Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]2=[O:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)Cl.C1COCC1>[ClH:1].[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:10]1([CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:24])[CH3:35]
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1c1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CCCC1(Cc2ccncc2)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,3-dihydro-1-phenyl-3-(4-pyridinylmethyl)-2H-indol-2-one hydrochloride (33.7 g, 0.1 mol) in 200 ml CH2Cl2 was treated with 150 ml 1N NaOH. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to an oil which solidified on cooling. The "free base" was dissolved in 150 ml dry THF, cooled in an ice bath, treated with Nail (2.88 g, 0.12 mol), and stirred under dry nitrogen for 30 min. The mixture was treated with ethyl 4-bromobutyrate (19.5 g, 0.1 mol) in 25 ml dry THF. The mixture was stirred in the ice for 1 h and 16 h at room temperature. The reaction mixture was concentrated in vacuo, and the residue was partitioned between 300 ml Et2O and 200 ml water. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, treated with 150 ml 1N HCl-Et2O, and concentrated in vacuo. The residue was dissolved in 100 ml anhydrous EtOH with warming and stirred at room temperature for 24 h. The resulting crystals were collected by filtration, washed with a small portion of cold EtOH and Et2O, and dried in vacuo at 80° C. to give the desired product in 86% (38.6 g) yield; mp 182.5°-183.0° C.; IR(nujol): C=O @1722 and 1703 cm-1 ; NMR(DMSOd6TMS: δ1.15 (t, 3H, CH3), 1.2, 1.3 (2m, 2H, CH2CCCO), 2.1 (m, 2H, CH2CCO), 2.26 (t, 2H, CH2CO), [3.43 (d, 1H, J12), 3.64 (d, 1H, J12) CH2 -Pyr], 4.02 (q 2H, OCH2), [6.54 (m, 1H), 7.2 (m, 2 H), 7.5 (m, 5H), 7.68 (m, 1H) Ar--N-Phe], [7.10 (d, 2H), 8.70 (d, 2H) 4-Pyr]; Anal calcd for C26H26N2O3HCl, MW 450.97: C, 69.25; H, 6.04; N, 6.21. Found: C, 69.02; H, 5.98; N, 6.52. Mass spec m/e 415(M+1-HCl).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.CN(C)C=O.Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][N:22]2[CH3:25])=[C:18]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:17]=1>O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:18]2[N:17]=[C:16]([N:5]3[C:4]([CH3:3])=[CH:8][C:7]([CH3:9])=[N:6]3)[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH3:25])=[CH:32][CH:31]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Temperature: 120 °C
Yield: 13.3 %

Procedure:
Sodium hydride (60% in mineral oil, 160 mg, 4.1 mmol) was added to 3,5-dimethylpyrazole (320 mg, 3.4 mmol) dissolved N,N-dimethylformamide (10 mL) and the mixture was stirred for 30 min. (2-Chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine (1.0 g 3.40 mmol) was added and the reaction mixture was heated at 120° C. for 4 days, cooled down and poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane/methanol/ammonia) to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-amine (160 mg, 13%) as a yellow crystalline compound.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.C(O)C>[CH2:9]([NH:16][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: OCCO
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(NCc2ccccc2)cc1
Yield: 44.3 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μL, 1.20 mmol), ethyl 4-iodobenzoate (167 μl, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and ethanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=5/1, Rf=0.4) afforded ethyl 4-(N-benzyl)aminobenzoate (113 mg, 50% isolated yield) as light yellow solid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Albright, J. D.; DeVries, V. G.; Largis, E. E.; Miner, T. G. Reich, M. F.; Schaffer, S.; Shepherd, R. G.; Upeslacis, J. J. Med. Chem. 1983, 26, 1378–1393; and Onaka, M.; Umezono, A.; Kawai, M.; Izumi, Y. J. Chem. Soc., Chem. Commun. 1985, 1202–1203.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:16]([O-])=O)=[C:4]2[C:8](=[CH:9][C:10]=1[Br:11])[CH2:7][CH:6]([NH:12][C:13](=[O:15])[CH3:14])[CH2:5]2>O1CCCC1.[Ni]>[NH2:16][C:3]1[C:2]([NH2:1])=[C:10]([Br:11])[CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([NH:12][C:13](=[O:15])[CH3:14])[CH2:7]2
Reactant: CC(=O)NC1Cc2cc(Br)c(N)c([N+](=O)[O-])c2C1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(=O)NC1Cc2cc(Br)c(N)c(N)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(5-Amino-6-bromo-4-nitro-indan-2-yl)-acetamide (0.7 g, 2.2 mmol) was dissolved in tetrahydrofuran (20 mL) and then treated with Raney nickel and stirred under a hydrogen atmosphere (1 atm) at room temperature for 1 h. The catalyst was removed by filtration through a celite pad, and washed repeatedly with methanol. The combined organic filtrate was removed by rotoevaporation to give a syrup that solidified upon standing. This product was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:21][C@@H:22]([C:24]3[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=3)[OH:23])[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[I-].[K+]>[CH3:36][O:35][C:33](=[O:34])[CH2:32][O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C@@H:22]([OH:23])[CH2:21][N:19]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=2)[CH3:20])[CH:25]=1
Reactant: CN(C[C@H](O)c1cccc(O)c1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc([C@@H](O)CN(C)c2cnc(-c3ccccc3)c(-c3ccccc3)n2)c1
Yield: 70.5 %

