Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]([CH3:12])[N:4]=1.[CH3:13][OH:14]>[N+]([O-])([O-])=O.[Ag+]>[Cl:11][C:6]1[N:5]([CH3:12])[N:4]=[C:3]([CH2:2][O:14][CH3:13])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CO
Reactant: Cn1nc(CBr)c([N+](=O)[O-])c1Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: COCc1nn(C)c(Cl)c1[N+](=O)[O-]
Yield: 40 %

Procedure:
A solution of 3-bromomethyl-5-chloro-1-methyl-4-nitropyrazole (5.0 g, 19.6 mmol) in methanol (50 ml) was treated with silver nitrate (5.75 g, 33.8 mmol) and the mixture heated under reflux for 2 hours. The cooled reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml) and the aqueous phase extracted with a further quantity of ethyl acetate (50 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum. Chromatography on silica gel, eluting with a 97:3 mixture of dichloromethane and methanol, gave the title pyrazole as a white solid (1.6 g, 40%), m.p. 59°-63° C. Found: C,34.65; H,3.83; N,20.05. C6H8ClN3O3 requires C,35.05; H,3.92; N,20.44%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3](=O)[CH2:2]1.Cl.[CH:8]1([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9]1.[S-:14][C:15]#[N:16].[K+].II>C(N(CC)CC)C>[CH:8]1([CH2:12][N:13]2[C:3]3[CH2:2][O:1][CH2:5][C:4]=3[S:14][C:15]2=[NH:16])[CH2:11][CH2:10][CH2:9]1
Reactant: N#C[S-]
Reactant: O=C1CCOC1
Reactant: NCC1CCC1
Agent: Cl
Agent: II
Agent: [K+]
Solvent: CCN(CC)CC
Product: N=c1sc2c(n1CC1CCC1)COC2

Procedure:
Commercially available dihydrofuran-3(2H)-one (Small Molecules Inc.), triethylamine, cyclobutylmethanamine hydrochloride (prepared from cyclobutanecarbonitrile as described in WO 2005075464), potassium thiocyanate (Aldrich) and iodine (EMD chemicals) were processed using the method described in Example 17A to afford the title compound. LC/MS (ESI+) m/z 211 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Cl:61][CH2:62][CH2:63][NH2:64]>CN(C)C=O>[Cl:61][CH2:62][CH2:63][NH:64][C:9](=[O:11])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([N:14]1[C:22]2[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)[CH2:12][CH3:13]
Reactant: NCCCl
Reactant: CCC(C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(=O)NCCCl)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of Step A (40 mg, 0.1 mmol), HATU (57 mg, 0.15 mmol), N,N-diisopropylethylamine (26 mg, 0.2 mmol) and 2-chloroethanamine (16 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature overnight. The crude product was purified by CombiFlash (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title compound as a white amorphous solid. LC/MS m/z=467.9[M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([Br:17])[C:6]1[CH:7]=[CH:8][C:9]([S:12]([Cl:15])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
(4-Chlorosulfonyl-phenyl)-acetic acid ethyl ester (1.6 gm, 6.45 mmol) was taken in carbon tetrachloride (13 ml). N-Bromosuccinimide (1.26 gm, 7.09 mmol) was added in one lot followed by benzoyl peroxide (171 mg, 0.7 mmol). The reaction mixture was refluxed for 2 days. The reaction mixture was cooled to room temperature and filtered; filtrate was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide bromo-(4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (2.08 gm) as a gummy mass. The crude material was used as such for further reaction.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].I[CH:13]1[C:18](OC)([O:19]C)[CH2:17][CH2:16][O:15][CH2:14]1>>[O:19]=[C:18]1[CH2:17][CH2:16][O:15][CH2:14][CH:13]1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC1(OC)CCOCC1I
Product: N#Cc1ccc(C2COCCC2=O)cc1

