Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH2:7][C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CS(C)=O>[C:1]([S:3][CH2:7][C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:4])[CH3:2]
Reactant: ClCc1cccc2nnsc12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)SCc1cccc2nnsc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 2.2 g of potassium thioacetate in 20 ml of absolute dimethyl sulfoxide, stirred at 20° C., is treated dropwise with stirring with a solution of 2.8 g of 7-chloromethylbenzo-1,2,3-thiadiazole in 10 ml of dimethyl sulfoxide, during which process the internal temperature rises to 37° C. The mixture is subsequently stirred overnight at room temperature and, on the following day, poured into ice-water and extracted using ethyl acetate. The extracts are washed five times with water, dried over sodium sulfate and evaporated. The residue which remains is distilled in vacuo, resulting in an oil of refractive index nd27 -1.6478.
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:31]/[C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[N:3]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
(1H-indazol-3-ylmethyl)triphenylphosphonium iodide (3.20 g, 6.15 mmol) obtained in Step 4 was dissolved in methanol (60 mL), and the solution was added with methyl p-formylbenzoate (1.00 g, 6.09 mmol) and potassium carbonate (2.55 g, 18.5 mmol), followed by stirring at room temperature overnight. The reaction mixture was added with water, and was extracted with ethyl acetate, then the organic layer was washed with saturated brine, and was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin-layer chromatography (chloroform/methanol=15/1), was further triturated in mixed solvent of ethyl acetate/diisopropyl ether to obtain methyl (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoate (0.87 g, 51%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(=S)=S>[C:19]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][CH:5]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCc2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C1CCc2c(C(=O)c3ccccc3)cccc21
Reaction time: 0.17 h

Procedure:
To 120 ml. of carbon disulfide is added 54 g. of anhydrous aluminum chloride powder on an ice bath, followed by the dropwise addition of a solution of 11.4 g. of ethyl indan-1-carboxylate in 60 ml. of carbon disulfide. The mixture is stirred for 10 minutes, after which a solution of 42 g. of benzoyl chloride in 60 ml. of carbon disulfide is added dropwise. After the dropwise addition has been completed, the temperature is gradually increased and the solution is stirred on reflux for 3 hours and thirty minutes to complete the reaction. Ice and hydrochloric acid are added to the reaction mixture followed by extraction with ether. The extract is washed with 1N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in the order mentioned and, then, dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is column-chromatographed on silica gel (conditions: 2 Kg. of silica gel; eluant solvent-benzene containing 2.5 % of ethyl acetate). The first-emerging fractions rich in ethyl 4-benzoylindan-1-carboxylate are pooled separate from the ensuing fractions rich in ethyl 6-benzoylindan-1-carboxylate. The former fractions are further purified by rechromatography on a column of silica gel, whereby ethyl 4-benzoylindan-1-carboxylate is obtained as an oily product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[CH:21]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:21]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: N#Cc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)cc1
Yield: 47.6 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75 mg, 0.22 mmol), 4-Formylbenzonitrile (32.0 mg, 0.244 mmol), and Ammonium acetate (34.2 mg, 0.444 mmol) were reacted to produce 47.01 mg (47%) of the title compound. (300 MHz, DMSO-d6) 13.60 (s, 1H), 8.29 (d, J=8 Hz, 2H), 8.08 (s, 1H), 7.76 (s, 1H), 7.31 (m, 1H), 7.24 (s, 1H), 6.42 (m, 1H), 6.37 (m, 1H), 5.20 (t, J=17 Hz, 8.5 Hz, 1H), 2.90 (s, 1H), 2.79 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.38 (d, J=8 Hz, 1H). MS=451 (M+H), HPLC: 2.43 min. (G Method)
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:39])[C:17]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[CH:19][C:18]=1[O:31]CC1C=CC=CC=1.[H][H]>C(O)(C)C.O.[C].[Pd]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:39])[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[OH:31]
Reactant: [H][H]
Reactant: COc1ccc(CCNCC(O)c2ccc(OCc3ccccc3)cc2OCc2ccccc2)cc1OC
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(CCNCC(O)c2ccc(O)cc2O)cc1OC
Yield: 92.7 %

