Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl>C(O)C>[F:25][C:2]([F:1])([F:26])[O:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CCO
Product: FC(F)(F)Oc1ccc(COC2CCNCC2)cc1
Temperature: 60 °C

Procedure:
19.21 kg of tert-butyl 4-(4-trifluoromethoxybenzyloxy)piperidin-1-carboxylate and 50 L of ethanol were mixed, and stirred at 60° C. The mixture was mixed with 8.28 L of a concentrated hydrochloric acid, stirred at 60° C. for 2 hours, and concentrated under reduced pressure. 80 L of toluene was added to the residue; the mixture was extracted with 150 L of water; and further the water layer was washed with 40 L of toluene. 15.5 L of a 25% NaOH aqueous solution was added to the water layer; the mixture was extracted twice with 80 L and 40 L of toluene; the organic layers were combined and the organic layer was twice washed with 80 L of water; the organic layer was concentrated under reduced pressure; then, 20 L of ethanol was added to the residue; and the mixture was concentrated under reduced pressure to obtain 10.40 kg of a yellow oily target substance.
Reaction SMILES: C1(CC([NH:10][CH:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[S:28])=[C:15]([C:18]4[S:19][C:20]5[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=5[N:22]=4)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>C(Cl)Cl>[NH2:10][CH:11]1[C:43](=[O:44])[N:13]2[C:14]([C:27]([O:29][CH:30]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[S:28])=[C:15]([C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:16][S:17][C@H:12]12
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12
Temperature: -15 °C
Reaction time: 3 h

Procedure:
557 mg of diphenylmethyl 7-phenylacetamido-3-(benzothiazol-2-yl)thio-3-cephem-4-carboxylate were dissolved in 6 ml of methylene chloride, and the resulting solution was then cooled to -15° C. Afterward, to the cooled solution were added 0.16 ml of pyridine and 268 mg of phosphorus pentachloride, followed by stirring the resultant mixture at -5° C. for 1 hour and 30 minutes. Next, the mixture was cooled to -20° C., and 2.1 ml of methanol were then added thereto. The resulting solution was stirred again at -5° C. for 3 hours to continue the reaction (for the removal of the 7-phenylacetyl group). Thereafter, 6 ml of water were added to the reaction solution which was then further stirred at the same temperature for 1 hour, followed by separation into the aqueous and organic layers. 6 ml of water were added to the resultant organic layer which was then adjusted to pH 7 with an aqueous saturated solution of sodium hydrogen carbonate. After separation from the aqueous layer, the collected organic layer was dried over anhydrous magnesium sulfate. The dried organic solution obtained was distilled under reduced pressure to remove the solvent therefrom, and the resultant residue was then purified by a column chromatography on 35 g of silica gel (as developed with mixed solvents of toluene and ethyl acetate at ratio of 1:1 by volume) to give diphenylmethyl 7-amino-3-(benzothiazol-2-yl)thio-3-cephem-4-carboxylate as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][CH:14]3[O:18][C:17]([NH2:19])=[N:16][CH2:15]3)[CH:5]=[CH:4][C:3]1=2.C([O:23][C:24](=O)[CH:25]([CH:28]=O)[CH2:26][CH3:27])C>C(O)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][C@H:14]3[O:18][C:17]4=[N:19][C:24](=[O:23])[C:25]([CH2:26][CH3:27])=[CH:28][N:16]4[CH2:15]3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCCc2cc(OCC3CN=C(N)O3)ccc21
Reactant: CCOC(=O)C(C=O)CC
Solvent: CCO
Product: CCc1cn2c(nc1=O)O[C@H](COc1ccc3c(c1)CCCC3(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a solution of 5-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol) in ethanol (16 mL) was added 2-formyl-butyric acid ethyl ester (0.39 g, 2.7 mmol). The reaction mixture was stirred at room temperature for one hour, and then heated at reflux for 24 hours. It was then concentrated and loaded on a silica gel column. Chromatography with (1-5%) 2-propanol/methylene chloride gave 0.15 g the title product. [α]D25=−26.8 (c=0.74, CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:8][C:7]=1[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[F:31])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[F:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2OC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(O)cc2OC(C)(C)C)c1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of ((2-(tert-butoxy)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)oxy)triisopropylsilane (96.2 mg) in THF (1.44 mL) was added a 1 M solution (431 μL) of tetrabutylammonium fluoride in THF at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (56.1 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14].[NH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[OH:27]>C(O)(C)C>[OH:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[NH:21][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[C:9]([CH3:11])[N:10]=1)[C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14]
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: Cc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Solvent: CC(C)O
Product: Cc1nc(N[C@@H]2CCC[C@H]2O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 22 h
Yield: 92.2 %