Procedure:
4-cyanophenylboronic acid was reacted as described in Intermediate X(2) with 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate X(1)) to give 4-(4-oxotetrahydro-2H-pyran-3-yl)benzonitrile (Intermediate AA(2)). LC-MS (M+H)+=202.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.66 (d, J=8.24 Hz, 2H) 7.38 (d, J=8.55 Hz, 2H) 4.23-4.31 (m, 2H) 3.94-4.02 (m, 2H) 3.85-3.92 (m, 1H) 2.55-2.65 (m, 1H) 2.52 (t, J=5.80 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH2:26][CH3:27])[CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[N-:30]=[N+:31]=[N-:32].[N-:33]=[C:34]=[O:35]>>[F:28][C:2]([F:1])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH2:26][CH3:27])[CH2:22][C:23]([N:30]=[N+:31]=[N-:32])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[N:33]([CH2:22][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:29])([F:28])[F:1])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1)[CH2:26][CH3:27])=[C:34]=[O:35]
Reactant: CCC(CC(=O)O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: [N-]=C=O
Reactant: [N-]=[N+]=[N-]
Product: CCC(CC(=O)N=[N+]=[N-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: CCC(CN=C=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared from 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1 H-1,2,4-triazol-3-yl)phenyl)pentanoic acid (CA12) to furnish a mixture of azide and isocyanate, 0.723 g, 72%): 1H NMR (400 MHz, CDCl3) δ 8.56 (two s, 1H), 8.20-8.15 (m, 2H), 7.85-7.74 (m, 2H), 7.39 (dt, J=9.0, 1.0 Hz, 2H), 7.34-7.29 (m, 2H), 3.62-3.38 (m, 2H), 2.77-2.59 (m, 1H), 1.93-1.59 (m, 2H), 0.94-0.83 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:13][CH:12]2[N:14](C(OC(C)(C)C)=O)[CH:8]([CH2:9][O:10][CH2:11]2)[CH:7]1[OH:22])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[OH:22][CH:7]1[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[CH2:13][CH:12]2[NH:14][CH:8]1[CH2:9][O:10][CH2:11]2
Reactant: CCOC(=O)CC1CC2COCC(C1O)N2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1CC2COCC(N2)C1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 123d (100 mg) in dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature for one hour, and concentrated under reduced pressure to give ethyl 2-(6-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 123a, which was used directly in next step without purification.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][NH:30][CH2:31]4)=[CH:26][CH:25]=3)[N:21]=[C:20]([NH2:34])[N:19]=2)[CH2:14][CH2:13]1.[Br:35][C:36]1[CH:37]=[C:38]([CH2:42][C:43](O)=[O:44])[CH:39]=[N:40][CH:41]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O>[Br:35][C:36]1[CH:37]=[C:38]([CH2:42][C:43]([N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:24]([C:22]4[CH:23]=[C:18]([N:15]5[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]5)[N:19]=[C:20]([NH2:34])[N:21]=4)=[CH:25][CH:26]=3)[CH2:31]2)=[O:44])[CH:39]=[N:40][CH:41]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3cncc(Br)c3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (16 uL, 0.12 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine trihydrochloride (50 mg, 0.1 mmol), (5-bromopyridin-3-yl)acetic acid (30.0 mg, 0.14 mmol) (Lancaster, Cat. #L13579), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (56 mg, 0.13 mmol) in N,N-dimethylformate (1.5 mL). The reaction mixture was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethane (0-10%) to afford the desired product. Analytic LCMS (M+H)+: m/z=521.95/523.95.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(OC(C)C)(C)C>[CH3:1][O:2][N:3]=[C:4]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([C:15]#[CH:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: C#CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 59 %

