Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]Cl)=[CH:20][CH:19]=1>>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(C2CCNCC2)c1
Reactant: Oc1ccc(CCCl)cc1
Product: Oc1ccc(CCN2CCC(c3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 65 %

Procedure:
The procedure described in Example 1 was repeated except that 4-(3-trifluoromethylphenyl)piperidine (the product of Preparation L) and 2-(p-hydroxyphenyl)ethyl chloride were the respective starting materials employed, using the same molar porportions as before. In this particular case, the corresponding final product obtained 4-{2-[4-(3-trifluoromethylphenyl)-piperidinyl]ethyl}phenol (yield, 65%), which was also converted to the hydrochloride salt. The pure base product was characterized by means of nuclear magnetic resonance data: NMR (CDCl3) δ6.8-7.6 (m, 8H), 0.6-4.0 (m, 14H). The hydrochloride salt melted at 207°-210° C. and was further characterized by means of elemental analysis.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16]2)[CH2:10]1)(OC(C)(C)C)=O.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>ClCCl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[N:15]1([CH2:14][C@@H:11]2[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[N:16]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Cn2ncc3ccccc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](Cn2ncc3ccccc32)C1

Procedure:
Deprotection of N1-BOC-(1S,3R)-3-(1H-indazol-1-ylmethyl)cyclopentan-1-amine (500 mg, 1.58 mmol), the less polar isomer, using TFA (3 ml) in dry dichloromethane (3 ml) as described in Example 1, Step 2 gave 341 mg of the amine as its TFA salt, which was used as such for the coupling reaction.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.CON(C)[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[O:25])=[CH:8][CH:9]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1ccc(C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (8.20 g) in THF (dry) (75 mL) was added TEA (23.4 mL) at 0° C. After being stirred at 0° C. for 20 min, 4-methylbenzoyl chloride (10 g) in THF (dry) (20 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 2 days. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give N-methoxy-N,4-dimethylbenzamide (11.7 g) as a yellow oil. n-Butyllithium (1.6 M in hexane) (25.1 mL) was added dropwise to a mixture of 1,4-dibromobenzene (8.29 g) in THF (dry) (105 mL) at −78° C. for 10 min. The mixture was stirred at the same temperature under nitrogen for 30 min to form white precipitates. A solution of N-methoxy-N,4-dimethylbenzamide (6 g) in THF (dry) (20 mL) was added to the reaction mixture at −78° C. and the mixture was stirred at the same temperature under nitrogen for 30 min and then at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with sat. NH4Cl aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (7.18 g) as a pale yellow solid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Mg].[F:6][CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]>CCOCC>[F:6][CH2:7][C:8]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:2]#[CH:1]
Reactant: C#CCBr
Reactant: CCCCC(=O)CF
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(CF)CCCC
Temperature: 25 °C

Procedure:
A 0.25 ml. portion of propargyl bromide is added to a stirred suspension of 0.73 g. of magnesium and 6 mg. of mercuric chloride in 7.5 ml. of ether. The reaction is initiated after a few minutes of vigorous stirring at room temperature. A mixture of 3 g. of 80% 1-fluoro-2-hexanone and 3.63 g. of propargyl bromide in 7.5 ml. of ether is added dropwise through a dropping funnel so that the reaction remains gently refluxing (25° C. to 32° C.). Cooling in a water bath is required. The reaction mixture is cooled in an ice bath, quenched with 8 ml. of cold saturated aqueous ammonium chloride, filtered through Celite and washed with ether. The mother liquor is evaporated to dryness giving a reddish oily residue, which is Kugheror-distilled at 45° C./4 mm giving the product as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH:10]=[CH:11][C:12]=1[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15].FC(F)(F)C(O)=O>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([Cl:35])[CH:34]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:10]=[CH:11][C:12]=1[C:13](=[O:18])[C:14]([F:16])([F:17])[F:15]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C(F)(F)F)c(NCc3cc(Cl)cc(Cl)c3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: O=C(c1ccc(N2CCNCC2)cc1NCc1cc(Cl)cc(Cl)c1)C(F)(F)F
Reaction time: 3 h
Yield: 136.5 %

