Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1OC2C=CC(C(NN)=O)=CC=2OC1.CC(C)(C(=O)CC)C.[CH2:24]([C:26](=[N:31][NH:32][C:33]([C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[C:36]=1[CH3:45])=[O:34])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:25].C([BH3-])#N.[Na+]>C(O)(=O)C.C(O)C>[CH2:24]([CH:26]([NH:31][NH:32][C:33]([C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[C:36]=1[CH3:45])=[O:34])[C:27]([CH3:30])([CH3:28])[CH3:29])[CH3:25]
Reactant: CCC(=NNC(=O)c1ccc2c(c1C)OCCO2)C(C)(C)C
Agent: CC1COc2cc(C(=O)NN)ccc2O1
Agent: CCC(=O)C(C)(C)C
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(NNC(=O)c1ccc2c(c1C)OCCO2)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.86 g (4.1 mmol) of -methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid hydrazide and 1.14 g (10 mmol) of 2,2 dimethyl pentan-3-one, 30 mL of ethyl alcohol and 20 drops of glacial acetic acid were refluxed for 6 hours. TLC indicated ca. a 60% conversion to 5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (1-ethyl-2,2-dimethyl-propylidene)-hydrazide (Rf=0.40, 1:1 ethyl acetate:hexane). The reaction was cooled, 3 mL of glacial acetic acid followed by 0.63 g (10 mmol) of sodium cyanoborohydride were added, and the reaction was stirred at room temperature for 3 hours. Most of the alcohol was removed on a rotary evaporator. 30 mL of water was added, followed by the addition of 10% NaOH/H2O until the reaction mixture was basic. The mixture was extracted extensively with ethyl acetate. The ethyl acetate extract was dried and evaporated to give 1.2 g of crude material. The product was purified by column chromatography on silica gel, eluting with 20-30% ethyl acetate/hexane. About 0.46 g of pure 5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid N′-(1-ethyl-2,2-dimethyl-propyl)-hydrazide was obtained. TLC: Rf=0.46 (1:1 ethyl acetate:hexane). 1H NMR (CDCl3, 500 MHz) δ (ppm): 7.1 (br, 1H[NH]), 6.85 (d, 1H), 6.71 (d, 1H), 4.8 (br, 1H), 4.29 (m, 2H), 4.25 (m, 2H), 2.4 (m, 1H), 2.29 (s, 3H), 1.7 (m, 1H), 1.3 (m, 1H), 1.15 (t, 3H), 0.98 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([OH:15])=O)=[CH:8][C:7]=2[CH:16]=1.[ClH:19].Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.P(C#N)(=O)(OCC)OCC.Cl>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[ClH:19].[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:30]3[CH2:29][CH2:28][N:27]([CH2:26][C:25]4[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:23]([O:22][CH3:21])[CH:24]=4)[CH2:32][CH2:31]3)=[O:15])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)O)=C2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1)=C2
Yield: 27.9 %

Procedure:
Using 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (2 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (3.5 g), N,N-dimethylformamide (30 ml), triethylamine (3.3 g) and diethyl phosphorocyanidate (2.5 ml), a reaction as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1) to give an oily product which is converted to the hydrochloride in ethyl acetate to yield 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.2 g) as colorless crystals, m.p. 138°-142° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.Cl.[F:10][C:11]([F:22])([F:21])[C:12]1[N:16]2[CH2:17][CH2:18][NH:19][CH2:20][C:15]2=[N:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:19]2[CH2:18][CH2:17][N:16]3[C:12]([C:11]([F:22])([F:10])[F:21])=[N:13][N:14]=[C:15]3[CH2:20]2)[CH:3]=1
Reactant: Fc1cc(Br)ccn1
Reactant: FC(F)(F)c1nnc2n1CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nnc2n1CCN(c1cc(Br)ccn1)C2
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-2-fluoropyridine (0.216 mL, 2.1 mmol), 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.399 g, 1.75 mmol) and potassium carbonate (0.482 g, 3.49 mmol) in anhydrous DMF (7.0 mL) was heated at 100° C. for 16 h. Reaction mixture was cooled, diluted with ethyl acetate, washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 50% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C11H10BrF3N5: 348.0. (M+H+); Found: 348.2 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])=[C:5]([O:23][CH3:24])[CH:4]=1)[CH3:2]>C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[C:19]([F:20])([F:22])[F:21])=[C:5]([O:23][CH3:24])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(N)cc2C(F)(F)F)c(OC)c1
Reaction time: 8 h

