Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:22])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[Br-].[Br-].[Br-].[Al+3].Cl.C(OCC)C>C1(C)C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:22])[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC(=O)CCc2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(CCc1ccc(O)cc1)CCc1ccc(O)cc1
Temperature: 80 °C
Yield: 105.7 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)-3-pentanone (2.1 g, 7 mmol), prepared as in step 1, and aluminum tribromide (10.64 g, 40 mmol) in toluene (60 mL) was refluxed at 80° C. for 30 minutes and then cooled to room temperature. The reaction mixture was slowly added to a mixture of aqueous 1N HCl (150 mL) and ethyl ether (150 mL). The ether layer was separated, washed with aqueous 1N HCl, water, and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 1,5-bis-(4-hydroxyphenyl)-3-pentanone (2 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O1CCOCC1.O>[F:27][C:12]([F:11])([F:26])[C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)c1cnc(Br)s1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 82.5 °C

Procedure:
A mixture of methyl 2-bromo-1,3-thiazole-5-carboxylate (10 g, 45 mmol) and 4-[2-(trifluoromethyl)phenoxy]piperidine (12.1 g, 50 mmol) in dioxane (160 mL) was heated at 80-85° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed twice with water, dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (eluting with 50% EtOAc/hexanes) to afford the title compound as a pale yellow oil.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]2([CH2:35][OH:36])[CH2:34][CH2:33]2)[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]3([CH2:35][OH:36])[CH2:33][CH2:34]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC2(CO)CC2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2F)C(CC2(CO)CC2)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 114b (0.4 g, 0.74 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-hydroxymethyl-cyclopropylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.4 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.Br[CH2:20][C@H:21]1[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C@H:21]1([CH2:20][C@H:7]2[C:6]([O:9][CH3:10])=[N:5][C@H:4]([CH:11]([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[N:8]2)[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: BrC[C@@H]1CC=CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@@H]1CC=CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution, cooled to -78°, of 1.78 ml (10 mmol) of (2R)-(-)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 5 ml of absolute tetrahydrofuran is treated dropwise with 6.8 ml (11 mmol) of a solution of butyllithium in hexane. The reaction solution is left at -78° for 1 hour and at -20° for 1 hour and then again cooled to -78°. Subsequently, a solution of 1.75 g (10 mmol) of (S)-1-(bromomethyl)-3-cyclohexene in 5 ml of absolute tetrahydrofuran is added. After 2 hours at room temperature the solution is again cooled to -10°, treated with 5 ml of saturated ammonium chloride solution and extracted with ether. The organic phase is washed with water, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue is chromatographed twice on silica gel using a 9:1 mixture of toluene and ethyl acetate as the eluent. (2S,5R)-2-[(S)-3-Cyclohexen-1-ylmethyl]-2,5-dihydro-5-isopropyl-3,6-dimethoxypyrazine is obtained as a colourless oil; MS: 278 (M)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13]C(C)(C)C)(=[O:12])=[O:11].FC(F)(F)C(O)=O>>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:11])=[O:12]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1CCCl
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
The product from Example 14 (15.8 g) was added to 96 ml of trifluoroacetic acid at room temperature. After being stirred for 30 minutes, the reaction mixture yielded white crystals which were collected by filtration, washed well with diethyl ether, and dried to afford 10.9 g of the title compound, m.p. 168°-171° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:21])[N:5]([CH2:18][CH2:19][OH:20])[CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17])[CH3:2].C(O)C>[Pd]>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]([O:16][CH3:17])=[C:7]([CH:12]=1)[CH2:6][N:5]([CH2:18][CH2:19][OH:20])[C:4]([NH:3][CH2:1][CH3:2])=[O:21]
Reactant: CCNC(=O)N(CCO)Cc1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: CCO
Product: CCNC(=O)N(CCO)Cc1cc(N)ccc1OC
Yield: 106.9 %

