Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=2[O:9][CH2:10][C:11]([O:13]CC)=O)[CH2:3][CH2:2]1.[NH2:20][CH2:21][CH:22]([OH:34])[CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1>CCO>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][N:24]1[CH2:23][CH:22]([OH:34])[CH2:21][NH:20][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=1[N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: CCOC(=O)COc1ccccc1N1CCOCC1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: O=C(COc1ccccc1N1CCOCC1)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
A mixture of ethyl 2-(2-morpholinophenoxy)acetate (53 mg, 0.2 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (41 mg, 0.2 mmol) in EtOH (1 mL) was stirred at 120° C. over microwave for 30 min. The solvent was removed by concentration and the crude product was purified by prep-HPLC separation to afford product the desired title compound (8.0 mg, Yield 10%). 1H NMR (400 MHz, MeOD): 7.09-6.98 (m, 8H), 4.64 (s, 2H), 3.95 (br.s, 1H), 3.89-3.87 (m, 4H), 3.63-3.46 (m, 2H), 3.33-3.30 (m, 1H), 3.07-3.03 (m, 4H), 2.88 (dd, J=6.0 Hz, 2H), 2.77 (dd, J=6.0 Hz, 2H), 2.49 (d, J=6.0 Hz, 2H). LCMS (m/z): 426.2 (M+1).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:37])[CH:7]([CH3:36])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH:27]C(OC(C)(C)C)=O)[CH2:11][C@@H:12]([CH:24]([CH3:26])[CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].[ClH:38]>O1CCOCC1>[ClH:38].[CH2:1]([NH:5][C:6](=[O:37])[CH:7]([CH3:36])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH2:27])[CH2:11][C@@H:12]([CH:24]([CH3:25])[CH3:26])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)C(C)C[C@H](O)[C@@H](N)C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
111 mg of N-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(p-tert-butyl-phenyl)-octanoic acid (N-butyl)amide are dissolved in 2 ml of 4N hydrochloric acid in dioxane at 0° C. and then stirred for 60 minutes at 20° C. The reaction mixture is concentrated by evaporation under reduced pressure and the residue is purified by means of FC (50 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained in the form of a diastereoisomeric mixture: Rf (dichloromethane/methanol=9:1)=0.20; Rt (I)=36.6 and 37.5 minutes; FAB-MS (M+H)+ =419.
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[O:10]=[C:11]1[NH:16][CH2:15][CH2:14][N:13]([C:17](=[NH:20])[CH2:18][Cl:19])[CH2:12]1.Cl>O>[ClH:19].[O:10]=[C:11]1[NH:16][CH2:15][CH2:14][N:13]([C:17](=[NH:20])[CH2:18][SH:5])[CH2:12]1
Reactant: N=C(CCl)N1CCNC(=O)C1
Reactant: [O-]P([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)N1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
12.0 g of trisodium phosphorothioate were added to a solution of 14.3 g of 2-(3-oxopiperazin-1-yl)-2-iminoethylchloride hydrochloride in 80 ml of water, kept cooled in ice-water, and the mixture was stirred at room temperature for one hour. After adding 66.5 ml of 1N hydrochloric acid, the mixture was heated to 50° C. for 30 minutes, and the solvent was then distilled off under reduced pressure. The concentrate was mixed with 200 ml of methanol, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was crystallized by adding ether, and the crystals were collected by filtration and washed with ether, giving 6.4 g of 2-(3-oxopiperazin-1-yl)-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: [CH2:1]1[CH2:6][O:5][C:3](=[O:4])[CH2:2]1.[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([NH:14][C:3](=[O:4])[CH2:2][CH2:1][CH2:6][OH:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCCO1
Product: O=C(CCCO)NCc1ccccc1
Yield: 42 %