Procedure:
A mixture of tert-butyl 4-(3-(3,5-dichlorobenzylamino)-4-(2,2,2-trifluoroacetyl)phenyl)-piperazine-1-carboxylate (0.25 g, 0.5 mmol), trifluoroacetic acid (5 mL) and dichloromethane (10 mL) was stirred for 3 h and concentrated in vacuo. The residue was dissolved in dichloromethane; this solution was washed with aqueous NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo. The yellow solid residue was dissolved in dichloromethane (1 mL), reacted with 1 N HCl in ether (1 mL) and concentrated in vacuo to yield the title compounds as a yellow solid (0.16 g, 73%). 1H NMR (400 MHz, CDCl3): δ 9.37 (br, 1 H), 7.62 (d, 1 H), 7.28 (s, 1 H), 7.22 (s, 2 H), 6.24 (dd, 1 H), 5.71 (d, 1 H), 4.43 (d, 2 H), 3.30 (m, 4 H), 2.93 (m, 4 H). MS (ESI) m/z: Calculated: 431; Observed: 432 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[NH2:18][NH2:19]>C(O)(C)C>[NH:18]([C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1)[NH2:19].[ClH:1]
Reactant: NN
Reactant: O=C(NCC1CCOCC1)c1ccc(Cl)nc1
Solvent: CC(C)O
Product: Cl
Product: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Temperature: 20 °C
Yield: 271.7 %

Procedure:
Combined 6-chloro-N-((tetrahydro-2 H-pyran-4-yl)methyl)nicotinamide (828 mg, 3.25 mmol) and hydrazine (0.510 mL, 16.25 mmol) in isopropanol (10 mL) and heated at 80° C. for 22 h. Cool to 20° C. and after 2 days a white precipitate formed and was collected by filtration, rinsed with isopropanol, and dried under vacuum to give the title compound as its HCl salt (322 mg) as a white solid. A second crop was collected from the filtrate (500 mg). The combined yield was 822 mg (88%). MS m/z 251 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.26 (m, 2 H) 1.57 (dd, J=12.9, 1.8 Hz, 2 H) 1.75 (dtt, J=14.9, 7.5, 7.5, 3.4, 3.4 Hz, 1 H) 3.11 (t, J=6.3 Hz, 2 H) 3.19-3.31 (m, 2 H) 3.83 (dd, J=11.4, 2.5 Hz, 2 H) 4.26 (br. s., 2 H) 6.68 (d, J=8.8 Hz, 1 H) 7.87 (dd, J=8.8, 2.3 Hz, 1 H) 7.97 (s, 1 H) 8.18 (t, J=5.7 Hz, 1 H) 8.49 (d, J=1.8 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:37]([OH:39])=O)[CH2:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[C:28]([NH2:35])=[C:27]([Cl:36])[CH:26]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:40]=1.[CH2:41]([O:43][C:44](=[O:58])[CH2:45][N:46]1[CH2:51][CH2:50][CH:49]([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:48][CH2:47]1)[CH3:42]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C@H:23]([CH2:24][C:25]4[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[C:28]([NH2:35])=[C:27]([Cl:36])[CH:26]=4)[C:37]([N:55]4[CH2:54][CH2:53][CH:52]([CH:49]5[CH2:48][CH2:47][N:46]([CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:58])[CH2:51][CH2:50]5)[CH2:57][CH2:56]4)=[O:39])=[O:21])[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:40]=1
Reactant: CCOC(=O)CN1CCC(C2CCNCC2)CC1
Reactant: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)O)CC1)C(=O)N2
Product: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5cc(OC)ccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 9 from 100 mg (0.17 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 48 mg (0.19 mmol) ethyl[4,4′]bipiperidinyl-1-yl-acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[C:5]([C:8]1[C:9]([C:29]([F:32])([F:31])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)(=O)[CH3:6].C([BH3-])#N.[Na+]>CO.CC(O)=O>[OH:4][CH2:3][CH2:2][NH:1][CH:5]([C:8]1[C:9]([C:29]([F:31])([F:32])[F:30])=[N:10][N:11]([CH2:13][C:14]([NH:16][C:17]2[S:21][C:20]3[CH2:22][CH2:23][CH2:24][CH2:25][C:19]=3[C:18]=2[C:26]([NH2:28])=[O:27])=[O:15])[CH:12]=1)[CH3:6]
Reactant: NCCO
Reactant: CC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(NCCO)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 100 °C
Yield: 14.9 %

Procedure:
To a solution of 2-aminoethanol (103 mg, 1.689 mmol) in MeOH (1.5 mL), AcOH was added until the pH reached 5. 2-(2-(4-acetyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (50 mg, 0.121 mmol) was added before the addition of (7.6 mg, 0.121 mmol) of sodium cyanoborohydride. The reaction was heated by microwave irradiation to 100° C. for 20 min. The reaction mixture was filtered before purification by preparative reverse phase HPLC. The product fractions were acidified to pH 4 before applying to a strong cation exchange cartridge (500 mg). The cartridge was washed with DCM/MeOH (1:1) before eluting the product with 2M NH3 in MeOH. The solvent was removed in vacuo to give the title compound (8.3 mg, 0.018 mmol, 15%).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15](F)[CH:14]=1.C(N(C(C)C)CC)(C)C.C(OCC)C.CCCC(C)C>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([NH:1][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:4][OH:5])[CH:14]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: NC(CCO)c1ccccc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC(C)C
Product: N#Cc1ccc(Cl)cc1NC(CCO)c1ccccc1
Temperature: 140 °C

