Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][CH:23]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=391.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([CH:18]=1)[CH:7]=[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[O:9]1.[Cl-].[NH4+].O>C(O)C>[NH2:19][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][C:6]=1[CH:7]=[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[O:9]1
Reactant: O=C1OC(=Cc2cc(Cl)ccc2[N+](=O)[O-])c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)cc1C=C1OC(=O)c2ccccc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
A mixture of 3-(5-chloro-2-nitrobenzylidene)-2-benzofuran-1(3H)-one (808 mg), reduced iron (750 mg), ammonium chloride (72 mg), water (2.5 mL), and ethanol (25 mL) was stirred at 80° C. for 4 hours. The reaction mixture was filtered using Celite and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-(2-amino-5-chlorobenzylidene)-2-benzofuran-1(3H)-one (466 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[NH:22][CH:21]=3)=[O:19])[CH:17]=2)=[O:10])=[CH:4][CH:3]=1.Br[CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32])[CH:21]=3)=[O:19])[CH:15]=[N:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 229 using 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308), methyl 2-bromopropionate and cesium carbonate. Purified using preparative HPLC (method 1) to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=1[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([Br:26])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(OC)cc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1cc(Br)c(OC)cc1OCc1ccccc1
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, 12.60 g (52.00 mmol) of 3-benzyloxy-4-ethyl-1-methoxybenzene (3) and 9.72 g (54.60 mmol) of NBS were combined in 350 mL of carbon tetrachloride, followed by the addition of 50 g of silica gel 60 (EM Science). The reaction was allowed to stir for 16 hours in the absence of light. The reaction mixture was filtered and the silica gel was washed with dichloromethane. The filtrate was washed with ethyl acetate (1×300 mL). The combined organic extracts were washed with 1M NaOH (2×300 mL), dilute NaHSO3 (1×200 mL) and brine (1×200 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to yield 16.82 g (100%) of crude, 5-benzyloxy-2-bromo-4-ethyl-1-methoxybenzene (4) as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][NH:30]1.[I-].[Na+]>COCCOC>[CH2:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][N:30]1[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: c1ccc2c(c1)CCNC2
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCc2ccccc2C1
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 173.0 mg (0.44 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 586.0 mg (4.4 mmol) of 1,2,3,4-tetrahydroisoquinoline and 66.0 mg (0.44 mmol) of sodium iodide in 4 mL of DME was heated at 135° C. for 16 hr. The work up gave 109.3 mg (50.6%) of the product as a yellow solid, m.p. 170-173° C., mass (electrospray, m/e): M+H 491.0
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH2:30])=[CH:28][C:23]=2[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:30][C:3]3[S:4]/[C:5](=[CH:9]\[C:10]4[CH:11]=[C:12]5[C:17](=[CH:18][CH:19]=4)[N:16]=[CH:15][CH:14]=[CH:13]5)/[C:6](=[O:8])[N:7]=3)=[CH:28][C:23]=2[CH2:22][CH2:21]1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCc1ccc2c(c1)CCO2
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2ccc3c(c2)CCO3)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (2,3-Dihydro-benzofuran-5-ylmethyl) amine and DIEA to give 2-[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 388 (MH+).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][C:12]([CH:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:11][CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2].O.P(Cl)(Cl)([Cl:27])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:27])=[CH:13][C:12]([CH:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:11][CH:10]=2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(C3CCCCCC3)cc2c1O
Solvent: O
Product: CCOC(=O)c1cnc2ccc(C3CCCCCC3)cc2c1Cl

