Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:41]([C:43]1[N:44]=[C:45]([C:56]([O-])=[O:57])[N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=1)#[N:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:56]([C:45]3[N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=[C:43]([C:41]#[N:42])[N:44]=3)=[O:57])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2ncccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC=C(c2ncccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.3 %

Procedure:
A solution of 80.0 mg (0.395 mmol) of 2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-ylamine (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 277 mg (0.593 mmol) of PyBroP, 133 mg (0.435 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 11, step (d)), and 207 μL (1.19 mmol) of DIEA. The mixture was stirred at RT for 17 h, diluted with CH2Cl2 (20 mL) and washed with water (1×10 mL). The aqueous layer was extracted with CH2Cl2 (1×10 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 10-g Isolute SPE column with 25% EtOAc-hexane afforded 95 mg (53%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 9.92 (br s, 1H), 8.72 (dd, 1H, J=8.0, 1.6 Hz), 8.37 (dd, 1H, J=4.4, 1.6 Hz), 7.77 (s, 1H), 7.23-7.18 (m, 1H), 6.00-5.94 (m, 1H), 5.93 (s, 2H), 3.70-3.63 (m, 2H), 2.51-2.43 (m, 2H), 2.18-2.11 (m, 2H), 1.61 (t, 2H, J=6.4 Hz), 1.12 (s, 6H), 1.00-0.94 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[CH:4][N:3]=1.[OH-].[K+].Cl.[F:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][N:16]2[CH2:17][CH2:18][CH:14]([F:13])[CH2:15]2)[CH:5]=[CH:4][N:3]=1
Reactant: F[C@H]1CCNC1
Reactant: BrCc1ccnc(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: FC1CCN(Cc2ccnc(Br)c2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.9 %

