Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=O)([CH2:3][CH3:4])[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23][NH2:24])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.C[O-].C([N+](C)(C)C)C1C=CC=CC=1>CN(C=O)C.C(OCC)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:21][CH2:22][CH2:23][NH:24][C:7](=[O:9])[C@@H:6]([NH:5][CH:1]([CH2:3][CH3:4])[CH3:2])[CH:10]([CH3:12])[CH3:11])=[CH:16][CH:15]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCC(C)N[C@H](C(=O)O)C(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(C)N[C@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
A solution of 291 mg (1.68 mmol) (S)-2-sec-butylamino-3-methyl-butyric acid, 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine, 0.29 mL (1.68 mmol) N,N-diisopropylethylamine, and 1.5 mL (3.36 mmol) benzyltrimethylammonium methoxide (40% solution in methanol) in 4 mL dry DMF was cooled to 3° C. and 637 mg (1.68 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate was added and the resulting mixture stirred at 3° for 30 minutes, warmed to 25° C., and stirred an additional 30 minutes at which time it was diluted with 20 mL diethyl ether, and washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 70% ethyl acetate/hexanes as eluant, followed by conversion to the hydrochloride salt by treating with excess diethyl ether which had been saturated with hydrogen chloride gas to give 270 mg (35%) of titled compound: mp 77-81° C. APCI-MS m/z417.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[N:14]=[C:13]([Cl:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+].Cl>CC(C)=O>[Cl:18][C:13]1[N:12]=[C:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:16]=[C:15]([NH:26][CH2:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:14]=1
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Reactant: NCC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(Nc2nc(Cl)nc(NCC3CCCCC3)n2)cc1Cl
Yield: 75.9 %

Procedure:
To a sample of 101 (0.3004 g, 1.0 mmol, prepared as indicated herein) dissolved in acetone (4 mL) was added a solution of cyclohexanemethylamine (0.13 mL, 1.0 mmol) in acetone (1 mL) followed by addition of a NaOH solution (0.0448 g, 1.0 mmol dissolved in 1 mL of H2O). The reaction mixture was allowed to stir at reflux for about 3 hours. The reaction mixture was then poured over crushed ice and neutralized with 10% HCl (aq) and 5% NaOH (aq). The resulting solid was collected by vacuum filtration, washed with water and dried overnight under vacuum to afford compound 102 (0.29 g, 76% recovery).
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[C:20]2[C:15](=[C:16]([OH:21])[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:11]1=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22]1[O:24][CH:23]1[CH2:25][OH:26]>CO>[CH2:3]([N:10]1[C:20]2[C:15](=[C:16]([O:21][CH2:22][CH:23]([OH:24])[CH2:25][OH:26])[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][C:11]1=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCC1CO1
Reactant: O=C1CCc2c(O)cccc2N1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2c(OCC(O)CO)cccc2N1Cc1ccccc1
Yield: 43.3 %

Procedure:
0.7 g of potassium hydroxide was dissolved in 30 ml of methanol, and 2.5 g of 1-benzyl-5-hydroxy-3,4-dihydrocarbostyril and 0.9 g of glycidol were added to the resulting solution followed by refluxing the mixture for 4 hours. After the mixture was concentrated to dryness, the residue was extracted with 50 ml of chloroform, and the extract was washed with a 5% aqueous potassium hydroxide and then water and then dried over anhydrous sodium sulfate. The chloroform was then removed by distillation and the resulting residue was recrystallized from ethyl acetate to give 1.4 g of 1-benzyl-5-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as colorless needle-like crystals having a melting point of 154° - 155° C.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].C([Li])CCC.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Br:26]>>[N:6]1[CH:7]=[CH:8][C:3]([C:24]2[CH:23]=[CH:22][C:21]([Br:26])=[CH:20][CH:25]=2)=[CH:4][CH:5]=1
Reactant: Brc1ccncc1
Reactant: Brc1ccccc1I
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Product: Brc1ccc(-c2ccncc2)cc1

