Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2([CH3:21])[CH:13]3[CH:9]2[CH2:10][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]3=[O:14])[CH:5]=[CH:6][CH:7]=1.N([O-])=[O:23].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>Cl.O>[CH2:15]([N:11]1[CH2:10][CH:9]2[CH:13]([C:8]2([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:23])[CH:3]=2)[CH3:21])[C:12]1=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
6-(3-Aminophenyl)-3-hexyl-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 84, 1.0 g, 3.5 mmol) was dissolved in aqueous hydrochloric acid (2.5 M, 3.5 ml) and cooled to 0° C. Sodium nitrite (0.25 g, 3.6 mmol) dissolved in water (I ml) was added to the reaction mixture and stirred for 30 min. The reaction mixture was neutralised with solid sodium carbonate and then diluted with water (5 ml). The reaction mixture was heated to 60° C. for 1 h during which time a dark brown oil formed on top of the aqueous layer. The product was extracted with dichloromethane (50 ml), and the organic extracts were dried (Na2SO4) and concentrated in vacuo to give a brown oil. The crude product was purified by chromatography on silica gel (20 g) eluting with ethyl acetate:hexane (1:1) to give the title compound (0.34 g, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[C:25]([C:38](O)=[O:39])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:55][C:56]([NH2:59])([CH3:58])[CH3:57].Cl>CN(C=O)C>[C:56]([NH:59][C:38]([C:25]1[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:36])([F:37])[F:35])=[CH:27][C:22]([CH2:21][N:10]2[C:11](=[O:20])[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:18])[F:16])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[CH:23][CH:24]=1)=[O:39])([CH3:58])([CH3:57])[CH3:55]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
30 mg (0.05 mmol) of the compound from Example 141 were initially charged in 0.75 ml of DMF, and 9 mg (0.074 mmol) of HOBt and 13 mg (0.07 mmol) of EDC were added. After 10 min of stirring at RT, 6 μl (0.06 mmol) of 2-methylpropane-2-amine were added, and the mixture was stirred at RT for 16 h. 50 μl of 1 N hydrochloric acid were then added, and the mixture was directly purified chromatographically [Method 19]. This gave 8.2 mg (24% of theory) of the target compound.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][NH:46][C:45](=[O:49])[CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:46]2[CH:47]=[CH:48][C:43]([O:42][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:44][C:45]2=[O:49])[CH:11]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: O=C(NCc1ccccc1)c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Product: O=C(NCc1ccccc1)c1ccnc(-n2ccc(OCc3ccccc3)cc2=O)c1
Temperature: 110 °C
Yield: 53.3 %

Procedure:
A mixture of N-benzyl-2-chloroisonicotinamide (1.00 g, 4.06 mmol), copper iodide(I) (0.12 g, 0.61 mmol), 8-hydroxyquinoline (0.09 g, 0.61 mmol), potassium carbonate (0.84 g, 6.09 mmol), 4-(benzyloxy)pyridin-2(1H)-one (0.82 g, 4.06 mmol) in N,N-dimethylormamide (20 mL) was heated to 110° C. for 16 hours under nitrogen atmosphere and concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with water (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography eluting with 60-75% ethyl acetate in petroleum ether to give 4-benzyloxy-2-oxo-2H-[1,2′]bipyridinyl-4′-carboxylic acid benzylamide as colorless solid (0.89 g, 53%): mp 158-161° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J=5.0 Hz, 1H), 8.19 (s, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.74 (d, J=5.0 Hz, 1H), 7.42-7.26 (m, 11H), 6.16-6.13 (m, 1H) 5.95 (d, J=2.3 Hz, 1H), 5.02 (s, 2H), 4.58 (d, J=5.6 Hz, 2H); MS (ES+) m/z 412.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]=[C:4]([O:11][CH3:12])[N:3]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22]>C(#N)C>[F:9][CH:8]([F:10])[C:6]1[N:5]=[C:4]([O:11][CH3:12])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:28])([F:13])[F:27])(=[O:22])=[O:23])=[O:26])[N:7]=1
Reactant: COc1nc(N)nc(C(F)F)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(F)(F)F
Solvent: CC#N
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(F)(F)F)nc(C(F)F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.65 g of 2-amino-4-difluoromethyl-6-methoxy-1,3,5-triazine (15 mmol) in 20 ml of acetonitrile was treated at 25° C. with 3.7 g of 2-trifluoromethylbenzenesulfonyl isocyanate (15 mmol). The mixture was subsequently stirred at 25° C. for 16 h, the solvent was removed in a water-jet vacuum at 40° C. and the solid residue was stirred vigorously with 100 ml of diethyl ether. The product was filtered off with suction, washed with a little ether and dried. 4.3 g (10 mmol, 67% of theory) of the title compound of m.p. 143-145° C. were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
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: c1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccccc2)nc1

Procedure:
10 g (42.2 mmol) of 2,5-dibromopyridine, 5.2 g (42.2 mmol) of phenylboronic acid and 30 ml of benzene are placed in a 250 ml three-necked round-bottomed flask, 1.5 g (1.3 mmol) of tetrakis(triphenylphosphine)palladium, 30 ml of benzene and 30 ml of aqueous 2 M sodium carbonate solution and 1.4 ml of ethanol are added and the mixture is refluxed for 17 h.
