Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:8]3[C:9](=[O:13])[NH:10][CH2:11][CH2:12][C:7]=3[C:6]=2[CH:15]=1.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:8]3[C:9](=[O:13])[N:10]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[CH3:23])[CH2:11][CH2:12][C:7]=3[C:6]=2[CH:15]=1
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2c1sc1ccc(F)cc21
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2c(sc3ccc(F)cc23)C1=O
Temperature: 120 °C
Yield: 37.5 %

Procedure:
6-Fluoro-3,4-dihydro-2H-benzo[4,5]thieno[2,3-c]pyridin-1-one (I-45e: 85 mg, 0.384 mmol) was reacted with 3-iodo-4-methyl-pyridine (101 mg, 0.461 mmol), K3PO4 (244 mg, 1.152 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (16.3 mg, 0.115 mmol), CuI (7.2 mg, 0.038 mmol) and 1,4-dioxane (10 mL). The resulting mixture was refluxed at 120° C. overnight to afford the crude product. Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 45 mg of the product (37.81% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(O)(C)C>C1COCC1.O>[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=2)[OH:25])=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCOc1cc(Br)ccc1OC
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(O)c2ccc(N(C)C)cc2)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (1.71 g, 7.4 mmol) and dry THF (18 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.0 mL, 7.4 mmol) and stirred for 20 min. Then a mixture of 4-dimethylamino-benzaldehyde (1.00 g, 6.7 mmol) in dry THF (10 mL) was added and stirred for 2 hour at −78° C. The mixture was quenched with isopropanol (3.1 mL, 40 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (4-dimethylamino-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol as an off-white solid (1.29 g, 64% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH2CH3), 2.04 (d, J=3 Hz, 1H, OH), 2.93 (s, 6H, N(CH3)2), 3.85 (s, 3H, OCH3), 4.07 (q, J=7 Hz, 2H, CH2CH3), 5.72 (d, J=3 Hz, 1H, CH), 6.68-7.23 (m, 7H, Ar). The product was used in the next step without further purification.
Reaction SMILES: C(O[CH:5]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=O)C.C(N(CC)CC)C.[H][H]>CN(C)C=O.[OH-].[Pd+2].[OH-]>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1cc2nccc(Oc3ccc(C(OC(C)=O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(Cc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Yield: 78.6 %

Procedure:
(4-Tert-butylphenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]-methyl acetate (Compound 31) (26 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Triethylamine (0.5 ml) and 20% palladium hydroxide (200 mg) were then added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hr. The reaction solution was filtered, water and ethyl acetate were added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give the title compound (18 mg, yield 79%).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:12](=[N:13]O)[CH:11]3[CH2:15][CH2:16][N:8]2[CH2:9][CH2:10]3)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Ni]>[N:1]1([CH2:6][CH:7]2[CH:12]([NH2:13])[CH:11]3[CH2:10][CH2:9][N:8]2[CH2:16][CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: ON=C1C2CCN(CC2)C1CN1CCCC1
Agent: [Ni]
Solvent: CO
Product: NC1C2CCN(CC2)C1CN1CCCC1
Reaction time: 16 h
Yield: 87.2 %

