Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[H-].[Na+].I[CH3:27].O>CN(C)C=O>[CH2:1]([O:3][N:4]=[C:5]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]([CH3:27])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCON=C(C)c1ccc(S(=O)(=O)NCc2ccncc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCON=C(C)c1ccc(S(=O)(=O)N(C)Cc2ccncc2)cc1
Temperature: 22.5 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
0.4 g (1.2 mmol) of the compound from Example 2 was added to a slurry of 0.04 g (1.32 mmol) of NaH (95% pure) in 50 ml of dimethylformamide (DMF), and the mixture was then stirred at 20-25° C. for 10 min. A solution of 0.17 g (1.2 mmol) of iodomethane in 10 ml of DMF was then added dropwise, and the combined reaction solution was stirred at 20-25° C. for about 18 hours, poured into water and then extracted with MtBE. The the organic phases were washed with water and then dried. Removal of the solvent gave 0.3 g of the title compound as a viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl>[C:28]([Si:25]([CH3:27])([CH3:26])[O:15][CH2:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a solution of [3-nitro-5-(trifluoromethyl)phenyl]methanol (2.80 g, 12.7 mmol) in DCM (20 mL) was added DIPEA (6.62 mL, 38.00 mmol). The reaction mixture was cooled to 0° C. tert-Butyldimethylsilyl chloride (3.82 g, 25.3 mmol) was added dropwise and the reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was diluted with DCM and washed with water and brine. The organic solution was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl(dimethyl)-{[3-nitro-5-(trifluoromethyl)benzyl]oxy}silane (3.71 g, 87%) as a white solid. 1H NMR (400 MHz,CDCl3, HCl salt) δ: 8.35-8.41 (m, 2H), 7.92 (s, 1H), 4.88 (s, 2H), 0.97 (s, 9H), and 0.15 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([O:27]C(C)C)[CH:24]=[C:23]([C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:22]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.ClB(Cl)Cl.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:31](=[O:37])[NH:32][CH2:33][CH:34]([CH3:35])[CH3:36])[CH:24]=[C:25]([OH:27])[CH:26]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(OC(C)C)cc(C(=O)NCC(C)C)c3)cc12
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(O)cc(C(=O)NCC(C)C)c3)cc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 250 mL RBF was added 2-(4-fluorophenyl)-5-(3-(isobutylcarbamoyl)-5-isopropoxyphenyl)-N-methylbenzofuran-3-carboxamide (1.3409 g, 2.67 mmol) in dichloromethane (20 mL). The flask was sealed with a septa, placed under N2 and stirred for 5 minutes. To this mixture was then added (cold) 1M trichloroborane (8.00 mL, 8.00 mmol) in dichloromethane. The solution was stirred at room temperature for 6 hours. The reaction mixture was cooled to 0° C. and methanol was added to quench the reaction. The flask was allowed to warm to room temperature and the volatiles were removed to give a quantitative yield of a tan solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.06 (d, J=6.78 Hz, 6H), 1.97-2.12 (m, 1H), 3.01-3.12 (m, 3H), 3.29 (t, J=6.53 Hz, 2H), 7.27-7.40 (m, 4H), 7.64 (s, 1H), 7.72 (s, 2H), 7.98 (s, 1H), 8.03 (dd, J=8.66, 5.40 Hz, 2H), 8.56 (br. s., 1H). LCMS Rt 2.157 min., m/z 461.03 (M+H), 97.6% purity.
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(C3C=CC(O)=CC=3)[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[C:9]1([OH:8])[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(C2(c3ccc(O)cc3)CCC(O)CC2)cc1
Solvent: Oc1ccccc1
Product: Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
The same reaction and post-treatment as described in Example 1 were carried out, except that 75.7 g (0.20 mole) of the phenol adduct of 4,4-bis(4-hydroxyphenyl) cyclohexanol was used in place of 56.9 g (0.20 mole) of 4,4-bis(4-hydroxyphenyl)cyclohexanol. 4,4'-Biphenol was obtained as white crystals in a yield of 33.8 g. The product had a purity of 98.1% based on liquid chromatography and a p-phenylphenol content of 1.2%.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH2:4][CH:5]=[CH2:6])[CH3:3].C(N(CC)CC)C.Cl[P:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][C:2]([O:7][P:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:4][CH:5]=[CH2:6])[CH3:3]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: C=CCC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCC(C)(C)OP(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a stirred solution of 2-methyl-pent-4-en-2-ol (5.0 g; CAS 624-97-5) in THF (50 ml) were added sequentially 4-dimethylaminopyridine (1.22 g), triethylamine (8.32 ml) and chlorodiphenylphosphine (10.2 ml). The resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated and purified by column chromatography (basic alumina; gradient: heptane/EtOAc) to give (2-methyl-pent-4-en-2-oxy)diphenylphosphine (8.0 g, 56%) as a colourless oil which was used immediately in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][OH:26]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:25][OH:26])[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NO
Agent: Cl
Product: CC(=NO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 72 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and hydroxylamine hydrochloride in 72% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, DMSO-d6), δ ppm 9.31 (s, 1H), 8.89 (d, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:10])[CH:5]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(C(=O)O)cc(-c2ccco2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(C(=O)NCc2ccccc2)cc(-c2ccco2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 35.3 %