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:14])[CH3:2].CC1NC2C=CC=CC=2N=1.C(C(CCCC)CBr)C.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[SH:45].[S]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:14]1[S:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=1)[CH3:2]
Reactant: CCCCC(CC)Cn1c(C)nc2ccccc21
Reactant: Nc1ccccc1S
Agent: CCCCC(CC)CBr
Agent: Cc1nc2ccccc2[nH]1
Agent: [S]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c(-c2nc3ccccc3s2)nc2ccccc21

Procedure:
48.8 g (0.2 mol) of 1-(2-ethylhexyl)-2-methylbenzimidazole (prepared by the alkylation of 2-methylbenzimidazole and 2-ethylhexyl bromide under phase transfer conditions), 25 g (0.2 mol) of o-aminothiophenol and 19.2 g (0.6 mol) of sulphur in 200 ml of pyridine are heated for 18 hours under reflux. Then the pyridine is distilled off and the remaining residue is dissolved by heating in 80 g of ethanol. After cooling, 55.2 g (76% of theory) of the product, which, according to its melting point and BPLC and UV analysis, is identical to the compound obtained in Example 18 by route A, are precipitated.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:8]=1.N1C=CN=C1.[CH3:22][CH:23]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH3:24]>CN(C1C=CN=CC=1)C.ClCCl>[CH:23]([Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:8]=1)([CH3:24])[CH3:22]
Reactant: CCOC(=O)c1cnc2ccc(CO)cn12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)c1cnc2ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate (59) (497.0 mg, 2.26 mmol), DMAP (12.2 mg, 0.1 mmol) and 1H-imidazole (154.0 mg, 2.26 mmol) in dichloromethane (10 mL), was added TIPSCl (523.0 mg, 2.71 mmol). The resulting mixture was stirred overnight at room temperature. The solvent was removed under vacuum to yield crude ethyl 6-(((triisopropylsilyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate (60). MS m/z 377.2 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:37][C:38](=[O:44])[CH2:39][CH2:40][C:41](Cl)=[O:42])[CH3:36].C1COCC1>CCOC(C)=O>[CH2:35]([O:37][C:38](=[O:44])[CH2:39][CH2:40][C:41]([NH:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:34])=[NH:9])[S:11][C:12]=2[S:32][CH3:33])(=[O:17])=[O:16])[CH:19]=1)=[O:42])[CH3:36]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: CCOC(=O)CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Temperature: 50 °C

Procedure:
{[4-(2′-Amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (38.5 mg, 0.07 mmol, Example 25: step c) and 3-chlorocarbonyl-propionic acid ethyl ester (13 μL, 0.09 mmol) were dissolved into THF (1 mL) and heated to 50° C. for one hour. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried, (MgSO4) and the solvents were removed in vacuo. Purification by preparative TLC (30% EtOAc/hexanes) yielded the title compound. ESI-MS (m/z): Calcd. for C30H35N3O7S3: 646.2 (M+1); found: 645.8.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)OC1.[NH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2.C(O)(=O)C>CO>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][CH:4]3[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]3)=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
1,4-Cyclohexanedione monoethylene ketal (3.90 g), 5-aminoindazole (2.66 g), and acetic acid (0.5 ml) were dissolved in methanol (50 ml), and a borane-pyridine complex (2.50 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr, was then cooled to room temperature, and was concentrated. The residue was dissolved in acetic acid-water (1:1, 50 ml), and the mixture was then stirred at 80° C. for 3 hr. The reaction mixture was concentrated to remove a major part of acetic acid. A saturated aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (3.21 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[Cl:11][C:4]1[S:3][C:2]([NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)sc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1sc(Cl)cc1C(=O)OC)C(=O)OCC

