Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([S:15]([C:18]2[CH:19]=[C:20]([S:23](Cl)(=[O:25])=[O:24])[S:21][CH:22]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:20]1[S:21][CH:22]=[C:18]([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)c2ccccc2)cs1
Product: Cc1noc(NS(=O)(=O)c2cc(S(=O)(=O)c3ccccc3)cs2)c1Br
Yield: 26 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-4-(benzenesulfonyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 4-benzenesulfonylthiophene-2-sulphonyl chloride in 26% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 181-184° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C(OO)(=[O:21])C>>[CH3:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N+:7]([O-:21])=[CH:6][C:5]=2[N:14]=1
Reactant: Cc1nc2cnc3cccnc3c2n1CC(C)C
Reactant: CC(=O)OO
Product: Cc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)C

Procedure:
In one aspect, the invention provides a method for making 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine. The method includes: providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in a carrier including toluene; combining the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst and isopropanol to form a mixture; subjecting the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; removing at least a portion of the hydrogenation catalyst from the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; removing at least a portion of the isopropanol from the mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier that includes toluene and isopropanol; heating the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier to a temperature of 20° C. to 55° C.; combining the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier with p-toluenesulfonic acid to form a mixture; combining the mixture that includes the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and p-toluenesulfonic acid with a trialkyl orthoacetate at a temperature of 70° C. to 100° C.; maintaining the temperature at 70° C. to 100° C. for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine; cooling the mixture that includes 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine to a temperature of 45° C. to 55° C.; combining the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent including peracetic acid to form a mixture; maintaining the mixture that includes the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine and peracetic acid at a temperature of 45° C. to 55° C. for a time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and isolating at least a portion of the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.
Reaction SMILES: [C:1]12([C:7]3[C:8]([O:12][C:13]4[N:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[C@:21]([CH3:25])([CH2:23][CH3:24])[NH2:22])=[CH:15][CH:14]=4)=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4]1)[CH2:3][CH2:2]2.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:23]([C@@:21]1([CH3:25])[NH:22][C:28](=[O:30])[N:19]([C:16]2[CH:17]=[N:18][C:13]([O:12][C:8]3[C:7]4[C:1]5([CH2:4][O:5][C:6]=4[CH:11]=[CH:10][CH:9]=3)[CH2:2][CH2:3]5)=[CH:14][CH:15]=2)[C:20]1=[O:26])[CH3:24]
Reactant: CC[C@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@@]1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)CO4)nc2)C1=O
Reaction time: 3 h

Procedure:
To a solution of N1-[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]-D-isovalinamide (Intermediate 93, 68 mg) and TEA (0.134 mL, 0.962 mmol) in dry dichloromethane (11 ml) at 0° C. was added dropwise a solution of triphosgene (25.7 mg, 0.087 mmol) in dry dichloromethane (3.14 m) and the mixture thus obtained was stirred at the same temperature. After 1 hour a solution of triphosgene (25.7 mg, 0.087 mmol) in dry dichloromethane (3.14 ml) was added. After 3 hours UPLC/MS showed the absence of the starting material and the presence of the desired compound. Water was then added, the organic phase was separated and the aqueous one was extracted again with dichloromethane. The organic phase was washed with brine, dried over sodium sulphate and concentrated under vacuum to give 87 mg of crude. This was purified by flash chromatography (Biotage KP-Sil 10 g SNAP column, eluant cyclohexane/ethyl acetate from 88/12 to 0/100 in 10CV) to give 47 mg of the title compound as a white foam.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[K+].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=1>C1OCCOCCOCCOCCOCCOC1>[CH3:1][C:2]1[N:3]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Product: Cc1cc2ccccc2n1Cc1ccc(C(=O)O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 2-methylindole (7.60 mmol, 1.00 g) was added 18-crown-6 (60 mg, 0.06 mmol) and subsequently powdered KOH (416 mg, 7.60 mmol) and methyl 4-(bromomethyl)benzoate (1 eq). The reaction was heated to 100° C. for 2 hr, and was added additional KOH (416 mg, 7.60 mmol). The reaction was stirred for another 1 hr. The reaction was cooled and then quenched with HCl and extracted with EtOAc (2×100 mL). The organic layers were collected, dried and concentrated in vacuo. The crude was flashed to yield the desired acid (798 mg, 40%). MS found: (M+H)+=274.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24](O)=[O:25])=[C:5]([O:27][CH3:28])[CH:4]=1)#[N:2].C(N1C=CN=C1)([N:31]1C=CN=C1)=O.N>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[C:14]([CH3:22])[CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([NH2:31])=[O:25])=[C:5]([O:27][CH3:28])[CH:4]=1)#[N:2]
Reactant: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C(=O)O)=C(C)N2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CCOC(C)=O
Product: CCOc1ncc(C)c2c1C(c1ccc(C#N)cc1OC)C(C(N)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.46 g (3.84 mmol) of the compound from Example 30A are introduced into 50 ml of ethyl acetate and, after addition of 777 mg (4.79 mmol) of 1,1′-carbonyldiimidazole, stirred at room temperature overnight. A TLC check (silica gel; mobile phase: ethyl acetate) shows complete conversion. The volatile components are removed in a rotary evaporator, and the residue is taken up in 20 ml of DMF. Then 10.74 ml of ammonia (28% by weight solution in water, 76.8 mmol) are added, and the reaction mixture is heated at 100° C. for 30 min. The solvent is distilled out under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). The residue after concentration of the product fractions is dissolved in 40 ml of dichloromethane/methanol (1:1 v/v) and mixed with 100 ml of ethyl acetate. The solvent is concentrated to a volume of about 20 ml, whereupon the product crystallizes. The precipitate is filtered off and washed with a little diethyl ether. Drying at 40° C. in a vacuum drying oven results in 1.40 g (96% of theory) of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:8]=[C:9]([C:24]2[CH:25]=[N:26][N:27]([CH2:29][C@@H:30]([C:32]([OH:34])=[O:33])[NH2:31])[CH:28]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:12]=1.[C:35](=O)(O)[O-].[Na+]>CO>[CH3:6][C:7]1[CH:8]=[C:9]([C:24]2[CH:25]=[N:26][N:27]([CH2:29][C@@H:30]([C:32]([O:34][CH3:35])=[O:33])[NH2:31])[CH:28]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=2)[CH:12]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C[C@H](N)C(=O)O)c2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](N)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 70 °C

