Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:6]1)(=[O:3])[CH3:2].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.C(Cl)(Cl)Cl.[Cl-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:14]2[CH:17]=[CH:21][CH:20]=[CH:19]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CC(=O)OC1Cc2cccc(N)c2C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1Cc2cccc(-n3cccc3)c2C1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A stirred solution of 0.70 g (0.004 mole) of 4-amino-2-indanyl acetate and 0.56 g (0.004 mole) of 2,5-dimethoxytetrahydrofuran in 1.5 mL of acetic acid was heated under reflux for 3 hours. The reaction mixture was cooled to ambient temperature and poured into 30 mL of chloroform. The mixture was stirred with 30 mL of an aqueous saturated solution of sodium chloride. The organic layer was removed, and the aqueous layer extracted with two portions of 30 mL each of chloroform. The combined organic phases were washed with two portions of 30 mL each of an aqueous saturated solution of sodium chloride. The organic layer was dried over potassium carbonate, filtered, and the filtrate concentrated under reduced pressure to give 0.89 g of 4-(1-pyrrolyl)-2-indanyl acetate.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([F:13])[C:10]2[C:9](=[O:14])[NH:8][C@@H:7]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2].[ClH:25]>C(OCC)C>[ClH:25].[CH2:1]([C:3]1[CH:12]=[C:11]([F:13])[C:10]2[C:9](=[O:14])[NH:8][C@@H:7]3[CH2:15][NH:16][CH2:17][C@H:6]3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(F)c2c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1NC2=O
Agent: Cl
Solvent: CCOCC
Product: CCc1cc(F)c2c(c1)[C@@H]1CNC[C@H]1NC2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To a solution of (3aS,9bR)-tert-butyl 8-ethyl-6-fluoro-5-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the second eluting peak from Example 47, Part D, (60 mg, 0.18 mmol) in 2 mL of diethyl ether was added 1 mL of 12 N HCl. The resulting mixture was stirred vigorously for 5 min at ambient temperature and then was concentrated and dried in vacuo. The resulting white solid was triturated twice with diethyl ether and dried in vacuo to afford 35 mg (71%) of the title compound of Example 48 as a white solid. 1H NMR (DMSO-D6): δ 10.12 (broad s, 1H), 10.00 (broad s, 1H), 8.64 (s, 1H), 7.09 (d, 1H), 6.96 (s, 1H), 3.88-3.82 (m, 1H), 3.61-3.55 (m, 1H), 3.48-3.43 (m, 1H), 3.26-3.20 (m, 1H), 3.18-3.12 (m, 1H), 3.09-3.02 (m, 1H), 2.63 (q, 2H, J=7.7 Hz), 1.18 (t, 3H, J=7.7 Hz). LRMS (ESI): 235.2 (M+H)+.
Reaction SMILES: C1(=O)OC(=O)C2=CC=CC=C12.CC(C(O)=O)C(O)=O.O=[C:21]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])[CH2:22]C.OCC1C=CC=CC=1C(O)CC.OCC1C=CC=CC=1C(O)C.[BrH:56]>ClCCl>[OH:27][CH2:26][C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[CH:21]([Br:56])[CH3:22]
Reactant: Br
Reactant: CCC(=O)c1ccccc1C(=O)O
Agent: CC(C(=O)O)C(=O)O
Agent: CC(O)c1ccccc1CO
Agent: CCC(O)c1ccccc1CO
Solvent: ClCCl
Product: CC(Br)c1ccccc1CO
Reaction time: 2 h

Procedure:
Similarly prepared from phthalic anhydride and methylmalonic acid were 2-(1'-oxopropyl)benzoic acid and thence 1-hydroxymethyl-2-(1'-hydroxypropyl)benzene (both as oils). (b) (i) 1-Hydroxymethyl-2-(1'-hydroxyethyl)benzene (10 g) was dissolved in dichloromethane (200 ml) and was saturated with hydrogen bromide gas. The solution was stirred for 2 hr. and volatile materials were evaporated to give 1-hydroxymethyl-2-(1'-bromoethyl)-benzene as an oil. Thionyl chloride (30 ml) was added to the oil and the solution was stirred for 1 hr; evaporation of thionyl chloride gave 1-chloromethyl-2-(1'-bromoethyl)benzene which was used immediately. (ii) Similarly prepared from 1-hydroxymethyl-2-(1'-hydroxypropyl)benzene were 1-hydroxymethyl-2-(1'-bromopropyl)benzene and thence 1-chloromethyl-2-(1'-bromopropyl)benzene (both as oils).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14](Br)[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1>CN(C=O)C.[Cu]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14]([O:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[N:15]=1