Procedure:
To a suspension of benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylate (syn isomer) (3.70 g) and anisole (5.58 g) was added trifluoroacetic acid (14.71 g) under ice-cooling and the resultant mixture was stirred at the same temperature for 30 minutes. The reaction mixture was dropwise added to diisopropylether (200 ml) and the precipitates were collected by filtration. The precipitates were added to water and ethyl acetate and the mixture was adjusted to pH 7.0 with saturated aqueous sodium bicarbonate. The separated aqueous layer was acidified to pH 3.0 with 10% hydrochloric acid and the precipitates were collected by filtration to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-ethynyl-3-cephem-4-carboxylic acid (syn isomer) (1.55 g).
Reaction SMILES: [CH2:1]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH:4]=C.[OH2:18]>C1COCC1.O.O=[Os](=O)(=O)=O>[C:12]1([C:10]2[CH:9]=[CH:8][N:7]=[C:6]([CH2:1][CH2:2][CH2:3][CH:4]=[O:18])[N:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCCCc1nccc(-c2ccccc2)n1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: O=CCCCc1nccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-penten-1-yl)-4-phenylpyrimidine (P5, 142 mg) in THF/H2O (5/1 mL) were added OsO4 (4% in water, 0.2 mL) and NaIO4 (404 mg). The solution was stirred at room temperature for 0.5 h. Water was then added and the mixture extracted with DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give 141 mg of the title compound as an oil, which was used in the subsequent step without further purification.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1)([F:7])[F:6])C.[NH2:18][NH2:19]>CO>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:5]([F:7])([F:6])[C:4]([NH:18][NH2:19])=[O:3])=[CH:16][C:12]=2[CH:13]=[CH:14]1
Reactant: CCOC(=O)C(F)(F)c1ccc2occc2c1
Reactant: NN
Solvent: CO
Product: NNC(=O)C(F)(F)c1ccc2occc2c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A mixture of the compound prepared in step c (127 mg, 0.53 mmol) and hydrazine (0.28 mL, 8.9 mmol) in dry methanol (3 mL) was stirred at reflux for 3 hr, cooled to RT and evaporated in vacuo to afford a semisolid product (0.12 g) 99%. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.90 (s, 1H), 7.76 (d, J=9.1 Hz, 1H), 7.52 (dd, J=8.5, 1.5 Hz, 1H), 7.09 (d, J=1.3 Hz, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].C(=O)(OC)OC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH3:17])[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(Br)cc2)nc2ccccc21
Temperature: 3 °C
Reaction time: 3.5 h
Yield: 150.8 %

Procedure:
12.69 g (46 mmole) of 2-(4-bromophenyl)-1H-benzo[d]imidazole, 3.17 g of K2CO3 (23 mmole), 120 ml of DMF, and 11.6 ml of dimethyl carbonate (138 mmole) were mixed together and heat to reflux. The reaction was completed in 3.5 hours. The reaction mixture was cooled to 3° C., and 250 ml of ice cold water was slowly added, The precipitated was filtered, and wash with 3*50 ml of water, this wet cake was dried under vacuum to get 9.96 g of product (yield=75.44%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C@@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=O)=[O:8])[CH2:3][CH2:2]1.[NH2:21][C@H:22]([C:29]([NH:31][C@H:32]([C@@H:40]([OH:46])[CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:30])[CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]([O:9][C@@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([NH:21][C@H:22]([C:29]([NH:31][C@H:32]([C@@H:40]([OH:46])[CH2:41][CH2:42][CH:43]([CH3:44])[CH3:45])[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:30])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:13])=[O:8])[CH2:5][CH2:6]1
Reactant: O=C(O)[C@H](Cc1ccccc1)OC(=O)N1CCOCC1
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)OC(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
To a mixture of 2(S)-morpholinocarbonyloxy-3-phenylpropionic acid (120 mg) and 2(S)-(L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (142 mg) in dry N,N-dimethylformamide (20 ml), which was cooled to 0° C., were added a solution of diphenyl phosphorylazide (108 mg) in dry N,N-dimethylformamide (5 ml) and triethylamine (40 mg). The mixture was stirred for 16 hours at ambient temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml). The solution was washed with 1M sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel thin layer chromatography (chloroform:methanol, 6:1, V/V) to give 2(S)-[Nα -(2(S)-morpholinocarbonyloxy-3-phenylpropionyl)-L-histidyl]amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (177 mg) as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][C:6]([CH2:8][CH2:9][CH2:10][Cl:11])=[O:7]>>[Cl-:11].[O:7]=[C:6]([CH3:5])[CH2:8][CH2:9][CH2:10][S:3][C:2]([NH2:4])=[NH2+:1]
Reactant: CC(=O)CCCCl
Reactant: NC(N)=S
Product: CC(=O)CCCSC(N)=[NH2+]
Product: [Cl-]
Yield: 71 %

