Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([Cl:24])=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]12[O:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][NH:27][CH2:26]2.C=CCCC=C.C(N)C1C=CC=CC=1.ClC(OC(Cl)C)=O>CCO.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([Cl:24])=[N:21][C:22]([N:27]4[CH2:26][CH:25]5[O:32][CH:29]([CH2:30][CH2:31]5)[CH2:28]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CC2CNCC1O2
Reactant: Clc1nc(Cl)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Agent: C=CCCC=C
Agent: CC(Cl)OC(=O)Cl
Solvent: NCc1ccccc1
Solvent: CCO
Solvent: CO
Product: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Reaction time: 18 h

Procedure:
To a solution of 1 mmol 1-(1-benzyl-piperidin-4-yl)-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine dissolved in EtOH (10 mL) was added 1 mmol 8-oxa-3-aza-bicyclo[3.2.1]octane, (Newth, F. H. and Wiggins, L. F. Journal of the Chemical Society. 1948, pages 155-158) prepared from 1,5-hexadiene by the four-step process of RuCl3-catalyzed NaIO4 oxidation, conversion to the bis tosylate, cyclization with benzyl amine, and deprotection with 1-chloroethyl chloroformate followed by methanol (Scheme 46). The reaction was stirred for 18 h. The solvents were evaporated and the reminder was triturated with diethyl ether/hexane. The solid was filtered off and washed with hexane. Drying on the fritted funnel provided a solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=O)OC(C)(C)C.N1(OC2[N:31]=[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH:43]=[CH:42][N:41]=[CH:40]4)=[C:35]([F:44])[CH:34]=3)[C:29]([C:45]([NH2:47])=[O:46])=[CH:28][N:27]=2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1.CCOC(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:43]=[CH:42][N:41]=[CH:40]3)=[C:35]([F:44])[CH:34]=2)[C:29]([C:45]([NH2:47])=[O:46])=[CH:28][N:27]=1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1Nc1ccc(-n2ccnc2)c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-n2ccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
A solution of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.30 M in NMP, 1.00 mL, 0.300 mmol) in NMP (1 mL) was added to 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(3-fluoro-4-(1H-imidazol-1-yl)phenylamino)pyrimidine-5-carboxamide (57 mg, 0.13 mmol). DIEA (0.100 mL, 0.57 mmol) was also added. The mixture was stirred at 90 C for 1 h. After being cooled to room temperature, water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was dissolved in CH2Cl2 (1 mL) and TFA (1 mL). The solution was stirred at room temperature for 60 min. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (23 mg). MS 411.3 (M+H). UV λ=247.8, 299.8 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[NH2:14][OH:15].C([O-])([O-])=O.[K+].[K+].Cl>C(O)C>[OH:15][NH:14][C:5](=[NH:6])[C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C#N)c(OC)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(=N)NO)c(OC)c1
Temperature: 85 °C
Reaction time: 27 h
Yield: 34.4 %

Procedure:
A mixture of 2,4-dimethoxybenzonitrile (3.25 g, 20 mmol), hydroxylamine hydrochloride (2.92 g, 42 mmol) and K2CO3 (5.80 g, 42 mmol) in ethanol (80 mL) is stirred at 85° C. for 27 h before it is poured onto water (250 mL). The solution is acidified by adding 1 N aq. HCl (75 mL) and extracted once with DCM (100 mL). The aq. layer is basified with 1 N aq. NaOH (90 mL) and extracted three times with DCM (3×150 mL). The organic extracts are dried over MgSO4, the solvent is evaporated and the residue is dried under high vacuum to leave N-hydroxy-2,4-dimethoxy-benzamidine (1.35 g) as a beige solid. LC-MS: tR=0.68 min, [M+1]+=197.11.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[CH2:14]([O:16][CH2:17][C:18](Cl)=[O:19])[CH3:15]>>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:18](=[O:19])[CH2:17][O:16][CH2:14][CH3:15])=[C:7]([CH3:12])[CH:6]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: CCOCC(=O)Cl
Product: CCOCC(=O)Nc1ccc(OC(=O)NC)cc1C

