Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:57]=[C:50]3[CH2:51][N:52]([CH3:56])[C:53](=[O:55])[CH2:54][N:49]3[N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:33])([CH3:34])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:57]=[C:50]3[CH2:51][N:52]([CH3:56])[C:53](=[O:55])[CH2:54][N:49]3[N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1)(=[O:3])[CH3:2]
Reactant: CN1Cc2cc(Nc3cc(Br)cn(C)c3=O)nn2CC1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CC(=O)N(C)C4)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 44.9 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyri-din-4-ylboronic acid 116c (165 mg, 0.40 mmol), 146e (141 mg, 0.40 mmol), K3PO4 (170 mg, 0.80 mmol), sodium acetate (66 mg, 0.80 mmol), Pd(dppf)Cl2 (15 mg, 0.020 mmol), and acetonitrile/water (8/0.2 mL). The mixture was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (30 mL) and water (30 mL). The organic layer was separated and the water layer was extracted with dichloromethane (2×30 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 146f (115 mg, 45%) as a yellow solid. MS-ESI: [M+H]+ 641.4
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([C@H:24](O)[CH3:25])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.CCCCCC>ClCCl>[Br:1][C@H:24]([C:16]1[CH:15]=[C:14]([C:13]([F:28])([F:27])[F:12])[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=1)[CH3:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CSC
Product: C[C@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.5 %

Procedure:
Under an argon atmosphere, a suspension of N-bromosuccinimide (103 mg, 0.58 mmol) in anhydrous dichloromethane (2.0 mL) was added dropwise with dimethyl sulfide (53 μL, 0.70 mmol) under ice cooling over 3 minutes. The mixture was added dropwise with a solution of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (100 mg, 0.39 mmol, >99.5% ee) in anhydrous dichloromethane (1 mL) at −20° C., and the mixture was stirred at room temperature for 6 hours. The reaction mixture was add with n-hexane, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent, n-hexane) to obtain 82 mg of (S)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[CH:13]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[C:25]([C:27]1[N:28]=[C:29]([C:40](O)=[O:41])[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=1)#[N:26].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N>>[C:9]([O:8][CH2:7][CH:6]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:40]([C:29]2[N:30]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:31]=[C:27]([C:25]#[N:26])[N:28]=2)=[O:41])=[C:14]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[CH:13]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: CC(=O)OCC(COC(C)=O)c1ccc(N)c(C2=CCCCC2)c1
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: CC(=O)OCC(COC(C)=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1

Procedure:
Acetic acid 3-acetoxy-2-(4-amino-3-cyclohex-1-enyl-phenyl)-propyl ester (as prepared in the previous step) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d)) as described in Example 1, step (1) to obtain the title compound: Mass spectrum (ESI, m/z): Calcd. for C30H40N4O6Si, 581.2 (M+H). found 581.0.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2>S(=O)(=O)(O)O>[I:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=C1Cc2c(I)cccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Cc2c(ccc([N+](=O)[O-])c2I)N1
Reaction time: 1 h

Procedure:
A mixture of concentrated sulfuric acid (0.73 mL) and concentrated nitric acid (0.14 mL) was added slowly to a solution of 1,3-dihydro-4-iodo-2H-indol-2-one (0.5 g, 1.93 mmol) (see Fukuyama et al., supra) in concentrated sulfuric acid (6 mL) at −5° C. with stirring. The mixture was stirred for an additional 15 min at −5° C. then poured into ice. After standing for 1 h, solid was collected by filtration and washed with water, and dried in a vacuum oven to give the above product. (Yield 0.46 g, 78%).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=2)[O:5][C:6]=1[C:7]1[N:11]=[CH:10][NH:9][N:8]=1.CCN(C(C)C)C(C)C.[CH3:32][Si:33]([CH2:36][CH2:37][O:38][CH2:39]Cl)([CH3:35])[CH3:34]>CN(C=O)C>[I:1][C:2]1[N:3]=[C:4]([C:12]2[C:17]([CH3:18])=[CH:16][N:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=2)[O:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:39][O:38][CH2:37][CH2:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[N:8]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)Nc1cc(-c2nc(I)c(-c3nc[nH]n3)o2)c(C)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(-c2nc(I)c(-c3ncn(COCC[Si](C)(C)C)n3)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a solution of N-{4-[4-iodo-5-(1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (6.2 g, 15 mmol) in DMF (60 mL) was added DIEA (4.0 mL, 23.0 mmol). The reaction mixture was allowed to stir at rt for 2 h and then SEM-Cl (4.1 mL, 23.0 mmol) was added. The reaction mixture was allowed to stir at rt overnight and then concentrated. The residue was purified by column chromatography to give N-{4-[4-iodo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (2.7 g) plus another SEM regioisomer (1.2 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH2:24])=[N:21][CH:22]=3)[N:17]([CH3:25])[N:16]=2)=[CH:11][C:10]=1[F:26])C1C=CC=CC=1.C1CC=CCC=1>CCO.CC(O)=O.[Pd]>[NH2:24][C:20]1[N:19]=[C:18]2[N:17]([CH3:25])[N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:26])[CH:11]=3)[C:23]2=[CH:22][N:21]=1
Reactant: Cn1nc(-c2ccc(OCc3ccccc3)c(F)c2)c2cnc(N)nc21
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Solvent: CC(=O)O
Product: Cn1nc(-c2ccc(O)c(F)c2)c2cnc(N)nc21
Temperature: 80 °C

