Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:37]=[CH:36][C:22]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]#[N:35])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)[CH:7]=1.C(=O)(O)[O-:41].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:37]=[CH:36][C:22]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([NH2:35])=[O:41])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)[CH:7]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(F)cc1-c1nnc(Nc2ccc(Oc3ccnc4cc(C#N)ccc34)cc2)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(F)cc1-c1nnc(Nc2ccc(Oc3ccnc4cc(C(N)=O)ccc34)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sealed tube was charged with 4-(4-(4-(5-fluoro-2-methoxyphenyl)phthalazin-1-ylamino)phenoxy)quinoline-7-carbonitrile (150 mg, 0.529 mmol) in neat concentrated sulfuric acid (3 mL). The tube was sealed and placed in a preheated oil bath at 80° C. for 1 h, at which point the reaction was determined complete by LCMS. The reaction was cooled to RT and added drop-wise to sat. sodium bicarbonate in an ice bath. Neutralized the mixture with 2N NaOH to a pH of 7 and extracted with ethyl acetate (3×). Organic layers were dried over magnesium sulfate, filtered and concentrated. The crude was purified via silica gel chromatography using a slow gradient of 90:10:1 (DCM:methanol:ammonium hydroxide) in DCM. Fractions contained the desired material were pooled and concentrated in vacuo to afford 4-(4-(4-(5-fluoro-2-methoxyphenyl)phthalazin-1-ylamino)phenoxy)quinoline-7-carboxamide as a tan solid. MS m/z=532 [M+H]+. Calc'd for C31H22FN5O3: 531.54.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[O:22]1[CH2:25][C:24](=[O:26])[CH2:23]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:24]4([OH:26])[CH2:25][O:22][CH2:23]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Reactant: O=C1COC1
Product: COC(=O)c1nc2n(c1C1(O)COC1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (0.3 g) was reacted with oxetan-3-one similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-9-fluoro-3-(3-hydroxyoxetan-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate was reacted via General Procedure L to provide 10-bromo-9-fluoro-3-(3-hydroxyoxetan-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted as a crude with 2-Methyl-3-butyne-ol via General Procedure F to afford 23 mg (51.1%) 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(3-hydroxyoxetan-3-yl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.C(#N)C>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1
Reactant: Nc1ccc(F)c(C23CN(c4ncc(F)cn4)CC2CSC(NC(=O)c2ccccc2)=N3)c1
Solvent: CC#N
Solvent: CO
Product: Nc1ccc(F)c([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1

Procedure:
Racemic N-[7a-(5-amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (1.694 g, 3.63 mmol) is chirally purified by HPLC (Column: Chiralcel OJ, 8×35 cm; eluent: 90% methanol (0.2% dimethylethylamine) and 10% acetonitrile; flow 400 mL/min at UV 280 nm). Analysis of the first eluting isomer (Column: Chiralcel OJ-H 0.46×15 cm; eluent: 10:90 acetonitrile:methanol (with 0.2% dimethylethylamine); flow: 0.6 mL/min at UV 280 nm) confirms the enantiomerically enriched (99% ee) enantiomer with Rt=6.70 minutes, (723 mg, 43%). ES/MS (m/e): 467 (M+H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1)=[O:12])C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Br:20][C:18]1[CH:19]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][CH2:9][OH:8])[CH:15]=[N:16][CH:17]=1
Reactant: O=C(CCOCc1ccccc1)Nc1cncc(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(CCO)Nc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-N-(5-bromo-pyridin-3-yl)-propionamide (Intermediate 31) (1 eq, 8.1 mmol, 2.8 g) in DCM (100 ml) at 0° C., boron tribromide (1 M in DCM, 1.1 eq, 8.9 mmol, 8.9 ml) is added within 10 min. The mixture is allowed to warm up to r.t. and stirred for 1 h at this temperature. The mixture is filtered, the solid residue is washed with DCM, and dried giving the title compound; [M+H]+=326.
Reaction SMILES: [K].[SH:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=[CH:22][N:21]=1>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:27][O:26][C:25]1[C:20]([CH2:19][S:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[N:21][CH:22]=[CH:23][C:24]=1[O:28][CH3:29]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COc1ccnc(CBr)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccnc(CSc2nc3ccccc3[nH]2)c1OC
Yield: 70.5 %