Procedure:
0.6 g of α-(3,4-dimethoxyphenethylaminomethyl)-2,4-dibenzyloxybenzylalcohol oxalate is suspended in a mixture of 40 ml of isopropanol and 10 ml of water. 0.2 g of 10 % palladium-carbon are added to the suspension. Then, the mixture is subjected to catalytic hydrogenation in a hydrogen atmosphere at room temperature for 2 hours under atmospheric pressure. After the reaction is completed, the mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure, whereby 0.39 g of α-(3,4-dimethoxyphenethylaminomethyl)-2,4-dihydroxybenzylalcohol oxalate is obtained as amorphous powder. Yield: 93 %
Reaction SMILES: [CH2:1]([NH:4][P:5](=[S:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH2:2][CH3:3].[S:13](Cl)[Cl:14].Cl.C(N(CC)CC)C>CCCCCC.C(N(CC)CC)C>[Cl:14][S:13][N:4]([CH2:1][CH2:2][CH3:3])[P:5](=[S:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: ClSCl
Reactant: CCCNP(=S)(OCC)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCCN(SCl)P(=S)(OCC)OCC
Reaction time: 0.5 h

Procedure:
A solution of 2.98 gm. (0.014 mole) O,O-diethyl n-propylphosphoramidothioate in 10 ml. hexane and 2 ml. triethylamine is added to a cold (0° C.) solution of 1.0 ml. (0.016 mole) sulfur dichloride in 10 ml. hexane slowly and with stirring. There is vigorous reaction and heavy precipitation of triethylamine hydrochloride. An additional 20 ml. hexane is added. The reaction mixture is kept at 0° to 5° C. and stirred for 30 minutes, then it is filtered. The filtrate is concentrated to a pale yellow oil by evaporating the hexane under reduced pressure. The oil comprises the desired O,O-diethyl N-(chlorothio)-n-propylphosphoramidothioate which can be used for further reactions with N-methylcarbamates.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N@:11]1[CH2:13][CH:12]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])(=[O:10])=[O:9].[I-].[Na+].[CH2:34]([N:37]=[C:38]=[O:39])[CH2:35][CH3:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:13][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[N:37]([CH2:34][CH2:35][CH3:36])[C:38]1=[O:39])(=[O:9])=[O:10]
Reactant: CCCN=C=O
Reactant: O=C(C1C[N@@]1S(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1
Agent: [I-]
Agent: [Na+]
Product: CCCN1C(=O)N(S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, [(S)-1-(2-chloro-benzenesulfonyl)-aziridin-2-yl]-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone was reacted with sodium iodide and n-propylisocyanate to give (S)-1-(2-chloro-benzenesulfonyl)-3-propyl-4-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-imidazolidin-2-one as a colorless foam. MS: 559.6 ([M+H]+)
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[C:13]3[CH2:14][O:15][C:16](=[O:17])[C:12]=3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CN(C)C=O.[Rh]>[C:1]1([C@H:7]([N:9]2[C@H:13]3[CH2:14][O:15][C:16](=[O:17])[C@H:12]3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](c1ccccc1)n1c2c([nH]c1=O)C(=O)OC2
Agent: [Rh]
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Reaction time: 10 h

Procedure:
A solution of 8.98 g (36.8 mmol) of 1-[(R)-(1-phenylethyl)]-1H-furo-[3,4-d]-imidazol-2,4(3H,6H)-dione in 90 ml of dimethylformamide was placed in a 250-ml autoclave and 0.90 g of Rh/Al2O3 (5 percent) is added. Then the autoclave was flushed twice successively with hydrogen, and filled to 40 bars. The mixture was stirred for 10 hours. Then the catalyst was filtered off. The solvent was evaporated at 13.3 mbar and the residue was recrystallized with 10 ml of ethyl acetate. (3aS,6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo-[3,4-d]-imidazol-2,4(3H,3aH)-dione was obtained as a white crystalline product in a yield of 4.89 g=54 percent. Concerning the product:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13](O)=[O:14])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH2:55][CH2:54]1>CC(N(C)C)=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:53]3[CH2:54][CH2:55][CH:56]([N:59]4[CH2:63][CH2:62][CH2:61][C:60]4=[O:64])[CH2:57][CH2:58]3)=[O:14])[N:10]=[C:9]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Reactant: O=C1CCCN1C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: O=C(Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1)N1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
To a solution of [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (164 mg, 0.53 mmol) in DMA (3 mL) at room temperature was added HOBt (78 mg, 0.58 mmol), EDCI (111 mg, 0.58 mmol), NMM (0.20 mL, 1.84 mmol) and 1-piperidin-4-ylpyrrolidin-2-one hydrochloride (150 mg, 0.73 mmol) and the mixture sonicated to a fine suspension and stirred for 64 hours at room temperature. The volatiles were removed under high vacuum and the residue partitioned between EtOAc (70 mL) and water (25 mL). The aqueous layer was removed and the organics washed with NaHCO3 (30 mL), brine (30 mL), dried over MgSO4, filtered and stripped to yield the title compound as an off-white solid, 123 mg, 51%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.51-8.54 (2 H, m), 7.64-7.69 (2 H, m), 7.25-7.35 (2 H, m), 7.11-7.21 (2 H, m), 6.53 (1 H, s), 5.11-5.28 (2 H, m), 4.37 (1 H, d, J=13.14 Hz), 3.90-4.05 (4 H, m), 3.23-3.31 (2 H, m), 3.08-3.20 (1 H, m), 2.57-2.70 (1 H, m), 2.22 (2 H, t, J=8.08 Hz), 1.84-1.95 (2 H, m), 1.40-1.73 (4 H, m); m/z (APCI+) for C26H28N5O2F 462.2 (M+H)+.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:8][S:9]([N:12]=C=O)(=[O:11])=[O:10]>C1C=CC=CC=1>[C:1]([NH:12][S:9]([Cl:8])(=[O:11])=[O:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCCC(=O)O
Solvent: c1ccccc1
Product: CCCCC(=O)NS(=O)(=O)Cl
Yield: 100.2 %

