Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.BrC1C=C([CH:30]=[C:31]([F:33])C=1)C#N>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[C:31]([F:33])[CH:30]=[C:21]([C:20]#[N:19])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(C#N)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 3-Bromo-5-fluorobenzonitrile instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow solid, MS (ISP): m/e=367.9 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:45][C:46](=[O:50])[CH2:47][NH:48][CH3:49])C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([N:48]([CH3:49])[CH2:47][C:46]([OH:45])=[O:50])=[O:36])=[CH:38][CH:39]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Reactant: CCOC(=O)CNC
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N(C)CC(=O)O)cc2)cc1

Procedure:
The product from Example 233 and N-methylglycine ethyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.13-13.26 (br.s, 1 H), 8.94 (s, 1 H), 7.23 (m, 7 H), 6.99 (m, 7 H), 6.82 (d, J=8.7 Hz, 2 H), 4.12 (s, 1 H), 4.04 (s, 2 H), 3.96 (m, 5 H), 3.01 (s, 3 H), 3.01 (s, 2 H), 2.82 (s, 1 H), 2.50 (m, 1 H), 2.37 (m, 4 H), 1.92 (m, 2 H); MS (ESI+) m/z 646 (M+H)+.
Reaction SMILES: C(N)C1C=CC=CC=1.C([O:12][CH:13]1[S:30][CH2:29][C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C>CCOCC>[C:16]([O:15][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[CH2:29][S:30][C@@H:13]1[OH:12])(=[O:18])[CH3:17]
Reactant: CC(=O)OC1SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCOCC
Solvent: NCc1ccccc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](O)SC[C@H]1OC(C)=O
Reaction time: 7 h
Yield: 47.3 %

Procedure:
22 ml (0.2 mol) of benzylamine are added under an inert atmosphere to a solution of 15 g (44.8.10-3 mol) of 1,2,3,4-tetra-O-acetyl-5-thio-D-xylopyranose in 450 ml of ether. After 7 hours at room temperature (15°-25° C.), the reaction mixture is concentrated under reduced pressure and the residue is dissolved in methylene chloride and washed with a 1N solution of hydrochloric acid, a saturated solution of ammonium chloride and then water. The solution obtained is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. 6.2 g (yield: 47%) of the expected product are obtained after purification by chromatography on silica gel using a hexane/ethyl acetate mixture (3/2 v/v) as the eluent, and crystallization from an ethyl acetate/hexane mixture, said product having the following physical characteristics:
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[N:21]1[CH:22]=[N:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][C:25]=12>CS(C)=O>[CH:17]1([C:3]2[C:2]([N:27]3[CH2:28][CH2:29][N:24]4[N:23]=[CH:22][N:21]=[C:25]4[CH2:26]3)=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: c1nc2n(n1)CCNC2
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Solvent: CS(C)=O
Product: c1ccc(-c2nnc3cc(C4CCC4)c(N4CCn5ncnc5C4)nn23)cc1
Temperature: 150 °C
Yield: 26.3 %

Procedure:
A mixture of 6-chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (150 mg, 0.53 mmol) and 5,6,7,8-tetrahydro-1,2,4-triazolo[1,5-α]pyrazine (190 mg, 1.53 mmol) in dimethyl sulphoxide (1 ml) was stirred and heated at 150° C. for 20 hours. The mixture was partitioned between dichloromethane and water. The aqueous phase was further extracted with dichloromethane (x2). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 3→4% methanol-dichloromethane to give the title compound (52 mg, 26%) as an off-white solid (after trituration with diethyl ether). 1H NMR (360 MHz, CDCl3) δ 2.00-2.28 (4H, m), 2.48-2.55 (2H, m), 3.68-3.80 (3H, m), 4.43 (2H, t, J=5.5 Hz), 4.67 (2H, s), 7.46-7.56 (3H, m), 7.97 (1H, s), 8.09 (1H, s),8.37 (2H, br d, J=8 Hz); MS (ES+) m/e 373 [MH]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH:7]=1.CCN(CC)CC.C[CH2:41][O:42][C:43](C)=[O:44]>CO.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].C(Cl)Cl>[CH3:41][O:42][C:43](=[O:44])[C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:17]=2)[CH3:31])[CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(Cl)cc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
To a solution of N-[4-(5-chloro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (160 mg, 338 μmol, example 82) in MeOH (1.2 mL) and EtOAc (1.2 mL) was added PdCl2(dppf)-CH2Cl2 complex (31.8 mg, 38.9 μmol, CAS RN 851232-71-8) and NEt3 (51.4 mg, 70.7 μL, 508 μmol). The reaction mixture was stirred at 150° C. at 70 bar under CO atmosphere for 24 hours. The reaction mixture was treated with silica gel and directly purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow oil (39 mg, 23%). MS (ESI): m/z=497.129 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[CH2:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18](=[O:25])[C:19]([CH3:24])([CH3:23])[CH2:20][CH2:21][Cl:22])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(CCCl)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Temperature: 40 °C
Yield: 82.6 %