Procedure:
A solution of 2-amino-6-(2-furyl)pyrimidine-4-carboxylic acid (103 mg, 0.5 mmol) in DMF (2 mL) was treated with benzylamine (59 mg, 0.55 mmol), EDCl (104 mg, 0.54 mmol) and 4-dimethylaminopyridine (66 mg, 0.54 mmol), stirred at room temperature for 17 h, poured into water (25 mL) and extracted with EtOAc (2×25 mL). The combined organic phase was washed with water (25 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; isopropyl ether:EtOAc, (100:0-0:100)] to give the title compound (52 mg, 40%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17]2)(=[O:15])=[O:14])[CH:9]=[C:8]([O:29][CH3:30])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:21][C@@H:18]1[CH2:19][CH2:20][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:29][CH3:30])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:2]=3[F:1])[N:11]=2)(=[O:14])=[O:15])[CH2:17]1
Reactant: COc1cc(NS(=O)(=O)N2CC[C@@H](NC(=O)OC(C)(C)C)C2)nc(SCc2cccc(F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CC[C@@H](N)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl {(3R)-1-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]pyrrolidin-3-yl}carbamate (0.75 g) in DCM (10 ml) was added TFA (10 ml) slowly. The reaction then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the subtitle compound as a white solid. Yield: 0.17 g
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[NH2:19][C:13]1[N:12]=[C:11]([NH2:20])[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])=[O:25])[CH2:2][CH2:3]2)[N:14]=1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: O=C(Cl)c1ccccc1F
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccccc4F)CC3)cccc2n1
Yield: 60 %

Procedure:
The amidation of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) was carried out using 2-fluorobenzoyl chloride (57 mg; 0.36 mmol) via Method AA to yield 43 mg. (60% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.49 (m, 1H), 7.33 (m, 4H), 7.17 (br s, 2H), 6.77 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.94 (br s, 2H), 4.56 (br d, J=12.8 Hz, 1H), 4.03 (d, J=6.0 Hz, 2H), 3.42 (br d, J=12.8 Hz, 1H), 3.12 (m, 1H), 2.86 (t, J=11.2 Hz, 1H), 2.22 (br s, 1H), 1.89 (br d, J=13.6 Hz, 1H), 1.73 (br d, J=11.2 Hz, 1H), 1.26 (m, 2H). MS m/z (ESI) 396 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:34][CH3:35]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:34][CH3:35])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=S(=O)(c1ccccc1)c1ccc2[nH]c3c(c2c1)CCN(Cc1ccccc1)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(Cc1ccccc1)CC2

