Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:48][C:43]2=[CH:44][N:45]=[CH:46][CH:47]=[C:42]2[CH:41]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[S:48][C:43]4=[CH:44][N:45]=[CH:46][CH:47]=[C:42]4[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccncc2s1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc3ccncc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (53 mg, 0.106 mmol), 2-(tributylstannyl)thieno[2,3-c]pyridine (44.9 mg, 0.106 mmol) and tetrakis(triphenylphosphine) palladium(0) (122 mg, 0.106 mmol) in toluene (3 mL) was heated to 120° C. in a microwave for 60 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined and dried over Na2SO4, and the solvent was removed in vacuo to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-3-oxo-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dispersed in TFA and DCM (10 mL). The mixture was stirred at room temperature for 60 minutes and then concentrated. The resulting crude material was reconstituted in MeOH and DCM (10.0 mL) and purified via preparative HPLC, eluting with a gradient of 10-25% ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined and dried over Na2SO4, and the solvent was removed in vacuo to give the title compound (5.8 mg, 14%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.83 (d, J=8.79 Hz, 1H), 2.10-2.27 (m, 1H), 3.81-3.92 (m, 2H), 3.98-4.16 (m, 3H), 4.34-4.48 (m, 1H), 4.52 (br s, 2H), 7.55 (d, J=5.37 Hz, 1H), 7.97-8.08 (m, 3H), 8.53 (br s, 1H), 8.75 (s, 1H), 9.34 (br s, 1H), 9.53 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H18FN5O2S, 400. found, 400.
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH:7][C:8](=O)[CH2:9][NH:10][C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH:20]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:21]([F:24])([F:23])[F:22])=[CH:14][C:13]=2[CH3:33])=[O:5])[CH2:3][CH2:2]1>O=P(Cl)(Cl)Cl>[CH:1]1([C:4]2[O:5][C:8]([CH2:9][NH:10][C:11](=[O:34])[C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH:20]([C:25]4[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=4)[C:21]([F:22])([F:24])[F:23])=[CH:14][C:13]=3[CH3:33])=[N:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NNC(=O)C1CC1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCc1nnc(C2CC2)o1
Temperature: 50 °C

Procedure:
A solution of (E)-N-(2-(2-(cyclopropanecarbonyl)hydrazinyl)-2-oxoethyl)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzamide (200 mg, 0.379 mmol) in POCl3 (2.0 mL) was stirred at ambient temperature for 10 min, then the resultant reaction mixture was heated to 50° C. for 1 h. The reaction mixture was quenched with ice water at 0° C. and extracted with ethyl acetate. The combined ethyl acetate layer was washed with saturated NaHCO3 solution and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 50% ethyl acetate/pet ether) afforded the title compound as a light brown gummy material (70.0 mg, 36%): 1H NMR (400 MHz, CDCl3) δ 7.43 (m, 2H), 7.27 (m, 2H), 7.23 (m, 2H), 6.58 (d, J=16.0 Hz, 1H), 6.41 (dd, J=16.0, 7.6 Hz, 1H), 4.79 (d, J=5.6 Hz, 2H), 4.14 (m, 1H), 2.48 (s, 3H), 2.18 (m, 1H), 1.16 (m, 4H); ESIMS m/z 509.89 ([M+H]+); IR (thin film) 1666, 1166, 1112, 800 cm−1.
Reaction SMILES: C([Li])CCC.CN(CCN(C)C)C.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[C:20]([C:23]1[S:27][C:26]([CH3:28])=[N:25][C:24]=1[CH3:29])(=[O:22])[CH3:21]>C(OCC)C>[CH3:28][C:26]1[S:27][C:23]([C:20]([C:16]2[N:15]([CH3:14])[CH:19]=[CH:18][CH:17]=2)([OH:22])[CH3:21])=[C:24]([CH3:29])[N:25]=1
Reactant: CC(=O)c1sc(C)nc1C
Reactant: Cn1cccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1nc(C)c(C(C)(O)c2cccn2C)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 20 ml) in dry diethyl ether was cooled to -70° C. under dry nitrogen and TMEDA (5.8 g) was added. After 5 minutes, 1-methylpyrrole (5.4 g) in diethyl ether was added dropwise. After a further 15 minutes, 5-acetyl-2,4-dimethylthiazole (4.5 ml) was added dropwise. After 30 minutes the mixture was allowed to warm to room temperature and was then worked up in the usual fashion.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:21][CH2:20][CH:19]3[CH:14]([CH:15]([NH:22]C(=O)OC(C)(C)C)[CH2:16][CH2:17][CH2:18]3)[CH2:13]2)=O)=[CH:4][CH:3]=1.B.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:12]2[CH2:21][CH2:20][CH:19]3[CH:14]([CH:15]([NH2:22])[CH2:16][CH2:17][CH2:18]3)[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC2CCN(C(=O)CCc3ccc(F)cc3)CC21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NC1CCCC2CCN(CCCc3ccc(F)cc3)CC12
Temperature: 25 °C
Yield: 95.6 %