Procedure:
Reaction of methyl 2-amino-5-chlorothiophene-3-carboxylate with diethyl ethoxymethylenemalonate is a similar manner to that used in Reference Example 10 yields diethyl (5-chloro-3-methoxycarbonylthienyl)aminomethylenemalonate as crystals melting at 89.5°-90.5° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:13](=[O:14])[C@H:12]([CH2:15][CH2:16][C@@H:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[OH:18])[C@H:11]2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][C@H:40]4[O:46][CH:44]([OH:45])[C@H:43]([OH:47])[C@@H:42]([OH:48])[C@@H:41]4[OH:49])[CH:33]=3)=[CH:28][CH:27]=2)=[CH:6][CH:5]=1>C(#N)C.O.C(#N)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:13](=[O:14])[C@H:12]([CH2:15][CH2:16][C@@H:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[OH:18])[C@H:11]2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][C@@H:40]([OH:46])[C@@H:41]([OH:49])[C@H:42]([OH:48])[C@@H:43]([OH:47])[CH2:44][OH:45])[CH:33]=3)=[CH:28][CH:27]=2)=[CH:6][CH:5]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(OC[C@H]4OC(O)[C@H](O)[C@@H](O)[C@@H]4O)c3)cc2)N1c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO)c3)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
Sodium borohydride (1.6 mg, 0.04 mmol) was added to 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucopyranose (26.3 mg, 0.04 mmol) dissolved in 80:20 acetonitrile-water (1 mL) at room temperature. The reaction was stirred for 10 min at room temperature monitoring by LCMS. Upon completion, the reaction was diluted with 50:50 acetonitrile:water (3 mL) and filtered through a Whatman 0.45 μM glass microfiber filter then purified by preparative HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) affording 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-D-glucitol (21.2 mg, 80% yield). 1H NMR (300 MHz, CDCl3/1% CD3OD) δ 7.58 (d, J=8.1 Hz, 2H), 7.39-7.24 (m, 7H), 7.17-7.15 (m, 2H), 7.04-6.92 (m, 5H), 4.71 (d, J=2.1 Hz, 1H), 4.68 (t, J=6.3 Hz, 1H), 4.31-4.27 (m, 1H), 0.19-4.14 (m, 1H), 4.08-4.02 (m, 1H), 3.97-3.95 (m, 1H), 3.86-3.65 (m, 4H), 3.14-3.12 (m, 1H), 2.01-1.88 (m, 4H) ppm; MS [M+HCO2−]− 694.0.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.N([O-])=[O:16].[Na+]>O>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[O:16])[S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c2ccc([N+](=O)[O-])cc2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
28.75 g of 2-amino-6-nitrobenzothiazole, 210 g of 30% hydrochloric acid and 29.5 g of water are introduced into a 750 ml pressure vessel at room temperature and subsequently heated to 50° C. After the reaction mixture has been stirred for 30 minutes, it is cooled to 20° C. 50.75 g of aqueous sodium nitrite solution are then metered in at a uniform rate in the course of 3 hours at 20°-30° C., with very vigorous stirring. After metering in has ended, stirring is continued for 2.5 hours at 20°-30° C. Then, excess nitrite is removed by adding approximately 15 g of 18% aqueous urea solution. The reaction vessel is subsequently sealed, and the reaction mixture is heated for 5 hours at 140°-150° C. (pressure approximately 4 bar). After the mixture has cooled to 20° C., the crystalline product is filtered off with suction, washed until neutral and dried at 60° C. to constant weight. 27.3 g of 6-nitrobenzothiazol-2-one with a pure substance content of 97.8% are obtained (corresponding to 92.4% yield). The product which is redissolved under alkaline conditions has a DSC melting point of 252.5° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4]O.P(Br)(Br)[Br:13].O>CCCCCC>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][Br:13]
Reactant: CC(C)CCCC(C)CCO
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCCCCC
Product: CC(C)CCCC(C)CCBr