Procedure:
A solution of 100 g of 3-carboethoxy-4-hydroxy-6-cycloheptyl-quinoline in 670 ml of phosphorus oxychloride is boiled for 21/2 hours under reflux, with exclusion of water. It is then evaporated to dryness in vacuo, the residue is partitioned between 3 times 500 ml of methylene chloride and 3 times 500 ml of 2 N sodium hydroxide solution and the organic solution is washed until neutral, dried over sodium sulphate and evaporated to dryness in vacuo. The evaporation residue is treated with active charcoal and then recrystallised twice from petroleum ether. 3-Carboethoxy-4-chloro-6-cycloheptyl-quinoline of melting point 61°-62°C is thus obtained.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][CH:3]=[N:2]1.[F:10][C:11]1[CH:39]=[CH:38][CH:37]=[CH:36][C:12]=1[CH2:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:15]1>>[N:1]1([CH2:6][C:7]([N:17]2[CH2:18][C@H:14]([CH2:13][C:12]3[CH:36]=[CH:37][CH:38]=[CH:39][C:11]=3[F:10])[CH2:15][C@H:16]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)=[O:20])=[O:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1
Reactant: O=C(O)Cn1cncn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2F)CN1C(=O)Cn1cncn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid and (2S,4R)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 106, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 7.42-7.38 (m, 2H), 7.27-7.18 (m, 3H), 7.13-6.86 (m, 7H), 5.06 (d, 1H), 4.98 (d, 1H), 4.78 (d, 1H), 3.72-3.66 (m, 1H), 3.31 (t, 1H), 3.004-2.92 (m, 1H), 2.90-2.77 (m, 2H), 2.60 (dd, 1H), 1.81-1.72 (m, 1H), 1.45-1.38 (m, 1H). MS (EI) for C28H25F2N5O3 found 518 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3](=[O:35])[CH2:4][C:5]1[C:32]([F:33])=[CH:31][C:8]([O:9][CH2:10][CH2:11][C@@H:12]2[CH2:14][C@@H:13]2[CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)=[C:7]([F:34])[CH:6]=1.[H][H]>CO.[Pd]>[F:33][C:32]1[CH:31]=[C:8]([O:9][CH2:10][CH2:11][C@@H:12]2[CH2:14][C@@H:13]2[CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[C:7]([F:34])=[CH:6][C:5]=1[CH2:4][C:3]([N:2]([CH3:36])[CH3:1])=[O:35]
Reactant: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Yield: 96.8 %

Procedure:
To a solution of benzyl 4-[(1R,2S)-2-(2-{4-[2-(dimethylamino)-2-oxoethyl]-2,5-difluorophenoxy}ethyl)cyclopropyl]piperidine-1-carboxylate (226 mg, 0.451 mmol) in 2 ml anhydrous methanol at RT was added 10% Palladium on carbon (25.0 mg, 0.211 mmol). The reaction was stirred with hydrogen balloon for 2 hours. It was filtered by Celite, and the filtrate was concentrated to give the title compound (160 mg, 97%). LC/MS (m/z): 368.4 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])[CH:13]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:8][CH:7]=1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[Cl:23])[CH2:16][CH:13]1[C:14]2[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:31](=[O:34])[CH2:32][CH3:33])[CH:15]=2)[CH2:10][CH2:11][CH:12]1[NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29]
Reactant: CCOC(=O)NC1CCc2ccc(OCCN)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(OCCNC(=O)CC)cc2C1Cc1ccc(Cl)c(Cl)c1
Yield: 86.7 %

