Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7]([NH2:26])=[O:8]
Reactant: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(N)=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of 4-methyl-2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (100 mg, 0.3 mmol) in DMF (3 mL) was added 1,1′-carbonyldiimidazole (60 mg, 0.36 mmol). The resulting reaction mixture was stirred for 1 h at 60° C. and then treated with an ammonium hydroxide solution (455 μL, 3.0 mmol) and stirred for 2 h at room temperature. The reaction mixture was then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 8:2 to 1:1) afforded the title compound (79 mg, 79%) as an off white solid. MS: m/e=329.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].Cl.[CH2:24](O)[CH3:25]>>[CH2:24]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[CH2:6][CH:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25]
Reactant: CN(C)CCC(Cc1ccccc1C(=O)O)c1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccccc1CC(CCN(C)C)c1ccccc1

Procedure:
A solution of 29.7 g. (0.1 mole) of 2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid in 200 ml. of ethanol is saturated with gaseous hydrochloride, and the resulting mixture is refluxed for 18 hours. The solvent is removed in vacuo and the residue is partitioned between ether and 2N sodium hydroxide. The ether extract is dried and evaporated in vacuo to give 2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid ethyl ester.
Reaction SMILES: C([O:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[N:37]=[CH:36][CH:35]=[N:34]3)=[O:30])[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[OH:16][B:15]1[CH:14]([NH:28][C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[N:37]=[CH:36][CH:35]=[N:34]3)=[O:30])[CH2:13][C:9]2[C:8](=[C:7]([C:6]([OH:5])=[O:43])[CH:12]=[CH:11][CH:10]=2)[O:23]1
Reactant: COc1c(CC(NC(=O)c2ccc3nccnc3c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: O=C(NC1Cc2cccc(C(=O)O)c2OB1O)c1ccc2nccnc2c1

Procedure:
Prepared from 2-Methoxy-3-[2-[(quinoxaline-6-carbonyl)-amino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 364.0 (MH)+.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][CH2:5]1>C1COCC1>[CH3:10][C:7]1([CH3:11])[CH2:8][CH2:9][CH:4]([CH:3]=[O:2])[CH2:5][CH2:6]1
Reactant: COC=C1CCC(C)(C)CC1
Solvent: C1CCOC1
Product: CC1(C)CCC(C=O)CC1
Temperature: 0 °C

Procedure:
A solution of flask 4-(methoxymethylene)-1,1-dimethylcyclohexane (2.3 g, 14.9 mmol) in a 4:1 THF/2N HCl mixture (100 mL) was refluxed fo(1 hour. The volatile was removed in vacuo and the residue was cooled to 0°C. and neutralized with 1N NaOH and extracted with Et2O (3×60 mL). The organic layer was washed with water (50 mL), brine (60 mL) and dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography with hexane-DCM 10% linear gradient as eluant to give the title compound as clear oil. 1H NMR (400 MHz, CDCl3) δ 9.64 (d, J=1.6 Hz, 1H), 2.19-2.12 (m, 1H), 1.79-1.72 (m, 2H), 1.59-1.40 (m, 5H), 1.25-1.18 (m, 1H), 0.92 (s, 3H), 0.87 (s, 3H). No ionization by LCMS.
Reaction SMILES: [K+].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cc1cc2c(cc1Cl)NC(=O)CN2
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a stirred bright orange solution of N-(4′-chloro-5′-methyl-2′-nitrophenyl)glycine potassium salt (0.097 g, 0.36 mmol) in water (5.0 mL) at 80° C., sodium dithionite (0.500 g, 2.87 mmol) was added in two equal portions. It instantly formed a white suspension, which was stirred at 80° C. for 1 h. It was then cooled at room temperature and the solid was vacuum filtered, washed with water (5.0 mL), and dried in vacuo to yield 0.062 g (86%) of the title compound as a white powder; 1H NMR (DMSO-d6): δ 2.10 (s, 3H), 3.66 (s, 2H, J=1.2 Hz), 5.98 (s, 1H), 6.53 (s, 1H), 6.67 (s, 1H), 10.20 (s, 1H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[OH-].[K+].[CH2:8]=[CH:9][CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.Cl>O>[CH2:8]=[CH:9][CH2:10][CH2:11][O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: OCCCO
Reactant: C=CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CCCOCCCO
Temperature: 75 °C
Reaction time: 3 h
Yield: 13.8 %

