Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:27]([O:29][C:30](=[O:47])[C:31]([CH3:46])([CH3:45])[NH:32][C:33]([C:35]1[N:39]2[N:40]=[C:41](Cl)[CH:42]=[CH:43][C:38]2=[N:37][N:36]=1)=[O:34])[CH3:28].CN(C)[CH:50]=[O:51]>>[C:30]([OH:29])(=[O:47])/[CH:31]=[CH:46]/[C:17]([OH:18])=[O:51].[C:50]([OH:51])(=[O:8])/[CH:45]=[CH:31]/[C:30]([OH:47])=[O:29].[CH2:27]([O:29][C:30](=[O:47])[C:31]([CH3:46])([CH3:45])[NH:32][C:33]([C:35]1[N:39]2[N:40]=[C:41]([O:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:42]=[CH:43][C:38]2=[N:37][N:36]=1)=[O:34])[CH3:28]
Reactant: CCOC(=O)C(C)(C)NC(=O)c1nnc2ccc(Cl)nn12
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)NC(=O)c1nnc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
1.04 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 14 ml of N,N-dimethylformamide; 141 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature under reduced pressure for 50 minutes. Under ice cooling, 1.00 g of N-(6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)-2,2-dimethylglycine ethyl ester was added, followed by stirring at ice temperature for 1 hour, then at room temperature for 2 hours. After saline was added, the reaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1) and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; 1.62 g of the residue was dissolved in 2 ml of pyridine; 1 ml of acetic anhydride was added, followed by stirring at room temperature for 15 hours. After saline was added, the reaction mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; 1.32 g of the residue was dissolved in ethanol; a solution of 511 mg of fumaric acid in ethanol was added, followed by concentration under reduced pressure. The residue was powdered from diethyl ether and dried to yield 1.53 g of the title compound.
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[N:17]=[C:16]([CH:18]=[N:19][C:20]([C:25]#[N:26])=[C:21]([NH2:24])[C:22]#[N:23])[CH:15]=[N:14]1.O1CCCC1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][NH:19][C:20]([C:25]#[N:26])=[C:21]([NH2:24])[C:22]#[N:23])[CH:15]=[N:14]1
Reactant: N#CC(N)=C(C#N)N=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#CC(N)=C(C#N)NCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(2-amino-1,2-dicyanoethenylimino)methyl]-2H-1,2,3-triazole (8 g) (prepared as in Example 1) was dissolved in methanol (50 ml) and tetrahydrofuran (75 ml) and then sodium borohydride (0.76 g) was added portionwise. This mixture was stirred for 20 minutes at room temperature and then poured into water to give a brown solid. This was purified by flash column chromatography to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(2-amino-1,2-dicyanoethenylamino)methyl]-2H-1,2,3-triazole, m.p. 191°-192°. A mixture of this compound (1.8 g), nicotinamide (0.6 g), N-chlorosuccinimide (0.6 g) and dimethylformamide was heated at 65°-70° for 10 minutes. The mixture was poured into water and extracted with diethyl ether. Conventional work-up and purification by flash column chromatography gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(4,5-dicyano-4-imidazolin-2-yl)-2H-1,2,3-triazole, m.p. 219°-220° (dec). (Compound 10).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[C:4]([OH:15])[CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:5]=[C:4]([O:15][CH2:27][CH2:26][CH2:25][CH2:24][S:23][C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)[CH:3]=1
Reactant: Cc1ccc(SCCCCCl)cc1
Reactant: CC1(C)OC(=O)Nc2c(Cl)cc(O)cc21
Product: Cc1ccc(SCCCCOc2cc(Cl)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 4 from 8-chloro-6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(4-methylphenylmercapto)-butylchloride.
