Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>C(#N)C>[Cl:19][S:20]([NH:23][C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:8]([C:6](=[O:7])[C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)[C:9]1=[O:18])=[O:25])(=[O:22])=[O:21]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Nc2ccc(Cl)cc2C1C(=O)c1cccs1
Solvent: CC#N
Product: O=C(c1cccs1)C1C(=O)N(C(=O)NS(=O)(=O)Cl)c2ccc(Cl)cc21

Procedure:
To a stirred slurry of 1.5 g. (5.4 mmole) of 3-(2-thenoyl)-5-chloro-2-oxindole in 15 ml. of dry acetonitrile was added 0.52 ml. (5.9 mmole) of chlorosulfonyl isocyanate, and the reaction mixture was stirred at room temperature for 2 hours. A small sample was removed, filtered and evaporated in vacuo to give a small sample of N-chlorosulfonyl-3-(2-thenoyl)-5-chloro-2-oxindole-1-carboxamide, mp 166°-169° C. To the remainder of the reaction mixture, 30 ml. of water was added slowly with stirring and stirring was continued for 1 hour. The reaction mixture was then poured into 50 ml. of 1N hydrochloric acid containing ice chips, and the resulting mixture was stirred for 20 minutes. The yellow solid was recovered by filtration, washed with water and diisopropyl ether and recrystallized from glacial acetic acid to give 200 mg. of a first crop of the title compound, mp 213°-215° C. The mother liquors from which the first crop had been recovered deposited a further yellow solid. The latter solid was recovered by filtration to give 470 mg. of a second crop of the title compound. The second crop was recrystallized from glacial acetic acid and combined with the first crop and recrystallized from glacial acetic acid. This gave 280 mg. of the title compound, mp 232°-234° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26]O>>[C:1]([NH:5][CH2:6][CH:7]([OH:24])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]([O:23][CH3:26])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)NCC(O)COc1ccc(-c2nc(C(=O)O)c[nH]2)cc1
Agent: Cl
Product: COC(=O)c1c[nH]c(-c2ccc(OCC(O)CNC(C)(C)C)cc2)n1
Reaction time: 2 h

Procedure:
A solution of crude 2-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-4-carboxyimidazole ◯1 (30 g.) in methanol (600 ml.) is heated to reflux, and then heating is discontinued as hydrogen chloride is bubbled rapidly through the solution with stirring for a half hour, followed by two and a half hours at reflux. Bubbling of hydrogen chloride is continued for another two hours followed by another hour at reflux and then the reaction mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate is then concentrated to dryness under reduced pressure. The residue is dissolved in water (150 ml.) and the pH is adjusted to 8 with saturated sodium carbonate solution. The basic mixture is extracted with ethyl acetate and the extracts are dried, filtered, and concentrated under reduced pressure to yield a solid which is recrystallized from acetonitrile to yield the methyl 2-[4-(3-tert.butylamino-2-hydroxypropoxy)phenyl]-imidazole-4-carboxylate as a cream-colored solid, m.p. 168°-172° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].C(N(CC)CC)C.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1>ClCCl>[CH:21]1([NH:25][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:24][CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NC1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (6.8 g, 30.8 mol) in dichloromethane (100 mL) at 0° C. was added triethylamine (14 g, 138.6 mol) and cyclobutanamine (2.2 g, 31 mmol) in several portions over 10-15 minutes. The reaction mixture was stirred at room temperature for 4 hours, concentrated and purified by silica gel chromatography to afford the product N-cyclobutyl-2-nitrobenzenesulfonamide (7 g, yield 88.9%). 1H NMR (400 MHz, CDCl3) δ ppm 8.14-8.16 (m, 1H), 7.84-7.87 (m, 1H), 7.72-7.74 (m, 2H), 5.45-5.47 (d, 1H, J=8.8 Hz), 3.93-3.99 (m, 1H), 2.11-2.18 (m, 2H), 1.84-1.90 (m, 2H), 1.59-1.69 (m, 2H).
Reaction SMILES: [OH:1][C:2]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:7][CH2:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH2:3]1.FC(F)(F)S(O[C:33]1[C:34]([CH3:62])([CH3:61])[C@H:35]2[C@:48]([CH3:51])([CH2:49][CH:50]=1)[C@@H:47]1[C@:38]([CH3:60])([C@@:39]3([CH3:59])[C@H:44]([CH2:45][CH2:46]1)[C@H:43]1[C@H:52]([C:55]([CH3:57])=[CH2:56])[CH2:53][CH2:54][C@:42]1([NH2:58])[CH2:41][CH2:40]3)[CH2:37][CH2:36]2)(=O)=O.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:58][C@:42]12[CH2:54][CH2:53][C@@H:52]([C:55]([CH3:57])=[CH2:56])[C@@H:43]1[C@@H:44]1[C@@:39]([CH3:59])([CH2:40][CH2:41]2)[C@@:38]2([CH3:60])[C@@H:47]([C@:48]3([CH3:51])[C@@H:35]([CH2:36][CH2:37]2)[C:34]([CH3:61])([CH3:62])[C:33]([C:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])[CH2:3][CH:4]=2)=[CH:50][CH2:49]3)[CH2:46][CH2:45]1
Reactant: CC1(C)OB(C2=CCC(O)(C(=O)OCc3ccccc3)CC2)OC1(C)C
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(O)(C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 56.5 %

