Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1)#[N:2].C(OC([N:19]1[CH2:24][CH2:23][O:22][C@@H:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20]1)=O)(C)(C)C>>[ClH:32].[Cl:32][C:27]1[CH:26]=[C:25]([C@@H:21]2[O:22][CH2:23][CH2:24][NH:19][CH2:20]2)[CH:30]=[CH:29][C:28]=1[NH:31][C:9](=[O:11])[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(Cl)c2)C1
Reactant: N#Cc1cccc(C(=O)O)n1
Product: Cl
Product: N#Cc1cccc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2Cl)n1

Procedure:
In analogy to example 79, step a) using 6-cyano-2-pyridinecarboxylic acid (CAS 872602-74-9) instead of 4-cyanopicolinic acid (CAS 640296-19-1) and (−)-(S)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. White solid. MS (ISP): 341.1 ([M+H]+)
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.O>[C:10]1([C:2]2[N:4]=[C:5]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[CH:26])[CH:20]=3)[N:7]=[C:8]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[CH:26])[CH:20]=3)[N:1]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C#Cc1cccc(N)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: C#Cc1cccc(Nc2nc(Nc3cccc(C#C)c3)nc(-c3ccccc3)n2)c1

Procedure:
One mole of cyanuric chloride was treated with phenylmagnesium bromide as described in Step I of Example I. The resulting reaction product (10.0 g, 0.044 mole) in CHCl3 (100 ml) was stirred in a 250 ml 3-neck round bottom flask while m-aminophenylacetylene (10.5 g, 0.09 mole) was added dropwise with cooling. To this mixture was added K2CO3 (12.4 g, 0.09 mole) and water (20 ml). The organic layer was separated, dried, and the solvent evaporated. The residue was triturated in benzene and dried to give 6-phenyl-2,4-bis(3-ethynylphenylamino)-s-triazine a compound that melted at 210° C. with polymerization. Thermo-gravimetric analysis showed that the polymer was stable to 425° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)o2)c1

Procedure:
The methyl ester (16) (100 mg, 0.30 mmol) was coupled to 4-(trifluoromethoxy)-phenylboronic acid (67 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][C@H:19]1[CH2:21][O:20]1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[OH:20][C@H:19]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:18][O:17][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:14][CH2:15][N:16]=3)[C:10]([NH2:13])=[N:11][C:12]=2[C:3]=1[O:2][CH3:1]
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1c(OC[C@H](O)CN2CCCC2)ccc2c1N=C(N)N1CCN=C21
Yield: 77.8 %