Procedure:
The preparation of subject compounds is known from the literature. For example, Spath, E., et al. Ber 69B, 2727-31 (1936) CA 31, 22728 react γ-hydroxybutyric acid lactone with benzyl amine at a temperature of 215°-220°C. to obtain as the reaction product, N-benzyl-γ-hydroxybutyramide in 42% yield. It is further known from the literature (Reppe, W. CA 50, 16786 ie) that when 214 g. benzyl amine (b.p. 187°C.) are reacted with 172 g. γ-butyrolactone (b.p. 204°C.) for 8 hours, there is obtained only 184 g. of reaction product amounting to a yield of 47.6% of the theoretical. After recrystallization of this latter reaction product from ethylacetate, the compound recovered has a melting point of 70°-72°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:11]2[CH2:10][CH2:9][C:8]3[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Product: CN1CCN(C2CCc3ccc([N+](=O)[O-])cc3CC2)CC1

Procedure:
1-Methyl-4-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-piper azine was prepared from 2-nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one and 1-methyl piperazine in a similar manner to Example 178a. Product was isolated as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[C:11]([N:10]=[C:13]([NH2:14])[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:12]
Reactant: COc1cccc(N)c1
Reactant: N#C[N-]C#N
Agent: [Na+]
Product: COc1cccc(NC(N)=NC#N)c1

Procedure:
3-Methoxyaniline and sodium dicyanamide were procesed as described in Example 71A to provide the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].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.Cl.[NH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]3([CH2:76][CH2:75][CH2:74][CH2:73]3)[O:71][B:70]([OH:77])[C:69]=2[CH:78]=1>CN(C=O)C>[OH:77][B:70]1[C:69]2[CH:78]=[C:65]([CH2:64][NH:63][C:19](=[O:21])[C:18]3[CH:22]=[CH:23][C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:25]([F:26])([F:28])[F:27])[O:14][N:13]=4)=[CH:16][C:17]=3[CH3:24])[CH:66]=[CH:67][C:68]=2[C:72]2([CH2:73][CH2:74][CH2:75][CH2:76]2)[O:71]1
Reactant: NCc1ccc2c(c1)B(O)OC21CCCC1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC21CCCC1
Reaction time: 0.17 h
Yield: 34.4 %

Procedure:
A solution of 4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (0.3 g, 0.67 mmol) and DIPEA (346 mg, 2.68 mmol) in DMF (10 mL) was stirred at rt for 5 min and then HATU (510 mg, 1.34 mmol) was added. The mixture was stirred for 10 min prior to the addition of 6-(aminomethyl)-1H-spiro[benzo[c][1,2]oxaborole-3,1′-cyclo-pentan]-1-ol hydrochloride (202 mg, 0.80 mmol). And the resulting mixture was stirred at rt overnight. It was then concentrated under vacuum, and the residue was partitioned between 1N HCl and ethyl acetate. The organic layer separated was concentrated under vacuum, and the residue was purified on column chromatography and prep-HPLC to provide the product (150 mg, yield 34%). 1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.89 (t, 1H), 7.82 (s, 2H), 7.59 (t, 3H), 7.44 (m, 2H), 7.36 (d, 1H), 4.45 (d, 2H), 4.36 (d, 1H), 4.28 (d, 1H), 2.41 (s, 3H), 1.99 (m, 8H) ppm; HPLC purity: 98.37% at 220 nm and 98.66% at 254 nm; MS: m/z=652.
Reaction SMILES: [NH2:1][CH2:2][C@:3]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([OH:5])[CH3:4].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].[OH-].[Na+]>C1COCC1.CC(OC)(C)C>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C@@:3]([OH:5])([CH3:4])[CH2:2][NH:1][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH:11]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C[C@@](O)(CN)c1cc(Br)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@](O)(CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-amino-2-(5-bromo-2-fluoro-phenyl)-propan-2-ol (34.7 g, 140 mmol) in THF (400 ml) was added 2-nitro-benzenesulfonyl chloride (34.9 g, 154 mmol) at 0-5° C. and afterwards 1N aqueous NaOH over a period of 0.5 h. The reaction mixture was stirred for 2 h at 20° C. The reaction mixture was diluted with TBME and washed with water and NaH2PO4 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound after crystallization from TBME-hexane as beige crystals: TLC (toluene-EtOAc 3:1): Rf=0.51; UPLC RtH5=1.118 min; ESIMS: 450, 452 [(M+NH4)+]; 1H NMR (360 MHz, CDCl3): δ 7.98 (m, 1H), 7.81 (m, 1H), 7.65 (m, 2H), 7.59 (dd, 1H), 7.24 (m, 1H), 6.79 (dd, 1H), 5.60 (t, 1H), 4.16 (br s, 1H), 3.55 (dd, 1H), 3.44 (dd, 1H), 2.51 (s, 1H), 1.51 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([OH:8])=O)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:47][C:48](=[NH:68])[C:49]1[CH:58]=[CH:57][CH:56]=[C:55]2[C:50]=1[CH:51]=[CH:52][N:53]=[C:54]2[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:47]=[C:48]([C:49]3[CH:58]=[CH:57][CH:56]=[C:55]4[C:50]=3[CH:51]=[CH:52][N:53]=[C:54]4[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[N:68]=2)[CH:9]=[CH:10][C:11]=1[F:12])#[N:2]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(F)c(C#N)c4)n3)cccc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
3-Cyano-4-fluorobenzoic acid (D31; 0.288 g, 1.744 mmol) was stirred at room temperature in 5 ml of DMF with HATU (0.723 g, 1.903 mmol) and DIPEA (0.831 ml, 4.76 mmol) for 10 mins. 1,1-Dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36, 0.5 g, 1.585 mmol) and 5 ml of DMF were added, and the resulting mixture was stirred in a Biotage Initiator microwave at 120° C. for 30 mins. The solvent was removed under vacuum and the residue was purified by column chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane, to give the title compound as a white solid (67 mg).
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[OH:13][CH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[NH2:2][O:13][CH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(CCO)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: N#Cc1ccc(CCON)cc1

