Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[H-]>O1CCCC1>[CH3:6][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1ccccc1CCCCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCCCC1CCOc1ccccc1CCCCc1ccccc1
Yield: 69.1 %

Procedure:
A solution of 820 mg of 1-t-butoxycarbonyl-2-{2-[2-(4-phenylbutyl)phenoxy]ethyl}piperidine [prepared as described in Example 31(a)] in 4 ml of tetrahydrofuran was added dropwise to a dispersion of 140 mg of lithium aluminum hydride in 4 ml of tetrahydrofuran, whilst ice-cooling. After the addition was complete, the reaction mixture was heated under reflux for 2 hours and then cooled. Sodium sulfate decahydrate was carefully added to the mixture in order to decompose any excess of the hydride. Insoluble materials were then filtered off, and the filtrate was concentrated by evaporation under reduced pressure. The resulting oily residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 455 mg (yield 69%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:5]=[N:6][CH:7]=1.B(O)(O)O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[C:18]1([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2COc2cncc(Br)c2)cc1
Agent: O=C([O-])O
Agent: OB(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2COc2cncc(-c3ccccc3)c2)cc1
Yield: 13.7 %

Procedure:
5-bromo-3-(1-tosyl-2-(S)-pyrrolidinylmethoxy)pyridine from step 51b (300 mg, 10.73 mmol), boric acid (107 mg, 10.88 mmol) and Pd(0) (26 mg) were mixed together in benzene (2 mL), and the mixture was heated at reflux for 16 hours. NaHCO3 solution (2%, 1 mL) was added, and the mixture was extracted with chloroform. The CHCl3 was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane 1:1 to afford the title compound (300 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[NH:7]1[C@@H:16]2[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]C[C:8]1=[O:17].S(Cl)(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH:29]([Cl:32])(Cl)[Cl:30]>>[Cl:30][C:29]1([Cl:32])[CH2:10][C@H:11]2[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:7][C:8]1=[O:17]
Reactant: O=C1CC[C@@H]2CCCC[C@@H]2N1
Reactant: ClC(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(=O)(Cl)Cl
Product: O=C1N[C@H]2CCCC[C@H]2CC1(Cl)Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
28.8 g of phosphorus pentachloride were added to a solution of 23 g of cis-octahydro-1H-quinolin-2-one in 350 ml of anhydrous chloroform. To this were added dropwise 43.1 g of sulfuryl chloride in 45 ml of anhydrous chloroform at 20° to 30° C. within 30 min and the reaction mixture was stirred at the boiling point for 5 hours. After allowing to stand overnight, the mixture was neutralized with aqueous potassium carbonate cooled to 0° C. The aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. The residue was recrystallized from ethanol with the addition of active charcoal. 32 g of pale yellow crystals, having a melting point of 176° to 177° C., were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([N:19](CCC=C)[CH2:20][CH2:21][CH:22]=[CH2:23])[C:13]1C=CC=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:12]([N:19]([CH2:20][CH2:21][CH:22]=[CH2:23])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCCN(CCC=C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCCN(CCC=C)C(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
11.2 mL benzylchloroformate was added to 14 g N-benzyl-N-(but-3-enyl)-but-3-en-1-amine in 100 mL toluene at 0° C. After being heated at 70° C. for 3 h, the reaction mixture was cooled to RT, basified with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed with brine, dried, concentrated, and purified by chromatographie on silica gel (hexane/ethyl acetate 20:1) to yield 16.8 g of the desired product. (M+H)+: 274
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19])([O-])=[O:2].C1(C=CC(O)=CC=1)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N(C1C=CC=CC=1)=NC1C=CC=CC=1.[N+](C1C=CC=CC=1N=NC1C=C(C(CC)(C)C)C=C(C(CC)(C)C)C=1O)([O-])=O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[OH:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:2])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
Water 70 ml, 97% sodium hydroxide, 5.2 g, 2-nitro-2'-hydroxy-5'-methylazobenzene 12.9 g and toluene 10 ml were mixed and heated to 60° C. After stirring, hydroquinone 0.6 g was added and glucose 5.0 g was added to the mixture over one hour at 40° to 45° C. The mixture was further stirred for two hours, and the azobenzene disappeared, thus the reaction of Process (b) being completed. The reaction liquor was neutralized with 62% sulfuric acid 5.8 g, and was cooled to 20° C. to precipitate a crystal. The crystal thus precipitated was separated by filtration and was dried, thus producing 10.8 g of 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide having a melting point of 138° to 140° C. at the yield of 90.0%.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:9]([CH2:13][C:14]#[CH:15])[CH2:10][CH2:11][CH3:12])[CH2:7][CH3:8].[CH2:16]([N:18]1[C:26]2[N:25]=[CH:24][N:23]([CH2:27][CH2:28][CH3:29])[C:22]=2[C:21](=[O:30])[N:20]([CH2:31][CH2:32][CH2:33][C:34](=[O:36])[CH3:35])[C:19]1=[O:37])[CH3:17].Cl>CCCCCC.O1CCCC1>[CH2:13]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:6][C:7]#[C:8][C:34]([OH:36])([CH3:35])[CH2:33][CH2:32][CH2:31][N:20]1[C:21](=[O:30])[C:22]2[N:23]([CH2:27][CH2:28][CH3:29])[CH:24]=[N:25][C:26]=2[N:18]([CH2:16][CH3:17])[C:19]1=[O:37])[CH2:14][CH3:15]
Reactant: C#CCN(CCC)CCC
Reactant: CCCn1cnc2c1c(=O)n(CCCC(C)=O)c(=O)n2CC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN(CC#CC(C)(O)CCCn1c(=O)c2c(ncn2CCC)n(CC)c1=O)CCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5.3 ml (8.45 mmol) of a 15% strength butyllithium solution in n-hexane were slowly added dropwise to a solution of 1.36 ml (7.8 mmol) of N,N-dipropyl-2-propynylamine in 6 ml of tetrahydrofuran at -78° C., and the mixture was stirred at -78° C. for one hour. After warming to room temperature, a solution of 2.0 g (6.5 mmol) of 3-ethyl-1-(4-oxopentyl)-7-propylxanthine in 8 ml of tetrahydrofuran was added. After 7 hours at room temperature, the mixture was adjusted to pH 6-7 with 4 N hydrochloric acid and partitioned between 5% strength sodium bicarbonate solution and dichloromethane. The organic phase was dried with magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography, dichloromethane/methanol=19/1.
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]3[N:16]=[N:17][NH:18][CH:19]=3)=[C:9]([O:20]C)[C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]3[N:16]=[N:17][NH:18][CH:19]=3)=[C:9]([OH:20])[C:8]2=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1c(O)c(CCc2c[nH]nn2)ccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.8 %