Procedure:
A flask containing benzyl 1-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (0.113 g, 0.221 mmol) and (1R,3aS,5aR,5bR,7aR,11aR,11bR,13 aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (0.082 g, 0.147 mmol) was diluted with 1,4-dioxane (1 mL) and water (0.25 mL). To the mixture was added sodium carbonate hydrate (0.075 g, 0.605 mmol) and the mixture was degassed with nitrogen for five minutes. To the mixture was added palladium tetrakis (5.10 mg, 4.41 mmol) then the flask was purged then refilled with nitrogen three times. The mixture was heated to 85° C. for 4 h then was cooled to rt and was purified by flash chromatography using a 20-80% ethyl acetate in hexanes gradient and a 25 g silica gel column. The fractions containing the expected product were combined and concentrated under reduced pressure to give benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-hydroxycyclohex-3-enecarboxylate (0.053 g, 0.083 mmol, 56.3% yield) as an off-white foam. LCMS: m/e 640.6 (M+H)+, 1.91 min (method 1).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].C(O)C.O.[Br:25][C:26]1[C:27]2[C:28]3[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30](S)[C:29]=3[CH:36]=[CH:37][CH:38]=2>C(O)C>[Br:25][C:26]1[C:27]2[C:28]3[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[C:29]=3[CH:36]=[CH:37][CH:38]=2
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Reactant: NCCCCCCCCCCn1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Brc1ccc2c3c(cccc13)C(NCCCCCCCCCCn1ccnc1)=N2
Yield: 70 %

Procedure:
A mixture of 2.8 g of 10-(1H-imidazol-l-yl)decanamine, dihydrochloride was treated with 2 ml of 10N sodium hydroxide in an ethanol-water mixture giving the base derivative. To this base was added 25 ml of ethanol, 2.33 g of 6-bromo-benz(cd)indole-2-thiol and 3.0 g of mercuric acetate. The procedure of Example 1 was then followed, giving 2.8 g of the desired product, mp 115° C.-116° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Cl.[Cl:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:17].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:22]3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: COc1ccc(C2CCCN(CCCCl)C2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2CCCN(CCCN3CCC(c4c[nH]c5ccccc45)CC3)C2)cc1
Yield: 98.3 %

Procedure:
To a suspended solution of 4-(3-indolyl)piperidine (48 mg, 0.24 mmol) and 1-(3-chloropropyl)-3-(4-methoxyphenyl)piperidine hydrochloride (61 mg, 0.2 mmol) in acetonitrile (13 mL) was added potassium carbonate (111 mg, 0.8 mmol), and the resulting mixture was refluxed for 12 hours. After the precipitated salt was filtered off, the filtrate was concentrated, and the resulting crude product was purified by column chromatography on a silica gel (eluent; chloroform:ammonia-saturated chloroform=10:1→3:1→1:2) to afford a free form (92 mg) of the title compound as a colorless viscous oil. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then freeze-dried to afford the title compound (81 mg, yield: 80%) as a white amorphous solid.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[C:19]([NH:22][CH2:23][C:24]1[S:28][C:27]([SH:29])=[N:26][N:25]=1)(=[O:21])[CH3:20].C(=O)(O)[O-].[Na+]>O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:27]3[S:28][C:24]([CH2:23][NH:22][C:19](=[O:21])[CH3:20])=[N:25][N:26]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)NCc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)NCc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 60 °C
Reaction time: 5 h
Yield: 51.4 %