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1F)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>O>[Cl:5][C:6]1[CH:7]=[C:8]2[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[N:27]1[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]1)[NH:15][C:14]1[CH:13]=[N:12][CH:11]=[CH:10][C:9]2=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a DMSO solution (4 ml) of 200 mg (0.755 mmol) of 6-chloro-7-fluoro-8-nitro-9H-β-carboline was added 1-methylpiperazine (226 mg, 2.26 mmol) and DIEA (400 mg, 3.09 mmol) via a syringe. The reaction was allowed to stir at RT overnight. Upon addition of water, an orange solid precipitated out. The solid was filtered, washed and dried to give 236 mg (91% yield) of the desired 6-chloro-7-(4-methyl-piperazin-1-yl)-8-nitro-9H-β-carboline.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 3-trifluoromethyl-phenyl boronic acid to give the title compound as colorless amorphous solid. MS: 461.3 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([Cl:13])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([C:20]23[CH2:25][CH:24]2[CH2:23][NH:22][CH2:21]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[ClH:13].[C:20]12([C:14]3[CH:15]=[CH:16][C:17]([C:5](=[O:12])[C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:18][CH:19]=3)[CH2:25][CH:24]1[CH2:23][NH:22][CH2:21]2
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(C23CNCC2C3)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cl
Product: O=C(c1ccccc1)c1ccc(C23CNCC2C3)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 12.9 g. of aluminum chloride and 9.7 g. of benzoyl chloride in 55 ml. of dichloromethane is stirred at -10° C. To this is added 5.6 g. of 1-phenyl-3-azabicyclo[3.1.0]hexane over a period of 10 minutes while the temperature is maintained at -10° C. to -5° C. The reaction is then stirred at 0° C. for 10 minutes, and then at room temperature for two days. The mixture is carefully poured onto ice and then extracted with dichloromethane. The extract is dried, filtered, and then concentrated to 25 ml. and diluted with ether. The resultant solid is collected, washed with ether, dried and recrystallized from acetonitrile to give 2.0 g. of the desired product, m.p. 171°-173° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]([CH2:20][CH:21]=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:25][O:26][C:27](=[O:40])[C@H:28]([NH2:39])[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:25][O:26][C:27](=[O:40])[C@H:28]([NH:39][CH2:21][CH2:20][N:9]([CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)CCN(CC=O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@H](N)CCOCc1ccccc1
Agent: Cl
Product: COC(=O)[C@@H](CCOCc1ccccc1)NCCN(CCC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 1E, 3-[(2-oxo-ethyl)-(3-trifluoromethyl-phenyl)-amino]-propionic acid tert-butyl ester (example 5A) and (R)-2-amino-4-benzyloxy-butyric acid methyl ester hydrochloride (intermediate 7) gave the title compound as yellow oil. MS: 539.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C[CH2:14][N:15]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN>CN(C=O)C.C(OCC)(=O)C>[NH2:12][C:8]1[C:9]([F:11])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([NH:15][CH3:14])=[O:5]
Reactant: Nc1cc(C(=O)O)c(F)cc1F
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(N)c(F)cc1F
Reaction time: 2 h
Yield: 40.8 %

Procedure:
To a solution of 2,4-difluoro-5-aminobenzoic acid (1.73 g, 10.0 mmol) in DMF (40 mL) were successively added EDCI (1.62 g, 12.0 mmol), HOBt (2.30 g, 12.0 mmol) and methylamine (6.0 mL, 12.0 mmol, 2 M in MeOH) in that order at RT. After stirring for 2 h, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with NaHCO3 (3×50 mL) followed by 10% LiCl (50 mL). The organic layer was dried, filtered and concentrated to afford 5-amino-2,4-difluoro-N-methylbenzamide (0.76 g, 41%) as a light brownish solid. MS (M+H)+=187. It was used without further purification (>92% pure by HPLC).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10]CC)=[O:9].[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cnn(C)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1ncc(C(=O)O)c1Cl

Procedure:
5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid, ethyl ester (13 grams, 0.07 mole) and potassium hydroxide (7.8 grams, 0.14 mole) were combined in 75 ml. of ethanol and refluxed for six hours. The solution was cooled, poured over water, acidified with concentrated hydrochloric acid, and the precipitated solid collected, dried, and recrystallized from water. The resulting 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid was obtained in the amount of 5.4 grams and melted at 195°-197° C.