Procedure:
Into a reactor, 1,3-propanediol (46.7 g) and potassium hydroxide (34.5 g) were charged and stirred, and heated at the internal temperature of 75° C. for 30 minutes. At the internal temperature of 80° C., CH2═CH(CH2)2OTs (69.5 g) obtained in EXAMPLE 3-1 was added thereto over 3 hours and standed as it is after stirring for 1 hour. The reaction mixture was poured into water (250 ml) and neutralized by adding hydrochloric acid. After filtration, the filtrate was extracted with t-butyl methyl ether (300 ml) four times. The organic layer put together was dried over magnesium sulfate and subjected to filtration, and the solvent was distilled off to obtain 5.5 g of CH2═CH(CH2)2O(CH2)3OH.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[N:18]#[C:19][NH2:20]>CO>[C:19]([NH:20][C:14](=[NH:17])[CH2:13][CH2:12][CH2:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)#[N:18]
Reactant: N#CN
Reactant: COC(=N)CCCCc1csc(NC(=N)N)n1
Solvent: CO
Product: N#CNC(=N)CCCCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
In 10 ml of methanol solution of 2.5 g of methyl 5-(2-guanidinothiazol-4-yl)pentanoimidate was added 0.6 g cyanamide, and the solution was stirred at room temperature for 1.5 hour. The solvent was distilled off, and to the residue was added 10 ml of acetone. The precipitated crystals were filtered off and the product was purified by using dimethylformamide-water. The purified product was dissolved in a mixture of 0.7 ml of acetic acid, 8 ml of ethanol and 16 ml of water, to the solution 11.6 ml of N-NaOH solution was added. The precipitated crystals were collected by filtration to provide 1.9 g of N-cyano-5-(2-guanidinothiazol-4-yl)pentanoamidine.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[S:8][C:9]([CH:12]=O)=[CH:10][N:11]=2)=[CH:4][CH:3]=1.[C:16]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[S:8][C:9](/[CH:12]=[CH:21]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cnc(Oc2ccc(Cl)cc2)s1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cnc(Oc2ccc(Cl)cc2)s1
Temperature: 25 °C

Procedure:
A solution of 2-(4-chlorophenoxy)-5-thiazolecarboxaldehyde from above and (carboethoxymethylene)triphenylphosphorane (9.51 g, 27.3 mmol) in toluene (125 mL) was refluxed for 1 hr. It was then cooled to r.t. and concentrated in vacuo. The residue was taken up in ether and the triphenylphosphine filtered off. The filtrate was concentrated to afford ethyl trans-3-(2-(4-chlorOphenoxy)-5-thiazolyl)propenoate which was used as is.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+].CC#N>C1COCC1>[CH:15]([C:14]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:13]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: O=C(O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1
Yield: 14.8 %

Procedure:
3-Hydroxyphenylacetic acid (1.0 g, 5.2 mmol), 2-fluoro-5-(trifluoromethyl)benzaldehyde (1.0 g, 6.6 mmol), and potassium carbonate (2.2 g, 15.6 mmol) were combined in THF (20 mL) and MeCN (20 mL) and heated to 70° C. for 3 days. After acidic work-up, the crude material was purified by silica gel chromatography (20-100% EtOAc in hexanes) to give the desired product (0.25 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O.C(#N)C>[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:23])([F:24])[F:1])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1)[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)C(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(=O)N(Cc1cccc(C)c1)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of methyl N-[4′-(trifluoromethoxy)biphenyl-4-yl]oxamate (250 mg, 0.737 mmol), 3-methylbenzyl bromide (0.299 ml, 2.21 mmol), potassium carbonate (306 mg, 2.21 mmol), 18-crown-6 (20 mg, 0.074 mmol) and acetonitrile (10 ml) was stirred at 50° for 3 hors under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (320 mg, 98%) as a colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O.Br>ClCCl>[CH3:1][C@@H:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: OCCBr
Agent: Br
Solvent: ClCCl
Product: C[C@H]1NCCc2ccccc21
Temperature: 51 °C
Reaction time: 50 h
Yield: 137.5 %