Procedure:
To an ice-cold solution of ii (3.0 g, 11.95 mmol) in DMSO (10 mL) was added KOH (1.0 g, 17.92 mmol) followed by the addition of (S)-3-fluoropyrrolidine hydrochloride (2.2 g, 17.92 mmol) under inert atmosphere. The mixture was stirred at 0° C. to RT for 20 min. The mixture was diluted with ice cold H2O followed by extraction with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to give Precursor 44 (3.0 g, 96%).
Reaction SMILES: [BH4-].[Na+].Cl[CH2:4][C:5]([C:7]1[CH:8]=[N:9][C:10]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[CH:11][CH:12]=1)=[O:6].[NH2:20][C@@H:21]([CH3:24])[CH2:22][OH:23].C(Cl)Cl>O1CCCC1.O>[CH3:19][C:14]1[N:13]([C:10]2[N:9]=[CH:8][C:7]([CH:5]([OH:6])[CH2:4][NH:20][C@@H:21]([CH3:24])[CH2:22][OH:23])=[CH:12][CH:11]=2)[C:17]([CH3:18])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)CCl)cn1
Reactant: C[C@H](N)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc(C(O)CN[C@@H](C)CO)cn1
Temperature: 15 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Water (15.0 L) was added to a suspension of sodium borohydride (4.11 Kg, 109 mol) in tetrahydrofuran (140 L) at 15° C. and the resulting solution stirred at 15° C. A solution of 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone (30.0 Kg, 120.6 mol) in tetrahydrofuran (100 L) and water (15 L) was added over 40 minutes maintaining the temperature below 30° C. The resulting solution was stirred for 60 minutes at 15° C. When all the 2-chloro-1-[6-(2,5-dimethylpyrrol-1-yl)pyridin-3-yl]ethanone was consumed the reaction mixture was treated with concentrated HCl (27% w/w, 47 Kg) over 80 minutes maintaining the temperature below 30° C. The mixture was cooled to 15° C. and NaOH (34% w/w, 79 Kg) was added over 60 minutes maintaining the temperature below 30° C. The mixture was then granulated at 20° C. overnight. When all the chloroalcohol intermediate was consumed, the aqueous phase was separated. DCM (150 L) and water (140 L) were added and the mixture was stirred before allowing the phases to separate. The organic phase was washed with water (2×30 L). (S)-(+)-2-amino-1-propanol (17.2 Kg, 229 mol) and tetrahydrofuran (15 L) were added over 20 minutes. The equipment was set for distillation and DCM was replaced by tetrahydrofuran to give a final volume of 160 litres. The reaction mixture was left at reflux overnight. After cooling to room temperature, DCM (150 L) was added and the mixture was washed with water (3×30 L). The equipment was set for distillation and the tetrahydrofuran and DCM were replaced by acetonitrile to give a final volume of 84 litres. ααα-trifluorotoluene (300 L) was added over 60 minutes, the mixture was cooled to 5° C. over 8 hours and granulated at 5° C. for 6 hours. The product was collected by filtration, washed with ααα-trifluorotoluene (2×30 L) and dried at 45° C. under vacuum overnight. Yield=65% (22.7 Kg) δH (CDCl3, 300 MHz) 1.10 (3H, t), 2.10 (6H, s), 2.7-3.2 (3H, m), 3.45 (1H, m), 3.70 (H, dd), 4.85 (1H, m), 5.90 (2H, s), 7.20 (1H, d), 7.90 (1H, dd), 8.60 (1H, d) ppm. MS m/z 290 (MH+). The intermediate epoxide was characterised as δH (CDCl3, 300 MHz) 2.10 (6H, s), 2.90 (1H, dd), 3.25 (1H, dd), 4.00 (1H, dd), 5.90 (2H, s), 7.20 (1H, d), 7.70 (1H, dd), 8.40 (1H, d) ppm. MS m/z 215 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:39]=1[NH2:53].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:53][C:39]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]4)=[CH:43][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCCN1CCN(c2ccc(N)c(OC)c2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: OCC(F)(F)F
Product: CCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OC)c2)CC1
Temperature: 175 °C
Yield: 70 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.20 mmol) and [2-(methyloxy)-4-(4-propyl-1-piperazinyl)phenyl]amine (Example 173, step B) (51 mg, 0.20 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (102 μL, 0.41 mmol). The mixture was stirred and heated on a Biotage microwave at 175° C. for 35 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (100 mg, 0.14 mmol, 70%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H), 9.35 (br s, 1H), 8.43 (s, 1H), 8.19 (d, 1H, J=5.13 Hz), 8.09 (m, 1H), 7.76 (m, 1H), 7.68 (d, 1H, J=8.97 Hz), 7.33-7.44 (m, 3H), 7.27 (d, 1H, J=8.61 Hz), 7.17 (t, 2H, J=8.06 Hz), 6.93 (t, 1H, J=6.87 Hz), 6.66 (d, 1H, J=2.20 Hz), 6.44-6.53 (m, 2H), 3.97 (s, 3H), 3.78 (s, 3H), 3.10-3.15 (m, 4H), 2.44-2.54 (m, 4H), 2.27 (t, 2H, J=7.42 Hz), 1.45 (q, 2H, J=7.45 Hz), 0.86 (t, 3H, J=7.32 Hz). MS (ESI): 705 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[H-].[Na+].Br[CH: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>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a stirred solution of 4-chloroisatin (9.10 g, 50.0 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (2.20 g, 55.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, followed by the addition of bromodiphenylmethane (14.80 g, 56.8 mmol). The mixture was stirred at ambient temperature for 20 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from diethyl ether and hexanes to afford 4-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione (14.20 g, 81%): 1H NMR (300 MHz, CDCl3) 7.37-7.17 (m, 11H), 6.98-6.95 (m, 2H), 6.42 (d, J=9.0 Hz, 1H); MS (ES+) m/z 369.9 (M+23), 371.9 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29](O)=[O:30])=[N:11][C:12]([CH2:16][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:45])[CH3:44])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C)C=O.ClCCl.O.CO>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH:43]([CH3:45])[CH3:44])[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[N:11]=1)=[O:30])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(Cc2ncccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ncccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 36.7 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(3-phenyl-pyridin-2-ylmethyl)-pyrimidine-4-carboxylic acid (164) (370 mg, 0.89 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) (292 mg, 1.34 mmol) in dimethylformamide (5 mL) was added N,N-diisopropylethylamine (0.5 mL, 2.69 mmol), the mixture was cooled to 0° C., T3P (50 wt % in ethyl acetate) (1.8 g, 2.69 mmol) was added, and the mixture was stirred for 16 h at room temperature. Silica thin layer chromatography was performed (5% methanol in dichloromethane, Rf=0.3). Water (100 mL) was added, the mixture was extracted with ethyl acetate, dried and concentrated, and purified by a CombiFlash column (eluted at 2-5% methanol in dichloromethane) to get 5-benzyloxy-6-hydroxy-2-(3-phenyl-pyridin-2-ylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (165) (200 mg, 36.46%) as a yellow sticky product.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH3:22]>>[OH:23][CH:20]([CH2:21][CH3:22])[CH2:19][NH:18][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12]
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: CCC(O)CN
Product: CCC(O)CNC(=O)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 54, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 1-aminobutan-2-ol (CAN 13552-21-1) as starting materials and isolated (65 mg, 32%) as colorless oil; MS (ESI, m/z): 305.5 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)=[N:7][CH:6]=1)[CH3:2].COC(OC)OC.[CH2:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:36][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: NCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCOC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)nc1
Reaction time: 3.5 h
Yield: 110.1 %

