Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][C@H:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:29][C:30](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:30]([CH2:29][C@H:28]([OH:27])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)C[C@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(C[C@H](O)c3ccccc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (3S)-3-hydroxy-3-phenylpropanoic acid, the title compound was obtained in 89% purity by HPLC. MS(ESI+): m/z=483.3.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]([CH2:15][CH:16]1[CH2:18][O:17]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([N:26]1[CH2:3][CH:2]([OH:1])[CH2:4][N:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:15][CH:16]([OH:17])[CH2:18]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)N(CC1CO1)CC1CO1
Solvent: CCO
Product: O=S(=O)(c1ccccc1)N1CC(O)CN(Cc2ccccc2)CC(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product from step (i) above was dissolved in ethanol (200 mL) and treated at room temperature with benzylamine (6.9 mL, 1 equiv.) in one portion (no exotherm was observed). The mixture was heated to reflux for 4 hours, and was then stirred at ambient temperature overnight. The solvent was removed in vacuo to give a viscous, colourless oil which was used in the subsequent step without further purification.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][CH2:11][C:12]([CH3:20])([CH3:19])[C:13]#[C:14][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[CH2:3]([O:10][CH2:11][C:12]([CH3:20])([CH3:19])[C:13]#[CH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C#C[Si](C)(C)C)COCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CC(C)(C)COCc1ccccc1
Temperature: 5 °C
Reaction time: 3.5 h

Procedure:
A 30 L jacketed reactor was charged with methanol (6 vol) which was then cooled to 5° C. Potassium hydroxide (85%, 1.3 equiv) was added to the reactor. A 15-20° C. exotherm was observed as the potassium hydroxide dissolved. The jacket temperature was set to 25° C. A solution of 4-benzyloxy-3,3-dimethyl-1-trimethylsilylbut-1-yne (1.0 equiv) in methanol (2 vol) was added and the resulting mixture was stirred until reaction completion, as monitored by HPLC. Typical reaction time at 25° C. is 3-4 h. The reaction mixture is diluted with water (8 vol) and then stirred for 0.5 h. Hexanes (6 vol) was added and the resulting mixture was stirred for 0.5 h. The phases were allowed to settle and then the aqueous phase (pH 10-11) was drained off and discarded. The organic phase was washed with a solution of KOH (85%, 0.4 equiv) in water (8 vol) followed by water (8 vol). The organic phase was then concentrated down using a rotary evaporator, yielding the title material as a yellow-orange oil. Typical purity of this material is in the 80% range with primarily a single impurity present. 1H NMR (400 MHz, C6D6) δ 7.28 (d, 2H, J=7.4 Hz), 7.18 (t, 2H, 1=7.2 Hz), 7.10 (d, 1H, J=7.2 Hz), 4.35 (s, 2H), 3.24 (s, 2H), 1.91 (s, 1H), 1.25 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:25]=[CH:26][CH:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:11](O)[CH:10]=2)=[N:6][CH:7]=1.FC1C=CC([N+]([O-])=O)=C([OH:40])C=1>>[F:1][C:2]1[C:3]([NH:21][C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:32])[CH:30]=[CH2:31])[CH:25]=[CH:26][CH:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:13][C:14]=2[OH:40])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCOC)c(O)c3)ncc2F)c1
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCOC)cc3O)ncc2F)c1

Procedure:
The synthesis of N-(3-((5-fluoro-2-((3-hydroxy-4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide was achieved as described above for N-(3-((5-fluoro-2-((3-hydroxy-4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (I-13) in Example 7 using 5-fluoro-2-nitrophenol in place of 2-fluoro-5-nitrophenol in the first step.
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][C:7](C)(C)C)=[O:5].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[NH2:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@H](N)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of tert-butyl (3S)-3-amino-3-phenylpropanoate (5.04 g, 22.9 mmol) in 2.25M methanolic hydrochloric acid (100 ml) was heated under reflux for 2½ hours. The mixture was cooled to room temperature, basified with saturated sodium carbonate solution to pH 8 and the phases separated. The aqueous layer was extracted with dichloromethane (4×), the combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound, 3.97 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A quantity of 6.0 g of 3-chloro-2,4-difluorobenzoic acid is suspended in 20 ml of dichloromethane. A quantity of 2.99 ml of oxalyl chloride and 2 drops of DMF are then added. The suspension is stirred at room temperature overnight and the desired product is collected after evaporation of the solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.CO>C1COCC1>[CH3:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:20]=1
Reactant: Cc1ccnc(N)c1
Reactant: Nc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccnc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)c1
Temperature: 25 °C