Procedure:
n-Pentanoic acid (1.02 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was taken up in benzene (10 mL) and the mixture concentrated in vacuo to provide the title compound (2.0 g, quantitative) as a crystalline, hygroscopic solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[S:21][C:22]([CH3:29])=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:24]2[CH:23]=[C:22]([CH3:29])[S:21][C:20]=2[CH3:19])(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)s1
Product: Cc1cc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)c(C)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene 1,2-diamine was reacted with 2,5-dimethylthiophene-3-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.39 (dd, J=1.8 & 10.2 Hz, 1H), 7.24-7.16 (br m, 2H), 7.13 (dd, J=9.0 & 17.4 Hz, 1H), 6.77 (d, J=9.6 Hz, 1H), 5.98 (dt, J=2.4, 8.7 & 17.4 Hz, 1H), 5.55 (br s, 1H), 2.33 (s, 6H).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25]Br)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:28]([OH:31])([CH3:30])[CH3:29]>>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:27])[CH2:25][O:31][CH:28]([CH3:30])[CH3:29])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CBr)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: CC(C)O
Product: CC(C)OCC(=O)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 21 except starting with N-(1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-4-piperidyl)-2-bromoacetamide and isopropanol, the title compound was obtained as a white solid (39%), mp 134.5°-5.5° C.; MS(CI): 405 (M+H); NMR (300 MHz,DMSO-d6): 1.10(d, 6H, J=6.0 Hz), 1.52-1.61(br m, 4H), 2.28(br m, 2H), 2.46(s, 2H), 2.95(br m, 2H), 3.35(s, 2H), 3.58(septet, 1H, J=5.7 Hz), 3.65(br s, 1H), 3.78(s, 2H), 4.31(s, 1H), 6.92(br m, 4H), 7.19(d, 2H, J=7.0 Hz), 7.27(d, 2H), J=6.5 Hz), 7.34(d, 1H, J=8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:14][CH:15]=1)=[O:20]
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc2c(Cl)c(NC(=O)c3ccc(-c4ccccc4)cc3)ccc2s1
Yield: 84 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-biphenylcarbonyl chloride (50 μL, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave biphenyl-4-carboxylic acid (4-chloro-2-methyl-benzothiazol-5-yl)-amide (79 mg, 0.21 mmol, 84% yield) as a pale pink powder after crystallisation in hexane/DCM.
Reaction SMILES: Cl[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[Cl:8].[NH2:11][CH2:12][CH2:13][CH2:14][OH:15]>O>[Cl:8][C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: NCCCO
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Solvent: O
Product: Cn1ncc(Cl)c(NCCCO)c1=O
Reaction time: 4 h
Yield: 19.3 %

Procedure:
3.58 g (20 mmoles) of 4,5-dichloro-2-methyl-3(2H)-pyridazinone and 3.76 g (50 mmoles) of 3-aminopropanol are dissolved in 35 ml of water. The mixture is boiled for 4 hours under stirring and reflux cooling, then it is cooled and extracted with 200 ml of dichloromethane. The organic phase is dried, evaporated and the crude product is subjected to chromatography on a silica gel column. Thus 0.84 g (19%) of the desired compound is obtained. M.p.: 65°-66° C., Rf =0.7.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:11]#[N:12])[N:6]=1.Cl.[NH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:11](=[N:20]\[OH:21])\[NH2:12])[N:6]=1
Reactant: N#C/C(=N\OCc1csc(N)n1)c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: NC(=N\O)/C(=N\OCc1csc(N)n1)c1ccccc1
Temperature: 80 °C
Yield: 115.5 %