Procedure:
4-Bromopyridine hydrochloride is free based with saturated NaHCO3 solution and extracted into methylene chloride. The organic solution is concentrated at room temperature and used immediately without further purification. A portion of the solid obtained (3 g, 19 mmol) is treated as described in EXAMPLE 53, Part A with n-butyl lithium (14.25 mL of a 1.6 M solution in TIF, 22.8 mmol) and iodobromobenzene (5.39 g, 19 mmol). The crude product is purified by chromatography (30% EtOAc/hexanes to 60% EtOAc/hexanes) to obtain the title compound (2.59 g, 11.06 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[N:11]1[C:18]([Cl:19])=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13].[NH4+].[Cl-]>O1CCCC1>[Cl:13][C:12]1[N:11]=[C:18]([Cl:19])[N:17]=[C:15]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:14]=1
Reactant: Oc1ccc(F)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1ccc(Oc2nc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
EX-44B) To a solution of p-fluorophenol 1.00 g (8.92 mmol) in 30 mL of tetrahydrofuran at 0° C. was added a 60% dispersion of sodium hydride in mineral oil (0.36 g, 8.92 mmol). After 30 min, cyanuric chloride (1.64 g, 8.92 mmol) was added as a heterogeneous mixture in tetrahydrofuran at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After 14 h, the mixture was cooled to 0° C., and a saturated aqueous NH4Cl solution was added. The aqueous solution was extracted with diethyl ether (3×50 mL). The combined ether extracts were washed with brine, dried (MgSO4), and concentrated in vacuo to afford 1.34 g (58%) of the desired 2,4-dichloro-6-(4-fluorophenoxy)-1,3,5-triazine product as an off white solid which was taken on to the next step without purification. MS m/z=260 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:8]=2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[CH2:12]([C:10]1[C:9]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:8]=2[C:7]([OH:25])=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[N:11]=1)[CH2:13][CH2:14][CH3:15]
Reactant: NCC(=O)O
Reactant: CCCCc1nc(C(=O)OCC)c(O)c2sc(-c3ccccc3)nc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 41.1 %

Procedure:
A mixture of 4-butyl-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (41 mg, 0.12 mmol) and glycine (175 mg, 2.32 mmol) in 0.5 M sodium methoxide/methanol (4.4 mL) was refluxed for 48 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 mL) and extracted twice with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.5 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (19 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.19 (br s, 1H), 8.17 (m, 2H), 7.63 (m, 3H), 4.05 (d, J=5.8 Hz, 2H), 3.33 (m, 2H), 1.88 (m, 2H), 1.41 (m, 2H), 0.97 (t, J=7.2 Hz, 3H); MS: (+) m/z 386.13 (M+1), (−) m/z 384.13 (M−1).
Reaction SMILES: O.C([N:9]1[CH2:14][CH2:13][CH:12]([CH3:15])[CH:11]([N:16]([CH3:26])[C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:10]1)C1C=CC=CC=1.C(O)(=O)C>[OH-].[OH-].[Pd+2].C(O)(C)C>[CH3:26][N:16]([C@@H:11]1[C@H:12]([CH3:15])[CH2:13][CH2:14][NH:9][CH2:10]1)[C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: CC1CCN(Cc2ccccc2)CC1N(C)c1ncnc2[nH]ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a clean, dry, nitrogen-purged 2 L hydrogenation reactor were charged 20 wt % Pd(OH)2/C (24.0 g, 50% water wet), water (160 ml), isopropanol (640 ml), (1-benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (160.0 g, 0.48 mol), and acetic acid (28.65 g, 0.48 mol). The reactor was purged with three times at 50 psi with nitrogen and three times at 50 psi with hydrogen. Once purging was complete, the reactor was heated to 45-55° C. and pressurized to 50 psi with hydrogen through a continuous feed. The hydrogen uptake was monitored until no hydrogen was consumed for 1 hour. The reactor was cooled to 20-30° C. and purged three times at 50 psi with nitrogen. The reaction mixture was filtered through wet Celite and the filtrate was sent to a clean, dry, nitrogen-purged vessel. A solution of sodium hydroxide (39.33 g) in water (290 ml) was charged and the mixture was stirred for a minimum of 1 hour then heated to 75-90° C. The isopropanol was removed by distillation. The reaction mixture was cooled to 20-30° C. and 2-methyltetrahydrofuran (1.6 L) was added. The aqueous layer was drained off and the 2-methyltetrahydrofuran was displaced with toluene (1.6 L). The distillation was continued until the final volume was 800 ml. The slurry was cooled to 20-30° C. and held for a minimum of 7 hours. The resulting solids were isolated by filtration and washed with toluene (480 ml). After drying under vacuum between 40-50° C. for a minimum of 24 hours with a slight nitrogen bleed 102.3 g (87.3%) of the title compound were isolated.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH:15]4[CH2:17][CH2:16]4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:15]1([N:12]2[CH2:13][CH2:14][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:25]5[CH:24]=[N:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=5)[CH:19]=[CH:18][C:5]=4[N:6]=3)[CH2:10][CH2:11]2)[CH2:17][CH2:16]1
Reactant: Brc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3nc(N4CCN(C5CC5)CC4)sc3c2)cn1
Temperature: 60 °C