Reactant: Nc1ncc(Br)nc1-c1nc2ccccc2[nH]1
Reactant: Oc1cccnc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncc(Oc2cccnc2)nc1-c1nc2ccccc2[nH]1
Yield: 11.4 %

Procedure:
3-(1H-Benzimidazol-2-yl)-5-bromo-pyrazin-2-amine (100 mg, 0.3447 mmol), dicesium carbonate (366 mg, 1.034 mmol), copper (2.2 mg, 0.034447 mmol) and pyridin-3-ol (327.8 mg, 3.447 mmol) in DMF (2 mL) were heated at 130° C. under microwave conditions for 1 hour. The reaction mixture was filtered through a pad of silica eluting with 90 to 100% EtOAc/Petroleum Ether and the relevant fractions concentrated in vacuo. The resiude was redissolved in EtOAc and washed with saturated aqueous NaHCO3 (×2) and brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (12 mg, 11% Yield). 1H NMR (400.0 MHz, CDCl3) δ 7.33-7.38 (2H, m), 7.77-7.8 (2H, m), 7.82-7.88 (1H, m), 8.05-8.1 (1H, m), 8.15 (1H, s), 8.8-8.55 (1H, m) and 10.2 (1H, s) ppm; MS (ES+) 305.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[C:3]=1[O:11][CH3:12]
Reactant: Oc1c(Br)ccc2ccsc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1c(Br)ccc2ccsc12
Temperature: 50 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
The product from Step G (1.08 g, 4.7 mmol) was dissolved in acetone (10 mL) and potassium carbonate (1.30 g, 9.4 mmol) and dimethyl sulfate (0.9 mL, 9.4 mmol) were added and the mixture was stirred at 50° C. for 24 hours. The mixture was cooled to room temperature and filtered over sodium sulfate. The reaction mixture was then concentrated to an oil and redissolved in methanol (10 mL), and sodium hydroxide (1.5 g) was added to decompose excess dimethyl sulfate. The mixture was stirred for 1 hour. Methanol was removed and the residue was dissolved in water (5 mL) and extracted (2×30 mL) with diethyl ether. The combined organic extract was dried over sodium sulfate, filtered and concentrated to an oil. The oil was purified on column chromatography (silica gel, 0-100% ethyl acetate/hexanes as an eluent) to give 6-bromo-7-methoxy-benzothiophene (0.96 g, 84%): 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J=8.4 Hz, 1H), 7.44-7.41 (m, 2H), 7.32 (d, J=5.4 Hz, 1H), 4.05 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN1CCCC1=O.C(OCC)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([S:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:12][CH:13]=1
Reactant: COC(=O)CS
Reactant: Fc1ccc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COC(=O)CSc1ccc(Br)cn1
Temperature: 90 °C
Yield: 39 %

Procedure:
Potassium tert-butoxide (740.0 mg, 6.60 mmol) was added portionwise at room temperature to a solution of 5-bromo-2-fluoropyridine A-5 (0.31 mL, 3.00 mmol) and methyl 2-mercaptoacetate (0.55 mL, 6.00 mmol) in anhydrous 1-methylpyrrolidin-2-one (12.0 mL) under an argon atmosphere, in a 20 mL microwave reactor vial. The reaction mixture was sealed and heated at 90° C. for 3 mins under microwave irradiation, then successively cooled to room temperature, diluted with diethyl ether (150 mL), quenched with water (80 mL) and decanted. The aqueous layer was extracted with diethyl ether (2×150 mL); the combined extracts were sequentially washed with water (2×150 mL), brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2-(5-bromopyridin-2-ylthio)acetate A-13 (300.0 mg, Yield=39%). MS (ESI), [M+1]+ 262, 264.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](C)=[CH:4][N:3]=1.Cl.[C:10]([Cl:14])(Cl)([Cl:12])[Cl:11]>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:10]([Cl:14])([Cl:12])[Cl:11])=[CH:4][N:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1cnc(Cl)nc1
Agent: Cl