Procedure:
Example 1 was repeated with thiourea and 3-chloropropyl methyl ketone, affording the title compound in a yield of 71%.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[S:26]([OH:29])(=[O:28])=[O:27].[O:30]=[S:31](=[O:33])=[O:32].[S:34](=O)(=O)([OH:36])[OH:35]>O>[O:35]=[S:34]1(=[O:36])[C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][C:4]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:5][CH:6]=3)[CH:12]=[CH:11][C:10]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([S:31]([OH:33])(=[O:32])=[O:30])=[CH:23][CH:24]=3)=[CH:15][C:14]1=2
Reactant: c1ccc(-c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)cc1
Reactant: O=S(=O)(O)O
Reactant: O=S(=O)=O
Solvent: O
Product: O=S(=O)(O)c1ccc(-c2ccc3c(c2)S(=O)(=O)c2cc(-c4ccc(S(=O)(=O)O)cc4)ccc2-3)cc1
Reaction time: 5 h

Procedure:
4,4′-(5,5-Dioxidodibenzo[b,d]thiene-3,7-diyl)dibenzenesulfonic acid (II) was prepared by sulfonation of 1,1′:4′,1″:4″,1′″-quaterphenyl. 1,1′:4′,1″:4″,1′″-Quaterphenyl (10 g) was charged into 20% oleum (100 ml). Reaction mass was agitated for 5 hours at ambient conditions. After that the reaction mixture was diluted with water (170 ml). The final sulfuric acid concentration was around 55%. The precipitate was filtered and rinsed with glacial acetic acid (˜200 ml). Filter cake was dried in oven at ˜110° C. The process yielded 8 g of 4,4′-(5,5-Dioxidodibenzo[b,d]thiene-3,7-diyl)dibenzenesulfonic acid.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:15]=[N:14][C:13]([CH3:16])=[N:12][CH:11]=2)[CH:5]=1.Br[CH2:19][C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26])=[O:21].Br>CS(C)=O>[C:4]([O:27][C:25](=[O:26])[CH2:24][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:15]=[N:14][C:13]([CH3:16])=[N:12][CH:11]=2)[CH:5]=1)=[O:17])([CH3:9])([CH3:5])[CH3:3].[O:2]=[CH:19][C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26])=[O:21]
Reactant: O=C(O)c1cccc(C(=O)CBr)c1
Reactant: COC(=O)c1cccc(-c2cnc(C)nn2)c1
Agent: Br
Solvent: CS(C)=O
Product: Cc1ncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Product: O=CC(=O)c1cccc(C(=O)O)c1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared from 3-(3-methyl-[1,2,4]triazin-6-yl)-benzoic acid methyl ester [prepared by the following procedure: To a solution of 3-bromoacetyl-benzoic acid (2.43 g, 10 mmol) in DMSO (17 ml) was added 48% aqueous HBr (3.4 ml) and the mixture was stirred at 55° C. for 0.5 h. The cooled mixture was partitioned between AcOEt and H2O, the organic layer was washed with brine, dried and evaporated in vacuum and the solid residue was triturated with Et2O/hexane to give 3-oxoacetyl-benzoic acid (1.08 g) as a white solid. A solution of this material (3.92 g, 20 mmol) and acetyl hydrazide (1.63 g, 22 mmol) in MeOH (20 ml) was stirred at RT for 1 h. The mixture was evaporated in vacuum and the residue was heated in an autoclave in 5N NH3-MeOH (30 ml) at 150° C. for 3 h. The mixture was cooled and partitionned between AcOEt and sat. NaHCO3-solution. The aqueous phase was acidified to pH 3with 3N HCl and extracted with AcOEt. The crude product obtained from the AcOEt extract was esterified by heating in 1N HCl-MeOH (80 ml) for 18 h at 50° C. and the crude ester obtained was purified by chromatography (silica gel, AcOEt) to give the methyl ester as light-yellow solid (0.45 g).] (0.8 g, 3.5 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a yellow solid (1.34 g, crude product).
Reaction SMILES: Cl[C:2]1[C:3]([OH:31])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=1[CH:15]=[CH:16][NH:17][C:18]3=[O:23])[C:7]([OH:28])([C:24]([F:27])([F:26])[F:25])[CH2:6][C:5]2([CH3:30])[CH3:29].[C-:32]#[N:33].[Na+]>CN1CCCC1=O.[Ni](Br)Br>[OH:31][C:3]1[C:4]2[C:5]([CH3:30])([CH3:29])[CH2:6][C:7]([OH:28])([C:24]([F:25])([F:27])[F:26])[CH:8]([NH:12][C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][NH:17][C:18]4=[O:23])[C:9]=2[CH:10]=[CH:11][C:2]=1[C:32]#[N:33]
Reactant: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2ccc(Cl)c(O)c21
Reactant: [C-]#N
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c(=O)[nH]ccc23)c2ccc(C#N)c(O)c21
Yield: 22 %