Procedure:
Ethyl 7-(2-aminoethoxy)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate hydrochloride (example 2.1, 100 mg, 0.229 mmol) and N,N-dimethyl amino pyridine (30.7 mg, 0.252 mmol) were dissolved in CH2Cl2 (20 ml) and propionyl chloride (30.7 mg, 0.252 mmol) was added at RT. After stirring at RT for 14 h 0.5 N HCl was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 and NaCl solution, dried over Na2SO4, and concentrated to afford a residue. White solid ethyl 1-(3,4-dichlorobenzyl)-7-(2-propionamidoethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (98 mg, 87%) was obtained from precipitation in ethyl acetate. Further transformation in analogy to example 2 and 97 finally gave N-[2-(7-Amino-8-benzyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-propionamide hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:13])[CH2:21][CH2:22]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-3-fluoro-benzoic acid (37.1 g, 145 mmol), 4-amino-1-benzylpiperidine (35.6 mL, 1.20 equiv.), 1-hydroxybenzotriazole (21.6 g, 1.1 equiv.), and triethylamine (44.1 g, 3.0 equiv.) in ethyl acetate (450 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.7 g, 1.1 equiv.) in one portion. Initially, everything went into solution, but a precipitate formed very rapidly. The reaction was fitted with a reflux condenser and heated at reflux for 5 h. The reaction was diluted with ethyl acetate, washed with water (2×), then 1N sodium hydroxide (2×), then brine, dried over magnesium sulfate, and concentrated to give 67.0 g (quant.) as a white solid which was used without purification. 1H-NMR (CDCl3, 500 MHz) δ 1.48 (s, 9H), 1.55 (m, 2H), 1.99 (bd, J=11.0, 2H), 2.17 (dd, J=11.0, 11.0, 2H), 2.84 (bd, J=11.3, 2H), 3.51 (s, 2H), 3.94 (m, 1H), 6.13 (bd, J=7.6, 1H), 7.10–7.28 (m, 4H), 7.31 (m, 4H), 7.59 (s, 1H). Mass spec.: 428.41 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])[CH3:2].[C:25]([Cu])#[N:26].Cl>CN1C(=O)CCC1.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:25]#[N:26])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(I)c2cc(Oc3cccnc3)ccc2c1O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOC(=O)c1nc(C#N)c2cc(Oc3cccnc3)ccc2c1O
Temperature: 120 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
A mixture of 4-hydroxy-1-iodo-7-(pyridin-3-yloxy)-isoquinoline-3-carboxylic acid ethyl ester (215 mg) and CuCN (89 mg) in NMP (2 mL) was heated at 120° C. for 2 h; the reaction was then cooled, diluted with DCM, and stirred at rt overnight; then diluted HCl solution was added and stirred for 1 h; the solids were filtered off, and DCM phase was separated, washed with water, and dil. NaCl solution, dried over anhydrous sodium sulphate, filtered, concentrated and the residue was column purified to give product (53 mg). LCMS ESI+: 336 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5][C:4]=2[C:3]=1[C:17]([OH:19])=O.[CH3:20][N:21](C)C=O.C(Cl)(=O)C(Cl)=O.CN>ClCCl>[Cl:1][C:2]1[C:3]([C:17](=[O:19])[NH:21][CH3:20])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: CN(C)C=O
Reactant: COc1nc2cc(Cl)c(Cl)c(C(=O)O)c2nc1OC
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reaction time: 0.5 h
Yield: 281.7 %

Procedure:
To a solution of 6,7-dichloro-2,3-dimethoxyquinoxaline-5-carboxylic acid (Preparation 6, 0.890 g, 2.93 mmol) in dichloromethane (25 mL) at room temperature under nitrogen was added dry N,N-dimethylformamide (50 μL, 47.2 mg, 0.64 mmol) followed by oxalyl chloride (0.338 mL, 3.8 mmol). After 0.5 hours, the mixture was concentrated under reduced pressure. Dichloromethane (10 mL) was added to the residue at room temperature under nitrogen, followed by methylamine (33% w/w solution in ethanol, 10 mL, 80.3 mol). After 10 minutes, the mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (20 mL) and 1M aqueous hydrochloric acid solution. The organic extract was dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (100:0 changing to 99:1, by volume) as the eluent to give a solid which was recrystallised from toluene to afford the title compound (0.570 g, 61%) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:15][CH2:14][C@:13]2([OH:16])[C@:4]34[CH2:19][CH2:18][N:17]([CH2:20][CH:21]5[CH2:23][CH2:22]5)[C@@H:12]2[CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:24][CH2:25][O:26][CH3:27])=[C:6]([O:28][C@@H:3]13)[C:5]4=2.C(N(CC)CC)C.[C:36]1([S:46](Cl)(=[O:48])=[O:47])[C:37]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH:21]1([CH2:20][N:17]2[CH2:18][CH2:19][C@:4]34[C:5]5[C:6]6[O:28][C@H:3]3[C@H:2]([N:1]3[S:46](=[O:48])(=[O:47])[C:36]7[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=7[S:42]3(=[O:44])=[O:43])[CH2:15][CH2:14][C@@:13]4([OH:16])[C@H:12]2[CH2:11][C:10]=5[CH:9]=[CH:8][C:7]=6[O:24][CH2:25][O:26][CH3:27])[CH2:22][CH2:23]1
Reactant: COCOc1ccc2c3c1O[C@H]1[C@H](N)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: O=S(=O)(Cl)c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc2c3c1O[C@H]1[C@H](N4S(=O)(=O)c5ccccc5S4(=O)=O)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 25 °C
Yield: 108.7 %

