Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[CH3:10][O:11][C:12]([C:14]1[CH2:15][N:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][CH2:18][C:19]=1OS(C(F)(F)F)(=O)=O)=[O:13]>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:11][C:12]([C:14]1[CH2:15][N:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][CH2:18][C:19]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:9])=[O:13]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1[Mg]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccccc2C)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 1 M solution of o-tolylmagnesium chloride in THF (6.26 ml, 41.5 mmol) was added dropwise a freshly prepared solution of dried zinc chloride (8.48 g, 62.2 mmol) in dry THF (200 ml) at 0° C. After completed addition the reaction mixture was allowed to slowly warm to room temperature over a period of 1 h. To this mixture were added a solution of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (10.7 g, 27.5 mmol) in THF (270 ml) and tetrakis(triphenylphosphine)palladium(0) (0.96 g, 0.83 mmol). After stirring for 6 h at room temperature the reaction was quenched with ice. The mixture was diluted with tert-butyl methyl ether and washed with 2 M aqueous sodium carbonate solution. The aqueous layer was extracted with two portions of tert-butyl methyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:17]([CH2:16][CH2:15][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[CH:9]=[CH:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCOc1ccccc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ccn(CCOc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To a solution of 1H-indole-6-carboxylic acid methyl ester (0.5 g, 2.9 mmol) and 1-(2-bromoethoxy)benzene (0.74 g, 3.7 mmol) in DMF (15 mL) was added K2CO3 (1.2 g, 8.6 mmol). After stirring at room temperature for 16 hr, the mixture was heated to 55° C. for 5 hr then cooled to room temperature and diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4), filtered and concentrated. The remaining residue was subjected to flash chromatography (20% ethyl acetate/hexane, then ethyl acetate) to provide 0.63 g (75%) of methyl 1-(2-phenoxyethyl)-1H-indole-6-carboxylate. 1H NMR (300 MHz, DMSO) δ 8.26 (d, 1H, J=1.0 Hz), 7.67-7.62 (m, 3H), 7.23 (td, 2H, J=7.6 Hz, J=1.0 Hz), 6.92-6.84 (m, 3H), 6.55 (dd, 1H, J=3.0 Hz, J=0.6 Hz), 4.66 (t, 2H, J=4.9 Hz), 4.28 (t, 2H, J=4.9 Hz), 3.86 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:6])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[F:1][C:2]([F:6])([CH3:5])[CH2:3][O:4][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CC(F)(F)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC(C)(F)F)cc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of 2,2-difluoropropanol (0.50 g, 5.20 mmol) in dichloromethane (52.0 mL) and triethylamine (0.50 g, 0.73 mL, 5.20 mmol) at 0° C. is added p-toluenesulfonyl chloride (0.99 g, 5.20 mmol). The mixture is allowed to slowly warm to room temperature over 24 h. The mixture is concentrated and is partitioned between diethyl ether and water. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The material is purified over silica gel to obtain 1.0 g of the title compound as clear crystals. MS (m/z) 250 (M+1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[F:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1>>[F:8][C:9]1[CH:10]=[C:11]([O:15][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)CCCCl
Reactant: Oc1cccc(F)c1
Product: O=C(CCCCl)Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Chlorobutyrylchloride (35.3 g) was added to 3-fluorophenol (25 g). This mixture was stirred during 48 h at room temperature. After the reaction was completed the product was purified by vacuo-destillation. Yield: 35,3 g (b.p. 106° C. 3 mmHg) of 4-chloro-butanoic acid 3-fluorophenyl ester as a white oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:16])[C:5]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:6]([F:8])[CH:7]=1.[Li]CCCC.[CH3:22][C:23]([CH3:25])=[O:24]>C(OC)(C)(C)C>[CH2:11]([O:10][CH:9]([O:13][CH2:14][CH3:15])[C:5]1[C:4]([F:16])=[CH:3][C:2]([C:23]([OH:24])([CH3:25])[CH3:22])=[CH:7][C:6]=1[F:8])[CH3:12]
Reactant: CC(C)=O
Reactant: CCOC(OCC)c1c(F)cc(Br)cc1F
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CCOC(OCC)c1c(F)cc(C(C)(C)O)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-(diethoxymethyl)-1,3-difluorobenzene (14.7 g, 0.05 mol) in t-butylmethylether (290 mL) was added n-BuLi (21 mL of 2.5 M in hexanes, 0.052 mol) at −78° C. under argon. The reaction was then stirred at −78° C. for 1 hour. Acetone (4.9 mL, 0.065 mol) was added dropwise to the reaction mixture. The reaction solution was then slowly warmed to 0° C. and stirred for 30 min. The reaction was quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to afford the title compound. No further purification was performed. 1H NMR (300 MHz, CDCl3): δ 10.34 (s, 1H), 87.03 (d, 2H), 5.74 (s, 1H), 3.85-3.71 (m, 2H), 3.60 (q, 2H), 1.52 (s, 6H), 1.24 (t, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:10][S:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[Br:25]Br>C1COCC1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[N:10][S:11][C:12]=1[Br:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1csnc1-c1ccc(Cl)cc1
Reactant: BrBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)nsc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 8 (3.50 g) in THF (60 ml) is cooled to −78° C. under N2 followed by drop wise addition of BuLi (8.0 ml, 1.6M in hexane). After complete addition stirring is continued at −78° C. for 15 min. Bromine (1.2 ml) is now added drop wise and stirring is continued at −78° C. for 15 min, after which the cooling bath is removed. The mixture is allowed to warm to room temp. TLC shows a good conversion into a slightly faster moving spot (Hep/EA, 9/1). 1N HCl (50 ml) is added and the THF is removed in vacuo. Water (100 ml), containing some sodium thiosulfate, is added and the product is extracted with EtOAc (150 ml). The organic layer is washed with sat. NaHCO3, brine, dried and concentrated. The orange/red oily residue is purified by flash column chromatography (˜50 g silica, 5% diisopropyl ether in heptane) yielding 3.1 g of 9 as a pale yellow oil.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.O=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CO>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH:17]=[C:16]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12]([OH:14])=[O:13])[CH:7]=3)[NH:3][CH:4]=2)[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(C(=O)O)cc23)CC1
Temperature: 65 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
Potassium hydroxide (5.17 g, 92.08 mmol) was added to 1H-indole-5-carboxylic acid (3.71 g, 23.02 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (9.17 g, 46.04 mmol) in methanol (80 mL) at ambient temperature and the resulting solution was stirred at 65° C. for 18 hours. The mixture was then cooled to ambient temperature, quenched in water (100 mL) and extracted with ethyl acetate (2×100 mL). The extracts were discarded and the aqueous phase acidified to pH 2-3 wth 2M hydrochloric acid to give a pale yellow solid. The solid was collected by filtration, washed sequentially with water and ether and air dried to give 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole-5-carboxylic acid (5.62 g, 71.3%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[CH:31]([S:34](Cl)(=[O:36])=[O:35])([CH3:33])[CH3:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:34]([CH:31]([CH3:33])[CH3:32])(=[O:36])=[O:35])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)C(C)C)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and isopropylsulfonyl chloride to give the title compound as an off-white solid. MS: 485.2 ([M+H]+)
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3].S(=O)(=O)(O)[OH:13]>>[CH:7]1([CH3:8])[CH2:6][CH2:5][CH:4]([C:2]([OH:13])([CH3:3])[CH3:1])[CH:10]([OH:11])[CH2:9]1
Reactant: O=S(=O)(O)O
Reactant: CC(C)=CCCC(C)CC=O
Product: CC1CCC(C(C)(C)O)C(O)C1