Procedure:
A 0° mixture of 3-benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (EXAMPLE 1, Step II, 301 mg, 0.723 mmol) in dry DMF (5 ML) is treated with sodium hydride (60% in oil, 32 mg, 0.795 mmol), and allowed to warm to 20-25° over 1.5 hr. The mixture is then cooled (0°), treated with iodoethane (64 μL, 0.795 mmol) and allowed to slowly warm to 20-25° under nitrogen over 72 hr. The resultant mixture is diluted with ethyl acetate (50 mL) and washed with H2O (3 X 25 mL) and saline (25 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a solid. The solid is purified via chromatography (20 g SG; ethyl acetate/heptane, 65/35) to give the indole as a solid, mp=188-191°; IR (drift) 1477, 1373, 1300, 1289, 1157, 1148, 1094, 766, 756, 738, 728, 701, 694, 645 and 621 cm−1; NMR (300 MHz, CDCl3) 8.10-8.20,7.90-8.05, 7.65-7.75, 7.20-7.50,4.11, 3.82, 2.85-3.05 and 1.27 δ; MS (EI) m/z 444 (M+), 326, 324, 312, 167, 154, 132, 118, 96, 91 and 64.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:16]1[CH:20]=[CH:19][S:18][C:17]=1[CH:21]=[O:22])=[CH:6][NH:7]2.[BH4-].[Na+].ClCCl>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:16]1[CH:20]=[CH:19][S:18][C:17]=1[CH2:21][OH:22])=[CH:6][NH:7]2
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccsc3C=O)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccsc3CO)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
3-(5-Fluoro-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl)thiophene -2-carbaldehyde (120 mg, 0.39 mmol) was suspended in ethanol (5 ml), and sodium borohydride (19.24 mg) was added to the suspension. The resulting mixture was stirred at room temperature for 1 hour. Dichloromethane was added to the reaction mixture, which was washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=30:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to thereby obtain 110 mg of powdery white 5-fluoro-3-(2-hydroxymethylthiophen-3-yl)-8-propoxy-1H-quinolin-4-one (yield: 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2cc(Cl)ccc2c1Cl

Procedure:
8.5 g 7-chloro-3-nitro-quinolin-4-ol (Example 15a) are heated for 7 h in 80 ml POCl3 under reflux. After standing over night, light yellow needles have formed, which are filtered off and washed with water. The POCl3-filtrate is poured into 1 l of ice-water; additional compound precipitates and is filtered off. The solid materials are dissolved in 300 ml CH2Cl2 and washed first with aqueous sodium hydroxide (300 ml water and 30 ml 2N NaOH), then again with pure water. The organic phase is dried over MgSO4 and evaporated. Colorless needles are formed which are filtered off, washed with hexane, and dried for 16 h at 60° C. (high vacuum). mp: 165-167° C.; MS: 244 (M++1); HPLC: tret=12.88 min (Grad 1).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([C:21]([N:23]1[CH2:29][CH2:28][CH2:27][N:26]([CH:30]2[CH2:33][CH2:32][CH2:31]2)[CH2:25][CH2:24]1)=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=O)(C)(C)C>CCO.Cl.O1CCOCC1>[CH:30]1([N:26]2[CH2:27][CH2:28][CH2:29][N:23]([C:21]([C@@:9]3([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)[CH2:10][CH2:11][CH2:12][NH:8]3)=[O:22])[CH2:24][CH2:25]2)[CH2:31][CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCCC1(Cc1cccc(F)c1)C(=O)N1CCCN(C2CCC2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(N1CCCN(C2CCC2)CC1)[C@@]1(Cc2cccc(F)c2)CCCN1
Yield: 54.3 %