Procedure:
A solution of tert-butyl {(4aSR,8SR,8aRS)-2-[3-(4-fluorophenyl)propanoyl]decahydroisoquinolin-8-yl}carbamate (220 mg, 544 μmol) in tetrahydrofuran (5 mL) was treated with a solution of borane in tetrahydrofuran (1.0 M; 1.0 mL, 1.0 mmol) and the mixture was heated at reflux for 3 hours. The mixture was cooled and treated with 1.0 N aqueous hydrochloric acid and then heated at reflux for 2 hours. The mixture was cooled again to room temperature and concentrated to provide a white solid. The white solid was partitioned between ethyl acetate and 2.0 N aqueous sodium hydroxide. The organic phase was separated, dried over magnesium sulfate and concentrated to provide a colorless oil (151 mg, 95%). 1H NMR (300 MHz, CDCl3) δ7.05 (m, 2H), 6.87 (m, 2H), 3.57 (t, J=6 Hz, 2H), 3.51 (t, J=7 Hz, 2H), 3.20 (m, 1H), 2.86 (m, 1H), 2.51 (m, 2H), 2.44 (broad s, 2H), 2.4-2.2 (m, 2H), 1.8-1.4 (m, 7H), 1.3-0.8 (m, 3H). Mass spec (ES+) m/z 291.3 (M+H+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I.Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]([CH3:31])[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nc4ccccc4[nH]3)c2)CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of 4-[3-(1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.83 g, 2.20 mmol) (obtained as described in method B) and NaH 60% oil (0.11 g, 4.39 mmol) in THF (10 mL) was stirred at room temperature for 1 h. Methyl iodide (0.27 mL, 4.39 mmol) was added and the resulting solution was stirred overnight. Water (15 mL) was added to the reaction solution, then the suspension was neutralized with 1N HCl and extracted with EtOAc (3×40 mL) The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was triturated with Et2O and the solid obtained filtered, to give 0.76 g (88%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][CH3:16])=[O:14])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: CNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCCN
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(NCCCN(C)C)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 98.6 %

Procedure:
N,N-Dimethy-1,3-propanediamine (1.39 g) was added to 4-chloro-N-methyl-3-nitrobenzamide (1.46 g) and the mixture was stirred for 5 hours at 120° C. The reaction mixture, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (1.88 g) as yellow solid.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:48]1[C:49]([C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([N+:70]([O-:72])=[O:71])[CH:65]=2)=[C:50]([CH3:63])[C:51]([C:61]#[N:62])=[C:52]2[C:56]=1[O:55][C:54]([C:57]([CH3:60])([CH3:59])[CH3:58])=[N:53]2.[CH3:73][N:74]([CH3:80])[C@H:75]1[CH2:79][CH2:78][NH:77][CH2:76]1.CC(C)([O-])C.[Na+].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:57]([C:54]1[O:55][C:56]2[C:52](=[C:51]([C:61]#[N:62])[C:50]([CH3:63])=[C:49]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([N+:70]([O-:72])=[O:71])[CH:65]=3)[C:48]=2[N:77]2[CH2:78][CH2:79][C@H:75]([N:74]([CH3:80])[CH3:73])[CH2:76]2)[N:53]=1)([CH3:60])([CH3:59])[CH3:58]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2cccc([N+](=O)[O-])c2)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cccc([N+](=O)[O-])c2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (180 mg, 0.29 mmol) was dissolved in toluene (8 ml) under heat, cooled to room temperature, then palladium(II) acetate (43 mg, 0.193 mmol) was added, followed by stirring for 5 minutes. 7-Bromo-2-tert-butyl-5-methyl-6-(3-nitrophenyl)-1,3-benzoxazole-4-carbonitrile (I-18) (400 mg, 0.966 mmol), (3S)-3-(dimethylamino)pyrrolidine (306 μl, 2.42 mmol), sodium tert-butoxide (260 mg, 2.71 mmol), toluene (5 ml) were successively put into it, followed by stirring at 80° C. for 13 hours. After cooling, brine (10 ml), saturated sodium bicarbonate water (25 ml) were added to the reaction liquid, the product was extracted with chloroform (25 ml×2). The organic layer was washed with saturated brine (10 ml×2), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified twice by silica gel column chromatography (chloroform:methanol=100:1) to obtain a fraction containing the entitled compound (35.1 mg) as a dark brown solid. Not further purified, this was used in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cncc(Br)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cncc(Br)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 5-bromopyridin-3-ylmethanol (Chem. Pharmo Bull. 1990, 38, 2446) (29 g, 154 mmoL) and tert-butylchlorodiphenylsilane (47.5 g, 173 mmoL) in CH2Cl2 (500 mL) at r.t., there was added imidazole (15.8 g, 232 mmoL). The mixture was stirred for 1 hr. and filtered. The filtrate was evaporated and the residue chromatographed on silica gel eluting with a 1:7 mixture of EtOAc and hexane, to afford the product as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:24][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:26]=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methylbenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:15](=O)[CH3:16])[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH2:15]([NH:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:18])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[CH3:16]
Reactant: CC(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Yield: 85 %

