Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=1)=[O:14])=[C:8]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[C:31]=1[F:38])[CH:7]=[CH:6]2.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl.C(O)(C)C>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:19][CH:20]=1)=[O:14])=[C:8]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[C:31]=1[F:38])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)c(F)c3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)c(F)c2F)ccc2cc(O)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Dissolve [6-methoxy-2-(2,3,4-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (880 mg, 1.69 mmol) in 100 mL methylene chloride and chill in ice. Add 4.0 mL of neat boron tribromide with swirling and stir in the ice bath for 30 minutes. Allow the mixture to come to room temp and stir for an additional 1 hour. Carefully pour the mixture into a two-phase system consisting of saturated sodium bicarbonate solution and a 3/1 mixture of chloroform/isopropanol. Separate the organic layer, dry over 3 Å molecular sieves and evaporate to give 800 mg of slightly impure product. Purify on a silica gel column eluting with 3% methanol/methylene chloride to give 635 mg (74%) of the title compound: 1H-NMR (CD3OD, 400 MHz) δ7.89 (d, J=8.8 Hz, 1H); 7.69-7.42 (m, 4H); 7.45-7.42 (m, 1H); 7.31 (d, J=2.4 Hz, 1H); 7.14 (dd, J=9.2, 2.4 Hz, 1H); 7.02-6.87 (m, 3H); 4.20 (t, J=5.6 Hz, 2H); 2.84 (t, J=5.6 Hz, 2H); 2.59-2.59 (m, 4H); 1.71-1.65 (m, 4H); 1.56-1.53 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1.[N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]=[O:14].C(N(CC)CC)C>C(C(C)=O)C>[C:16]([CH2:15][NH:12][C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[S:7][C:6]=2[CH:11]=1)=[O:14])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCOC(=O)CNC(=O)Oc1ccc2oc(=O)sc2c1
Reaction time: 15 h

Procedure:
5-hydroxy-1,3-benzoxathiol-2-one (14.0 grams), was mixed with ethyl isocyanatoacetate (11.9 grams) and 0.84 gram of triethylamine in 165 milliliters of methyl ethyl ketone. The resulting mixture was then heated at reflux temperature for one hour and ten minutes and was allowed to cool and stand at ambient temperature for 15 hours. The solvent was then removed by evaporation in vacuo. The white, solid residue was recrystallized from a solution of 2% ethyl acetate in carbon tetrachloride. The resulting white crystalline solid had a melting point of 94.5°-96.5° C. This product was then recrystallized from a mixture of ethyl acetate and methylcyclohexane to give the desired purified product, 5-[(carbethoxymethyl)-carbamoyloxy]-1,3-benzoxathiol-2-one as colorless crystals having a melting point of 97.5°-98.5° C. Elemental analysis calculated for C12H11NO6S (percent): carbon--48.48; hydrogen--3.73; nitrogen--4.71. Found: carbon--48.6; hydrogen--3.84; nitrogen--4.80.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>CN(C)C=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]2[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]2=[O:33])[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(C(C#N)(CCCCCI)Sc2ccc(C)cc2)cc1OC
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)(CCCCCN2C(=O)c3ccccc3C2=O)Sc2ccc(C)cc2)cc1OC
Yield: 77.8 %

Procedure:
A mixture of 6.12 g of α-(5-iodopentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 2.22 g of potassium phthalimide and 50 mL of N,N-dimethylformamide is heated on a steam bath for 2 hours. The reaction solution is concentrated in vacuo and the residue is distributed between diethyl ether-water, with agitation. The organic layer is washed with 1N sodium hydroxide, followed by aqueous potassium bicarbonate. The solution is dried (sodium sulfate), and the volatiles removed in vacuo. Chromatography on silica gel, with gradient elution progressing from hexane to chloroform to methyl alcohol, affords 4.77 g of the desired product as a fluorescent oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][S:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:28]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cccc(S(C)(=O)=O)c3)cccc2c1N
Yield: 83.1 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 3-(methylsulfonyl)phenylboronic acid (200 mg, 1.000 mmol) were reacted to afford the title compound (155 mg, 83% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.51 (br, 1H), 8.21 (m, 1H), 8.11-7.67 (m, 6H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 3.12 (s, 3H), 1.67 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=385 (M+H) HPLC 1.75 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:17])[O-:16].[CH3:18]N[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].I[C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][CH2:41][CH2:40][C:39]=2[CH:44]=1>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:35]3[CH:36]=[CH:37][C:38]4[O:43][CH2:42][CH2:41][CH2:40][C:39]=4[CH:44]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:16])[O:17][CH3:18]
Reactant: CN[C@@H]1CCCC[C@H]1NC
Reactant: O=C([O-])NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: Ic1ccc2c(c1)CCCO2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)CCCO4)n2)ccc1Cl
Temperature: 95 °C

