Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[Cl-].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C@@H:21]([NH3+:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:21]([NH:28][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([Br:1])[CH:3]=1)[CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])[CH3:27]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CCOC(=O)C[C@H]([NH3+])Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccccc1Cl)NC(=O)c1ccc(C)c(Br)c1
Reaction time: 1 h

Procedure:
3-Bromo-4-methylbenzoic acid (331 mg, 1.5 mmol, 1.0 eq.) and (R)-2-(2-chloro-phenyl)-1-ethoxycarbonylmethyl-ethyl-ammonium chloride (428 mg, 1.5 mmol, 1.0 eq.) were combined with DIPEA (844 μL, 3.2 eq.) and HATU (585 mg, 1.5 mmol, 1.0 eq.) in DCM (8 mL). The resulting mixture was stirred for 1 hour, then chromatographed (0-80% EtOAc/hexanes gradient) to yield (R)-3-(3-bromo-4-methyl-benzoylamino)-4-(2-chloro-phenyl)-butyric acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH2:19][CH2:20][CH2:21][S:22][CH2:23][CH3:24])=[C:16]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:15]([C:32]#[N:33])=[N:14]1.[H-].[Na+].I[CH3:37].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([N:18]([CH2:19][CH2:20][CH2:21][S:22][CH2:23][CH3:24])[CH3:37])=[C:16]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:27])[C:15]([C:32]#[N:33])=[N:14]1
Reactant: CI
Reactant: CCSCCCNc1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSCCCN(C)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-(3-ethylthiopropylamino)-4-trifluoromethylsulfonylpyrazole (2.0 g, 3.6 mmol) in tetrahydrofuran at 20° C. under nitrogen, was added sodium hydride (0.461 g, 60% in oil, 11.5 mmol), and stirred for 0.5 hour. Iodomethane (2.065 g, 14.4 mmol) was added and the mixture stirred for 4.5 hours at 20° C., then allowed to stand for 2.5 days. The mixture was added to ethyl acetate and saturated ammonium chloride solution. The organic layer was washed with water and brine, dried (sodium sulfate), evaporated and chromatographed on silica gel eluting with heptane-ethyl acetate (3:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-[N-(3-ethylthiopropyl)-N-methylamino]-4-trifluoromethylsulfonylpyrazole as a light brown solid (Compound number 2-14, 1.3 g, 57% yield), mp 89° C.
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC(C(C(O)=O)C3C=CC=CC=3)=O)C(=[O:9])N2[C@H]1C(O)=O.CC(S[C@@H:31]1[O:36][C@H:35]([CH2:37][OH:38])[C@H:34]([OH:39])[C@H:33]([OH:40])[C@H:32]1[OH:41])C.[Mg+2].[Cl-].[Cl-].[Na+].[Cl-].C([O-])([O-])=O.[Ca+2]>>[O:38]=[C:37]1[O:40][C@H:33]([C@H:32]([CH2:31][OH:36])[OH:41])[C:34]([OH:39])=[C:35]1[OH:9]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)C(C(=O)O)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 2 h

Procedure:
Five ml of one overnight culture of E. coli BL21 (DE3)/pET21b-SNDHaiHis in LB with carbenicillin 50 μg/ml was inoculated into 200 ml of the same medium. The cells were cultivated at 230 rpm at 37° C. for 2 h, then induced with 1 mM IPTG and continued to be cultivated at 230 rpm at 25° C. for 3 h. The resulting culture was centrifuged and washed twice with saline and the cell pellet was resuspended in 2 ml of water. The cells were used for resting cell reaction with the reaction mixture (500 μl in 5 ml tube) containing cells at OD600=10, 1% sorbosone monohydrate, 5 μM PQQ, 5 mM MgCl2, 0.3% NaCl, and 1% CaCO3 conducted at 30° C. for 15 h. 0.14 g/L of L-ascorbic acid was produced after incubation for 15 h. When the resting cell reaction was done with 1 μM PQQ (the other conditions were same as those described above), 0.05 g/L of L-ascorbic acid was produced after incubation for 3 h.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(N(C(C)C)CC)(C)C.Br[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]#[N:34])=[O:27]>CN(C)C=O>[CH2:13]([O:12][C:10]([C:5]12[CH2:4][CH2:3][C:2]([NH:1][CH2:25][C:26]([N:28]3[CH2:32][CH2:31][CH2:30][C@H:29]3[C:33]#[N:34])=[O:27])([CH2:9][CH2:8]1)[CH2:7][CH2:6]2)=[O:11])[CH3:14]
