Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[NH2:23]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C.ClCCl>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:23][O:16][C:8]=3[C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: CCn1ncc2c(Cl)c(C(=O)c3cccc(C)c3)cnc21
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCn1ncc2c3noc(-c4cccc(C)c4)c3cnc21
Yield: 75.4 %

Procedure:
4-Chloro-1-ethyl-5-(3-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (2.0 g) and hydroxylamine hydrochloride (6.0 g) were suspended in 200 ml of acetic acid, and to this was added 0.5 g of p-toluenesulfonic acid monohydrate. The reaction mixture was refluxed for 2 hours and then distributed between water and dichloromethane. The organic phase was washed four times with water and once with saturated sodium bicarbonate solution. It was then evaporated and chromatographed over 230-400 mesh silica gel, eluting with 10% ethyl acetate/dichloromethane. By combining the appropriate fractions, 1.40 g of product was obtained, mp 178°-179°. This product was combined with the product of another run and recrystallized from ethyl acetate to give product of mp 180°-181° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].S(=O)(=O)(O)O.C(Cl)(Cl)Cl.[CH2:24](O)[CH3:25]>>[OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH2:24][CH3:25])=[O:9])=[O:5]
Reactant: CCO
Reactant: O=C(O)CCC(=O)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCC(=O)c1ccccc1O
Temperature: 0 °C

Procedure:
A solution of 3-(o-hydroxybenzoyl)propionic acid (18.8 g.) in ethanol (120 ml.) was treated with concentrated sulphuric acid (1 ml.) and the mixture heated at reflux temperature for 12 hours. It was cooled, poured into ice-water (350 ml.) and the oily solid isolated with chloroform. It (18.6 g.) was purified by distillation at reduced pressure and had bp 112°-113°C at 0.1 mm; nD24.5 = 1.5301.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[N+:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)([O-:10])=[O:9]
Reactant: OB(O)c1cccnc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccnc(-c2cccnc2)c1
Temperature: 80 °C
Yield: 68 %

Procedure:
A mixture of 2-chloro-4nitropyridine (0.40 g, 2.56 mmol), pyridin-3-ylboronic acid (0.408, 3.32 mmol), tetrakis(triphenylphosphinepalladium(0) (0.18 g, 0.15 minol) and sodium carbonate (0.489 g, 4.6 mmol) in acetonitrile (9 mL) and water (9 mL) was heated at 80° C. overnight. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on basic alumina to give 4-nitro-2,3′-bipyridine (350 mg, 70%) as a pale yellow solid. LCMS: (FA) ES+ 202.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:36])([CH3:35])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[C:30]([NH:29][C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[C:10]([CH3:36])([CH3:35])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1)=[O:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(=O)NC(C)(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a stirred mixture solution of 2-(4′-tert-butylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (968 mg, 2 mmol) in methanol (15.0 mL) and tetrahydrofuran (16.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by 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-(4′-tert-butylcarbamoyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (820 mg, 90%) as a white solid: LC/MS m/e calcd for C29H32N2O3 (M+H)+: 457.56, observed: 457.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:5][N:6]=1.[C:11]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([S:19](Cl)(=[O:21])=[O:20])=[CH:17][CH:16]=1)(=[O:13])[CH3:12].Cl>N1C=CC=CC=1>[C:7]([C:4]1[S:3][C:2]([NH:1][S:19]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:11](=[O:13])[CH3:12])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:6][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(C)(C)C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
2-Amino-5-tert-butyl-1,3,4-thiadiazole (1.0 g, 6.36 mmol) was suspended in pyridine (1.6 mL). N-Acetylsulfanilyl chloride (1.9 g, 5.1 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3N HCl and the mixture extracted with ethyl acetate. The organic extracts were washed with water (3×65 mL), brine (3×65 mL), dried over anhydrous Na2SO4, filtered, and volatiles evaporated. The residue was crystallized from MeOH to give the product (1.59 mg, 4.3 mmol, 84%) as a solid, mp 137-138° C.; 1H NMR (500 MHz, DMSO) δ 1.28 (9, t, J=7.0 Hz), 2.08 (3, s), 7.73 (2, d, J=8.5 Hz), 7.78 (2, d, J=8.5 Hz), 10.48 (1, s), 14.00 (1, brs); 13C NMR (125 MHz, DMSO) δ 24.1, 29.3, 36.1, 118.6, 126.8, 135.6, 142.8, 166.9, 167.2, 169.0; MS (LCQ, ESI+) Calculated for C14H19N4O3S2 355.1. found 355.1 (M+H)+. HRMS (FAB+, m/z) Calculated for C14H19N4O3S2 355.0899. found 355.0900 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7](O)[CH2:8][CH3:9].[N:11](C([C@H]1CCCO1)CC)=[N+:12]=[N-:13]>>[N:11]([CH:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)[CH2:8][CH3:9])=[N+:12]=[N-:13]
Reactant: CCC(O)c1cnccn1
Reactant: CCC(N=[N+]=[N-])[C@H]1CCCO1
Product: CCC(N=[N+]=[N-])c1cnccn1