Procedure:
3-Ethyl-1-(2-hydroxy-ethyl)-1-(2-methoxy-5-nitro-benzyl)-urea (0.43 g, 0.0014 mol) in Ethanol (50 mL, 0.8 mol) was hydrogenated with 10% Pd/C (10:90, Palladium:carbon black, 0.027 g) catalyst overnight. The reaction was filtered and the filtrate evaporated to give 1-(5-Amino-2-methoxy-benzyl)-3-ethyl-1-(2-hydroxy-ethyl)-urea as a yellow oil (0.40 g, 75%). 0.020 g was chromatographed on Alumina with DCM/IPA (20-1) giving 1-(5-Amino-2-methoxy-benzyl)-3-ethyl-1-(2-hydroxy-ethyl)-urea as an oil (0.010 g). LCMS (m/e) 268 (M+1); 1H-NMR (DMSO, 400 MHz) δ 6.68 (d, 1H, J=8.59 Hz), 6.44-6.39 (d, 1H, J=9.6 Hz), 6.32 (s, 1H), 6.26-6.23 (t, 1H, J=5.30 Hz), 4.79-4.76 (t, 1H, J=5.06 Hz), 4.59 (s, 2H), 4.15 (s, 2H), 3.65 (s, 3H), 3.47-3.43 (q, 2H, J=5.30 Hz), 3.20-3.17 (t, 2H, J=6.06 Hz), 3.08-3.00 (q, 2H, J=5.81 Hz), 1.07-0.98 (t, 3H, J=7.07 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][C:20]1[O:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][CH:22]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: Cc1nc(C(=O)O)co1
Product: Cc1nc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)co1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2-methyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=369.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([F:27])=[C:4]2[O:9][C:8]3([CH2:12][CH2:11][CH2:10]3)[CH2:7][N:6]3[CH:13]=[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:15](=[O:21])[C:16]([C:17]=1[N+:18]([O-])=O)=[C:5]23>CN(C=O)C.[Pd]>[NH2:18][C:17]1[C:16]2[C:15](=[O:21])[C:14]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][N:6]3[CH2:7][C:8]4([CH2:12][CH2:11][CH2:10]4)[O:9][C:4]([C:5]=23)=[C:3]([F:27])[C:2]=1[F:1]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OC1(CCC1)C2
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OC1(CCC1)C2
Yield: 67 %

Procedure:
A solution of ethyl 9′,10′-difluoro-8′-nitro-7′-oxo-spiro[cyclobutane-1,2′(3′H)-[7H]pyrido[1,2,3-de][1,4]benzoxazine]-6′-carboxylate (450 mg, 1.15 mmol) and 10% Pd/C (40.5 mg) in DMF (20 mL) was stirred under hydrogen atmosphere(0.3 MPa) at 50° C. for 3 hours. The catalyst was removed by filtration over Celite and the filtrate was concentrated in vacuo. The resulting solid was dissolved in EtOH—CH2Cl2 (1:5) and filtered. CH2Cl2 was removed, and the resulting precipitate was removed by filtration, washed with EtOH and dried to yield the title compound (270 mg, 67%) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.27 (3H, t, J=7.3 Hz), 1.74-1.96 (2H, m), 2.02-2.13 (2H, m), 2.14-2.25 (2H, m), 4.20 (2H, q, J=7.3 Hz), 4.33 (2H, s), 7.33 (2H, brs), 8.43 (1H, s). ESIMS (+): 350[M+H]+.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([CH3:36])[C:23]2=[O:37]>>[CH3:36][CH:24]1[CH:23]([OH:37])[C:22]2[C:27](=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=2)[O:26][CH:25]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC1C(=O)c2cc(O)ccc2OC1c1ccccc1
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: CC1C(O)c2cc(O)ccc2OC1c1ccccc1

Procedure:
3-Methyl-2-phenylchroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 474 mg of 6-hydroxy-3-methyl-2-phenylchroman-4-one. 1H NMR (300 MHz, d6-DMSO) δ: 8.79 (s, 1H), 7.42-7.33 (m, 5H), 6.88 (bs, 1H), 6.53 (m, 2H), 5.37 (d, 1H, J 8.0 Hz), 4.70 (d, 1H, J 10.6 Hz), 1.94 (m, 1H), 0.73 (d, 3H, J 6.7 Hz).
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(C)C=CC=CC=1>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:2][CH:3]=1
Reactant: Cc1ccccc1
Reactant: c1ccc2ncccc2c1
Product: c1ccc2ccccc2c1