Procedure:
To a solution of 158a (0.10 g, 0.338 mmol) in dry CH2Cl2 (8 mL) was slowly added 1M BBr3 (1.2 equiv) at −30° C. under argon atmosphere. The reaction mixture was stirred for 48 h at room temperature. The mixture was again cooled to −30° C. and the MeOH (5 mL) was slowly added to the mixture. After evaporation of solvent, the residue was adjusted to pH 7 with 1M NaOH and then extracted with CHCl3 (30 mL×3). The combined organic layer dried over Na2SO4 to give 79 mg (83%) of 159a as slightly brownish solid without any further purification required. 1H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.51 (s, 1H), 7.78 (d, J=7.3 Hz, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.31 (t, J=7.3 Hz, 1H), 6.75 (d, J=5.9 Hz, 1H), 6.64 (d, J=6.0 Hz, 1H), 5.95 (t, J=7.0 Hz, 1H), 4.76 (t, J=5.5 Hz, 2H), 4.42 (t, J=5.6 Hz, 2H). 13C NMR (100 MHz, DMSO) δ 158.25, 147.17, 146.77, 131.11, 129.34, 128.41, 128.31, 125.54, 122.23, 115.38, 105.76, 49.42, 48.33. HRMS (EI) calcd for C15H14N4O2 [M]+ 282.1117. found 282.1120.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:28][C:23]1[CH:22]=[C:21]([C:9]2([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][C:11]=3[O:10]2)[CH:26]=[C:25]([Cl:27])[CH:24]=1
Reactant: O=C(O)c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2
Reactant: C1CCNCC1
Product: O=C(c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2)N1CCCCC1