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To neat 3,7-dimethyloctanol (5 ml) was added phosphorus tribromide (1.01 ml). The mixture was stirred for 4 hours at 60° C. The reaction mixture was added to a mixture of water and n-hexane. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 3,7-dimethyloctyl bromide (4.40 g).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[N:43][C:42]=2[C:50]2[C:51]([F:58])=[C:52]([NH2:57])[CH:53]=[CH:54][C:55]=2[F:56])[CH:38]=[CH:37][N:36]=1.FC1C=CC=C(F)C=1S(Cl)(=O)=O>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[N:43][C:42]=2[C:50]2[C:51]([F:58])=[C:52]([NH:57][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:53]=[CH:54][C:55]=2[F:56])[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)c1c(F)cccc1F
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}amine (500 mg, 1.313 mmol) and 2,6-difluorobenzenesulfonyl chloride (0.214 mL, 1.575 mmol) the title compound of Step C was obtained as a light yellow solid (653 mg, 89% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 8.63 (d, J=5.3 Hz, 1H), 7.63-7.74 (m, 1H), 7.52 (td, J=8.7, 6.0 Hz, 1H), 7.17-7.35 (m, 3H), 6.99 (d, J=5.3 Hz, 1H), 1.42 (s, 9H). MS (ESI): 556 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1>[CH3:13][C:5]1[CH:4]=[C:3]([CH2:2][O:1][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(CO)cc1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
A mixture of methyl 4-(hydroxymethyl)-2-methylbenzoate (126 mg, 0.7 mmol), phenol (66 mg, 0.7 mmol), triphenylphosphine (275 mg, 1.0 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for half hour. And then azodicarboxylic acid diisopropyl ester (212 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 12 hours. The resultant mixture was washed with water (20 mL×2). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 2-methyl-4-(phenoxymethyl)benzoate as a colorless oil (66 mg, 37%). 1H NMR (300 MHz, CDCl3): δ 7.92 (d, J=8.4 Hz, 1H), 7.30-7.24 (m, 4H), 6.97-6.94 (m, 3H), 5.06 (s, 2H), 3.88 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[NH:22][C:13](=[O:15])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: Nc1nc2ccccc2s1
Reactant: CC(C)CO/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CO/N=C(/C(=O)Nc1nc2ccccc2s1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 59.5 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid (prepared as in Example 24, 104 mg, 0.31 mmol), 2-aminobenzothiazole (47 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.94 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluoro-phosphate (119 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 30% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isobutoxyimino-acetamide (86 mg, 60%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C20H20ClN3O4S2 [M+] 465.06, found 466 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 0.97 (d, J=6.6 Hz, 6 H, 2×CH3), 2.09 (m, 1 H, CH), 3.32 (s, 3 H, SO2CH3), 4.12 (d, J=6.8 Hz, 2 H, OCH2), 7.35 (brt, J=7.8 Hz, 1H, Ar), 7.48 (brt, J=7.8 Hz, 1H, Ar), 7.63 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.74 (d, Jm=1.6 Hz, 1 H, Ar), 7.83 (m, 2H, Ar), 8.24 (d, Jo=8.2 Hz, 1 H, Ar), 10.25 (brs, 1 H, NH).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]>O1CCCC1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:25])=[CH:22][C:21]=1[N+:29]([O-:31])=[O:30]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2ccccc12)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.8 g (0.02 mol) of 1-naphthylamine and 2.0 g (0.02 mol) of triethylamine in 50 ml tetrahydrofuran is added dropwise at 15-20° C. a solution of 4.4 g (0.02 mol) of 4-chloro-3-nitro-benzoic acid chloride in 20 ml tetrahydrofuran. The solution is stirred for 30 minutes at ambient temperature. Then the solvent is evaporated off and the residue is chromatographed on silica gel, eluting with methylene chloride. The desired fractions are concentrated by evaporation, triturated with ether, suction filtered and dried.