Procedure:
Prepared by a similar procedure as described for preparation 31. Starting materials: N-hydroxyphthalimide and 4-(2-hydroxyethyl)benzonitrile (Maybridge). 13C-NMR (DMSO-d6) δ 145.6, 131.9, 129.9, 118.9, 108.7, 74.6, 34.3.
Reaction SMILES: BrC1C=C(C2C=CC(C(OCC)=O)=CC=2)C=CC=1[OH:8].C(C1C=C(B(O)O)C=CC=1N1CCCC1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[C:44]([C:48]1[CH:49]=[C:50]([C:59]2[CH:60]=[C:61]([C:66]3[CH:71]=[CH:70][C:69]([C:72]([O:74][CH2:75][CH3:76])=[O:73])=[CH:68][CH:67]=3)[CH:62]=[CH:63][C:64]=2O)[CH:51]=[CH:52][C:53]=1[N:54]1[CH2:58][CH2:57][CH2:56][CH2:55]1)([CH3:47])([CH3:46])[CH3:45]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:44]([C:48]1[CH:49]=[C:50]([C:59]2[CH:60]=[C:61]([C:66]3[CH:71]=[CH:70][C:69]([OH:8])([C:72]([O:74][CH2:75][CH3:76])=[O:73])[CH2:68][CH:67]=3)[CH:62]=[CH:63][CH:64]=2)[CH:51]=[CH:52][C:53]=1[N:54]1[CH2:58][CH2:57][CH2:56][CH2:55]1)([CH3:45])([CH3:46])[CH3:47]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(Br)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)c1cc(B(O)O)ccc1N1CCCC1
Agent: O=C([O-])[O-]
Product: CCOC(=O)C1(O)C=CC(c2cccc(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)=CC1
Yield: 63 %