Procedure:
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene (1.90 mmol; 651 mg) was dissolved in anhydrous THF (8 mL) under argon. Palladium on charcoal (0.095 mmol; 20 mg) was added and the reaction was flushed twice with hydrogen, then left to stir overnight. The reaction mixture was filtered on celite, rinsed with methanol (3*10 mL). Concentration yielded a light brown oil (579 mg; 98%) used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23]C(C)C)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC(C)C)o1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2O)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-[2-(2-propyloxy)phenoxy]propyl]oxazole (200 mg), titanium(IV) chloride (380 mg) and methylene chloride (5 ml) was stirred at 0° C. for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate (10 ml) and extracted with ethyl acetate (10 ml×2). The organic layer was dried over anhydrous magnesium sulfate and then concentrated, and the residue was recrystallized from acetone-isopropyl ether to give 4-(4-chlorophenyl)-5-[3-(2-hydroxyphenoxy)propyl]-2-(2-methyl-1-imidazolyl)oxazole as colorless prisms (90 mg, 51%). Melting point 110-111° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([Br:12])=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([F:11])[C:5]([Br:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)c(F)c1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: Nc1ccc(Br)c(F)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of 6-amino-3-bromo-2-fluorobenzoic acid (9.0 g, 38.46 mmol) in THF (150 mL) was added BH3-THF (1 M, 193 mL) at 0° C., and the mixture was stirred at room temperature overnight. The reaction was slowly quenched with methanol (50 mL), and the solvents were removed under reduced pressure. The residue was diluted with 200 mL of ethyl acetate, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to afford the title product (8.3 g, 98%), which was directly used in the next step without further purification. MS (ES+) C7H7BrFNO requires: 219, found: 220, 222 [M+H]+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:17][CH:16]2[CH:11]([C:12]([F:31])([F:30])[CH2:13][CH2:14][C:15]2([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C:24]1([C:15]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:13][C:12]([F:31])([F:30])[CH:11]3[CH:16]2[CH2:17][NH:9][CH2:10]3)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C(c1ccccc1)(c1ccccc1)CCC2(F)F
Agent: Cl
Solvent: C1COCCO1
Product: FC1(F)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
20 cm3 of dioxane and 20 cm3 of 6.3N hydrochloric acid are added to 1.8 g of (3aRS, 7aRS)-2-tert-butyloxycarbonyl-4,4-diphenyl-7,7difluoroperhydroisoindole. After stirring for 20 hours at room temperature, the white suspension obtained is concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The residue is washed with diisopropyl oxide, the solid obtained is drained and then dried. 1.51 g of (3aRS, 7aRS)-4,4-diphenyl-7,7-difluoroperhydroisoindole hydrochloride are obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH3:12])=[CH:5]2.[CH3:13][CH:14](C)[CH2:15]CC1NC2C(C=1)=CC=CC=2>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH:14]([CH3:15])[CH3:13])=[CH:5]2
Reactant: CCc1cc2cc(N)ccc2[nH]1
Reactant: CC(C)CCc1cc2ccccc2[nH]1
Product: CC(C)CCc1cc2cc(N)ccc2[nH]1

Procedure:
Refer to 41a) using 2-(3-methyl-n-butyl) indole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:9][CH:8]=1)[CH3:2].[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]=[C:37]=[O:38]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:37]([NH:36][C:30]2[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=2[F:28])=[O:38])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCCNCCOc1ccc(CC(OCC)C(=O)OCC)cc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClCCl
Product: CCCCCCCN(CCOc1ccc(CC(OCC)C(=O)OCC)cc1)C(=O)Nc1ccc(F)cc1F
Reaction time: 16 h