Procedure:
3-(4-Benzyloxy-3-fluoro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 35) (0.52 g, 1.49 mmol) is suspended in a mixture of EtOH and AcOH (5:1, 120 ml). The reaction mixture is degassed with argon before the addition of 10% palladium on activated charcoal (0.50 g) and 1,4-cyclohexadiene (1.4 ml, 14.88 mmol). The reaction mixture is heated at 80° C. overnight and filtered hot through Celite® (filter agent) washing copiously with MeOH (˜300 ml). The solvents are removed in vacuo and the resulting residue is triturated with EtOAc (˜20 ml) to afford the title compound as a white solid.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([N:13]([CH3:17])[C:14](=[O:16])[O-:15])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][C@@H:5]([N:13]([CH3:17])[C:14](=[O:16])[O:15][C:7]([CH3:12])([CH3:8])[CH3:6])[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1
Reactant: CN(C(=O)[O-])[C@H](CN=[N+]=[N-])C[C@H]1CCCOC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)[C@H](CN)C[C@H]1CCCOC1
Yield: 91 %

Procedure:
Hydrogenation of (S)-1-azido-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-yl(methyl)carbamate (62 mg, 0.51 mmol) was carried out in EtOAc (20 mL), 10% Pd/C (15 mg) under 40 psi of H2 for 2 h. After filtration 52 mg of tert-butyl (S)-1-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamate was obtained, yield 91%. MS ESI +ve m/z 273 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].Br[CH2:32][C:33]#[N:34]>>[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:32][C:33]#[N:34])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: N#CCBr
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2O)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OCC#N)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared in a similar manner as described for Example 32 starting from N-(2,6-dichlorobenzoyl)-4-(2-hydroxyphenyl)-L-phenylalanine methyl ester and bromoacetonitrile. ESMS: m/z 483 (MH+).
Reaction SMILES: [C:1]([CH:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2]>[Ni].C(O)C>[NH2:2][CH2:1][CH:3]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCCC(C#N)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)CCCC(CN)c1ccccc1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
About 10 ml of Raney nickel were added to a solution of 58 g of ethyl 5-cyano-5-phenylvalerate [prepared as described in step (a) above] in 400 ml of ethanol, and the mixture was stirred for 2.5 hours at 40° C., under a hydrogen pressure of 3 kg/cm2. The catalyst was filtered off and the filtrate was condensed to give ethyl 6-amino-5-phenylhexanoate as an oily substance. The whole of this oily substance was dissolved in 300 ml of methylene chloride, and 40 ml of triethylamine were added to the mixture. 55 g of di-t-buty pyrocarbonate were added to this solution in an ice-bath. The mixture was stirred for 1 hour, and then the solvent was evaporated off under reduced pressure. The residue was dissolved in ethyl acetate and water. The ethyl acetate layer was separated and washed with an aqueous solution of potassium bicarbonate and then with an aqueous solution of sodium chloride. It was then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residual syrup was mixed with cyclohexane and allowed to stand. The crystals which separated out were collected by filtration as the title product, yield 25 g. The filtrate was condensed and subjected to silica gel column chromatography using a 1:5 by volume mixture of ethyl acetate and cyclohexane as eluent, to give a further 20.5 g of the title compound as crystals, melting at 82°-84° C. Total yield 45.5 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][CH2:11]2)[C:5]([C:24]#[N:25])=[C:4]([SH:26])[N:3]=1.Cl[CH2:28][C:29]1[N:30]=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[S:32][CH:33]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C@H:10]2[CH2:11][CH2:12][C@@H:13]([O:16][Si:17]([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:18])[CH3:19])[CH2:14][CH2:15]2)[C:5]([C:24]#[N:25])=[C:4]([S:26][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[S:32][CH:33]=2)[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
35 mg (0.08 mmol) of the compound from Example 12A (cis isomer), 23 mg (0.09 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 26 mg (0.31 mmol) of sodium bicarbonate are initially charged in 2 ml of dry DMF and stirred at RT for 20 h. The mixture is then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [I:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.C(Cl)Cl>C(Cl)Cl.CO>[I:1][C:2]1[CH:26]=[CH:25][C:5]([CH:6]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[CH2:16][CH2:15][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCN(C(=O)c2ccc(I)cc2)c2ccccc2)c1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)CCN(c1ccccc1)C2c1ccc(I)cc1