Procedure:
A mixture of 6-chloro-2-methyl-9-(β-D-ribofuranosyl)-9H-purine (902 mg), trans-2-aminocyclopentanol (404 mg), DEA (517 mg) and isopropanol (35 ml) was heated under reflux with stirring for 22 h under nitrogen. Additional trans-2-aminocyclopentanol (202 mg) and DEA (259 mg) were added and heating under reflux was maintained for a further 5 h. The cooled mixture was concentrated in vacuo and the residual foam (1.9 g) was purified by column chromatography on silica (Merck 9385, deactivated with triethylamine) eluting with System B (10:1) to give a solid (1.01 g). This was repurified by column chromatography on silica (Merck 9385) eluting with System B (10:1) to give the title compound (0.57 g), m.p. 188°-192°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:10]([Si:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)Cl)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>C(Cl)Cl>[C:10]([Si:14]([O:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Oc1cc(F)cc(F)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cc(F)cc(F)c1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
To a well stirred ice cooled solution of 3,5-difluorophenol (30.0 g) in CH2Cl2 (500 ml) under N2 were added tert-butyldiphenylchlorosilane (63.4 g) and imidazole (17.3 g). The reaction mixture was stirred 15 min before removing the cooling bath. After 3.5 h the reaction was stopped by washing 1 N HCl sol. (2×300 ml and 1×200 ml), sat. aq. Na2CO3 sol. (200 ml) and brine (200 ml). The aqueous layers were extracted with more CH2Cl2 (200 ml). After drying (MgSO4) the solvent was evaporated to obtain 84.8 g (100%) of tert-butyl-(3,5-difluoro-phenoxy)-diphenyl-silane. Colorless oil. MS 368.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][OH:19])[CH2:13]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:19][CH2:18][CH:14]2[CH2:15][CH2:16][CH2:17][N:12]([CH3:11])[CH2:13]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN1CCCC(CO)C1
Product: CN1CCCC(COc2cc(N)ncc2C#N)C1

Procedure:
From intermediate 21 and racemic (1-methylpiperidin-3-yl)methanol, reacted in an analogous manner to the preparation of intermediate 47. (UPLC-MS 3) tR 0.33 min; ESI-MS 247.2 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:7]2=[N:6][N:5]=1)[CH3:3].[CH3:13][C:14]([CH3:34])([O:16][C:17]([NH:19][C@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:21][C:22](O)=[O:23])=[O:18])[CH3:15].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:15][C:14]([CH3:34])([O:16][C:17]([NH:19][C@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:21][C:22]([N:11]1[CH2:10][CH2:9][N:8]2[C:4]([CH2:2][CH3:3])=[N:5][N:6]=[C:7]2[CH2:12]1)=[O:23])=[O:18])[CH3:13]
Reactant: CCc1nnc2n1CCNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(F)c(F)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCc1nnc2n1CCN(C(=O)C[C@@H](Cc1ccc(F)c(F)c1)NC(=O)OC(C)(C)C)C2
Yield: 38.4 %