Procedure:
The title compound is prepared from 1-(pyrazin-2-yl)propan-1-ol (prepared according to the procedure of ‘Some reactions of mono substituted pyrazine monoxides’ Journal of Heterocyclic Chemistry (1982), 19(5), 1061-7, Compound 18) analogously to (2R)-2-(1-azidopropyl)tetrahydrofuran (Intermediate DA, step 4).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH3:59])[NH:5][C:6](=[O:58])[C@@H:7]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51]C2C=CC=CC=2)=[CH:46][CH:45]=1)[NH:8][C:9](=[O:42])[C@H:10]([CH2:33][O:34][CH2:35]C1C=CC=CC=1)[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[NH3:61].CO>>[C:18]([O:17][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([NH:8][C@@H:7]([C:6]([NH:5][C@@H:4]([C:3]([NH2:61])=[O:2])[CH3:59])=[O:58])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:46][CH:45]=1)=[O:42])[CH2:33][O:34][CH2:35][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:32])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: N
Reactant: COC(=O)[C@@H](C)NC(=O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Solvent: CO
Product: C[C@@H](NC(=O)[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O

Procedure:
The methyl ester of Example 10, 300 mg., is dissolved in 100 ml. of methanol saturated with ammonia and kept for 4 days at room temperature. The crude product is chromatographed on silica gel in chloroform-methanol-water (60:30:5) to yield 0.14 g.; m.p. 180°-185° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.CN(C=O)C.C(NC(C)C)(C)C.[CH3:47][C:48]([OH:52])([C:50]#[CH:51])[CH3:49]>CCOC(C)=O.[Cu]I.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>[NH2:25][C:22]1[O:23][CH2:24][C@:20]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)[CH:18]=3)[O:13][C:10]3[C:9]2=[CH:8][C:7]([C:51]#[C:50][C:48]([CH3:49])([OH:52])[CH3:47])=[CH:12][CH:11]=3)[N:21]=1
Reactant: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)cc1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(C#CC(C)(C)O)ccc2O3)cc1

Procedure:
A vial was charged with (S)-2′-amino-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (209 mg, 0.426 mmol), copper(i) iodide (8.11 mg, 0.043 mmol), and tetrakis(triphenylphosphine)palladium (49.2 mg, 0.043 mmol). The vial was flushed with Ar (g), then DMF (1704 μL, 0.426 mmol), diisopropylamine (1194 μL, 8.52 mmol), and 2-methylbut-3-yn-2-ol (208 μL, 2.130 mmol) were added in sequence. The vial was sealed and placed in a 70° C. oil bath for 2 hours. The mixture was diluted with EtOAc (15 mL), washed with water (10 mL), washed with brine (15 mL), dried over sodium sulfate, filtered, and evaporated. The residue was taken up in DCM/MeOH (not completely soluble) and chromatographed on a 40-g Redi-Sep column, eluting with 0-8% MeOH/DCM (product came out in a streak) to give (S)-4-(2′-amino-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl)-2-methylbut-3-yn-2-ol as a light yellow solid
Reaction SMILES: C(O)(=O)CO.FC(F)(F)S([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])(=O)=O.[C:21](Cl)(=O)[C:22]([Cl:24])=[O:23]>N1C=CC=CC=1.ClCCl.CN(C=O)C>[Si:12]([O:11][CH2:21][C:22]([Cl:24])=[O:23])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C(O)CO
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(=O)Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 31.4 %

