Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C(C)=CC=CC=1C.B(Br)(Br)Br.COC(C1C=C(OC)C2CC(C)OC=2C=1)=O.[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([O:43]C)[CH:36]=[C:37]2[O:41][CH:40]([CH3:42])[CH2:39][C:38]=12)=[O:32]>C(Cl)Cl>[CH3:29][O:30][C:31]([C:33]1[CH:34]=[C:35]([OH:43])[CH:36]=[C:37]2[O:41][CH:40]([CH3:42])[CH2:39][C:38]=12)=[O:32]
Reactant: COC(=O)c1cc(OC)cc2c1CC(C)O2
Agent: BrB(Br)Br
Agent: COC(=O)c1cc(OC)c2c(c1)OC(C)C2
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1cc(O)cc2c1CC(C)O2
Temperature: 0 °C
Yield: 23.2 %

Procedure:
2,6-Lutidine (2.64 mL, 22.7 mmol) and BBr3 (22.7 mL, 22.7 mmol, 1.0 M solution in CH2Cl2) were added to a mixture of 4-methoxy-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester and 6-methoxy-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1d) (1.68 g, 7.58 mmol) in CH2Cl2 (30 mL) at 0° C. The mixture was stirred at 0° C. and the warmed to room temperature overnight. The mixture was quenched with H2O (80 mL) and extracted with CH2Cl2 (2×80 mL). The organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 20-30% EtOAc in hexanes to give a pale brown colored solid (366 mg, 23% yield). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J=2.27 Hz, 1 H) 6.49 (d, J=2.27 Hz, 1 H) 5.46 (s, 1 H) 4.86-5.07 (m, 1 H) 3.89 (s, 3 H) 3.57 (dd, J=16.93, 8.84 Hz, 1H) 3.03 (dd, J=16.93, 7.33 Hz, 1 H) 1.46 (d, J=6.32 Hz, 3 H); LCMS for C11H12O4 m/z 209.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)#[CH:16]>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CCOC(C)=O>[CH2:1]([NH:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:16]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[CH3:6])[CH3:2]
Reactant: C#Cc1ccc(OC)cc1
Reactant: CCNC(=O)C(C)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCNC(=O)C(C)c1ccc(C#Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
300 mg (0.99 mmol) N-Ethyl-2-(4-iodo-phenyl)-propionamide (XVIII.1) are added to 148 μL (1.14 mmol) 1-ethynyl-4-methoxybenzene in 8 mL ACN under inert gas atmosphere. 276 μL (1.99 mmol) TEA as base, 6 mg (0.03 mmol) copper(I)iodide and 42 mg (0.060 mmol) bis(triphenylphosphine)palladium(II)chloride as catalyst are added and the mixture is stirred at rt under inert gas atmosphere for 5 h. After that time, the mixture is diluted with EtOAc, washed with saturated ammonium chloride solution and brine, and the organic layer is dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silicia gel; heptane:EtOAc 50:50).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.FC(F)(F)C(O)=O>[C:1]([NH:5][C:6](=[O:7])[C:8]1[CH:28]=[CH:27][CH:26]=[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[CH3:25])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNCCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Yield: 51.3 %

Procedure:
(R)-tert-Butyl 4-(3-(tert-butylcarbamoyl)benzyl)-3-methylpiperazine-1-carboxylate (8.03 g, 20.61 mmol) was stirred in a mixture of dichloromethane:trifluoroacetic acid (1:1) for 2 hours. The reaction mixture was concentrated under vacuum and purified by strong cation exchange column chromatography to afford the title compound (3.06 g).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:35][C:36](Cl)=[O:37].[OH-].[K+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:17]=2)[O:11][CH2:35][C:36]1=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCOc1ccc(C(O)CNCc2ccccc2)cc1
