Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][CH2:12][CH2:13]O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.C(=O)([O-])O.[Na+].S(Cl)([Cl:23])=O>>[Cl:23][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: O=S(Cl)Cl
Reactant: OCCCc1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: ClCCCc1ccc2ncccc2c1
Temperature: 70 °C
Yield: 72 %

Procedure:
0.52 g (2.77 mmol) 3-quinolin-6-yl-propan-1-ol were dissolved in 5.5 ml thionylchloride and heated to 70° C. for 50 minutes. Water and aqueous sodium hydrogencarbonate were added and the mixture was extracted three times with DCM. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give 0.41 g (72%) of a brown oil. MS(ISP): 206.2 [MH]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:31]([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH3:31])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(C)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 100 %

Procedure:
The compound (625.7 mg) obtained in Example 115-1 was dissolved in methanol (25.0 ml) and added with a 36% formaldehyde aqueous solution (0.246 ml) and sodium cyanoborohydride (220.9 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 27 hours. The reaction solution was concentrated under reduced pressure and the residue was added with a 1 mol/l sodium hydroxide aqueous solution, followed by separation/extraction with chloroform. After having been washed with saturated saline solution, the extract was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (648.1 mg) as a colorless oily substance.
Reaction SMILES: CO[C:3](=[O:16])[C:4]([CH3:15])([CH3:14])[CH2:5][O:6][Si](C(C)(C)C)(C)C.[C:17](#[N:19])[CH3:18].[H-].[Na+]>C1(C)C=CC=CC=1.Cl>[OH:6][CH2:5][C:4]([CH3:14])([CH3:15])[C:3](=[O:16])[CH2:18][C:17]#[N:19]
Reactant: COC(=O)C(C)(C)CO[Si](C)(C)C(C)(C)C
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(CO)C(=O)CC#N
Temperature: 110 °C
Yield: 90.7 %

Procedure:
A solution of 9.22 g of 3-(tert-Butyl-dimethyl-silanyloxy)-2,2-dimethyl-propionic acid methyl ester and acetonitrile (2.34 mL, 44.88 mmol) in toluene (25 mL) is added dropwise over 1 h at reflux to a suspension of 1.80 g (44.88 mmol) NaH (60% dispersion in mineral oil) in anhydrous toluene (50 mL). The reaction mixture is heated to 110° C. for 18 h. The reaction mixture is diluted with 1M aqueous HCl solution to pH 7 and extracted with ethyl acetate (3×200 mL). The organic layers are combined, washed with water and brine, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 4.79 g of 5-hydroxy-4,4-dimethyl-3-oxo-pentanenitrile as a dark biphasic oil which is used crude in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (s, 6H), 3.55 (s, 2H), 3.61 (s, 2H).
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][C@@H:4]([OH:8])[C:5]#[C:6][CH3:7].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21](O)=[O:22])([O-:17])=[O:16].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([O:8][C@H:4]([CH2:3][C@H:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]#[C:6][CH3:7])=[O:22])([O-:17])=[O:16]
Reactant: CC#C[C@H](O)C[C@H](C)CCCC(C)C
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC#C[C@@H](C[C@H](C)CCCC(C)C)OC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
This compound was prepared similar to the method described in Example 44 from 4.22 g (21.6 mmol) of 6(R),10-dimethyl-undecan-2-yn-4(R)-ol, 4.58 g (21.6 mmol) of 3,5-dinitrobenzoic acid and 8.25 g (43.2 mmol) of p-toluenesulfonyl chloride in dry pyridine (total 55 ml) at 4° C. for 31/2 hr. It was worked up as described in Example 44 to give after recrystallization once from methanol 6.73 g (84.2%) of pure 6(R),10-dimethyl-undecan-2-yn-4(R)-ol 3,5-dinitrobenzoate, m.p. 90°-91°.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>N1C=CC=CC=1>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]4[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]4)=[CH:8][CH:9]=3)[NH:4][N:3]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc3c(N)n[nH]c3c2)C1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc3c(NC(=O)c4ccc(F)cc4)n[nH]c3c2)C1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
Tert-butyl 2-(3-amino-1H-indazol-6-yl)morpholine-4-carboxylate (43 mg, 0.135 mmol) was dissolved in pyridine (0.2 ml) and the solution was cooled to −5° C. 4-fluorobenzoyl chloride (21.4 mg, 0.135 mmo) was slowly added. After 5 min, the cooling bath was removed and stirring was continuing overnight. The reaction mixture was diluted with ethylacetate (2 ml) and washed with 1M citric acid solution (2 ml). The organic layer was dried over MgSO4 and concentrated in vacuo to give a brown oil which was further purified by flash column chromatography (silica gel, 50% to 100% ethyl acetate in heptane). The product was isolated as a yellow solid (40 mg, 67%), MS (ISP): 441.3 (100%, ([M-tBu+H]+), 385.2 (38%, [M+H]+).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1)([O-])=O.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>O1CCOCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:13]([C:9]1[CH:8]=[CH:7][C:6]([NH:10][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[CH:5][CH:4]=1)(=[O:17])[CH2:14][CH3:15]
Reactant: C=C(C)C(=O)Cl
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: C=C(C)C(=O)Nc1ccc(C(=O)CC)cc1
Reaction time: 0.5 h