Procedure:
A solution of 2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-2-(3-fluoro-benzyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (40.0 mg) in EtOH (5.0 mL) and 4 M HCl in dioxane (2.0 mL) was stirred for 10 h. The mixture was concentrated and the residue diluted with CH2Cl2 and treated with Et3N. The mixture was washed with water and concentrated to yield title compound (17 mg, 54%). MS (ESI): mass calcd. for C26H38FN3O3, 359.60; m/z found, 360.3 [M+H]+. 1H NMR (CDCl3): 7.23-6.84 (m, 4H), 3.87-3.40 (m, 4H), 3.15-3.0 (m, 1H), 2.97-2.71 (m, 4H), 2.68-2.40 (m, 4H), 2.10-1.98 (m, 3H), 1.93-1.54 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.C([Li:15])CCC.CCCCCC>CCOCC>[CH3:7][N:6]([CH3:8])[C:5]1[CH:9]=[CH:10][C:2]([Li:15])=[CH:3][CH:4]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]c1ccc(N(C)C)cc1
Reaction time: 4 h

Procedure:
A solution of 20 g (0.1 mol) of p-bromo-N,N-dimethylaniline in 150 mL of anhydrous ether was treated dropwise over 1 h at 0°-5° with a solution of 40 mL of 2.45 M n-butyl lithium in hexane (0.1 mol) in 50 mL of anhydrous diethyl ether. The mixture was stirred at 0.5° for 11/4 h and then allowed to warm to 22°. An additional 1.0 mL of n-butyl lithium solution was added. The mixture was connected to a vacuum line and a distillation receiver bulb cooled in a dry ice bath. The solvents and volatile by-products were removed in vacuo (mechanical pump) at 15°-20°, leaving a pale cream powder of 4-dimethylaminophenyl lithium reagent. The solid was pulverized under argon in the same flask and then further pumped in vacuo at 25° for 20 minutes to remove all volatiles. The lithium reagent was then dissolved in 150 mL of anhydrous ether and treated rapidly with a solution of 5.8 g (5.8 mL×0.03 mol) of di(n-butyl)phosphite in 50 mL of anhydrous ether at 5°-10°. The resulting white slurry was treated with 50 mL of tetrahydrofuran, and the resulting colorless solution was allowed to stir for 12 h at 23°. The mixture was then poured into 200 mL of water and adjusted to neutral pH with a few drops of dilute aqueous sulfuric acid. The organic layer was separated, the aqueous layer was extracted once with 75 mL of diethyl ether, and the combined ether layers were washed (brine) and dried (sodium sulfate) and stripped of solvent to give the crude product as a colorless oil. Addition of 50 mL of fresh ether caused precipitation of 6.6 g (76%) of bis-(4-dimethylaminophenyl)phosphine oxide as a colorless solid, mp 140°-165°. Two recrystallizations from benzene gave 3.1 g (36%) of analytically pure product, mp 150°-170° (in air).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[N:21]=[C:20]2[NH:22][N:23]=[CH:24][C:19]2=[C:18]([N:25]2[CH2:31][CH:30]3[O:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:17]=1.[O:33]1[C:37]2([CH2:42][CH2:41][CH:40](O)[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:15][C:16]1[N:21]=[C:20]2[N:22]([CH:40]3[CH2:41][CH2:42][C:37]4([O:33][CH2:34][CH2:35][CH2:36]4)[CH2:38][CH2:39]3)[N:23]=[CH:24][C:19]2=[C:18]([N:25]2[CH2:31][CH:30]3[O:32][CH:27]([CH2:28][CH2:29]3)[CH2:26]2)[N:17]=1
Reactant: OC1CCC2(CCCO2)CC1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cn[nH]c2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCC4(CCCO4)CC3)c2n1
Temperature: 25 °C