Reaction SMILES: N[CH2:2][CH:3]1[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(O)(C(F)(F)F)=[O:15].CCN(C(C)C)C(C)C.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40])([O-:32])=[O:31]>C(Cl)Cl>[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([N:5]1[CH2:4][CH:3]([CH2:2][OH:15])[CH2:6]1)(=[O:41])=[O:40])([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC(CO)C1
Reaction time: 17 h
Yield: 26 %

Procedure:
Tert-butyl 3-(aminomethyl)-1-azetidinecarboxylate (J. Med. Chem., (2001) 44:94-104) (441 mg, 2.35 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (1.5 mL) and the mixture was stirred for 2 hours at room temperature. The volatiles were removed under reduced pressure and the residue was dissolved in dry MeOH (5 mL). Solid NaHCO3 was added (˜500 mg) and the mixture was stirred for 17 hours. MeOH was removed, CH2Cl2 (50 mL) was added and the mixture was filtered through a plug of Celite. The filtrate was concentrated and the residue was dissolved in DMF (15 mL). DIPEA (0.817 mL, 4.70 mmol) and 2-nitrobenzenesulfonyl chloride (580 mg, 2.58 mmol) were added and the mixture was stirred for 2 hours. The mixture was concentrated and the residue was purified by column chromatography on silica gel (100% EtOAc) to provide [1-(2-nitro-benzenesulfonyl)-azetidin-3-yl]-methanol (167 mg, 26%). 1H NMR (CDCl3) δ 2.73-2.80 (m, 1H), 3.76 (dd, 2H, J=5.4, 5.7 Hz), 3.90 (dd, 2H, J=5.7, 8.1 Hz), 4.17 (dd, 2H, J=8.1, 8.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH:14]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:28])[C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1>C(#N)C>[C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH2:14][CH2:15][N:28]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])[CH2:17][C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN)cc1OC
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: CC#N
Product: COc1ccc(CN(CCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)CCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc1OC
Yield: 10.9 %

Procedure:
A solution of 1.0 g (4.44 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.33 ml (2.22 mmol) veratrylamine in 25 ml acetonitrile was stirred for 16 h at 80° C. Concentration in vacuo abash chromatography (gradient: 0-10% MeOH in EtOAc) afforded 150 mg (10%) of the title compound as a light brown oil. MS m/e (%): 618 (M+H+, 100).
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH2:3][CH2:4][CH3:5].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl>[Br:23][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][C@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC[C@@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCC[C@@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
2-{[(1R)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (5.05 g, 16.54 mmol) was dissolved in chloroform (30 ml) and cooled to 0° C. To this solution N-bromosuccinimide (3.24 g, 18.19 mmol) was added portionwise keeping the temperature below 2° C. This gave a dark green solution which was stirred at 0° C. for 30 minutes before allowing to warm to room temperature and stirring for 6 hours. The reaction mixture was washed with water (2×50 ml) and the layers separated using hydrophobic frit. The organic layer was concentrated to give a dark brown gum which was dissolved in dichloromethane and purified by chromatography silica (100 g) using a 0-50% gradient of ethyl acetate-cyclohexane over 60 mins on a Flashmaster II. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow foam (5.23 g).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([Cl:25])[C:17]=2[F:26])=[C:11]([F:27])[CH:10]=1.C1COCC1>CO>[CH3:1][O:23][C:22](=[O:24])[C:21]1[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=2[F:27])=[C:17]([F:26])[C:18]([Cl:25])=[N:19][CH:20]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A hexanes solution of TMSCH2N2 (9.46 mL, 18.9 mmol) was added to 4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid (4.59 g, 12.62 mmol) in a solution of 3:1 THF:MeOH (48 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. After quenching with AcOH, the reaction mixture was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to give 4.40 g (92%) clean desired product.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([C:9]#[C:10][Si](C)(C)C)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:15]([S-:20])(=[S:19])OCC.[K+].O.Cl>CN(C=O)C>[C:9]([C:7]1[CH:6]=[CH:5][C:3]2[N:4]=[C:15]([SH:20])[S:19][C:2]=2[CH:8]=1)#[CH:10]
Reactant: CCOC(=S)[S-]