Procedure:
Concentrated sulfuric acid (16 uL, 0.3 mmol) was added to a stirred solution of 3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]-L-alanine (100 mg, 0.3 mmol) in MeOH (1 mL). The reaction mixture was heated to 70° C. overnight, cooled to room temperature, and treated with aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc, washed with sodium hydroxide solution (1N, 2×) and brine, dried over sodium sulfate, concentrated under reduced pressure to afford methyl 3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]-L-alaninate. MS ESI calcd. for C19H26F3N6O2 [M+H]+ 421. found 421. 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.34 (s, 1H), 7.26 (d, J=4.6 Hz, 1H), 7.06 (s, 1H), 4.25-4.34 (m, 2H), 3.78-3.80 (m, 1H), 3.62 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:7]=2[S:8][CH:9]=1.Cl[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[O:20][N:19]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][O:14][C:11]3[CH:12]=[CH:13][C:6]4[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[CH:9][S:8][C:7]=4[CH:10]=3)[CH:22]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Product: O=C(O)Cc1csc2cc(OCc3cc(-c4ccc(Cl)cc4)on3)ccc12

Procedure:
The title compound was prepared from compound 5C and commercially available 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole in the manner analogous to example 5F. MS m/z 414 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([NH:11][C:12](=[O:32])[C:13]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])[C@@H:14]([NH:18]C(=O)OC(C)(C)C)[CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:18][C@@H:14]([CH2:15][CH2:16][CH3:17])[C:13]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])[C:12]([NH:11][CH:8]1[CH2:9][CH2:10]1)=[O:32]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(OCC)(OCC)C(=O)NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](N)C(OCC)(OCC)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
TFA (2.45 mL, 32.1 mmol) was added to a solution of (S)-tert-butyl 1-(cyclopropylamino)-2,2-diethoxy-1-oxohexan-3-ylcarbamate (2.3 g, 6.41 mmol) in 45 mL CH2Cl2 and the mixture was stirred at room temperature for 18 hours. A saturated NaHCO3 solution was carefully added to the mixture, the aqueous phase was extracted with CH2Cl2 (2×30 mL) and the combined organic phases were dried over Na2SO4. Removal of the solvent in vacuo yielded 1.44 g (3S)-3-Amino-N-cyclopropyl-2,2-diethoxyhexanamide as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([N+:23]([O-])=O)=[CH:17][CH:16]=3)=[O:11])=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>[Ni].O>[NH2:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:10]([NH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:11])=[C:21]2[OH:22]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc([N+](=O)[O-])cc2c1O
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Yield: 84.5 %

Procedure:
N-[(4-chlorophenyl)methyl]-4-hydroxy-6-nitro-3-quinolinecarboxamide (500 mg) is suspended in 50 mL of freshly degassed dimethylformamide and treated with 0.5 mL of 50% Raney nickel in water (Aldrich). The mixture is agitated under 45 psi hydrogen pressure for 24 h, and then it is filtered through celite. The solvent is removed by evaporation at reduced pressure and the residue is suspended in 5 mL of absolute ethanol and it is collected by filtration. After drying at 0.1 torr/100 ° C./1.5 h, the product is obtained as 387 mg of a pale yellow powder.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[CH2:5]([OH:11])[C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].Cl>C(Cl)(Cl)Cl>[Cl:4][P:1]1[O:11][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][O:8]1
Reactant: ClP(Cl)Cl
Reactant: CC(C)(CO)CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)COP(Cl)OC1
Yield: 95.3 %