Reactant: O=C(Cl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(C2CN(Cc3ccccc3)C(=O)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 2-benzylamino-1-(4-octyloxy-phenyl)-ethanol (22.50 g; 63.3 mmol) and Et3N (9.7 mL; 69.6 mmol) in CH2Cl2 (500 mL) was added dropwise a solution of chloroacetyl chloride (5.5 mL; 69.6 mmol) in CH2Cl2 (25 mL), at 0° C. After 1 hour at 0° C. the reaction mixture was quenched with 1M aqueous HCl (200 mL). The layers were separated and the organic layer washed with a 5% aqueous NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in 2-propanol (250 mL) and KOH (4.26 g; 76 mmol) was added. The resulting mixture was stirred at RT for 1 hour and subsequently concentrated in vacuo. The crude product was partitioned between EtOAc and 0.5 M aqueous HCl. The layers were separated and the organic layer was washed with 5% aqueous NaHCO3 solution, dried (Na2SO4) and evaporated in vacuo to afford 4-benzyl-6-(4-octyloxy-phenyl)-morpholin-3-one (22.30 g) which was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)=[O:3].[CH3:15][O:16][CH2:17][CH2:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:15][O:16][CH2:17][CH2:18][N:19]([CH3:20])[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN(C)c1ccc(C(C)=O)cc1C(F)(F)F
Yield: 81.8 %

Procedure:
A solution of 4-fluoro-3-(trifluoromethyl)acetophenone (500 mg, 2.43 mmol), N-(2-methoxyethyl)methylamine (649 mg, 7.28 mmol) and potassium carbonate (335 mg, 2.43 mmol) in DMSO (6 mL) was stirred for 30 min at 150° C. in the microwave. The cooled reaction mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulphate, filtered and the solvent was removed under reduced pressure. Finally 547 mg (yield: 82%) of the title compound was obtained.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:33]([OH:35])[CH3:34])[C@@H:3]1[O:5][C@H:4]1[CH2:6][C@@H:7]1[C@@H:12]([OH:13])[C@@H:11]([OH:14])[C@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])[O:9][CH2:8]1.[O-2:36].[Ca+2:37]>CC(CC(C)C)=O.O>[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[CH3:1][C@H:2]([C@H:3]1[C@H:4]([CH2:6][C@H:7]2[CH2:8][O:9][C@@H:10]([CH2:15]/[C:16](/[CH3:32])=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30])=[O:19])[C@H:11]([OH:14])[C@@H:12]2[OH:13])[O:5]1)[C@H:33]([CH3:34])[OH:35].[OH2:36].[OH2:5].[Ca+2:37]
Reactant: [O-2]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: [Ca+2]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C/C(=C\C(=O)OCCCCCCCCC(=O)[O-])C[C@@H]1OC[C@H](C[C@@H]2O[C@H]2[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
Pseudomonic acid (10 g) was dissolved in isobutyl methyl ketone (120 ml). Calcium oxide (0.57 g) was suspended in water (68 ml), and added to the solution of pseudomonic acid. The mixture was stirred for one hour, and the phases were separated. The volume of the aqueous phase was reduced to 40 ml by vacuum distillation. The mixture was cooled to 5° C., and after standing for 15 hours, the crystalline product was filtered and washed with cooled water (10 ml). The product was then dried in an air circulated oven at RT. Mupirocin calcium dihydrate (3.7 g, 35%) was obtained.
