Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30].C(=O)=O.CC(C)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:29](=[O:30])[C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:34]([O:35][CH3:36])=[C:33]([O:37][CH3:38])[CH:32]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
2-[3-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (5.885 g, 22.64 mmol) and dichloromethane (135 mL) were combined. 4-Methylmorpholine (5.0 mL , 45.48 mmol, 2 eq.) was added. The mixture was cooled in a dry-ice/acetone bath and a solution of 3,4,5-trimethoxy-benzoyl chloride (5.22 g, 22.63 mmol) in dichloromethane (100 mL) was added dropwise. After the addition was complete, the dry-ice/acetone bath was changed to an ice bath and the mixture was stirred for 1 h. The solution was extracted with 1N HCl (50 mL), 5% NaHCO3 (50 mL), and H2O (50 mL) . The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by chromatography on silica gel (400 g) eluting with ethyl acetate and then 6% methanol in dichloromethane to give the title compound:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20](F)[CH:19]=1>CS(C)=O.O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:19]=1)[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Aniline (930 mg, 10.0 mmol) was added to a solution of DIPEA (1.94 g, 15.0 mmol) and 4-bromo-2-fluoro-1-nitrobenzene (2.2 g, 10.0 mmol) in DMSO (16 mL). The reaction mixture was stirred at 60° C. for 4 h. Upon completion, the mixture was diluted with water (50 mL), and the resulting precipitate collected by filtration, washed with water and dried in vacuo. The crude product was used in next step without further purification. LCMS (m/z): 293.1/294.1 [M+H]+/[M+2H]+
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2nc(C)ccc2-n2nccn2)nc1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 406 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#N.C(O[C:15]([C:17]1[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=1)=[O:16])C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:10])[C:15]([C:17]1[CH:18]=[N:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=1)([OH:16])[C:23]([F:26])([F:25])[F:24]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)nc1
Reactant: N#CCc1ccc(Cl)cc1Cl
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccc(C(F)(F)F)nc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 2, steps 1-4, from 2,4-dichlorobenzeneacetonitrile [CAS Reg. No. 6306-60-1] and 6-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester [CAS Reg. No. 597532-36-0]. MS (m/e)=418.1 [MH+].
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C.C(OCC)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:7]([C:8]1[CH:13]=[C:12]2[C:11](=[CH:10][CH:9]=1)[NH:14][CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:17])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(Cc3ccccc3)cc2c1=O
Temperature: 110 °C

Procedure:
A mixture of 4-aminodiphenylmethane (20.3 g) and diethyl ethoxymethylenemalonate (24.3 mL) was heated at 110° C. for 3.5 hr under nitrogen. The resulting mixture was diluted with phenyl ether (50 mL) and heated at 220° C. for 7.5 hr. After cooling, ethyl ether was added to the reaction mixture. The precipitate was collected by filtration, and washed with ethyl ether to afford the title compound (12.6 g) as a pale brown powder: mp 265-270° C.; 1H NMR (400 MHz, CDCl3—CD3OD (1:1, v/v)) δ 1.39 (t, J=6.8 Hz, 3H), 4.12 (s, 2H), 4.35 (q, J=6.8 Hz, 2H), 7.14-7.33 (m, 4H), 7.47 (d, J=8.3 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.65-7.75 (m, 2H), 8.23 (s, 1H), and 8.59 (s, 1H).
Reaction SMILES: [CH2:1]([Mg]Br)C.[F:5][C:6]1[CH:7]=[C:8]([C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][C:11]=1[F:12].CCCCCC.CCOC(C)=O>C(OCC)C>[F:5][C:6]1[CH:7]=[C:8]([C:13]([OH:15])([CH3:1])[CH3:14])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: CC[Mg]Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethylmagnesium bromide in ether (38.0 mL, 38.0 mmol) at 0° C., was added a solution of 3',4'-difluoroacetophenone (5.0 g, 32.0 mmol) in diethyl ether (35 mL). The reaction mixture was stirred at 0° C. for 1 h when TLC analysis indicated that the reaction was complete (Rf =0.3, 3:1 hexane/EtOAc). The reaction was quenched carefully by adding 38 mL of water. It was extracted with diethyl ether (2×30 mL), washed with Rochelle's salt followed by brine and the organic layer was dried over Na2SO4. The solvent was removed in vacuo after filtration and 2-(3,4-difluorophenyl)propan-2-ol was obtained as a colorless oil (crude wt.=5.4 g, 97%) which looked >90% pure by NMR. It was used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[C:3]1[C:19]([O-:21])=[O:20].[K+].Cl.[H][H]>[Pd]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:4]1[C:5]([CH3:8])=[C:6]([CH3:7])[N:2]([CH3:1])[C:3]=1[C:19]([OH:21])=[O:20]
Reactant: [H][H]
Reactant: Cc1c(Nc2ccccc2[N+](=O)[O-])c(C(=O)[O-])n(C)c1C
Agent: [Pd]
Agent: Cl
Agent: [K+]
Product: Cc1c(Nc2ccccc2N)c(C(=O)O)n(C)c1C