Procedure:
A solution of the compound obtained in Step e (30.9 mg) in methylene chloride (2 ml) was added with 2,4-difluorophenyl isocyanate (14 μl, Aldrich) and stirred for 16 hours. The reaction mixture was concentrated, and the resulting residue was applied on a silica gel column and eluted with hexane/ethyl acetate (4:1) to obtain the title compound (41.6 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:8]([O:22][CH2:23][C:24](OCC)=[O:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1>CO>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCO)c2cccc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.5 %

Procedure:
To a solution of (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)-methyl)piperidine-1-carboxylate (4.368 g, 10.2 mmol) in MeOH (85 mL) was added NaBH (3.18 g, 81.5 mmol) in portions such that the temperature remained below 40° C. After addition, the mixture was stirred at rt for 2-3 h. TLC showed the starting material had disappeared. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated to give (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (3.5 g, 89%). 1H NMR (400 MHz, CDCl3): 1.18 (m, 1H), 1.38-1.46 (s, 9H), 1.65 (m, 1H), 1.85 (m, 2H), 2.66 (m, 1H), 3.25 (m, 1H), 3.38 (m, 2H), 3.69 (m, 3H), 3.93 (m, 1H), 4.52 (m, 6H); MS (E/Z): 388 (M+1)
Reaction SMILES: C([N:4]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]3[C:35]([F:36])=[CH:34][CH:33]=[C:32]([NH2:37])[C:28]=3[C:29](=[O:31])[CH:30]=2)=[CH:21][CH:20]=1)[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])(=O)C.Cl.[OH-].[Na+].O>O1CCOCC1>[NH2:37][C:32]1[C:28]2[C:29](=[O:31])[CH:30]=[C:25]([C:22]3[CH:21]=[CH:20][C:19]([NH:4][CH2:5][CH2:6][CH2:7][N:8]4[C:9](=[O:18])[C:10]5=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]5[C:12]4=[O:13])=[CH:24][CH:23]=3)[O:26][C:27]=2[C:35]([F:36])=[CH:34][CH:33]=1
Reactant: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(-c2cc(=O)c3c(N)ccc(F)c3o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)cc3)cc(=O)c12
Yield: 79.9 %

Procedure:
5.78 g of Compound 18 was dissolved in 90 ml of dioxane, 60 ml of concentrated hydrochloric acid was added and the mixture was heated at reflux for 4 hours. The reaction solution was cooled on ice and adjusted to pH 7 by addition of a 10N aqueous solution of sodium hydroxide thereto, water was further added, and the precipitated crystals were collected by filtration to give 4.23 g (80%) of Compound 19.
Reaction SMILES: C1C([N+]([O-])=O)=CC=C([Cl-][C:11]([O-])=[O:12])C=1.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1.N1C=CC=CC=1.[N+](C1C=CC(NC(=O)[O-])=CC=1)([O-])=O.Cl.[Cl:47][C:48]1[CH:49]=[C:50]([CH2:54][CH2:55][NH:56][C:57]([C:59]2[N:60]=[C:61]([CH2:64][NH2:65])[S:62][CH:63]=2)=[O:58])[CH:51]=[CH:52][CH:53]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.[Cl-].[NH4+].CN(C=O)C.O.CCOC(C)=O.C(Cl)Cl>[F:14][C:15]([F:25])([F:26])[O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:22][C:11](=[O:12])[NH:65][CH2:64][C:61]2[S:62][CH:63]=[C:59]([C:57](=[O:58])[NH:56][CH2:55][CH2:54][C:50]3[CH:51]=[CH:52][CH:53]=[C:48]([Cl:47])[CH:49]=3)[N:60]=2)=[CH:19][CH:18]=1
Reactant: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Reactant: OCc1ccc(OC(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1)OCc1ccc(OC(F)(F)F)cc1
Reaction time: 12 h
Yield: 53.5 %

