Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:31](OCC)(=[O:33])[CH3:32].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[C:31]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]([CH2:22][P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)(=[O:33])[CH3:32]
Reactant: CCOP(=O)(CN(c1ccc2[nH]ccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOP(=O)(CN(c1ccc2c(ccn2C(C)=O)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C

Procedure:
100 mg diethyl {[(3,5-dichloro-phenylsulphonyl)-(1H-indol-5-yl)-amino]-methyl}-phosphonate are dissolved in 1 ml acetic anhydride and refluxed overnight. After cooling to ambient temperature the mixture is divided between ethyl acetate and ice water. Then it is neutralised by the addition of saturated sodium hydrogen carbonate solution. The phases are separated and the organic phase is washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (petroleum ether/ethyl acetate 1:2 to 1:3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:33](=[O:34])[NH:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.8 %

Procedure:
N-[5-(3-Amino-4-chlorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2.0 ml), 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (89 mg, 0.40 mmol) was added, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (63 mg, 33%) as a colorless powder.
Reaction SMILES: N1C=C[CH:4]=[CH:3][C:2]=1[C:7]([C:9]1C=CC=CN=1)=O.CO.[CH3:17][C:18]([OH:20])=[O:19].C(Cl)Cl>>[C:18]([OH:20])(=[O:19])/[CH:17]=[CH:4]/[CH2:3][CH2:2][CH2:7][CH3:9]
Reactant: O=C(c1ccccn1)c1ccccn1
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCCC/C=C/C(=O)O
Yield: 70 %

Procedure:
Prepared as above from 376.4 mg (0.86 mmol) of the (±)-pyridyl ketone and 790.6 mg (1.73 mmol) of the Wittig salt. Preparative HPLC with MeOH-AcOH-CH2Cl2 (4:1:95) gave in ~92% yield a mixture of Wittig product (E/Z=~96:4) from which 320.9 mg (70%) of (±)-(E)-heptenoic acid was isolated cleanly: mp 68°-73° C.; 1H NMR, (CDCl3) δ8.61 (br s, 1H), 8.49 (br s, 1H), 8.28 (s, 1H), 8.06 (d, J=8.1 Hz, 2H), 7.52 (br s, 1H), 7.46 (br d, J=8.0 Hz, 1H), 7.28 (d, 2H), 7.27 (buried, 1H), 6.21 (t, J=7.4 Hz, 1H), 4.04 (dt, J=13.3, 1.9 Hz, 1H), 3.69 (br s, 4H), 3.50 (m, 5H), 2.33 (dd, J=7.1, 6.7 Hz, 2H), 2.21 (ddd, J=7.2, 7.0, 6.7 Hz, 2H), 1.89-1.26 (m, 10H); FDMS 534 (M+1). Anal. (C30H35N3O6.0.25C2H4 O2) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(O[BH-](O[C:24](=[O:26])[CH3:25])OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:6][C:5]2[O:26][C:24]3[C:25](=[N:8][CH:3]=[CH:2][CH:7]=3)[CH:4]=2)[CH2:10][CH2:9]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Fc1ccccc1N1CCNCC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Fc1ccccc1N1CCN(Cc2cc3ncccc3o2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-(2-Fluorophenyl)piperazine (0.18 g, 1.0 mmol) and sodium triacetoxyborohydride (0.32 g, 1.5 mmol) in dichloroethane (2 mL) were treated with the product from Example 35B (2 mL, 1.0 mmol) as a 0.5M solution in dichloroethane dropwise. The mixture was allowed to stir at room temperature for 17 hours. The mixture was diluted with dichloromethane (10 mL) and washed with 1N NaOH. The organic layer was dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica (dichloromethane to 2% methanol in dichloromethane) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 2.81 (br, 4H), 3.19 (br, 4H), 3.85 (s, 2H), 6.89 (s, 1H), 7.00 (m, 4H), 7.20 (dd, J=4.75, 8.14 Hz, 1H), 7.74 (d, J=8.48 Hz, 1H), 8.52 (d, J=4.75 Hz, 1H); MS (DCI/NH3) m/z 312.2 (M+H)+; Anal. Calcd for C18H18FN3O: C, 69.44; H, 5.83; N, 13.50. Found: C, 69.36; H, 5.59; N, 13.28.
Reaction SMILES: C[C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.[CH2:13]([Li])[CH2:14][CH2:15]C.CN1CC(=O)CC2C=CC=C[C:21]=2[O:20]1>O1CCCC1.CCCCCC>[O:20]=[C:21]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:6][C:2]=2[NH:3][C:4](=[O:5])[C:7]2[S:8][CH:9]=[CH:10][C:11]1=2
Reactant: CC1(C)COC(c2cccs2)=N1
Reactant: CN1CC(=O)Cc2ccccc2O1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=c1c2ccccc2[nH]c(=O)c2sccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9.0 g at 4,5-dihydro-4,4-dimethyl-2-(2-thienyl)oxazole in 200 ml of tetrahydrofuran, cooled to -78° C., is added 20 ml of a 2.5 molar solution of n-butyl lithium in hexane. The mixture is stirred -78° C. for 15 minutes and at 0° C. for 30 minutes. To the stirred solution is added 6.0 g of 2-methylbenzoxazepine-4-one. The mixture is stirred at room temperature for 16 hours quenched with ice cold water and extracted with chloroform. The extract is concentrated to dryness and 100 ml of 40% H2SO4 is added. The mixture is refluxed for 4 hours, cooled to room temperature and filtered to give 9,10-dihydro-4,10-dioxo-4H-thieno [2,3-c][1]benzazepine. The solid is washed with water to give 2.5 g of crystals. The solid is dissolved in 100 ml of dry tetrahydrofuran and 1.0 g of lithium aluminum hydride added. The mixture is refluxed for 16 hours, chilled and ice cold water is added dropwise. The mixture after dilution with water is extracted with chloroform-methanol (3:1) and the extract dried (MgSO4). The solvent is removed and the residue chromatographed over silica gel with ethyl acetate-hexane (1:1) as solvent to give 1.8 g of solid; Mass spectrum (CI) 202 (M+H).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCCCCC.[OH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]=1[NH2:24]>CO.C1(C)C=CC=CC=1>[CH3:1][O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([OH:14])[C:16]=1[NH2:24]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1c(O)cccc1C(=O)O
Solvent: CCCCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(O)c1N
Reaction time: 16 h