Procedure:
7-Aminocephalosporanic acid (1.36 g.), 5-acetamidomethyl-1,3,4-thiadiazole-2-thiol(1.04 g.) and sodium bicarbonate (885 mg.) were dissolved in water (70 ml.), and the solution was stirred at 60° C for 5 hrs. After the reaction, the reaction mixture was adjusted to pH5, and then allowed to stand overnight in a refrigerator. The precipitating crystals were collected by filtration to give 7-amino-3-(5-acetamidomethyl-1,3,4-thiadiazol-2yl)thiomethyl-3-cephem-4-carboxylic acid (1.03 g.) m.p. 195°-197° C (dec.).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:69]([NH2:73])([CH3:72])([CH3:71])[CH3:70]>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:73][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NC(C)(C)C)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and t-butylamine (9.54 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (17.4 mg, 52%). LC-MS m/z 563 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=O)[O:26]C3C=CC=CC=3)=[CH:20][CH:19]=2)[N:7]=1)(=[O:4])=[O:3].C([N:36](CC)CC)C.NC1N=CC=CN=1>CN(C=O)C>[CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH2:36])=[O:26])=[CH:22][CH:23]=2)[N:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: CCN(CC)CC
Agent: Nc1ncccn1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(N)=O)cc2)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Phenyl N-[4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]carbamate (110 mg) was dissolved in DMF (2 mL) and triethylamine (0.098 mL) added. 2-Aminopyrimidine (108 mg) was added and the reaction stirred at 40° C. for 2 hours. The crude mixture was purified by prep-HPLC (basic), however, only [4-[4-(Methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]urea was isolated from the mixture (8 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[CH:8][C:7]=12)#[N:2]>CO.CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:16](=[O:25])[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8][C:7]=12)#[N:2]
Reactant: COc1ccc(C(=O)c2cc(C#N)c3cnc4ccccc4n23)cc1
Solvent: CO
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2cc(C#N)c3n2-c2ccccc2NC3)cc1
Reaction time: 4 h
Yield: 496.8 %

Procedure:
A mixture of 3-cyano-1-(4-methoxy-benzoyl)-pyrrolo[1,2-a]quinoxaline (14.5 mg, 0.0044 mmol) in 10 mL of methanol and 0.5 mL acetone was hydrogenated on PtO2 at 40 psi for 4 h. The reaction mixture was filtered, concentrated under vacuum and the residue was purified by chromatography (25% ethyl acetate/hexane) to yield 7.2 mg (50%) of the title compound. 1H NMR (CDCl3): 7.97 (m, 2H), 6.97 (m, 7H), 4.48 (s, 2H), 4.25 (s, broad, 1H), 3.92 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C.O>[C:1]([O:5][C:6](=[O:11])/[C:7](=[N:12]\[OH:13])/[C:8](=[O:9])[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
592.1 g of acetoacetic acid tert.butyl ester are dissolved in 560 ml of glacial acetic acid. To this solution is added dropwise at 5°-10° C. during 21/2 hours a solution of 290.6 g of sodium nitrite in 655 ml of water. The resulting yellow suspension is stirred for 30 minutes at 20° C., treated with 940 ml of water and stirred for a further 2 hours. The mixture is treated with 900 ml of water and 900 g of ice and extracted in the stirring vessel three times with 1 l of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 1 l of water each time, then treated with 5 l of water and the pH-value is adjusted to 6.8 with sodium hydrogen carbonate. After separating the aqueous phase, the organic phase is washed once with water. Thereafter, the ethyl acetate solution is dried over sodium sulphate and evaporated in vacuo at 40 ° C. There is obtained (Z)-2-hydroxyimino-3-oxo-butyric acid tert-butyl ester as a yellow oil which is dried for a further 9 hours in a high vacuum at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:5]2=[N:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1cnc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Clc1cnc2c(c1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 5-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine, 31, (11.6 g, 38.5 mmol), and Na2CO3 (12.2 g, 115 mmol) in N,N-dimethylformamide (200 mL) was added trityl chloride (11.8 g, 42.4 mmol). The mixture was stirred at room temperature overnight. After 16 hr, additional trityl chloride (1.61 g, 5.78 mmol) was added. And the mixture was heated to 60° C. for 45 min. The mixture was cooled, diluted with Et2O, washed with water (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-40% EtOAc-Hexanes, gradient elution) provided the desired product as a colorless material which was further purified by flash chromatography (SiO2, 100% DCM, isocratic elution): 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H) and 7.23-7.18 (m, 15H) ppm.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[CH2:12]([SiH:16]([CH2:23]F)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH:14]=[CH2:15]>C1COCC1>[CH2:12]([SiH:16]([CH2:23][CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: C1CSCSC1
Reactant: C=CCC[SiH](CF)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[SiH](CC1SCCCS1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 1,3-dithiane (11.1 g, 91.9 mmol) in THF (150 mL) at −78° C. was added dropwise over 10 min n-butyllithium (1.6 M in hexane, 76.6 mmol), and the solution was stirred for 2 h under argon. A solution of 42 (11.9 g, 61.3 mmol) in THF (120 mL) was added dropwise over 30 min, and the mixture was stirred for 3 h at −78° C. and overnight at rt. The reaction mixture was quenched with water (100 mL) and extracted thrice with 100-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave 43 contaminated with 1,3-dithiane. The latter was removed by sublimation (54° C., 8.0 mm Hg) to provide pure 43 as a yellow oil (9.0 g, 50% for three steps from dichlorosilane): Rf=0.55 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.63–7.61 (m, 2H), 7.42–7.38 (m, 3H), 5.97–5.84 (m, 1H), 5.06–4.90 (m,2H), 3.95 (s, 1H) 2.93–2.83 (m, 2H), 2.72–2.67 (m, 2H), 2.21–1.97 (m, 4H), 1.18–1.09 (m, 2H), 0.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 141.0, 134.5, 134.1, 129.9, 127.9, 113.2, 32.9, 31.1, 31.0, 27.2, 25.8, 10.8, −7.0; MS (FAB) m/e (rel. intentsity) 293 (MH+, 23), 239 (21), 175 (20), 159 (9), 149 (58), 121 (100), 119 (37), 115 (23), 105 (34), 97 (28), 92 (22); HRMS (FAB) calcd for C15H23S2Si: 293.0854, found: 293.0861. Anal. Calcd for C15H22S2Si: C, 61.16; H, 7.53. Found C, 61.31; H, 7.74.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:8]CC)(=[O:7])[CH3:6].C(C1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:15][CH:14]=1)#N.[OH-].[Na+]>C(O)(=O)C>[C:23]1([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]([C:5]([OH:8])=[O:7])=[CH:14][N:15]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1cnc(-c2ccccc2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(O)c1cnc(-c2ccccc2)c2ccccc12