Procedure:
The above-mentioned problems are resolved by the production method of this invention wherein citronellal is treated with aqueous sulfuric acid solution of 0.02 to 1.0 wt. % in concentration to produce para-menthane-3,8-diol. In case of recovering the produced para-menthane-3,8-diol, a method is preferably adopted, wherein after the reaction product is extracted with an aliphatic hydrocarbon solvent of 5 to 8 in carbon number, the extract is cooled down at temperature higher than the melting point of said aliphatic hydrocarbon solvent and of -10° C. or less to crystallize para-menthane-3,8-diol.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:13][O:14][C:15](=[O:26])[C:16](=[CH2:25])[CH:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:13][O:14][C:15](=[O:26])[C:16](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:25][O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C(=O)OC)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(=Cc1ccccc1)COC(C)=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
The product (108.8 g) in Reference Example 1, namely 3-hydroxy-2-methylene-3-phenylpropionate methyl ester, is dissolved in acetic anhydride (113 ml; 1.20 mol), to which sulfuric acid (0.2 ml) is added, and the resulting mixture is stirred at 100° C. for 4 hours. The reaction solution is concentrated under reduced pressure, to give a crude product of the title compound at a yield of 143.9 g. 1H-NMR analysis reveals that the compound is a mixture of the E form and the Z form at a ratio of 87:13.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].Cl.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH:30]([OH:35])[C:31](=N)OC>C(O)C.O>[NH2:1][C:2]1[C:3]2[N:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:31]([CH:30]([C:24]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=3[Cl:22])[OH:35])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cccc1N
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reaction time: 14 h
Yield: 84.6 %

