Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:22][NH:23][C:24]([NH2:26])=[O:25].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][CH:16]=2)[C:3]([NH:26][C:24]([NH:23][CH3:22])=[O:25])=[O:21])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionic acid methyl ester (350 mg, 1.13 mmol) and methyl urea (184 mg, 2.48 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 6.0 mL, 4.18 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C., filtered through celite, and the celite was thoroughly washed with ethyl acetate. The ethyl acetate filtrate was washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionyl]-3-methyl urea (124 mg, 31%) as a white solid: mp 205-206° C.; EI-HRMS m/e calcd for C17H24N2O4S (M+) 352.1457, found 352.1445.
Reaction SMILES: OC[C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([CH3:32])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:38]1(N)[CH2:40][CH2:39]1.[CH3:42][N:43](C=O)C>ClCCl>[CH:38]1([NH:5][CH2:4][C:3]2[N:7]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([CH3:32])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[N:6]=[CH:42][N:43]=2)[CH2:40][CH2:39]1
Reactant: CN(C)C=O
Reactant: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2
Reactant: NC1CC1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3ncnc3CNC3CC3)c1)CC(=O)N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 132) (180 mg, 0.42 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (108 mg, 55%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl[S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=1)(=[O:31])=[O:30].C([O-])(O)=O.[Na+]>C1COCC1>[C:14]([C:5]1[CH:4]=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:2]([O:1][S:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:41])[CH:33]=2)(=[O:31])=[O:30])=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=1)(=[O:15])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: O=C(c1ccccc1)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc(-c2ccccc2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2ccccc2)c1
Reaction time: 3.5 h
Yield: 20.5 %

Procedure:
At ambient temperature, to a stirred solution of (2'-hydroxy-[1,1';3',1"]terphenyl-5'-yl)-phenyl-methanone (2.02 g, 5.77 mmol) in THF (55 mL) was added portionwise 4-chlorosulphonyl-2-hydroxybenzoic acid (2.70 g, 11.4 mmol, RN 98273-15-5) while maintaining the pH at 8 with the simultaneous addition of 0.5M aq. NaHCO3. After the addition was complete the reaction was stirred for 3.5 h. To the reaction was added 4-chlorosulphonyl-2-hydroxybenzoic acid (2.70 g, 11.4 mmol) while maintaining the pH at 8 with the simultaneous addition of 0.5 M aq. NaHCO3. After the addition was complete the reaction was stirred for 18 h. To the reaction was added 4-chlorosulphonyl-2-hydroxybenzoic acid (2.05 g, 8.66 mmol) while maintaining the pH at 8 with the simultaneous addition of 0.5M aq. NaHCO3. After 2h, the reaction was quenched with 2N HCl (25 mL), extracted with EtOAc and concentrated. Purification by preparative HPLC (C18, eluting with 75% CH3CN/H2O containing 0.1% TFA) and crystallization from EtOAc/hexane gave 0.65 g (20%) of the title compound as a yellow solid, mp 217° C.; 1H NMR (DMSO-d6) δ 6.60 (d, 1H), 6.74 (dd, 1H), 7.30-7.35 (m, 6H), 7.46-7.49 (m, 4H), 7.57-7.61 (m, 3H), 7.68-7.72 (m, 3H), 7.83-7.85 (m, 2H). mass spectrum (EI) ml/z 550 (M+). Anal. Calcd. for C32H22O7S 0.4H2O: C,68.91; H,4.12; N,0.00. Found: C,68.87; H,4.10; N,0.16.
Reaction SMILES: COC1C=CC(CCCC)=CC=1CCl.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][C:18]=1[CH2:19]Cl.[P:29]([O:34]C)([O:32][CH3:33])[O:30][CH3:31]>>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][C:18]=1[CH2:19][P:29](=[O:34])([O:32][CH3:33])[O:30][CH3:31]
Reactant: COP(OC)OC
Reactant: COc1ccc(C(C)(C)C)cc1CCl
Agent: CCCCc1ccc(OC)c(CCl)c1
Product: COc1ccc(C(C)(C)C)cc1CP(=O)(OC)OC
Yield: 55 %