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C12CCC(NCC(=O)N3CCC[C@H]3C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate (115 mg) was dissolved in N,N-dimethylformamide (1.5 mL) and diisopropylethylamine (100 μL) was added to the solution. (2S)-1-(2-Bromoacetyl)pyrrolidine-2-carbonitrile (120 mg) in N,N-dimethylformamide (1 mL) was then added dropwise at room temperature. The mixture was stirred for 2 hours at room temperature and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant:chloroform:methanol=10:1) to give (2S)-1-[[N-(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (95.1 mg).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C@H:7]([OH:19])[C@H:8]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:36].[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[OH:19][C@H:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([I:36])=[CH:3][CH:4]=2)[C@@H:8]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1c2cc(N)ccc2C[C@@H]1O
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1c2cc(I)ccc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Cool a suspension of tert-butyl N-[(1S,2S)-6-amino-2-hydroxy-indan-1-yl]carbamate (25.0 g, 94.6 mmol) in acetonitrile (800 mL) in an ice bath for 30 min and add p-toluenesulfonic acid monohydrate (53.97 g, 283.7 mmol) in one portion. Add a solution of sodium nitrite (13.05 g, 189.2 mmol) in water (30 mL) to the mixture in portions for 5 min and stir for 30 min. Add a solution of potassium iodide (39.25 g, 236.5 mmol) in water (50 mL) dropwise to the mixture over 10 min. and stir for 20 min. in an ice bath. Allow the mixture to warm up to room temperature and stir for 1.5 hr. Make the dark red solution alkaline with 10% aqueous sodium carbonate. Concentrate the resulting mixture in vacuo to remove the acetonitrile. Collect the brown precipitate by filtration and dry in a vacuum oven at 50° C. overnight to obtain the title compound (33.9 g, 96%). LC-ES/MS m/z 320 [M+H]+.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=2)=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12.[Br:28]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:28][C:6]1[N:7]=[C:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=2)=[O:16])[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: COc1cc(C(=O)c2ncc3ccccn23)ccc1[N+](=O)[O-]
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)c2nc(Br)c3ccccn23)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
3.51 g (0.043 mol) of sodium acetate are added to 9.8 g (0.033 mol) of (imidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone obtained in example 1 in 170 ml of chloroform, followed, dropwise, by a solution of 1.85 ml (0.036 mol) of bromine in 15 ml of chloroform, the medium being maintained at ambient temperature. On completion of the introduction, the mixture is stirred for a further 1 hour at the same temperature. The reaction medium is poured onto a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase is separated by settling, washed with an aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in a toluene/dichloromethane mixture and then purified by filtration through a bed of silica gel, elution being carried out with toluene. After evaporation, 7.71 g of a yellow solid are collected. Melting point: 189° C.; 1H NMR (CDCl3): 4.10 (3H, s), 7.23-7.29 (1H, m), 7.41-7.46 (1H, m), 7.78 (1H, d), 7.96 (1H, d), 8.14-8.20 (2H, m), 9.90 (1H, d)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3C)CC2)c(C)c1
Yield: 9.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (822 mg) described in Preparation Example 67 and (R)-4-methyloxazolidin-2-one (364 mg) described in Preparation Example 25, the title compound (82 mg) was obtained.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:15]Br>ClCCl>[Br:15][C:3]1[C:4]2=[N:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=[C:9]2[O:1][CH:2]=1
Reactant: CCOC(=O)c1ccc2occc2n1
Reactant: BrBr
Solvent: ClCCl
Product: CCOC(=O)c1ccc2occ(Br)c2n1
Reaction time: 3.5 h
Yield: 35.4 %

Procedure:
To a solution of ethyl furo[3,2-b]pyridine-5-carboxylate (0.30 g, 1.57 mmol) in dichloromethane (5 mL) was added dropwise bromine (7.82 mL, 157 mmol) at room temperature, and the resulting mixture was stirred for 3.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). To this solution was added dropwise a 1 M potassium hydroxide ethanol solution (10 mL) at 0° C., and the resulting mixture was stirred at room temperature for 5 min. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=17/3-1/1) to give the title compound (0.15 g, yield 36%) as colorless crystals.