Procedure:
The product obtained in 116a (550 mg, 2.74 mmol) in 5 mL THF was added to a mixture of 2-amino-4-methyl-pyridine (750 mg, 6.94 mmol) in 10 mL THF under stirring at ambient temperature. The mixture was stirred for 20 min at ambient temperature, then 1 mL methanol was added and the mixture was concentrated i.vac. The residue was purified by HPLC (C18 symmetry, eluent-gradient: (water+0.15% HCOOH)/acetonitrile=90:10->0:100). Conc. ammonia (aq) was added to the product containing fractions until alkaline, and acetonitrile was removed by evaporation. The aqueous mixture was extracted with dichloromethane/methanol 9:1, the combined organic layers dried over MgSO4 and concentrated to dryness i. vac. and the residue triturated with methanol. After filtration, the solid was washed with methanol and dried at 55° C.
Reaction SMILES: C([S:4][CH2:5][C:6]1[C@:7]2([CH2:24][CH2:23][C@H:22]3[C:12](=[CH:13][CH:14]=[C:15]4[C@:20]3([CH3:21])[C@@H:19]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:18][C@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:16]4)[C@@H:9]2[CH2:10][CH:11]=1)[CH3:8])(=O)C.Br/[CH:42]=[CH:43]/[CH2:44][C:45]([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])([CH3:47])[CH3:46].CO.[OH-].[K+]>O1CCCC1>[Si:26]([O:25][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@H:9]3[CH2:10][CH:11]=[C:6]2[CH2:5][S:4]/[CH:42]=[CH:43]/[CH2:44][C:45]([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])([CH3:47])[CH3:46])[CH2:16][C@@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:18]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C/Br
Reactant: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C/C=C/SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 90 %

Procedure:
17-Acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene (304 mg, 0.504 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2E)-pentene (296 mg, 1.01 mmol), a 1M potassium hydroxide methanol solution (3 ml) and tetrahydrofuran (2 ml) were subjected to reaction using a procedure similar to that of Example 31(1) (at room temperature for 10 min.), worked up and purified by column chromatography (hexane:toluene=6:1) to give the titled compound (351 mg, 90%) as a pale yellow solid.
Reaction SMILES: [Cl-].[CH:2]1([CH2:5][NH2+:6][CH2:7][CH2:8]Cl)[CH2:4][CH2:3]1.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=[S:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]2[N:6]([CH2:5][CH:2]3[CH2:3][CH2:4]3)[CH2:7][CH2:8][S:20]2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: ClCC[NH2+]CC1CC1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2CC2CC2)cc1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:9]2[C:10]([CH3:27])=[CH:11][C:12]([O:15][CH2:16][C:17]3[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.C1COCC1.[OH-].[Na+].Cl>CO>[F:14][C:13]1[C:8]2[S:7][CH:6]=[C:5]([CH2:4][C:3]([OH:28])=[O:2])[C:9]=2[C:10]([CH3:27])=[CH:11][C:12]=1[O:15][CH2:16][C:17]1[N:21]([CH3:22])[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1
Reactant: COC(=O)Cc1csc2c(F)c(OCc3cc(C(F)(F)F)nn3C)cc(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2cc(C(F)(F)F)nn2C)c(F)c2scc(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a mixture of methyl(7-fluoro-4-methyl-6-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (150.6 mg), THF (dry) (2.0 mL) and MeOH (2.0 mL) was added 1N NaOH (1.085 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1N HCl and concentrated. The precipitate was collected by filtration to give a solid. The solid was crystallized from EtOAc-hexane to give the title compound (123.5 mg).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1>CN(C=O)C.O>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Reactant: Cc1cc(CBr)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(C)c2)c1-c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
Methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (15 mg, 0.036 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. Sodium hydride (0.175 mmol, 7 mg, 60% dispersion in oil) was added followed by dropwise addition of 4-(bromomethyl)-1-fluoro-2-methylbenzene. The reaction was stirred at ambient temperature 15 minutes, diluted with water and extracted with ethyl acetate, dried over sodium sulfate and purified by silica-gel chromatography (0-50% ethyl acetate/hexanes gradient elution) to give the title compound as a colorless oil 17 mg, 85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.52-7.46 (m, 1 H), 7.42-7.35 (m, 1 H), 7.34-7.26 (m, 2 H), 7.16 (d, J=7.2 Hz, 1 H), 7.11 (td, J=2.3, 5.3 Hz, 1 H), 7.02-6.92 (m, 2 H), 6.15 (d, J=3.5 Hz, 1 H), 5.44-5.39 (m, 2 H), 3.77 (s, 3 H), 2.74 (s, 3 H), 2.47 (s, 3 H), 2.26 (d, J=1.4 Hz, 3 H), 1.67 (s, 1 H), 0.93 (s, 9 H); LCMS (m/z) ES+=489 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][C:14]([C:20]([F:23])([F:21])[F:22])=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: Nc1cnc2cc(C(F)(F)F)ccc2c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cnc2cc(C(F)(F)F)ccc2c1O
Reaction time: 16 h
Yield: 83.8 %