Procedure:
A solution of N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (1.5 g, 6.1 mmole) in 8 mL THF was treated with 2.5 mL of lithium aluminium hydride solution (1M in THF). The reaction mixture was heated to reflux for 3.5 hours. The mixture was cooled to 0° C. and treated with 0.95 mL water, 0.95 mL 15% aqueous sodium hydroxide solution and 3.0 mL water. The mixture was stirred at room temperature until a white precipitate formed. MgSO4 was added, the mixture was filtered and concentrated in vacuo, giving a pale yellow oil. The product was purified by flash chromatography (SiO2, 15% ethyl acetate/hexanes), yielding 1.2 g (86%) of N-ethyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amine, as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:12])[CH3:2].[OH-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:15]1([S:21]([OH:23])(=[O:3])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH:12][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCOc1cccc(C=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(O)c1ccccc1
Temperature: 75 °C
Yield: 98 %

Procedure:
3-Ethoxysalicylaldehyde (498 g, 3 moles) and sodium hydroxide (140 g, 3.5 moles) in 1.5 liters of water are introduced into a 4 liter reactor provided with mechanical stirring, a condenser and a nitrogen inlet. The mixture is taken to 60° C. and benzenesulphonyl chloride is added dropwise over three-quarters of an hour. The mixture is heated to 75° C. for a quarter of an hour. It is cooled. An oil forms which crystallizes with time. It is filtered, washed with water and dried. The 2-hydroxy-3-ethoxybenzaldehyde benzenesulphonate (901 g, yield=98%) is used for the following stage. It can be recrystallized from 90:10 acetic acid/water. A white powder is obtained, m.p.=68°-69° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>ClCCl.CO>[CH3:16][C:2]([CH3:1])([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([C:13]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[O:15])[CH2:11][CH2:12]1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Yield: 76 %

Procedure:
Prepared analogously to Example A15a) from 1-(1,1-dimethylethoxycarbonyl)-4-piperidinecarboxylic acid and 1-methylpiperazine in the presence of TBTU in a yield of 76% of theory. Colourless, amorphous substance, Rf=0.64 (eluant: dichloromethane/methanol/conc. ammonia 50/50/1 v/v/v).
Reaction SMILES: [Br-].[CH3:2]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Br:32][C:33]1[CH:34]=[C:35]([CH:39]=O)[CH:36]=[N:37][CH:38]=1>O1CCCC1>[Br:32][C:33]1[CH:38]=[N:37][CH:36]=[C:35]([CH:39]=[CH2:2])[CH:34]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Br-]
Agent: [Na]
Solvent: C1CCOC1
Product: C=Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyltriphenylphosphine bromide (3.16 g, 8.87 mmol) in tetrahydrofuran (20 mL) is added sodium hexamethyldisilazane (1M solution in THF, 9.67 mL, 9.67 mmol) dropwise. The reaction mixture is stirred at room temperature for 30 min, whereupon 5-bromo-pyridine-3-carbaldehyde (1.5 g, 8.06 mmol) is added. The reaction mixture is allowed to stir at room temperature for 1 h. The mixture is concentrated and the residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 7:3) to afford 3-bromo-5-vinyl-pyridine as a colorless oil. MS (ESI) m/z 185.91 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:36]=[CH:35][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:25][C:26]=3[CH3:27])=[C:18]([O:37][CH3:38])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:39]([P:48](=[O:55])([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:53]([O:52][P:48](/[CH:39]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:36]=[CH:35][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:25][C:26]=3[CH3:27])=[C:18]([O:37][CH3:38])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)([O:49][CH2:50][CH3:51])=[O:55])[CH3:54]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3C=O)cc2OC)c(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3/C=C/P(=O)(OCC)OCC)cc2OC)c(C)o1
Reaction time: 2 h
Yield: 69.5 %

