Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[NH4+:22].O>CO>[N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([NH2:22])=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C

Procedure:
Methyl 4-((1H-indol-1-yl)methyl)benzoate 1 was dissolved in MeOH (10 mL) and to it was added a 30% solution of ammonium hydroxide (5 mL). The reaction was heated to reflux for 16 h after which it was cooled to RT and H2O (30 mL) was added. The organic products were extracted with EtOAc (3×15 mL), washed with brine (15 mL), dried with Na2SO4 and concentrated in vacuo. The crude product was dissolved in DMF and purified by preparatory HPLC method 1. The title compound was isolated as a white solid (37 mg, 13%). 1H NMR (400 MHz, MeOD): δ 7.79 (d, J=7.9 Hz, 2H), 7.58 (d, J=7.8 Hz, 1H), 7.29 (m, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.11 (t, J=7.2 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H), 5.47 (s, 2H). 13C NMR (100 MHz, MeOD): δ 170.59, 142.41, 136.24, 132.64, 128.93, 128.14, 127.57, 126.36, 121.13, 120.32, 118.99, 109.29, 101.14, 48.93. ESI-LRMS: [M+H]+=251.1 m/z. ESI-HRMS: calc. for C16H14N2O: [M+H]+=251.1179 m/z, found: [M+H]+=251.1179 m/z.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:18]([N:20]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:21]1[CH2:26][C@@H:25]([C:27](=[O:32])N(OC)C)[CH2:24][N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22]1)=[O:19].[CH3:44][Mg]Br.[Cl-].[NH4+]>C1COCC1>[C:27]([C@@H:25]1[CH2:26][C@H:21]([N:20]([C:18]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:19])[CH2:40][CH:41]([CH3:42])[CH3:43])[CH2:22][N:23]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:24]1)(=[O:32])[CH3:44]
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N(C)OC)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl (3S,5R)-3-[{[5-(4-methoxybutyl)-1-phenyl-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (230 mg) was dissolved in THF (5 ml), a 1M solution (1.9 ml) of methylmagnesium bromide in THF was added at 0° C., and the mixture was stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:5-1:2) was concentrated under reduced pressure to give the object product (177 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl.ClC[C@H:21]1[CH2:23][O:22]1.[OH-].[Na+]>ClCCl.O1CCOCC1>[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:21]3[CH2:23][O:22]3)[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: ClC[C@H]1CO1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C1CC1CN1CCN(C[C@@H]2CO2)CC1
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (2 g, 8.30 mmol) was dissolved in 40 mL of dichloromethane followed by the addition of 20 mL of a 4 M solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure followed by the addition of 40 mL of dichloromethane and dropwise with 20 mL of triethylamine to adjust pH to 10 to 11. The resulting solution was concentrated under reduced pressure. The residue was added with 50 mL of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure, added with 50 mL of ethyl acetate and 20 mL of water, then added with (R)-2-chloromethyl-oxirane (0.92 g, 9.96 mmol) and sodium hydroxide (0.66 g, 16.60 mmol). The reaction solution was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, added with 50 mL of water and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-(cyclopropylmethyl)-4-[[(2R)-oxiran-2-yl]methyl]piperazine 31b (0.91 g, yield: 57.0%) as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:26]=[CH:25][C:14]([CH2:15][O:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH2:18])=[CH:13][CH:12]=1)=O>>[OH:8][CH2:9][C:11]1[CH:26]=[CH:25][C:14]([CH2:15][O:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH2:18])=[CH:13][CH:12]=1
Reactant: C=C(OCc1ccc(C(=O)OC)cc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=C(OCc1ccc(CO)cc1)c1ccccc1

Procedure:
This compound was prepared by lithium aluminium hydride reduction of α-(4-methoxycarbonylbenzyloxy)styrene: 1H NMR (CCl4) δ 2.65 (1H, t, J 4.5 Hz), 4.15 (1H, d, J 3 Hz), 4.43 (2H, d, J 4.5 Hz), 4.60 (1H, d, J 3 Hz), 4.80 (2H, s), 7.1-7.7 (9H, m).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[C:27]([C:29]([O:31][CH2:32]C)=[O:30])[CH:28]=1)[NH:25][CH:24]=[CH:23]2.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:28]=1)[NH:25][CH:24]=[C:23]2[CH:3]1[CH2:4][CH2:5][S:1][CH2:2]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CCSC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c(C3CCSC3)c[nH]c12
Temperature: 25 °C
Yield: 46.5 %