Procedure:
To a stirred solution of tert-butyl {3-[(2,6-diaminophenyl)amino]propyl}carbamate (5.47 g, 19.5 mmol) in ethanol (39 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (5.80 g, 19.5 mmol) at room temperature. After 14 h, the reaction mixture was diluted with water. The resultant precipitate was collected by filtration and washed with water and ethyl acetate to give the title compound as a colorless solid (7.67 g, 16.5 mmol, 85%).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[C:5]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[CH:6]=[CH:7][C:8]=2[NH:12]C(=O)OC(C)(C)C)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][C:8]1[CH:7]=[CH:6][C:5]([C:20]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])=[C:4]2[C:9]=1[C:10](=[O:11])[N:2]([CH3:1])[CH2:3]2
Reactant: CN1Cc2c(C(=O)N3CCCC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(C(=O)N3CCCC3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl [2-methyl-3-oxo-7-(pyrrolidin-1-ylcarbonyl)-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 116B) was added DCM (0.5 mL) and TFA (0.5 mL). The reaction mixture was stirred at room temperature for 30 minutes, after which it was concentrated to dryness an used without further purification. MS (ES+): m/z 260.30 (100) [MH+]; HPLC: tR=0.69 min (UPLC, Analytical).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH:37][CH2:38][CH2:39][N:40]1[CH:45]=[CH:44][C:43]2[C:46](=[O:57])[C:47](I)=[C:48]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:49][C:42]=2[C:41]1=[O:58]>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:47]3[C:46](=[O:57])[C:43]4[CH:44]=[CH:45][N:40]([CH2:39][CH2:38][OH:37])[C:41](=[O:58])[C:42]=4[O:49][C:48]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(=O)n(CCO)ccc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(=O)n(CCO)ccc4c3=O)cc2)CCC1
Yield: 96 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-(2-hydroxy-ethyl)-3-iodo-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione was reacted to give the title compound (56 mg, 96%) as a colourless solid. LCMS (Method A): RT=4.41 min, [M+H]+=529.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]#[CH:19])=[CH:11][C:10]=1[CH3:20])([CH3:7])[CH3:6])[CH3:2].I[C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]#[C:19][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=2)=[CH:11][C:10]=1[CH3:20])[CH3:7])[CH3:2]
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#CCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC#Cc2ccc(OC(F)(F)F)cc2)cc1C

Procedure:
In analogy to the procedure described in example 13B], 2-(4-but-3-ynyloxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 16A]) and 1-iodo-4-trifluoromethoxy-benzene gave the title compound as a light yellow viscous oil.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[S:20][C:18]=2[N:19]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[N:20]([CH3:32])[C:21](=[O:31])[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=4)=[CH:23][C:13]3=2)[S:8][CH:9]=1)=[N+]=[N-]>CO.C(O)(=O)C.[Pd]>[NH2:1][CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[N:20]([CH3:32])[C:21](=[O:31])[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=4)=[CH:23][C:13]3=2)[S:8][CH:9]=1
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4nc(CN=[N+]=[N-])cs4)ccc3n(C)c21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4nc(CN)cs4)ccc3n(C)c21
Reaction time: 48 h

Procedure:
370 mg (0.73 mmol) of compound B 6-(4-azidomethylthiazol-2-yl)-3-(4-bromophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one are dissolved in 40 ml of methanol and 40 ml of glacial acetic acid. 40 mg of Pd/C are added. The mixture is hydrogenated under 60 psi at 25° C. for 48 hours. The reaction medium is filtered over celite. Washing is carried out with ethanol. The filtrate is evaporated to dryness. The residue is dissolved in a CH2Cl2/MeOH mixture and the product is adsorbed onto silica. Purification is carried out on a silica column, elution being carried out with 97/02/01 CH2Cl2/MeOH/NH4OH and then with 93/05/02 CH2Cl2/MeOH/NH4OH.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:10]1[CH:12]([CH3:13])[CH2:11]1>>[OH:10][CH:12]([CH3:13])[CH2:11][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[CH3:1]
Reactant: Cc1cccc(N)c1C
Reactant: CC1CO1
Product: Cc1cccc(NCC(C)O)c1C
Yield: 71.8 %