Solvent: CCOCC
Product: Clc1ncc(C(Cl)(Cl)Cl)cn1

Procedure:
2-Chloro-5-methylpyrimidine (5.0 g) was finely powdered and dissolved in dry carbon tetrachloride (250 ml). The solution was treated with dry hydrogen chloride gas to precipitate the hydrochloride salt. The reaction mixture was heated to reflux and illuminated with an internal ultra-violet lamp whilst chlorine was bubbled through the stirred suspension. After 41/2 hours the solution was cooled and filtered and the filtrate concentrated under reduced pressure to give a semi-crystalline residue. The residue was dissolved in ether and filtered and the filtrate concentrated to a colourless oil which on standing gave crystals of 2-chloro-5-trichloromethylpyrimidine (8.9 g).
Reaction SMILES: [CH2:1]([CH2:11][C:12](=[CH:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH3:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][C:41](O)=[O:42].CCCCCC>C(CC(C)(C)C)(C)C>[C:41]([O:21][CH2:20]/[CH:19]=[C:17](/[CH2:16][CH2:15]/[CH:14]=[C:12](\[CH3:13])/[CH2:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4])\[CH3:18])(=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=[CH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: CC(C)=CCC/C(C)=C/CCC(C)=CCC/C(C)=C/CO
Solvent: CC(C)CC(C)(C)C
Solvent: CCCCCC
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)OC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 24 h

Procedure:
There were dissolved, in 1 g of isooctane, 100 mg of geranyl geraniol and 600 mg of ethyl ester of eicosapentaenoic acid, followed by the addition of lipase in an amount of 1% relative to the total amount of the resulting solution and then stirring the mixture at 60° C. for 24 hours. After confirming whether the reaction system reached its equilibrium state or not by the GC technique, the reaction solution was diluted by the addition of hexane to the solution in an amount of 10 times the volume thereof, followed by the removal of the lipase from the reaction solution through filtration and then the removal of the hexane through distillation to thus give a crude reaction product. The crude product was purified by silica gel column chromatography to give 102 mg of geranyl-geranyl eicosapentaenoate.
Reaction SMILES: [CH3:1][CH:2]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3][NH:4][C@H:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([N:14]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH2:10]1)=[O:7].[CH3:42]I>>[CH3:1][CH:2]([N:34]([CH3:42])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3][NH:4][C@H:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([N:14]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:15](=[O:19])[CH:16]([CH3:17])[CH3:18])[CH2:10]1)=[O:7]
Reactant: CI
Reactant: CC(CN[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC[C@H](N(C(=O)C(C)C)C2CCCCC2)C1)NC(=O)OC(C)(C)C
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NCC(C)N(C)C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared following the procedure described in Step A of Example 128 using (2R)-2-{methyl[2-(BOC)aminoethyl]}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in the above Step A and methyliodide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[Cl:27])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:29]1([CH2:38][C:39](O)=[O:40])[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[Cl:27])=[N:16][N:17]=1)(=[O:11])=[O:12])[C:39](=[O:40])[CH2:38][N:29]1[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]1=[O:31])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2Cl)s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc([N+](=O)[O-])cc2Cl)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(2-chloro-4-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with (thymin-1-yl)-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 11.28 (s, 0.6H), 11.25 (s, 0.4H), 9.16 (brs, 1H), 8.62–8.57 (m, 1H), 8.54–8.48 (m, 1H), 8.42–8.36 (m, 1H), 7.33 (s, 0.6H), 7.24 (s, 0.4H), 4.66 (s, 1.2H), 4.47 (s, 0.8H), 4.33 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (q, 1.2H), 4.06 (s, 1.2H), 3.57 (t, 1.2H), 3.45–3.40 (m, 2H), 3.28 (t, 0.8H), 1.75 (s, 1.8H), 1.74 (s, 1.2H), 1.24 (t, 1.2H), 1.18 (t, 1.8H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][O:18][CH3:19].Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[N:17]([O:18][CH3:19])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: Cl
