Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[O-].[Na+]>C(O)C>[C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12][C@H:11]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Temperature: 50 °C
Yield: 41.3 %

Procedure:
A solution of 252C (2.90 g, 7.71 mmol) in ethanol (70 mL) was treated with 21% NaOEt in ethanol (7.5 mL). The reaction mixture was heated to 50° C. for three hours, cooled to room temperature, and then concentrated. The resulting oil was taken up in dichloromethane (150 mL), washed with 20% NH4Cl (2×50 mL). The organic layer was dried (Na2SO4) and concentrated to an oil. Purification by flash chromatography (10 to 25% EtOAc/Hexane gradient) on silica gel afforded 1.20 g (yield: 41%) of Compound 252D as an oil.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][CH:25]2O)=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[Si:1]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][CH:25]2[N:43]=[N+:44]=[N-:45])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1ccc2c(c1)C(O)CC2)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](Oc1ccc2c(c1)C(N=[N+]=[N-])CC2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-tert-butyldiphenylsilyloxy-1-indanol, as described above in Step B, (5.80 g, 14.9 mmol) and diphenylphosphoryl azide (4.98 g, 18.1 mmol) in toluene (30 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.50 mL, 16.4 mmol), dropwise. The mixture was allowed to slowly warm to ambient temperature and was stirred for 18 hours, then washed with H2O (10 mL), then dilute HCl (10 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexane—1% EtOAc, to yield the titled product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:16]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH:15]=1)(C)(C)C.[ClH:59]>C(OCC)(=O)C>[ClH:59].[ClH:59].[CH2:40]([O:39][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:13][NH:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]
Reactant: CCCCCCCCC=CCCCCCCCCOc1ccc(CNCCCCNC(=O)OC(C)(C)C)cc1OCCCCCCCCC=CCCCCCCCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCC=CCCCCCCCCOc1ccc(CNCCCCN)cc1OCCCCCCCCC=CCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A concentrated solution of the amine 15 (0.158 g, 0.19 mmol) in ethyl acetate was added cooled to 0° C. A total of 4 mL of a freshly prepared saturated solution of HCl in ethyl acetate was added dropwise and the solution stirred for 1 h at room temperature during which time a white precipitate formed. The ethyl acetate was removed in vacuo and the residue co-evaporated with ethyl acetate and chloroform to give the product 22 as an off white powder (0.15 g, 98%); 1H NMR (500 MHz, CDCl3) d 9.50 (br s, 2H, R2N+H2), 8.22 (br s, 3H, RN+H3), 7.24 (s, 1H, aryl), 7.05 (d, 1H, aryl), 6.82 (d, 1H, aryl), 5.34 (m, 4H, olefinic), 4.02 (q, 4H, OCH2), 3.93 (t, 2H, benzylic), 3.07 (m, 2H, CH2) 2.81 (m, 2H, CH2), 2.01 (m, 8H, CH2C═C), 1.95 (m, 2H, CH2), 1.85 (m, 2H, CH2), 1.78 (m, 4H, CH2CH2O), 1.45 (m, 4H, 2×CH2), 1.38-1.20 (m, 40H, 20×CH2), 0.89 (t, 6H, CH3); 13C NMR (300 MHz, CDCl3) d 150.00, 149.37, 130.12, 130.09, 129.95, 122.58, 115.81, 113.49, 69.63, 69.38, 51.44, 51.06, 45.80, 39.63, 32.29, 30.24, 30.21, 30.16, 30.00, 29.93, 29.71, 27.61, 26.63, 26.49, 24.83, 23.75, 23.08, 14.54; HRMS (FAB): theory for C47H87N2O2 (M+1), 711.6768; found (M+1), 711.6827; Anal. (C47H88Cl2N2O4.1.2H2O): C, H, N.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:22]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc(Br)c2[nH]ccc2c1OCc1ccccc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2c(OCc3ccccc3)c(F)cc(Br)c21
Yield: 85.5 %

Procedure:
A solution of 17-1 (9 g, 28 mmol), potassium hydroxide (2.36 g, 42 mmol) and methyl iodide (6 g, 42 mmol) in DMF (30 mL) was stirred at room temperature for 2 h. The mixture was poured into water (50 mL), extracted with ethyl acetate (3×50 mL). The extracts were washed with water (3×50 mL) and brine (2×50 mL), dried over MgSO4, filtered, and evaporated to afford 33-3 (8 g, 90%) which was used directly in next step. LRMS: calc 333.0 and found: 334.0 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:5](=O)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=O.[NH2:19][C:20]1[CH:28]=[C:24]([C:25]([OH:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1>C(O)(=O)C>[C:25]([C:24]1[CH:28]=[C:20]([N:19]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=3[CH:6]=[C:5]2[C:4]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=2)[CH:21]=[CH:22][C:23]=1[OH:29])([OH:27])=[O:26]
Reactant: O=C(CC1CCCCC1=O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc(Cl)c(Cl)c3)cc3c2CCCC3)ccc1O