Procedure:
To a solution of 0.66 g of (R)-3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-1-hydroxyethyl}phenol and 0.28 g of methyl bromoacetate in 10 ml of acetonitrile, 2 mg of potassium iodide and 0.28 g of potassium carbonate were added and the mixture was heated at reflux for 4 hours. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.55 g of the desired compound as a pale orange amorphous.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:3]=1.[C:11](=O)([O:22][CH:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)[O:12]C1C=CC([N+]([O-])=O)=CC=1>C1COCC1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]2([NH:10][C:11](=[O:12])[O:22][CH:23]3[CH:28]4[CH2:27][CH2:26][N:25]([CH2:30][CH2:29]4)[CH2:24]3)[CH2:9][CH2:8]2)[CH:3]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN2CCC1CC2
Reactant: CC(C)(N)c1csc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(NC1(c2csc(Br)c2)CC1)OC1CN2CCC1CC2
Yield: 49.5 %

Procedure:
To a stirred solution of 2-(5-bromothiophen-3-yl)propan-2-amine (0.366 g, 1.66 mmol) in THF (10 mL) was added 4-nitrophenyl quinuclidin-3-yl carbonate (0.571 g, 1.95 mmol) and a few granules of 4-(dimethylamino)pyridine. The mixture was refluxed overnight, concentrated and partitioned between ethyl acetate (50 mL) and aqueous NaHCO3 (50 mL). The organic layer was washed again with aqueous NaHCO3 (1×50 mL), dried (Na2SO4) and concentrated. The resulting dirty yellow gum was purified by flash chromatography using a chloroform/methanol/ammonia gradient to afford quinuclidin-3-yl (1-(5-bromothiophen-3-yl)cyclopropyl)carbamate as an off-white solid (0.305 g, 49%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C[O:12][P:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([P:13]1(=[O:12])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1)=[O:6]
Reactant: COP1Oc2ccccc2-c2ccccc21
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)c1
Temperature: 115 °C

Procedure:
46.6 g (0.3 mol) of 3-methylbenzoyl chloride were warmed to 85° C. under a nitrogen atmosphere. 69 g (0.3 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]-oxaphosphorin were added dropwise while stirring. The temperature was then increased in steps to 115° C. When the reaction was complete, 50 ml of toluene were added at room temperature. After crystallization, 85 g (84% of theory) of the abovementioned compound of melting point 108° to 111° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>>[N:16]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Following the general procedure of Example 5 using the Mannich intermediate of Example 1 and 2-hydroxy-4-n-octyloxybenzophenone, the title compound is obtained as an off-white crystalline solid melting at 128°-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:21]C(C)([O-])C.[K+].C1COCC1.IC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:21])[CH:6]=[C:5]2[S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: CC(C)(C)[O-]
Reactant: O=S(=O)(c1ccc(F)cc1)c1c[nH]c2ccc(Br)cc12
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(S(=O)(=O)c2ccc(F)cc2)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a stirred solution of 5-bromo-3-(4-fluoro-benzenesulfonyl)-1H-indole (0.315 g, 0.89 mmole) in tetrahydrofuran (4 mL) was added 1M potassium t-butoxide/THF (1.0 mL, 1.0 mmol). After 10 minutes iodomethane (0.16 g, 1.1 mmole) was added. The reaction mixture was stirred at room temperature overnight and then passed through a pad of silica gel (230–400 mesh) eluting with 50% ethyl acetate/hexane. The eluate was concentrated under reduced pressure to provide a residue that was crystallized from ethanol/hexanes to give 0.3 g of 5-Bromo-3-(4-fluoro-benzenesulfonyl)-1-methyl-1H-indole.
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5]CC[CH2:2]1.[C:10]([C:12]1[CH:36]=[CH:35][C:15]([CH2:16][NH:17][C:18]2[S:19][C:20]([C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[CH:33][N:34]=4)[CH:31]=3)=[O:24])=[CH:21][N:22]=2)=[CH:14][CH:13]=1)#[N:11].NC1C=CC(C(OC)=O)=CC=1>>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][N:17]([C:7](=[O:8])[CH2:6][CH:1]([CH3:5])[CH3:2])[C:18]2[S:19][C:20]([C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[CH:33][N:34]=4)[CH:31]=3)=[O:24])=[CH:21][N:22]=2)=[CH:35][CH:36]=1)#[N:11]
Reactant: O=C(Cl)CC1CCCC1
Reactant: N#Cc1ccc(CNc2ncc(C(=O)Nc3ccc4nccn4c3)s2)cc1
Agent: COC(=O)c1ccc(N)cc1
Product: CC(C)CC(=O)N(Cc1ccc(C#N)cc1)c1ncc(C(=O)Nc2ccc3nccn3c2)s1