Procedure:
Glycolic acid (5.0 g, 66 mmol) in pyridine (65 ml) was purged with argon and then treated with tert-butyldimethylsilyl trifluoromethanesulfonate (42 g, 36 ml, 158 mmol) at 0° C., and the mixture was stirred for 2.5 hours. The 2-phase mixture was separated and the upper phase diluted with diethyl ether. This solution was cooled to 0° C., washed briefly with 10% hydrochloric acid, dried (MgSO4) and evaporated to the disilyl material (18 g, 97%). The disilyl material (3.48 g, 12.4 mmol) in dichloromethane (30 ml) at 0° C. was treated with DMF (6 drops) followed by oxalyl chloride (1.84 g, 1.30 ml, 14.50 mmol). After stirring for 3.5 hours, the solution was evaporated and the crude material purified by bulb-to-bulb distillation to afford the title product (60 mbar, 120° C.<T<150° C.) (0.95 g, 37%) contaminated with tert-butyldimethylsiloxane.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:15]([NH:16][C:17](=O)[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:20])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C1(C)C(C)=CC=CC=1>[C:24]([O:23][C:21]([N:19]([CH2:18][C:17]1[NH:16][C:15]2[CH:14]=[CH:13][CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]=2[N:5]=1)[CH3:20])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)c1cccc(NC(=O)CN(C)C(=O)OC(C)(C)C)c1N
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: COC(=O)c1cccc2[nH]c(CN(C)C(=O)OC(C)(C)C)nc12
Yield: 90 %

Procedure:
Acetic acid (45 ml) was added to a solution of methyl 2-amino-3-(2-(tert-butoxycarbonyl(methyl)amino)acetamido)benzoate (19.28 mmol, 1.0 eq.) in xylene (130 ml) and the reaction mixture was heated under reflux for 1 h. When the reaction was complete (checking by TLC), the solvent was evaporated to dryness, the residue was dissolved in ethyl acetate and the solution was washed with water and NaCl solution. The organic phase was concentrated to dryness in vacuo in order to obtain the desired product, which was employed in the next stage without further purification. Yield: 90%
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([OH:14])=O)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:46]1[CH2:51][CH2:50][C:49]2([C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][O:52]2)[CH2:48][CH2:47]1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]([N:46]3[CH2:51][CH2:50][C:49]4([C:59]5[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=5[CH2:53][O:52]4)[CH2:48][CH2:47]3)=[O:14])=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1C(=O)O
Reactant: c1ccc2c(c1)COC21CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c2cc(Cl)ccc2c1C(=O)N1CCC2(CC1)OCc1ccccc12
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a solution of 0.040 g (0.19 mmol) 6-chloro-2-methyl-1H-indole-3-carboxylic acid, 0.069 ml (0.40 mmol) N,N-diisopropylethylamine and 0.061 g (0.19 mmol) 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in 1 ml dry N,N-dimethylformamide were added 0.036 g (0.19 mmol) spiro[isobenzofuran-1(3H), 4′-piperidine] at room temperature. After stirring for 1 h the reaction mixture was quenched with 0.5 M aqueous sodium hydroxide solution (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with water (2×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give the title compound (0.036 g, 49%) as a white solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.[CH3:26][O-:27].[Na+].O>CO.N1C=CC=CC=1.[Cu]I>[CH3:26][O:27][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(Br)c23)CC1
Agent: [Cu]I
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: COc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 65 °C

Procedure:
A suspension of Intermediate 71 (600 mg) and copper(I) iodide (141 mg, Kanto Chemicals) in methanol (5.5 ml) and pyridine (5.5 ml) was added with sodium methoxide (28% methanol solution, 1.7 ml, Wako Pure Chemical Industries) and stirred with heating at 65° C. for 24 hours. The reaction mixture was cooled to room temperature, then added with water (30 ml) and extracted three times with ethyl acetate (20 ml for each time). The combined organic layer was washed twice with saturated brine (30 ml for each time) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to obtain the title compound (364 mg).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([SnH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH2:14]([Sn:9]([CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH3:13])/[CH:3]=[CH:2]/[CH2:1][OH:4])[CH2:15][CH2:16][CH3:17]
Reactant: C#CCO
Reactant: CCCC[SnH](CCCC)CCCC
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CCCC[Sn](/C=C/CO)(CCCC)CCCC
Temperature: 80 °C