Procedure:
Butyryl chloride (1.5 mL, 14.5 mmol) was added dropwise to a mixture of 3-amino-7-(trifluoromethyl)-4-quinolinol hydrochloride (3.5 g, 13.2 mmol), triethylamine (6.1 mL, 43.6 mmol) and anhydrous tetrahydrofuran (30 mL). The reaction mixture was allowed to stir for 16 hours. A small amount of aqueous sodium bicarbonate was added and the reaction mixture was stirred for 0.5 hours. The tetrahydrofuran was removed under vacuum. The resulting solid was stirred with diethyl ether, isolated by filtration, washed with water and diethyl ether, and then dried in a vacuum oven at 80° C. overnight to provide 3.3 g of N-[4-hydroxy-7-(trifluoromethyl)quinolin-3-yl]butanamide as a cream colored solid.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[CH:20]2>>[Br:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: Brc1cccc2cc[nH]c12
Product: CCC1(c2c[nH]c3c(Br)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-bromoindole, the title compound is prepared as in example 1. 51 mg (16%). NMR (400 MHz, CDCl3): δ 0.82 (t, 3H), 2.12 (m, 1H), 2.21 (m, 1H), 2.30 (m, 1H), 2.59 (m, 1H), 2.97 (m, 2H), 6.82 (m, 2H), 6.90 (s, 1H), 6.99 (m, 2H), 7.12 (d, 1H), 7.28 (d, 1H), 8.08 (s, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11](O)=[O:12].B.C1COCC1>C1COCC1.O>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][OH:12]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CO)oc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
A solution of 3-methyl-benzofuran-2-carboxylic acid (2.0 g, 11.4 mmol, 1 eq) in 60 mL of THF under nitrogen was placed in water bath. Then 30 mL of BH3.THF (1.0 M in THF, 30 mmol, 2.6 eq) was added dropwise. The reaction mixture was allowed to stir at room temperature for 12 h. Then the reaction was quenched with methanol (10 mL). Solvent was removed in vacuo and the residue was subjected to column chromatography eluting with 20% ethyl acetate/hexane to give (3-methyl-benzofuran-2-yl)-methanol (1.6 g) in 87% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.2 (s, 3 H) 4.5 (d, J=5.8 Hz, 2 H) 5.3 (t, J=5.8 Hz, 1 H) 7.3 (m, 2 H) 7.5 (m, 1 H) 7.6 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17][CH2:18]C)=[O:16])=[CH:4][CH:3]=1.[Cl:21][C:22]([Cl:27])([Cl:26])[C:23](Cl)=[O:24].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][N:10]2[CH:14]=[C:13]([C:23](=[O:24])[C:22]([Cl:27])([Cl:26])[Cl:21])[CH:12]=[C:11]2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccn1CC(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)cn1CC(=O)c1ccc(Cl)cc1
Yield: 42.5 %