Procedure:
4-Nitrophenylchloroformate (0.1 g, 0.5 mmol) was added to a stirring solution of 4-(trifluoromethoxy)benzyl alcohol (0.09 g, 0.5 mmol), pyridine (0.07 mL, 0.9 mmol), and methylene chloride (2 mL). DMAP (6 mg) was added and the mixture was stirred for 12 hours. The mixture was diluted with saturated ammonium chloride and extracted 3× with methylene chloride. The combined organic layers were washed with 0.5 N NaHSO4 and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc/hexane). The 4-nitrophenylcarbamate was mixed with 2-aminomethyl-thiazole-4-carboxylic acid [2-(3-chlorophenyl)ethyl]amide hydrochloride (0.14 g, 0.4 mmol) and DIEA (0.2 mL) in DMF (5 mL). The mixture was stirred for 12 hours. The mixture was diluted EtOAc and water. The layers were separated and the aqueous layer was extracted with 3×EtOAc. The combined organic layers were washed with 5% aqueous lithium chloride and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The material was purified by flash chromatography (EtOAc/hexane) to afford the title compound (0.11 g, 50%): 1H NMR (400 MHz, d6-DMSO): 8.42 (t, 1H), 8.30 (t, 1H), 8.11 (s, 1H), 7.48 (d, 2H), 7.36 (d, 2H), 7.27 (m, 3H), 7.17 (d, 1H), 5.11 (s, 2H), 4.49 (d, 2H), 3.48 (m, 2H), 2.84 (t, 2H); MS (ESI-LCMS) for C22H20ClF3N3O4S: 514 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:28]=[CH:27][C:26]([C:29]7[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][CH:34]=7)=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][CH:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:42]>O1CCOCC1>[ClH:42].[NH:32]1[CH2:33][CH:34]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[N:22][C:17]4[N:18]([C:14]([C:11]5([C:7]6[CH:6]=[C:5]7[C:10](=[CH:9][CH:8]=6)[N:1]=[CH:2][CH:3]=[CH:4]7)[CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:19]=3)=[CH:28][CH:27]=2)[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4n3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1=C(c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4n3)cc2)CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-{4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (36.0 mg, 0.0661 mmol) was dissolved in 4M of hydrogen chloride in 1,4-dioxane (5.0 mL) and stirred at RT for 2 h. The volatiles were removed under vacuum and the residue was azeotropically washed with acetonitrile. The crude material was used in the next step. LCMS: (M+H)=445.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.CCN=C=NCCCN(C)C.[NH:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH3:13])[C:10](=[O:12])[N:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CSCCN1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)N1CCSCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5 mmol), HOBt (22.2 mmol), NMP (22.2 mmol) and EDCI (22.2 mmol) in CH2Cl2 was added thiomorpholine (2.29 g, 22.2 mmol) at 0° C. The reaction mixture was stirred at 0° C. overnight, then washed with 2% aqueous NaOH, water, brine, and dried over Na2SO4. The solvent was removed under vacuum to give (1-Methyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (5.0 g) yield 98%. MS (M+H)=275.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:9]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[N:27]([CH3:29])[CH3:28])=[CH:21][CH:20]=2)[N:7]=1)(=N)N.BrC[C:33]#[N:34].[OH-].[Na+]>CN(C=O)C.O>[C:33]([CH2:1][S:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:9]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[N:27]([CH3:28])[CH3:29])=[CH:21][CH:20]=2)[N:7]=1)#[N:34]
Reactant: C[C@H]1COCCN1c1cc(CSC(=N)N)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: N#CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1cc(CSCC#N)nc(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
3-[4-[4-(Carbamimidoylsulfanylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-1,1-dimethyl-urea (0.38 mmol) was dissolved in DMF (2 mL). This was treated with bromoacetonitrile (0.030 mL) and then the sodium hydroxide (61 mg) in water (1 mL) and stirred at RT for 15 minutes. The reaction mixture was concentrated in vacuo and the residue loaded onto a SCX-2 column, washed with methanol and the desired material removed with 7N ammonia in methanol. The desired material was isolated and used without further chromatography.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH:20]([OH:23])[CH2:21]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:23][CH:20]([C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[CH2:21][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: OCC(O)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: Clc1ccc(C2(CBr)OCC(c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
A mixture of 11.6 parts of 2-bromo-4'-chloroacetophenone, 12.4 parts of 1-(2,4-dichlorophenyl)-1,2-ethanediol, 0.1 parts of p-toluenesulfonic acid, 80 parts of n-butanol and 160 parts of benzene in stirred and refluxed for 24 hours with water-separator. The solvent is removed in vacuo and the residue is triturated in methanol. The precipitated product is filtered off and crystallized from petroleum ether, yielding 2-(bromomethyl)-2-(p-chlorophenyl)-4-(2,4-dichlorophenyl)-1,3-dioxolane; m.p. 82.7° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([NH:16][C@H:17]3[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[Pd]>[NH2:13][C:12]1[C:7]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][C:9]([NH:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([OH:23])[CH2:21][CH2:22]2)=[N:10][CH:11]=1
Reactant: O=[N+]([O-])c1cnc(N[C@H]2CC[C@H](O)CC2)nc1NC1CCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc(N[C@H]2CC[C@H](O)CC2)nc1NC1CCCC1