Procedure:
76.61 g(630 mmole) of (R)-(+)-α-methylbenzylamine was dissolved in 77 ml of dichloromethane and 94.8 g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 ml(2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and then allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate, and then dried to obtain 127.5 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)CCCCCCl
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)CCCCCCl)c(C)c1
Yield: 43 %

Procedure:
Prepared analogously to Example 83a from methyl 4-amino-3-methyl-benzoate and 5-chloropentyl-sulphonic acid chloride in pyridine. Yield: 43%
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([CH2:13][C:14]([O-:16])=O)=O)=[CH:9][CH:8]=2)[C:5]([CH3:19])=[N:4][C:3]=1[CH:20]1[O:24]CCO1.[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29]([NH2:33])=[C:28]([NH2:34])[CH:27]=1.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH3:25][C:26]1[C:31]([CH3:32])=[CH:30][C:29]2[NH:33][C:14](=[O:16])[CH2:13][C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:6]4[C:2]([Cl:1])=[C:3]([CH:20]=[O:24])[N:4]=[C:5]4[CH3:19])=[CH:18][CH:17]=3)=[N:34][C:28]=2[CH:27]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: Cc1nc(C2OCCO2)c(Cl)n1-c1ccc(C(=O)CC(=O)[O-])cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)NC(=O)CC(c1ccc(-n3c(C)nc(C=O)c3Cl)cc1)=N2
Temperature: 70 °C

Procedure:
A solution of 4-[5-chloro-4-(1,3-dioxolan-2-yl)-2-methylimidazol-1-yl]benzoylacetate from Preparation 5 (155 mg, 0.38 mmol), and 4,5-dimethyl-1,2-diaminobenzene (55 mg, 0.4 mmol) in toluene (4 ml) was heated at reflux for 4.5 hours, then evaporated to dryness and purified by flash chromatography (eluting with ethyl acetate) to afford a pale yellow gum. 1M HCl (2 ml) was added to a solution of the residue in THF (2 ml) and the mixture was heated to 70° C. for 1 hour. The THF was evaporated and the residue was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was dried over magnesium sulphate and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].N1C=CC=CC=1.[Cl:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21].Cl>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])=[O:21]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: NCc1ccc(F)cc1F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(CCl)C(=O)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
28.6 g (0.20 mol) of 2,4-difluorobenzylamine and 19.0 g (0.24 mol) of pyridine are dissolved in 100 ml of toluene. 34.1 g (0.22 mol) of chloropivaloyl chloride are added dropwise to this solution at 20°-25° C. over the course of 15 minutes with ice-bath cooling. A suspension forms and is stirred for a further 3 hours at room temperature until the reaction is complete (GC check). For work-up, the pH is adjusted to between 1 and 2 using 50 ml of 2N hydrochloric acid. The white emulsion produced is extracted three times with 100 ml of toluene. The extract is washed with 100 ml of water, dried using magnesium sulfate and evaporated on a vacuum rotary evaporator. 49.2 g (94% of theory) of a yellow oil are obtained.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[C:16](Cl)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>N1C=CC=CC=1>[C:16]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reaction time: 0.33 h

Procedure:
To 1-hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo-(4,5-b)pyridine (2.37 grams) in 5 milliliters of pyridine was added octanoyl chloride (1.63 grams). The addition was carried out portionwise with stirring and resulted in the precipitation of a white solid. The reaction mixture was set on a steam bath for 20 minutes, then poured over ice cold aqueous HCl. An oil separated and subsequently crystallized on vigorous stirring. This precipitate was removed by filtration, dissolved in ether, dried over magnesium sulfate, filtered, and ether removed by evaporation under vacuum. The substance was purified by distillation, m.p., 33.5°-35.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([F:21])[CH:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1cccc(F)c1
Product: O=C(NCc1cccc(F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 3-fluorobenzylamine (14.0 mg, 0.12 mmol). The title compound was obtained as a solid (22.5 mg, 49% yield). MS m/z: 457.96, 459.96 [M+H]+.
Reaction SMILES: [CH3:1][N:2](C1CCCCO1)[C:3]1[S:4][C:5]([CH2:8][NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][N:7]=1>C(O)(C(F)(F)F)=O.C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]1[S:4][C:5]([CH2:8][NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[CH:6][N:7]=1
Reactant: CN(c1ncc(CNc2nccs2)s1)C1CCCCO1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncc(CNc2nccs2)s1
Yield: 77.3 %