Procedure:
A solution of (trimethylsilyl)diazomethane in hexane (2.0 M, 10.9 mmol) is added dropwise (10 min) to a mixture of 3-hydroxyanthranilic acid (9.93 mmol) in MeOH (10.5 mL) and toluene (42 mL). The mixture is stirred for 16 h, concentrated in vacuo, diluted with ether and EtOAc and washed several times with water. The organic layer is dried over MgSO4 and concentrated under reduced pressure. The residue is purified by FC (heptane to heptane/EtOAc 7/3) to give the desired ester as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:16]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:17]([C:30](ON1C(=O)CCC1=O)=[O:31])[CH2:18][CH2:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(CC)CC.CO>CN(C=O)C>[NH:16]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@H:17]([C:30]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:31])[CH2:18][CH2:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(=O)O

Procedure:
Boc-Val-Val-OH (40.5 g, 128 mmol) was treated with 1.8 l of 4N HCl in THF for 60 minutes. Evaporation to remove excess acid and solvent followed by treatment with ether provided 34.5 g of HCl.H-Val-Val-OH as a white amorphous powder. It was treated with Boc-Glu(OBzl)-OSu (55.6 g, 128 mmol) in 1 liter DMF for 24 hours in the presence of 54 ml Et3N. The reaction mixture was filtered to remove some insoluble material and the filtrate evaporated to dryness. The remaining oily residue was taken up in EtOAc (1.5 l) and washed with 5% HOAc (2×) followed by water (3×). The organic layer was dried (Na2SO4) and evaporated to dryness to give a colorless clear oil which did not crystallize. It was thus dissolved in 3.2 l of ether and treated with cyclohexylamine (CHA) (17 ml) until the pH (moist pH paper) of the mixture was 7.5. The solid salt obtained was collected and recrystallized from MeOH and ether: Yield, 58.9 g (72.7%); mp 158°-;60°; [α]D25 = -33.41° (c 1, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:22]([O-])=O)[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=2)=[N:6][CH:7]=1.[C:25](OCC)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[N:22]=[CH:25][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH:10]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(CN2CCOCC2)c1
Product: Brc1cnc2c(c1)ncn2-c1cccc(CN2CCOCC2)c1