Procedure:
To a mixture of potassium salt of 2-mercaptobenzimidazole (1.45 g), potassium carbonate (1.0 g) and dimethylformamide (10 ml) was added dropwise with stirring a solution of 2-bromomethyl-3,4-dimethoxypyridine (1.18 g) in dimethylformamide (2 ml), and the mixture was stirred at room temperature for 30 minutes, to which chloroform (100 ml) was added. The reaction mixture was washed with water, 1N-sodium hydroxide and water in this order, dried (with sodium sulfate) and evaporated. The residue was purified by column chromatography on silica gel (chloroform-methanol (50:1)), to give 2-[(3,4-dimethoxypyrid-2-yl)methylthio]benzimidazole (1.08 g) as a light yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(C)(C)C.Br[CH2:19][CH2:20]Br>>[N+:14]([C:10]1[CH:9]=[C:8]([C:7]2([C:6]([OH:5])=[O:17])[CH2:20][CH2:19]2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)Cc1cccc([N+](=O)[O-])c1
Product: O=C(O)C1(c2cccc([N+](=O)[O-])c2)CC1

Procedure:
Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,2-dibromoethane (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 1-(3-nitrophenyl)cyclopropanecarboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:14])[C:7]([CH2:10][CH2:11][C:12]#[N:13])=[N:8][CH:9]=1)([O-])=O.O.NN>[Ni].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH3:14])[C:7]([CH2:10][CH2:11][CH2:12][NH2:13])=[N:8][CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1CCC#N
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cnc1CCCN
Yield: 145.2 %

Procedure:
Raney nickel (24 g) was added to a stirred solution under nitrogen of 5-nitro-2-(2-cyanoethyl)-3-methylpyridine (10.36 g) in ethanol (700 ml). Hydrazine hydrate (13.5 ml) in ethanol (30 ml) was added over 2.75 hr., followed by further additions of Raney nickel (15 g) and hydrazine hydrate (60 ml) over two days which included two periods of eight hours at 50° C. The solution was decanted off, filtered through a hyflo pad and concentrated to dryness to give a green oil (13 g). This oil was chromatographed on silica in ethylacetate/ethanol/0.880 ammonia 15:10:2 to give the title compound as an oil (8.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:23][CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28].ClCCl>CC(O)CC>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C@H:12]([OH:23])[C@@H:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:28][CH2:27][CH:26]([O:29][CH3:30])[O:25][CH3:24])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COC(CN)OC
Reactant: COc1ccc(C2OC2c2ccc(OC)c(OC)c2)cc1OC
Solvent: ClCCl
Solvent: CCC(C)O
Product: COc1ccc([C@@H](NCC(OC)OC)[C@@H](O)c2ccc(OC)c(OC)c2)cc1OC

Procedure:
57 g (0.17 mol) of 3,3',4,4'-tetramethoxy-stilbene oxide, 120 ml (1.1 mol) of aminoacetaldehyde dimethyl acetal, 1.5 l of dichloromethane, 80 ml of 2-butanol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].FC(F)(F)S(OCC(F)(F)F)(=O)=O>C1COCC1>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:3][C:2]([F:7])([F:6])[F:1])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CC(F)(F)F)CC3)cc1OCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.9 %