Procedure:
The title compound was prepared by analogy to Preparation 65 except that 4-iodo-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide was used instead of 4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide, and the final residue was subjected to flash chromatography using a gradient from neat CH2Cl2 to CH2Cl2:MeOH 60:1.
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][N:9]2[C:18]([C:20]2[C:21]([C:29]3[N:37]4[C:32]([CH2:33][C:34](=[O:38])[CH2:35][CH2:36]4)=[C:31]([C:39]([O:41][CH3:42])=[O:40])[CH:30]=3)=[CH:22][C:23]3[O:27][CH2:26][O:25][C:24]=3[CH:28]=2)=[O:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO>[OH:38][CH:34]1[CH2:33][C:32]2[N:37]([C:29]([C:21]3[C:20]([C:18]([N:9]4[C@H:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[CH2:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH2:10]4)=[O:19])=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)=[CH:30][C:31]=2[C:39]([O:41][CH3:42])=[O:40])[CH2:36][CH2:35]1
Reactant: COC(=O)c1cc(-c2cc3c(cc2C(=O)N2Cc4ccccc4C[C@H]2CN2CCOCC2)OCO3)n2c1CC(=O)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2cc3c(cc2C(=O)N2Cc4ccccc4C[C@H]2CN2CCOCC2)OCO3)n2c1CC(O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.55 g of the compound obtained in Step B (4.47 mmol) in 30 mL of methanol there are added in portions 558 mg (14.75 mmol) of sodium borohydride. The reaction mixture is stirred for one hour at ambient temperature. 50 mL of 1M HCl are subsequently added, and the methanol is evaporated off. The aqueous phase is subsequently neutralised with NaHCO3 and then extracted with dichloromethane. The organic phase is washed in succession with H2O, dried over MgSO4, filtered and concentrated to dryness. The oil so obtained is purified by flash chromatography (dichloromethane/ethanol-ammonia gradient). The title product is obtained in the form of a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[CH:19]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[N:17]=[CH:19][NH:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1N
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(Oc2cc3nc[nH]c3cc2Br)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A solution of 4-bromo-5-(2,4-difluorophenoxy)benzene-1,2-diamine (0.090 g, 0.28 mmol) in tetrahydrofuran (1.1 mL) was treated with ethyl orthoformate (0.142 mL, 0.857 mmol) followed by p-toluenesulfonic acid monohydrate (0.005 g, 0.03 mmol) and stirred at 50° C. for 1 h. The reaction mixture was concentrated and diluted with ethyl acetate and saturated sodium bicarbonate. The organic layer was separated and washed with brine, dried with magnesium sulfate, filtered, and concentrated to give a crude oil. Purification by flash column chromatography (100% hexanes to 100% EtOAc) gave the desired product (69 mg, 74%). LCMS calculated for C13H8BrF2N2O (M+H)+: m/z=325.0, 327.0. found: 325.0, 327.0.
Reaction SMILES: O1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[N:7]1([CH2:12][C:13]2C=CC(NN)=C[CH:14]=2)C=NC=N1>O1CCOCC1.O>[NH:7]1[C:12]2[C:4](=[CH:5][CH:6]=[CH:14][CH:13]=2)[CH:3]=[CH:2]1
Reactant: C1=COCCC1
Reactant: NNc1ccc(Cn2cncn2)cc1
Solvent: O
Solvent: C1COCCO1
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 37.2 %

Procedure:
3,4-Dihydro-2H-pyran (3.9 ml, 42.7 mmol) was added to a stirred solution of 4-(1,2,4-triazol-1-ylmethyl)phenylhydrazine (EP 497,512; 4.0 g, 21.1 mmol) in dioxane/water/5N HCl (38 ml/14 ml/4.7 ml) and stirred at room temperature for 1.75 h. The solution was then refluxed for 1.5 h and the solvent removed under vacuum. The residue was taken up into CH2Cl2 and saturated aqueous K2CO3 solution. The aqueous was separated and further extracted with CH2Cl2 (×4). The combined organic extracts were dried (MgSO4) and evaporated and the residue chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (80:8:1) to give the title-indole (0.919 g, 17%), δ(250 MHz, CDCl3) 1.91-2.03 (2H, m, CH2), 2.84 (2H, t, J=7.9 Hz, CH2), 3.73 (2H, t, J=7.9 Hz, CH2), 5.43 (2H, s, CH2), 7.04 (1H, d, J=2.3 Hz, Ar--H), 7.11 (1H, dd, J=2.3 and 8.3 Hz, Ar--H), 7.35 (1H, d, J=8.3 Hz, Ar--H), 7.58 (1H, s, Ar--H). 7.97 (1H, s, Ar--H). 8.02 (1H, s, Ar--H), 8.18 (1H, s, NH).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>C(O)(=O)C>[C:11]1(=[O:16])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14](=[O:15])[N:1]1[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: NC1Cc2ccccc2C1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1C1Cc2ccccc2C1
Temperature: 0 °C
Yield: 86.3 %