Procedure:
In a manner similar to that of Example 1d, by reacting 1 g of ethyl 3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (3 mmol) with 1.2 g of 3-tert-butyl-4-pyrrolidinophenylboronic acid (4.5 mmol) in the presence of 5 mL of 2M potassium carbonate (10 mmol) and 360 mg of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), 900 mg of ethyl 3″-tert-butyl-4′-hydroxy-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=63%) in the form of a yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[Br:9]Br>Cl>[Br:9][CH:3]([C:2](=[O:1])[CH3:8])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Product: CC(=O)C(Br)CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
Concentrated hydrochloric acid (20 ml) was added to 4-oxopentanoic acid (5.0 g), and bromine was added dropwise thereto at −15° C. The mixture was stirred at a room temperature. After 4 hours, the reaction solution was poured into ice water (45 ml). The reaction solution was subjected to extraction with ethyl ether, and the organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure to give the title compound (7.06 g, 84%).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C[O-].[Na+].CO.[CH2:10]([O:12][CH:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=O)[C:24]([NH:26][CH3:27])=[O:25])[CH3:14])[CH3:11]>CO.[Cl-].[Na+].O>[CH2:10]([O:12][CH:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[N:4][O:3][CH3:2])[C:24]([NH:26][CH3:27])=[O:25])[CH3:14])[CH3:11]
Reactant: CCOC(C)OCc1ccccc1C(=O)C(=O)NC
Reactant: CON
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CCOC(C)OCc1ccccc1C(=NOC)C(=O)NC
Yield: 92.9 %

Procedure:
Methoxyamine hydrochloride (0.50 g, 0.006 mol) was dissolved in methanol (6 ml), and a 28% sodium methoxide-methanol solution (1.45 g, 0.0075 mol) was added to the solution to obtain a suspension. A mixed solution of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (0.80 g, 0.003 mol) and methanol (3 ml) was added to the suspension, and the mixture was stirred under reflux for 1 hour. After completion of the reaction, half-saturated brine (150 ml) was added, and the mixture was extracted with dichloromethane (100 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain an E/Z mixture of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-methoxyimino-N-methylacetamide (0.82 g, Yield: 92.8%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:37])[CH2:11][N:12]2[N:18]=[C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[N:14]([CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:13]2=[O:36])[CH:6]=[CH:7][CH:8]=1.[NH2:38][C:39]([NH2:41])=[S:40].[Na+].[I-]>CC(C)=O>[C:39]([S:40][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:37])[CH2:11][N:12]2[N:18]=[C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[N:14]([CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:13]2=[O:36])[CH:6]=[CH:7][CH:8]=1)(=[NH:38])[NH2:41]
Reactant: NC(N)=S
Reactant: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(CCl)c2)N=C(C2CCCCC2)c2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(CSC(=N)N)c2)N=C(C2CCCCC2)c2ccccc21