Procedure:
A mixture of 3-amino-3-phenylpropanol (1 g, 6.6 mmol) and 4-chloro-2-fluorobenzonitrile (1 g, 6.4 mmol) in diisopropylethylamine (1.2 ml, 6.9 mmol) was heated at 140° C. for 5 h. The crude reaction mixture was cooled to room temperature and applied to a silica column. The title compound was isolated as a colourless solid (1.1 g, 58%) by elution with 20% diethyl ether/isohexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:14][O:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([NH:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:22])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: COc1cc(N)c2nccc(C)c2c1
Reactant: CC(C)CNC(=O)CCCCCBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(NCCCCCC(=O)NCC(C)C)c2nccc(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A stirred mixture of 22.6 g (0.120 mole) of 8-amino-6-methoxy-4-methylquinoline and 29.6 g (0.118 mole) of 6-bromo-N-(2-methyl-1-propyl)-hexanamide was heated in an oil bath (130° ) while 12.2 g (16.8 ml; 0.120 mole) of triethylamine was added dropwise over 30 minutes. The temperature of the bath was kept at 130° for 30 minutes, at 150° for 60 minutes, between 150° and 190° for 30 minutes, and at 190° for 30 minutes. The mixture was cooled to room temperature then diluted with 25 ml of ethyl acetate. The solid that separated was collected on a filter, extracted with boiling ethyl acetate (3×100 ml), then discarded. The filtrate and extracts were combined, then concentrated in vacuo to a solid; yield 44 g. The solid was dissolved in 130 ml of dichloromethane and purified by elution chromatography on a column (8 cm dia× 40 cm) of silica gel (1000 g; activity III) using 1 l of dichloromethane-ether (1:1), followed by 2 l of ether, as eluents. The fractions (100 ml each) containing pure product were combined then concentrated in vacuo. The fractions containing mixtures were concentrated in vacuo then triturated with diethyl ether to yield 25.4 g (60.2%) of crude product. The product was suitable for further transformation. Analytically pure compound was readily obtained (84% recovery) by recrystallization from methylene chloride and ether; mp 111°-112°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=C(C3C=NC=CN=3)C=[CH:20][N:19]=2)=[CH:12][CH:11]=1.N1C=CN=CC=1C(=O)C.[OH:40][CH2:41][C:42]1[C:46]([C:47](=O)[CH3:48])=[C:45]([CH3:50])[O:44][N:43]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]2[N:23]=[C:47]([C:46]3[C:42]([CH2:41][OH:40])=[N:43][O:44][C:45]=3[CH3:50])[CH:48]=[CH:20][N:19]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Reactant: CC(=O)c1c(CO)noc1C
Agent: CC(=O)c1cnccn1
Product: Cc1onc(CO)c1-c1ccnc(NCc2ccc(C(=O)Nc3ccccc3N)cc2)n1

Procedure:
Title compound was obtained according to the scheme 6 similarly to the compound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone as the starting material the ketone 324 (Table 11). Characterization of the title compound is provided in the Table 12.
Reaction SMILES: CS[C:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=O)[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=[O:5].C(Cl)Cl.O>C(O)(=O)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[O:24]=[C:15]1[C:16]2[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][N:14]1[C:11]1[CH:12]=[CH:13][C:8]([CH:3]([CH3:7])[C:4]([OH:6])=[O:5])=[CH:9][CH:10]=1
Reactant: CSC(C)(C(=O)O)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 97.7 %

Procedure:
α-Methylthio-α-(p-phthalimidophenyl)propionic acid (123 mg), 300 mg of zinc powder and 16 mg of anhydrous copper sulfate were stirred in 1.5 ml of acetic acid at the refluxing temperature for 5 hours. After cooling, 30 ml of methylene chloride and 20 ml of water were added, and the insoluble precipitate was separated by filtration. The filtrate was adjusted to pH 1 with conc. hydrochloric acid, and extracted three times with 20 ml of methylene chloride. The organic layer was washed with 10 ml of water, and dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure to afford 99 mg of α-[p-(1-oxo-2-isoindolinyl)phenyl]propionic acid in a yield of 98%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:1][N:2]([C:44](=[O:45])[C:43]1[CH:47]=[C:39]([CH2:38][C:32]2[C:33](=[O:37])[C:34]([O:35][CH3:36])=[C:29]([O:28][CH3:27])[C:30](=[O:53])[C:31]=2[CH3:52])[CH:40]=[CH:41][C:42]=1[O:48][C:49](=[O:51])[CH3:50])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CNc1ccc(OC)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N(C)c3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.8 %