Procedure:
To a solution of methyl N-[[(2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]carbamate (prepared according to a procedure described in World Patent Publication WO 2008/124092) (600 mg, 2.2 mmol) in dioxane (60 mL) was added trans-N,N′-dimethylcyclohexane-1,2-diamine (60 mg, 0.452 mmol) under nitrogen atmosphere. Then copper(I) iodide (86 mg, 0.452 mmol) and potassium carbonate (1.87 g, 13.5 mmol) were added to form a dark-green-colored reaction mixture. To the reaction mixture was added 3,4-dihydro-6-iodo-2H-1-benzopyran (882 mg, 3.39 mmol). The reaction mixture was heated at 95° C. under nitrogen overnight, the solvent was evaporated, and the residue was purified by silica gel column chromatography (30% ethyl acetate/petroleum ether as eluant) to provide the title product, a compound of the present invention, as solid (0.318 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[NH2:44][C:45]1[S:46][CH:47]=[CH:48][N:49]=1>C(Cl)Cl>[S:46]1[CH:47]=[CH:48][N:49]=[C:45]1[NH:44][C:41]([C:33]1[C:32]2[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=2)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=1)=[O:43]
Reactant: Nc1nccs1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)n1cc(C(=O)Nc2nccs2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.6 %

Procedure:
A solution of triphenylphosphine (179 mg, 0.68 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (122 mg, 0.68 mmol). This solution was stirred at 0° C. for 15 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (125 mg, 0.53 mmol). This solution was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 2-amino-thiazole (121 mg, 1.21 mmol) and was stirred at 25° C. for 3 d. At this time, the reaction was partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was separated and then washed with a 1N aqueous hydrochloric acid solution (1×20 mL), a saturated aqueous sodium bicarbonate solution (1×20 mL), water (1×20 mL), and a saturated aqueous sodium chloride solution (1×20 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (62 mg, 37%) as a pink solid: mp 202-204° C.; EI-HRMS m/e calcd for C17H16ClN3O (M+) 319.0546, found 319.0547.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.CI.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)=[N:10][C:4]=2[CH:3]=1
Reactant: C1CNCCN1
Reactant: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CI
Product: Clc1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1O2
Temperature: 130 °C
Yield: 41.6 %

Procedure:
A mixture of 8-chloro-10H-dibenzo[b,f][1,4]oxazepin-11-one (189JO29C) (17 mg, 0.069 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (16 mg, 0.040 mmol) in toluene (2 mL) was heated in capped tube using microwave assisted heating (130° C., 20 minutes). The reaction mixture was cooled to room temperature and MeI (18 μL, 0.29 mmol) was added and the resulting mixture was heated in capped tube using microwave assisted heating (120° C., 20 minutes). The mixture was concentrated and the residue was taken up in pyridine (2 mL) and piperazine (25 mg, 0.29 mmol) was added. The resulting mixture was heated in a capped tube at 130° C. over night then using microwave assisted heating (160° C., 30 minutes). The mixture was concentrated, diluted with EtOAc and washed with water. The organic phase was applied onto a SCX-2 ion exchange column. The column was washed with MeOH, and then the product was eluted with NH3 (7 N in MeOH) to give 9.0 mg (57%) of the title compound (189JO31). MS (ESI) 314 (MH+). Purity for MH+ (UV/MS) 92/100.
Reaction SMILES: C(OC(=O)C1C=CC(N[C:12](=[O:38])[CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=CC=1)C.ClC1C=CC(C2N(C(C3CCCCC3)C(O)=O)C3C=C(F)C(F)=CC=3N=2)=CC=1.[CH3:68][O:69][C:70]([C:72]1([O:75][C:76]2[CH:81]=[CH:80][C:79]([NH2:82])=[C:78]([F:83])[CH:77]=2)[CH2:74][CH2:73]1)=[O:71]>CN(C)C1C=CN=CC=1>[CH3:68][O:69][C:70]([C:72]1([O:75][C:76]2[CH:81]=[CH:80][C:79]([NH:82][C:12](=[O:38])[CH:13]([N:20]3[C:24]4[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=4[N:22]=[C:21]3[C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)=[C:78]([F:83])[CH:77]=2)[CH2:74][CH2:73]1)=[O:71]
Reactant: COC(=O)C1(Oc2ccc(N)c(F)c2)CC1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: COC(=O)C1(Oc2ccc(NC(=O)C(C3CCCCC3)n3c(-c4ccc(Cl)cc4)nc4cc(F)c(F)cc43)c(F)c2)CC1