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[CH3:12][CH:13]([CH3:35])[C:14]([O:16][CH:17]([O:21][C:22]([NH:24][CH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]1)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15].C(=O)(O)[O-].[Na+:40].C(#N)C>O>[CH3:12][CH:13]([CH3:35])[C:14]([O:16][CH:17]([O:21][C:22]([NH:24][CH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([O-:34])=[O:33])[CH2:28][CH2:27]1)=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15].[Na+:40]
Reactant: CC(C)C(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)C(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 3.434 g (10.0 mmol) of trans-4-{[1-(2-methylpropanoyloxy)-2-methylpropoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid 44 was reacted with 840.1 mg (10.0 mmol) of sodium bicarbonate (NaHCO3) in 60 mL of a mixture of acetonitrile and water (1:2) to yield 3.654 g (quant.) of the title compound 45 as a colorless powder. 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.84 (m, 2H), 0.87-0.92 (m, 6H), 1.04-1.20 (m, 8H), 1.20-1.32 (m, 1H), 1.59-1.73 (m, 3H), 1.74-1.83 (m, 2H), 1.88-1.98 (m, 1H), 2.46-2.56 (m, 1H), 2.72-2.84 (br. m, 2H), 6.42 (d, J=5.6 Hz, 1H), 7.37 (t, J=5.6 Hz, 1H). MS (ESI) m/z 366.14 (M+Na)+; 342.16 (M−H)−.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[O:2].[N+:13]([O-])([OH:15])=[O:14]>>[CH:1]([NH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=2)[CH2:5]1)=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=CNC1Cc2ccccc2C1
Product: O=CNC1Cc2ccc([N+](=O)[O-])cc2C1
Reaction time: 1 h

Procedure:
2-Formylaminoindane (15 g) was added portionwise to fuming nitric acid (30 ml, density=1.5 g/ml) whilst keeping the temperature at between 0° and -5° . Stirring was continued for 1 hour at 0° before pouring the reaction mixture onto ice/water and extracting with methylene chloride. The organic layer was washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo to give an oil which was purified by column chromatography on silica eluting with methylene chloride containing hexane (20% down to 0%) and then methylene chloride containing methanol (0% up to 2%). The product-containing fractions were combined and evaporated to give the title compound, yield 7.7 g, m.p. 91°-92°.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:30]=[O:31])[CH2:25][CH2:24]4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH3:13])=[C:10]([F:29])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C=O)CC3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(rac)-5,7-Difluoro-6-[1-(6-piperazin-1-yl-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-quinoline (Example 6, 50 mg, 0.127 mmol) and 4-nitrophenyl formate (29.7 mg, 0.177 mmol) were dissolved in DCM (1.27 mL) and triethylamine (0.021 mL, 0.152 mmol) was added. The RM was stirred at RT for 0.5 h. The mixture was concentrated and the residue was purified by flash chromatography and afforded the title compound as a white foam (tR 3.25 min (conditions 1), MH+=423).