Procedure:
To 200 ml of acetic acid were added 26.4 g of 2-amino-indane and 44.5 g of phthalic anhydride, and the mixture was refluxed under heating for 17 hours. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration, washed, dried and then recrystallized from ethyl acetate to obtain 45.04 g of 2-(1,3-isoindolinedion-2-yl)indane.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[NH2:11]>C(Cl)(Cl)Cl>[CH3:18][O:17][C:13]1[CH:12]=[C:10]([NH:11][S:2]([Cl:1])(=[O:5])=[O:3])[CH:9]=[C:8]([O:7][CH3:6])[C:14]=1[O:15][CH3:16]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(NS(=O)(=O)Cl)cc(OC)c1OC
Reaction time: 1 h
Yield: 6 %

Procedure:
At −5° C., chlorosulfonic acid (0.22 mL, 3.33 mmol) was slowly added to a chloroform solution (10 mL) of 3,4,5-trimethoxyaniline (1.83 g, 10 mmol). After 1 hour at 25° C., the suspension was filtered, and the solid was washed with CH2Cl2. The residue was dissolved in Na2CO3 solution (0.5M, 20 mL), which was washed with ethyl ether (2×20 mL). The aqueous solution was concentrated to give a solid, which was extracted with boiling ethanol (20 mL). After evaporation of ethanol, the solid (200 mg) was treated with PCl5 (200 mg) in refluxing benzene (15 mL). The precipitate was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (50% EtOAc in hexanes), affording 56 mg (5% yield) of the sulfamoyl chloride as a off-white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:27])[CH2:11][C:12]#[C:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([O:8][CH2:9][C@H:10]([OH:27])[CH2:11]/[CH:12]=[CH:13]\[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#CC[C@@H](O)COCc2ccccc2)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(/C=C\C[C@@H](O)COCc2ccccc2)CC1
Reaction time: 0.67 h

Procedure:
The alcohol from step 1 of this example (9.1 g, 24.4 mmol) was dissolved in EtOAc (100 ml) and quinoline (0.48 ml, 4.03 mmol) was added. Lindlar's catalyst (1.04 g) was added and the vessel evacuated and refilled three times with H2. The slurry was stirred under a H2 atmosphere for 40 min. The starting material was completely consumed. The mixture was filtered through CELITE and rinsed with EtOAc (4×50 ml). The volume of EtOAc was reduced ˜80% in vacuum. The remaining solution was diluted with ether (100 ml) and washed with 2N HCl (100 ml). The aqueous fraction was re-extracted with ether (2×50 ml), organics combined and washed with 15 ml 2 N HCl. The organic fraction was washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered, and stripped. The resulting oil was purified by chromatography on SiO2 30% eluting with EtOAc:Hexanes to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10](Cl)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][CH:7]=1.[I:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]=[C:25](N3CCOCC3)[C:24]2=[O:35])=[CH:19][CH:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:25]3[C:24](=[O:35])[N:23]([C:20]4[CH:21]=[CH:22][C:17]([I:16])=[CH:18][CH:19]=4)[CH2:28][CH2:27][C:26]=3[C:10]([S:11]([CH3:14])(=[O:13])=[O:12])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)C(Cl)=NNc1cccc(Cl)c1
Reactant: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc(I)cc1)C2=O
Temperature: 70 °C
Reaction time: 14 h
Yield: 63.7 %

Procedure:
The methanehydrazonoyl chloride (8.47 g, 31.7 mmol) and 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (12.17 g, 31.7 mmol) were combined in anhydrous toluene. The solution heated to 70° C. and triethylamine (13.2 mL, 95.1 mmol) was added dropwise. After the addition was complete the reaction was warmed to 90° C. and stirred at this temperature for 14 h. Analysis by LC/MS indicated formation of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-7-a-morpholin-4-yl-1, 3a, 4,5,6,7a-hexahydro-pyrazolo[3,4-c]pyridin-7-one complete with less than 5% of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one remaining. The solvent was removed in vacuo. To the viscous oil was added dichloromethane (50 mL) then trifluoroacetic acid (30 mL) and heated to reflux for 4 h. The solvent was evaporated and the residue purified by flash column chromatography eluting with a gradient of hexane to 40% ethylacetate/hexane to give 10.65 g (64%) of 1-(3-chloro-phenyl)-6-(4-iodo-phenyl)-3-methanesulfonyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one.