Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[NH:18][CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:45][CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4]
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1nc2[nH]ccn2c(=O)c1OC(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1nc2n(CCN3CCOCC3)ccn2c(=O)c1OC(C)=O
Temperature: 25 °C
Yield: 34.3 %

Procedure:
The product from Example 18.1.1.2 (30 mg, 0.12 mmol) and 18-crown-6 (3 mg, 10% w/w) were mixed with acetonitrile (5 mL) at room temperature. To this stirred solution was added anhydrous potassium carbonate (83 mg, 0.60 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (25 mg, 0.132 mmol). The mixture was heated at reflux for 2 h and then cooled down to room temperature. The reaction was concentrated to near dryness in vacuo and ethyl acetate (15 mL) was added and the mixture washed with water (2×10 mL). The organic layer was separated, dried and concentrated in vacuo and the residue was purified by column chromatography using dichloromethane/methanol (20:1) as eluent. 6-Acetoxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (15 mg, 34%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:5]1[C:6]([Cl:34])=[C:7]([C:11]2[NH:33][C:14]3[C:15]([O:29][CH2:30][CH:31]=O)=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][NH:36][CH3:37].C1COCC1.C([BH3-])#N.[Na+]>CCOC(C)=O.CO.CC(O)=O>[C:1]([C:5]1[C:6]([Cl:34])=[C:7]([C:11]2[NH:33][C:14]3[C:15]([O:29][CH2:30][CH2:31][N:36]([CH3:37])[CH3:35])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:26])([F:27])[F:28])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(OCC=O)c2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCOc1nc(-c2ccccc2C(F)(F)F)cc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[nH]c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of [2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy]-acetaldehyde (40.0 mg, 0.0813 mmol, prepared as described in Example 12, STEP A) in 30:1 MeOH/AcOH (2 mL) was added 2.0 M dimethyl amine in THF (81.3 μL, 0.163 mmol) followed by sodium cyanoborohydride (10.2 mg, 0.163 mmol). After stirring at room temperature for 18 h, the resulting mixture was treated with EtOAc (50 mL) and washed with saturated aqueous NH4Cl (20 mL), H2O (20 mL) and brine (20 mL). The organic layer was dried with Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (0:100-10:90 MeOH/DCM) to yield {2-[2-(5-tert-Butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy]-ethyl}-dimethyl-amine as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ: 7.84 (d, J=7.6 Hz, 1H), 7.67-7.75 (m, 1H), 7.58-7.66 (m, 2H), 7.37-7.43 (m, 1H), 4.80-4.86 (m, 2H), 4.03 (s, 3H), 3.47-3.55 (m, 2H), 2.88 (s, 6H), 1.45 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C25H28ClF3N6O: 521.2 (M+H). Measured: 521.2.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl>ClC(Cl)C>[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:14]=[CH:13][CH:12]=[C:9]([C:10]#[N:11])[CH:8]=3)[CH2:2][CH2:3]2)[CH:19]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: N#Cc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(CN2CCN(c3cccc(C#N)c3)CC2)c1
Reaction time: 24 h
Yield: 80.5 %