Reaction SMILES: [CH3:1][C:2]1[C:3]([Br:11])=[C:4]([C:6]([Br:10])=[CH:7][C:8]=1[Br:9])[NH2:5].[Br:12][CH2:13][C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Br:12][CH2:13][C:14]([NH:5][C:4]1[C:6]([Br:10])=[CH:7][C:8]([Br:9])=[C:2]([CH3:1])[C:3]=1[Br:11])=[O:15]
Reactant: O=C(Cl)CBr
Reactant: Cc1c(Br)cc(Br)c(N)c1Br
Solvent: Cc1ccccc1
Product: Cc1c(Br)cc(Br)c(NC(=O)CBr)c1Br
Temperature: 100 °C
Yield: 48.8 %

Procedure:
To a solution of 3-methyl-2,4,6-tribromoaniline (4.36 g, 12.7 mmol) in toluene (40 mL) at room temperature was added bromoacetyl chloride (1.20 mL, 14.6 mmol) and the slurry heated to 100° C. for 24 h. The reaction was cooled, filtered, washed with and placed on a high vacuum pump to provide 2.88 g (49%) of the title compound as a white solid. mp 207-209° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.52 (s, 3H) 4.07 (s, 2H) 8.05 (s, 1H) 10.38 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 24.2, 28.6, 121.3, 123.4, 127.2, 134.3, 134.9, 137.6, 164.4; MS (DCI/NH3) m/e 482 (M+NH4+); Anal. calcd for C9H7Br4NO: C, 23.26; H, 1.52; N, 3.01. Found: C, 23.30; H, 1.45; N, 2.94.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].O>CN(C)C=O.C(O)(=O)C>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:21][C:20]=1[CH2:19][O:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]=[C:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(O)cc2)S1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C=C2SC(=O)NC2=O)cc1
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
60% sodium hydride in oil (0.24 g) was added to a solution of 5-(4-hydroxybenzylidene)-2,4-thiazolidinedione (0.664 g) in N,N-dimethylformamide (20 ml), and the mixture was stirred for 30 minutes. A solution of 4-chloromethyl-5-methyl-2-phenyloxazole (0.623 g) in N,N-dimethylformamide (10 ml) was added dropwise to the mixture under ice-cooling. After stirring at room temperature for 5 hours, the reaction solution was poured into water. The aqueous mixture was made acid with acetic acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was chromatographed on a column of silica gel (50 g). From the fractions eluted with ethyl acetatehexane (1:2, V/V), there was obtained 5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidene]-2,4-thiazolidinedione (0.49 g, 40.8%). Recrystallization from chloroform-methanol afforded colorless prisms, m.p. 225°-226° C. Elemental analysis for C21H16N2O4S, Calcd.: C, 64.27; H, 4.11; N, 7.14. Found: C, 64.49; H, 3.96; H, 6.86.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([Cl:12])[C:5]=1[NH2:13].[C:15](O)(=O)C.C(N)=N>>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:13])=[C:6]([Cl:12])[C:7]2[NH:11][CH:15]=[N:10][C:8]=2[CH:9]=1)=[O:14]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(N)c(N)c(Cl)c1N
Agent: N=CN
Product: COC(=O)c1cc2nc[nH]c2c(Cl)c1N
Temperature: 80 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
See step e) of example H7 using 2,4,5-triamino-3-chloro-benzoic acid methyl ester as starting material and 2 equivalents of formamidine acetate. The reaction is stirred 2 days at a temperature of 80° C. Then the mixture is extracted with a solution of NaHCO3 saturated (2 times) and EtOAc. The organic phase is washed once with brine, dried on Na2SO4, filtrated and evaporated. A red-violet solid is obtained within 64% yield. LC/MS: 226/228 (M+1)+
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=1>>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[N:22][CH:23]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: COc1ncc(Br)cn1