Procedure:
The solution of 61 g (0.19 mole) of potassium 1,4,5-trimethyl-3-[(2-nitrophenyl)amino]-1H-pyrrole-2-carboxylate obtained in Example 3 is adjusted to pH 2 with concentrated hydrochloric acid in a circulatory hydrogenation apparatus, and 0.5 g of palladium-on-charcoal (10%) is added. When the internal temperature reaches 40° C., hydrogenation is started. Sufficient hydrogen is metered to keep the internal temperature at about 100° C. When a sudden drop in the absorption of hydrogen is observed, the solution is allowed to cool; it is filtered under nitrogen, and the residue on the filter is washed 6 times with 5 ml of 1-methyl-2-pyrrolidone each time. The combined filtrates are concentrated to half their volume on a rotary evaporator. The resulting solution is subsequently processed in Example 5 without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+]=[N-])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[CH2:10][C@H:9]1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N)CC[C@@H]2NC(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
±(1S*,2R*,4R*)-[4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (from example 55d), (100 mg) was dissolved in MeOH (1 ml) prior to the addition of 5% Pd/BaSO4 (120 mg). A hydrogen balloon was added and the solution was stirred for 1.5 h. The palladium was filtered off and the solution was concentrated to give ±(1S*,2R*,4R*)-[4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (94 mg). MS found: (M+H)+=415.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]1[NH:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10]1.[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([N:13]1[CH:12]([C:14]([OH:16])=[O:15])[CH2:11][S:10][CH:9]1[C:3]1[CH:4]=[C:5]([O:8][C:2](=[O:1])[CH3:3])[CH:6]=[CH:7][C:2]=1[O:1][C:5](=[O:8])[CH3:4])(=[O:19])[CH3:18]
Reactant: O=C(O)C1CSC(c2cc(O)ccc2O)N1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(OC(C)=O)c(C2SCC(C(=O)O)N2C(C)=O)c1
Temperature: -30 °C
Reaction time: 8 h

Procedure:
To a solution of 0.241 g (0.85 mmol) of 2-(2,5-dihydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid (1:1 mixture of isomers at C2) was added 3 mL of pyridine, and the solution was cooled to −30° C. with a dry ice acetone bath. To the heterogeneous mixture was added 0.34 mL of acetyl chloride under constant stirring. The cooling bath was removed and the reaction mixture was allowed to warm up gradually to room temperature. After overnight stirring at room temperature, the solvent was removed under high vacuum. To the remaining oily residue were added 19 mL of water and 1 mL concentrated HCl. The precipitate was filtered and washed with 2×5 mL of water. After drying at high vacuum, 0.13 g of acetylated product (5) was obtained (34%), as a mixture of diastereoisomers and rotamers. 1H NMR (DMSO-d6) 67 ; 1.76 s, 1.79 s, 1.99 s, 2.03 s, 2.06 s, 2.26 s, 2.33 s, 2.34 s, 9H; 3.2-3.4 m, 3H; 5.11 d, J=8 Hz and 5.36 d, J=8 Hz, 1H; 6.10 s, 6.20 s, 6.33 s and 6.36 s 1H; 6.99-7.22 m, 2H; 12.95 bs, 1H.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[S:9][CH:10]=[C:11]([CH3:13])[N:12]=2)[CH2:3]1.[Cl:14]C(OC(Cl)C)=O.CCOCC>ClC(Cl)C>[ClH:14].[CH3:13][C:11]1[N:12]=[C:8]([C:4]2[CH2:3][NH:2][CH2:7][CH2:6][CH:5]=2)[S:9][CH:10]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Cc1csc(C2=CCCN(C)C2)n1
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: Cc1csc(C2=CCCNC2)n1
Product: Cl