Product: CON(C)C(=O)C1CCCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from (RS)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (14.8 g) and N,O-dimethylhydroxylamine.HCl (7.37 g) according to a procedure similar to that for Example 4.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]4([CH2:25][CH2:24]4)[C:16]3=[O:26])[CH2:8][CH2:7]2)[N:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][N:3]1[CH2:33][C:34]1[CH:46]=[CH:45][CH:44]=[CH:43][C:35]=1[C:36]([O:38]C(C)(C)C)=[O:37].C([SiH](CC)CC)C>C(O)=O>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]4([CH2:25][CH2:24]4)[C:16]3=[O:26])[CH2:8][CH2:7]2)[N:5]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:4][N:3]1[CH2:33][C:34]1[CH:46]=[CH:45][CH:44]=[CH:43][C:35]=1[C:36]([OH:38])=[O:37]
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCN3C(=O)C4(CC4)c4ccccc43)CC2)C1=O
Agent: CC[SiH](CC)CC
Solvent: O=CO
Product: O=C(O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCN3C(=O)C4(CC4)c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To tert-butyl 2-((4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.18 g, 0.29 mmol) was added concentrated formic acid (3 mL) and triethylsilane (0.05 mL). After stirring at room temperature for 18 hours, the reaction mixture was concentrated, taken in 4M HCl in dioxane and lyophilized to obtain the title compound as a hydrochloride salt (0.165 g, 95%); 1H NMR (DMSO-d6): δ 1.52-1.63 (m, 4H), 1.98 (d, 2H, J=14.8 Hz), 2.08-2.10 (m, 2H), 2.92 (t, 2H, J=7.6 Hz), 3.21 (br, 2H), 3.45-3.71 (m, 4H), 3.84 (t, 2H, J=6.8 Hz), 4.68 (s, 2H), 4.92 (s, 2H), 6.80 (t, 1H, J=7.6 Hz), 6.98-7.05 (m, 4H), 7.20-7.32 (m, 5H), 7.42 (t, 1H, J=7.6 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.92 (dd, 1H, J=8 and 1.6 Hz), 10.32 (br, 1H), 13.19 (s, 1H); MS for C34H36N4O4 m/z 565.14 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]([S:29][CH3:30])[C:17]([NH:19][C:20]([CH3:28])([CH2:23][O:24][CH2:25][C:26]#[CH:27])[CH2:21][OH:22])=[O:18])=[CH:10][CH:9]=2)#[CH:4].[CH2:31]1[CH2:35]OC[CH2:32]1.C(Br)C#C>C(OCC)(=O)C.O>[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]([S:29][CH3:30])[C:17]([NH:19][C:20]([CH3:28])([CH2:21][O:22][CH2:35][C:31]#[CH:32])[CH2:23][O:24][CH2:25][C:26]#[CH:27])=[O:18])=[CH:10][CH:9]=2)#[CH:4]
Reactant: C#CCOCC(C)(CO)NC(=O)C(Oc1ccc2ncc(C#C)cc2c1)SC
Reactant: C1CCOC1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCOCC(C)(COCC#C)NC(=O)C(Oc1ccc2ncc(C#C)cc2c1)SC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (55% in dispersion in oil) (0.097 g) was added portionwise to a solution of 2-(3-ethynyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methyl-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl-acetamide (0.4 g) from Example 12b, Stage 3 described above in dry THF (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. Propargyl bromide (0.166 ml) was added dropwise at 0° C. and the resulting mixture was stirred at room temperature for 23 hrs. The reaction mixture was diluted with ethyl acetate and water was added dropwise. The two phases were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed once with brine dried over sodium sulphate, filtered and evaporated to give a dark orange oil which was purified by column chromatography (hexane/ethyl acetate 4:2, 1:1) to yield 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-methyl-2-prop-2-ynyloxy-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl-acetamide as a white solid (m.p.: 95-100° C.). 