Procedure:
To the stirred mixture of dihydro-3(2H)-thiophenone (0.167 mL, 1.97 mmol) in DCM (25 mL) under N2 was added TMS-OTf (0.71 mL, 3.9 mmol) slowly over about 5 minutes at 0° C. (ice-bath). A solution of ethyl 5-bromo-1H-indole-7-carboxylate (0.50 g, 1.97 mmol) in DCM (5 mL) was added dropwise over 60 min, then triethylsilane (1.26 mL, 9.8 mmol) was added in one portion, and the reaction was allowed to warm slowly to room temperature. Then saturated NaHCO3 and DCM were added, the layers were separated and the aqueous layer was extracted with DCM twice. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified using Companion, giving 312 mg (46%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2.C(O)(=O)C>C1COCC1.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[CH:17]=[C:18]([S:21]([N:24]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]2=3)=[C:2]([Br:1])[CH:7]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc([N+](=O)[O-])cc2Br)cc1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(N)cc2Br)cc1
Temperature: 70 °C

Procedure:
4-(2-bromo-4-nitrophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.025 g, 0.040 mmol) was dissolved in THF (0.135 mL) and acetic acid (0.127 mL, 2.227 mmol), and iron (0.023 g, 0.405 mmol) was added. The flask was sealed and heated to 70° C. for 1 hour. The reaction was cooled to rt, diluted with THF, and filtered through Celite® (diatomaceous earth), washing well with THF. The filtrate was concentrated, and partitioned between saturated aqueous sodium bicarbonate solution and EtOAc. The layers were separated, and the aqueous was then extracted (×2) with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to yield 4-(4-amino-2-bromophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a light brown solid. The material was carried forward without further purification. m/z (ESI) 587.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[N:4][N:3]=[N:2]1.NC1C=CC=CC=1C#N.[N-]=[N+]=[N-].[Na+].[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>ClCCl.N1C=CC=CC=1>[N+:26]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]2[NH:1][N:2]=[N:3][N:4]=2)=[O:34])=[CH:36][CH:37]=1)([O-:28])=[O:27]
Reactant: Nc1ccccc1-c1nnn[nH]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: N#Cc1ccccc1N
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1-c1nnn[nH]1)c1ccc([N+](=O)[O-])cc1

Procedure:
3.0 g (18.6 mmol) 2-(tetrazol-5-yl)aniline (prepared by heating of 2-aminobenzonitrile in the presence of sodium azide according to E. R. Wagner, J. Org. Chem. 1973, 38, 2976) and 3.2 ml pyridine were dissolved in 50 ml dichloromethane. A solution of 3.7 g (19.9 mmol) 4-nitrobenzoyl chloride in 50 ml dichloromethane was added via a dropping funnel, and the mixture was heated with reflux for 1 h. The title compound precipitated from the solution, was filtered with suction, washed with hexane, and dried in vacuo to give a yellow powder, m.p. 223-225 (dec.)
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]#[CH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(BC(C(C)C)C)(C(C)C)C.[Br-:42]>>[Br:42]/[CH:11]=[CH:10]/[CH:9]([O:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: [Br-]
Reactant: C#CC(CCCCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)C(C)BC(C)C(C)C
Product: CCCCCCCC(/C=C/Br)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 3-triphenylmethoxy-1-decyne (Example 129) with disiamylborane and the bromide by the procedure described in Example 1173 is productive of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].OO.[OH-].[Na+].[ClH:15]>O>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: Cl
Reactant: NC(=O)c1cccnc1N
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc(Cl)cnc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
(Step 1) To a solution of 2-aminonicotinamide (0.5 g) in concentrated hydrochloric acid (3 ml) was added dropwise 30% aqueous hydrogen peroxide (0.3 ml). After stirring at 60° C. for 1 hr, the reaction mixture was diluted with water and basified with 1N aqueous sodium hydroxide solution. The mixture was extracted with a mixed solution of ethyl acetate and THF, washed with saturated brine and dried over magnesium sulfate. The reaction solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to give 2-amino-5-chloronicotinamide as crystals (0.25 g).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.Cl.[Br:31]C1C=C2C(C=C(C(O)=O)N2)=CC=1OC1CCN(C(C)C)CC1.BrC1C=C2C(C=C(C(N3CCOCC3)=O)N2C2C=CN=C(Cl)C=2)=CC=1OC1CCN(C(C)C)CC1>>[Br:31][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:8]([N:5]3[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]3)=[O:9])[NH:11]2)=[CH:16][C:15]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Agent: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCOCC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(F)(F)CC4)[nH]c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride salt with 1 eq. lithium chloride (example 41, step 5). The title compound was obtained in 77% yield as light yellow solid. MS (m/e): 486.2 (MH+, 100%).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:24]1(C2C=CC=CC=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:25]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:29]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:24]=[CH:25][C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)([CH3:14])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=3)[N:34]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccc(Cl)cc2)C(=O)O)cc1