Procedure:
A small amount of m-dinitrobenzene and copper(II) acetate were added whereupon a solution of 124.5 g of methacrylyl chloride (1 mole) in 125 ml of dioxan were added dropwise. The temperature was kept at 20°-25° C. Stirring was then continued for 30 min whilst slowly heating until reflux. Light yellow needles were sucked off, washed with ether, and dried under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:21][CH:22]3[CH2:24][O:23]3)[N:9]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[NH:33][C:32](=[O:34])[N:31]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:30]=2[CH:41]=1>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:21][CH:22]([OH:23])[CH2:24][N:38]3[CH2:37][CH2:36][CH:35]([N:31]4[C:30]5[CH:41]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=5[NH:33][C:32]4=[O:34])[CH2:40][CH2:39]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCNCC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2CC2CO2)C1
Solvent: CCO
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(Br)cc3)nn2CC(O)CN2CCC(n3c(=O)[nH]c4ccc(Cl)cc43)CC2)C1
Yield: 61.7 %

Procedure:
A stirred solution of 25.0 mg (0.061 mmol) of 3-(4-bromo-phenyl)-5-methanesulfonyl-1-oxiranylmethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine and 19.0 mg (0.073 mmol) of 6-chloro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one in EtOH (0.5 mL) was heated to 80° C. in a sealed vessel for 16 h. The reaction was cooled and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica, 0-5% MeOH/CH2Cl2) to afford 0.025 g (63%) of the title compound. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.4. MS (electrospray): m/z calculated for C28H32BrClN6O4S [M++H] 663.11, observed 663.0. 1H NMR (400 MHz, CDCl3): 10.2 (s, 1H), 7.52 and 7.46 (A and B of AA′BB′, J=8.6 Hz, 4H), 7.15 (br d, J=1.5 Hz, 1H), 7.04-6.95 (m, 2H), 4.52 and 4.49 (A and B of AB quartet, Jab=14.5 Hz, 2H), 4.33-4.14 (m, 3H), 4.07-3.97 (m, 1H), 3.74-3.58 (m, 2H), 3.17-2.89 (m, 4H), 2.86 (s, 3H), 2.57-2.30 (m, 5H), 2.20 (t, J=11.1 Hz, 1H), 1.87-1.73 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[C:30]([F:36])[CH:29]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][C:30]=2[F:36])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Temperature: 50 °C

Procedure:
A mixture of ethyl 6-[(5-chloro-2-hydroxyphenyl)methyl]-2-pyridinecarboxylate (92 mg, 0.31 mmol), potassium carbonate (109 mg, 2.5 equivalents) and 4-chloro-2-fluorobenzyl bromide (78 mg, 1.1 equivalents) in acetone (˜6 ml) was heated at 50° C. for 3-4 hours until there was no more SM (starting material). Cooled down, filtered off and washed with acetone. LC/MS okay, Rt4.05. Purified by SPE, product came off with ˜20% ethyl acetate in iso-hexane. 108 mg of a white solid. Rt=4.05 [MH+] 434, 437.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20]C)=[O:19].Cl>CN(C)C=O.O>[C:18]([CH2:17][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])([OH:20])=[O:19]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of thymine (0.317 mole) and potassium carbonate (0.634 mole) in dimethylformamide (900 ml) is added methyl bromoacetate (0.634 mole) and the mixture is stirred vigorously overnight under nitrogen. The mixture is filtered, washed with ether and evaporated to dryness, in vacuoto afford a colorless solid. The solid residue is treated with water (300 ml) and 4N hydrochloric acid (12 ml), stirred for 20 minutes at 0° C., filtered and washed with water (2×100 ml). The precipitate is treated with water and 2N sodium hydroxide (60 ml), and is boiled for 10 minutes. The mixture is cooled at 0° C., filtered, and then pricipitated by the addition of 4N hydrochloric acid (70 ml) to give the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.[C:29]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:40]5[CH:41]=[C:36]([CH:37]=[CH:38][CH:39]=5)[C:34]([O:33][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:35])[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
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: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 80 °C
Yield: 97.1 %