Procedure:
6-Bromo-3-[3-(morpholin-4-ylmethyl)phenyl]-3H-imidazo[4,5-b]pyridine was prepared from N-(5-bromo-3-nitropyridin-2-yl)-N-[3-(morpholin-4-ylmethyl)phenyl]amine as described in Example 1. Maleate salt, cream-coloured powder, m.p. 176-178° C. (from ethyl acetate); δH (400 MHz, d6-DMSO @ 340K) 2.64-2.68 (4H, m), 3.68-3.72 (4H, m), 4.00 (2H, s), 6.13 (2H, s), 7.51 (1H, d, J 8), 7.64 (1H, t, J 8), 7.89 (1H, d, J 8), 7.94 (1H, s), 8.47 (1H, d, J 2), 8.52 (1H, d, J 2), 8.89 (1H, s); m/z (ES+) 373 and 375 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])=[C:9]([Br:24])[C:8]2=[O:25])=[CH:4][CH:3]=1.CN1CCOCC1.[C:35]([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=[O:37])[CH3:36].CN=C=O>ClCCl>[C:35]([O:38][CH:39]([CH3:43])[C:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])=[C:9]([Br:24])[C:8]2=[O:25])=[CH:26][CH:27]=1)=[O:41])(=[O:37])[CH3:36]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(N)cc1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: CN=C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)OC(C)C(=O)Nc1ccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added compound of Example 611 (0.300 g, 0.69 mmol) and dichloromethane (3.0 mL). A stock solution of N-methylmorpholine (0.30 M, 3.0 mL) was added and the parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 10 minutes. (S)-(−)-2-Acetoxypropionyl chloride (0.131 mL, 1.04 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature for 1.5 hours. At this time the reaction was diluted with dichloromethane (20 mL) and treated with approximately 2.1 g of polyamine resin (2.63 mmol/g) and approximately 3.8 g of methylisocyanate fucntionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature overnight. The reaction vessel was then opened and the solution Phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with dichloromethane (2×10 mL). The filtrate was evaporated by blowing N2 over the vial to afford an off-white solid (0.375 g, 99%). 1H NMR (400 MHz, DMF-d6) δ 10.14 (s, 1H), 7.75 (app dt, J=6.98, 8.59 Hz, 1H), 7.67-7.64 (m, 2H), 7.30 (ddd, J=2.55, 9.26, 11.81 Hz, 1H), 7.21-7.17 (m, 3H), 6.61 (s, 1H), 5.37 (s, 4H), 5.11 (q, J=6.85 Hz, 1H), 2.40 (s, 3H), 2.10 (s, 3H), 1.46 (d, J=6.85 Hz, 3H). ES-HRMS m/z 549.0790 (M+H calcd for C25H23BrF2N2O5 requires 549.0831).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:26][C@H:25]([O:27][CH3:28])[C@H:24]([O:29][CH3:30])[CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O>O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][C@H:24]([O:29][CH3:30])[C@H:25]([O:27][CH3:28])[CH2:26]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CO[C@H]1CN(c2cccc(Cc3ccccc3)n2)C[C@H]1OC
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC
Reaction time: 8 h
Yield: 89.4 %

Procedure:
708 mg of N-iodosuccinimide was added little by little to a mixture of 783 mg of 2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)pyridine and 7.0 ml of N,N-dimethylformamide under ice-cooling, followed by stirring overnight as it was. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with sodium thiosulfate, water and brine, and the solvent was removed. Then, the residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (5:1) and then with hexane/ethyl acetate (3:1), to give 995 mg of the target compound.
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11](S(C)=O)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.FC(F)(F)C(O)=O>C(#N)C>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[CH:23][CH:24]=3)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NCc2cnc(S(C)=O)nc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)N1C(=O)NCc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 85 °C
Yield: 78.5 %