Product: COc1ncc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1

Procedure:
Example 144 (E144) was prepared from 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) and 5-bromo-2-(methyloxy)pyrimidine (PCT Int. Appl. PCT (2002), WO 02/62423) using the method described for Example 140 (E140); MS (ES+) m/e 326 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH:9]([O:12][C:13]1[CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]2=[C:20]([C:22](OC)=[O:23])[CH:21]=1)([CH3:11])[CH3:10]>>[CH:9]([O:12][C:13]1[CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]2=[C:20]([C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)=[O:23])[CH:21]=1)([CH3:11])[CH3:10]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)c1cc(OC(C)C)cc2occc12
Product: Cc1ccc(NC(=O)c2cc(OC(C)C)cc3occc23)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 2-amino-5-methyl pyridine and methyl 6-isopropoxybenzofuran-4-carboxylate (344a) to give a white solid (28 mg, 37% yield). 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1 H) 8.29 (d, J=8.56 Hz, 1 H) 8.04 (d, J=2.52 Hz, 1 H) 7.65 (d, J=2.27 Hz, 1 H) 7.58 (dd, J=8.31, 2.27 Hz, 1 H) 7.34 (d, J=2.01 Hz, 1 H) 7.21-7.23 (m, 2 H) 4.55-4.64 (m, 1 H) 2.30 (s, 3 H) 1.37 (d, J=6.04 Hz, 6 H); LCMS for C18H18N2O3 m/z 311.10 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]=[N:19][NH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH3:34]OC(OC)N(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:9][CH2:10][N:11]([S:14]([C:17]2[N:18]=[N:19][N:20]([CH3:34])[CH:21]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1)=[O:5]
Reactant: O=C(NCC1(c2ncccc2F)CCN(S(=O)(=O)c2c[nH]nn2)CC1)c1ccc(Cl)cc1Cl
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: Cn1cc(S(=O)(=O)N2CCC(CNC(=O)c3ccc(Cl)cc3Cl)(c3ncccc3F)CC2)nn1

Procedure:
To a suspension of 2,4-dichloro-N-{[4-(3-fluoropyridin-2-yl)-1-[(1H-1,2,3-triazol-4-yl)sulfonyl]piperidin-4-yl]methyl}benzamide (0.15 g; 0.29 mmol) in toluene (5 ml) was added N,N-dimethylformamide dimethyl acetal (0.35 g; 0.4 ml; 2.92 mmol) and the mixture heated at reflux for 1 hour. The solvent was removed under vacuum and the residue azeotroped twice with toluene. The crude product was purified by preparative TLC on silica gel eluted with 3% methanol in DCM to give the title compound as the most polar isomer.(30 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=2[O:22][CH3:23])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]>[CH2:1]([N:8]1[C:12]([C:13]2[C:14]([O:22][CH3:23])=[CH:15][CH:16]=[CH:17][C:18]=2[NH2:19])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COc1cccc([N+](=O)[O-])c1-c1nnnn1Cc1ccccc1
Agent: [Pt]
Solvent: CCO
Product: COc1cccc(N)c1-c1nnnn1Cc1ccccc1
Reaction time: 18 h
Yield: 94.8 %

Procedure:
1-Benzyl-5-(2-methoxy-6-nitrophenyl)-1H-tetrazole (Intermediate 14, 0.14 g) was dissolved in ethanol (5 mL) under a nitrogen atmosphere. Platinum on carbon (10%, 0.01 g) was added and the nitrogen atmosphere was replaced by hydrogen. The mixture was stirred for 18 hours and then filtered through celite. The filtrate was evaporated to dryness to give the title compound as a brown gum (0.12 g).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](Cl)=[O:41].O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=3)=[O:41])[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Cl)c1ccccn1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(Nc1noc2ccccc12)N1CCN(C(=O)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added picolinoyl chloride hydrochloride (148 mg, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 53.0 mg (27.2%) of the desired product as a solid.