Procedure:
Naphthalene was polymerized at a temperature of from 200° to 300° C. in the presence of a HF·BF3 catalyst. After the reaction, the catalyst was recovered in a gas state, and a low boiling point component was removed to obtain a pitch. The optically anisotropic phase was 2 volume % as observed under a polarization microscope, the softening point was 176° C., the quinoline-insoluble content was 1.6% by weight, and the toluene-insoluble content was 34% by weight.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.O=[C:30]([NH:41][NH:42][C:43](=[O:46])[CH2:44][CH3:45])[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>ClCCl>[CH2:44]([C:43]1[O:46][C:30]([CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[N:41][N:42]=1)[CH3:45]
Reactant: CCC(=O)NNC(=O)CCNC(=O)OC(C)(C)C
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nnc(CCNC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
11.49 g (24.70 mmol) PS-triphenylphosphine are placed in 240 ml dichloromethane, 6.27 g (24.70 mmol) iodine are added. The mixture is stirred for 0.1 hours at ambient temperature, then 7.00 ml (50.50 mmol) triethylamine are added dropwise. 3.20 g (12.34 mmol) tert-butyl [3-oxo-3-(N′-propionyl-hydrazino)-propyl]-carbamate dissolved in 150 ml dichloromethane are added. The reaction mixture is stirred for 24 hours at ambient temperature, then the precipitate is filtered off. The filtrate is evaporated down and purified by chromatography.
Reaction SMILES: C(O)(C(F)(F)F)=O.[I:8][C:9]1[NH:13][C:12]([C@@H:14]2[CH2:19][C@@H:18]3[C@@H:16]([CH2:17]3)[N:15]2C(OC(C)(C)C)=O)=[N:11][CH:10]=1>C(Cl)Cl>[I:8][C:9]1[NH:13][C:12]([C@@H:14]2[CH2:19][C@@H:18]3[C@@H:16]([CH2:17]3)[NH:15]2)=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(I)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Ic1cnc([C@@H]2C[C@H]3C[C@H]3N2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
TFA (1 mL, 12.98 mmol) was added dropwise to a solution of (1R,3S,5R)-tert-butyl 3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (450 mg, 1.20 mmol) in DCM (5 mL) at room temperature. The mixture was stirred for 2 h at room temperature, then, the volatiles were removed and the residue was taken in MeOH (5 mL) and filtered through a Strata XC MCX cartridge. The cartridge was washed with methanol (30 mL) and the compound was release from the cartridge by eluting with a solution of 2M of ammonia/methanol (40 mL) and concentrated to give (1R,3S,5R)-3-(5-iodo-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (283 mg, 1.03 mmol, 86% yield) as white solid. LC-MS retention time 0.448 min; m/z 275.94 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.17 (s, 1H), 4.20 (dd, J=10.4, 7.3 Hz, 1H), 3.08 (td, J=6.2, 2.6 Hz, 1H), 2.38 (dd, J=12.5, 7.3 Hz, 1H), 2.19 (ddd, J=12.7, 10.5, 4.9 Hz, 1H), 1.68-1.74 (m, 1H), 0.85 (ddd, J=6.6, 4.4, 2.8 Hz, 1H), 0.61-0.67 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:27])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[O:13][CH:14]=1)C1C=CC=CC=1.OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1>>[OH:8][C:9]1[C:10](=[O:27])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[O:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)co2)cc1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1O
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(O)co2)cc1
Yield: 73 %

Procedure:
N-(5-Hydroxy-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (8-06) (14.0 g, crude) was synthesized as a light brown solid from N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (7-06) (25.0 g, 64.93 mmol) following the procedure described for N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-01).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][C:11](Cl)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].C(N(CC)CC)C>O1CCCC1>[C:17]([C:16]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:15]=1[NH:14][C:11](=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:19])=[O:18]
Reactant: O=C(Cl)C=CC=Cc1ccccc1
Reactant: Nc1ccc(F)cc1C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=CC=Cc1ccccc1)Nc1ccc(F)cc1C(=O)O

Procedure:
Prepared analogously to Example 31 from 5-phenyl-penta-2,4-dienoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine.
Reaction SMILES: CO[C:3]1[CH:7]=[CH:6][S:5][C:4]=1OC.[Cl:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:10][CH2:11][CH:12]1[O:15][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:14][CH2:13]1
Reactant: COc1ccsc1OC
Reactant: OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: ClCC1COc2cscc2O1