Procedure:
The title compound was prepared as described in Example 52A, substituting 3-methylbutanoyl chloride for 2-cyclopentylacetyl chloride and 2-(4-cyanobenzylamino)-N-(imidazo[1,2-a]pyridin-6-yl)thiazole-5-carboxamide for methyl 4-aminobenzoate. 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.62 (s, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 7.99-7.89 (m, 2H), 7.82 (dd, J=18.8, 8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 5.63 (s, 2H), 2.14 (dt, J=13.4, 6.7 Hz, 1H), 0.88 (d, J=6.7 Hz, 6H); (APCI(+)) m/e 459 (M+H)+.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[S].S>>[CH:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[CH:4]=1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: S
Agent: [S]
Product: Oc1cccc2ccccc12
Yield: 34 %

Procedure:
A mixture of 50.0 g (0.28 mole) of 6-methoxy-1-tetralone and 9.2 g (0.29 mole) of elemental sulfur was stirred and heated at 250°-260° for three hours (until the evolution of hydrogen sulfide gas had ceased). The mixture was cooled and then subjected to bulb-to-bulb distillation. The distillate was dissolved in 300 ml of dichloromethane, and the solution was extracted with 1.0N potassium hydroxide solution (3×150 ml). The base extracts were combined, cooled in ice, and acidified with 10% hydrochloric acid to precipitate the crude naphthol product as a gum. Trituration of the gum with tert-butyl methyl ether yielded 16.8 g (34% yield) of the analytically pure naphthol, mp 84°-86° (a mp of 83°-84° is given by M. P. Sibi, J. W. Dankwardt, and V. Snieckus, J. Org. Chem., 51, 271 (1986)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cu][C:23]#[N:24]>C(OC)(C)(C)C>[C:23]([C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)=[CH:15][C:16]=1[F:21])#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Reactant: N#C[Cu]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(C#N)c(F)c2)C1
Temperature: 180 °C
Yield: 7.9 %

Procedure:
To a 20 mL microwave vial were added 2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (1.5 g, 4.16 mmol) N-methyl-pyrrolidone (10 ml) and copper(I)-cyanide (559 mg, 6.25 mmol). The vial was capped and heated in a microwave synthesizer (Personal Chemistry Emrys Optimizer) at 180° C. for 30 min. The reaction mixture was poured into tert-butylmethylether (150 ml) and extracted with brine (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 70% ethyl acetate in heptane) to yield a yellow solid (101 mg, 8%), MS (ISP): 307.2 ([M+H]+).
Reaction SMILES: [OH-].[K+].[OH:3][C@H:4]1[C@H:9]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6](C(OCC)=O)[CH2:5]1>CC(O)C>[C:12]1([CH2:11][NH:10][C@@H:9]2[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]2[OH:3])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)N1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: O[C@@H]1CNCC[C@H]1NCc1ccccc1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
A mixture of 195.4 parts of potassium hydroxide and 1065 parts of 2-propanol was stirred and warmed till all solid entered solution. After cooling to room temperature, 97 parts of ethyl trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidinecarboxylate were added and the whole was stirred and refluxed for 4 hours. The reaction mixture was evaporated to dry and 500 parts of water were added. The whole was concentrated to a volume of about 300 parts. After cooling to room temperature, the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The oily residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 51 parts (70.8%) of trans-4-[(phenylmethyl)amino]-3-piperidinol; mp. 136° C.(intermediate 39).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=1)[CH2:7][CH2:6]2.B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[C:19]1[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)C2
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: O=C(NCCCCN1CCc2cc(O)ccc2C1)c1ccc(-c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A mixture of 6-methoxy-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline (1.18 g, 2.8 mmol) and dichloromethane (50 ml) was treated dropwise with a solution of boron tribromide in dichloromethane (1M; 8.4 ml). The mixture was stirred at 20° C. for 18 h, then poured into a mixture of ice (100 g) and 0.880 ammonia (100 ml). Resulting mixture was extracted with dichloromethane (3×50 ml) and the combined extracts were dried (Na2SO4) and evaporated in vacuo. The residue was triturated with ether to give the title compound (0.86 g, 77%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:17]=3[N:18]=2)=[C:10]([O:25]C)[CH:9]=1)=[O:6].B(Br)(Br)Br.CCCCCC.CCOC(C)=O.CO>C(Cl)Cl>[OH:2][C:3]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:27][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=3[N:18]=2)=[C:10]([OH:25])[CH:9]=1)=[O:6]
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4cc(OC(F)(F)F)ccc4OC)cc3OC)sc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2nc3ccc(O)cc3s2)c(O)c1)c1cc(OC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 32 %