Procedure:
92.5 g (0.72 mol) of 4-chlorophenol and 99.4 g (0.72 mol) of potassium carbonate in 500 ml of toluene are heated under reflux for 2 hours, the water of reaction distilling off azeotropically. The mixture is cooled to 40° C., and 110 g (0.6 mol) of 1,5-dichloro-3,3-dimethyl-pentan-2-one in 300 ml of toluene are added. The reaction mixture is heated at 100° C. for 5 hours, and is then cooled and filtered off under suction from the inorganic residue. The filtrate is washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and evaporated down. 136.3 g (82.6% of theory) of crude 1-(4-chlorophenoxy)-5-chloro-3,3-dimethyl-pentan-2-one are obtained, and this product is directly reacted further. ##STR32##
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:26][C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:17]=[CH:16][C:11]3[O:12][CH2:13][CH2:14][O:15][C:10]=3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:26][C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:17]=[CH:16][C:11]3[O:12][CH2:13][CH2:14][O:15][C:10]=3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C(=C(c1ccc2c(c1)OCCO2)c1cc2cccnc2[nH]1)C1CCCC1
Agent: [Pd]
Solvent: CO
Product: c1cnc2[nH]c(C(CC3CCCC3)c3ccc4c(c3)OCCO4)cc2c1
Temperature: 50 °C
Yield: 57.4 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (70 mg, 0.2 mmol) and 10% palladium on activated carbon (21 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. The mixture was cooled to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-cyclopentyl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (40 mg, 57%): LC/MS m/e calcd for C22H24N2O2 [M+H]+ 349.45, observed 349.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (m, 2H), 1.47 (m, 2H), 1.61 (m, 2H), 1.77 (m, 3H), 2.08 (m, 1H), 2.16 (m, 1H), 4.07 (m, 1H), 4.22 (s, 4H, 2×OCH2), 6.33 (s, 1H), 6.79 (m, 3H), 7.05 (dd, J=4.6, 7.8 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 8.15 (d, J=4.6 Hz, 1H), 10.66 (br, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])C.CO.C1COCC1.[OH-].[Na+]>O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([CH3:11])=[N:8]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C)cc2C(=O)O)cc1

Procedure:
To a solution of 2-(4-Methoxy-phenyl)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (400 mg) in a 1:1:1 mixture of MeOH:THF:water was added 10% NaOH (20 mL). The mixture was heated to reflux and the reaction monitored by TLC and HPLC until hydrolysis was complete. The solution was cooled and concentrated under reduced pressure. The residue was acidified with 10% HCl and extracted with EtOAc. The organic fractions were combined and dried over MgSO4 and concentrated under reduced pressure. The resulting solid was used without further purification (Yield 242 mg). LC-MS (C12H12N2O3 calculated 232) m/z 231 (M−H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][CH3:13].O>C1COCC1>[CH3:11][N:12]([CH3:13])[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of benzenesulfonylchloride (10 ml; 78 mmol) in THF (100 ml) was added a 40% solution of dimethylamine in H2O (20 ml; 160 mmol) such that the reaction temperature was kept below 50° C. The reaction mixture was stirred 1 h at rt. The reaction mixture was added H2O and THF removed by evaporation. The precipitate formed was isolated by filtration and air dried to give 14 g (97%) of N,N-dimethylbenzenesulfonamide.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH:9]=[N:10][OH:11])[CH2:2]1.[Cl:12]N1C(=O)CCC1=O>>[OH:11][N:10]=[C:9]([Cl:12])[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:3]21[CH2:2][CH2:1]2
Reactant: ON=CC1CCCCC12CC2
Reactant: O=C1CCC(=O)N1Cl
Product: ON=C(Cl)C1CCCCC12CC2

Procedure:
N-hydroxyspiro[2.5]octane-4-carbimidoyl chloride (I-11J) was prepared by reaction of spiro[2.5]octane-4-carbaldehyde oxime and N-chloro-succinimide following the same protocol as described for I-6B. MS m/z 188.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[NH2:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+].C(C1CCCCC1=O)(=O)C>CN(C=O)C.O.[Cu]I>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:3][C:4]=1[F:11])(=[O:7])[NH2:8]
Reactant: CC(C)(N)C(=O)O
Reactant: NC(=O)c1ccc(Br)cc1F
Agent: [Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(Nc1ccc(C(N)=O)c(F)c1)C(=O)O
Temperature: 97.5 °C