Procedure:
To a solution of 6-bromo-2-(4-cyclopropylpiperazin-1-yl)benzothiazole (400 mg, 1.18 mmol) and 2-methoxy-5-pyridineboronic acid (217 mg, 1.42 mmol) in THF—H2O (16 mL, 5:1) was added Pd2(dba)3 (191 mg, 0.118 mmol), followed by P(t-Bu)3BF4 (68 mg, 0.236 mmol) and K3PO4.H2O (1.57 g, 5.9 mmol). The mixture was heated to 60° C. for 3 h. The mixture was filtered and the filtrate was evaporated. the residue was diluted with water (5 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried (Na2SO4) and concentrated to give the crude product, which was purified by column chromatography on silica gel eluting with CH2Cl2/MeOH (1:50). This afforded 253 mg (58%) of 2-(4-cyclopropyl-piperazin-1-yl)-6-(6-methoxypyridin-3-yl)benzothiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]2[C:6]([N:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:18])=O.CCCCCC>C(OCC)(=O)C>[Cl:18][C:9]1[CH:8]=[N:7][C:6]2[C:11](=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2ncc(=O)[nH]c2c1OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)nc2c1OC
Temperature: 25 °C
Yield: 77.1 %

Procedure:
A solution of 7,8-dimethoxy-quinoxalin-2-one (5.0 g, 24.25 mmol, 1.0 eq) in phosphorus oxychloride (25 mL, 268.21 mmol, 11.06 eq) is heated under reflux for 1 hour. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water, the resulting mixture is neutralized with saturated sodium hydrogen carbonate and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: hexane:ethyl acetate, 2:1 to 1:1, v/v) to afford 2-chloro-7,8-dimethoxy-quinoxaline as a light yellow solid (4.2 g, 77% yield).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]1([N:11]2[CH2:10][CH2:9][C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([C:14]#[N:15])[CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccccc1
Reactant: N#CC1(c2ccccc2)CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccccc2)CCN(c2ccccc2)CC1

Procedure:
To a suspension of 4-phenylpiperidine-4-carbonitrile hydrochloride (6.7 mmol) in toluene (30 mL) are successively added bromobenzene (8.0 mmol), sodium tert-butoxide (17 mmol), tri-o-tolylphosphine (1.3 mmol), and tris(dibenzylideneacetone)dipalladium (0.7 mmol), then the mixture is refluxed for 20 h. The reaction mixture is cooled, diluted with water, then extracted with AcOEt. The organic extracts are washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give the title compound; 1H NMR (CDCl3) δ: 2.12-2.20 (2H, m), 2.23-2.28 (2H, m), 2.94-3.01 (2H, m), 3.86 (2H, d), 6.83 (1H, t), 7.04 (2H, d), 7.22-7.28 (2H, m), 7.36-7.41 (1H, m), 7.45-7.49 (2H, m), 7.56-7.59 (2H, m).
Reaction SMILES: [N+](C1C=CC([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=O)=CC=1)([O-])=O.[NH2:21][C:22]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27]([NH:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:28]([F:33])[CH:29]=2)[N:24]([CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:23]=1.N1C=CC=CC=1.O>ClCCl>[CH:35]1([NH:34][C:27]2[CH:26]=[C:25]3[C:30]([C:31](=[O:32])[C:22]([NH:21][C:9]([NH:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:8])=[CH:23][N:24]3[CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:29][C:28]=2[F:33])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCC(CC)n1cc(N)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reactant: CCOC(=O)CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCNC(=O)Nc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
180 mg of 4-nitrophenyl chloroformate was dissolved in 3.0 ml of dichloromethane, and 140 mg of ethyl 3-aminopropanoate hydrochloride and 0.15 ml of pyridine were added, followed by overnight stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and then concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 180 mg of ethyl 3-{[(4-nitrophenoxy)carbonyl]amino}propanoate was obtained. 180 mg of ethyl 3-{[(4-nitrophenoxy)carbonyl]amino}propanoate was dissolved in 2.0 ml of dichloromethane, and 220 mg of 3-amino-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoroquinolin-4(1H)-one and 0.15 ml of pyridine were added, followed by overnight stirring at room temperature. Water was added, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then filtered and concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 120 mg of ethyl 3-[({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}carbonyl)amino]propanoate was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([NH2:17])=[CH:4][N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:26]1[CH:38]=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:27][C@H:26]1[CH2:38][NH:17][C:5]1[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(Oc2nc(Cl)ncc2N)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(Oc2nc(Cl)ncc2NC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of Compound 1c (191 mg, 0.759 mmol) in 1,2-dichloroethane (4 mL) was added Compound 27d (250 mg; 0.759 mmol) and acetic acid (0.2 mL) at ambient temperature, and the mixture was stirred at room temperature for 1.5 h. The mixture was then treated with NaB(OAc)3H (240 mg; 1.14 mmol) and continually stirred at room temperature for 4 h. The resultant mixture was diluted with CH2Cl2, then washed with saturated NaHCO3 (aq) and water. The organic phase was washed sequentially with water and brine, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 27e. 1H-NMR (400 MHz, CDCl3): δ 7.70-7.75 (m, 1H), 7.10-7.13 (m, 2H), 6.94-7.01 (m, 2H), 5.79 (br. s, 0.6H), 4.73 (br. s, 0.4H), 4.30-4.39 (m, 2H), 3.84 (s, 3H), 3.12-3.69 (m, 4H), 2.06-2.16 (m, 1H), 1.80-1.87 (m, 1H), 1.45-1.48 (m, 9H), 0.88 (s, 9H), 0.08 (s, 6H); MS: m/z 565.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH:3]=1.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C>CC(N(C)C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:4]1[CH:3]=[C:2]([NH:1][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:9]2
Reactant: CCCCC(=O)Cl
Reactant: Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCCCC(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
1-[7-amino-5-(2-chloro-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone (71 mgs, 0.2 mmoles) was dissolved in anhydrous dimethylacetamide (1 ml) to which was added valeryl chloride (36 ul, 0.3 mmoles) and finally triethylamine (41.6 ul, 0.3 mmoles). The vial was flushed with nitrogen and stirred at room temperature overnight. The product was twice purified by semi-preparative C18 HPLC (11.5 mgs, 13.1% yield, 94% pure, CO-AAW00030).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH:13][CH3:14].O>CCO>[CH3:12][N:13]([CH3:14])[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CNC
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(N)cc1[N+](=O)[O-]
Yield: 98.3 %