Procedure:
A mixture of 2-(4-chlorophenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 26, Part C), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 2, Part F) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-chloro-phenoxy)-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3δ 8.12 (t, 1H, J=19.94 Hz), 7.87 (td, 1H, J=19.16 Hz, 7.43 Hz), 7.61 (t, 3H, J=7.43 Hz), 7.48–7.28 (m, 4H), 7.08 (t, 4H, J=6.65 Hz), 6.77 (td, 4H, J=24.63 Hz, 12.12 Hz), 4.16 (t, 2H, J=6.65 Hz), 3.18 (d, 1H, J=13.29 Hz), 3.00 (d, 1H, J=13.29 Hz), 2.90 (t, 2H, J=6.65 Hz), 2.52 (d, 1H, J=15.25 Hz), 2.32 (t, 2H, J=19.55 Hz), 1.29 (s, 3H) MS (ES+) m/z mass calcd for C34H31ClNO5 568.19, found 568.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:11](=[O:21])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=[O:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:22][NH:23][C:24](=[O:25])[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:21])[N:12]2[CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: O=C1CCC(c2ccc(O)cc2)N1CCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc(C2CCC(=O)N2CCN2CCOCC2)cc1
Yield: 52.3 %

Procedure:
To a solution of 5-(4-hydroxyphenyl)-1-[2-(4-morpholinyl)ethyl]pyrrolidin-2-one (0.99 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.22 ml) at ambient temperature, with stirring, over ten rains. Milled potassium carbonate (0.565 g) was added, the reaction mixture was stirred for 2 days and filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, 1% triethylamine/1-10% methanol/ether) and (silica gel, 5% methanol/ether). The appropriate fractions were collected and concentrated to afford 0.62 g (52.3%) of product. Recrystallization from absolute ethanol/ether gave the analytical sample, mp 119°-120° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[CH3:10].[C-:11]#[N:12].[K+]>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CBr)ccc1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(CC#N)ccc1Br
Reaction time: 6 h
Yield: 86.6 %