Procedure:
To N-(1-bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (508 mg, 1.14 mmol) in 1,2-dimethoxyethane (11 mL) was added 3-(tert-butoxycarbonyl)phenylboronic acid (328 mg, 1.48 mmol), tetrakis(triphenylphosphine)palladium (0) (131 mg, 0.114 mmol), and 2 M Na2CO3 (1.71 mL, 3.41 mmol). The mixture was heated at 80° C. overnight before it was diluted with ethyl acetate (10 mL) and washed with water (20 mL). The organics were dried over Na2SO4 and evaporated. The resulting crude material was purified by silica gel chromatography eluting with 0-10% ethyl acetate in hexanes to yield tert-butyl 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoate (603 mg, 97%). ESI-MS m/z calc. 544.6. found 545.3 (M+1)+. Retention time 2.76 minutes.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH2:3]1>C1COCC1.[Ni]>[CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][CH:10]=2)[CH2:3]1
Reactant: CC1CN(c2ccc([N+](=O)[O-])nc2)CC(C)O1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC1CN(c2ccc(N)nc2)CC(C)O1
Reaction time: 4 h
Yield: 87.3 %

Procedure:
2,6-Dimethyl-4-(6-nitro-pyridin-3-yl)-morpholine (4.00 g, 16.86 mmol) was dissolved in THF (100 mL) to which Raney Nickel (3.10 g) was added. The reaction mixture was shaken under a hydrogen atmosphere (50 psi) for 4 hours. The catalyst was filtered and the solvent evaporated to give 5-(2,6-dimethyl-morpholin-4-yl)-pyridin-2-ylamine as a purple solid (3.05 g, 87.4%). 1H NMR δ (400 MHz, CDCl3) 7.74 (d, J=2.4 Hz, 1H), 7.16 (dd, J=2.9, 8.8 Hz, 1H), 6.49 (dd, J=0.7, 8.8 Hz, 1H), 3.79 (m, 2H), 2.34 (dd, J=10.5, 10.5, 2H), 1.22 (d, J=6.3 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.O.Cl.[NH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1>O1CCOCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1
Reactant: Clc1ncccn1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCN(c2ncccn2)CC1
Temperature: 80 °C
Yield: 69 %

