Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N=C2C(NC=N2)=C([Cl:11])N=1.C(=O)([O-])[O-].[K+].[K+].O.NC1N=C2C(N=CN2[CH:29]2[C:31]([C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39])([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C:30]2([Cl:45])[Cl:44])=C(Cl)N=1>CS(C)=O>[Cl:11][C:30]([Cl:44])([Cl:45])[CH:29]=[C:31]([C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])[C:38]([O:40][CH:41]([CH3:42])[CH3:43])=[O:39]
Reactant: CC(C)OC(=O)C1(C(=O)OC(C)C)C(n2cnc3c(Cl)nc(N)nc32)C1(Cl)Cl
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)OC(=O)C(=CC(Cl)(Cl)Cl)C(=O)OC(C)C
Temperature: 25 °C
Yield: 67.9 %

Procedure:
In a 0.3-liter four-necked flask, 15.0 g (88.5 mmol) of 2-amino-6-chloropurine (manufactured by Sumika Fine Chemicals Co., Ltd.) and 26.9 g (194.6 mmol) of potassium carbonate were added to 195 ml of dimethylsulfoxide, and 8.0 g (442.5 mmol) of water was then added to the resulting mixture. The resulting mixture was stirred at room temperature. Next, 42.2 g (132.9 mmol) of diisopropyl 2,2,2-trichloroethylidenemalonate, which was prepared by the process described in U.S. Pat. No. 3,495,012, was added to the resulting mixture, and the mixture was stirred for two hours and a half at room temperature. Thereafter, the reaction mixture was filtered, and the filtrate was poured into water. The precipitated crystals were washed with 100 ml of water, collected by filtration, and then recrystallized from isopropyl alcohol, to give 27.1 g (60.1 mmol) of pale yellow crystals of 2-amino-6-chloro-9-(3,3-dicarboisopropoxy-2,2-dichlorocyclopropyl)purine. The yield was 67.9%.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[OH:6][C:7]1[CH:31]=[CH:30][C:10]([CH2:11][NH:12][C:13]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[NH:17])=[NH:14])=[CH:9][CH:8]=1.[CH3:32][C:33]([CH3:35])=O>>[ClH:3].[CH2:19]([NH:18][C:16]1[NH:15][C:13]([NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:31][CH:30]=2)=[N:14][C:33]([CH3:35])([CH3:32])[N:17]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCNC(=N)NC(=N)NCc1ccc(O)cc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(O)cc2)N1

Procedure:
25 ml of methanol, 40 ml of acetone and 0.1 ml of concentrated hydrochloric acid were added to 2.0 g (4.5 mmol) of N1-(4-hydroxybenzyl)-N5-undecyl-biguanide dihydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (8:1.5)), and then recrystallized with 80% aqueous acetonitrile to obtain 0.73 g of colorless crystals having a melting point of 110 to 112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]2[C:12](=O)[CH:11]3[CH2:14][CH2:15][N:8]2[CH2:9][CH2:10]3)=[CH:4][CH:3]=1.[OH-].[K+].O.[NH2:21][NH2:22]>C(O)CO>[NH:8]1[CH2:15][CH2:14][CH:11]([C:12]2[CH:7]=[C:6]([C:5]3[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:22][N:21]=2)[CH2:10][CH2:9]1
Reactant: NN
Reactant: O=C1C(=Cc2ccc(Cl)cc2)N2CCC1CC2
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Clc1ccc(-c2cc(C3CCNCC3)n[nH]2)cc1
Temperature: 110 °C
Yield: 85 %