Procedure:
To a suspension of (2Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)acetonitrile (4.5 g, 17.42 mmol, 1 eq.) in iPrOH/H2O (10/1, 110 ml) were added hydroxylamine hydrochloride (3.63 g, 52.26 mmol, 3 eq.) and potassium carbonate (7.22 g, 52.2 mmol, 3 eq.). The reaction was heated to 80° C. for 6 h and the solvent was evaporated to ¾th. The residue was extracted with EtOAc (3×50 ml) and washed with aq. sat. NaCl. The organics were combined, dried over MgSO4 and concentrated to give (1Z,2Z)-2-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}-N′-hydroxy-2-phenylethanimidamide (5.86 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.C([Li])CCC.[CH3:15][CH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.Cl>CCCCCC.C(OCC)C>[CH3:15][C:16]1[CH2:20][CH:19]=[C:18]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=2)[CH:17]=1
Reactant: CC1CCCC1=O
Reactant: Cc1cc(C)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=CC(c2cc(C)cc(C)c2)=CC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
1-Bromo-3,5-dimethylbenzene (13.6 g, 73.6 mmol) was dissolved in a mixed solution of hexane (150 mL) and diethyl ether (20 mL) and added dropwise at 0° C. with a solution (46.6 mL, 1.58M) of n-butyllithium in hexane. The solution was immediately warmed to room temperature, stirred night and day and added dropwise at −78° C. to a solution of 3-methyl-2-cyclopentanone (7.3 mL, 74 mmol) in diethyl ether (100 mL). The resultant solution was warmed to room temperature immediately after dropwise addition and stirred for 2 hours. After termination of the reaction, the reaction solution was added with dilute hydrochloric acid, stirred at room temperature for 30 minutes and then subjected to layer separation. The organic layer was dried with magnesium sulfate and then had the solvent distilled off under reduced pressure. The crude product was distilled under reduced pressure (125 to 127° C./0.5 mmHg) to obtain 1-methyl-3-(3,5-dimethyl-phenyl)-cyclopentadiene (6.2 g, yield: 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:5]2.[H-].[Na+].I[CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:21])[C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:5]2
Reactant: CI
Reactant: Fc1cc(Cl)cc2cc(-c3cccnc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2cccnc2)cc2cc(Cl)cc(F)c21
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-7-fluoro-2-pyridin-3-yl-1H-indole (Example 86, 276 mg, 1.12 mmol) in DMF (4 mL) is added 60% sodium hydride in mineral oil (120 mg, 3.0 mmol) and the suspension is stirred for 30 min. Iodomethane (213 mg, 1.5 mmol) is then added to the reaction mixture and stirred at ambient temperature for 1 h. Water (2 mL) is added to quench the reaction. The mixture is filtered and purified by HPLC using Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to afford 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 261 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>C1(C)C=CC=CC=1>[CH2:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:28]([NH:27][CH2:25][CH3:26])=[O:29])[S:3][C:4]=2[CH:10]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCN=C=O
Reactant: Nc1nc2ccc(Cc3ccccc3)cc2s1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(Cc3ccccc3)cc2s1
Temperature: 95 °C
Yield: 54.8 %

Procedure:
A suspension of 2-amino-6-benzyl-benzothiazole (0.040 g, 0.17 mmol), triethylamine (0.104 mL, 0.77 mmol, 4.5 eq), and ethyl isocyanate (0.049 mL, 0.64 mmol, 3.8 eq) in 1 mL toluene was heated at about 95° C. for about 16 hours. The precipitate was filtered off, washed with Et2O and MeOH, and dried under vacuum to give the desired compound 0.029 g (56%). LC/MS 312.3 (M+1); LC retention time 2.62 min.
Reaction SMILES: [CH3:1][S:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)(=[N:4][N+:5]([O-:7])=[O:6])=[O:3].[OH-].[Na+]>C1COCC1.Cl>[NH2:14][C:10]1[CH:9]=[C:8]([S:2]([CH3:1])(=[N:4][N+:5]([O-:7])=[O:6])=[O:3])[CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=N[N+](=O)[O-])c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=N[N+](=O)[O-])c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 100 mg (0.41 mmol) of (RS)-S-methyl-N-nitro-S-(3-nitrophenyl)sulfoximide in 8 ml of THF is mixed at room temperature with 3.1 ml of an approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid. After 1 hour, another 1.0 ml of the approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid is added, and it is stirred for another 45 minutes at room temperature. The batch is made basic with 1N NaOH solution and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The residue that is obtained is purified by chromatography (DCM/EtOH 95:5). 40 mg (0.19 mmol, corresponding to 45% of theory) of the product is obtained.