Procedure:
To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 80° C. overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2×10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 1-pyrimidin-2-yl-piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J=6.4 Hz, 2H), 6.61 (t, J=6.4 Hz, 9H), 4.16 (t, J=5.6 Hz, 2H), 2.53 (t, J=5.6 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].[CH2:19](Br)[C:20]#[CH:21]>>[CH2:21]([O:15][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])=[CH:18][CH:17]=1)[C:20]#[CH:19]
Reactant: C#CCBr
Reactant: CC(C)=CCCC(C)Oc1ccc(C(=O)O)cc1
Product: C#CCOC(=O)c1ccc(OC(C)CCC=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethyl-4-hexenyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(1,5-dimethyl-4-hexenyl)oxy]benzoic acid propargyl ester; nD22 = 1.5252.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].O>CN(C=O)C>[C:3]1([O:13][CH2:15][CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@@H](CCOc1cccc2ccccc12)c1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a mixture of 8 ml of DMF and 0.44 g of 60% sodium hydride in mineral oil at 5° C. in an ice bath was added dropwise a solution of 1.44 g of 1-naphthol in 8 ml of DMF. The reaction mixture was stirred at 5° C. for two hours and a solution of 1.71 g of (S)-(-)-3-chloro-1-phenyl-1-propanol in 5 ml of DMF was added. After stirring overnight at room temperature, the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate (3×50 ml). The combined extracts were combined and washed with water and 1N sodium hydroxide solution and dried over sodium sulfate. Yield: 2.56 g (92%). The crude product can be recrystallized from 95:5 hexane/ethyl acetate to give 1.5 g (54%) of purified (S)-(+)-3-(1-naphthalenyloxy)-1-phenyl-1-propanol, mp 76°-78° C.
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.[Cl:40][CH2:41][C:42]([N:44]=[C:45]=[O:46])=[O:43]>C1COCC1>[Cl:40][CH2:41][C:42]([NH:44][C:45](=[O:46])[NH:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)=[O:43]
Reactant: O=C=NC(=O)CCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC(=O)NC(=O)CCl)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 0.38 mmol) in THF (15 mL) was added a solution of 2-chloroacetyl isocyanate (100 mg, 0.78 mmol) in THF (1 mL) dropwise under nitrogen. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the resulting residue was obtained 6-(3-(2-chloroacetyl)ureido)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (203 mg, yield: 81%) without further purification. MS (M+H)+: 642.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([NH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#N)=[CH:17][CH:16]=1)[CH:12]=[CH2:13].C[OH:24]>C1(C)C=CC=CC=1>[CH2:11]([NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:24])=[CH:17][CH:16]=1)[CH:12]=[CH2:13]
Reactant: C=CCNc1ccc(C#N)cc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C=CCNc1ccc(C=O)cc1
Temperature: 0 °C

Procedure:
Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 12.1 g. of 4-(allylamino)benzonitrile under a nitrogen atmosphere. After addition is completed, the solution is stirred for one hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into 500 ml. vigorously stirred ice-cold 50% aqueous sulfuric acid. The mixture is filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The product is recrystallized from dichloromethane/hexane giving colorless needles.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[S:56]([C:60]1[CH:61]=[C:62]([CH:64]=[CH:65][CH:66]=1)[NH2:63])([OH:59])(=[O:58])=[O:57]>CN(C=O)C.C(N(CC)CC)C>[S:56]([C:60]1[CH:61]=[C:62]([NH:63][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])[CH:64]=[CH:65][CH:66]=1)([OH:59])(=[O:58])=[O:57]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N[C@@H](CCC(=O)Nc1cccc(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Boc-Glu-OtBu (75 mg, 0.247 mmol), HATU (112 mg, 0.296 mmol) and HOAt (41 mg, 0.296 mmol) were dissolved in 1 mL of DMF. Triethylamine (52 μL) was added thereto and stirred at room temperature for 10 minutes. 3-Sulfoaniline (43 mg, 0.247 mmol) was added thereto and stirred overnight at room temperature. After removing a solvent, purification was conducted in accordance with the purification process A. The obtained intermediate was dissolved in 2 mL of a trifluoroacetic acid and stirred at room temperature for 3 hours, and a solvent was removed therefrom. The obtained product was purified in accordance with the purification process A to obtain a title compound.
Reaction SMILES: C([CH:8]([NH2:32])[C:9]1[CH:31]=[CH:30][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22]C(=O)OC(C)(C)C)=[O:14])=[CH:11][CH:10]=1)(OC(C)(C)C)=O.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:32][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[O:14])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(N)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 391 (840 mg, 1.9 mmol) in 2:1 mixture of DCM/TFA (6 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to afford the title compound as a mixture of the mono and di-TFA salt. (1.33 g, 100% yield). LRMS: (calc) 241.2; (found) 242.2 (M+H1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8].[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH:17]([N:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:9](=[O:10])[C:7]2=[O:8])[CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1C(=O)N(CCCCBr)c2ccccc21
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A mixture of 1-(4-bromobutyl)isatin (5.64 g), 1-benzhydrylpiperazine (7.56 g) and triethylamine (3.0 g) in N,N-dimethylformamide (48 ml) was stirred for 30 minutes at 80° C. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to column chromatography on silica gel (50 g) using chloroform as an eluent. The fractions containing the object compound were collected and evaporated. The remaining oil (3.25 g) was crystallized from diisopropyl ether, washed with diethyl ether, and then recrystallized from acetonitrile to give crystals of 1-[4-(4-benzhydryl-1-piperazinyl)butyl]isatin (2.69 g), mp. 127° to 129° C.