Procedure:
A solution of 2-methoxy-5-butylbenzylchloride (10 (1.65 g, 7.76 mmol) in trimethyl phosphite (25 ml) was heated at reflux for 22 h under argon. The excess trimethyl phosphite was distilled off under reduced pressure and the residue was purified by column chromatography over silica (dichloromethane/methanol; 49:1), by distillation under reduced pressure (b.p. 215° C. at 0.075 mm Hg) and finally by column chromatography over silica (dichloromethane/methanol; 19:1) to yield a colourless oil of (11) (1.21 g, 55%); 67H (CDCl3) 1.33 (9 H, s, tert-butyl), 3.17 (2 H, d, J=21.8 Hz, CH2P), 3.64 (3 H, s, OCH3), 3.69 (3 H, s, OCH3), 3.86 (3 H, s, Ar-OCH3), 6.83 (1 H, d, J=8.6 Hz, H3), 7.08 (t H, d, J=16.4 Hz, vinylic H), 7.24, 7.29, 7.41, 7.48, and 7.50 (5 H, m, PhH and vinylic H), and 7.57 (1 H, d, J=2.4 Hz, PhH).
Reaction SMILES: [CH:1]([N:4]([CH3:33])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].CCOCC>Br.CC(O)=O>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:33])[CH2:6][C@H:7]2[CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:12]1=[O:27]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(C)(=O)=O)C1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(C)(=O)=O)C1
Yield: 121.5 %

Procedure:
The material from above benzyl (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (600 mg) was dissolved in 33% HBr/AcOH (10 mL) at rt. The solution was stirred for 30 min before Et2O was added. This resulted in a precipitate which was isolated to afford the bis-hydrogen bromide salt of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (525 mg). MS found: (M+H)+=346.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.6 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (26 mg, 23%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].[ClH:19]>CCOC(C)=O>[ClH:19].[OH:10][C@H:8]1[CH2:7][NH:6][C@H:5]([C:3]([N:2]([CH3:18])[CH3:1])=[O:4])[CH2:9]1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 11.0 g of the compound obtained in Step 88-1 in EtOAc (100 ml) was added dropwise a solution of 4 mol/l hydrochloric acid in EtOAc (100 ml) over 20 minutes. The solution was stirred at room temperature for two hours and then the solvent was evaporated under reduced pressure. EtOAc was added, and the solution was stirred for 30 minutes. Thereafter, the precipitated solid was filtered and then dried to obtain 8.21 g of the title compound (colorless solid).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[OH-].[Li+:26].O1CCCC1.CO>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[Li+:26]
Reactant: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)[O-])cc3)oc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 106.9 %

Procedure:
Methyl 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoate (118 mg, INTERMEDIATE 2, Step A) and lithium hydroxide (18 mg) were combined in 10 ml of a 1:1:1 mixture of tetrahydrofuran, methanol, and water. The solution was stirred at 50° C. for 5 h. The solvents were removed in vacuo to provide the title compound as an off-white solid (123 mg). Mass spectrum (ESI) 307.0 (M+1).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][N:27]=1)[C:23]#[N:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:23]([C:22]1[CH:25]=[CH:26][N:27]=[C:20]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)[CH:21]=1)#[N:24]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C#N)ccn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2 g, 8 mmol, 1 eq.) and 2-chloroisonicotinonitrile (2.78 g, 20 mmol, 2.5 eq.) in 50 ml DMF was added cesium carbonate (7.82 g, 24 mmol, 3 eq.). The reaction was stirred at room temperature overnight. The starting material was gone but no right mass was observed. The reaction was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=39:1 to 19:1) to give desired product as yellow oil (1.57 g, yield 56%). MS (ESI) m/z=353 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C@@H:6]1[C@H:11]2[CH2:12][CH2:13][N:8]([CH2:9][C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>CCO>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]([C@@H:6]1[C@H:11]2[CH2:12][CH2:13][N:8]([C:9](=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]2=[O:14])[CH2:7]1)=[O:5])[CH3:16]
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1C(=O)C2
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)C(=O)[C@H]1CN2CC[C@H]1C(=O)C2=Cc1ccccc1
Temperature: 25 °C
Yield: 83.1 %