Procedure:
Prepared from 400 mg (1.57 mmol) of 1-isopropyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 600 mg (3.14 mmol) of 1-(4-aminophenyl)-4-methylpiperazine and 605 μL (7.85 mmol) of trifluoroacetic acid in 6.4 mL of acetonitrile. The reaction mixture is heated at 85° C. for 48 hours. After the workup, the crude residue is triturated in ethyl acetate/dichloromethane and filtered. The solids are redissolved in dichloromethane, and the solvent is evaporated under a flow of nitrogen while ethyl acetate is added to maintain a volume of 5 mL. The suspension is filtered, and the solids are washed with ethyl acetate/dichloromethane, and dried to give 470 mg (78%) of the title compound:
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([C:6]#[N:7])=[O:5].[H][H].[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C.O=[Pt]=O>[C:15]([NH:7][CH2:6][C:4]([C:3]1[CH:8]=[CH:9][CH:10]=[C:11]([Cl:12])[C:2]=1[Cl:1])=[O:5])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Reactant: N#CC(=O)c1cccc(Cl)c1Cl
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(=O)NCC(=O)c1cccc(Cl)c1Cl

Procedure:
150 g of 2,3-dichlorobenzoyl cyanide are hydrogenated with elemental hydrogen under normal pressure at 70° C. in 1.5 l of glacial acetic acid and 84.15 g of acetic anhydride over 5 g of PtO2. After absorption of 112% of the calculated amount of hydrogen (time taken: c. 5 hours), the hydrogenation is discontinued, the reaction mixture is filtered and the filtrae is concentrated by evaporation. The residual yellow oil is crystallised by addition of hexane/diethyl ether. The crystalline product is isolated by filtration and dried. M.p. 107°-109° C. IR (solid/KBr) in cm-1 : 3300 (NH); 1735 (CO); 1650 (CO). 1H-NMR (CDCl3) in ppm: 2.08 (s, 3H); 4.55 (d, 2H); 6.2-6.6 (broad s, 1H); 7.25 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH:7]1([N+:13]#[C-:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O>Cl(O)(=O)(=O)=O>[CH:7]1([NH:13][C:14]2[N:3]3[NH:4][CH:5]=[N:6][C:2]3=[N:1][C:21]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=Cc1ccccn1
Reactant: Nc1nc[nH]n1
Reactant: [C-]#[N+]C1CCCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Product: c1ccc(-c2nc3nc[nH]n3c2NC2CCCCC2)nc1

Procedure:
Compound 11 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) cyclohexylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-pyridinecarbaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][N:26]3[CH3:32])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:32][N:26]1[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CC(C)(C)C[C@H]1c1nnc2ccc(F)cn12
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CC(C)(C)C[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of Intermediate A (552 mg, 3.89 mmol) in DMF (25 mL) was added NaH (60% in oil, 338 mg, 8.46 mmol) and the mixture stirred at RT for 20 min, before Intermediate 87c (700 mg, 2.82 mmol) was added. This mixture was stirred at 60° C. for 1 h. The cooled reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% (2M NH3 in MeOH) in DCM gave the title compound (820 mg, 74%). LCMS (Method 4): Rt 1.53 min, m/z 392 [MH+].
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:10].C(C1C=C(C=C(C)C=1O)[C:16]#[N:17])C>>[OH:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([C:16]#[N:17])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: COc1cccc(C)c1O
Product: COc1cc(C#N)cc(C)c1O