Procedure:
A solution of 7-Methoxy-8-[(2R)-oxiran-2-ylmethoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate F, 1.00 g, 3.47 mmol) and pyrrolidine (2.87 mL, 34.7 mmol, 10 equiv.) in DMF (18 mL) was in a microwave reactor for 45 min. at 140° C. The resulting mixture was concentrated under reduced pressure. The residue (2.5 g) was purified using MPLC to give N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (0.97 g, 78%): HPLC ret. time 0.71 min.; 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.82-1.92 (m, 2H), 1.94-2.03 (m, 2H), 3.02-3.14 (m, 3H), 3.27-3.33 (m, 2H), 3.52-3.61 (m, 2H), 3.80 (s, 3H), 4.06-4.16 (m, 4H), 4.23 (br sextet, J=4.3 Hz, 1H), 4.28-4.34 (m, 2H), 7.22 (d, J=9.4 Hz, 1H), 7.81 (d, J=9.1 Hz, 1H); mass spectrum m/z 360 ((M+1)+, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.N1C2C(=CC=CC=2)[C:23]2([C:33]3=[CH:34][C:35]4[O:39][CH2:38]O[C:36]=4C=C3OC2)C1=O.BrCC1CCCCO1.ClC1SN=C(CCl)N=1>>[CH3:1][C:2]1[C:3]([CH3:20])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:36][CH:35]4[CH2:34][CH2:33][CH2:23][CH2:38][O:39]4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Cc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Agent: ClCc1nsc(Cl)n1
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)N(CC2CCCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 6 and making non-critical variations using 5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)-tetrahydro-2H-pyran to replace 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole, 5,6-dimethyl-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (72%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.28 (dd, J=7.6, 7.6 Hz, 1H), 7.15-6.97 (m, 1H), 6.75 (s, 1H), 6.47 (d, J=4.9 Hz, 1H), 4.89 (dd, J=8.9, 1.8 Hz, 1H), 4.65 (dd, J=8.9, 2.9 Hz, 1H), 4.03-3.60 (m, 2H), 3.44-3.32 (m, 1H), 2.19 (s, 3H), 2.05 (s, 3H), 1.92-1.80 (m, 1H), 1.73-1.27 (m, 1H); 13C NMR (75 MHz, CDCl3) δ178.0, 159.1, 143.2, 138.3, 132.6, 129.3, 128.6, 126.3, 123.9, 123.6, 123.1, 111.4, 109.7, 79.7, 75.6, 68.4, 58.0, 45.7, 29.6, 25.8, 23.0, 20.3, 19.4; MS (ES+) m/z 364.3 (M+1).
Reaction SMILES: BrC1C=CC(O)=C(C2(O)C3C(=CC=CC=3)N(CCCCC)C2=O)C=1.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([C:33]2(O)[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]2=[O:47])=[C:28]([OH:49])[CH:27]=1>>[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([CH:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]([CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:34]2=[O:47])=[C:28]([OH:49])[CH:27]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc(Cl)c(Cl)cc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21
Product: CCCCCN1C(=O)C(c2cc(Cl)c(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 15B, and making non-critical variations to replace 3-(5-bromo-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4,5-dichloro-2-hydroxyphenyl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (86%): 1H NMR (300 MHz, CDCl3) δ 10.0-9.50 (br, 1H), 7.42 (t, 1H), 7.32 (d, 1H), 7.22 (td, 1H), 7.09 (s, 1H), 6.95 (d, 1H), 6.93 (s, 1H), 5.04(s, 1H), 3.77-3.68 (m, 2H), 1.77-1.62 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 348 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22]O)[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.CS([Cl:37])(=O)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17](/[CH:20]=[CH:21]/[CH2:22][Cl:37])[CH2:16][CH2:15]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(CC[C@H]1CC[C@H](/C=C/CO)CC1)C(=O)Oc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CN(CC[C@H]1CC[C@H](/C=C/CCl)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To an ice-cooled solution of 135 mg (0.384 mmol) trans-{2-[4-(3-hydroxy-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester and 0.089 ml (0.77 mmol) 2,6-lutidine in 2 ml of dichloromethane was added under stirring 0.033 ml (0.422 mmol) methane sulfonylchloride. The reaction mixture was stirred for 20 hours at room temperature, then taken up in ether and washed with 1N hydrogen chloride solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 4:1 v/v mixture of hexane and ethylacetate as the eluent giving 90 mg (63.4%) of trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 370 (MH+, 2 Cl).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1>C(Cl)Cl.O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:27]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:38][CH:37]=2)[CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(CBr)cc2)cc1
Reaction time: 12 h

Procedure:
A solution of 4-(bromomethyl)benzenesulfonyl chloride (5.6 mmol) in 5 mL of CH2Cl2 at 25° C. is treated with Et3N (8.4 mmol) followed by bis-(4-methoxy-benzyl)-amine (5.8 mmol). The reaction is stirred for 12 hours, diluted with H2O, extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. The resultant crude material is purified by silica flash chromatography (20% EtOAc/hexanes) to yield 4-bromomethyl-N,N-bis-(4-methoxy-benzyl)-benzenesulfonamide: 1H NMR (400 MHz, CDCl3): δ 7.72 (apparent t, J=8.4 Hz, 2H), 7.44 (dd, J1=1.6 Hz, J2=8.4 Hz, 2H), 6.91-6.86 (m, 4H), 6.69 (d, J=8.8 Hz, 4H), 4.5 (s, 2H), 4.19 (s, 4H), 3.71 (s, 3H); LC/MS: (ES+) 490.1 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:3]([NH:16][NH2:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C(O)(=[O:30])C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]2[N:4]3[C:5]4[C:10]([NH:11][C:2](=[O:30])[C:3]3=[N:16][N:17]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2nc(NN)c(Cl)nc2c1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)c1nnc(-c3ccc(OC)cc3)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.00 g of methyl 3-chloro-2-hydrazinoquinoxaline-6-carboxylate, 2.9 mL of 4-methoxybenzaldehyde, and 150 mL of acetic acid was stirred at room temperature for 3 hours. To the reaction mixture was added 4.74 g of copper(II) acetate, followed by stirring at 100° C. for 3 hours. Water was added thereto at room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure. The obtained mixture was purified by silica gel column chromatography (chloroform/methanol) to obtain 5.27 g of methyl 1-(4-methoxyphenyl)-4-oxo-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Cl.[NH2:35][C:36]1[S:40][N:39]=[C:38](/[C:41](=[N:45]/[O:46][CH3:47])/[C:42](Cl)=[O:43])[N:37]=1.P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[NH2:35][C:36]1[S:40][N:39]=[C:38](/[C:41](=[N:45]/[O:46][CH3:47])/[C:42]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]23)=[O:43])[N:37]=1
Reactant: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)CC(C)=O)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C