Procedure:
A mixture of 2-(4-chlorobenzylidene)quinuclidin-3-one (35.0 g), potassium hydroxide (15.0 g) and hydrazine hydrate (11.0 cm3) in ethylene glycol(100 cm3) was heated at 110° C. for 15 minutes to produce a dear, dark brown solution. Hydrazine hydrate and water were distilled from the solution over 1 hour at 110° C. to 195° C. The brown solution was then heated at reflux for 3 hours. The mixture was cooled to room temperature and diluted with water (300 cm3). The resulting white precipitate was collected and washed with water (500 cm3) and ethyl acetate (200 cm3). The white powder was dried in vacuo to give the title compound (31.5 g, 85%), m.p. 174°-176° C.; δH (250 MHz; d6 -DMSO) 1.52 (2H, apparent qd, J=12 and 4, 2×NCH2CHAHB), 1.85 (2H, apparent d, J=10, 2×NCH2CHAHB), 2.56 (2H, apparent td, J=12 and 2, 2×NCHAHB), 2.71 [1H, tt, J=8.1 and 4.5, (CH2)2CH], 2.99 (2H, apparent d, J=12.1, 2×NCHAHB), 6.48 (1H, s, N=C--CH=C), 7.44 (2H, d, J=8.6, 2×ArH o to Cl; and 7.79 (2H, d, J=8.6, 2×ArH m to Cl); δC (90 MHz; d6 -DMSO) 39.9 (t), 34.2 (d), 46.2 (t), 98.9 (d), 126.8 (d), 128.7 (d), 131.7 (s), 132.4 (broad, s), 147.5 (broad, s) and 151.1 (broad, s); m/z (CI+, NH3) 262 (M+ +H; 60%) and 139 (100).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([Br:38])[CH:32]=1>>[Br:38][C:33]1[CH:32]=[C:31]([CH2:30][CH2:29][NH:28][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:36]=[CH:35][C:34]=1[OH:37]
Reactant: NCCc1ccc(O)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: Oc1ccc(CCNc2nccc(-c3cccc(NC4CCNCC4)c3)n2)cc1Br

Procedure:
Intermediate 7 was coupled with 4-(2-Amino-ethyl)-2-bromo-phenol following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 468. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.8 (m, 5H) 8.4 (d, 1H) 7.4 (m, 2H) 7.3 (m, 1H) 7.0 (d, 1H) 6.9 (m, 1H) 3.7 (m, 2H) 3.4 (m, 1H) 3.1 (m, 2H) 2.9 (m, 3H) 2.1 (m, 1H) 1.8 (m, 2H) 1.5 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]([CH3:13])[CH2:9][NH:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[Br:20][CH2:21][C:22](Br)=[O:23]>C(OCC)(=O)C>[Br:20][CH2:21][C:22]([CH2:12][CH2:11][NH:10][CH2:9][C@@H:8]([NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:13])=[O:23]
Reactant: CCNC[C@H](C)NC(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@@H](CNCCC(=O)CBr)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a cold (0° C.) stirred solution of tert-butyl[(1S)-2-(ethylamino)-1-methylethyl]carbamate (11.0 g, 54.6 mmol) in a mixture of ethyl acetate (107 mL) and saturated aqueous sodium bicarbonate (65 mL), bromoacetyl bromide (12.1 g, 60.0 mmol) was added portionwise under an atmosphere of nitrogen. The mixture was allowed to warm up to room temperature over a period of 3.5 hours. The organic phase was separated, washed successively with saturated aqueous sodium bicarbonate, and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was concentrated as a solution in toluene under vacuum to afford the title compound. ES MS M+1=323, 325.
Reaction SMILES: [C:1]1([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]([O:20]C)=[O:19])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[Na+:31]>O1CCOCC1>[C:22]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]([O-:20])=[O:19])[CH2:12][CH2:11]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1.[Na+:31]
Reactant: COC(=O)CN1CCCN(CCC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C([O-])CN1CCCN(CCC(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Methyl [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (0.327 g, 0.89 mmol) was dissolved in a mixture of dioxane (3.1 mL). MeOH (1.1 mL) and 4N NaOH (0.22 mL). After stirring for 30 min. 5 more drops of 4N NaOH were added and stirring was, continued until hydrolysis of the methyl ester was complete. The mixture was concentrated in vacuo and the residue subjected to flash silica gel column chromatography (eluent: CH2Cl2/MeOH, 1/1, v/v) to give sodium [4-(3,3-diphenylpropyl)homopiperazine-1-yl]acetate (0.278 g) in 88% yield, TLC Rf=0.22 (10% CH3OH—CH2Cl2); RPLC tR=1.98 min (>85%), 220 nm (Method B); ESI/MS m/e 353.3 (M++H, C22H29N2O2).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[O:36])=[CH:14][CH:13]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:26][CH:27]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Sc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(S(=O)c2ccc(Cl)cc2)cc1