Procedure:
A suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoro acetate (250 mg, 0.51 mmol) in THF (5 mL) was treated with TEA and the mixture flushed with argon. 2,2,2-trifluoroethyl trifluoromethane sulfonate (0.15 mL, 1.02 mmol) was added and the mixture stirred at RT for 72 h. The reaction mixture was partitioned between DCM and water, the organic layer washed with saturated aqueous sodium hydrogen carbonate followed by brine and then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was dissolved in 1.25 M HCl in methanol then concentrated in vacuo to give a solid which was triturated in IPA then diethyl ether. The resultant solid was subjected to RPHPLC (C18 column, gradient 10 to 98% methanol in water+0.1% HCO2H) to give 361 as a white solid (49 mg, 23%). LCMS: RT=4.59 min, [M+H]+=461. 1H NMR 400 MHz (DMSO-d6) δ: 8.33 (1H, d, J=8.29 Hz), 7.91-7.91 (2H, m), 7.08 (1H, dd, J=8.36, 1.79 Hz), 6.92 (1H, m), 5.91-5.90 (1H, m), 4.51 (4H, q, J=5.90 Hz), 3.21 (2H, q, J=10.30 Hz), 3.03 (2H, d, J=11.25 Hz), 2.45 (3H, m), 1.76 (2H, m), 1.69-1.67 (2H, m), 1.49 (6H, d, J=6.60 Hz)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][CH3:14])[C@H:9]1[C:15](=[O:17])[NH2:16])=O)(C)(C)C.CO.[ClH:20]>>[ClH:20].[CH3:14][O:13][C@H:10]1[CH2:11][CH2:12][NH:8][C@@H:9]1[C:15]([NH2:16])=[O:17]
Reactant: CO[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(N)=O
Agent: Cl
Solvent: CO
Product: CO[C@H]1CCN[C@@H]1C(N)=O
Yield: 38 %

Procedure:
(2S,3S)-2-Carbamoyl-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 0.49 mmol) was stirred in hydrochloric acid (5 mL, 3M in methanol) and methanol for 4 h. The reaction mixture was concentrated in vacuo and the residue triturated in diethyl ether and methanol to give (2S,3S)-3-Methoxy-pyrrolidine-2-carboxylic acid amide hydrochloride salt as a white solid (69 mg, 38%). 1H NMR 400 MHz (DMSO-d6) δ: 8.28 (1 H, br, s), 7.82 (1 H, br, s), 4.23 (1 H, m), 4.11-4.10 (1 H, m), 3.37 (1H, m), 3.35 (3 H, s), 3.19-3.16 (1 H, m), 2.07 (1 H, m), 1.84-1.83 (1 H, m)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.[H-].[Na+].[F:32][C@H:33]1[C@@H:38](OS(C)(=O)=O)[CH2:37][CH2:36][N:35]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:34]1.CS(OC1CCN(C(OC(C)(C)C)=O)CC1)(=O)=O>CC(N(C)C)=O>[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:4]2[CH:5]=[N:1][N:2]([C@@H:38]3[CH2:37][CH2:36][N:35]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:34][C@H:33]3[F:32])[CH:3]=2)[N:8]=1)[CH3:29]
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H](F)C1
Agent: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCc1nn(Cc2cnn([C@@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3F)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.10 mmol; prepared according to Example 21, Step A) in DMA (5 mL) was added sodium hydride (7.5 mg, 0.31 mmol) and a mixture (approximately 9:1) of (3R,4S)-tert-butyl 3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (prepared as in WO 2008/124323) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (62 mg). The reaction mixture was heated to 80° C. and stirred for 3 hours. The mixture was concentrated under reduced pressure and silica gel chromatography (DCM/MeOH 10:1) gave the product (21 mg).
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27](F)=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27]([N:5]3[CH2:6][C:3]([F:7])([F:2])[CH2:4]3)=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[O:15]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(N3CC(F)(F)C3)c(Cl)c2)cc1F
Temperature: 90 °C
Reaction time: 15 h
Yield: 24.6 %