Procedure:
In 5 mL of dichloromethane, 117 mg (0.30 mmol) of 6β-amino-17-cyclopropylmethyl-4,5α-epoxy-3-methoxymethoxy-morphinan-14-ol was dissolved, and 0.04 mL (0.29 mmol) of triethylamine and 79 mg (0.31 mmol) of benzene-1,2-disulfonyl dichloride were added, followed by heating the mixture to reflux for 1 hour. After allowing the reaction solution to cool to room temperature, aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain 192 mg of 2-(17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-3-methoxymethoxy-morphinan-6β-yl)-benzo[1,3,2]dithiazol-1,1,3,3-tetroxide as a crude product.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:17][C:11]1[N:10]=[C:9]([NH2:18])[C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:26])[CH2:3][CH2:2]2)[N:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(C(=O)c4ccccc4)CC3)cccc2n1
Yield: 31 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and benzoyl chloride (57.6 mg; 0.41 mmol) to obtain 21.3 mg. (31% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.46 (m, 5H), 7.39 (t, J=6.0 Hz, 1H), 7.14 (br s, 1H), 6.98 (d, J=6.4 Hz, 1H), 6.86 (d, J=5.6 Hz, 1H), 5.92 (br s, 2H), 4.59 (br s, 1H), 3.66 (br s, 1H), 3.44 (m, 1H), 3.13 (m, 3H), 2.77 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[O:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:14]([N:12]1[CH2:11][CH2:10][CH:9]([CH2:8][NH2:7])[O:13]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccccc2)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCN(Cc2ccccc2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (2-benzyl-isoxazolidin-5-ylmethyl)-carbamic acid tert-butyl ester (Step A, 0.5 g) in dichloromethane (10 ml) was treated with trifluoroacetic acid (1.95 g). The solution was stirred at room temperature for 4 hours then concentrated in vacuo to afford the crude title product, which was used directly for the next step. LCMS (Method F) 0.20 min, M+H 194.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH3:14]>CO.O>[CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([NH2:14])=[O:6]
Reactant: N
Reactant: COC(=O)c1ccccc1N(C)C
Solvent: CO
Solvent: O
Product: CN(C)c1ccccc1C(N)=O
Temperature: 25 °C
Yield: 5 %

Procedure:
A solution of methyl 2-dimethylamino-benzoate (1.79 g, 10 mmol) in 2 M ammonia in methanol (20 mL) was heated at 80° C. in a sealed reaction vessel for 3 d. Upon cooling to room temperature, it was diluted with water. The product was extracted with diethyl ether. The ethereal extracts were washed with brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 20% ethyl acetate in hexanes yielded 2-dimethylamino-benzamide (85 m g, 5%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(#N)C>[O:22]=[C:19]1[CH2:20][CH2:21][N:3]2[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]2[NH:1]1
Reactant: CCOC(=O)c1c[nH]c(N)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn2c(n1)NC(=O)CC2
Temperature: 0 °C
Yield: 26.5 %

Procedure:
Ethyl 2-amino-1H-imidazole-4-carboxylate (6.45 mmol, 1 g) and triethylamine (10.04 mmol, 1.016 g) were suspended in dry ACN (30 ml) and cooled to 0° C. Acryloyl chloride (9.67 mmol, 0.875 g) dissolved in dry ACN (4 ml) was added dropwise. The resulting mixture was slowly warmed to RT and subsequently heated to 50° C. for 16 h. The solvent was evaporated and the residue purified by flash chromatography. 0.358 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.37 (t, 3H), 2.92 (t, 2H), 4.18 (t, 2H), 4.37 (q, 2H), 7.40 (s, 1H), 8.78 (bs, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:39]>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:39])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(CCc1ccccc1O)NCCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.56 ml) and octadecyl isocyanate (1.26 ml) were added to a solution containing 3-(2-hydroxyphenyl)-N-(3-morpholinopropyl)propanamide (1.05 g) in methylene chloride (11 ml) and stirred for 3 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform: methanol=60:1 to 50:1), thereby yielding the entitled compound (1.78 g) as white solid.