Procedure:
To a solution of 1,8 g of methyl (p-chlorophenoxy)[p-(p-chlorophenylthio)phenyl]acetate in 10 ml of dichloromethane is added dropwise a solution of 0.891 g of 83% m-chloroperbenzoic acid in 10 ml of dichloromethane. The mixture is chilled overnight, filtered and the filtrate washed with 10% sodium sulfite solution, saturated sodium bicarbonate and sodium chloride solutions. After drying (MgSO4), the solvent is removed under reduced pressure to give a gum. Crystallization from dichloromethane-zepane given 1.65 g of product as white crystals, mp 134°-144° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1OB(O)O>>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH3:14])[CH:3]=2)[CH:8]=1
Reactant: COc1ccccc1OB(O)O
Reactant: COc1ccc2cc(Br)ccc2c1
Product: COc1ccc2cc(-c3ccccc3OC)ccc2c1
Reaction time: 18 h

Procedure:
The compound is prepared by the reaction of 2-bromo-6-methoxynaphthalene (300 mg, 1.26 mmol, 1 eq) with 2-methoxyphenylboric acid (192 mg, 1.26 mmol, 1 eq) according to method A within 18 h. Purification by column chromatography was not performed, but the raw product was used for further syntheses.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C@H:49]([CH3:52])[C@H:48]([C:53](O)=[O:54])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[CH3:52][C@H:49]1[CH2:50][CH2:51][N:46]([C:44]([O:43][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:45])[CH2:47][C@H:48]1[C:53]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:54]
Reactant: C1CCNC1
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (4.12 g, 10.85 mmol), diisopropylethylamine (2.33 g, 18.08 mmol) and pyrrolidine (782 mg, 10.85 mmol) were added to a solution of cis-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (2.2 g, 9.04 mmol) in anhydrous dichloromethane (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was quenched with water and was extracted with dichloromethane. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford cis-tert-butyl 4-methyl-3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (2.6 g).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:26][C:13]1[CH:14]=[N:15][C:16]([NH:18]C(=O)OC(C)(C)C)=[CH:17][C:12]=1[CH2:11]2.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[NH2:18][C:16]1[N:15]=[CH:14][C:13]2[CH2:26][C:3]3([CH2:11][C:12]=2[CH:17]=1)[C:4]1[C:5](=[N:6][CH:7]=[CH:8][CH:9]=1)[NH:10][C:2]3=[O:1]
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A solution of (±)-tert-butyl (2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)carbamate from Step A (131 mg, 0.372 mmol) was stirred in CH2Cl2 (10 mL) and TFA (3 mL) for 18 h and then concentrated in vacuo to provide the title compound. MS: m/z=253 (M+1).
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:21](=[O:49])[NH:22][C@@H:23]([C:36](=[O:48])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[CH2:17][C:18](O)=[O:19])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:50]([O:54][C:55]([NH:57][CH2:58][CH2:59][NH:60][CH2:61][CH2:62][NH:63][C:64](=[O:70])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[C:50]([O:54][C:55]([NH:57][CH2:58][CH2:59][N:60]([CH2:61][CH2:62][NH:63][C:64]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:70])[C:18]([CH2:17][C@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:10])([CH3:9])[CH3:11])[C:21](=[O:49])[NH:22][C@@H:23]([C:36](=[O:48])[NH:37][C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[CH:43][CH:42]=[CH:41]2)[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1)=[O:19])=[O:56])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2ncccc2c1
Yield: 72 %