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinic acid ethyl ester (0.62 g, 2.29 mmol), MeOH (12 mL), Trimethylorthoformate (8 mL), and Phenethylamine (0.26 mL, 2.06 mmol). After the reaction stirs at room temperature under a Nitrogen atmosphere for 3.5 hours, add NaBH4 (251.0 mg, 2.75 mmol). After the reaction stirs at room temperature for 12 hours, concentrate under reduced pressure and add the mixture to a 5 g SCX column. Wash the column with MeOH and elute with 1N NH3 MeOH to afford 854.0 mg (99% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.8 (2H, t), 2.8-3.0 (4H, m), 3.8 (2H, s), 3.9 (3H, s), 6.9 (1H, d), 7.1-7.4 (9H, m), 8.3 (1H, d), 8.8 (1H, s); MS m/z 377 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29])#[N:7]
Reactant: CNCCc1cccc(C(=O)OCCOC)c1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: COCCOC(=O)c1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2n produced 3as. MS found M+H=497. The oxalate salt of 3ar was recrystallized from methanol/ether.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:28])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1.CC(O)=O>CO.[Pd]>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:28])[S:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CN(C)CCCC#Cc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)CCCCCc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 3 h
Yield: 67 %

Procedure:
A solution of 40 mg (0.094 mmol) of N-[4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 3 ml MeOH/0.3 ml dioxane was treated with 0.094 ml 1N AcOH in MeOH followed by 4 mg Pd/C10%, type EION (under argon) and then hydrogenated (1 atm) for 3 h. The reaction mixture was filtered (Celite) and extracted with aqueous sat. NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution, dried (Na2SO4) and evaporated to yield 27 mg (66%) of N-[4-(5-Dimethylamino-pentyl)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 429 (MH+).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[NH:18][C:19]2[C:25](=[CH:26][C:14]=1[CH2:13]3)[CH:24]=[CH:23][C:21](=O)[CH:20]=2)=[O:11].C[OH:29].C(Cl)(Cl)Cl>FC(F)(F)C(O)=O>[CH3:1][CH2:2][C@@:3]1([OH:27])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:16](=[CH:17][C:4]1=2)[C:15]1[N:18]=[C:19]2[C:25]([CH:24]=[C:23]([OH:29])[CH:21]=[CH:20]2)=[CH:26][C:14]=1[CH2:13]3)=[O:11]
Reactant: CO
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(=O)cc-3[nH]c2-1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(O)ccc3nc2-1

Procedure:
Naturally available mixture of 10 and 11-hydroxy camptothecin (1.0 g) is dissolved in anhydrous trifluoroacetic acid (5 ml) and anhydrous methanol (10 ml) to form a homogeneous solution of the quaternized components of the mixture. The homogeneous solution is then absorbed over enough silica gel (60 A; 60-230 mesh) to form a thick slurry. This slurry is dried by evaporating methanol and excess acid in vacuo on a rotary evaporator, leaving a powdery mass. The powder is then loaded over a pre-equilibrated silica gel column using chloroform. The column is washed using 1000 ml of a solvent mixture of 80% chloroform-20% methanol to remove non polar impurities, occluded trifluoroacetic acid and 11-hydroxcamptothecin (fraction A). Elution is then continued with chloroform-methanol-triethyl amine (in the approximate ratio of 1:1:0.01) and the band migrating away from the origin is collected using this eluent (Fraction B). Fractions A and B are evaporated separately and analyzed. Fraction B corresponds to the 10-hydroxy camptothecin isolate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[O:24])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CC(C)(O)CN
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCC(C)(C)O)c2n1
Yield: 55 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and 1-amino-2-methylpropan-2-ol to yield the title compound as a white solid (17 mg, 55% yield). MS (apci) m/z=428.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5](Cl)=[O:6].[OH:20]S(O)(=O)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:5]([OH:20])=[O:6]
Reactant: O=S(=O)(O)O
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1Br
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(C(=O)O)cc1Br
Temperature: 0 °C
Reaction time: 48 h