Procedure:
Dissolve 3-piperazin-1-yl-benzonitrile (0.19 g, 1.00 mmol), 3-formyl-benzoic acid methyl ester (0.33 g, 2.00 mmol) and AcOH (0.64 mL, 10.0 mmol) in 5 mL dichloroethane. Add NaBH(OAc)3 (0.42 g, 2.00 mmol) and stir the mixture overnight. Add another portion of NaBH(OAc)3 (0.42 g, 2.00 mmol) and stir the mixture an additional 24 h. Concentrate the crude reaction mixture under a stream of N2. Dissolve the residue into 5% HCl and apply to a Dowex column. Wash the column with 1×50 mL 5% HCl, 2×50 mL H2O, 2×50 mL of MeOH and 2×50 mL of dichloromethane. Liberate the basic residues by washing the resin with 3×30 mL of 10% NH3/MeOH and 2×20 mL of dichloromethane. Concentrate the basic washings to give 0.27 g of 3-[4-(3-cyano-phenyl)-piperazin-1-ylmethyl]-benzoic acid methyl ester as a clear oil. 1H NMR indicates some contamination with starting amine. The mixture is carried on without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10]O.P(Cl)(Cl)(Cl)(Cl)[Cl:13].O>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1]
Reactant: COc1cccc(CO)c1F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(CCl)c1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of (2-fluoro-3-methoxyphenyl)methanol (13 g, 83.2 mmol) in CCl4 (75 mL), PCl5 (26 g, 128.7 mmol) was added. The resulting mixture was heated at 90° C. for 30 min and then stirred at room temperature for 1 h. The mixture was poured into water (160 mL) and extracted with dichloromethane (2×150 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (1:15 EtOAc/petroleum ether) to give the title compound (11.5 g). 1H NMR (CDCl3): δ 7.10-6.91 (m, 3H), 4.63 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26]>>[CH3:21][O:22][C:23]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:24]=1[C:25]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:26]
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Product: COc1ccc(C(=O)N2CC3CN(c4nccc(-c5ccccc5)n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2,4-dimethoxybenzoic acid. MS (ESI) mass calcd. for C25H26N4O3, 430.51; m/z found, 431.2 [M+H]+.
Reaction SMILES: FC1C=CC2OC(C(N3CCN(CC4C=CC=CC=4)CC3)=O)CC=2C=1.Cl.[O:27]([CH:34]([CH2:50][CH3:51])[C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:39][CH2:38]1)=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:27]([CH:34]([CH2:50][CH3:51])[CH2:35][N:37]1[CH2:38][CH2:39][N:40]([CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:41][CH2:42]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC(Oc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C(C1Cc2cc(F)ccc2O1)N1CCN(Cc2ccccc2)CC1
Product: CCC(CN1CCN(Cc2ccccc2)CC1)Oc1ccccc1

Procedure:
By carrying out the preparation as in Example 1, but replacing 1-[(5-fluoro-2,3-dihydrobenzofur-2-yl) carbonyl]-4-benzylpiperazine with the 1-(2-phenoxybutyryl)-4-benzylpiperazine hydrochloride obtained in Example 8, the title product is obtained.
Reaction SMILES: [CH2:1]([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27].Cl>C(=S)=S>[C:26]([C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[C:11](=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:21][CH:20]=3)[CH2:12][C:13]=2[CH:14]=1)(=[O:28])[CH3:27]
Reactant: CCCCCCCCc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCCCCc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2
Temperature: -20 °C
Reaction time: 0.83 h
Yield: 76.6 %

Procedure:
To a solution of 4.50 g (16.2 mM) of 2-octylfluorene in 50 ml of dry carbon disulfide, 2.70 g (20.2 mM) of pulverized anhydrous aluminum chloride was added while being cooled on an ice-common salt bath. Under cooling on the bath, 1.20 ml (16.9 mM) of acetyl chloride was added dropwise to the mixture below 7° C., followed by stirring for 1 hour and 50 minutes at 10° C. or below. After the reaction, the reaction mixture was poured into a mixture of 50 g of ice and 15 ml of hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate, and condensed, followed by cooling to about -20° C. to precipitate a crystal. The crystal was recovered by filtration to obtain 3.97 g of 2-acetyl-7-octylfluorene (Yield: 76.6%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](Br)[CH:26]([CH3:28])[CH3:27].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC(C)C)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][CH:26]([CH3:28])[CH3:27])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)Cn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)Cn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 51 %

Procedure:
The title compound (0.031 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using isobutyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-isobutyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester from the alkylation step. MS (ESI): exact mass calculated for C17H22ClN3, 303.15; found, m/z 304.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.64 (d, J=6.6 Hz, 2H), 7.56 (d, J=6.6 Hz, 2H), 4.20 (d, J=7.4 Hz, 2H), 3.72-3.69 (br m, 2H), 3.62-3.60 (br m, 2H), 3.44-3.42 (br m, 2H), 3.29-3.27 (br m, 2H), 2.35 (m, 1H), 1.14 (d, J=6.7 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:25]4[CH:26]=[CH:27][S:23][CH:24]=4)[C:3]=3[F:22])[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: OB(O)c1ccsc1
Reactant: NC(=O)c1cc(Br)c(F)c2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2ccsc2)c(F)c2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 130 °C
Reaction time: 0.3 h
Yield: 60.1 %