Procedure:
A suspension of 2-(1-pyrrolidinylmethyl)-1-azabicyclo-[2.2.2]octan-3-one oxime (8.94 g, 40 mmoles) in methanol (250 ml) in a Parr bottle was treated with Raney Nickel and subjected to hydrogenation over 16 hours at 50-60 psi pressure. The resultant solution was filtered through Celite® under nitrogen, and concentrated in vacuo to provide 7.30 g (87%) of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=4[Cl:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,4-dichloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=630.5)=91%.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)[CH:9]=[C:10]([C:11](O)=[O:12])[C:4]=2[O:3]1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>O.O1CCCC1>[CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)[CH:9]=[C:10]([CH2:11][OH:12])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cc(-n3cnnn3)cc(C(=O)O)c2O1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1(C)Cc2cc(-n3cnnn3)cc(CO)c2O1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A solution of 2,2-dimethyl-5-(1H-tetrazol-1-yl)-2,3-dihydrobenzofuran-7-carboxylic acid (677) (135 mg, 0.519 mmol), N-methylmorpholine (57 L, 0.519 mmol), and tetrahydrofuran (10 mL) at 0° C. was added isobutylchloroformate (68 L, 0.519 mmol) and stirred for 2 hours. Sodium borohydride (58.9 mg, 1.56 mmol) in water (3 mL) was added and stirred for 1 hour and at room temperature for an additional 1 hour. The reaction was concentrated in vacuo and water was added. The aqueous phase was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (60%) to afford (2,2-dimethyl-5-(1H-tetrazol-1-yl)-2,3-dihydrobenzofuran-7-yl)methanol (678) (77.8 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([CH2:24]O)[CH:21]=[C:20]([Cl:26])[C:3]=1[O:4][CH:5]([C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:24][C:22]1[CH:23]=[C:2]([Cl:1])[C:3]([O:4][CH:5]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:20]([Cl:26])[CH:21]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)C(Oc1c(Cl)cc(CO)cc1Cl)c1ccc2c(c1)OCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Oc1c(Cl)cc(CBr)cc1Cl)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a magnetically stirred solution of 0.206 g (0.52 mmol) of the product of step A dissolved in 2 mL methylene chloride was added 0.162 g (0.62 mmol) of triphenylphosphine followed by 0.205 g (0.62 mmol) of carbon tetrabromide at 0° C. The reaction mixture was held at 0° C. for 10 minutes, then allowed to warm to room temperature and stirred for 2.5 hours. The reaction mixture was then concentrated in vacuo and the residue was applied to a silica gel flash chromatography column and eluted with 15% EtOAc-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 0.220 g (92%) yield of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)CCC.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:33]4[S:34][CH:35]=[CH:36][CH:37]=4)=[CH:7][C:6]=3[C:5]2([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
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: CCO
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)c2cc(Br)ccc2-c2ccc(-c3cccs3)cc21
Reaction time: 1 h

Procedure:
A mixture of 2,7-dibromo-9,9-dihexylfluorene (7) (8.0 g, 16 mmol), 2-tributylstannylthiophene (2.98 g, 8.0 mmol), tetrakis(triphenylphosphine)palladium (0) (200 mg, 1.73×10′ mol) aqueous sodium carbonate (2M, 2 cm3), toluene (5 cm3) and ethanol (2 cm3) was heated under reflux for 24 h under argon. Toluene and ethanol were removed and hexane (10 cm3) and aqueous KI (2%, 10 cm3) added and the mixture stirred vigorously for 1 h. Diethyl ether (10 cm3) and dilute HCl(nq) (3M, 10 cm3) were added, the aqueous layer separated and washed with diethyl ether (2×10 cm3). The organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated to a dark brown oil which was purified by column chromatography [silica gel, hexane] to yield a pale jade coloured oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19](=[N:25]O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]1[O:6][N:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(-c2cc(F)ccc2F)n1
Yield: 35.8 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2,5-difluorobenzoic acid (0.299 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.172 g (36%) of ethyl 5-(2,5-difluorophenyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:23][CH2:22][N:10]3[C:11](=[O:21])[CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)[N:14]=[C:9]3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].[ClH:36]>CN(C)C=O.C(O)C.C(O)(C)C.O>[ClH:36].[O:29]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][N:8]1[C:9]2=[N:14][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:12][C:11](=[O:21])[N:10]2[CH2:22][CH2:23][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1cc(-c2ccncc2)nc2n1CCC(c1ccccc1)N2
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: O=C(CN1c2nc(-c3ccncc3)cc(=O)n2CCC1c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A solution of 0.3 g (98 mmoles) of 8-phenyl-2-(4-pyridinyl)-6,7,8,9-tetrahydro-4H-pyrimido[1.2-a]pyrimidin-4-one in 8 ml of anhydrous dimethylformamide was treated with 51 mg (1.28 mmoles) of sodium hydride (60% in mineral oil). The resulting suspension was stirred at 0° C. for 30 mins and then treated with 0.255 g (1.28 mmoles) of 2-bromoacetophenone. After stirring for 18 h at room temperature, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with a saturated solution of aqueous sodium chloride and was evaporated under reduced pressure to give crude product. Purification using silica gel chromatography eluting with a gradient comprising dichloromethane/methanol in the proportions 99/1 to 95/5 gave pure product which was dissolved in ethanol and treated with 1 equivalent of a solution of hydrochloric acid in isopropanol. The resulting salt was recrystallized from a mixture of isopropanol/diisopropylether to give 0.16 g (39%) of pure product. Mp: 134-137° C.
Reaction SMILES: [Cl-:1].[Cr+3:2].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][NH:13][CH2:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=1.[Cl-].[Cl-].[K+].[Br-]>CN(C=O)C>[Cl-:1].[Cr+3:2].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][N:13]([CH2:14][C:15]1[NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl-:1].[Cl-:1]
Reactant: c1ccc2[nH]c(CNCc3nc4ccccc4[nH]3)nc2c1
Agent: [Cr+3]
Agent: [Br-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(CN(Cc3nc4ccccc4[nH]3)C3CCCCC3)nc2c1