1H NMR (CDCl3) δ ppm: 8.84 (1H, d); 8.22 (1H, d); 8.04 (1H, d); 7.49 (1H, dd); 7.21 (1H, d); 6.98 (1H, s br); 5.61 (1H, s); 4.19-4.16 (4H, m); 3.82-3.61 (2H, dd); 3.73 (2H, s); 3.29 (1H, s); 2.47-2.43 (2H, m); 2.21 (3H, s); 1.46 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.[S:10]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])(=[O:12])[NH2:11].O1CCOCC1.O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.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]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:17]2[CH:18]=[CH:19][C:14]([S:10]([NH2:11])(=[O:13])=[O:12])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Fc1ccc(Br)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(-c2cc(Br)ccc2F)cc1
Temperature: 120 °C
Yield: 55 %

Procedure:
To 4-bromo-1-fluoro-2-iodobenzene (361 mg, 1.2 mmol) and 4-sulfamoyl-phenylboronic acid (240 mg, 1.20 mmol) in 4:1 dioxane/H2O (5 mL) was added Na2CO3 (382 mg, 3.60 mmol) and [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (34.3 mg, 0.042 mmol). The reaction was heated under microwave irradiation at 120° C. for 15 minutes, cooled and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers dried over Na2SO4. The solvent was removed in vacuo and the resulting residue purified via silica gel column chromatography eluting with EtOAc:heptanes 0:1 to 1:1 to afford the desired product 55%, 218 mg, 55%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.O.C1C=CC([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)=CC=1>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1noc(-c2ccc(Br)c(C)c2)n1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)n1
Yield: 79.7 %

Procedure:
A stirred solution of 5-(4-bromo-3-methylphenyl)-3-methyl-1,2,4-oxadiazole (EP 0533268 A1) (0.65 g, 0.0026 mole) in a mixture of DME (30 ml) and water (30 ml) under argon was treated with 4-boronobenzoic acid (0.43 g, 0.0026 mole), sodium carbonate (1.16 g, 0.011 mole) and tetrakis(triphenylphosphine)palladium(0) (40 mg), then heated under reflux for 4 hours. The mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to leave the title compound as a white solid (0.61 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[N:9]1[C:10](=[O:18])[CH2:11][CH:12]=[CH:13]2.[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[N:9]1[C:10](=[O:18])[CH2:11][CH2:12][CH2:13]2
Reactant: [H][H]
Reactant: O=C1CC=C[C@@H]2CCC[C@H](c3ccccc3F)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@@H]2CCC[C@H](c3ccccc3F)N12
Yield: 83.3 %

Procedure:
Platinum oxide (16 mg) was added to a solution of (6R*,9aS*)-6-(2-fluorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (368 mg) in methanol (8 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for two hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 309 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[N:5].CCN(CC)CC.[CH3:13][C:14]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])[CH3:15]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:17]([O:1][CH2:2][CH2:3][C:4]#[N:5])([C:14]([CH3:16])([CH3:15])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#CCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCCC#N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol) and DMAP (1.22 g, 0.01 mmol) in dry DCM (30 mL) at room temperature was added NEt3 (30.3 g, 0.3 mol), followed by TBDPSCl (27.5 g, 0.1 mol). A lot of white solid appeared. After stirring at room temperature overnight, the reaction mixture was quenched with sat. NH4Cl solution, extracted with DCM, dried over Na2SO4, and evaporated in vacuo. Flash chomatography (SiO2, hexane/EtOAc=100:2 to 100:5 to 100:10) of the crude material gave the title compound as a white solid.