 1H: 10.04(2H,s), 7.98(2H,d), 7.35(2H,d).
Reaction SMILES: [Br-].[CH2:2]([PH3+])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CC(C)([O-])C.[K+].[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH:19]=O>O1CCCC1.COC(C)(C)C>[CH:19](/[C:18]1[CH:21]=[CH:22][C:23]([CH3:24])=[C:16]([OH:15])[CH:17]=1)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC[PH3+]
Reactant: Cc1ccc(C=O)cc1O
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCCC/C=C\c1ccc(C)c(O)c1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Under an atmosphere of Argon, to a solution of n-hexylphosphonium bromide (1.07 g) in tetrahydrofuran (10 mL) was added potassium t-butoxide (336 mg) at room temperature and the solution was stirred for 30 minutes. After cooling in ice bath, 3-hydroxy-4-methylbenzaldehyde (136 mg) was added to the reaction solution, which was stirred at room temperature for 1.5 hours. The reaction solution was diluted with t-butyl methyl ether. The solution was washed with dilute hydrochloric acid, water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to give the title compound (180 mg) having the following physical data.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1.C(N(C(C)C)C(C)C)C.[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>C(Cl)Cl>[C:23]([NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc(CN)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=O)C(C)C)nc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To an ice-cold suspension of methyl 6-(aminomethyl)nicotinate hydrochloride (1.00 g, 4.18 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.89 g, 2.55 mL, 14.6 mmol) in DCM (10 mL) was added dropwise a solution of isobutyryl chloride (535 mg, 526 μL, 5.02 mmol) in DCM (3 mL). The reaction mixture was allowed to warm to room temperature, washed with water (5 mL), 10% aqueous citric acid solution (5 mL), saturated aqueous sodium bicarbonate solution (5 mL), brine (5 mL), dried over magnesium sulfate, filtered and evaporated to yield the title compound as a pale orange solid (0.988 g, 100%):
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[F:27][C@H:28]1[C@@H:33]([CH2:34][OH:35])[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:29]1>CN(C)C=O>[F:27][C@H:28]1[C@@H:33]([CH2:34][O:35][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[N:11]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=3)=[CH:4][CH:3]=2)[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:29]1
Reactant: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](F)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
4-fluoro-N-isobutyl-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (30 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (DMF) (3 mL) and to this solution was added sodium hydride (2 mg, 0.10 mmol, 60% wt in mineral oil) followed by tert-butyl cis-3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (24 mg, 0.10 mmol). The reaction was stirred for 3 hours at room temperature, under nitrogen, then quenched with water and concentrated in vacuo. The crude product was extracted to the organic phase of an aqueous workup between ethyl acetate and water. The organic phase was then passed through a hydrophobic frit and concentrated in vacuo to give the title compound (47 mg). LCMS (2 min, formic) Rt 1.50 min, m/z (ES+) 564 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]2)[C:13]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(OC2C=CCCC2)C(=O)O)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(OC2C=CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
To a solution of rac-(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetic acid (50 mg, 0.15 mmol) in dichloromethane (10 mL) at 25° C. was added 2-aminothiazole (22 mg, 0.22 mmol), BOP reagent (96.2 mg, 0.22 mmol) and triethylamine (0.06 mL, 0.44 mmol). The mixture was stirred at 25° C. for 16 h, then was diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide (1×10 mL), 1N hydrochloric acid (1×10 mL) and brine (1×10 mL), then were dried over sodium sulfate, filtered and evaporated under reduced pressure. The product was purified by chromatography (Biotage Flash 40S column, 60/40 hexanes/ethyl acetate) to furnish rac-2-(3-chloro-4-methanesulfonyl-phenyl)-2-(cyclohex-2-enyloxy)-N-thiazol-2-yl-acetamide (39 mg, 63% yield) as a glassy solid: EI-HRMS m/e calculated for C18H19N2O4S2Cl (M+) 426.0475, found 426.0479.