Procedure:
A solution of 15 g. (0.05 mole) of 2-(3,4-dichlorophenacyl)cyclohexanone, 7.7 g. (0.05 mole) of 5-aminosalicylic acid, and 63 ml. of glacial acetic acid was heated under reflux under nitrogen for 11/2 hours, cooled and filtered. The collected solid was washed with water and recrystallized from acetonitrile to provide 19.4 g. (97%) of yellow crystals, m.p. 210°-211°.
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:9]O[CH2:7]1)(=[O:4])=[O:3].Br[C:20]1C=CC(O[C@@H]2CCC[C@H]2O)=CC=1>>[CH3:1][S:2]([O:5][C@@H:6]1[CH2:7][CH2:20][CH2:9][C@H:10]1[O:11][C:12]1[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=1)(=[O:3])=[O:4]
Reactant: O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Product: CS(=O)(=O)O[C@@H]1CCC[C@H]1Oc1ccc(Br)cc1

Procedure:
The title compound of Step 2 was prepared according to the general procedure for the synthesis of trans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate in Example 2, except that trans-2-(4-bromophenoxy)cyclopentanol was used in place of trans-4-(4-bromophenoxy)tetrahydrofuran-3-ol, and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution. The organic layer was then washed with saturated aqueous ammonium chloride solution, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide product as a brown oil. Yield: 3.86 g, 11.5 mmol, 98%. 1H NMR (400 MHz, CDCl3) δ 1.79-2.00 (m, 4H), 2.14-2.26 (m, 2H), 3.03 (s, 3H), 4.78 (m, 1H), 5.07 (m, 1H), 6.82 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[CH:4][N:3]=1.Cl[CH2:22][C:23]1[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:20][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][CH2:22][C:23]2[O:27][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:24]=2)[C:7]=1[C:8]#[C:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=1
Reactant: Cc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CNc2ncnc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine (2.8 g), ethyl 5-chloromethyl-2-furancarboxylate (1.8 g), sodium hydrogencarbonate (1 g) and N,N-dimethylformamide (120 ml) was heated while stirring at 80° C. for 12 hours. The mixture thus obtained was concentrated under reduced pressure. To the resultant residue, water was added. After extraction was performed with ethyl acetate, an organic phase was dried over anhydrous sodium sulfate and evaporated. The resultant residue was purified by column chromatography to obtain a target substance (0.8 g). The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:9]([O:15][C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=2)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:7][CH2:6][NH:5]1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CN(C=O)C.[Cl-].[NH4+]>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:5]2[CH2:6][CH2:7][CH2:8][C:9]([O:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[C:18]([F:24])[CH:17]=3)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]2=[O:3])=[CH:29][CH:28]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)C1(Oc2cc(F)c(F)c(F)c2)CCCNC1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Oc2cc(F)c(F)c(F)c2)CCCN(Cc2ccc(OC)cc2)C1=O
Reaction time: 0.5 h

Procedure:
To a mixture of sodium hydride (60%, 59.6 mg) in DMF (5 mL) was added ethyl 2-oxo-3-(3,4,5-trifluorophenoxy)piperidine-3-carboxylate (430 mg) at 0° C. under a nitrogen atmosphere, and the mixture was stirred for 30 min. To the reaction mixture was added 4-methoxybenzyl chloride (0.221 mL), the mixture was stirred at 0° C. for 30 min and diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (352 mg).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:18]1[C:22]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=2)=[CH:21][N:20]=[CH:19]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH3:17])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[N:24][CH:25]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Reactant: Cc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-methyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=0.93 min; Mass spectrum (ESI+): m/z=405 [M+H]+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]1([CH:15]=[O:16])[CH2:14][CH2:13]1.[N:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>ClCCl>[OH:18][N:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([CH:12]1[CH2:14][CH2:13]1)=[O:16]
Reactant: O=Nc1ccccc1
Reactant: O=CC1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(C1CC1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of cyclopropanal (70 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:29]1[C:34]([C:2]2[N:6]([S:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:18][N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2Br)c1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
tert-butyl ({5-bromo-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (459 mg), (2-fluoropyridin-3-yl)boronic acid (169 mg), sodium carbonate (254 mg), and tetrakis(triphenylphosphine)palladium (173 mg) were suspended in 1,2-dimethoxyethane (10 mL) and water (4 mL), and the mixture was stirred at 105° C. for 2 hr. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 303 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25](=[O:27])[N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: C1CCNC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC1(C)CN(CC(=O)N2CCCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 82 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and pyrrolidine in 82% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.21 (s,3H), 1.29 (s,3H), 1.75-1.92 (m,4H), 2.46 (d,1H), 2.77 (d,1H), 3.35-3.68 (m,7H), 3.94 (m,2H), 8.08 (s,1H), 8.19 (d,1H), 8.23 (s,1H), 8.41 (d,1H), 9.05 (s,1H), 10.71 (s,1H), 11.51 (s,1H). Retention Time (LC, method: ammonium acetate standard): 1.75 min. MS (M+H+): 470.3.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH:22]=[CH2:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH:22]=[CH2:23])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:24])[CH:5]=1
Reactant: C=CC12CCC(=O)C=C1c1c(cc(OCC(=O)OC)c(Cl)c1Cl)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2