Reaction SMILES: [N:1]1[C:2]([CH:13]=O)=[CH:3][N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.[Cl-].[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1.N12CCCN=C1CCCCC2>C1COCC1>[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH:26]=[CH:13][C:2]3[N:1]=[C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH2:12][N:4]4[CH:3]=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1
Reactant: O=Cc1cn2c(n1)-c1ccccc1C2
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ncc(C)n2nc(C=Cc3cn4c(n3)-c3ccccc3C4)nc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 5H-Imidazo[2,1-a]isoindole-2-carbaldehyde (150 mg, 0.81 mmol) in dry THF (5.3 mL) was added to (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium chloride (374 mg, 0.81 mmol) under argon and 1,8-diazabicyclo [5.4.0]undec-7-ene (120 micro L, 0.81 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours after which it was evaporated onto silica gel (2 g). Silica gel chromatography (gradient elution; A:B 100:0 to 0:100, where A is ethyl acetate and B is 10% MeOH in ethyl acetate) afforded the title compound as a mixture of the cis and trans isomers (139 mg, 52%). LC-MS: m/z=329.3 (MH+), tR=0.96 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](O)([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O.ClCCl>C(O)(=O)C>[C:10]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH3:9])=[CH:4][C:5]=1[OH:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cc(O)ccc1Cl
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(O)c(C(C)(C)C)cc1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
The starting compound 2-tert-butyl-4-chloro-5-methyl-phenol was prepared by t-butylation in the following manner: 4-chloro-3-methyl-phenol (10.0 g, 70 mmol) was dissolved in glacial acetic acid (30 mL) at ambient temperature. tert-Butanol (10.1 mL, 1.5 equivalents) was added, and subsequently 95% sulfuric acid (3.75 mL, 1 equiv.). The reaction vessel was closed with a drying tube and heated at 50° C. After 1 d, additional amounts of tert-butanol (5 mL) and sulfuric acid (1.8 mL) were added and heating was continued. After 3 d, dichlormethane (150 mL) was added, and the solution was washed three times with saturated aqueous sodium chloride (150 mL). Drying and evaporation of the solution provided 14.9 g of a pale yellow oil. Pure 2-tert-butyl-4-chloro-5-methyl-phenol was obtained by flash chromatography (silica/toluene-heptane 7:3) as a colourless oil, 1H NMR (CDCl3): δ 7.19 (s, 1H), 6.52 (s, 1H), 4.70 (s, 1H), 2.26 (s, 3H), 1.37 (s, 9H); TLC (silica/toluene-heptane 7:3) Rf=0.45.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[CH:11][CH:10]=[C:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:20]([OH:24])[C:21]([NH2:23])=[O:22].O[NH-].O=[N-]>>[NH2:23][C:21](=[O:22])[C:20](=[O:24])[CH:19]([NH:18][C:15]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13](=[O:14])[CH:12]=[CH:11][CH:10]=1)=[O:17])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)c1cccc(=O)n1Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccc(=O)n1Cc1ccccc1

Procedure:
Coupling of 1-benzyl-6-oxo-1,6-dihydro-pyridine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH:21]=[O:22]>O1CCCC1.CCCCCC>[S:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[CH:21]([C:20]1[CH:23]=[C:16]([Br:15])[CH:17]=[CH:18][C:19]=1[F:24])[OH:22]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cc2ccccc2s1)c1cc(Br)ccc1F
Temperature: -17.799999237060547 °C
Reaction time: 0.67 h
Yield: 84.8 %

Procedure:
Into a tetrahydrofuran (100 liters) solution of benzo[b]thiophene (17.4 kg) was dropwise added a n-hexane solution (56.2 kg) of n-butyl lithium (15.08%) in an argon atmosphere at −24.2 to −13.5° C., followed by stirring at −22.1 to −13.5° C. for 40 minutes. Into this solution was dropwise added a tetrahydrofuran (18 liters) solution of 5-bromo-2-fluorobenzaldehyde (25.5 kg) at −22.1 to −11.8° C., followed by stirring at −23.5 to −16.1° C. for 2 hours. To the reaction mixture were added water (100 liters), toluene (130 liters) and 38% hydrochloric acid (12.3 kg), and extraction was conducted. The organic layer was washed with water (130 liters) and then subjected to distillation at normal pressure to distill off the solvent until the residue became 100 liters. Toluene (130 liters) was added to the residue and the mixture was subjected to distillation at normal pressure to distil off the solvent until the residue became 100 liters. The operation of adding toluene to the residue and subjecting the mixture to distillation under reduced pressure to distill off the solvent, was repeated twice: Then, n-heptane (310 liters) was added to the residue, followed by heating to dissolve the residue. To the solution was added, as a seed crystal, about 26 g of the 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol produced in the same manner as that shown in the first step of Reference Example 1, followed by stirring at 1.2 to 5.0° C. for 13 hours. The separated-out crystals were collected by filtration, washed twice with a toluene-n-heptane (1:6) mixed solvent (26 liters), and subjected to vacuum drying to obtain, as white crystals, 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol [35.91 kg, yield: 84.8%, purity: 99% (HPLC)].