Procedure:
75 mg (0.166 mmol) of 5-(6-chloro-2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalin-1-ylamino)-2H-isoquinolin-1-one is dissolved in 1.3 ml of 1-methyl-2-pyrrolidinone and reacted in the microwave with 16.27 mg (0.332 mmol) of sodium cyanide and 36.27 mg (0.166 mmol) of nickel(II) bromide as described in Example 160. The black reaction mixture is added through a glass-fiber filter. After washing with ethyl acetate, the filtrate is mixed with an additional 60 ml of ethyl acetate. It is shaken with water and with brine. After drying, the solvent is spun off, and the residue is chromatographed on silica gel (amine plate: mobile solvent methanol/dichloromethane). 16.2 mg (22.1%) of the desired nitrile is isolated.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:14])[CH:3]=1.S(Cl)([Cl:17])=O>ClCCCl>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[C:4]([F:14])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: Nc1cc(F)c(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 53a from 4-amino-5-nitro-2-fluoro-benzoic acid and thionyl chloride in 1,2-dichloroethane.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([Mg]C(C)C)(C)C.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.C(OC)(C)(C)C>[OH:27][CH:20]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: O=Cc1ccccc1
Agent: CC(C)[Mg]C(C)C
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 552 mg (2 mmol) of ethyl 4-iodobenzoate in 20 ml of THF was cooled to −40° C. and 1.06 mmol of diisopropylmagnesium in methyl tert-butyl ether were added. After 1 h at −40° C. 233 mg (2.2 mmol) of benzaldehyde were added. After 3 h, the reaction mixture was hydrolyzed and the org. phase was concentrated. Chromatography of the crude product with 4/1 pentane/ether afforded 460 mg (90%) of the alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])/[CH:9]=[CH:14]/[N:15]([CH3:17])[CH3:16])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(C)O
Product: CN(C)/C=C/C(=O)c1cc(Cl)ccc1O
Temperature: 45 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
1-(5-chloro-2-hydroxyphenyl)ethanone, (165 g, 0.967 mol) was slurried in 2-propanol (1000 mL) then 1,1-dimethoxy-N,N-dimethylmethanamine (258.28 mL, 1.93 mol) was added and the resulting yellow solution was stirred at 45° C. for 18 hours. The resulting suspension was cooled to room temperature and stirred for a further 48 hours. The solid was filtered off, washed with 2-propanol (2×200 mL) and then tert-butylmethyl ether (200 mL) then dried to give the title compound as a bright yellow solid, (204.59 g).
Reaction SMILES: Cl[CH2:2][N:3]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([O:18][CH3:19])=[CH:10][C:11]=2[CH:15]([CH3:17])[CH3:16])[S:4]1(=[O:6])=[O:5].[Na].[C:21]1([N:27]2[C:31]([SH:32])=[N:30][N:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[C:21]1([N:27]2[C:31]([S:32][CH2:2][N:3]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][C:9]([O:18][CH3:19])=[CH:10][C:11]=4[CH:15]([CH3:17])[CH3:16])[S:4]3(=[O:6])=[O:5])=[N:30][N:29]=[N:28]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CSc1nnnn1-c1ccccc1)C2=O
Temperature: 0 °C
Yield: 81.8 %

Procedure:
A mixture of 2-chloromethyl-4-isopropyl-6-methoxysaccharin (0.25 g) and 1-phenyltetrazole-5-thiol sodium salt (0.173 g) in dimethylformamide (10 mL) was heated at 60°-80° C. for 8 hours, then poured into ice-water containing saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ether. The ether extract was washed with water and saturated aqueous sodium chloride, passed through silica gel and is stripped of ether affording 2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-6-methoxysaccharin as a foam (0.3 g, 83% yield).