Procedure:
To a solution of CDMT (37 mg, 0.20 mmol) in DCM (10 mL) and cooled to 0° C. was added N-methylmorpholine (0.023 mL, 0.20 mmol). The mixture was stirred for min before adding (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}propanoic acid (110 mg, 0.18 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate X was then added and the mixture stirred at r.t. overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was then purified on a silica gel column (100:1 CHCl3/MeOH) and finally crystallized from ethyl ether/hexane to give tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1R)-1-[(quinolin-6-yl)carbamoyl]-3-[4-(trifluoromethyl)phenyl]propyl]carbamoyl}ethyl]carbamate XI (110 mg, 0.13 mmol, 72% yield). 1H NMR (CDCl3) 1.43 (s, 18H), 1.50 (s, 9H), 1.69 (brs, 2H), 2.03 (brs, 2H), 2.78 (brs, 2H), 3.23 (brs, 2H), 3.46 (brs, 4H), 4.60 (brs, 4H), 4.96-5.11 (m, 1H), 5.98-6.14 (m, 1H), 6.91-7.01 (m, 1H), 7.28-7.38 (m, 3H), 7.47-7.58 (m, 3H), 7.88-8.03 (m, 2H), 8.12 (d, J=7 Hz, 1H), 8.52 (s, 1H), 8.81 (brs, 1H), 9.31 (brs, 1H); 19F NMR (DMSO-d6) −61.75 (s, 3F); ESIMS found for C43H58F3N7O9 m/z 874 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCCCOc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 73.7 %

Procedure:
To a mixture of 1-bromo-4-(3-bromopropoxy)benzene (300 mg, 1.02 mmol) and tert-butyl piperazine-1-carboxylate (144 mg, 1.02 mmol) in acetonitrile (6.0 mL) was added Cs2CO3 (365 mg, 1.10 mmol). The mixture was stirred at 75° C. for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the title compound (300 mg, 75% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.40 (d, 2H), 6.75 (d, 2H), 3.95 (m, 2H), 3.42 (m, 4H), 2.54 (t, 2H), 2.40 (m, 4H), 2.01-1.89 (m, 2H), 1.50-1.40 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[C:35]([C:36]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)OCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(3-hydroxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 542.2 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:26][C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[CH2:11][CH2:10][C:9]=2[CH:27]=1)(=O)C.Cl.[OH-:29].[Na+]>CO>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:26][C:12]3([CH2:13][CH2:14][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)[CH2:11][C:10](=[O:29])[C:9]=2[CH:27]=1
Reactant: [OH-]
Reactant: CC(=O)Nc1ccc2c(c1)CCC1(CCN(Cc3ccc(N)cc3)CC1)O2
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(CN2CCC3(CC2)CC(=O)c2cc(N)ccc2O3)cc1
Yield: 88 %

Procedure:
A solution of 3,4-dihydro-6-acetamido-1'-(4-aminobenzyl)spiro[(2H)-1-benzopyran-2,4'-piperidine](136 mg, 0.36 mmol) and hydrochloric acid (6N solution, 13. 6 ml) in methanol (13.6 ml) was heated at reflux temperature for 1 hr. The reaction mixture was cooled to 0° C. and basified with 20% sodium hydroxide solution. Extraction with methylene chloride, drying and solvent evaporation gave 3,4-dihydro-6-amino-1'-(4-aminobenzyl)spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (107 mg, 88%);
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>C1COCC1>[C:12]1([C:11]2[O:5][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[N:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino benzoic acid (10 mmol) in THF was added benzoyl chloride (2.8 g, 20 mmol) followed by pyridine (1.58 g, 20 mmol). The mixture was stirred for 1 h at room temperature. The 2-phenyl-benzo[d][1,3]oxazin-4-one formed was filtered and the residue was washed with water and dried in vacuum desiccator.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H][H]>C(O)C.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2ccccc2c1
Yield: 93.3 %