Procedure:
540 mg (≃0.002 mole) of ##STR17## C5H11 and 700 mg (≃0.002 mole) of 3-bromo-4 octyloxybenzoic acid chloride are charged in a reactor containing 10 ml of pyridine and kept at ambient temperature for 48 hours. The reaction mixture is then poured into a solution containing 10 ml of concentrated H2SO4 and 100 g of ice. The organic fraction is extracted three times with ether then washed three times with water and finally dried on anhydrous Na2SO4. The solvent is evaporated and the product is recrystallised three times in ethanol. 850 ml of product are obtained. The molar efficiency is 73%. Step (d) of substituting the cyanide group for the bromine group
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:15]([C:17]1[CH:40]=[CH:39][C:20]2[CH:21]([C:31]3[C:32](=[O:38])[NH:33][C:34](=[O:37])[NH:35][CH:36]=3)[C:22]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:23]=3[CH:24]=[CH:25][C:19]=2[CH:18]=1)[CH3:16]>>[CH2:15]([C:17]1[CH:40]=[CH:39][C:20]2[CH:21]([C:31]3[C:32](=[O:38])[NH:33][C:34](=[O:37])[N:35]([C:2]4[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=4)[CH:36]=3)[C:22]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:23]=3[CH:24]=[CH:25][C:19]=2[CH:18]=1)[CH3:16]
Reactant: CC(C)(C)OC(=O)c1ccnc(Cl)n1
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2nccc(C(=O)OC(C)(C)C)n2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of step (iii) and the product of example 15 step (vii) by the method of example 19 step (ii).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Br:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Br:30])[CH:19]=1>CN(C=O)C>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Br:30])[CH:19]=1
Reactant: C=C(c1cc(Br)cc(Br)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Br)cc(Br)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.7 %

Procedure:
To a solution of (Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (850 mg, 3.55 mmol) and 1,3-dibromo-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.75 g, 5.32 mmol) in DMF (10 mL) at rt was added TEA (0.5 mL, 3.55 mmol). The reaction mixture was stirred at rt for 18 h, poured into ice-water and extracted with EA (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the desired title compound 5-(5-(3,5-dibromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (600 mg; 32% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.06 (d, J=2.0 Hz, 1 H), 7.79 (m, 4H), 7.73 (dd, J=8.0 Hz, 0.8 Hz, 1H), 4.45 (d, J=18.8 Hz, 1H), 4.33 (d, J=18 Hz, 1H), 1.50 (d, J=2.8 Hz, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=534.0 (M+1, ESI+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)c2ccc(NC(=O)C(C)(O)C(F)(F)F)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2cccc(O)c2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
To a stirred suspension of N-[4-(3-methoxyphenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.25 g, 3.1 mmol) in dry methylene chloride (30 mL) was added boron tribromide (9.3 mL of a 1.0M solution of boron tribromide in methylene chloride, 9.3 mmol). The resulting solution was stirred at room temperature for 2 hours, diluted with methylene chloride (50 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting tan solid was triturated with methylene chloride to yield the title propanamide as a white solid (0.98 g, 78%); mp 164-167° C. 1H-NMR (300 MHz, d6-DMSO): 1.57 (s, 3H, CH3) 7.00-7.04 (m, 1H, aromatic) 7.24 (t, 1H, J=1.6 Hz, aromatic) 7.31-7.40 (m, 2H, aromatic) 7.55 (s, 1H, OH) 7.89 (d, 2H, J=8.9 Hz, aromatic) 8.00 (d, 2H, J=9.0 Hz, aromatic) 10.22 (s, 1H, NH), 10.41 (s, 1H, ArOH). MS (CI, CH4): 390 (M+1).