Procedure:
3.64 g of [1-methyl-3-(4-methylthiazol-2-yl)-1,2,5,6-tetrahydropyridine] is dissolved in 70 cm3 of dichloroethane, 2.95 g of alphachloroethyl chloroformate is added at 0° C. under inert atmosphere, and the whole is heated under reflux for one hour 30 minutes. The solvent is eliminated, te residue is taken up with ether and filtered. The filtrate is concentrated to dryness, the residue is taken up in 40 cm3 of methanol and heated for 30 minutes under reflux. The solvent is eliminated and the residue is crystallized twice from ethanol and ether and 2.67 g of expected product is obtained. M.p.=184°-185° C. (decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1)#[N:2].[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH2:33][CH2:32]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([C:7]([C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[C:26]5[C:21](=[N:22][CH:23]=[CH:24][CH:25]=5)[NH:20][C:19]4=[O:27])[CH2:14][CH2:13]3)[CH:5]=1)=[O:9])[CH2:33][CH2:32]2
Reactant: Fc1ccc2c(c1)CCN2
Reactant: N#Cc1ccc(C(=O)O)cc1N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)N2CCc3cc(F)ccc32)cc1N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
70 mg (0.19 mmol) 4-cyano-3-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-benzoic acid and 30 mg (0.21 mmol) 5-fluoro-2,3-dihydro-(1H)-indole in 0.10 mL (0.72 mmol) TEA and 1.5 mL DMF were mixed with 65 mg (0.20 mmol) TBTU and the mixture was stirred for 1 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Product: CSc1nc(-c2cccc(OC(=O)OCc3ccc([N+](=O)[O-])cc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) with p-nitrobenzyl chloroformate (554 mg) was performed according to the methods described in example 1g. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/H2O=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=1>C1(C)C=CC=CC=1.O>[CH2:3]([O:10][CH2:11][CH2:12][O:13][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Br:14])[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(OCCOCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (900 mg, 60% dispersion in mineral oil, 22.5 mmol) was added portionwise to an ice-cold solution of 2-(benzyloxy)ethanol (3.0 g, 20.0 mmol) in toluene (100 ml), and the solution stirred for 30 minutes. 2,6-Dibromopyridine (4.75 g, 20.0 mmol) was added, and the reaction heated under reflux for 2 hours. The cooled mixture was diluted with water (100 ml), and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo to give the title compound as a yellow oil, (quantitative).
Reaction SMILES: Cl.[NH2:2][OH:3].O.O.O.C([O-])(=O)C.[Na+].[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=1[C:20](=O)[CH2:21][CH3:22]>CCO.O.O>[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=1[C:20](=[N:2][OH:3])[CH2:21][CH3:22]
Reactant: NO
Reactant: CCC(=O)c1c(O)cccc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(=NO)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A solution of hydroxylamine hydrochloride (510 mg, 7.3 mmol) and sodium acetate trihydrate (629 mg, 4.6 mmol) dissolved in 20 ml of a mixture EtOH/H2O (7/3) was added to a solution of 1-(2,6-dihydroxyphenyl)-1-propanone (Intermediate 28, 1.0 g) in 15 ml of a mixture EtOH/H2O (7/3). After refluxing and stirring under N2 overnight, additional hydroxylamine hydrochloride (510 mg, 7.3 mmol) and sodium acetate trihydrate (629 mg, 4.6 mmol) dissolved in 4.5 mL of water were added. The reaction mixture was heated at reflux an additional 3 hours. After cooling down to room temperature, the volatiles were removed. Then water was added and reaction mixture was extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound (1.05 g).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH:7]([CH2:11]C1C=CC(C2CCCCC2)=C(Cl)C=1)[C:8]([OH:10])=[O:9]>CCCCCC>[CH2:1]([NH2+:3][CH2:4][CH3:5])[CH3:2].[C:8]([O-:10])(=[O:9])[CH2:7][CH3:11]
Reactant: O=C(O)C(Cl)Cc1ccc(C2CCCCC2)c(Cl)c1
Reactant: CCNCC
Solvent: CCCCCC
Product: CCC(=O)[O-]
Product: CC[NH2+]CC