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1(C(O)=O)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC#N>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([NH2:39])([CH2:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=2[CH3:1])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1CC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 55 °C

Procedure:
To a mixture of 4-(2-methylbenzyl) N-t-butoxycarbonyl isonipecotic acid (1.0 g, 3.0 mmol) in CH3CN (20 ml) add diphenyl phosphoryl azide (0.99 g, 3.6 mmol) and triethylamine (0.50 ml, 3.6 mmol). After stirring at 55° C. (oil bath temp.) concentrate the reaction in vacuo and partion the residue between EtOAc and saturated aqueous NaHCO3. The organic phase is washed with brine, dried (MgSO4), and concentrated in vacuo to afford the crude product.
Reaction SMILES: COC1C=CC(OC)=CC=1C(=O)CN1C(C(OCC)=O)=CC(C2C=NC=CC=2)=N1.[CH3:30][Si:31]([CH3:43])([CH3:42])[C:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34][N:33]=1.Br[CH2:45][C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)=[O:47].Br>>[O:47]=[C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)[CH2:45][N:34]1[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][C:32]([Si:31]([CH3:42])([CH3:43])[CH3:30])=[N:33]1
Reactant: O=C(CBr)c1cccnc1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Agent: Br
Agent: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Product: CCOC(=O)c1cc([Si](C)(C)C)nn1CC(=O)c1cccnc1

Procedure:
This compound was made in an analogous fashion to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate and 2-bromo-1-(pyridin-3-yl)ethanone.HBr (purchased from Aldrich). 1H-NMR δ 9.20 (d, 1H), 8.84 (dd, 1H), 8.25 (dt, 1H), 7.46 (dd, 1H), 7.07 (s, 1H), 6.05 (s, 2H), 4.26 (q, 2H), 1.31 (t, 3H), 0.32 (s, 9H). Calculated mass for C16H21N3O3Si, 331.14, observed, 332.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O-:27].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[C:24]([O:27][CH3:26])=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1NCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
4-[(3-Chloro-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (2.72 g, 7.54 mmol) and 0.5 M sodium methoxide in methanol (40 mL) were heated under nitrogen at 60° C. for 2 days, cooled, evaporated and the residue partitioned between EtOAc and water. The organic layer was washed with brine, dried and solvent evaporated to afford crude material, purified by flash chromatography on silica (gradient 25 to 100% EtOAc hexane) to give the desired compound as a solid. The solid was stirred with approx. (10 ML) 2:1 isopropyl acetate:hexane and filtered to give the title compound as white solid. M.S. (M+1): 357
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[C:18]([F:19])=[C:17]2[C:12]([C:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:14][C:15]([C:20](O)=[O:21])=[N:16]2)=[CH:11][CH:10]=1.C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[NH4+]>CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[C:18]([F:19])=[C:17]2[C:12]([C:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:14][C:15]([C:20]([NH2:31])=[O:21])=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)c(F)c2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)c(F)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