Procedure:
4-Bromo-2-fluorobenzamide (0.5 g, 2.29 mmol), 2 aminoisobutyric acid (0.354 g, 3.54 mmol), CuI (87 mg, 0.458 mmol), and K2CO3 (0.790 g, 5.72 mmol) were mixed in DMF (5 mL). H2O (0.5 mL) and TEA (11 mg, 0.1 mmol) were added followed by 2-acetyl cyclohexanone (60 mg, 0.428 mmol). The reaction mixture was heated to 95-100° C. for 48 h. The reaction mixture was diluted with H2O (20 mL) and the aqueous layer was washed with ethyl acetate (20 mL). The aqueous layer was acidified with 1M citric acid to pH 4 and the product was extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the product. 1H NMR (DMSO, Freebase): δ (ppm) 7.55-7.45 (t, 1H), 7.20 (bs, 1H), 7.05 (bs, 1H), 6.80 (bs, 1H), 6.35-6.30 (d, 1H), 6.18-6.10 (d, 1H), 1.42 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.O1CCCC1>[C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][OH:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cccc(-c2ccccc2)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 5.47 g (30 mmol) of 3-phenylbenzaldehyde in 50 ml of dry methanol and 50 ml of dry tetrahydrofuran was added 1.34 g (32 mmol) of sodium borohydride portionwise with ice-cooling, and further the mixture was stirred for 1 hour with ice-cooling. The reaction mixture was added to 400 ml of an about 5% aqueous solution of ammonium chloride, and the mixture was extracted with tert-butyl methyl ether. The organic layer was dried and concentrated to obtain 5.57 g (30 mmol) of 3-phenylbenzylalcohol.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([I:9])=[CH:7][C:6]([C:10](=[O:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[F:17].[BH4-].[Na+]>>[NH2:2][C:3]1[C:8]([I:9])=[CH:7][C:6]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:14])[CH3:15])=[CH:5][C:4]=1[F:17]
Reactant: CC(C)NCC(=O)c1cc(F)c(N)c(I)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)NCC(O)c1cc(F)c(N)c(I)c1

Procedure:
m.p. of the hydrochloride: 203°-205° C. (decomp.), was prepared from 4'-amino-3'-fluoro-2-isopropylamino-5'-iodo-acetophenone and sodium borohydride analogous to Example 49.
Reaction SMILES: C(=O)=O.[CH:4](O)([CH3:6])[CH3:5].[Li].[Li].C(OCC)C.BrC=CC.[CH3:19][C:20]1[CH:25]=[CH:24][CH2:23][C:22]([CH3:27])([CH3:26])[C:21]=1[CH:28]=[O:29].[Cl-].[NH4+]>C(OCC)C>[CH3:19][C:20]1[CH:25]=[CH:24][CH2:23][C:22]([CH3:26])([CH3:27])[C:21]=1[CH:28]([CH:5]=[CH:4][CH3:6])[OH:29]
Reactant: CC(C)O
Reactant: CC1=C(C=O)C(C)(C)CC=C1
Agent: CC=CBr
Agent: O=C=O
Agent: [Cl-]
Solvent: CCOCC
Product: CC=CC(O)C1=C(C)C=CCC1(C)C
Temperature: -10 °C