Procedure:
20.5 g of 1-phenylisoquinoline are dissolved in 100 ml of carbon tetrachloride, and 16 g of bromine are added at room temperature. The temperature is raised slowly and the mixture is kept under reflux for 1 hour. 7.9 g of pyridine in 10 ml of carbon tetrachloride are added dropwise to the boiling reaction mixture in the course of 2 hours, and the mixture is then heated at reflux temperature for a further 18 hours. The reaction solution is decanted off from the resinous precipitate and is concentrated, and the residue is crystallized from diisopropyl ether. 11.7 g of 4-bromo-1-phenylisoquinoline of melting point 123°-125° C. are obtained. 0.7 g of 4-bromo-1-phenylisoquinoline, 0.45 g of copper cyanide and 10 ml of dimethylformamide are heated at 160° C. for 6 hours. The reaction solution is decanted off, diluted with methylene chloride and washed with water. 0.75 g of crude product are isolated from the methylene chloride phase, and 0.2 g of 4-cyano-1-phenylisoquinoline of melting point 138°-140° is obtained from this crude product by column chromatography over silica gel using a 98:2 mixture of chloroform and ethyl acetate. 0.2 g of 4-cyano-1-phenylisoquinoline is heated with 10 ml of 20% strength sodium hydroxide solution at 100° C. for 4 hours. The solution is cooled and acidified with acetic acid. The precipitate is filtered off and dried. 0.18 g of 1-phenylisoquinoline-4-carboxylic acid of melting point 215°-217° is isolated.
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([Cl:24])[C:18]([CH2:22]Br)=[C:19]([Cl:21])[CH:20]=1.Cl>CN(C=O)C.C(OCC)C>[Br:14][C:15]1[CH:16]=[C:17]([Cl:24])[C:18]([CH2:22][N:2]2[CH2:3][CH2:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:1]2=[O:11])=[C:19]([Cl:21])[CH:20]=1
Reactant: Clc1cc(Br)cc(Cl)c1CBr
Reactant: O=C1NCCC12CCCCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1N(Cc2c(Cl)cc(Br)cc2Cl)CCC12CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
Treat a solution of 2-aza-spiro[4.5]decan-1-one (0.138 g, 0.901 mmol) in DMF (5 mL) with 60% sodium hydride (0.054 g, 1.35 mmol) and stir at room temperature for 15 minutes under N2. Cool the reaction to 0° C., treat with 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene (0.316 g, 0.991 mmol), and stir for 15 minutes at 0° C. Warm to room temperature and stir for 2 hours under N2. Acidify the reaction with 1 N HCl. Dilute with diethyl ether and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.258 g (73%) of the titled product. Rf=0.24 (3/1 ethyl acetate/hexanes). MS (m/z): 392 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14]C.F[C:26]1C=C(F)C=C[C:27]=1C(O)(CN1C=NC=N1)C(F)(F)SCCO.CI.C(I)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:24][CH2:26][CH3:27])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([S:11][CH2:12][CH2:13][OH:14])([F:17])[F:16]
Reactant: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CI
Solvent: CCI
Product: CCOC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SCCO

Procedure:
In a similar manner to Example 1 except that 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-methoxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol was replaced with 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-hydroxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol and methyl iodide was replaced with ethyl iodide, the experiment was carried out, whereby 2-{[2-(2,4-difluorophenyl)-2-ethoxy-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propyl]thio}-1-ethanol was obtained as a colorless oil.