Procedure:
3g was synthesised by an analogous procedure to that described for 3a using 2g (1 g, 2.79 mmol) and CrCl3(THF)3 (1.04 g, 2.79 mmol). Yield 1.07 g (74%). Anal. Calc. for C22H25Cl3CrN5 (in %): C, 51.03; H, 4.87; N, 13.52. Found C, 50.93; H, 4.71; N, 13.64. IR (KBr, cm−1), υ 3225 (NH, s), υ 1623-1540 (ArC═C, C═N, m), δ 1455, 1478, 1496 (N—H, s, m), υ 1276 (CN, m), δ 750 (CH, s). UV-VIS (DMF, 298 K): λmax/nm (εmax/dm3 mol−1 cm−1)=459 (160), 704 (65), 733 (shoulder). +FAB-MS: (m/z): 481 ([M-Cl]+), 446 ([M-2Cl]), 360 ([M-CrCl3]). μeff·=3.88 MB.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:38])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([O:34]CC)=[O:33])=[N:20][C:19]=2[CH3:37])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O>O1CCCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:38])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([OH:34])=[O:33])=[N:20][C:19]=2[CH3:37])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(C)c(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(NC(=O)OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.9 %

Procedure:
A mixture of ethyl 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate (1.36 g, 2.38 mmol) and lithium hydroxide, monohydrate (0.399 g, 9.50 mmol) in tetrahydrofuran (30 mL), methanol (10 mL), and water (12 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure, and the residue was suspended in water (˜20 mL) and 1N aqueous hydrochloric acid (9.5 mL). The pH was adjusted to 5 with 1N aqueous sodium hydroxide, and the suspension was stirred for 60 min. The solid was collected by vacuum filtration, washed with water, and dried overnight to give 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylic acid (1.10 g, 2.02 mmol, 85% yield) as a yellow solid. LC/MS M+1=544.3 and 546.3.
Reaction SMILES: II.[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[Mg].[CH2:13]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOCC>[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]([CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[F:3])([OH:25])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Fc1ccccc1CCl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: OC1(Cc2ccccc2F)CCN(Cc2ccccc2)C1

Procedure:
A crystal of iodine followed by a few mls of a solution of 20.6 g of 2-fluorobenzyl chloride in 100 ml of ether is added to a suspension of 3.4 g of magnesium shavings in 50 ml of ether. Thereafter, the reaction is initiated via a hot air gun before adding dropwise, while maintaining the reaction at reflux, the remaining 2-fluorobenzyl chloride solution. After total addition, the reaction is maintained at reflux with stirring for an additional hour before successively adding 100 ml of ether and adding dropwise, with vigorous stirring, a solution of 25.0 g of N-benzyl-3-pyrrolidinone in 100 ml of ether. After complete addition, the resulting suspension is refluxed for an additional 2 hours, stirred at ambient temperature for 16 more hours, and then filtered. The filter cake is washed well with ether and then hydrolyzed by stirring in an ice-ammonium chloride solution. The aqueous solution is extracted thrice with ether and the combined ether extracts are washed successively with water and a sodium chloride solution and then dried. The solvent is removed and the residue is distilled at 135°-140° C., 0.1 mm pressure, to provide a viscous yellow oil which solidifies upon standing. The solid is recrystallized twice from an ethanol-water mixture to give the product, 1-benzyl-3-(2-fluorobenzyl)-3-pyrrolidinol, mp 75°-77° C.
Reaction SMILES: C(OC([O:6][C:7]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:8]=1[C:9]([NH:11][CH2:12][CH2:13][SH:14])=[O:10])=O)C.[OH-].[Na+]>CO>[OH:6][C:7]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:8]=1[C:9]([NH:11][CH2:12][CH2:13][SH:14])=[O:10]
Reactant: CCOC(=O)Oc1cc(OC)ccc1C(=O)NCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)NCCS)c(O)c1
Reaction time: 0.75 h
Yield: 77 %