Procedure:
According to the procedure of Example 5, 3-methyl-4-aminophenyl N-methylcarbamate was reacted with ethoxyacetyl chloride to yield the desired product m.p. 118°-21° C.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].O>CN(C=O)C>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-(1-methylpropoxy)phenol (44.3 mmol) in 25 ml of DMF is added, under N2, potassium carbonate (51.0 mmol) followed by dropwise addition of N-(bromoethyl)phthalimide (51.0 mmol) in 30 ml of DMF. The mixture is stirred at RT overnight. Water is then added and the aqueous phase is extracted with ether. The combined organic layers are washed with 5% sodium hydroxide, with water and with brine, dried and the solent removed to give N-{2-[4-(1-methylpropoxy)phenoxy]ethyl}phthalimide. Following the procedures of Example 7, the above phthalimide (5.7 mmol) is reacted with hydrazine hydrate (5.7 mmol) to give 2-[4-(1-methylpropoxy)phenoxy]ethylamine.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[CH:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:27])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: OC(COCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COCc1ccccc1
Yield: 48.8 %

Procedure:
By the same procedure as in Example 26-D), (2S)-2-(2-benzyloxy-1-hydroxyethyl)pyrrolidine (297 mg) and N-(tert-butoxycarbonyl)-L-proline (318 mg) were subjected to dehydration condensation reaction to give 274 mg of the title compound.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:12][C@H:11]([O:13][CH2:14][CH:15]=[CH2:16])[CH2:10][C@@H:9]2[C@@H:17]([OH:54])[C@@H:18]([NH:28][C:29](=[O:53])[C@@H:30]([N:39]2[CH2:43][CH2:42][C@:41]([NH:48][C:49](=[O:51])[CH3:50])([CH2:44][CH:45]([CH3:47])[CH3:46])[C:40]2=[O:52])[CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[C:49]([NH:48][C@:41]1([CH2:44][CH:45]([CH3:46])[CH3:47])[CH2:42][CH2:43][N:39]([C@@H:30]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:29]([NH:28][C@@H:18]([CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[C@H:17]([OH:54])[C@H:9]2[CH2:10][C@@H:11]([O:13][CH2:14][CH2:15][CH3:16])[CH2:12][NH:8]2)=[O:53])[C:40]1=[O:52])(=[O:51])[CH3:50]
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@@](CC(C)C)(NC(C)=O)C2=O)N(Cc2ccc(OC)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)[C@H](CCc2ccccc2)N2CC[C@@](CC(C)C)(NC(C)=O)C2=O)C1
Reaction time: 18 h
Yield: 64.1 %

Procedure:
Step 1 (B): Preparation of(S)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide. To a solution of (S)-N-((1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanamide (Step 1 (A), 55 mg, 0.071 mmol) in MeOH (5 ml) was added a catalytic amount of Pd(OH)2. The reaction mixture was stirred under 1 atm. of H2 for 18 h. The mix was then filtered through Celite and concentrated in vacuo. Flash chromatography (silica gel, 0-30% methanol/chloroform) gave 29.9 mg (64%) of (S)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide, the title compound of Example 1 as an opaque glass: 1H NMR (CDCl3, 500 MHz) δ 0.88 (3H, t, J=7.5 Hz), 1.00 (6H, dd, J=5, 7.5 Hz), 1.54 (3H, q, J=5 Hz), 1.69 (1H, dd, J=5, 15 Hz), 1.85 (1H, m), 1.92-1.97 (1H, m), 1.99 (3H, s), 2.11-2.17 (3H, m), 2.36-2.48 (3H, m), 2.52-2.57 (1H, m), 2.72 (1H, dd, J=10, 15 Hz), 2.92 (1H, dd, J=5, 15 Hz), 3.12-3.19 (3H, m), 3.29-3.42 (4H, m), 3.62 (1H, dd, J=5, 10 Hz), 3.98 (1H, m), 4.09-4.15 (1H, m), 4.63 (2H, brd s), 6.06 (1H, s), 6.52 (1H, m), 6.84 (2H, d, J=5 Hz), 7.10 (2H, d, J=5 Hz), 7.15 (1H, t, J=7.5 Hz), 7.24 (2H, t, J=7.5 Hz), 7.54 (1H, d, J=10 Hz). HPLC retention time: 1.69 min (method A). MS (ESI) (M+H)+ 657.38.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([NH:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:5].[C:18](Cl)(Cl)=[O:19]>Cl>[Cl:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][C:18](=[O:19])[N:6]([N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)[C:4]2=[O:5]
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)NN1CCOCC1
Agent: Cl
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)n1N1CCOCC1