Procedure:
This compound was prepared in analogy to example 22, intermediate d, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid, 1-(4-amino-3-fluoro-phenoxy)-cyclopropanecarboxylic acid methyl ester and using 4-(dimethylamino)pyridine as base.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10]([O-])(=[O:12])=[O:11])[CH3:2].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>>[Cl:17][S:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])(=[O:12])=[O:11]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)CCCCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CCOC(=O)CCCCCS(=O)(=O)Cl
Yield: 61 %

Procedure:
Sodium 6-ethoxy-6-oxo-1-hexanesulfonate (62b) (1.68 g, 6.8 mmol) was mixed with phosphorus pentachloride and the mixture was carefully pestled in a mortar. After the reaction came to the end (the foaming of the reaction mixture ceased) the mixture was extracted with dry benzene (50 ml). The extract was evaporated under reduced pressure and the residue was dried in vacuum to give crude title compound (1.03 g, 61%) as a hygroscopic oil. The chloride (63b) was used in further reactions without additional purification.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:24]([N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl>[C:27]([O:26][C:24]([N:31]1[CH2:36][CH2:35][CH:34]([NH:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:13])=[O:12])[CH2:33][CH2:32]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of [3-(1-naphthylsulfonyl)-1H-indazol-5-yl]amine (400 mg, 1.24 mmol), 1-Boc-4-piperidone (493 mg, 2.47 mmol), sodium triacetoxyborohydride (524 mg, 2.47 mmol), and acetic acid (149 mg, 2.47 mmol) in 1,2-dichloroethane was stirred at room temperature overnight, diluted with CH2Cl2, washed with water, dried over Na2SO4 and concentrated in vacuo. The resultant residue was purified by column chromatography with 1% MeOH in CH2Cl2 as eluent to provide the title compound, 390 mg (62% yield), characterized by HNMR and mass spectral analyses.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[F:25][C:26]1[C:36]([F:37])=[CH:35][C:29]2[C:30](=[O:34])[O:31][C:32](=[O:33])[C:28]=2[CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[C:21]([O:20][C:18]([N:5]1[CH2:4][C@@H:3]([CH2:2][NH:1][C:30]([C:29]2[CH:35]=[C:36]([F:37])[C:26]([F:25])=[CH:27][C:28]=2[C:32]([OH:33])=[O:31])=[O:34])[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)c2cc(F)c(F)cc2C(=O)O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in DMF (2 mL) was added 5,6-difluoro-2-benzofuran-1,3-dione (73.6 mg) at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (102 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[OH-].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O.C(OCC)(=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CCOC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 3,6-dibromocarbazole (325.0 mg, 1.0 mmol, 1 equiv) in anhydrous N,N-dimethylformamide (5 mL) was added crushed KOH (67.3 mg, 1.2 mmol, 1.2 equiv). The mixture was stirred for 30 minutes. Ethyl bromoacetate (277.2 μL, 2.5 mmol, 2.5 equiv) was added into the mixture and it was stirred at room temperature overnight. The reaction crude was diluted with ethyl acetate (30 mL) and washed with 1M HCl and water. The organic layer was dried with MgSO4 and the concentrated to afford 396.3 mg white solid as product (96.4%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=3)[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O1CCC[CH2:30]1>C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]([CH:26]=[CH:27][CH:28]=3)[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:30])=[O:24])=[CH:17][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)CCc1ccc(OCc2cccc(-c3ccc4[nH]ccc4c3)c2)cc1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc4[nH]ccc4c3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 3-(4-{[3-(1H-indol-5-yl)benzyl]oxy}phenyl)propanoic acid (1.0 g, 2.69 mmol) in tetrahydrofuran (30 mL) was added a 2 mol/L trimethylsilyldiazomethane diethyl ether solution (1.5 mL, 3.0 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, and the mixture washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5-1:3-1:2) to give the title compound (0.90 g, yield 86%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O=S(Cl)[Cl:16].[CH2:18](O)[CH3:19]>>[ClH:16].[CH2:18]([O:12][C:11](=[O:13])[CH2:10][NH:9][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:5])[CH3:6])[NH2:1])[CH3:19]
Reactant: CC(C)C[C@H](N)C(=O)NCC(=O)O
Reactant: CCO
Reactant: O=S(Cl)Cl
Product: CCOC(=O)CNC(=O)[C@@H](N)CC(C)C
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of leucylglycine (5 g, 27 mmol) in 30 ml ethanol cooled to 0° was added SOCl2 (4.1 g, 35 mmol). The reaction solution was stirred overnight at room temperature. The ethanol was removed in vacuo, yielding a glassy product with a consistent mass spectrum, nmr and a single peak in the HPLC.
Reaction SMILES: [N+:1](C(Br)C1C=CC=CC=1)([O-:3])=[O:2].C([O:14][P:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])C.[C:22]1([CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:20]([O:19][P:15]([CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:1]([O-:3])=[O:2])(=[O:14])[O:16][CH2:17][CH3:18])[CH3:21]
Reactant: O=[N+]([O-])C(Br)c1ccccc1
Reactant: CCOP(OCC)OCC
Reactant: Cc1ccccc1
Product: CCOP(=O)(Cc1ccccc1[N+](=O)[O-])OCC