Procedure:
This compound was prepared from 2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and piperidine according to Example 269f; waxy solid,
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:37]=[C:36](F)[CH:35]=[CH:34][C:13]=1[C:14]([NH:16][C:17]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]([O-:42])([O-])=O.[K+].[K+]>N1CCOCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:37]=[C:36]([N:8]2[CH2:6][CH2:39][O:42][CH2:10][CH2:9]2)[CH:35]=[CH:34][C:13]=1[C:14]([NH:16][C:17]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Agent: [K+]
Solvent: C1COCCN1
Product: CC(C)(C)OC(=O)NCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 100 °C

Procedure:
A mixture of 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-fluorobenzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (0.8 g, 1.5 mmol), morpholine (10 mL), and K2CO3 (0.2 g) was heated in a sealed tube at 100° C. for 12 hours and then 120° C. for 4 h.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:13]([NH2:15])=[O:14].[CH:16](=O)[CH3:17].S([O-])([O-])(=O)=O.[Mg+2].C([BH3-])#N.[Na+]>C(O)(=O)C.CO.O1CCCC1>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]([C:13]([NH2:15])=[O:14])=[C:2]([NH:1][CH2:16][CH3:17])[S:12][C:5]=2[CH2:6]1)[CH3:11]
Reactant: CC=O
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNc1sc2c(c1C(N)=O)CCN(CC)C2
Reaction time: 23 h
Yield: 80.4 %

Procedure:
To a stirred mixture of compound F4 (200 mg, 0.888 mmol), acetaldehyde (5 M in tetrahydrofuran, 0.360 mL, 1.80 mmol), acetic acid (two drops), anhydrous magnesium sulfate (200 mg) in anhydrous methanol (6 mL) and anhydrous tetrahydrofuran (3 mL) was added sodium cyanoborohydride (167 mg, 2.66 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 23 h and then filtered. The filtrate was concentrated. The resulting residue was purified by flash column chromatography on silica gel eluting with 10% to 20% methanol/methylene chloride to afford compound R1 as a colourless syrup (181 mg, 80%): MS (M+H) 254.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCNC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCC(O)C1
Yield: 6.5 %