Procedure:
N-(3-Chloromethyl-phenyl)-2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetamide (Example 49, step a) (52 mg, 0.0 mmol) was reacted with thiourea (7.6 mg, 0.0 mmol) and NaI (2 mg) in refluxing acetone (10 ml) for 3 h. After cooling, the solvents were concentrated in vacuo, affording the title compound as a yellow solid after trituration with Et2O (18 mg, 30%). 1H NMR (DMSO-d6) 9.89 (1H, br s), 8.99 (3H, br s), 7.75-7.46 (3H, m), 7.29-7.04 (5H, m), 4.77 (2H, m), 4.40 (2H, m), 4.38 (1H, m), 3.93 (1H, m), 2.86 (1H, m), 1.73-1.64 (6H, m), 1.21-1.08 (13H, m).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([C:25]1[S:29][CH:28]=[C:27]([C:30]([N:32]2[CH2:37][C:36]3([CH2:42][CH2:41][N:40]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][CH2:51][OH:52])[CH:45]=4)[CH2:39][CH2:38]3)[O:35][CH2:34][CH2:33]2)=[O:31])[CH:26]=1)[CH3:24].FC(F)(F)C(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:23]([C:25]1[S:29][CH:28]=[C:27]([C:30]([N:32]2[CH2:37][C:36]3([CH2:42][CH2:41][N:40]([CH2:43][C:44]4[CH:45]=[C:46]([CH2:50][CH:51]=[O:52])[CH:47]=[CH:48][CH:49]=4)[CH2:39][CH2:38]3)[O:35][CH2:34][CH2:33]2)=[O:31])[CH:26]=1)[CH3:24]
Reactant: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4cccc(CC=O)c4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (0.232 g) was added to a stirred solution of (5-ethylthiophen-3-yl)(9-(3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 86, step a) (0.180 g) and trifluoroacetic acid (0.042 mL) in DCM (5 mL). After 1 h, ethyl acetate (30 mL) was added followed by a mixture of saturated sodium thiosulphate solution (5 mL) and saturated sodium bicarbonate solution (5 mL). The reaction mixture was shaken well and separated. The ethyl acetate solution was washed with saturated sodium bicarbonate solution, water and brine. Acetic acid (0.08 mL) was added, the solution was dried over sodium sulphate, filtered and evaporated in vacuo (bath temperature ˜30° C.) to give the subtitled compound as a gum. Yield 0.17 g. Used directly.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:32]=1[CH2:33]Br)#[N:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:33][C:32]1[CH:35]=[C:36]([C:39]#[N:40])[CH:37]=[CH:38][C:31]=1[C:29]#[N:30])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: N#Cc1ccc(C#N)c(CBr)c1
Product: N#Cc1ccc(C#N)c(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 2,5 dicyanobenzylbromide as in the procedure of Example 43. MS (ESI) m/z 520.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(S(F)(F)[F:29])CC)C.O>ClCCl>[F:29][CH2:21][CH2:20][CH2:19][CH2:18]/[CH:17]=[CH:16]/[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1ccccc1/C=C/CCCCO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCc1ccccc1/C=C/CCCCF
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 8.17 g of -(2-nonylphenyl)-1-trans-hexen-6-ol in 20 ml of dichloromethane is added dropwise over a period of 20 minutes to a mixture, cooled with an ice-bath and stirred under an argon atmosphere, of 4.68 g of diethylaminosulphur trifluoride in 20 ml of dichloromethane. After further stirring at room temperature for 14 hours, water is added, and the organic layer is separated off and washed with saturated sodium bicarbonate solution and water. The crude product remaining after the organic phase has been dried and concentrated by evaporation is purified by flash chromatography on silica gel with petroleum ether. The title compound is obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5]2[CH:10]=[CH:11][N:12]=[CH:13][C:4]=2[S:3]1(=[O:15])=[O:14].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCOCC>O1CCOCC1>[CH2:16]([NH:23][C:7]1[N:2]([CH3:1])[S:3](=[O:15])(=[O:14])[C:4]2[CH:13]=[N:12][CH:11]=[CH:10][C:5]=2[N:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CSC1=Nc2ccncc2S(=O)(=O)N1C
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN1C(NCc2ccccc2)=Nc2ccncc2S1(=O)=O

Procedure:
A solution of 2-methyl-3-methylsulfanyl-2H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g) and benzylamine (0.5 mL) in dioxane (2.5 mL) was refluxed until completion of the reaction (t.l.c.). After cooling, the addition of ether gave rise to the precipitation of the title compound. The precipitate was collected by filtration, washed with ether and recrystallized from methanol-ether (yield: 0.4 g); m.p. 142°-146° C. (Compound 20).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=[C:35]([O:37]C)C=CC=1B(O)O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:37][CH3:35])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: COc1ccc(B(O)O)c(Cl)c1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 2-chloro-4-methoxyphenylboronic acid and making non-critical variations provided the title compound as an off-white amorphous solid. IR (diffuse reflectance) 2969, 2934, 1604, 1568, 1550, 1482, 1448, 1439, 1392, 1287, 1228, 1203, 1180, 1045, 740 cm−1; OAMS supporting ions at: ESI+ 423.9; MS (CI) m/z 424 (MH+); HRMS (FAB) calcd for C24H26CLN3O2+H1 424.1792, found 424.1789. Anal. Calcd for C24H26ClN3O2: C, 68.00; H, 6.18; N, 9.91. Found: C, 67.86; H, 6.29; N, 9.79.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1>>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]2)=[CH:3][CH:4]=1
Reactant: OC1CCCNC1
Reactant: Brc1ccc(-c2ncco2)cc1
Product: OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Yield: 44.8 %

Procedure:
1-(4-(Oxazol-2-yl)phenyl)piperidin-3-ol (245 mg, 1.00 mmol) was synthesized in 45% yield, as described in General Procedure B using 2-(4-bromophenyl)oxazole (500 mg, 2.232 mmol) and piperidin-3-ol (451 mg, 4.46 mmol). Anal. Calcd. for C14H16N2O2 m/z 244.2, found: 245.0 (M+H)+.