Procedure:
A mixture of 1.02 g of nitrobenzylbromide and 1.08 ml of triethylphosphite in 10 ml of toluene is heated to reflux for 12 hours. From the mixture obtained solvent is evaporated. (2-Nitro-benzyl)-phosphonic acid diethyl ester is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]3[CH:22]=[CH:23][CH:24]=[C:18]3[CH:17]1[CH2:25][C:26]([OH:28])=O)(=[O:15])=[O:14])[CH:7]=[CH:6]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:62][NH:63][CH:64]1[CH2:73][CH2:72][C:71]2[C:66](=[CH:67][CH:68]=[C:69]([CH2:74][N:75]3[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]3)[CH:70]=2)[CH2:65]1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]3[CH:22]=[CH:23][CH:24]=[C:18]3[CH:17]1[CH2:25][C:26]([N:63]([CH3:62])[CH:64]1[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([CH2:74][N:75]4[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]4)[CH:70]=3)[CH2:65]1)=[O:28])(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: CNC1CCc2cc(CN3CCCCC3)ccc2C1
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)N(C)C3CCc4cc(CN5CCCCC5)ccc4C3)ccc2c1
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To a solution of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazin-1-yl)acetic acid (S2) (200 mg, 0.5 mmol, 1.0 eq.) in THF (6 ml) were added DIPEA (300 μl, 2.0 mmol, 4.0 eq.) and HATU (190 mg, 0.5 mmol, 1.0 eq.) at 0° C. and the resulting mixture was stirred for 15 min at same temperature. A solution of N-methyl-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine (A51) (0.6 mmol, 1.2 eq.) in THF (4 ml) was added to the reaction mixture and it was allowed to stir at RT for 16 h. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with sat. NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel; 2-4% MeOH/DCM) to yield the desired product as a white solid. Yield: 47% (150 mg, 0.234 mmol); MS, Rt=3.7 min; m/z=641.1 [MH]+
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:19]O>>[F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(F)cc(OC)cc1F

Procedure:
To methanol (300 ml) was dissolved 2,6-difluoro-4-methoxybenzoic acid (102 g) and then concentrated sulfuric acid (1 ml) was added and stirred under reflux for 3 hours. After the reaction, the mixture was extracted with ethyl acetate (400 ml). The organic layer separated was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give methyl 2,6-difluoro-4-methoxybenzoate (90 g).
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.[Cl:18][CH2:19]I.C[Li]>C1COCC1>[Cl:18][CH2:19][C:7]([CH:4]1[CH2:3][CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1)=[O:9]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCI
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CCl)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (3.6 g, 14.9 mmol) in THF (100 mL) was cooled to −78° C. under nitrogen and then charged with neat chloroiodomethane (1.8 mL, 24.7 mmol). A solution of methyllithium (16.5 mL, 1.5 M in Et2O) was added dropwise. The reaction was stirred for 60 min at −78° C. and then quenched with half-saturated NH4Cl. After warming to room temperature, the mixture was extracted twice with EtOAc. The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield impure tert-butyl 4-(2-chloroacetyl)piperidine-1-carboxylate as a dark oil. Key non-solvent resonances in 1H-NMR (400 MHz, d6-DMSO) δ=4.68 (s, 2H), 4.1-3.8 (m, 4H), 2.75 (m, 1H), 1.8 (m, 1H), 1.7-1.5 (m, 2H), 1.4 (s, 9H), 1.4-1.2 (m, 2H).