Procedure:
A solution of N-methyl-N-(tetrahydro-2H-pyran-2-yl)-5-((thiazol-2-ylamino)methyl) thiazol-2-amine (50 mg, 0.16 mmol) in 10% TFA in CHCl3 (5 mL) was stirred at RT overnight. After evaporating the solvent, the residue was dissolved in MeOH, neutralized with Na2CO3 and extracted with CHCl3. The organic phase was dried, concentrated and purified by column chromatography yielding N-methyl-5-((thiazol-2-ylamino)methyl)thiazol-2-amine (28 mg, 77%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH:22][OH:23])([CH3:21])[CH3:20]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:22]([CH:19]([CH3:21])[CH3:20])[O-:23])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NO
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Product: COc1cc(C=[N+]([O-])C(C)C)ccc1OCc1ccccc1

Procedure:
The title compound was prepared according to the procedures described in Examples 11 using 4-benzyloxy-3-methoxybenzaldehyde and N-isopropylhydroxylamine. The title compound was isolated in 54.6% yield as a solid, m.p. 95.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>>[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:19][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[CH3:18])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:25]
Reactant: O=C(O)c1cccc(F)c1
Reactant: Cc1cc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Product: Cc1cc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1cccc(F)c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine with 3-fluoro-benzoic acid. LCMS: RT=2.26 minutes, MS: 382 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[S:21])[NH2:6]
Reactant: NC(=O)c1c(F)cccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)c1c(F)cccc1F
Yield: 99 %

Procedure:
A solution of 2, 6 difluorobenzamide (1 eq) and Lawesson's reagent (0.5 eq.) in toluene (0.2 M) was heated at 90° C. for 14 hours. Upon cooling the volatiles were removed in vacuo and purified by SiO2 chromatography (25% EtOAc/hexanes) yielding 2,6-difluorobenzothioamide as a light yellow solid (99%). LCMS (m/z): 174.1 (MH+); LC Rt=2.19 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:17]O)[CH:13]=2)[CH:8]=[N:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:48])C(=O)C1>C(Cl)Cl>[Br:48][CH2:17][C@@H:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[N:7][N:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCn1ncc2ccc(C[C@@H](CO)C(C)C)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCCn1ncc2ccc(C[C@@H](CBr)C(C)C)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of (R)-2-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutan-1-ol (100 mg, 0.3 mmol) in dry CH2Cl2 (3 mL) at 0° C., Ph3P (140 mg, 0.6 mmol) and NBS (95 mg, 0.6 mmol) were added in portions. After stirring for 12 h at rt, the mixture was evaporated and the residue was purified by flash chromatography on silica gel to afford (R)-6-(2-(bromomethyl)-3-methylbutyl)-1-(3-methoxypropyl)-1H-indazole (70 mg, 62%). 1H NMR (400 MHz, CDCl3): 1.02 (m, 6H), 1.74 (m, 1H), 1.89 (m, 1H), 2.17 (m, 2H), 2.71 (m, 1H), 2.95 (m, 1H), 3.32 (s, 3H), 3.43 (m, 1H), 4.45 (m, 2H), 6.98 (d, 1H), 7.27 (s, 1H), 7.63 (d, 1H), 7.95 (s, 1H); MS: 432 (M++1)
Reaction SMILES: CN1CCOCC1.[CH3:8][C@H:9]1[C:13](=[O:14])[O:12][C:11](=[O:15])[NH:10]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:16]([N:10]1[C@@H:9]([CH3:8])[C:13](=[O:14])[O:12][C:11]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H]1NC(=O)OC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: C[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reaction time: 2 h
Yield: 73.9 %

Procedure:
4-Dimethylaminopyridine (61 mg, 0.5 mmol) and N-methylmorpholine (152 mg, 1.5 mmol) were dissolved in ethyl acetate (15 mL), followed by the addition of (S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (230 mg, 2.0 mmol) under ice cooling. Further, a solution of benzoyl chloride (281 mg, 2.0 mmol) in ethyl acetate (7 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound as white crystals (324 mg, 74%).