Procedure:
The title compound was prepared from 3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride (400 mg, 2.12 mmol, from Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (668 mg, 2.12 mmol), DIPEA (1.1 mL, 4.24 mmol), HOBT (343.8 mg, 2.54 mmol) and EDC (609.6 mg, 3.18 mmol) in 20 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. The crude product was purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100×20 mm I.D.; solvent gradient from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.% trifluoroacetic acid) to give 366.3 mg of the title compound as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 1.31-1.34 (m, 12H), 2.67-2.92 (m, 6H), 4.03-4.12 (m, 4H), 5.03-5.31 (m, 3H), 6.93 (s, 1H), 7.05 (m, 2H). ESI-MS 450 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[OH:26].[Cl-].[NH4+]>CN(C)C=O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: C#CCOc1cc(Cl)ncn1
Reactant: Oc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2c(F)cccc2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 79.2 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.43 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.52 g of potassium carbonate, and 0.4 g of 2,6-difluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.53 g of 4-(2,6-difluorophenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (21)), m.p.: 67.2° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22]O.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:25][CH2:22][CH2:21][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:6]=1[CH3:20]
Reactant: BrC(Br)(Br)Br
Reactant: CSc1ccc(/C=C2/C(C)=C(CCO)c3cc(F)ccc32)cc1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(/C=C2/C(C)=C(CCBr)c3cc(F)ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the alcohol from Step 1 (4.8 g, 14.7 mmol) and carbon tetrabromide (6.34 g, 19.1 mmol) in methylene chloride (100 mL) at 0° C. there was added, in portions, 1,2-bis(diphenylphosphino)ethane (6.34 g, 17.3 mmol). The mixture was stirred at 0° C. for 1 hour, and the solvent was evaporated. The residue was stirred in a mixture of ethyl acetate and water (150 mL each) for 30 minutes. After filtration, the organic portion of the filtrate was evaporated and the crude product purified by column chromatography on silica gel using 10% ethyl acetate in hexane as eluent to afford pure title compound as a yellow oil which solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](Br)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Li]CCCC.[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(O)CC[N+](F)(CC2)C1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)F)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([F:18])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: F[B-](F)(F)F
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: O[N+]12CC[N+](F)(CC1)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-5-bromo-7H-pyrrolo[2,3-d]pyrimidine (800 mg, 3.45 mmol) in THF (50 mL) at −78° C. was treated with n-BuLi (1.6 M in hexane, 2.2 eq, 7.6 mmol, 4.7 mL) dropwise, and stirred for 30 minutes at the same temperature. The mixture was treated with a solution of ACCUFLUOR® NFSi (2.0 eq, 7 mmol, 2.2 g) in THF (10 mL). The reaction mixture was allowed to warm to room temperature, was stirred for 10 h, and then concentrated to dryness. The residue was dissolved in EtOAc (100 mL), washed with water (3×15 mL) and brine (15 mL), dried with Na2SO4, and purified by reverse phase HPLC (10×250 mm C18 Luna column, 4.7 mL/min, 10-90% acetonitrile in water over 20 min) to provide intermediate compound 1. ESI-MS m/z=172.1 (MH+).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:17])[NH:8][C:7]1=[O:31])(=[O:3])[CH3:2].[OH2:32].[OH-].[Li+]>O1CCCC1.O>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:17])=[O:32])[NH:8][C:7]1=[O:31])(=[O:3])[CH3:2]
Reactant: O
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)NC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The more polar major chiral isomer of N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-(R)-4-benzyl-2-oxazolidinone (1.23 g, 2.75 mmol) is dissolved in tetrahydrofuran (45.0 mL) and water (15.0 mL), and the reaction is cooled to 0° C. Lithium hydroxide hydrate (0.116 g, 2.75 mmol) is added, and the reaction is stirred at 0° C. for 45 minutes. The solvent is then evaporated, and the residue is partitioned between saturated sodium bicarbonate and methylene chloride. The aqueous layer is extracted several times with methylene chloride, and then the aqueous layer is acidified with 2.5N hydrochloric acid to pH=3. The aqueous layer is extracted several times with ethyl acetate, the combined organic layers dried (MgSO4) and the solvent is evaporated, to give one enantiomer of trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid, m.p. 144°-145° C.; [α]D +88.36° (c=6.9 mg/ml, CH2Cl2), which is assigned the 3R, 10S configuration.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.Cl.[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>C(O)C>[CH3:13][N:14]([CH3:15])[C:4]1[CH:3]=[C:2]([NH2:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)c1cc(N)c([N+](=O)[O-])cn1
Yield: 113.6 %

Procedure:
In a microwave tube, a solution of 4-amino-2-chloro-5-nitropyridine (prepared as described for compound 9) (200 mg; 1.16 mmol) in ethanol (2 ml) was treated sequentially with dimethylamine hydrochloride (471 mg; 5.78 mmol) and triethylamine (781 μl; 6.96 mmol). The tube was quickly sealed and irradiated in the microwave (CEM Discover, 150 W, 85° C., 10 min). The ethanol was evaporated, dichloromethane (15 ml) was added to dissolve the products, and the solution washed with 1M sodium hydroxide solution (2×10 ml). The organic layer was dried (sodium sulphate), the mixture filtered and the filtrate evaporated to dryness to afford N2,N2-dimethyl-5-nitro-pyridine-2,4-diamine (240 mg, 114%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.O.[NH2:13][NH2:14]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:13][NH2:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: NN
Solvent: O
Product: NNc1ccc2ncc(Br)n2n1
Temperature: 70 °C