Procedure:
To a solution of ethyl 1-[2-(4-Chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (150 mg, 0.54 mmol) in CH2Cl2 (10 ml) was added trichloroacetyl chloride (120 μL, 1.1 mmol) and aluminium chloride (290 mg, 2.2 mmol). After 16 h the reaction was quenched by the addition of a saturated aqueous solution of NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic extracts were combined, dried (MgSO4) and concentrated in vacuo to give a residue that was purified using flash chromatography (2× Biotage SP4, 12 g cartridge, 20-100% EtOAc gradient in n-hexanes) to give methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-4-(trichloroacetyl)-1H-pyrrole-2-carboxylate (97 mg, yield 42%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21](SC)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:30])[F:29])[CH:4]=1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21]([N:32]5[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]5)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:29])[F:30])[CH:4]=1
Reactant: O=C(O)C1CCNCC1
Reactant: COc1ccc(Cn2ncc3cc(C=C4SC(SC)=NC4=O)ccc32)c(C(F)(F)F)c1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCC(C(=O)O)CC5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
1-{5-[1-(4-M ethoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid was prepared from 5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:48])[C:7]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29]C(=O)C)[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][C:8]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44]C(=O)C)C.Cl>O.C(O)C>[OH:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:8]1[CH:9]=[C:10]([C:11]([OH:13])=[O:12])[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:17][C:7]=1[C:6]([OH:48])=[O:5]
Reactant: CCOC(=O)c1cc(OCCCCCCCCCCOC(C)=O)c(C(=O)OCC)cc1OCCCCCCCCCCOC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(OCCCCCCCCCCO)c(C(=O)O)cc1OCCCCCCCCCCO

Procedure:
A solution of 20.0 g (303 mmol) 85% aqueous KOH in 200 ml water is added to 38.0 g (58.4 mmol) diethyl-2,5-bis-(10-acetoxydecoxy)terephthalate in 200 ml ethanol and the whole is heated under reflux for 1.5 hours. 28.0 ml conc. HCl are then added dropwise with ice-cooling and stirring until the solution shows an acidic pH. The precipitated, colourless crude product is filtered off, washed neutral and recrystallized from ethanol and methanol/acetone.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CC(=C(C)C(C1C=CC([Cl:31])=C(Cl)C=1)=O)C(O)=O>>[Cl:31][C:2]1[CH:3]=[C:4]([C:10](=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C(=O)O)=C(C)C(=O)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C(=O)/C=C/C(=O)O)cc1F
Product: COc1ccc(C(=O)/C=C/C(=O)O)cc1Cl

Procedure:
(E)-4-(3'-fluoro-4'-methoxyphenyl)-4-oxo-2-butenoic acid, and 2,3-dimethyl-4-(3',4'-dichlorophenyl)-4-oxo-2-butenoic acid.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Cn1ccnc1S
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nccn3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3 H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2-mercapto-1-methylimidazole was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]1)[CH2:6][CH2:5]2.Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]([F:46])([F:45])[F:44])=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:19][C:16]1([CH3:20])[O:17][CH2:18][C:13]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH2:12][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]([F:44])([F:45])[F:46])=[CH:35][CH:36]=4)[CH:3]=3)[CH2:8]2)[CH2:14][O:15]1
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(O)ccc3C2)COC(C)(C)OC1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CN2CCc3cc(OCc4ccc(-c5ccccc5C(F)(F)F)cc4)ccc3C2)COC(C)(C)OC1

Procedure:
A mixture of the product of Step A (0.105 g; 0.27 mmol), the product of Step B (0.08 g; 0.03 mmol) and Cs2CO3 (0.09 g; 0.27 mmol) in anhydrous DMF (1 ml) was stirred overnight at room temperature and solvent was removed in vacuo. The residue was diluted to 15 ml EtOAc and washed with H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2, hexane/EtOAc 9:1) to give the tilted compound (0.12 g; 71%), as colourless solid. 1H-NMR (CDCl3) 1.4 (s, 3H); 1.43 (s, 9H); 1.46 (s, 3H); 2.84 (s, 4H); 2.94 (s, 2H); 3.7 (s, 2H); 3.82 (d, 2H, J=11.5 Hz); 4.07 (d, 2H, J=11.5 Hz); 4.88 (broad s, 1H); 5.07 (s, 2H); 6.74 (d, 1H, J=2.4 Hz); 6.78 (dd, 1H, J=2.4, 8.4 Hz); 6.91 (d, 1H, J=8.4 Hz); 7.29-7.35 (m, 3H); 7.43-7.48 (m, 3H); 7.55 (tr, 1H, J=7.7 Hz); 7.73 (d, 1H, J=7.7 Hz).