Procedure:
To phosphorus trichloride (775.4 g, 5.5 M, 10% molar excess) was added dropwise with stirring over two hours a solution of neopentylene glycol (520.8 g, 5.0 M) in chloroform (1200 ml). After the slight endotherm and evolution of HCl had subsided, the clear colorless solution was freed of most of the chloroform and excess PCl3 by distillation at atmospheric pressure to a pot temperature of 100° C. Distillation of the residue through a short vacuum-jacketed Vigreaux column yielded 803.6 g (95.3% yield) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane (III), bp 65° C./10 mm nD25 1.4738, % Cl found 20.71 (21.03 calculated).
Reaction SMILES: N1C=CN=C1.[C:6]([O:10][C:11](=[O:22])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]O)[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].[I:23]I.C(OCC)(=O)C.ClCCl>ClCCl>[C:6]([O:10][C:11](=[O:22])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][I:23])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: II
Reactant: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cccc(CI)c1
Reaction time: 16 h
Yield: 119.7 %

Procedure:
Stir polystyrene-bound triphenylphosphine (4.27 g, 12.8 mmol) and imidazole (0.86 g, 12.7 mmol) in dichloromethane (45 mL). Add a solution of (3-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (1.70 g, 6.1 mmol) in dichloromethane (45 mL). Add iodine (3.22 g, 12.7 mmol) in 3 portions. Stir 16 hrs. Filter through a pad of diatomaceous earth. Wash with aqueous sodium thiosulfate. Dry the organic portion over sodium sulfate. Filter and concentrate. Chromatograph the residue on silica eluting with 25% ethyl acetate/dichloromethane to provide the title compound (2.53 g, 7.3 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:35][CH:36]([CH3:38])[CH3:37])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CC(C)COS(=O)(=O)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: COc1cn(C(CC(C)C)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
416 mg (1.00 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 1.20 ml (1.20 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 309 mg (1.50 mmol, 1.5 eq.) of isobutyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 370 mg (75% of theory)
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=O.[F:22][C:23]([F:31])([F:30])[C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27]>C(O)(=O)C.S(=O)(=O)(O)O>[F:22][C:23]([F:31])([F:30])[C:24]([C:25]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:26]=1[CH3:27])=[O:29]
Reactant: CS(=O)(=O)c1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 27.3 %