Procedure:
A mixture of 13 (34.6 g, 154 mmole), benzaldehyde (17.4 g, 164 mmole) and NaOH (6.5 g, 164 mmole) in EtOH (400 ml) was refluxed for 3 hours. After cooling the reaction mixture to room temperature, the resulting yellow crystal was collected by filtration and washed with cold EtOH and dried in vacuo to give 14 (38.4 g, 128 mmole). The filtrate was concentrated under reduced pressure to give a second crop (3.3 g, 11 mmole) (total 41.7 g, 139 mmole, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[N:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[CH:10]=2)=[C:4]([F:22])[CH:3]=1.BrC1C=C[C:27]([NH:30]C2C(C(O)=O)=NN3C=CN=C3C=2)=C(F)C=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.NN.CCN(CC)CC>CC(N(C)C)=O.CCOC(C)=O>[NH2:30][C:27]1[O:16][C:15]([C:14]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:22])=[CH:10][C:11]3[N:12]([CH:19]=[CH:20][N:21]=3)[N:13]=2)=[N:17][N:18]=1
Reactant: O=C(O)c1nn2ccnc2cc1Nc1ccc(Br)cc1F
Reactant: NNC(=O)c1nn2ccnc2cc1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: NN
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Nc1nnc(-c2nn3ccnc3cc2Nc2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Preparation of 7-(4-bromo-2-fluorophenylamino)-imidazo[1,2-b]pyridazine-6-carboxylic acid hydrazide: A mixture of 7-(4-bromo-2-fluorophenylamino)-imidazo[1,2-b]pyridazine-6-carboxylic acid (1.00 equiv), EDCI (1.50 equivalents), and HOBt (1.50 equivalents) in DMA is stirred for 30 minutes at room temperature under N2. Hydrazine (3.00 equivalents) is added followed by Et3N (2.50 equivalents). After the reaction mixture is stirred for 16 hours at room temperature, it is diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and saturated NaCl. The organic layer is dried (Na2SO4) and concentrated under reduced pressure to yield the desired product. The product may be purified by flash column chromatography if further purification is necessary.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[C:22]([CH3:23])=[CH:21][C:20]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=4[C:12]=3[O:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:14][O:13][C:12]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=4[CH:21]=[C:22]([CH3:23])[C:11]2=3)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc2c(c3occ(-c4ccc(C(C)C)cc4)c13)CCCC2
Solvent: CO
Product: Cc1cc2c(c3c1C(c1ccc(C(C)C)cc1)CO3)CCCC2
Yield: 80 %

Procedure:
Using 3-(4-isopropylphenyl)-4-methyl-6,7,8,9-tetrahydronaphtho[1,2-b]furan obtained in Reference Example 196, the title compound was synthesized in the same manner as in Reference Example 199. Yield 80%. Melting point: 54-55° C. (methanol).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:24][O:25][C:26]=2[CH2:27][OH:28])=[CH:16][N:15]=1)=O)C>O1CCOCC1>[CH:1]([NH:4][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[N:24][O:25][C:26]=2[CH2:27][OH:28])=[CH:16][N:15]=1)=[O:11])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a stirred solution of isopropylamine (47.8 mg, 0.8 mmol) in dioxane (3.75 mL) was added dropwise a trimethylaluminium (603 μL, 2 M solution in toluene, 1.21 mmol) and the resulting solution stirred under argon for 30 min. A solution of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (75 mg, 0.2 mmol) in dioxane (3.75 mL) was then added and the resulting solution stirred under argon for a further 1 h at 50° C. The reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (17 mg, 21%) as a colourless gum. MS: m/e=386.2 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH:17]([C:18](=[O:34])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]3=[O:32])=[CH:22][C:21]=2[F:33])[CH2:16]C2N=CC=CC=2C1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[F:33][C:21]1[CH:22]=[C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]2=[O:32])[CH:24]=[CH:25][C:20]=1[NH:19][C:18]([CH:17]1[NH:8][CH2:6][C:31]2[N:26]=[CH:27][CH:28]=[CH:29][C:30]=2[CH2:16]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N1Cc2cccnc2CC1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2ccccc2=O)cc1F)C1Cc2cccnc2CN1

Procedure:
A solution of 7-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (310 mg) in 8 ml dichloromethane and 1.53 ml TFA was stirred for 4 hrs at rt. The reaction mixture was poured onto 1M NaOH/ice and extracted twice with dichloromethane. The organic layers were dried over magnesium sulfate, evaporated and purified by chromatography (silica gel, AcOEt/methanol 9:1) to deliver the title compound as a light yellow solid (151 mg). MS: 365.5 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30]>O1CCCC1.CCCCCC>[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)#[N:30]
Reactant: N#CCCCCBr
Reactant: Cc1cccc2cncn12
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCCCCCc1cccc2cncn12
Temperature: 0 °C

Procedure:
A solution of 5-methylimidazo[1,5-a]pyridine (4.0 g) and tetramethylethylene diamine (4.9 g) in 100 ml of tetrahydrofuran is cooled to 0° under nitrogen and 26.5 ml of 1.6 N n-butyllithium in hexane is added dropwise maintaining the temperature below 2°. After 30 minutes this solution is transferred under nitrogen over 45 minutes to an ice-cold solution of 5-bromovaleronitrile (4.86 g) in 80 ml of tetrahydrofuran. After 15 minutes the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is reextracted with 2 N hydrochloric acid (3×15 ml). Basification of the aqueous phase to pH=10 with 50% sodium hydroxide, extraction with ethyl acetate (2×75 ml), drying over magnesium sulfate, evaporation and chromatography (SiO2, ethyl acetate) yields 5-(5-cyanopentyl)-imidazo[1,5-a]pyridine.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=2[CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:27][C:28]1([CH3:42])[O:33][C:32]2[CH:34]=[CH:35][C:36]([C:38]([OH:40])=O)=[CH:37][C:31]=2[C:30](=[O:41])[O:29]1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=2[CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:38]([C:36]2[CH:35]=[CH:34][C:32]3[O:33][C:28]([CH3:27])([CH3:42])[O:29][C:30](=[O:41])[C:31]=3[CH:37]=2)=[O:40])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCNCc1ccccc1C#Cc1ccc(CCCC)cc1
Reactant: CC1(C)OC(=O)c2cc(C(=O)O)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCN(Cc1ccccc1C#Cc1ccc(CCCC)cc1)C(=O)c1ccc2c(c1)C(=O)OC(C)(C)O2
Yield: 86.3 %