Procedure:
4.29 g of this ethyl 3-(2-naphthyl)-2-propenoate were dissolved in 60 ml of ethanol. The solution was stirred at room temperature for 3 hours in an atmosphere of hydrogen at atmospheric pressure and in the presence of 500 mg of 5% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.04 g (yield 93%) of ethyl 3-(2-naphthyl)propionate as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([CH2:7][C:8]([O-])=[O:9])[C:3]([O:5][CH3:6])=[O:4].CO>O1CCCC1>[F:1][C:2]([F:11])([CH2:7][CH2:8][OH:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)(F)CC(=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(F)(F)CCO
Temperature: 80 °C

Procedure:
In a 4 L flask equipped with a reflux condenser and 1 L dropping funnel, a solution of BH3.Me2S complex (10M, 88 mL) in dry dicholoromethane (1 L) is slowly added over a 2 hour period to a stirred solution of the methyl 2,2-difluorosuccinate (120 g, 0.714 moles) in dry tetrahydrofuran at 20° C. After refluxing (bath temperature 80° C.) for about 15 hours, the mixture is allowed to cool to room temperature and methanol (1 L) is slowly added. Evaporation yields methyl 2,2-difluoro-4-hydroxybutyrate as an oil which is stripped with methanol (1 L) and finally with CCl4 to yield a yellow oil: 100 g (92%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH2:30]([C:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:30]([C:33]1([S:36]([N:11]2[C:4]3=[CH:5][C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:38])=[O:37])[CH2:35][CH2:34]1)[CH:31]=[CH2:32]
Reactant: O=c1[nH]c2cc3ocnc3c(F)c2n1-c1ccc(I)cc1F
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c4ncoc4cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]oxazol-6(7H)-one (100 mg, 0.24 mmol) in DCM (5 mL) was added triethylamine (74 mg, 0.73 mmol) at 0° C. followed by 1-allylcyclopropane-1-sulfonyl chloride (66 mg, 0.36 mmol) and DMAP (15 mg). After stirring at room temperature for 1 h, the mixture was washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with DCM (20 mL×2). The combined organic phase was washed by water (20 mL) and brine (20 mL) sequentially, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (120 mg, 89.0% yield). 1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 7.99 (s, 1H), 7.70-7.68 (d, 2H), 7.27 (m, 1H), 5.75-5.58 (m, 1H), 5.05 (m, 2H), 2.90-2.80 (m, 1H), 2.10-2.0 (m, 1H), 1.95-1.86 (m, 2H), 1.25-1.10 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([CH:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:11]=2[O:22][CH2:23][CH3:24])[OH:9])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[CH:13]=[C:12]([CH:19]([CH3:20])[CH3:21])[C:11]=2[O:22][CH2:23][CH3:24])=[O:9])[CH:7]=1
Reactant: CCOc1c(C(C)C)cc(C(C)C)cc1C(O)c1cc(Br)ccc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOc1c(C(=O)c2cc(Br)ccc2F)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
(5-Bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanol (1.88 g, 4.6 mmol) was dissolved in dichloromethane (5 ml) and added to a suspension of pyridinium chlorochromate (1.1 g, 5.1 mmol) in dichloromethane (20 ml). After stirring at ambient temperature under and atmosphere of nitrogen for 4 h the reaction was diluted with ether (50 mL) and filtered through a plug of florosil. The remaining solvent was evaporated to yield (5-bromo-2-fluoro-phenyl)-(2-ethoxy-3,5-diisopropyl-phenyl)-methanone as yellow crystals (1.75 g, 94%). 1H NMR (250 MHz, CDCl3): δ 7.81 (dd, 1H, J=3.1, J=6.9), 7.62 (m, 1H), 7.33 (d, 1H, J=2.5), 7.28 (d, 1H, J=2.5), 7.02 (dd, 1H, J=11.2, J=9.4), 3.67 (q, 2H, J=6.9), 3.34 (m, 1H), 2.95 (m, 1H), 1.31 (s, 3H), 1.28 (s, 6H), 1.25 (s, 3H), 1.02 (t, 3H, J=6.9). MS [EI+] 407, 409 (M+H)+.