Procedure:
23.5 g 2-Amino-5-chloro-N-morpholinobenzamide are dissolved in 500 cc 2N hydrochloric acid. A phosgene stream is passed through the solution for 1 hour. When the reaction is complete, the equipment is purged, after which the resulting material is suction filtered and washed with water. It is purified by crystallization from ethanol, M.P.=335° C.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].N1C=CC=CC=1.[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1>C(Cl)Cl.CCCCCC>[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH:29][S:1]([CH3:4])(=[O:3])=[O:2])[CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2nc3ccc(N)cc3s2)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(-c2nc3ccc(NS(C)(=O)=O)cc3s2)cn1
Temperature: 25 °C
Reaction time: 144 h
Yield: 70.2 %

Procedure:
Mesylchloride (3 μL, 0.037 mmol) and pyridine (3 μL, 0.037 mmol) was added to a sol. 2-(6-methoxypyridin-3-yl)-1,3-benzothiazol-6-amine (9 mg, 0.034 mmol) in DCM (1 mL). The r.m. was stirred at r.t. for 6 days. A few drops of hexane was added and the precipitated solid was collected and dried in vacuo. The crude product was purified by flash column chromatography (20 to 100% ethyl acetate in heptane), to give the title compound (8 mg) as an off-white solid. 1H NMR δ 9.84 (s, 1 H) 8.63 (d, 1 H) 8.11 (dd, 1H) 7.77 (d, 1 H) 7.71 (d, 1 H) 7.14 (dd, 1 H) 6.79 (d, 1 H) 3.73 (s, 3 H) 2.82 (s, 3 H); MS m/z (M+H) 336, (M−H) 334.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH:20]=O)=[CH:19][C:14]=2[N:13]=[N:12]1.N1CCCCC1>CCO>[NH:11]1[C:15]2[CH:16]=[CH:17][C:18](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: O=Cc1ccc2[nH]nnc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]nnc2c1
Temperature: 90 °C
Yield: 74.8 %

Procedure:
A scintillation vial was charged with indolin-2-one (101 mg, 0.760 mmol), 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (123 mg, 0.836 mmol), piperidine (7.5 uL, 0.076 mmol) and EtOH (4 mL). The reaction was then heated to 90° C. for 2 hrs. A yellow precipitate formed which was further precipitated by cooling to room temperature and adding more EtOH (5 mL). The yellow solid was then filtered and washed with EtOH (20 mL) giving 149 mg, 75% of the title compound. 1H NMR (400 MHz, d6-DMSO) δ 15.94 (s, 1H), 10.65 (s, 1H), 8.27 (bs, 1H), 8.05 (bs, 1H), 7.80 (s, 1H), 7.77 (bs, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H); MS ESI 263.0 [M+H]+, calcd for [C15H10N4O+H]+ 263.09.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:34][CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH2:39]([O:38][C:36]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33][CH2:34]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37])[CH3:40]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A174) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[BH4-].[Na+].O>CO>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)c1ccccc1COC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(O)c1ccccc1COC1CCCCO1
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A solution of ethyl 2-oxo-2-[2-(tetrahydropyran-2-yloxymethyl)phenyl]acetate (22.60 g, 77.3 mmol) in methanol (20 ml) was stirred at 0° C., and sodium borohydride (1.46 g, 38.6 mmol) was added to thereto. After 10 minutes, water (100 ml) was added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4/1) to give the desired compound ethyl α-hydroxy-2-(tetrahydropyran-2-yloxymethyl)phenylacetate (20.47 g, 90.0%) as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH:5]=[O:6].B(Br)(Br)Br.C(=O)=O.CC(C)=O>C(Cl)Cl>[OH:2][C:3]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[C:7]([CH3:18])[C:4]=1[CH:5]=[O:6]
Reactant: COc1cc(Oc2ccccc2)cc(C)c1C=O
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cc(Oc2ccccc2)cc(O)c1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A light yellow solution of 2-methoxy-6-methyl-4-phenoxy-benzaldehyde (6.33 g, 26.13 mmol) in DCM (250 mL) was treated with boron tribromide (1.0 M solution in DCM, 76 mL, 76 mmol) dropwise at −78° C. (dry ice/acetone bath). The red/brown mixture was stirred at −78° C. for 30 minutes, 0° C. (ice-water bath) for 30 minutes, then rt for 3 h. The mixture was quenched with ice water, then extracted with EtOAc. The extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to a brown residue. The residue was purified by column chromatography (SiO2, EtOAc/hexanes; 1:9) to afford 2-hydroxy-6-methyl-4-phenoxy-benzaldehyde (5.06 g, 85%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 12.32 (s, 1H), 10.14 (s, 1H), 7.42 (t, J=7.42 Hz, 2H), 7.30-7.21 (m, 1H), 7.08 (d, J=7.42 Hz, 2H), 6.35 (s, 1H), 6.21 (s, 1H), 2.54 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:21][CH2:20]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)CCCBr
Agent: Cl
Product: CCOC(=O)CCCN1CCN(c2ccccc2OC)CC1