Procedure:
4.50 g of the N-(2-ethoxycarbonyloxy-4-methoxybenzoyl)cysteamine was dissolved in 70 ml of methanol, and 17 ml of 2N aqueous solution of sodium hydroxide was added to the solution. The mixture was agitated for 45 minutes. The solvent was distilled off in evacuated atomosphere, and 2N aqueous solution of sodium hydroxide and methylene chloride were added to the mixture for separation. The aqueous phase was further washed with methylene chloride, acidified by adding 6N aqueous hydrochloric acid, and extracted with methylene chloride. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off in evacuated atomosphere. The residue was subjected to column chromatography using silica gel, and there was obtained 2.63 g of N-(2-hydroxy-4-methoxybenzoyl)cysteamine (I).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[N:7]([C:18]([C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1.[C:25](#N)C>>[I:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:19][C:18]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[N:7][N:8]=2)=[CH:11][CH:12]=1
Reactant: CN(NC(=O)c1ccc(I)cc1)C(=O)c1ccc[nH]1
Reactant: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cccc1-c1nnc(-c2ccc(I)cc2)o1
Temperature: 100 °C

Procedure:
Phosphorousoxychloride (2 ml) was added to 1H-pyrrole-2-carboxylic acid, 1-methyl-2-(4-iodobenzoyl)hydrazide (Intermediate 39) (150 mg) in acetonitrile (1 ml) and the reaction heated at 100° C. for 18 hours. The cooled reaction was poured onto ice/water (60 ml) and extracted with ethyl acetate (3×40 ml). The combined extracts were reduced to dryness under vacuum and the residue applied to a bond-elut (silica) and eluted with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvent, 2-(4-iodophenyl)-5-(1-methyl-1H-pyrrol-2-yl)-1,3,4-oxadiazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@H:5]([C:7]([N:9]2[CH2:13][C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=3)[C@@:11]([C@H:24]([OH:26])[CH3:25])([CH3:23])[CH2:10]2)=[O:8])[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:39]1[CH2:42][N:41]([CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)(=O)=O.C(OCC)(=O)C>C(#N)C>[CH3:27][C:2]1([CH3:1])[O:6][C@H:5]([C:7]([N:9]2[CH2:13][C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:39]4[CH2:42][N:41]([CH:43]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)[CH2:40]4)[CH:15]=3)[C@@:11]([C@H:24]([OH:26])[CH3:25])([CH3:23])[CH2:10]2)=[O:8])[CH2:4][O:3]1
Reactant: COc1ccc([C@@H]2CN(C(=O)[C@@H]3COC(C)(C)O3)C[C@@]2(C)[C@@H](C)O)cc1O
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc([C@@H]2CN(C(=O)[C@@H]3COC(C)(C)O3)C[C@@]2(C)[C@@H](C)O)cc1OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Yield: 18.9 %

Procedure:
To a suspension of (1R)-1-[(3S,4S)-1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]carbonyl}-4-(4-methoxy-3-hydroxyphenyl)-3-methylpyrrolidin-3-yl]ethanol (2.0 g) and potassium carbonate (1.46 g) in acetonitrile (30 mL) is added 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (2.51 g). The mixture is heated at 80° C. overnight. Cool the reaction mixture and pour into ethyl acetate (100 mL), wash with water (40 mL) and brine (40 mL), dry over sodium sulfate, filter and evaporate the filtrate to dryness. Purify the resulting residue (silica gel, 60% ethyl acetate/hexanes to ethyl acetate) to provide 0.6 g of the title compound. MS (ES+)=601 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:30][CH2:31][N:32]4[C:33](=[O:42])[C:34]5[C:35](=[CH:38][CH:39]=[CH:40][CH:41]=5)[C:36]4=[O:37])[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Yield: 7.7 %

Procedure:
Intermediate (6) was prepared by alkylation of Compound (1) (210 mg, 0.45 mmol) with N-(2-bromoethyl)phthalimide (230 mg, 0.90 mmol) according to the procedure in Method C, Step a. The crude material was purified by flash column chromatography eluting with EtOAc/hexane (5-80%) to afford 2-(4-bromophenyl)-5-cyclopropyl-6-{[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl](methylsulfonyl)amino}-N-methyl-2H-indazole-3-carboxamide (6) as an off-white solid (22 mg).