Procedure:
1-Bromo-4-(bromomethyl)-2-methylbenzene (45 of crude from step b, 68.2 mmol) dissolved in CH2Cl2 (500 mL) is mixed and stirred with potassium cyanide (24 g, 364 mmol) and N-tetra(n-butyl)ammonium bromide (1.2 g, 3.64 mmol) in distilled water (500 mL). This reaction mixture is stirred vigorously for 6 h. The organic phase is separated, dried over MgSO4, filtered and concentrated. The resulting residue is purified on silica gel using a 0 to 30% gradient of ethyl acetate in heptane to provide the expected product 2-(4-bromo-3-methylphenyl)acetonitrile (12.4 g, 87% over two steps) as a clear yellow oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.41 (s, 3H) 3.68 (s, 2H) 7.01 (dd, J=8.50, 2.05 Hz, 1H) 7.21 (d, J=1.37 Hz, 1H) 7.53 (d, J=8.20 Hz, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:10]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:29](=[O:31])[CH3:30])[C:10]=1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCNCc1nc2ccccc2c(OCc2ccccc2)c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCN(Cc1nc2ccccc2c(OCc2ccccc2)c1C)C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-{[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}heptane-1-amine (153 mg) in pyridine (5 mL) was added acetic anhydride (0.06 mL), followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and water (10 mL) and 1M hydrochloric acid (10 mL) were added to the residue, followed by extraction with ethyl acetate (50 mL). The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N-{[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}-N-heptylacetamide (158 mg).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].S(Cl)(Cl)=O.[C:17]1([C@@H:23]([NH:25][CH2:26][C:27]([C:29]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][CH2:30]2)=[O:28])[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>C1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1.CN(C=O)C>[CH2:7]([O:6][P:4]([CH2:9][C:10]([N:25]([CH2:26][C:27]([C:29]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:30][CH2:31]1)=[O:28])[C@H:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:24])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)C1(C(=O)CN[C@@H](C)c2ccccc2)CC1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)CN(C(=O)CP(=O)(OCC)OCC)[C@@H](C)c2ccccc2)CC1
Yield: 57.9 %

Procedure:
Diethylphosphonoacetic acid (32.8 g, 166 mmol) was dissolved in anhydrous benzene (700 ml), and after adding N,N′-dimethylformamide (1 ml, thionyl chloride (18.2 ml, 250 mmol) was added thereto and heated under reflux for 1.5 hours. After letting the reaction solution cool, it was concentrated under a reduced pressure, and after adding dried toluene (100 ml) thereto, its concentration under a reduced pressure was performed again. After repeating this operation 3 times, the concentrate was dissolved in anhydrous tetrahydrofuran (300 ml) and after adding dropwise an anhydrous tetrahydrofuran (300 ml) solution of ethyl 1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate (45.7 g, 166 mmol) and triethylamine (25.1 ml, 183 mmol) while stirring and cooling with ice, it was stirred while cooling with ice for 1.5 hours and then stirred at room temperature for 2 hours. After adding 1 mol/l hydrochloric acid (300 ml) and ethyl acetate (300 ml) to the reaction solution and performing an extraction operation, the organic layer was separated. The aqueous layer was then subjected to extraction with ethyl acetate (300 ml) and the combined organic layer was washed with saturated sodium bicarbonate water (300 ml) and saturated saline solution (300 ml) in that order, and then dried over anhydrous sodium sulfate. After filtering and then concentrating the filtrate under a reduced pressure, 43.6 g (70%) of the title compound was obtained as a yellow syrup.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[N:6]=[CH:5]2.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:16])[N:6]=[CH:5]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc2c(F)c(Br)ccc2n1
Product: Fc1c(Br)ccc2nc(Cl)ncc12

Procedure:
A solution of 6-bromo-5-fluoroquinazolin-2-ol (3.0 g, 12.34 mmol) in phosphoryl trichloride (10 mL) was refluxed at 135° C. for 5 hours. Most of phosphoryl trichloride was removed under reduced pressure, and the residue was dropwise added to ice water (200 mL). The resulting precipitate was collected via filtration as a yellow solid (3.1 g, 96%). MS (ES+) C8H3BrClFN2 requires: 260, found: 261, 263 [M+H]+.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O:18]1[CH2:20][CH2:19]1>>[CH2:1]([NH:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][O:16][CH2:20][CH2:19][OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)CCCO
Reactant: C1CO1
Product: CCCCCCCCCCNC(=O)CCCOCCO
Reaction time: 2 h
Yield: 97.8 %

Procedure:
In a steel autoclave, 243 grams (1 mole) of N-decyl-4-hydroxy-butyramide at a temperature of 130° C. was admixed with 44 grams (1 mole) of oxirane which was added to the autoclave as a compressed gas. The reaction mixture was stirred and autogenous pressure caused a drop in pressure during the reaction. After the reaction was complete in a period of about 2 hours, 281 grams of product were obtained. The product was then cooled to room temperature whereupon a light solid having a melting point of 48° C. was obtained. IR=6.11 mu.