Procedure:
Ethyl 4-(4-(2-methoxyphenyl)piperazin-1-yl)butanoate (17c) (Scheme 3) was synthesized from ethyl 4-bromobutanoate 16 and the piperazine 4 (R12═OMe, R13═H) according to protocol described for 17a (Example 19). Brown oil, 9.6 g (99%). 1H NMR (400 MHz, CDCl3): δ 1.23 (t, J=7.2 Hz, 3H), 1.82 (quintet, J=7.2 Hz, 2H); 2.35 (t, J=7.2 Hz, 2H); 2.43 (t, J=7.2 Hz, 2H); 2.63 (broad s, 4H); 3.07 (broad s, 4H); 3.84 (s, 3H); 4.13 (q, J=7.2 Hz, 2H); 6.83-6.99 (m, 4H). MS (ESI): m/z=307.50 (M+H+).
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].P([O-])(O)(O)=O.[Na+].[CH3:12][C:13]([O:16][C:17]([N:19]([C:27]1[NH:28][CH:29]=[C:30]([CH:32]=[O:33])[N:31]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:18])([CH3:15])[CH3:14].CC(=CC)C>O.C1COCC1.CC(O)(C)C>[CH3:15][C:13]([O:16][C:17]([N:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C:27]1[NH:28][CH:29]=[C:30]([C:32]([OH:5])=[O:33])[N:31]=1)=[O:18])([CH3:12])[CH3:14]
Reactant: O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C=O)c[nH]1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(C(=O)O)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A solution of sodium chlorite (0.505 g, 5.59 mmol) and sodium dihydrogenphosphate monohydrate (0.463 g, 3.35 mmol) in water (4 mL) was added to a solution of bis(1,1-dimethylethyl)(4-formyl-1H-imidazol-2-yl)imidodicarbonate (0.174 g, 0.559 mmol), 2-methyl-2-butene (2M in THF) (3.49 mL, 6.99 mmol), t-BuOH (2 mL) and THF (6 mL). The mixture was stirred at RT overnight. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was triturated with ether and the resulting white solid was dried under vacuum to give 0.098 g (53%) of the title compound. MS m/z 326 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([F:24])[C:12]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[N:13][CH:14]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1>Cl.O1CCOCC1>[ClH:1].[ClH:1].[NH2:16][CH2:15][C:12]1[N:13]=[CH:14][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:25]([F:28])([F:27])[F:26])=[CH:10][C:11]=1[F:24]
Reactant: CC(C)(C)OC(=O)NCc1ncc(Nc2ccc(Cl)cc2C(F)(F)F)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: NCc1ncc(Nc2ccc(Cl)cc2C(F)(F)F)cc1F
Yield: 84 %