Procedure:
In 240 ml of dichloromethane is suspended 9.06 g of 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid. To the suspension is added 28.9 g of bistrimethylsilylacetamide and the mixture is stirred at room temperature until complete dissolution and cooled in an ice-water bath. To this solution, 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetyl chloride hydrochloride prepared from 5.83 g of 2-(5-amino-1,2,4-thiadiazol-3yl)-2(Z)-methoximinoacetic acid and 6.02 g of phosphorus pentachloride in 90 ml of dischloromelthane is added and the mixture is stirred for a while. The whole mixture is stirred with ice-cooling for 60 minutes. The dichloromethane is evaporated off and the residue is dissolved in melthyl ethyl ketone. The solution is washed with water and dried. The solvent is then evaporated off and diethyl ether is added to the residue to give a fine precipiate, which is collected by filtration, giving 11.8 (82% yield) g of the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Cl:12][C:13]1[C:20]([Cl:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[CH:17][C:14]=1[CH:15]=[O:16].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][N:7]1[C:11]([CH:15]([OH:16])[C:14]2[CH:17]=[C:18]([O:24][CH3:25])[C:19]([O:22][CH3:23])=[C:20]([Cl:21])[C:13]=2[Cl:12])=[CH:10][CH:9]=[N:8]1
Reactant: COc1cc(C=O)c(Cl)c(Cl)c1OC
Reactant: Cn1cccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccnn2C)c(Cl)c(Cl)c1OC
Reaction time: 1 h
Yield: 90.5 %

Procedure:
18 ml of 1.6M n-butyl lithium in n-hexane is added dropwise to a solution of 2.26 g of 1-methyl-pyrazole in tetrahydrofuran at -60° C. under argon gas atmosphere and the mixture is stirred at the same temperature for 1 hour. A solution of 5.88 g of 2,3-dichloro-4,5-dimethoxybenzaldehyde in tetrahydrofuran is added dropwise to the mixture at -60° to -50° C. and the mixture is stirred at -50° C. to room temperature for 1 hour. An aqueous ammonium chloride solution is added to the reaction mixture and the mixture is concentrated to remove organic solvent. The residue is extracted with ethyl acetate, and the extract is washed, dried and evaporated to remove solvent. The residue is crystallized from isopropyl ether to give 7.18 g of α-(1-methylpyrazol-5-yl)-2,3-dichloro-4,5-dimethoxybenzylalcohol.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=O)[CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])(=[O:3])[CH3:2].C([O-])([O-])=[O:16].[K+].[K+].[Cl:21][CH2:22][CH2:23][CH2:24]Br>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:12][CH:13]=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH2:24][CH2:23][CH2:22][Cl:21])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: ClCCCBr
Reactant: CC(=O)Nc1cc(C(C)=O)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(CC=O)ccc1OCCCCl
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl] ethanone (7.7 g, 40 mmol), K2CO3 (5.7 g), 3-chloro-1-bromopropane (8.9 g, 56 mmol) and acetone (100 ml) was refluxed for 16 hours. The reaction was allowed to cool to ambient temperature and filtered. Concentration of the filtrate yielded 8.5 g of a white solid. The solid was recrystallized from toluene and then from ethanol to afford 6.5 g of an off-white solid. A 3.3 g sample of this material was flash chromatographed on silica gel with ethyl acetate as eluent. Concentration of the appropriate fractions afforded 2.8 g of a solid. The solid was recrystallized from toluene and then from ethanol-water to yield 2.2 g (51%) of a solid, m.p.=124-126° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C@:20]([CH3:33])([OH:32])[C@@H:19]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC#N.O.CCOC(C)=O>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C@:20]([CH3:33])([OH:32])[C@@H:19]([CH2:34][OH:35])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:17])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](OCC[Si](C)(C)C)[C@H](OCc2ccccc2)[C@@H](OC(=O)Oc2ccccc2)[C@]1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: C[C@]1(O)[C@H](OC(=O)Oc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCC[Si](C)(C)C)O[C@@H]1CO
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a stirred solution of 5.10 (4.7 g, 7.6 mmol) in CH3CN (30 mL) and H2O (30 mL) was added p-toluenesulfonic acid monohydrate (115 mg, 0.76 mmol). The reaction was stirred for 3 h then diluted with EtOAc and washed sequentially with saturated aqueous NaHCO3, H2O, and brine. After concentration of the organic phase in vacuo, the crude residue was purified by silica gel chromatography (50% EtOAc/petroleum ether) to afford the title compound (3.7 g, 7.3 mmol, 96%). 1H NMR (500 MHz, CDCl3): δ ppm 7.39-7.22 (m, 8H, PhH), 7.10 (d, J=7.3 Hz, 2H, PhH), 4.94, 4.67 (ABq, J=11.2 Hz, 1H each, OCH2Ph), 4.88 (d, J=9.8 Hz, 1H, H-3), 4.53 (d, J=7.8 Hz, 1H, H-1), 4.04-3.96 (m, 1H, OCHHCH2SiMe3), 3.91 (dd, J=11.7, 4.9 Hz, 1H, H-6), 3.78 (dd, J=11.7, 6.8 Hz, 1H, H-6), 3.67-3.59 (m, 1H, OCHHCH2SiMe3), 3.46 (dd, J=6.8, 5.4 Hz, 1H, H-5), 3.39 (dd, J=10.0, 7.6 Hz, 1H, H-2), 1.29 (s, 3H, Me), 1.04 (t, J=8.5 Hz, 2H, OCH2CH2SiMe3), 0.04 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 154.43, 151.15, 138.34, 129.61, 128.50, 127.81, 127.73, 126.31, 121.06, 103.64, 84.03, 79.21, 77.45, 74.92, 73.40, 68.21, 61.05, 18.73, 15.90, −1.27; HRMS calcd for C26H40NO8Si [M+NH4]+: 522.2523. found 522.2501.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21].[C:31](=[S:33])=O>O.O1CCOCC1>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][C:31]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[S:33])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C=S
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)[C@H](Cc1ccccc1)NC(=S)Cc1ccc([N+](=O)[O-])cc1
Yield: 54.6 %

Procedure:
8.3 G (0.05 mol) of L-phenylalanine and 13.9 ml (0.1 mol) of triethylamine were dissolved in 50 ml of water. To the solution was added 100 ml of dioxane solution containing 8.6 g (0.5 mol) of 4-nitrobenzylchloride. 3.0 g (0.05 mol) of carbonyl sulfide was blown into the solution at a temperature of from 10° to 15° C. in 15 minutes. After completion of blowing, the mixture was subjected to reaction at room temperature for 2 hours. After completion of reaction, the solid material obtained in a similar manner to that described in Example 1 was recrystallized from 50 ml of ethylacetate and 20 ml of n-hexane to yield 9.4 g of pale yellow crystals.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[C:21]2[O:26][CH3:27])(=[O:14])=[O:13].C(ON=O)(C)(C)C>CC(O)=O.C1COCC1>[CH3:27][O:26][C:21]1[C:20]2[C:25](=[C:16]3[C:17](=[CH:18][CH:19]=2)[C:2]2[C:3](=[CH:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=2)[S:12](=[O:14])(=[O:13])[NH:15]3)[N:24]=[CH:23][CH:22]=1
Reactant: COc1ccnc2c(NS(=O)(=O)c3ccc(C(F)(F)F)cc3N)cccc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccnc2c3c(ccc12)-c1cc(C(F)(F)F)ccc1S(=O)(=O)N3
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
A solution of 2-amino-N-(4-methoxy-quinolin-8-yl)-4-trifluoromethyl-benzenesulfonamide (Intermediate 196) (454 mg, 1.1 mmol) in AcOH/THF (1:1, 10 ml) was cooled to 0° C. and tert-butylnitrite (235 mg, 2.2 mmol) was added. The reaction was stirred at 0-5° C. for 2 h. The reaction was quenched water (5 ml) and the solvent partially evaporated. The residue was dissolved in EtOAc (150 ml), washed with sat. sodium bicarbonate solution, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (1:0-99:1) gradient elution followed by recrystallisation from iPA/MeCN to give the title compound (45 mg, 11%).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:5]#[N:6].N[OH:19].Cl>C(O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[N:6][O:19][C:3]=2[NH2:2])=[CH:8][CH:9]=1
Reactant: CN(C)C=C(C#N)c1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Nc1oncc1-c1ccc(C(F)(F)F)cc1

Procedure:
3-Dimethylamino-2-(4-(trifluoromethyl)phenyl)-acrylonitrile (2.5 g), and NH2OH.HCl (1.5 g) were refluxed in ethanol for 2 hours. After evaporation of the solvent, water was added and the final product was filtered, recrystallized from methylene chloride, and identified by NMR analysis.
Reaction SMILES: Br[CH:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[CH2:8][CH3:9])[CH3:7]
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)C(Br)CC
Product: CCOC(=O)C(CC)Sc1ccc(OC)cc1

Procedure:
2-(4-Methoxy-phenylsulfanyl)-butyric acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromobutyrate (10.71 g, 55 mmol) and 4-methoxythiophenol (7 g, 50 mmol), 5.19 g (40%); clear oil; MS: 255.2 (M+H)+.
Reaction SMILES: C(O)(=O)C(O)=[O:3].[CH3:7][N:8]([CH2:10][C@H:11]1[O:32][N:14]2[C:15]3[CH:27]=[C:26]([C:28]([O:30]C)=[O:29])[CH:25]=[CH:24][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C@@H:13]2[CH2:12]1)[CH3:9].[OH-].[Na+]>C(O)C.O>[OH2:3].[CH3:9][N:8]([CH2:10][C@H:11]1[O:32][N:14]2[C:15]3[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C@@H:13]2[CH2:12]1)[CH3:7].[CH3:9][N:8]([CH2:10][C@H:11]1[O:32][N:14]2[C:15]3[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C@@H:13]2[CH2:12]1)[CH3:7]
Reactant: O=C(O)C(=O)O
Reactant: COC(=O)c1ccc2c(c1)N1O[C@H](CN(C)C)C[C@H]1c1ccccc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)C[C@@H]1C[C@H]2c3ccccc3Oc3ccc(C(=O)O)cc3N2O1
Yield: 41.6 %

Procedure:
(±)-Methyl cis-2-[(dimethylamino)methyl]-3,3a-dihydro-2H-dibenz[b,f]isoxazolo-[2,3-d][1,4]oxazepine-11-carboxylate ethanedioate(1:1)(1.53g), prepared following the procedure in example 7, in ethanol (60 ml) was added dropwise to a mixture of sodium hydroxide (0.3 g) in water (7.5 ml) and the mixture was stirred and refluxed for 2 hours. The solvent was evaporated in vacuo and the residue was acidified with HCl (4N) to a pH of 3.6. The precipitate was filtered off, dried with P2O5 and purified by short pad column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 7/3). The pure fractions were collected and evaporated and the residue (1 g) was treated with CH2Cl2 /C2H5OH/H2O 25ml/5ml/5ml. The precipitate was filtered off and dried, yielding 0.5 g (38%) of (±)-cis-2-[(dimethylamino)methyl]-3,3a-dihydro-2H-dibenz[b,f]isoxazolo[2,3-d][1,4]oxazepine-11-carboxylic acid hemihydrate; mp. 229.8° C. (comp. 4).