Procedure:
Anhydrous diethylamine (0.11 moles) is added dropwise to a stirred solution of α-chloro-β-(3-chloro-4-cyclohexylphenyl)propionic acid (0.10 moles) in 100 ml. of n-hexane at 0°C. The precipitate is collected on a filter, washed with n-hexane, and dried in a vacuum desiccator to obtain α-chloro-β-(3-chloro-4-cyclohexylphenyl(propionic acid, diethylammonium salt.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1.O1C2C=CC=CC=2C=CN1>O1CCOCC1.C(OCC)(=O)C.C(O)(=O)C>[Cl:20][C:19]1[C:14]([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc2c(c1)NCCO2
Reactant: Clc1cccnc1Cl
Agent: C1=Cc2ccccc2ON1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1cccnc1N1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a solution of 3,4-dihydro-2H-1,4-benzoxazine (198 mg, 1-47 mmol) in dry dioxane (3 mL) was added 60% sodium hydride/mineral oil (90 mg, 2.25 mmol) and let stir at ambient temperature for 15 min. Then 2,3-dichloropyridine (264 mg, 1.78 mmol) was added and the mixture was warm to 80 C. Over 24 hours periodically added small portions (˜10 mg) of NaH and another 90 mg of 2,3-dichloropyridine until all of the benzoxazine was gone. Cooled and diluted with ethyl acetate, neutralized with acetic acid and then washed with NaHCO3 solution, followed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. This residue was purified by chromatography on silica gel eluting with a 10-15% acetone/hexane gradient to give the title compound as a viscous oil which slowly solidified (168 mg, 46% yield). 1H-NMR (500 MHz, CDCl3): δ 8.35 (1H, d, J=4.6 Hz), 7.74 (1H, d, J=8.1 Hz), 7.05 (1H, dd, J=4.7, 8.0 Hz), 6.90 (1H, d, J=7.4 Hz), 6.83 (1H, t, J=7.3 Hz), 6.75 (1H, t, J=7.3 Hz), 6.55 (1H, d, J=7.8 Hz), 4.39 (2H, t, J=4.3), 3.84 (2H, t, J=4.Hz). m/e (m+1): 247.0
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:12].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl.CC(C)=O>[Cl:21][CH2:22][C:23]([NH:1][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:12])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc2cc(N)c(=O)[nH]c12
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cccc2cc(NC(=O)CCl)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution prepared by 2.9 g of 3-amino-8-methylcarbostyril, 3.5 ml of triethylamine in 50 ml of dichloromethane was added dropwise a solution prepared by 1.9 ml of chloroacetyl chloride in 10 ml of dichloromethane under ice-cooled condition. After the dropwise addition, the reaction mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was concentrated by removing the solvent by evaporation under reduced pressure, the residue thus obtained was suspended in aceton and the suspension was poured in an ice-water. The crystals formed were collected by filtration, washed with water, dried, then recrystallized from acetone-water to obtain 3.6 g of 3-chloroacetylamino-8-methylcarbostyril. White powdery substance. Melting point: 271.5°-272° C. (decomposed).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23](OC2C=CC([N+]([O-])=O)=CC=2)=[O:24])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].[NH2:36][CH2:37][CH2:38][C@H:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([OH:42])=[O:41].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([NH:36][CH2:37][CH2:38][C@H:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([OH:42])=[O:41])=[O:24])=[CH:18][CH:17]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Temperature: 75 °C

Procedure:
4.0 g (8.22 mmol) of the compound from example 1A was dissolved in 60 ml dichloromethane. 1.795 (8.22 mmol) (2S)-4-Amino-2-[(tert-butoxycarbonyl)amino]butanoic acid and 1.43 ml (8.22 mmol) N,N-diisopropylethylamine were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 75° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 4/1, dichloromethane/ethyl acetate 1/1, dichloromethane/methanol 4/1 and dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.02 g (6.54 mmol, 80% of theory) of the desired product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]2[C:8]=1[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:11]2)(=O)=O.C(OC1C=CC(CN)=CC=1)C1C=CC=CC=1.[CH2:44]([O:51][C:52]1[CH:78]=[CH:77][C:55]([CH2:56][NH:57][C:58]2C=C(OC)C=C3C=2CC(C2C=CC(OC)=CC=2)C3)=[CH:54][CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:44]([O:51][C:52]1[CH:53]=[CH:54][C:55]([CH2:56][NH:57][CH2:58][C:7]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]3[C:8]=2[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:11]3)=[CH:77][CH:78]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: COc1ccc(C2Cc3cc(OC)cc(NCc4ccc(OCc5ccccc5)cc4)c3C2)cc1
Reactant: COc1ccc(C2Cc3cc(OC)cc(OS(=O)(=O)C(F)(F)F)c3C2)cc1
Agent: NCc1ccc(OCc2ccccc2)cc1
Product: COc1ccc(C2Cc3cc(OC)cc(CNCc4ccc(OCc5ccccc5)cc4)c3C2)cc1

Procedure:
Synthesized from 6-methoxy-2-(4-methoxyphenyl)indan-4-yl trifluoromethanesulfonate and 4-benzyloxybenzylamine according to an analogous synthetic method to Example 116, (4-benzyloxybenzyl)[6-methoxy-2-(4-methoxyphenyl)indan-4-yl]amine (1.2 g) was used according to an analogous synthetic method to Preparation Example 18 to provide the title compound (1.0 g).