Reactant: C[Si](C)(C)C#Cc1ccc(N)c(F)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1ccc2nc(S)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 2-fluoro-4-((trimethylsilyl)ethynyl)aniline (4.4 g, 21.2 mmol) from Step 1 of this Example in 20 mL of DMF was added potassium O-ethyl carbonodithioate (7.48 g, 46.8 mmol). The resulting mixture was heated under reflux for 4 h. After cooling to rt, the reaction mixture was treated with water (30 mL) and 1N HCl (100 mL). The mixture was stirred at rt for 2 h before the precipitates were collected by filtration and washed with water to give the crude 6-ethynylbenzo[d]thiazole-2-thiol (4.0 g, 99%) as a dark brown solid. LCMS (ESI) m/z 192 (M+H)+.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([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.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.[NH2:72][C@H:73]1[C@@H:76]([CH2:77][OH:78])[NH:75][C:74]1=[O:79]>C(Cl)Cl.CN(C=O)C>[C:35]([O:34][C:32]([NH:31][C:28]1[S:29][CH:30]=[C:26](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([O:14][CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:16])[CH2:19][CH2:18]2)/[C:23]([NH:72][C@@H:73]2[C:74](=[O:79])[NH:75][C@@H:76]2[CH2:77][OH:78])=[O:24])[N:27]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: N[C@@H]1C(=O)N[C@@H]1CO
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CO)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.9 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (6.66 g, 12.38 mmol) at 0° C. in DCM (61.9 ml, ratio: 1) and DMF (61.9 ml, ratio: 1) were added DIPEA (6.49 ml, 37.2 mmol) and HATU (5.65 g, 14.86 mmol). After 20 min, (3S,4S)-3-amino-4-(hydroxymethyl)azetidin-2-one (1.44 g, 12.38 mmol) was added. After stirring for 2 h at rt, the reaction mixture was concentrated in vacuo and diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM) to afford the title compound (4.4 g, 56%). LCMS: Rt=0.97 min, m/z=636.1 (M+1), Method 2m_acidic. 1H NMR (400 MHz, DMSO-d6): 11.80 (br s, 1H), 9.08 (d, J=9.0 Hz, 1H), 8.41 (s, 1H), 7.48-7.32 (m, 5H), 7.32-7.15 (m, 6H), 6.84 (s, 1H), 5.20 (ddd, J=9.2, 5.1, 0.9 Hz, 1H), 4.77 (t, J=5.3 Hz, 1H), 3.76-3.70 (m, 1H), 3.62-3.48 (m, 1H), 3.47-3.33 (m, 1H), 1.56-1.33 (m, 13H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.CN(C)C=O>[CH2:31]([O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A mixture of 2,4-dinitrophenol (85 wt %, 6.72 g, 31 mmol), octadecyl bromide (20.7 g, 62 mmol), sodium carbonate (6.57 g, 62 mmol) and dimethylformamide (31 mL) was heated to 100° C. under a nitrogen atmosphere for 22 h. The cooled mixture was diluted with water (200 mL), acidified with 10N hydrochloric acid (50 ml,) and extracted with ether. The extracts were washed with water and brine, and dried over magnesium sulfate. The solvent was removed and the solid recrystallized to give 1-octadecyloxy-2,4-dinitrobenzene (10.7 g, 79%): mp 63.5°-64.0° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:21]([O-])=O)[N:3]=1>[Pd].CCOC(C)=O.CO>[NH2:21][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(N)ccc1Oc1ccnc(NC(=O)C(C)C)c1
Yield: 82.3 %

Procedure:
A solution of N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (0.55 g, 1.739 mmol) in 2:1 EtOAc/MeOH (30 mL) was treated with palladium on carbon (50% wet, 0.206 g, 0.174 mmol) and hydrogenated (1 atm) for 2 days. The solids were removed via filtration through diatomaceous earth, washed well with MeOH and the filtrate was concentrated to dryness to afford N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (410 mg, 82%). 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 8.12 (d, J=5.7 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 6.58 (dd, J=5.7, 2.4 Hz, 1H), 6.35 (d, J=8.7 Hz, 1H), 5.95 (s, 2H), 2.69 (m, 1H), 2.04 (s, 3H), 1.02 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 287.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1
Reactant: COc1cc(N2CCCCC2)c(Cl)cc1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCCCC2)c(Cl)cc1CCO
Reaction time: 2 h

Procedure:
A solution of 14.2 g (50 mmole) of 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylacetic acid in 50 ml of absolute tetrahydrofuran is added dropwise over a period of approximately 15 minutes to a suspension of 1.6 g (42 mmole) of lithium aluminium hydride in 90 ml of absolute tetrahydrofuran. The whole is subsequently stirred for a further 2 hours at 50°. After the addition of 50 ml of water, the whole is filtered over Hyflo and then washed with THF. The solvent is concentrated in a vacuum rotary evaporator and the residue is partitioned between ether and water. The ether phases are combined, dried over sodium sulphate and concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using chloroform/ethyl acetate (1:1) as eluant. Recrystallisation from ether/petroleum ether yields 2-[5-chloro-2-methoxy-4-(piperidin-1-yl)-phenyl]-ethanol having a melting point of 56°-57°.