Procedure:
In an alternative preparation: 4-Fluoro-3-nitro-aniline (20 g, 128 mmol) was dissolved in EtOH (300 mL) and dimethylamine (5.6 M solution in EtOH, 360 mL, 2.02 mol) was added in a steady stream. After refluxing for 18 h, the reaction mixture was cooled and 100 mL water was added. EtOH was removed by evaporation and the residue was extracted with Et2O (3×100 mL). The combined organics were washed with brine, filtered, and the solvent was evaporated to afford 22.8 g of 4-(dimethylamino)-3-nitroaniline as a black oil. This was dissolved in EtOH (80 mL) and HNO3 (69% aq, 18.5 mL, 22.1 mmol) added dropwise followed by cyanamide (50% wt in water, 37 mL, 476 mmol). The mixture was heated at reflux for 18 h. Once cooled, the mixture was poured into Et2I (1 L). The ethereal supernatant was decanted and the residue was treated with propan-2-ol, followed by Et2O to give 19.0 g of the corresponding guanidine nitrate as a tan solid. This was stirred with K2CO3 (15.04 g, 108.8 mmol) in 2-methoxyethanol (250 mL) for 10 min before adding 3-dimethylamino-1-(2,4-dimethylthiazol-5-yl)-propenone (9.53 g, 45.33 mmol). The mixture was heated at 125° C. for 18 h. The reaction mixture was concentrated and diluted with EtOAc, filtered through a pad of silica and evaporated to give a dark oil, which was purified by chromatography, using EtOAc to elute the title product as a reddish solid. Recrystallisation from toluene yielded 7.3 g pure title compounds.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22]([OH:24])=O)=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([NH:35][C:22](=[O:24])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[CH:19][CH:18]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)O
Reactant: NCc1ccccc1
Product: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)NCc1ccccc1
Yield: 67.9 %

Procedure:
The title compound (0.25 g, 67%) was prepared as a white solid from 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.8 mmol) obtained in example 26 and benzyl amine (0.095 g, 0.88 mmol) by a procedure analogous to that described in example 32. mp: 94-96° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].C1(C)C=CC=CC=1.[CH:18]1([C:23]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([OH:29])[C:24](OCC)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]1>CCCCCC>[CH:18]1([C:23]([C:30]#[C:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([OH:29])[C:24]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCC1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(OC1CN2CCC1CC2)C(O)(C#Cc1ccccc1)C1CCCC1

Procedure:
3-Quinuclidinol (3.8 g., 0.030 mole) and about 0.05 g. of sodium were refluxed in 50 ml. of toluene, in a flask equipped with a reflux head, until all the sodium reacted. Then, ethyl α-cyclopentyl-α-phenylethynylglycolate (5.4 g., 0.02 mole) in 35 ml. of solvent was added dropwise over an hour period. No temperature drop was noted in the reflux head. The reaction mixture was refluxed for about 18 hours and then about 40 ml. of solvent was distilled from the reaction flask over a four hour period. The reaction mixture was cooled, and dry 20°-40° petroleum ether was added. A tarry solid formed and was filtered. The solid was treated with hot hexane to yield 3.2 g. (45%) of crude product melting about 115° C. The pure compound, m.p. 137°-39°, was obtained by recrystallization from hexane.