Procedure:
3,3-Difluoroazetidine hydrochloride (98 mg, 0.76 mmol) was added to a suspension of 5-chloro-4-(5-chloro-6-fluoropyridin-3-yloxy)-2-fluoro-N-(methylsulfonyl)benzamide (Example 19, 150 mg, 0.38 mmol) and potassium carbonate (74 mg, 0.53 mmol) in dimethylsulfoxide (1 mL). The reaction mixture was stirred at 90° C. in the microwave for 15 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude compound was purified by reverse phase preparative HPLC eluting with acetonitrile:water (from 5:95 to 95:5) to give the title compound as a colourless solid (44 mg, 25%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[O:5][N:4]=1.C1N2CN3CN(C2)C[N:15]1C3.Cl>CCO>[Cl:13][C:10]1[S:9][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH2:15])[CH:7]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCO
Product: NCc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.00 g (3.59 mmol) 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole and 503.3 mg (3.59 mmol) urotropin were dissolved in 40 mL EtOH. The reaction mixture was stirred at room temperature for 16 h. The next day 3 mL of a conc. HCl-solution were added and the resulting mixture was refluxed for 45 minutes. After cooling the precipitate was filtered off and washed with water. The white crystalline material was dried under reduced pressure at 40° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:16]=1[NH2:17])[CH3:14].C(O)=O>CCCCCCC>[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH3:23])[C:16]=1[N:17]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11])[CH3:14]
Reactant: CCc1cccc(CC)c1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CCCCCCC
Solvent: O=CO
Product: CCc1cccc(CC)c1N=C(C)c1cccc(C(C)=O)n1
Yield: 41.6 %

Procedure:
10.35 g of 2,6-diacetylpyridine (0.0634 mol), 7.10 g of 2,6-diethylaniline (0.0476 mol) and 2 ml of formic acid were stirred in 300 ml of heptane at room temperature for 71 h. The insoluble solid was filtered off (11.10 g) and dissolved in 150 ml of toluene and the solution was extracted with 10 ml of a saturated Na2CO3 solution. The toluene phase was dried over Na2SO4 and filtered and the solvent was distilled off in vacuo. 5.58 g (0.0198 mol) of the product were obtained in a purity of 99% (GC/MS) in a yield of 40%. The mother liquor of the reaction solution was freed completely from the solvent and the residue was recrystallized from hot heptane. 2.00 g (0.0068 mol) of the product were additionally obtained in a purity of 100% (GC/MS). The total yield was 54%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:36])[C:32]([F:35])([F:34])[F:33])=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:9](=[O:14])[C:24]1[CH:25]=[CH:26][C:27]([O:30][CH:31]([CH3:36])[C:32]([F:33])([F:34])[F:35])=[CH:28][CH:29]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(Oc1ccc(Br)cc1)C(F)(F)F
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Product: CC(Oc1ccc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)cc2)cc1)C(F)(F)F