Procedure:
Prepared as described in the Demethylation section using 2-methoxy-N-[3-methoxy-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-5-(trifluoromethoxy)benzamide (0.30 g, 0.595 mmol) in dry DCM (12 ml) and BBr3 (1.0M in DCM, 1.9 ml, 1.9 mmol) at −78° C. under an atmosphere of argon. Additional BBr3 (1.0 M in DCM, 1.9 ml, 1.9 mmol) was added dropwise and the reaction mixture stirred at room temperature for 4 d to give the title compound (88 mg, 32%) as a pale yellow solid after work-up and flash chromatography (4:2:0.3 Hexane/EtOAc/MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:21])=[CH:9][C:10]([O:19][CH3:20])=[CH:11][C:12]=3[C:13]2([CH:17]=[CH2:18])O)=[CH:4][CH:3]=1.[CH3:22][OH:23].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:21])=[CH:9][C:10]([O:19][CH3:20])=[CH:11][C:12]=3[C:13]2=[CH:17][CH2:18][O:23][CH3:22])=[CH:4][CH:3]=1
Reactant: C=CC1(O)c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COCC=C1c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Temperature: 55 °C
Yield: 42.8 %

Procedure:
To a 250 mL of RBF were added 7-bromo-4-fluoro-2-methoxy-9-vinyl-9H-xanthen-9-ol (8.69 g, 24.75 mmol), methanol (100 mL, 2475 mmol) and sulfuric acid (0.2M in water) (12.4 mL, 2.48 mmol). The mixture was heated to 55° C. for 25 min. The solvent was removed and the residue was diluted with EtOAc. The organic layer was washed by saturated aqueous NaHCO3. The aqueous layer was further extracted with EtOAc. The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude material as an oil. The crude product was purified by 35% to 50% to 75% to 100% DCM in Heptane to yield 7-bromo-4-fluoro-2-methoxy-9-(2-methoxyethylidene)-9H-xanthene (3.87 g, 10.60 mmol).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:33][CH2:34][CH2:35]Cl)=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[I-:37].[Na+]>C(#N)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:33][CH2:34][CH2:35][I:37])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: [I-]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCCl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Temperature: 90 °C

Procedure:
To ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-chloropropyl)thiazole-4-carboxylate (2B) (9.3 g, 17.2 mmol) in acetonitrile (125 mL) was added sodium iodide (25.8 g, 172 mmol). The reaction mixture was purged with nitrogen twice. The reaction mixture was then heated at 90° C. for 5 hours, cooled to rt, and concentrated under reduced pressure. The concentrate was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was slurried in Et2O, filtered, washed with additional Et2O and dried under reduced pressure to provide the desired product ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-iodopropyl)thiazole-4-carboxylate (2C) in 93% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.89 (1H, s), 8.04 (1H, d), 7.79 (1H, d), 7.66 (1H, d), 7.43 (4H, m), 4.83 (2H, s), 4.19 (2H, q), 3.72 (2H, t), 3.26 (2H, t), 3.06 (4H, m), 2.03 (2H, m), 1.21 (3H, t).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1)#[CH:2].[OH-].[Li+].CO>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][CH:7]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=2[CH2:9][CH2:8]1)#[CH:2]
Reactant: C#Cc1cccc(CC2CCc3[nH]c(C(=O)OC)cc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cccc(CC2CCc3[nH]c(C(=O)O)cc32)c1

Procedure:
The title compound was synthesized from methyl 4-(3-ethynylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.014 g, 0.050 mmol) and lithium hydroxide (0.021 g, 0.50 mmol in 0.5 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (1 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford the title compound: 2.8 mg, 21% yield. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.04-2.13 (m, 1H), 2.48-2.59 (m, 1H), 2.59-2.66 (m, 2H), 2.76 (d, J=7.22 Hz, 2H), 3.22-3.29 (m, 1H), 3.41 (s, 1H), 6.30 (s, 1H), 7.18-7.22 (m, 1H), 7.25 (t, J=7.81 Hz, 1H), 7.28-7.30 (m, 1H), 7.31 (s, 1H); LCMS (ESI−) 264.2 (M−H); HPLC (UV=96.60%), (ELSD=100%).