Procedure:
2,3-Dimethylaniline is reacted with 1,2-epoxypropane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxypropyl)-2,3-dimethylaniline; b.p.: 153°-155° C./1 mm Hg, yield: 71.8%.
Reaction SMILES: C(C1C=NC(N2CCC(C[C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)CC2)=NC=1)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:29]1[CH2:28][CH:27]=[C:26]([C:24]2[CH:23]=[CH:22][C:20]3[N:21]=[CH:17][S:18][C:19]=3[CH:25]=2)[CH2:31][CH2:30]1
Reactant: CCCc1cnc(N2CCC(Cc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2ccc3ncsc3c2)CCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of tert-butyl 4-(2-((1-(5-propylpyrimidin-2-yl)piperidin-4-yl)methyl)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (253 mg, 0.474 mmol) in DCM (4 mL) was added TFA (0.45 mL, 5.7 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (4 mL), washed with aq NaOH (1 N, 10 mL) and brine. The combined organic layers were dried (Na2SO4), filtered, and concentrated to afford 2-O-(5-propylpyrimidin-2-yl)piperidin-4-yl)methyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (206 mg, 0.451 mmol, 95% yield) as an off white solid. LCMS (m/z)=434 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]([Cl:10])([Cl:9])[Cl:8])[C:3](O)=[O:4].S(Cl)([Cl:13])=O>CN(C)C=O>[Cl:1][CH:2]([CH2:6][C:7]([Cl:10])([Cl:9])[Cl:8])[C:3]([Cl:13])=[O:4]
Reactant: O=C(O)C(Cl)CC(Cl)(Cl)Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C(Cl)CC(Cl)(Cl)Cl
Yield: 93.2 %

Procedure:
226 g (1 mol) of 2,4,4,4-tetrachlorobutyric acid [produced according to CA, 63, 13089e (1965)], 600 g of thionyl chloride and 1 ml of N,N-dimethylformamide are heated for 2 hours at 50° C. and for 2 hours at 75° C. After the unreacted thionyl chloride has been evaporated off, the residue is distilled to obtain 227.6 g (93% of theory) of 2,4,4,4-tetrachlorobutyric acid chloride; b.p. 90°-91° C./15 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[S:25](Cl)(=[O:28])(=[O:27])[NH2:26]>>[NH2:24][C:23]1[C:3]2[C:4]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=[CH:22][C:2]=2[NH:1][S:25](=[O:28])(=[O:27])[N:26]=1
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1cccc(N)c1C#N
Product: CC(C)(C)OC(=O)NCCCCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Yield: 59.5 %

Procedure:
Prepared as in Example 224 from tert-butyl 6-(3-amino-2-cyanophenoxy)hexylcarbamate (Example 229a) and sulfamoyl chloride in 59.5% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.274 (m, 2H), 1.339 (s, 9H), 1.361 (m, 4H), 1.779 (pentet, J=7 Hz, 2H), 2.878 (q, J=6 Hz, 2H), 4.122 (t, J=6 Hz, 2H), 6.580 (d, J=8 Hz, 1H), 6.722 (d, J=8 Hz, 1H), 6.75 (br t, J=6 Hz, 1H), 7.428 (t, J=8 Hz, 1H), 7.798 (br. s, 1H), 8.323 (br. s, 1H), 10.921 (s, 1H). MS 413 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:27]([CH3:29])[CH3:28])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Na+]>C(O)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[C:8]2[O:26][CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(F)cc3)c(OC(C)C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(C)C)c1Cc1ccc(F)cc1

Procedure:
A solution of [8-chloro-3-(4-fluorobenzyl)-4-isopropoxy-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.020 g), methanol (1.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.25 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (30% to 90% of organic modifier) gave title compound as a pale yellow solid, 0.012 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][CH3:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C(N(CC)CC)C.O1CCCC1.[Cu]I.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>[CH3:12][O:11][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: COC1(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 88.7 %

Procedure:
Using General Procedure D; 1-bromo-4-(1-methoxycyclopropyl)-benzene (Intermediate 59, 300.0 mg, 1.32 mmol) in triethylamine (4 mL) and anhydrous tetrahydrofuran (4 mL) was treated with copper(I)iodide (93.0 mg, 0.13 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.39 g, 14.2 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (93.0 mg, 0.13 mmol). The resulting reaction mixture was heated to 70° C. for 60 h. The title compound (286.0 mg, 90%) was isolated by chromatography (0-3% EtOAc-hexanes).