Procedure:
A suspension of 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (2.16 g, 10 mmol) in hydrazine monohydrate (10 mL) was heated at 70° C. for 30 minutes. The mixture was cooled to room temperature, and the titled compound (1.78 g) was collected by filtration. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.27 (br. s., 2H) 6.78 (d, J=9.60 Hz, 1H) 7.51 (s, 1H) 7.73 (dd, J=9.60, 1.52 Hz, 1H) 8.20 (br. s., 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:7]=[CH:6][C:5]=1[NH2:20])([O-:3])=[O:2].[O:21]1[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:24][C:23]([C:31](O)=[O:32])=[N:22]1>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:17])[F:18])[N:7]=[CH:6][C:5]=1[NH:20][C:31]([C:23]1[CH2:24][C:25]2([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[O:21][N:22]=1)=[O:32])([O-:3])=[O:2]
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Reactant: Nc1cnc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Product: O=C(Nc1cnc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-])C1=NOC2(CCCCC2)C1

Procedure:
The title compound was prepared from 4-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-3-ylamine (as prepared in the previous step) and 1-oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (as prepared in Example 1, step B) according to the procedure described in Example 16, step D. 1H-NMR (400 MHz, CDCl3) δ: 9.45 (s, 1H), 8.93 (s, 1H), 7.80 (d, J=7.3 Hz, 1H), 7.65 (t, J=7.1 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 2.97 (s, 2H), 1.73-1.90 (m, 5H), 1.62-1.73 (m, 3H), 1.40-1.54 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H19F3N4O4: 449.1 (M+H). found: 449.2.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C@@H:33]([NH:37]C(=O)C2C=CC(C)=CC=2)[CH:34]([CH3:36])[CH3:35])[CH2:28][CH2:27]1>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C@H:33]([NH:37][S:15]([C:12]2[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:34]([CH3:36])[CH3:35])[CH2:28][CH2:27]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(C(=O)N[C@H](CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](CN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)NS(=O)(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 66.9 %

Procedure:
Triethylamine (21 ml, 0.15 mmol) and 4-fluorobenzenesulfonyl chloride (29 mg, 0.15 mmol) were added to a solution of 1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (50 mg, 0.15 mmol) [prepared as described in Example 1 above] in methylene chloride (1.5 ml). The reaction mixture was stirred for 2 h, then concentrated. Purification by flash chromatography with 20:1 methylene: methanol as the eluant gave N-{1-(R)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-4-fluorobenzenesulfonamide (49 mg) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N+:16]([O-])=O)[C:7]1=[O:19])[CH2:4][OH:5].CO>[Pd]>[NH2:16][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[CH:15][N:6]([CH:3]([CH2:2][OH:1])[CH2:4][OH:5])[C:7]2=[O:19]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1C(CO)CO
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c(=O)n(C(CO)CO)ccc12

Procedure:
2-(1,3-dihydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (1.2 g, 0.0045 mol) was stirred with palladium 10% wt. on calcium carbonate (0.1 g, 0.0005 mol) in methanol (100 mL, 2 mol) under hydrogen (balloon) over 1 hr at room temperature. The catalyst was filtered, the filtrate was concentrated to dryness gave light green oil. MS m/z=235.0 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:1]1([CH2:4][C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13]([CH3:14])=[O:24])[N:8]=2)[CH2:3][CH2:2]1
Reactant: CSc1nccc(CC(=O)CC2CC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nccc(CC(=O)CC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 1-cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one (2) (3.00 g, 13.49 mmol) in DCM (54.0 mL) at rt, mCPBA (3.99 g, 16.19 mmol) was added in portions. The reaction mixture was stirred at rt for 1 hour. The reaction was partitioned between saturated sodium carbonate solution and DCM and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [100% DCM to 5% MeOH/DCM] to afford the desired product as a viscous yellow oil (1.88 g, 58.5% yield), which was still contaminated with residual m-chlorobenzoic acid and carried on to the next step. MS (ES+): m/z=239.2 (100) [MH+2]. HPLC: tR=0.73 minute over 3 minutes. Purity: 67.7% [HPLC (LC/MS) at 220 nm].