Procedure:
Into a 500 ml reaction flask equipped with immersion thermometer, mechanical stirrer, 250 ml addition funnel, Freidrich's condenser, dry-ice/isopropyl alcohol bath and gas bubbler is placed 1.9 grams (0.28 gram atoms) of lithium wire cut up (44.7 cm in length), and 100 ml anhydrous diethyl ether. The lithium/diethyl ether mixture is cooled with stirred to -10° C. 15.7 Grams (0.13 moles) of 1-bromo-1-propene dissolved in 40 ml diethyl ether is then added dropwise from the addition funnel while maintaining the reaction temperature at from -10° up to -5° C. Following addition of the 1-bromo-1-propene, the reaction mass is stirred for 30 minutes at 0° C. and for a period of 1.5 hours at 20° C. The reaction mass is then chilled to -20° C. and 15.0 grams of Safranal (0.10 moles) is approximately 60 ml diethyl ether is added to the reaction mass dropwise while maintaining the temperature between -20° and -15° C. Following additional of the safranal, the reaction mass is stirred at about -20° C. for a period of 15 minutes and at room temperature (20° C.) for a period of 2.5 hours. The reaction mass is monitored using GLC at 30 minutes, 90 minutes and 150 minutes, at which point, the reaction mass is poured into saturated aqueous ammonium chloride. The resulting mixture is then washed with diethyl ether and the aqueous phase is separated from the organic phase. The organic phase is dried and concentrated to 18.67 grams of oil. 1.0 Grams of crude is set aside for silica gel chromatography; 0.1 grams is set aside for GLC; and the remaining 17.56 grams is distilled in a vacuum distillation apparatus after adding 0.9 grams of sodium carbonate and 19.0 grams of Primol® yielding the following fractions:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([SH:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH:28]([CH2:33][CH:34]3[O:36][CH2:35]3)[C:29]([O:31]C)=[O:30])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][CH:28]([CH2:33][CH:34]([OH:36])[CH2:35][S:9][C:4]3[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[N:3]=3)[C:29]([OH:31])=[O:30])(=[O:25])=[O:26])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: Cc1cc(C)nc(S)n1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc(C)cc(C)n3)C(=O)O)cc2)cc1

Procedure:
Example 46 is prepared from 4,6-dimethyl-2-mercaptopyrimidine and 1d using the procedure described for compound 20.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)=[O:5])[CH3:2].[H-].[Na+].Cl.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][Cl:29])[CH3:25]>CN(C)C=O>[ClH:29].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2ccccc12
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2ccccc2c(-c2ccccc2)n1CCN(CC)CC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of 26.5 g. of 3-phenylisoindole-1-carboxylic acid ethyl ester in 600 ml. of dimethylformamide is treated under nitrogen at -10° C. with 0.40 mol. of sodium hydride (17.5 g. of a 55% dispersion in mineral oil) and stirred at the same temperature for 15 minutes. Then, at -10° C. to -5° C. there are added 34.5 g. of 2-diethylaminoethyl chloride hydrochloride. The mixture is stirred for 1 hour at room temperature and subsequently heated for 3 hours at 60° C. The mixture is cooled and poured into 8 liters of ice-water. After the addition of 300 g. of sodium chloride, the oily precipitate is separated by decantation and immediately dissolved in methylene chloride. The solution, shielded from daylight, is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is dissolved in 200 ml. of ether, treated with 280 ml. of 0.5 -N hydrochloric acid and thoroughly shaken. After cooling in an ice-bath, the separated hydrochloride is removed by filtration under suction, washed with water and ether and then dissolved in methylene chloride. The aqueous layer is separated and the methylene chloride solution is dried over sodium sulfate and filtered. After the addition of ether, there is obtained 2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 230°-232° C. (decomposition).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(Sc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CCN1CCOCC1)S(=O)(=O)c1ccc(Sc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of 10 g (26.3 mmol) of N-[[4-(phenylthio)phenyl]sulfonyl]glycine, 1,1-dimethylethyl ester from Example 6a in 50 mL of anhydrous dimethylformamide, was added 9.80 g (52.7 mmol) of 4-(2-chloroethyl)morpholine hydrochloride, followed by 10.9 g (79.0 mmol) of powdered potassium carbonate. The mixture was heated to 50° C. with vigorous stirring and maintained there for 20 hours. A sample was removed and analyzed by HPLC and shown to contain starting material, whereupon 4.90 g (26.3 mmol) of 4-(2-chloroethyl)morpholine hydrochloride, followed by 3.63 g (26.3 mmol) of powdered potassium carbonate was added and heating continued for an additional 4 hours at 70° C. The solution was cooled, ethyl acetate and water added, the organic layer separated and washed 4 times with brine, dried with sodium sulfate, filtered and concentrated to afford crude product. This was chromatographed on silica gel using 0-5% methanol/ethyl acetate to yield 12.9 g of pure N-[[4-(phenylthio)phenyl]sulfonyl]-N-[2-(4-morpholinyl)ethyl]glycine, 1,1-dimethylethyl ester, m/e=490 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[CH:22][C:23]([F:28])=[C:24]([CH:27]=1)[C:25]#[N:26].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:28][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(-c2cccc3[nH]ccc23)ccc1F
Temperature: 83 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (4 g, 16.4 mmol), and 5-bromo-2-fluorobenzonitrile (3.28 g, 16.4 mmol) in THF (564 mL) were added Palladium catalyst Pd(PPh3)4 (0.6 g, 0.5 mmol) and the freshly prepared sodium carbonate solution (5.22 g in 23 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 83° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 2.18 g (56%) of 2-fluoro-5-(1H-indol-4-yl)-benzonitrile.