Procedure:
In the manner described in Example 28 (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (225 mg, 0.427 mmol) from Example 27B was reacted with pyrrolidin-3-ol (0.103 mL, 1.281 mmol) to yield 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{7-[3-(3-hydroxy-pyrrolidin-1-yl)-propoxy]-6-methoxy-quinazolin-4-yloxy}-phenyl)-urea (16 mg, 4%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.28 (s, 1H), 8.52 (s, 1H), 7.55 (d, 2H), 7.35 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.70 (brs, 1H), 4.25 (m, 3H), 3.95 (s, 3H), 2.80-2.30 (m, 6H), 1.95 (m, 2H), 1.55 (m, 2H), 1.30 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: B1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:2]1[CH2:3][CH2:4][CH2:5]2.C=CCCCCCC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[K+].[Br-].O.[O:29]=[C:30]1[CH2:39][CH2:38][CH2:37][C:36]2[CH:35]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:33]=[CH:32][C:31]1=2>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>[CH2:8]([C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:29])[CH2:39][CH2:38][CH2:37]2)[CH2:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: B1C2CCCC1CCC2
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Solvent: C=CCCCCCC
Solvent: O
Product: CCCCCCCCc1ccc2c(c1)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
9-BBN (0.5 M solution in THF, 20.2 mL, 10.1 mmol) was added to 1-octene (1.6 mL, 10.1 mmol) at room temperature. The solution was stirred, at room temperature, overnight. After this time, K3PO4 (2.93 g, 13.8 mmol), Pd(Ph3P)4 (191 mg, 0.17 mmol, 1.8 mol %), KBr (1.2 g, 10.1 mmol) and degassed H2O (0.18 mL, 10 mmol) were added. This was followed by a solution of compound 2 (2.7 g, 9.2 mmol) in dry degassed THF (10 mL). The reaction mixture was heated at 65° C. under argon for 2 hours. After cooling, the solution was acidified to pH 1 and extracted into EtOAc (100 mL). The aqueous layer was re-extracted with EtOAc (50 mL) and the combined organics washed with H2O (20 mL) and brine (40 mL). The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, 5% EtOAc in hexanes) to provide 1.93 g of compound 3 (82%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]([CH3:15])[CH2:13][C@H:12]([CH2:16][CH2:17][C:18]2([CH3:23])OCC[O:19]2)[C:11]1=[O:24])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]([CH3:15])[CH2:13][CH:12]([CH2:16][CH2:17][C:18](=[O:19])[CH3:23])[C:11]1=[O:24])[CH3:2]
Reactant: CCOC(=O)C(CCCCN1C(=O)[C@@H](CCC2(C)OCCO2)CC1C)c1ccc(OC)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCOC(=O)C(CCCCN1C(=O)C(CCC(C)=O)CC1C)c1ccc(OC)nc1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-4 (1.1 g) in acetone (50 mL) was added p-toluenesulfonic acid (470 mg) and the mixture was heated at reflux for 2 h, then cooled to ambient temperature. The reaction mixture was concentrated at reduced pressure and the residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give 3-5 as an oil , which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].[Cl-].[NH4+]>C1COCC1>[Cl:32][C:31]([Cl:34])([Cl:33])[CH2:30][O:29][C:27](=[O:28])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (16.8 g) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) and triethylamine (11.32 mL) in THF (338 mL) was added 2,2,2-trichloroethyl chloroformate (11.2 mL). The mixture was stirred at room temperature overnight, and poured into saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (19.0 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[N:17]=[C:16](S(C)(=O)=O)[N:15]=[C:14]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].[NH2:45][CH2:46][CH2:47][OH:48]>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[N:17]=[C:16]([NH:45][CH2:46][CH2:47][OH:48])[N:15]=[C:14]([NH:22][S:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(S(C)(=O)=O)nc2OCCOCc2ccccc2)cc1
Reactant: NCCO
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(NCCO)nc2OCCOCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
##STR152## (1) A solution of N-[6-(2-benzyloxyethoxy)-5-(4-methylphenyl)-2-methylsulfonylpyrimidin-4-yl]-4-tert-butylbenzenesulfonamide obtained in Reference Example 11-(6) (300 mg) in 2-aminoethanol (4 ml) is heated with stirring at 120° C. for three hours. After cooling, to the reaction solution is added an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=10:1), and recrystallized from isopropyl ether-n-hexane to give N-[6-{2-benzyloxyethoxy)-2-(2-hydroxyethylamino)-5-(4-methylphenyl)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (260 mg) as a crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[C:19]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:36])[C:23]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:1]([O:8][C:9]1[CH:20]=[C:19]2[C:12](=[CH:11][CH:10]=1)[NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH:18][CH:26]1[CH2:25][CH2:24][C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([N:22]([CH3:36])[CH3:21])[CH2:28][CH2:27]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(NCCc2c[nH]c3ccc(OCc4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
5-Benzyloxytryptamine (440 mg, 1.65 mmol) were dissolved in 1,2-dichloroethane (14 ml) under argon (slightly cloudy solution). After addition of 4-dimethylamino-4-phenylcyclohexanone (359 mg, 1.65 mmol) and glacial acetic acid (189 μl, 3.3 mmol), the mixture was stirred for two hours at RT. Sodium triacetoxyborohydride (462 mg) was then added and the suspension was stirred for four days at RT. For working up, water (15 ml) was added to the reaction mixture. The phases were separated and the aqueous phase was washed with ether (20 ml) and then rendered strongly alkaline with sodium hydroxide solution. The aqueous phase was extracted with ether (2×10 ml) and ethyl acetate (4×10 ml), the combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (686 mg) was recrystallized from a mixture of ethyl acetate/cyclohexane (35 ml/5 ml). 396 mg N′-[2-(5-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a cis/trans mixture (m.p. 130-134° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:1][N:33]3[C:34](=[O:43])[C:35]4=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]4[C:37]3=[O:38])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCc1ccc2ncccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1ccc2ncccc2c1
Reaction time: 8 h
Yield: 78.6 %

Procedure:
6-(hydroxymethyl)quinoline (520 mg, 3.27 mmol), triphenyl phosphine (900 mg, 3.44 mmol, 1.05 equiv) and N-hydroxyphthalimide (560 mg, 3.43 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (574 μL, 3.63 mmol, 1.11 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture filtered to give a white solid. The filtrate was concentrated and a second crop of material was obtained by triturating with Et2O. This was combined with the original solid and recrystallization from EtOH gave the desired product (782 mg) as a fluffy white solid. MS(CI) m/e 305 (M+H)+.