Procedure:
A solution of N-{2-[(4-butylphenyl)ethynyl]benzyl}-1-hexanamine (174 mg, 0.50 mmol), 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carboxylic acid (122 mg, 0.55 mmol), EDC.HCl (115 mg, 0.60 mmol), DIEA (102 μl, 0.60 mmol) and HOBT (81 mg, 0.60 mmol) in DCM (10 mL) was stirred at rt for 3 hrs. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3, an aqueous solution of HCl (1N) and brine. The organic layer was dried over MgSO4 and the solvent Was removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (20/80)) gave 238 mg (87%) of the title compound. HPLC, Rt: 6.14 min (purity: 86.7%).
Reaction SMILES: [OH:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[Br:22][C:23]1[CH:24]=[N:25][C:26](Cl)=[N:27][CH:28]=1.O>CCO>[Br:22][C:23]1[CH:24]=[N:25][C:26]([N:5]2[CH2:4][CH2:3][C:2]([OH:1])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]2)=[N:27][CH:28]=1
Reactant: CCOC(=O)C1(O)CCNCC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(O)CCN(c2ncc(Br)cn2)CC1
Temperature: 80 °C
Yield: 50.2 %

Procedure:
To an ice-cold solution of ethyl 4-hydroxypiperidine-4-carboxylate (0.60 g, 3.44 mmol) in EtOH (15 mL) was added DIPEA (2.95 mL, 17.24 mmol) followed by the addition of 5-bromo-2-chloropyrimidine (0.67 g, 3.44 mmol). The reaction was heated to 80° C. for 3 h then cooled to rt, water added and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 20% EtOAc:hexane to obtain the desired product as a yellow solid (0.57 g, 88%). 1H NMR (DMSO-d6): δ 8.44 (s, 2H), 5.58 (s, 1H), 4.27 (m, 2H), 4.10 (q, J=7.20 Hz, 2H), 3.28 (m, 2H), 1.81 (m, 2H), 1.66 (m, 2H), and 1.18 (t, J=7.20 Hz, 3H).
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[CH2:13][CH2:14][C@:15]4([CH3:21])[C@@H:19]([OH:20])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C@H:8]1[CH2:7][C:5](=[O:6])[CH2:4][CH2:3]2.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl.ClCl>[Cl:29][CH2:30][C:31]([O:20][C@H:19]1[CH2:18][CH2:17][C@H:16]2[C@H:11]3[C@H:12]([CH2:13][CH2:14][C@:15]12[CH3:21])[C@:2]1([CH3:1])[C@H:8]([CH2:7][C:5](=[O:6])[CH2:4][CH2:3]1)[CH2:9][CH2:10]3)=[O:32]
Reactant: O=C(Cl)CCl
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: ClCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)CCl)CC[C@@H]12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Dihydrotestosterone (2.6 mmol) was dissolved in anhydrous methylene chloride (3 mL) and triethylamine (2.6 mmol) under argon. The solution was stirred at 0° C. for 30 minutes at which time chloroacetyl chloride (3.75 mmol) dissolved in anhydrous methylene chloride (2 mL) was added. The resulting mixture was stirred for an additional 30 min at 0° C. and at room temperature for 4 hr. The solution was diluted with CH2 Cl2 (30 mL) and was washed with aqueous 0.05N hydrochloric acid (2×30 mL) and water (2×30 mL). The organic layer was dried over sodium sulfate and evaporated under vacuum to give crude product as a white solid. The product was purified by silica gel column chromatography (Davisil grade 633, 200-425 mesh, 60 Å) using CHCl3 as eluent. Yield, 0.38 g (41%); mp 135°-136° C. (lit. Ferguson et al., J. Chem. Soc., Perkin II, 3, 267-272 (1978)), 138° C.); 1H NMR δ0.78 (s, 3 H, CH3 -19), 0.98 (s, 3 H, CH3 -18), 0.78-2.49 (m, 22 H), 4.37 (d, 2 H, CH2Cl), 4.62 (t, 1 H, H-17); MS (EI) calcd m/z for C21H31O335Cl 366.1961, found, 366.1932; calcd. m/z for C21H31O337Cl 368.1932, found, 368.1911.