Procedure:
A mixture of 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-fluoro-1H-indole-7-carboxamide (15 mg, 0.039 mmol), 3-thiopheneboronic acid (9.86 mg, 0.077 mmol), and K2CO3 (15.98 mg, 0.116 mmol) was taken up in 1,4-dioxane (0.2 mL) and water (0.100 mL). The mixture was degassed with argon for 10 min, and PdCl2(dppf) (2.82 mg, 3.85 μmol) was added. The vial was sealed, and the reaction was heated in a Biotage microwave for 30 min at 130° C. on high absorption. The aqueous layer was removed via pipette, and the reaction mixture was filtered through a Stratosphere PL-Thio MP SPE cartridge (0.5 g), eluting with 1:1 DCM/MeOH (10 mL). The eluent was concentrated under a stream of nitrogen at 50° C., and the crude product was dissolved in DMSO (1.2 mL) and purified on a Gilson HPLC (XBridge C18 5 mm OBD 19×100 mm preparatory column), eluting at 15 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1% NH4OH) to 70% CH3CN/H2O (0.1% NH4OH) over 18 min. The desired fractions were concentrated under a stream of nitrogen at 50° C. and dried under high vacuum, giving 9.2 mg (61%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]([C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)C(=O)C)=[N:6][C:5]=1[CH3:19])(=[O:3])[CH3:2].[BrH:20].BrBr>CC(O)=O>[BrH:20].[Br:20][CH2:2][C:1]([C:4]1[S:8][C:7]([NH:9][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[N:6][C:5]=1[CH3:19])=[O:3]
Reactant: CC(=O)c1sc(N(C(C)=O)c2cnccn2)nc1C
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1nc(Nc2cnccn2)sc1C(=O)CBr
Temperature: 60 °C
Reaction time: 2 h
Yield: 1249.3 %

Procedure:
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-N-pyrazin-2-ylacetamide (511.2 mg; 1.85 mmol; 1 eq.) is dissolved in AcOH (10 ml). Hydrobromic acid (32 μl; 0.19 mmol; 0.10 eq.) is added, followed by a solution of bromine (95 μl; 1.85 mmol; 1 eq.) in AcOH (2 ml). The mixture is stirred 3 h at rt and 2 h at 60° C. To complete the reaction, bromine (95 μl; 1.85 mmol; 1 eq.) in AcOH (2 ml) is added and the mixture is stirred 4 h at 60° C. Solvents are evaporated and the resulting dark brown solid is suspended in THF, filtered and washed with cyclohexane, affording Intermediate 3 as yellow solid (467.7 mg; 64%). It is used in bisthiazol synthesis as HBr salt or as parent, after 5 min treatment with Amberlyst A21 in DCM/MeOH mixture. 1H NMR (DMSO-d6, 300 MHz) δ 2.60 (s, 3H), 4.64 (s, 2H), 8.24 (d, J=2.6 Hz, 1H), 8.43 (dd, J=1.5 Hz, J=2.6 Hz, 1H), 8.50 (d, J=1.5 Hz, 1H). M+ (ESI): 312.9. HPLC (Method A), Rt: 2.80 min (purity: 97%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:30]/[O:31][CH:32]([F:34])[F:33])/[C:27](O)=[O:28])[N:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:36][C@@H:37]1[C:60](=[O:61])[N:39]2[C:40]([C:48]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=3)=[O:49])=[C:41](/[CH:44]=[CH:45]\[CH2:46][Cl:47])[CH2:42][S:43][C@H:38]12>>[C:1]([NH:20][C:21]1[S:25][N:24]=[C:23](/[C:26](=[N:30]/[O:31][CH:32]([F:33])[F:34])/[C:27]([NH:36][C@@H:37]2[C:60](=[O:61])[N:39]3[C:40]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=4)=[O:49])=[C:41](/[CH:44]=[CH:45]\[CH2:46][Cl:47])[CH2:42][S:43][C@H:38]23)=[O:28])[N:22]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)/C(=N\OC(F)F)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: Cl
Product: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(F)F)c4nsc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 88.8 %

Procedure:
In the same manner as described in Experiment 3, 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-difluoromethoxyiminoacetic acid (2.00 g) was reacted with p-methoxybenzyl 7β-amino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride (1.795 g) to obtain the object product (3.17 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10](O)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.NC1C=CC=C2C=1[CH:24]=[C:23]([OH:26])[CH:22]=[CH:21]2.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:9]=2[CH:24]=[C:23]([OH:26])[CH:22]=[CH:21]3)[CH2:4][CH2:3]1
Reactant: Nc1cccc2ccc(O)cc12
Reactant: CN1CCN(c2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc3ccc(O)cc23)CC1
Yield: 48 %