Procedure:
Methyl [(5,6-dichloro-3-oxo-9a-vinyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate (4.0 gm., 0.011 mole) is added to a solution composed of 20% aqueous sodium hydroxide solution (4.32 ml., 0.022 mole) and methanol (45 ml.). The mixture is stirred and heated at reflux for two hours and then concentrated in vacuo at 50° C. The residue is dissolved in water (50 ml.) and made acid to Congo red paper with 6 normal hydrochloric acid. The solid that separates is removed by filtration, washed with water, then with a little methanol and finally with a little ether. After recrystallization from acetic acid, there is obtained pure [(5,6-dichloro-3-oxo-9a-vinyl-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][NH:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH2:26](Br)[C:27]#[CH:28]>O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]([CH2:28][C:27]#[CH:26])[C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCc2cccnc2N1c1cccc(Br)c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1Cc2cccnc2N(c2cccc(Br)c2)C1=O
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 3.0 g of 1-(m-bromophenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 100 ml of dry dimethylformamide was added 0.6 g of 50% sodium hydride and the mixture was stirred for 30 minutes. To this was further added 3.5 g of propargyl bromide and the whole was reacted for one hour at room temperature. After the reaction was complete, the solvent was distilled off from the reaction mixture under reduced pressure. The residue thus obtained was diluted with water to release an oily product, which was then extracted with ether. The ether solution was dehydrated over magnesium sulfate, and separation and purification were accomplished by passing the solution through a column of alumina. The eluate thus obtained was concentrated to give 2.9 g of 1-(m-bromophenyl)-3-propargyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 118° - 119° C.
Reaction SMILES: ClC1C=C(Cl)C=CC=1CCC(C1C=CC=CC=1)=O.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28]/[C:29](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28]/[C:29](/[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)cc1Cl)c1ccccc1
Agent: O=C(CCc1ccc(Cl)cc1Cl)c1ccccc1
Product: CCOC(=O)/C=C(\CCc1ccc(Cl)cc1Cl)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(2,4-dichlorophenyl)-1-phenylpropan-1-one, (Z)-ethyl 5-(2,4-dichlorophenyl)-3-phenylpent-2-enoate and (E)-ethyl 5-(2,4-dichlorophenyl)-3-phenylpent-2-enoate were obtained as colourless oils.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]2[C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[O:16][C:3]=12.O=P(Cl)(Cl)[Cl:24]>>[Br:21][C:19]1[CH:18]=[CH:17][C:15]2[O:16][C:3]3[C:4](=[N:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:7][C:2]=3[Cl:24])[C:14]=2[CH:20]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccccc2)nc2c1oc1ccc(Br)cc12
Product: Clc1cc(-c2ccccc2)nc2c1oc1ccc(Br)cc12
Yield: 71.01 %

Procedure:
4-hydroxyl-8-bromo-2-phenyl-benzofuro[3,2-b]pyridine (8.7 g, 25.72 mmol) was added to POCl3 (100 mL) The mixture was refluxed for 4 hours. TLC showed the reaction completed. POCl3 was evaporated under reduced pressure. The residue was poured into ice-water under stirring. The yellow solids precipitated out were collected by filtration to give 8-bromo-4-chloro-2-phenyl-benzofuro[3,2-b]pyridine (M6) (6.52 g, 71.01% yield).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)(=[O:4])=[O:3].[ClH:20]>CO>[ClH:20].[CH3:1][S:2]([CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCS(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)CCC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To 1,1-dimethylethyl 4-[2-(methylsulfonyl)ethyl]-1-piperidinecarboxylate (240 g, 824 mmol) in MeOH at 0° C. was added saturated HCl in MeOH slowly. The suspension was stirred at rt overnight. The mixture was washed with MeOH then dried by vacuum to provide the title compound of Step E (135 g, 593 mmol, 72%). 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.40 (m, 2H), 1.52-1.65 (m, 3H), 1.70-1.80 (m, 2H), 2.68-2.83 (m, 2H), 2.79 (s, 3H), 3.07-3.20 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3=[N:15][C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=4[N:13]3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([CH3:28])[CH:3]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[CH3:56][NH:57][CH3:58]>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]>[Cl:22][C:21]1[C:16]2[N:15]=[C:14]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([N:57]([CH3:58])[CH3:56])=[CH:3][C:4]=4[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]3[C:17]=2[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:19][CH:20]=1
Reactant: CNC
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Br)cc1C
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(N(C)C)cc1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
A mixture of 1-(4-bromo-2-methylphenyl)-10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (700 mg, 1.65 mmol), sodium tert-butoxide (396 mg, 4.13 mmol), 2-(di-tert-butylphosphino)biphenyl (39.4 mg, 0.132 mmol), tris(dibenzylideneacetone)dipalladium (151 mg, 0.165 mmol), and dimethylamine (2.0 M solution of tetrahydrofuran, 2.5 mL, 5.0 mmol) in toluene (2.5 ml) was stirred at 70° C. under nitrogen for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (341 mg, 0.802 mmol, 49%).