TEA (105 μl, 0.757 mmol) was added to a solution of 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylic acid 7-12 (100 mg, 0.252 mmol) and HATU (96 mg, 0.252 mmol) in DMF (1262 μl). Ammonium Hydroxide (50.5 μl, 0.757 mmol) was added and the reaction stirred for 15 min at rt. The reaction was quenched with aqueous sodium hydrogen carbonate (saturated) and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on a silica gel column, eluting with EtOAc/hexane (0-100%) to afford 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxamide 7-13 (63 mg, 63% yield) as a white solid, LCMS shows the compound is 100% pure 1H NMR (500 MHz, CDCl3): δ 8.28 (1H, s), 8.14 (1H, s), 7.68 (1H, d, J=8.85 Hz), 7.54 (1H, dd, J=8.86, 6.65 Hz), 7.50-7.46 (2H, m), 7.25-7.20 (2H, m), 5.69 (1H, s), 4.99 (2H, s), 2.78 (4H, s). LRMS m/z (M+H)+ 396.2 found, 396.1 required.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([OH:36])[CH2:27][CH2:28]2)=[CH:23][CH2:22]3)[CH2:19][CH2:18]1)=[CH2:16]>CC(C)=O>[CH3:16][C:15]([C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[C:23](=[O:3])[CH2:22]3)[CH2:19][CH2:18]1)=[CH2:14]
Reactant: C=C(C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C=C(C)[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.33 h
Yield: 57.4 %

Procedure:
Jones reagent (2.67 M, 1.83 ml, 4.89 mmol) was added to a solution of 20-methylpregna-5,20-dien-3β-ol (400.0 mg, 1.272 mmol) in 45 ml of acetone and the reaction was stirred 20 min. After quenching with 2-propanol (0.91 ml) the mixture was poured into 85 ml of water and extracted three times with 40 ml portions of ethyl acetate. The combined organic extracts were washed with 40 ml of saturated sodium bicarbonate+40 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization of the solid residue from aqueous ethanol gave yellow crystals (235.0 mg, 0.7298 mmol, 57%), m.p. 148-150° C. TLC (20% ethyl acetate/hexanes on silica gel) showed a major product at Rf 0.24 with a minor impurity at the origin.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[OH:18].C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[O:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(Cl)c(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl chloride (3.51 g, 25 mmol) was added dropwise to a solution of 2-chloro-5-methylphenol (3.92 g, 27.5 mmol) and triethylamine (5 mL) in dichloromethane (100 mL), The mixture was stirred for 18 hours at room temperature and concentrated under reduced pressure. Diethylether (200 mL) and water (100 mL) were added. The organic layer was separated and extracted with 2N NaOH (2×100 mL) and brine (50 mL), dried over sodium sulphate and concentrated under reduced pressure. The resulting colourless oil solidified in the freezer. Yield: 5.82 g (94%). 1H-NMR (400 MHz, CDCl3) δ 2.38 (s, 3H, —CH3), 7.05 (d, J=8.2 Hz, 1H), 7.11 (s, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.51-7.56 (m, 2H), 7.64-7.7.70 (m, 1H), 8.22-8.28 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ=21.41, 123.97, 124.58, 128.07, 128.85, 129.15, 130.07, 130.55, 134.01, 138.38, 146.98, 164.51.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH:8]([C:12]1[C:13]([CH:28]2[CH2:30][CH2:29]2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:9][CH2:10][CH3:11].[C:31]([O:35][C:36](=[O:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([SH:45])=[CH:41][C:40]=1[CH3:46])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.CCOCC>[C:31]([O:35][C:36](=[O:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45][CH:8]([C:12]2[C:13]([CH:28]3[CH2:30][CH2:29]3)=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)[CH2:9][CH2:10][CH3:11])=[CH:41][C:40]=1[CH3:46])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCCC(Cl)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: Cc1cc(S)ccc1OCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCC(Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
231 mg (0.7 mmol) cesium carbonate was added to a solution of 210 mg (0.59 mmol) [rac]-5-(1-chloro-butyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 30D]) and 151 mg (0.59 mmol) (4-mercapto-2-methyl-phenoxy)-acetic acid tert-butyl ester (example 28C]) in 3 ml DMF. After stirring for 3 h at RT, the reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:9 providing 257 mg of pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester.