Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:34]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:33])[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][S:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl>[CH2:1]([S:8][CH:9]([CH2:34][N:36]1[CH2:41][CH2:40][S:39][CH2:38][CH2:37]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:33])[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1cccc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: C1CSCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CN(c1cccc2cc(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a mixture of N-[2-(benzylthio)-3-oxopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (0.60 g), thiomorpholine (0.21 mL) and 1,2-dichloroethane (25 mL) was added sodium triacetoxyborohydride (0.65 g), and the mixture was stirred at room temperature for 15 hr. The reaction solution was acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=35:65-55:45) to give the title compound (0.67 g, yield: 95%) as a colorless oil. MS: 596 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[O:14])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([NH:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1)=[O:32].ClS([N:43]=[C:44]=O)(=O)=O.CN(C)C=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:44]#[N:43])=[C:7]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:17]([F:18])([F:20])[F:19])=[O:14])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([NH:33][C:34]1([C:37]#[N:38])[CH2:35][CH2:36]1)=[O:32]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3(C#N)CC3)c(Cl)cc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)c(C#N)c2cc(C(=O)NC3(C#N)CC3)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
6-Chloro-N5-(1-cyanocyclopropyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide (0.100 g, 0.18 mmol) is initially charged in dry acetonitrile (2 ml) under argon and cooled to 0° C., and chlorosulphonyl isocyanate (0.028 g, 0.19 mmol) is added dropwise. After 30 min, N,N-dimethylformamide (0.015 g, 0.19 mmol) is added and the mixture is stirred at 0° C. for a further 30 min and at room temperature overnight. Then the mixture is cooled again to 0° C. and chlorosulphonyl isocyanate (0.028 g, 0.19 mmol) is added dropwise, N,N-dimethylformamide (0.015 g, 0.19 mmol) is added after 30 min, and the mixture is stirred at room temperature for a further 48 h. The reaction mixture is then concentrated under reduced pressure, and the residue is admixed with sodium hydrogencarbonate and extracted with dichloromethane. The organic phase is dried with sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by means of preparative HPLC (Kromasil100, C18 250×20; eluent: acetonitrile in water, gradient: 10-100%) to obtain 0.006 g (5% of theory) of 6-chloro-3-cyano-N5-(1-cyanocyclopropyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[C:7]1([C:13](=O)[CH:14](Br)[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]2[S:1][C:2]3=[N:6][CH:5]=[CH:4][N:3]3[C:13]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:16][CH:17]=1)(=[O:22])=[O:23]
Reactant: Sc1ncc[nH]1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccccc2)cc1
Product: CS(=O)(=O)c1ccc(-c2sc3nccn3c2-c2ccccc2)cc1

Procedure:
Following the procedure of example 17, the title compound was prepared from 2-mercaptoimidazole and the bromoketone of step 3, example 1. 1H NMR (CDCl3): δ3.03 (s, 3H), 7.33 (d, 2H, J=3.5 Hz), 7.4-7.5 (m, 7H), 7.81 (d, 2H, J=8.4 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][C:25]1[O:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1.BrCC1CCCCO1>>[F:31][C:30]([F:33])([F:32])[C:27]1[O:26][C:25]([CH2:24][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:29][CH:28]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccc(CBr)o1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using (S)-(2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)-5-(trifluoromethyl)furan to replace 2-(bromomethyl)tetrahydro-2H-pyran, (S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 53-56° C. (methanol/water); 1H NMR (300 MHz, CDCl3) δ7.30 (dd, J=7.8, 7.8 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.74 (dd, J=2.1, 0.9 Hz, 1H), 6.50 (s, 1H), 6.38 (d, J=3.0 Hz, 1H), 6.19 (s, 1H), 5.06 (d, J=16.2 Hz, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.89 (d, J=16.2 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.17 (m, 2H), 4.14-4.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 155.3, 152.2, 144.8, 141.8 (q, J=43.0 Hz), 141.5, 138.5, 132.2, 129.1, 124.2, 123.9, 120.9, 118.9 (q, J=267 Hz), 112.8 (q, J=2.8 Hz), 111.6, 109.3, 109.0, 99.5, 80.1, 64.6, 64.0, 58.1, 37.1; MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[CH:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].C[Si](Cl)(C)C>O1CCCC1.O>[OH:18][CH:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]#[C:7][C:6]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#CC(=O)OCC
Reactant: CC(C)CC=O
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)CC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5M in hexanes, 22.5 ml) was added dropwise over 40 minutes with stirring to fresh ethyl propiolate (6.0 ml) in dry tetrahydrofuran (75 ml) under nitrogen, with the temperature being maintained below −68° by external cooling. After 30 minutes, isovaleraldehyde (6.5 ml) in dry tetrahydrofuran (15 ml) was added over 15 minutes with the temperature maintained below −69°. After one hour, trimethylsilyl chloride (10 ml) was added and the reaction was allowed to warm to room temperature. Water was added and the mixture was extracted with ethyl acetate, which was washed with brine, dried, and evaporated to give ethyl 4hydroxy-6-methyl-2-heptynoate as an oil (9.5 g).
Reaction SMILES: [CH3:1][CH:2]1[CH:10]2[CH:6]([N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8](=[O:11])[O:9]2)[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:3]1>CO.C(OCC)(=O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[CH:4]1[CH2:5][CH:6]2[N:7]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:8](=[O:11])[O:9][CH:10]2[CH:2]([CH3:1])[CH2:3]1
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC2C1OC(=O)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CC(c2ccncc2N)CC2C1OC(=O)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of (+/−)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv.) in MeOH and ethyl acetate (1:1, 0.07 M) was added 10% Pd/C (0.1 equiv.) and the reaction was stirred at room temperature under an atmosphere of hydrogen. Upon completion of the reaction, the solution was filtered through a pad of Celite, washed with MeOH and ethyl acetate, the filtrate was concentrated to dryness under vacuo to give (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate as a mixture of diastereomers in >99% yield. LC/MS=348.2 (M+H), Rt=0.50 min.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([F:43])=[N:41][CH:42]=1>>[F:43][C:40]1[N:41]=[CH:42][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:38][CH:39]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Fc1ccc(Br)cn1
Product: C[C@@H](c1ccc(-c2ccc(F)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 71 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 5-bromo-2-fluoro-pyridine following a procedure analogous to that described in Example 1. Yield: 71% of theory; Mass spectrum (ESI+): m/z=449 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:34].[Na+].[C:36]([C:39]12[CH2:46][CH2:45][N:42]([CH2:43][CH2:44]1)[CH2:41][CH2:40]2)(=[O:38])[NH2:37]>CC(C)=O>[I-:34].[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18][N+:42]45[CH2:45][CH2:46][C:39]([C:36](=[O:38])[NH2:37])([CH2:44][CH2:43]4)[CH2:40][CH2:41]5)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: NC(=O)C12CCN(CC1)CC2
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(C[N+]34CCC(C(N)=O)(CC3)CC4)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
p-Methoxybenzyl 7β-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate (980 mg) was suspended in acetone (20 ml), and sodium iodide (362 mg) was added to the suspension and stirred at room temperature for 1 hour. To the resulting suspension was added 4-carbamoylquinuclidine (313 mg) under ice-cooled condition, and the mixture was stirred for 2 hours. The reaction mixture was filtered, and diethyl ether (70 ml) was added to the filtrate. The deposited solid was filtered to obtain the desired product (500 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][CH2:21][CH3:22])[N:13]=2)[CH:3]=1.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20][CH2:21][CH3:22])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: CCCc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1OC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1OC
Temperature: 140 °C
Reaction time: 7 h
Yield: 30.9 %

Procedure:
To a solution of 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (200 mg, 622 μmol) in NMP (2.07 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) and the mixture heated at 140° C. for 20 h. A second portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) was added and the mixture stirred for a further 7 h. A final portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (133 mg, 622 μmol) was added and the mixture heated for 16 h, then cooled, diluted with ethyl acetate, and washed with brine (4×). The organic layer was collected, concentrated in vacuo, and the residue obtained was purified by chromatography (silica, 1 to 5% methanol in dichloromethane) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-methoxy-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (96 mg, 192 μmol, 31%) as a light brown solid. MS (EI/CI) m/z: 500.2 [M+H].
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:27])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[O:28]C(=O)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>O1CCCC1.CO>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[C:24]4[C:23]([CH3:25])=[C:22]([CH3:26])[S:21][C:20]=4[C:19]([Br:27])=[C:18]4[C:13]=3[CH:14]=[CH:15][CH:16]=[CH:17]4)[CH:9]=[CH:8][C:7]=2[OH:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C4CCCC4)c3)c2c1C
Yield: 98.5 %

Procedure:
To acetic acid 2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (2.7 g, 5.4 mmol) in tetrahydrofuran (88 mL) and methanol (30 mL) at room temperature was added dropwise an aqueous potassium hydroxide (6.5 mL of a 1N solution, 6.5 mmol). After 1.5 h the reaction mixture was concentrated under reduced pressure. The resulting residue was combined with water (200 mL) and acidified with 10% aqueous hydrochloric acid to a pH of 1. The solution was extracted with diethyl ether (300 mL) and the diethyl ether layer was washed twice with water and dried (Na2SO4). Concentration under reduced pressure gave the title compound as a white solid (2.4 g, 100%): (DMSO-d6): δ9.54 (s, 1H), 8.16 (d, 1H), 7.61 (m, 1H), 7.52 (s, 1H), 7.43 (m, 1H), 7.03 (s, 1H), 6.93 (m, 2H), 3.32 (m, 1H), 2.41 (s, 3H), 1.94 (m, 2H), 1.58 (s, 3H), 1.72-1.42 (m, 6H); MS(EI): [M+], 1 bromine isotope pattern, 450/452; Anal. Calc. for C25H23BrOS: C, 66.52; H, 5.13; N, 0.00. Found: C, 67.17; H, 5.25; N, 0.04.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([NH:23][S:20]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]([O:9][CH3:10])=[C:3]([CH:1]=[O:2])[CH:4]=1)(=[O:22])=[O:21])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and benzoyl chloride, gave N-benzoyl-5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.
Reaction SMILES: [CH2:1]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]1[O:12][CH2:11][CH:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:13][O:14]1
Reactant: O=Cc1cccc(F)c1F
Reactant: CCCCCCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCC1COC(c2cccc(F)c2F)OC1

Procedure:
Quantities: compound from Example 10 (31.4 g, 0.155 mol), 2,3-difluorobenzaldehyde (21.5 g, 0.15 mol) and 4-toluenesulphonic acid (100 mg). The experimental procedure was as described in Example 114.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:45]=[C:46]([CH:54]=[CH:55][CH:56]=1)[CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(C(C)C)CC)(C)C>ClCCl>[O:17]=[C:15]([N:51]1[CH2:50][CH2:49][N:48]([CH2:47][C:46]2[CH:54]=[CH:55][CH:56]=[C:44]([C:43]([F:57])([F:58])[F:42])[CH:45]=2)[CH2:53][CH2:52]1)[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1=[O:1]
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
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: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
To 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.057 g, 0.244 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.098 g, 0.257 mmol) and 1-(3-(trifluoromethyl)benzyl)piperazine (0.066 g, 0.269 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.064 mL, 0.367 mmol) and the reaction was allowed to stir at room temperature. After stirring overnight, the reaction was loaded directly onto a silica gel column (Analogix®, SF15-12), and the product was eluted using a gradient of 0.4% to 3.75% methanol/dichloromethane over 25 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.58-7.60 (br s, 1H), 7.49-7.55 (m, 2H), 7.41-7.47 (m, 1H), 7.27-7.35 (m, 3H), 7.18-7.26 (m, 2H), 4.47 (d, J=15.7 Hz, 1H), 4.03 (d, J=15.7 Hz, 1H), 3.68-3.73 (m, 1H), 3.59-3.67 (m, 2H), 3.56-3.62 (m, 1H), 3.53-3.59 (m, 2H), 3.47-3.52 (m, 2H), 3.39-3.45 (m, 1H), 2.42-2.49 (m, 4H), 2.17-2.28 (m, 1H), 1.87-2.05 (m, 3H); MS (ESI−) m/z 458 (M−H)−.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[N-:22]=[N+:23]=[N-:24].[Na+].O>C(O)C>[N:22]([CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)=[O:4])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NCC(=O)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Yield: 58.9 %

Procedure:
A mixture of 2.0 g of 2-chloro-4'-(m-chlorophenylsulfonyl)acetanilide, 0.41 g of sodium azide, 20 ml of water and 40 ml of ethanol was refluxed for 3.5 hours and then evaporated to dryness. The residue was crystallized from ethanol, giving 1.2 g of 2-azido-4'-(m-chlorophenylsulfonyl)acetanilide, mp 125°-126° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10](O)[CH2:11][C:5]=2[CH:4]=1.[Cl-:21].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:21][CH:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7][C:6]2[CH:17]=[CH:18][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][C:5]=2[CH2:11]1
Reactant: OC1Cc2cc(C(F)(F)F)ccc2Sc2ccccc21
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: FC(F)(F)c1ccc2c(c1)CC(Cl)c1ccccc1S2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.4 g of 10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]-thiepin-10-ol 100 ml of benzene and 4 g of calcium chloride are saturated with hydrochloric acid gas for 2 hours at 15° C and subsequently stirred at room temperature for 3 hours. The mixture is filtered and concentrated under reduced pressure. There is obtained 10-chloro-10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin in the form of yellow crystals.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[CH2:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: C#CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 96 h
Yield: 97.8 %

Procedure:
A solution of but-3-yn-1-ol (10.00 g, 143 mmol) in dichloromethane (310 mL) was treated with dihyropyran (18.10 g, 215 mmol) and pyridinium p-toluene sulfonate (3.60 g, 14.30 mmol). The reaction mixture was stirred at room temperature for 4 days. Water was added and the layers were partitioned. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 1:1 ethyl acetate: heptane to give 21.57 g (98%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 4.65 (m, 1H), 3.90-3.80 (m, 2H), 3.60-3.50 (m, 2H), 2.50-2.45 (m, 2H), 1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.79-1.10 (m, 1H), 1.65-1.50 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[Cl:15])=[CH:6][CH:7]=1.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[CH3:17][C:16]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=3[Cl:15])[CH:6]=[CH:7][C:2]2=[N:20][N:19]=1
Reactant: CC(=O)NN
Reactant: Cc1ccc(Cl)c(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: Cc1ccc(Cl)c(-c2ccc3nnc(C)n3n2)c1

Procedure:
As described in Example 35, 2-chloro-5-methylbenzaldehyde is reacted with morpholine and potassium cyanide to give γ-(2-chloro-5-methylphenyl)-4-morpholineacetonitrile. In a similar manner as described in Example 35, the preceding compound is converted to 3-chloro-6-(2-chloro-5-methylphenyl)pyridazine which is reacted with acetic acid hydrazide in refluxing n-butanol for 24 hours to give the product of the example.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.[CH3:10][NH2:11]>Br>[CH3:10][NH:11][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CN
Reactant: Cc1cc(CO)ccn1
Agent: Br
Product: CNCc1ccnc(C)c1
Yield: 68 %

Procedure:
A stirred solution of 0.86 g (6.98 mmol) of 2-methyl-4-hydroxymethylpyridine (R. B. Katz et al., Synthetic Communications, 19, 1989, 317-325) in 48% aqueous HBr was heated at reflux for four days. The reaction mixture was cooled and added dropwise to 20 ml of 40% aqueous methylamine. The volatiles were removed under reduced pressure, and the residue was slurried in CH2Cl2 and then filtered. The filter cake was washed with CH2Cl2, EtOAc, CH3CN, and 10% MeOH in CH3CN. The filtrate was concentrated, and the residue was flash chromatographed on silica, eluting CH2Cl2 :NH3 -saturated MeOH (9:1). Consequently, 0.65 g (68% yield) of methyl-(2-methyl-pyridin-4-ylmethyl)-amine (39) was obtained as a colorless liquid.