Procedure:
To a mixture of ethyl (2E)-3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (0.80 g), tetraethyl methylenediphosphonate (0.49 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.07 g) at room temperature, and the mixture was stirred at the same temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl (2E)-3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-propenoate as colorless crystals (0.70 g, yield 71%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 130-131° C.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:17])[CH3:16])=O>>[CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[Cl:1])([CH3:17])[CH3:16]
Reactant: CC(C)c1ccccc1OC(=O)Cl
Reactant: [Cl-]
Agent: [Al+3]
Product: CC(C)c1ccccc1Cl
Temperature: 200 °C
Yield: 20 %

Procedure:
0.35 g of anhydrous aluminium chloride was added to 25 g of 2-isopropylphenyl chloroformate and the mixture was heated at 200° C. for 3 hours at normal pressure. The reaction mixture was cooled and worked up as described in Example 1. 2-Isopropylchlorobenzene was obtained in a yield of 20%, which is considerable despite the unfavourable substitution pattern.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:38](=[O:39])[N:30]2[CH:31]([C:35]([O-:37])=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].Cl.[O:41]=[C:42]1[NH:47][CH2:46][CH2:45][N:44]([C:48](=[NH:51])[CH2:49][SH:50])[CH2:43]1>C(#N)C.O1CCCC1.P([O-])([O-])([O-])=O.[C].[Pd]>[O:41]=[C:42]1[NH:47][CH2:46][CH2:45][N:44]([C:48](=[NH:51])[CH2:49][S:50][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:38](=[O:39])[N:30]3[C:31]=2[C:35]([OH:37])=[O:36])[CH2:43]1
Reactant: N=C(CS)N1CCNC(=O)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])C(=O)C[C@H]12
Agent: [Pd]
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CCNC(=O)C3)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
1.62 ml of diisopropylethylamine and 1.92 ml of diphenylphosphoryl chloride were added dropwise to an ice-cooled solution of 3.0 g of (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate in 36 ml of anhydrous acetonitrile, and the mixture was stirred for one hour with ice-cooling. The reaction mixture was then added to an ice-cooled mixture of 1.86 ml of diisopropylethylamine in 180 ml of tetrahydrofuran and 160 ml of 0.1M phosphate buffer solution (pH 7.0), together with 20 ml of an aqueous solution of 2.79 g of 2-(3-oxopiperazin-1-yl)-2-iminoethylmercaptan hydrochloride, and the resulting mixture was stirred for 50 minutes. The reaction mixture was then subjected to hydrogenation at room temperature for 2.5 hours, in the presence of 3.0 g of 10% palladium-carbon. The hydrogenated mixture was filtered over "Celite" (Trade Mark) filter aid, and the filtrate was extracted with 200 ml of ether. The aqueous layer was concentrated under reduced pressure, and the concentrate was subjected to chromatography through a 250 ml column of "Dowex 50W" (Trade Mark) cation exchange resin (Na+ type), giving 850 mg of the title product from the fraction eluted with water.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([Cl:21])=[C:13]2[Cl:22])[C:7](=[O:11])[N:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C>[Cl:22][C:13]1[N:12]([C:6]2[C:7](=[O:11])[N:8]([CH3:10])[N:9]=[C:4]([CH:1]([OH:3])[CH3:2])[C:5]=2[O:23][CH3:24])[C:20]2[C:15]([C:14]=1[Cl:21])=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: COc1c(C(C)=O)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1c(C(C)O)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
To a stirred solution of 6-acetyl-4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-pyridazin-3-one (500 mg, 1.37 mmol) in ethanol (1 mL) at 0° C. is added sodium borohydride (79 mg, 2.05 mmol). After stirring for 20 min, the reaction is quenched with water (10 mL), then concentrated under reduced pressure to remove most of the ethanol. The aqueous solution is then extracted with Et2O (20 mL×2), then concentrated under reduced pressure to give the desired product 4-(2,3-dichloroindol-1-yl)-6-(1-hydroxyethyl)-5-methoxy-2-methyl-pyridazin-3-one (379 mg, 1.03 mmol, 75%) as a white solid.