Procedure:
Tert-butyl [5-(4-chloro-2-trifluoromethyl-phenylamino)-3-fluoro-pyridin-2-ylmethyl]-carbamate (50 mg, 0.12 mmol) was stirred for 2 hours at 60° C. in a mixture of 2 mL of semi-concentrated hydrochloric acid and 3 mL of dioxane. This was then concentrated to dryness, the residue was stirred with 3 mL of toluene and evaporated down once more. The product was thus obtained in a yield of 84% of theory.
Reaction SMILES: [CH2:1]([C:3](=[CH:8][CH3:9])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:2].[C:10](OC(=O)C)(=[O:12])[CH3:11]>ClCCl>[C:10]([NH:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])(=[O:12])[CH3:11]
Reactant: CC=C(C=CCN)CC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC=C(C=CCNC(C)=O)CC
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A mixture of N-(4-ethyl-2,4-hexadien-1-yl)phthalimide (500 mg), hydrazine monohydrate (147 mg), and ethanol (5 ml) was refluxed for 40 minutes under nitrogen atmosphere. After cooling, the precipitate was filtered and washed with ethanol. Evaporation of the filtrate gave a crystalline residue which was dissolved in 1N sodium hydroxide solution and extracted with dichloromethane. The organic extract was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated to give 4-ethyl-2,4-hexadien-1-ylamine (205 mg) as an oil. This oil was used in the next reaction without further purification. To a solution of crude 4-ethyl-2,4-hexadien-1-ylamine (205 mg) in dichloromethane (2 ml) at 0° C. was added dropwise acetic anhydride (335 mg). After one hour, the reaction mixture was evaporated to dryness. The residue was chromatographed on silica gel (2% methanol in dichloromethane) to give 1-acetylamino-4-ethyl-2,4-hexadiene (122 mg) as an oil.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH2:20])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]=[CH:9][C:10]([NH2:20])=[CH:11]2
Reactant: COc1ccc2c(c1)C=C(N)CN2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(N)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-tert-butyloxycarbonyl-6-methoxy-3-aminoquinoline (Step F, 3 g, 0.011 mol) in CH2Cl2 (50 mL) cooled at 0° C. was added TFA (8.4 mL, 0.11 mL). The reaction mixture was warmed to RT and stirred for 8 h. The reaction mixture was concentrated under vacuum. The residue was suspended into MTBE. The yellow solid was filtered off and washed with MTBE. The dry yellow solid was suspended in NaOH 1N and the suspension was stirred for 15 min. The resulting slurry was filtered. The solid was washed with water and dried over P2O5 to give 6-methoxy-3-aminoquinoline as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][Si](C(C)(C)C)(C)C)[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:23]1[CH2:24][CH2:25][N:20]([C:2]2[CH:3]=[C:4]([OH:12])[C:5]3[N:6]=[CH:7][CH:8]=[N:9][C:10]=3[CH:11]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc2nccnc12
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Oc1cc(N2CCOCC2)cc2nccnc12
Temperature: 100 °C

Procedure:
As shown in step 6-vii of Scheme 6, a mixture of 7-bromo-5-((tert-butyldimethylsilyl)oxy)quinoxaline (700 mg, 2.06 mmol), morpholine (270 mg, 270 μL, 3.09 mmol), Pd2(dba)3 (94.50 mg, 0.1032 mmol), (rac)-BINAP (129 mg, 0.206 mmol), cesium carbonate (2.02 g, 6.19 mmol) in toluene (7 mL) was flushed with nitrogen for 10 minutes. The mixture was then heated overnight at 100° C. After cooling, the reaction mixture was diluted with EtOAc, filtered through a layer of diatomaceous earth, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 30% EtOAc/hexanes gradient) to provide 7-morpholinoquinoxalin-5-ol. This compound (450 mg, 1.3 mmol) was dissolved in THF (20 mL) and tetra-n-butylammonium fluoride (539 mg, 2.06 mmol) was added. The reaction mixture was stirred for 0.5 hour, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 100% EtOAc/hexanes gradient) to provide 7-morpholinoquinoxalin-5-ol (compound 1019) as a yellow solid: 1H-NMR (300 MHz, CDCl3) δ 8.75 (d, J=2.0 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 7.70 (d, J=41.8 Hz, 1H), 7.01 (d, J=2.6 Hz, 1H), 6.89 (d, J=2.5 Hz, 1H), 4.12-3.78 (m, 4H), 3.51-3.24 (m, 4H).
Reaction SMILES: N.N[C@H](C([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][S:14][CH3:15])=O)CCSC>>[NH2:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][S:14][CH3:15]
Reactant: CSCC[C@H](NC(=O)[C@@H](N)CCSC)C(=O)O
Agent: N
Product: CSCC[C@H](N)C(=O)O
Yield: 21 %

Procedure:
When the reaction was carried out under otherwise the same conditions but without addition of ammonia there was formed methionine in a yield of 64.5% besides a yield of 21% of methionine dimer (N-methionyl-methionine).