Procedure:
The title compound is prepared from commercially available 2-hydroxy-3-methoxy-toluene in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile); LC-MS: tR=0.84 min. 1H NMR (CDCl3): δ2.27 (s, 3H), 3.93 (s, 3H), 6.24 (s, 1H), 6.97 (d, J=1.3 Hz, 1H), 7.12 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[O:12][C:13]([F:16])([F:15])[F:14].CC(C[AlH]CC(C)C)C.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:12][C:13]([F:14])([F:16])[F:15]
Reactant: COC(=O)c1ccc(Br)c(OC(F)(F)F)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Br)c(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled and stirred solution of methyl 4-bromo-3-(trifluoromethoxy)benzoate (28.2, 2.60 g, 8.70 mmol) in THF (20 mL) under nitrogen, was added DIBAL-H (19.2 mL, 1.0 M in toluene) at −78° C. The reaction mixture was stirred at 0° C. for 10 minutes and 5.0 mL of water was added. The resulting mixture was stirred at room temperature for 2 hours. The solid was then filtered off. EtOAc (100 mL) was added, and the mixture was washed with brine (20 mL) and dried with Na2SO4. The solvent was removed to give 28.3. 1H NMR (CDCl3) δ 1.91 (s, 1H), 4.71 (s, 2 H), 7.18 (d, J=6.3 Hz, 1H), 7.36 (s, 1H), 7.63 (d, J=6.3 Hz, 1 H).
Reaction SMILES: [CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[S:15])[NH:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1.[H-].[Na+].IC.[CH2:25](O)C>CN(C)C=O>[CH:1]1([N:4]2[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([S:15][CH3:25])=[N:7][C:6]3[C:16]([CH3:20])=[CH:17][CH:18]=[N:19][C:5]2=3)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: Cc1ccnc2c1NC(=S)c1cccnc1N2C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSC1=Nc2c(C)ccnc2N(C2CC2)c2ncccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a warm (40° C.) solution of 1.0 g (3.54 mmol) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-thione in 25 mL of dry dimethylformamide under argon was added 200 mg (4.43 mmol) of a 60% sodium hydride on mineral oil dispersion. The suspension was heated at 60° for 30 min., cooled to 40° C., and 0.3 mL (4.43 mmol) of iodomethane was added in one portion. After stirring the mixture for 1 hr at room temperature, ethanol was added dropwise until bubbling ceased. The mixture was then poured over 200 mL of water, and the product was extracted with 2×200 mL of ethyl ether. The combined organics were washed with 300 mL of water, dried (Na2SO4), and concentrated. The resulting reddish solid was flash chromatographed over silica gel (eluted with 83% methylene chloride/ethyl acetate) to give a yellow solid. Recrystallization from ethyl ether/petroleum ether gave 350 mg of the title compound, m.p. 173°-177° C.
Reaction SMILES: C[S:2][C:3](=[S:25])[NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:14]([F:24])[CH:13]=2)[CH2:7]1.Cl[C:27]1[N:36]=[C:35]2[C:30]([C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33][N:34]2[CH:37]2[CH2:39][CH2:38]2)=[CH:29][C:28]=1[F:44].[CH3:45][Si](C)(C)Cl>C(#N)C>[CH:37]1([N:34]2[C:35]3[C:30](=[CH:29][C:28]([F:44])=[C:27]([N:21]4[CH2:20][CH2:19][N:18]([C:15]5[CH:16]=[CH:17][C:12]([N:8]6[CH2:7][C@@H:6]([CH:5]([CH3:45])[NH:4][C:3]([SH:2])=[S:25])[O:10][C:9]6=[O:11])=[CH:13][C:14]=5[F:24])[CH2:23][CH2:22]4)[N:36]=3)[C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33]2)[CH2:39][CH2:38]1
Reactant: C[Si](C)(C)Cl
Reactant: CSC(=S)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Product: CC(NC(=S)S)[C@@H]1CN(c2ccc(N3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
A mixture of 100 mg [(5S)-3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-dithiocarbamic acid methyl ester (0.26 mmol), 73,51 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.26 mmol) 108 μl triethylamine (0.78 mmol) and 65 μl trimethyl-chlorsilane (0.52 mmol), in acetonitrile was stirred in a micro wave oven for 8 min at 150° C. The solution was decanted from sticky solid, evaporated and the residue digested in water. The solid was filtered and the purified by chromatography using a 9/1 dichloromethane/methanol mixture with 1% acetic acid.