Procedure:
The title compound was prepared from rac-[(4-chloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 8) and rac-1-bromo-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzene (Intermediate 35) in analogy to Example 1a): MS (ISP): 458.2 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.CN(C)[CH:23]=[O:24]>O1CCCC1.O.C(O)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:23]=[O:24]
Reactant: Fc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=Cc1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of diisopropylamine (7.9 mL, 55 mmol) in anhydrous tetrahydrofuran (70 mL) cooled to 0° C. was treated dropwise with butyllithium (1.6 M in hexanes, 34.9 mL, 56 mmol). The mixture was stirred at 0° C. for 15 min, then it was cooled to −78° C., and 1-bromo-3-fluoro-benzene (6.1 mL, 56 mmol) was added over 10 min. The mixture was stirred at −78° C. for 1 h, then anhydrous N,N-dimethylformamide (4.9 mL, 64 mmol) was added dropwise over 5 min. The mixture was stirred for another 20 min, then acetic acid (8 mL) and water (180 mL) were added, warmed up to RT, and extracted with ethyl acetate (2×175 mL). The combined organic layers were washed with water (2×75 mL), brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to yield the crude product which was purified by silica gel chromatography (20-30% EtOAc in hexanes) to give 2-bromo-6-fluorobenzaldehyde as a pale yellow solid. MS (ESI, pos. ion) m/z: 204 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(NC([N:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][C:35]3[C:36]4[CH:43]=[C:42]([C:44]5[CH:49]=[CH:48][C:47]([O:50][CH2:51][C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)=[CH:46][CH:45]=5)[N:41](COCC[Si](C)(C)C)[C:37]=4[N:38]=[CH:39][N:40]=3)=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)=O)C>O1CCCC1>[CH2:51]([O:50][C:47]1[CH:48]=[CH:49][C:44]([C:42]2[NH:41][C:37]3[N:38]=[CH:39][N:40]=[C:35]([O:34][C:30]4[CH:29]=[C:28]5[C:33](=[CH:32][CH:31]=4)[NH:25][CH:26]=[CH:27]5)[C:36]=3[CH:43]=2)=[CH:45][CH:46]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CCNC(=O)n1ccc2cc(Oc3ncnc4c3cc(-c3ccc(OCc5ccccc5)cc3)n4COCC[Si](C)(C)C)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(COc2ccc(-c3cc4c(Oc5ccc6[nH]ccc6c5)ncnc4[nH]3)cc2)cc1
Yield: 13.3 %

Procedure:
After dissolving 1.5 ml of tetrahydrofuran in 22 mg of 5-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-indole-1-carboxylic ethylamide, a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran was added and the mixture was refluxed for 2 hours. After returning it to room temperature, water was added and the precipitated crystals were filtered out and subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 2 mg of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:1][C@@H:2]2[CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]4[C@@H:18]3[CH2:17][CH2:16][C@@:15]3([CH3:23])[C@H:8]4[CH2:9][CH2:10][C@@H:11]3[C:12](=[O:14])[CH3:13])[CH2:3]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3α-Hydroxy-5α-pregnan-20-one (5.12 g) in pyridine (40 mL) was treated with toluene-p-sulphonyl chloride (5.6 g), and the reaction mixture was stirred at room temperature for 18.0 h. This solution was poured into dilute (5%) hydrochloric acid (200 mL) and washed three times with chloroform (150 mL portions). The combined organic phase was extracted with more 5% hydrochloric acid and water, dried over magnesium sulfate and evaporated to an oil which on standing crystallized and gave 3α-toluene-p-sulphonyloxy-5α-pregnan-20-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:24])[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][OH:23].[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:28]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:24])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:25][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([OH:36])=[O:35])=[CH:31][CH:32]=1)[CH2:20][CH2:21][CH2:22][OH:23]
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCO)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCO)Cc3ccc(CC(=O)O)cc3)c2n1
Reaction time: 0.17 h

Procedure:
To 6-amino-2-butoxy-9-{3-[(3-hydroxypropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one (described in WO2007/031726 Example 1 step (viii)) (0.5 g) in NMP, the product from step (i) (0.35 g) was added and the mixture stirred for 10 mins. Sodium triacetoxyborohydride (1.25 g) was then added and stirred at rt for 16 hrs. The reaction mixture was diluted with water and passed through a SCX column, eluted with MeCN/2% NH3 (aq), and solvent removed to give the crude product. The product was purified via RPHPLC to afford the subtitle compound as a solid; 1H NMR DMSO 67.14-7.20 (m, 4H), 6.40 (s, 2H), 4.12 (t, 2H), 3.67 (t, 2H), 3.51 (s, 2H), 3.47 (s, 2H), 3.39 (t, 2H), 2.36-2.44 (m, 4H), 1.78-1.86 (m, 2H), 1.52-1.65 (m, 4H), 1.32-1.41 (m, 2H), 0.90 (t, 3H) MS multimode (+) 487