Procedure:
Diisopropyl azodicarboxylate (2.6 mL, 13 mmol) was added in drops to a mixture of 3-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (2.6 g, 10 mmol), 1-oxaspiro[4.5]decan-8-ol (U.S. Pat. No. 4,438,130, Mar. 20, 1984, 1.6 g, 11 mmol), and triphenylphosphine (2.9 g, 11 mmol) in tetrahydrofuran (80 mL). After stirring at room temperature, the mixture was purified by reverse phase high performance liquid chromatography on a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 15% acetonitrile/85% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide two separable diastereomers of 3-(6-chloro-1-(1-oxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane. MS (ES+): 404.2 (M+H)+
Reaction SMILES: [C:1]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)([OH:3])=O.[ClH:18].CN(CCCN=C=NCC)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:18].[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:1]([CH2:4][CH:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]2)=[O:3])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CC1CCNCC1)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77 %

Procedure:
4-Carboxymethyl-1-tert-butoxycarbonylpiperidine (207 mg, 0.85 mmol, commercially available from Neosystem), 1-(3-(N,N-dimethylamino)-prop-1-yl)-3-ethylcarbodiimide hydrochloride (EDC) (177 mg, 0.92 mmol) and 4-(N,N-dimethylamino)pyridine (2 mg, 0.02 mmol) were dissolved in 4 mL of CH2Cl2. (4-(Trifluoromethyl)benzyl)amine (0.114 mL, 0.8 mmol) was added and the reaction was stirred at rt for 14 h. The mixture was diluted with CH2Cl2, washed with 1 N NaOH, 1 N HCl and brine and dried over MgSO4. The solvent was removed, the residue was redissolved in 1% HCl/methanol and the solution was heated to 50° C. for 24 h. The solution was then concentrated to afford 208 mg (77%) of the title compound. ESI-MS: 301.1 (M+H); HPLC A: 1.66 min.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: Cc1ccccc1C=C1c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccccc1CC1c2ccccc2CCc2ccccc21
Reaction time: 17 h

Procedure:
Add the 5-(2-methyl-benzylidene)-10,11-dihydro-5H-dibenzo [a,d]cycloheptene (0.19 g, 0.64 mmol) to a mixture of 10% Pd/C (0.075 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (2.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite, evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product: MS (m/e) 298 (M+). Analysis for C23H22: Calcd: C, 91.99 H, 7.39. Found: C, 91.95 H, 7.39.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33]/[C:34]/2=[CH:37]\[C:38]([NH2:40])=[O:39])=[CH:30][CH:29]=1>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br:1][CH:33]1[CH2:32][C:31]2[C:35](=[CH:36][C:28]([F:27])=[CH:29][CH:30]=2)/[C:34]/1=[CH:37]/[C:38]([NH2:40])=[O:39]
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)/C=C1\CCc2ccc(F)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: NC(=O)/C=C1/c2cc(F)ccc2CC1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.4 %

Procedure:
N-Bromosuccinimide (22.57 g, 126.8 mmoles, Aldrich) and benzoyl peroxide (1.89 g, 7.8 mmoles, Aldrich) were added to a suspension of (E)-2-(6-fluoro-1-indanylidene)acetamide (21.00 g, 109.8 mmoles) in carbon tetrachloride (400 mL) and benzene (400 mL). The mixture was refluxed under a calcium chloride drying tube while shining an infrared lamp on it for two hours, after which time an orange solution formed. The heat and light were removed, and the solution was stirred at ambient temperature for 18 hours. The mixture was filtered, and the solids were washed with ethyl acetate. The washings and filtrate were combined and evaporated in vacuo. The residue was dissolved in ethyl acetate (800 mL) and washed with water (3×200 mL) and brine (200 mL), dried over sodium sulfate, filtered and evaporated in vacuo. The residue was chromatographed on silica gel eluting first with hexane:ethyl acetate (2:1) gradually increasing the polarity to hexane:ethyl acetate (1:1). The fractions containing the major spot were combined and evaporated in vacuo to give a yellow solid which was dried in a vacuum at 70° C. for 18 hours to give 1.022 g (3%) of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide as a yellow solid, mp 162-163° C. 1H-NMR