Procedure:
To neat propargyl alcohol (1 ml) were added tributyltin hydride (5.8 ml) followed by 1,1′-azobis(cyclohexanecarbonitrile) (213 mg). The mixture was heated for 2 h at 80° C., cooled to RT and directly purified by CC (EA/Hept 4/96 to 5/95) to afford 2.98 g of the desired compound.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([CH2:32][CH2:33][OH:34])[CH:27]=[CH:26]4)=[N:19][CH:20]=2)=[CH:11][CH:10]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1.N1C=CC=CC=1>[CH3:35][S:36]([O:34][CH2:33][CH2:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([C:22]#[C:21][C:18]3[CH:17]=[CH:16][C:15]([C:12]4[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)=[CH:20][N:19]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1)(=[O:38])=[O:37]
Reactant: OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCn1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere 7.1 mL (51.5 mmol) triethylamine are added to a solution of 16.0 g (42.9 mmol) 2-{5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-indol-1-yl}-ethanol in 480 mL THF and 30 mL pyridine and this is cooled to 0° C. Then a solution of 4 mL (51.5 mmol) methanesulphonic acid chloride in 20 mL THF is slowly added dropwise, the mixture is allowed to warm up to RT and stirred for a further 2 h at RT. The reaction solution is filtered and evaporated down i.vac. The residue is combined with 1 L DCM, washed with 400 mL water and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is suspended with 600 mL PE/DCM (5:1), suction filtered and finally dried in the air until a constant weight is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:29][CH3:30].C1(=O)C=CC(=O)C=C1>C1COCC1.C(OCC)(=O)C.CC#N.CC#N.Cl[Pd]Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:13][C:12](=[O:14])[C:11]3[C:10]([CH:9]=2)=[CH:18][CH:17]=[C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH:15]=3)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: COc1ccc(COc2ccc(/C=C/c3ccc(F)c(OC)c3)c(C(=O)O)c2)cc1
Agent: Cl[Pd]Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc3cc(-c4ccc(F)c(OC)c4)oc(=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.3 %

Procedure:
A solution of (E)-2-[2-(4-fluoro-3-methoxyphenyl)vinyl]-5-(4-methoxybenzyloxy)benzoic acid (600 mg, 1.47 mmol) in anhydrous THF (5 mL) was sparged with nitrogen for 5 min, then PdCl2(MeCN)2 (39 mg, 0.15 mmol), p-benzoquinone (175 mg, 1.62 mmol), and molecular sieves (10 mg) were added and the mixture stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with 1 N NaOH (aq.). The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by chromatography on silica gel with hexanes:EtOAc (2:1, v/v) as eluent to afford 3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)isochromen-1-one (300 mg, 0.74 mmol, 50%).
Reaction SMILES: C(NC1C=CC=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.FC1C=C(CC(O)=O)C=CC=1OCCN1CCCCC1.[CH2:43]([N:45]([CH2:64][CH2:65][C:66]1[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH2:74][N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)=[C:68]([F:81])[CH:67]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH:52]1[CH2:61][CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[C:57]([O:62]C)[CH:58]=2)[CH2:53]1)[CH3:44]>>[CH2:43]([N:45]([CH2:64][CH2:65][C:66]1[CH:71]=[CH:70][C:69]([O:72][CH2:73][CH2:74][N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)=[C:68]([F:81])[CH:67]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[CH:52]1[CH2:61][CH2:60][C:59]2[CH:58]=[C:57]([OH:62])[CH:56]=[CH:55][C:54]=2[CH2:53]1)[CH3:44]
Reactant: CCN(CCc1ccc(OCCN2CCCCC2)c(F)c1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1ccccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(O)Cc1ccc(OCCN2CCCCC2)c(F)c1
Product: CCN(CCc1ccc(OCCN2CCCCC2)c(F)c1)c1ccccc1C1CCc2cc(O)ccc2C1
Yield: 79.2 %

Procedure:
Synthesized from ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]acetic acid hydrochloride according to an analogous synthetic method to Example 337 described below, ethyl{2-[3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]ethyl}[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (302 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (233 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH2:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[C:22](N=C(N(C)C)N(C)C)([CH3:25])([CH3:24])[CH3:23].BrCC(C)C>C(#N)C>[CH2:23]([N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=1)[S:11]([C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH2:21])=[CH:18][CH:19]=1)(=[O:12])=[O:13])[CH:22]([CH3:25])[CH3:24]
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Solvent: CC(C)CBr
Solvent: CC#N
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(5-isopropylpyridin-2-yl)-4-vinylbenzenesulfonamide (507 mg, 1.677 mmol) in acetonitrile (10 mL), was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.676 mL, 3.35 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.676 mL, 3.35 mmol) added. The reaction was then heated by microwaves to 150° C., for 30 minutes. After cooling, the solvent was removed under a stream of nitrogen and the crude purified by normal phase chromatography on silica (Si) (0-50% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title product, 179 mg, as a yellow oil which solidified on standing. LCMS (2 min, High pH) Rt 1.49 min, m/z (ES+) 359 (M+H).