Procedure:
N-Methyl-4-methoxyaniline (0.220 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.142 g, 0.288 mmol, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:21][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([OH:20])=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:22])=[O:4].[CH3:23][O:24][C@@H:25]1[CH2:30][CH2:29][C@H:28](O)[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[S:21][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][C@H:28]4[CH2:29][CH2:30][C@H:25]([O:24][CH3:23])[CH2:26][CH2:27]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:22])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3O)c2c1C
Reactant: CO[C@H]1CC[C@@H](O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](OC)CC3)c2c1C

Procedure:
Prepared analogously to example XVI.1 from 1.215 g 4-(2-hydroxy-pyridin-3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 0.6 g cis-4-methoxycyclohexanol using DTAD and triphenylphosphine (polymerically bound from Aldrich).
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:9]=2[CH:10]=1)=[O:5])C.[CH2:16]([Mg]Br)[CH3:17].[CH2:20]1COC[CH2:21]1>>[Br:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:4]([OH:5])([CH2:16][CH3:17])[CH2:20][CH3:21])=[CH:10][C:9]=2[CH:11]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Reactant: CC[Mg]Br
Product: CCC(O)(CC)c1cc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a stirred solution of 5-bromo-benzofuran-2-carboxylic acid ethyl ester (24.3 g, 90.3 mmol) in THF (300 mL) at −40° C. is added ethyl magnesium bromide (90.3 mL, 3.0 M). The reaction is allowed to warm to RT and stirred for 2 h before quenched with water and HCl (1.0 M) till pH˜2. The THF is removed in vacuum and the mixture is extracted with EtOAc (200 mL, 100 mL). The organic layer is dried over Na2SO4, concentrated, purified on column chromatography (10-15% EtOAc/Hex), to give the title compound as an oil (22.4 g, 88%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12](Br)=[O:13].O=C1NC2C=C(C#N)C=CC=2OC1>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH2:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Br)CBr
Reactant: Nc1cc(Br)ccc1O
Agent: N#Cc1ccc2c(c1)NC(=O)CO2
Product: O=C1COc2ccc(Br)cc2N1

Procedure:
2-Amino-4-bromophenol (2.1 g, 11 mmol) and bromo acetyl bromide (1.4 mL, 16.5 mmol) were reacted according to the procedure for Intermediate 60 to afford product as a solid, 2.1 g (85%).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.CC(C[AlH]CC(C)C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O.[CH2:35]([OH:38])[CH2:36][OH:37]>C(Cl)Cl.C1C=CC=CC=1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:38][CH2:35][CH2:36][O:37]2)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: OCCO
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O
Product: FC(F)(F)c1cc(I)ccc1C1OCCO1
Reaction time: 0.08 h

Procedure:
To a solution of 4-iodo-2-(trifluoromethyl)benzonitrile (1.89 g; 6.38 mmol, Note 1) in CH2Cl2 (15 mL) at −40° C. was added DIBAL-H (9.6 mL of a 1.0M solution in CH2Cl2; 9.6 mmol), dropwise over 5 min. The mixture was stirred 30 min, quenched by dropwise addition of MeOH and removed from the cooling bath. To the still-cold mixture was slowly added HCl (10 mL of a 6M solution), and after stirring 30 min at room temperature the layers were separated. The aqueous layer was extracted with CH2Cl2 (×2), combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in PhH (15 mL), along with TsOH.H2O (0.12 g; 0.64 mmol) and ethylene glycol (3.5 mL; 63 mmol), and the solution was heated under reflux for 2 h using a Dean-Stark trap to remove water. Upon cooling, the mixture was diluted with <solvent>, washed (water, brine), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.00-4.11 (m, 2H), 4.11-4.24 (m, 2H), 6.06 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.99 (s, 1H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([Br:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(OCC)(=O)C>C(#N)C>[Br-:15].[CH2:6]([C:2]1[SH+:1][CH:5]=[CH:4][CH:3]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: C1CCSC1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc[sH+]1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
In 400 ml of acetonitrile was dissolved 53.2 g of tetrahydrothiophene, and to the solution was gradually added a solution containing 100 g of phenacyl bromide dissolved in 300 ml of acetonitrile. The solution was stirred at room temperature for 3 hours to deposit powder. The reaction solution was poured into 1,500 ml of ethyl acetate, and the powder deposited was collected by filtration and dried to obtain 137 g of phenacylthiophenium bromide.