Procedure:
Under a nitrogen atmosphere in a 500 mL round bottom flask equipped with a reflux condenser, 20.0 g (0.139 mol) dimethoxythiophene, 17.8 g (0.161 mol) 3-chloro-1,2-propanediol, and 5 g p-toluenesulfonic acid was dissolved in 350 mL toluene. The reaction was then heated to ˜90 C overnight. At this time TLC indicated consumption of starting material. After cooling the reaction mixture was concentrated to ˜100 mL and poured into saturated potassium carbonate solution. The mixture was extracted with DCM and the combined extracts were dried with magnesium sulfate. Solvent removal gave a dark oil that was purified by column chromatography using 3:1 hexanes/DCM. Solvent removal gave the product as a white solid. Structure and purity were confirmed by 1H/13C NMR and LC-MS.
Reaction SMILES: O1CCC[CH2:2]1.[NH:6]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:7]1.[H-].[Na+].COS(OC)(=O)=O>CCCCCC.C(OCC)C>[CH3:2][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:7]1
Reactant: C1CCOC1
Reactant: c1cc(-c2cc[nH]n2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cn1ccc(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To 150 mL tetrahydrofuran was added 4-(1H-pyrazol-3-yl)pyridine (4.96 g; Example 3, Step 1) and the solution cooled in ice. To this was added slowly 1.64 g of a 60% suspension of sodium hydride in mineral oil. After gas evolution ceased, the mixture was stirred at ambient temperature for 30 min, cooled back down in ice, and 3.4 mL dimethylsulfate was added. The mixture was allowed to slowly warm to ambient temperature. After 1 hour the reaction mixture was evaporated and the dark brown residue partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate was washed with saturated aqueous sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to afford 4.6 g crude product as a pale yellow solid. The crude material was taken up in a diethyl ether and hexane mixture, filtered through celite, and allowed to crystallize. A total of 2.98 g (55% yield) pale yellow crystals were obtained. 1H NMR (CDCl3) was consistent with a single isomer of the desired structure. LC/MS showed one peak with a M+1 molecular ion of m/z 160.5 by positive ESI.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:26]2[CH:27]=[CH:28][S:24][CH:25]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccsc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2ccsc2)cc1
Yield: 37.4 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(thiophen-3-ylmethyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.080 g; 0.230 mmol), thiophen-3-ylboronic acid (0.031 g; 0.242 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.019 g; 0.023 mmol), sodium carbonate (0.050 g; 0.460 mmol), sodium iodide (0.069 g; 0.460 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 20 to 80% ethyl acetate in heptane) furnished 0.034 g (37%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH:8]([F:10])[F:9])=[N:6][CH:7]=1.[CH3:16][N:17](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1(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)C=CC=CC=1>[C:16]([C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH:8]([F:10])[F:9])=[N:6][CH:7]=1)#[N:17]
Reactant: CCOC(=O)c1cc(Br)cnc1C(F)F
Reactant: CN(C)C=O
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1cc(C#N)cnc1C(F)F
Temperature: 100 °C

Procedure:
In a flask, dissolve ethyl 5-bromo-2-(difluoromethyl)pyridine-3-carboxylate (150 g, 536 mmol, 1.0 equiv) in DMF (1.5 L). Degas the resulting mixture by evacuating then backfilling the flask with nitrogen three times. Add zinc(II) cyanide (51 g, 434 mmol, 0.81 equiv), followed by tetrakis(triphenylphosphino)palladium (25.2 g, 21.8 mmol, 0.04 equiv). Heat the resulting suspension to an internal temperature of 100° C. for 3 h. Cool the mixture to room temperature; dilute with water (2 L); and extract with diethyl ether (3×2.5 L). Wash the combined organic phases with brine (3×2.5 L). Extract the combined aqueous phases with Et2O (2.5 L). Combine all organic phases, and dry over MgSO4. Remove the solids by filtration, and concentrate the filtrate under reduced pressure. Purify the resulting material by flash chromatography on silica gel (2 kg), eluting with a gradient of 1:1 DCM/isohexane to 100% DCM. Obtain the title compound as colorless oil, which solidifies on standing (114 g, 94.1%). MS (m/z) 227 (M+1).
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:25]C)[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C1COCC1.CC(C)=O.Cl>CCCCCC.CO>[Cl:1][CH2:2][C:3](=[O:25])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: COC(=CCl)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CCl

Procedure:
21-Chloro-17α-hydroxy-20-methoxypregna-4,9(11),20-trien-3-one (IX, Example 4, 1.0 g), THF (4 ml), acetone (4.9 ml), and methanol (1.4 ml) are mixed. Aqueous hydrochloric acid (6 N, 0.44 ml) is added and the resulting slurry heated at 40° for 1.5 hours. The mixture is cooled to 20°-25° and diluted with hexane (3 ml). The solids are isolated by filtration and washed with hexane/ethyl acetate (85/15, 13 ml) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:12]([CH3:13])=[C:11]([NH:14][CH3:15])[C:5]([C:6](OCC)=[O:7])=[CH:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[C:11]([NH:14][CH3:15])[C:12]=1[CH3:13]
Reactant: CCOC(=O)c1cnc(Cl)c(C)c1NC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1c(CO)cnc(Cl)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
To a solution of ethyl 6-chloro-5-methyl-4-(methylamino)nicotinate (2.0 g, 8.8 mmol) in tetrahydrofuran (60 mL) was added lithium aluminium hydride at 0° C., and the mixture was stirred at RT for 1.5 h. LCMS monitored the reaction was completed. The reaction was quenched by sodium sulfate decahydrate (1.5 g) and filtrated. The filtrate was concentrated to get the title compound (1.4 g, crude) as a white solid. MS (ES+) C8H11ClN2O requires: 186, 188. Found: 187, 189 [M+H]+.