Procedure:
Compound 16A is prepared according to the same procedure as 13A, using the following reactants: 8-aminonaphthalen-2-ol (1.6 g, 10 mmol) 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (2 g, 10.4 mmol), sodium carbonate (0.54 g, 5 mmol), 1-butanol (20 ml).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@H]2CC(C)C)=CC=1)(O)C.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2CC(C)C)=CC=1)(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:31][C:2]([F:1])([F:30])[C@@:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:20])[CH2:14][C@H:13]2[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: CC(C)C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@@](C)(O)C(F)(F)F)cc1
Agent: CC(C)C[C@@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Agent: CC(C)C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@](C)(O)C(F)(F)F)cc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: CC(C)C[C@@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc([C@@](C)(O)C(F)(F)F)cc1

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(2-methylpropyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(2-methylpropyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(2-methylpropyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CDCl3) δ 7.64-7.62 (m, 1H), 7.57-7.55 (m, 1H), 7.43-7.40 (d, J=8.8 Hz, 2H), 7.17-7.14 (m, 1H), 6.81-6.79 (d, J=8.8 Hz, 2H), 3.97-3.90 (m, 1H), 3.75-3.68 (m, 2H), 3.44-3.39 (m, 1H), 3.34-3.27 (m, 1H), 2.71-2.67 (m, 1H), 2.63-2.57 (m, 1H), 1.87-1.79 (m, 1H), 1.65-1.60 (m, 1H), 1.74 (s, 3H), 1.23-1.19 (m, 1H), 0.92-0.88 (m, 6H). m/z (ESI, +ve ion) 477.1 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.655 μM; GK-GKRP EC50 (LC MS/MS)=1.02 μM.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.[F:31][C:32]([F:43])([F:42])[CH2:33]OS(C(F)(F)F)(=O)=O>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[CH2:33][C:32]([F:43])([F:42])[F:31])=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(CC(F)(F)F)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 1, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and 2,2,2-trifluoroethyltrifluoromethanesulfonate. The desired product was obtained in a yield of 15% as white solid. MS (m/e): 580.1 (M+H, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1.Cl.[OH-].[Na+]>O.CO.C(O)C>[NH2:28][C:24]1[N:25]=[C:26]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([CH2:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[CH:22][N:23]=1
Reactant: Nc1nccc(Cl)n1
Reactant: N#Cc1c[nH]c2nccc(Cc3ccc(N)cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: N#Cc1c[nH]c2nccc(Cc3ccc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
120 mg (0.45 mmol) of 4-(4-amino-2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 64 mg (0.50 mmol) of 4-chloropyrimidine-2-amine are suspended in 4 ml of water, 2 ml of ethanol and 0.23 ml of 4N hydrochloric acid. The reaction mixture is heated at reflux for 2 hours. After cooling, the mixture is made alkaline using dilute aqueous sodium hydroxide solution, a little methanol is added, the mixture is extracted with ethyl acetate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC. This gives crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:6][C:7]([N+:13]([O-])=O)=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10]>CO.[Fe]>[NH2:13][C:7]1[CH:6]=[C:5]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:4]([O:3][CH3:2])=[CH:12][C:8]=1[C:9]([NH2:11])=[O:10]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(C(N)=O)c(N)cc1OCCCN1CCOCC1
Temperature: 60 °C

Procedure:
Concentrated hydrochloric acid (30 ml) was added to a suspension of 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzamide (5.67 g) in methanol (150 ml) and the mixture was heated to 60° C. When the 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzamide had dissolved, iron powder (5.6 g, 100 mmol) was added in portions to the reaction mixture which was then heated for 90 minutes. After cooling, the insolubles were removed by filtration through diatomaceous earth, the volatiles were removed from the filtrate by evaporation and the residue was purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water and then with hydrochloric acid (pH2). Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 2-amino-5-methoxy-4-(3-morpholinopropoxy)benzamide as a hydrochloride salt (4.67 g, 75%) as beige crystals.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][CH:21]=3)[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:24]>O1CCOCC1>[ClH:24].[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][CH:21]=3)[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1
Reactant: O=c1[nH]c2ncncc2n1C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ncncc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 7-(1-benzylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one (1.2 g, 3.7 mmol) in 4 N hydrogen chloride in dioxane (50 mL), was stirred vigorously at room temperature for 3 h. The reaction was concentrated in vacuo to give the title compound as a white solid. MS 220 (M+1)