Procedure:
4-{[4-(Cyclopentylamino)-5-nitropyrimidin-2-yl]amino}trans-cyclohexan-1-ol (2.18 mmol, 700 mg) was dissolved in 20 ml EtOH and hydrogenated overnight at 1 bar with Pd/C (10%) as catalyst. The catalyst was filtered and the solvent evaporated to give the desired product (635 mg, 100% yield) which was carried on to the next step without further purification. ES-MS: 292 (M+1). This reduction can be also accomplished using the following procedure: Na2S2O4 (140.0 mmol, 14 eq.) is dissolved in 150 mL water and 75 mL dioxane and 7.5 mL NH4OH solution are added. The corresponding nitro compound (10.0 mmol, 1 eq.) is added and the reaction mixture is stirred for 12 to 72 hours. Dioxane is evaporated and the product is extracted by using EtOAc or brine/THF. The organic phase is dried over MgSO4 and evaporated to give the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[O:15]1[CH2:20][CH2:19][N:18]([C@@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.F[C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=1[N+:39]([O-:41])=[O:40].C(N(CC)CC)C>O1CCCC1>[O:15]1[CH2:16][CH2:17][N:18]([C@@H:21]2[CH2:22][CH2:23][C@H:24]([NH:27][C:29]3[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=3[N+:39]([O-:41])=[O:40])[CH2:25][CH2:26]2)[CH2:19][CH2:20]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@@H](N2CCOCC2)CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N[C@H]2CC[C@@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1

Procedure:
A solution of EXAMPLE 39B (0.40 g), 4-fluoro-3-nitrobenzenesulfonamide (0.478 g) and triethylamine (2 mL) in tetrahydrofuran (10 mL) was stirred for 3 days at room temperature. The reaction mixture was concentrated and purified by flash chromatography (silica gel, 0-30% methanol/dichloromethane) providing the product.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[S:25][C:26]1[S:27][C:28]([NH2:31])=[N:29][N:30]=1)[C@H:20]([NH:32][C:33](=[O:63])[C:34]([C:56]1[N:57]=[C:58]([NH2:62])[S:59][C:60]=1[Cl:61])=[N:35][O:36]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]2=[O:64])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:62][C:58]1[S:59][C:60]([Cl:61])=[C:56]([C:34](=[N:35][OH:36])[C:33]([NH:32][C@@H:20]2[C:19](=[O:64])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([S:25][C:26]2[S:27][C:28]([NH2:31])=[N:29][N:30]=2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:63])[N:57]=1
Reactant: Nc1nnc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC(c4ccccc4)(c4ccccc4)c4ccccc4)c4nc(N)sc4Cl)C3SC2)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nnc(SC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=NO)c4nc(N)sc4Cl)C3SC2)s1
Temperature: 0 °C

Procedure:
To a solution of (7R)-7-[2-(2-amino-5-chloro-thiazol-4-yl)-2-trityloxyiminoacetylamino ]-3-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (150 mg, 0.17 mmol) in dichloromethane (7.5 mL) was added triethylsilane (1.5 mL). The mixture was cooled to 0° C. and trifluoroacetic acid (7.5 mL) was added. After 2 hr at 0° C. the reaction mixture was concentrated under vacuum and disopropyl ether was added to the oily residue. The title compound precipitated and was filtered, washed with additional diisopropyl ether and dried under vacuum (85 mg, 65%).