Procedure:
To a stirred solution of 50 mg (0.15 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-methanesulfonyl-phenyl)-methanone in 2 ml acetic acid was added 0.020 ml (0.15 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 20 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 18 mg (27%) 2,2,2-trifluoro-1-[4-(4-methanesulfonyl-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light brown solid. ES-MS m/e (%): 440 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[F:1][C:2]1[C:3](/[C:15](/[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:25]\[OH:26])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: NO
Reactant: Cc1ccncc1-c1ccnc(C(=O)c2ccc(F)cc2)c1F
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccncc1-c1ccnc(/C(=N\O)c2ccc(F)cc2)c1F
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of (3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)(4-fluorophenyl)methanone (0.029 g, 0.093 mmol) and hydroxylamine hydrochloride (0.044 g, 0.636 mmol) in pyridine (Volume: 0.467 ml) was refluxed for 1.5 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 80-100% EtOAc in hexanes over 12 min, tr=2 5 min) gave the title compound (22 mg, 0.068 mmol, 72.4% yield) as a yellow solid. ESI MS (M+H)+=326.2.
Reaction SMILES: OS(O)(=O)=O.Cl[CH2:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:29][CH2:30][CH2:31][N:32]([CH2:45][CH3:46])[S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[N+:42]([O-:44])=[O:43])(=[O:35])=[O:34])[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([C:24](=[O:28])[CH2:25][CH2:26]Cl)=[CH:18][CH:17]=3)=[O:10]>C(Cl)Cl.C(OCC)(=O)C>[O:28]=[C:24]1[C:19]2[CH:18]=[CH:17][C:16]3[N:15]([CH2:29][CH2:30][CH2:31][N:32]([CH2:45][CH3:46])[S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[N+:42]([O-:44])=[O:43])(=[O:34])=[O:35])[C:14]4[CH:13]=[CH:12][C:11]5[C:9](=[O:10])[CH2:8][CH2:7][C:23]=5[C:22]=4[C:21]=3[C:20]=2[CH2:26][CH2:25]1
Reactant: CCN(CCCn1c2ccc(C(=O)CCCl)cc2c2cc(C(=O)CCCl)ccc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CCCn1c2ccc3c(c2c2c4c(ccc21)C(=O)CC4)CCC3=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
H2SO4 (110 mL) was heated to 40° C. Compound 61 (7.6 g, 12.3 mmol) was added in portions. The reaction mixture was heated to 100° C., kept at this temperature for 2 h (TLC monitoring, CH2Cl2/ethyl acetate 4:1), and poured into ice. The formed gray precipitate was filtered off. Then CHCl3/MeOH 4:1 (500 mL) was poured into the filter. The solid on the filter dissolved, and the formed solution was transferred into a separation funnel An aqueous solution of Na2CO3 was added. The organic layer was separated, dried with Na2SO4, and evaporated. Acetonitrile was added to the residue. A beige precipitate was filtered off, washed with acetonitrile, with ether, and dried to give 1.56 g (23%) of a beige crystalline product.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>ClCCl>[CH:23]1([C:26]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)=[O:27])[CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a mixture of 4-piperazin-1-yl-benzoic acid (20 g, 71.6 mmol) and triethylamine (58 g, 573 mmol) in dichloromethane (500 mL) was added cyclopropanecarbonyl chloride dropwise at 0° C. The reaction mixture was stirred at RT overnight. The solvent was removed by rotary evaporation. The residue was diluted with water, treated with sodium hydroxide, and washed with ethyl acetate and dichloromethane. The aqueous phase was acidified to pH 6 with 5 N HCl. The resulting precipitate was collected by filtration and concentrated to dryness to provide the title compound (10 g, 51% yield) as a white solid. 1H NMR(CH3OD, 400 MHz) δ (ppm) 7.87 (m, 2H), 6.95 (m, 2H), 3.90 (s, 2H), 3.73 (s, 2H), 3.29 (m, 4H), 1.99 (m, 1H), 0.86 (m, 4H).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1([S:10](Cl)(=[O:12])=[O:11])[NH:8][C:7]([Cl:9])=[CH:6][S:5]1>>[CH3:1][NH:2][S:10]([C:4]1([Cl:3])[NH:8][C:7]([Cl:9])=[CH:6][S:5]1)(=[O:12])=[O:11]
Reactant: CN
Reactant: O=S(=O)(Cl)C1(Cl)NC(Cl)=CS1
Product: CNS(=O)(=O)C1(Cl)NC(Cl)=CS1
Reaction time: 0.5 h

Procedure:
21 g of a 30% strength aqueous methylamine solution were added dropwise at approx. -75° C. in the course of 45 minute$ to 25.25 g (0.1 mol) Df 2,4-dichloro-thiazole-sulphonyl chloride from Example 1 in 250 ml of the cold bath was then removed and the temperature was subsequently allowed to rise to room temperature, the mixture was subsequently stirred for 30 minutes, the resulting suspension was evaporated under a waterpump vacuum, and the residue was stirred with 300 ml of water. The solid was filtered off with suction and chromatographed on silica gel (eluent toluene/EtOH 15:1) in order to remove small amounts of starting material and product which is substituted in the 2-position. 22 g of product were obtained (89% of the theoretical yield) m.p.: 72-3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[C:5]2[CH2:19][CH2:20][C:21](O)=[O:22].[C:24]1([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[C:5]2[CH2:19][CH2:20][C:21]([N:34]1[CH2:35][CH2:36][N:31]([CH2:30][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:32][CH2:33]1)=[O:22]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Solvent: C1CCOC1
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCN(Cc3ccccc3)CC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
1,1-Carbonyl diimidazole (47 mg, 0.29 mmol) was added to a solution of 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoic acid (Description 12, 100 mg, 0.29 mmol) in tetrahydrofuran (4 mL) and the mixture was heated under reflux for 2 h. The mixture was cooled and 1-(phenylmethyl)piperazine (48 mg, 0.27 mmol) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. Water (4 mL) was added and the mixture was stirred at 80° C. for 2 h. The mixture was cooled, the water was decanted and the residue was dissolved in dichloromethane. Using a Bond Elut™ cartridge to separate the layers the solution was washed with hydrochloric acid (1M), and aqueous sodium hydroxide (2M). The organic fraction was evaporated under reduced pressure to a small volume and filtered through a plug of silica on a Bond Elut™ cartridge, eluting with hexane/EtOAc (85:15 increasing to 70:30), to give the title compound as a colorless solid (95 mg, 65%). 1H NMR (360 MHz, CDCl3) δ2.10-2.13 (2H, m), 2.25-2.28 (2H, m), 2.40-2.43 (2H, m), 2.89-2.93 (2H, m), 3.13-3.16 (2H, m), 3.78 (2H, s), 3.46 (3H, s), 3.48-3.51 (2H, m), 7.10-7.26 (9H, m), 7.40 (2H, d, J 8.3 Hz), and 7.50 (1H, s). m/z (ES+) 506, 508 (M+1).