Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][CH:23](O)[CH3:24].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([CH2:15][C:16]([O:18][CH:23]([CH3:24])[CH3:22])=[O:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: O=C(O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-benzyloxy-2-nitrophenylacetic acid (25.1 g) in methylene chloride (250 ml) were added in turn 2-propanol (27 ml), 4-dimethylaminopyridine (1.07 and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.4 g) and the resulting mixture was stirred at room temperature for one hour and then allowed to stand overnight. After the solvent was distilled off under reduced pressure, the resulting residue was diluted with ethyl acetate, washed subsequently with 1N hydrochloric acid and saturated saline. The organic layer was dried over magnesium sulfate and distilled off under reduced pressure. The dark yellow oily substance thus obtained (29.7 g) was purified by a silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (22.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:11]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[CH:32][C:33]([N:36]([CH3:38])[CH3:37])=[N:34][CH:35]=3)=[CH:26][CH:25]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>C1COCC1.[Pt](=O)=O>[CH3:37][N:36]([CH3:38])[C:33]1[N:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([N:11]3[CH:12]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[CH2:13][CH2:14][CH:10]3[C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)=[CH:29][CH:28]=2)=[CH:31][CH:32]=1
Reactant: CN(C)c1ccc(-c2ccc(N3C(c4ccc([N+](=O)[O-])cc4)CCC3c3ccc([N+](=O)[O-])cc3)cc2)cn1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2ccc(N3C(c4ccc(N)cc4)CCC3c3ccc(N)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
The product from Example 99A (26.8 mg, 0.053 mmole) was dissolved in THF (526 L) in a round bottom flask to which was subsequently added ethanol (526 L) resulting in a yellow precipitate. To this suspension was added platinum (IV) oxide (3.16 mg, 0.014 mmole). The flask was capped with a septum and the contents vacuum degassed three times. Hydrogen was introduced via a balloon and the mixture allowed to stir at room temperature for two and one half hours. The reaction mixture was vacuum filtered through a sand and celite plug, which was rinsed with THF and methanol until the filtrate was u.v.(−). The filtrate was concentrated in vacuo to provide the title compound in quantitative yield as a white solid as a mixture of stereoisomers. MS ESI(+), m/z@450.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[Br:11]Br.Br.[OH-].[K+]>CC(O)=O.O>[Br:11][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[C:9]=1[F:10]
Reactant: COc1c(N)cccc1F
Reactant: BrBr
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(N)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a solution of 2-methoxy-3-fluoroaniline (2.18 g, 15.46 mmol) in AcOH (10 mL) was added a solution of bromine (1.98 g, 12.37 mmol) in AcOH (2 mL) dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The resulting solid was filtered and washed with acetic acid to give the title and a di-bromo-compound as the HBr salt. The solid (2.53 g) was dissolved in water, basified by addition of KOH, and extracted with EtOAc. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with 15% EtOAc in cyclohexanes to give the title compound as white solid (1.24 g, 36%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:13][N:14]([CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN(C)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a solution of methyl 4-formylbenzoate (1 g, 6.1 mmol) and N-methylbenzenamine (650 mg, 6.1 mmol) in methanol (50 mL) was added acetic acid (2 drops) and the mixture was stirred for 0.5 hour. Then sodium cyanoborohydride (660 mg, 10 mmol) was added in portions. The mixture was stirred at room temperature for 24 hours. The mixture was washed with water (50 mL) and extracted with dichloromethane (50 mL). The organic phase was separated and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to give methyl 4-((methyl(phenyl)amino)methyl)benzoate (400 mg, 26%) as a yellow oil. LRMS (M+H+) m/z: calcd 255.13. found 255. 1H NMR (300 MHz, CD3OD): δ 7.96-7.32 (m, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.18-7.12 (m, 2H), 6.74-6.60 (m, 3H), 4.60 (s, 2H), 3.88 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[S:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2ccc(Cl)cc2)no1

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide; hydrochloride (110 mg; 0.382 mmol) in DMF (1.5 mL) is added 4-chlorobenzenesulfonyl chloride (80.6 mg; 0.382 mmol) and N,N-diisopropylethylamine (0.133 mL; 0.764 mmol). The reaction mixture is left stirring at room temperature for 18 hours in the presence of catalytic amount of 4-dimethylaminopyridine. The reaction mixture is quenched with water and extracted with ethyl acetate twice. The combined organics are washed with water then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/Hexanes provides the title compound, m/z 426 [M+H+].
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=1)=[O:19])C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:30][C:26]3[C:25]([F:31])=[CH:24][C:23]([CH:21]4[CH2:22][CH:20]4[C:18]([OH:19])=[O:17])=[CH:28][C:27]=3[F:29])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CC1c1cc(F)c(O)c(F)c1
Reactant: ClCc1cccnc1SC1CCCC1
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccnc2SC2CCCC2)c(F)c1
Yield: 102.4 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.030 g, 0.13 mmol) obtained in Step C of Preparation Example 8 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.032 g, 0.13 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.054 g, 99%).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:15]=[C:14]([C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=3[CH2:35]O)[CH:12]=2)[N:7]=1>ClCCl>[NH2:5][C:6]1[N:15]=[C:14]([C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=3[CH2:35][Cl:3])[CH:12]=2)[N:7]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CCl)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
67 μl of thionyl chloride in 2 ml of dichloromethane are added dropwise to 200 mg of [2-amino-6-(2-hydroxymethyl-4,5-difluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 2 ml of dichloromethane, and the mixture is stirred at 25° C. for 2 h. The mixture is evaporated to dryness in vacuo, the residue is taken up in 10 ml of toluene, and the operation is repeated. The residue is employed in the subsequent reactions without further treatment.
Reaction SMILES: O.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH3:17]O>>[F:2][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:17])=[O:7])[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c(F)c1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(F)c1

Procedure:
A commercial product, 3-fluoro-4-hydroxybenzoic acid hydrate (1.1 g) was dissolved in methanol (11 mL), and in an ice bath, thionyl chloride (0.77 mL) was added thereto, and heated under reflux for 2 hours. After the reaction, the reaction liquid was entirely concentrated to obtain the entitled compound (1.1 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]=O.[C:13]([O:17][C:18](=[O:25])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([CH3:16])([CH3:15])[CH3:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:13]([O:17][C:18](=[O:25])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:11][C:3]1[N:2]([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(CNCCCCNC(=O)OC(C)(C)C)nc2ccccc21

Procedure:
Using General Procedure B, reaction of 1-methyl-1H-benzoimidazole-2-carbaldehyde and (4-amino-butyl)-carbamic acid tert-butyl ester in CH2Cl2 with NaBH(OAc)3 gave {4-[(1-methyl-1H-benzoimidazol-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a sticky white foam. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.54-1.64 (m, 4H), 1.80-1.82 (m, 2H), 2.67-2.75 (m, 2H), 3.12-3.13 (m, 2H), 3.82 (s, 3H), 4.06 (s, 2H), 7.23-7.30 (m, 2H), 7.31-7.38 (m, 1H), 7.70-7.76 (m, 1H).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32](=[O:34])[NH2:33])[CH:27]=3)[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1>C(O)C>[C:32]([C:28]1[CH:27]=[C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[CH2:16][C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)[CH:31]=[CH:30][CH:29]=1)(=[O:34])[NH2:33]
Reactant: NC(=O)c1cccc(-c2ccc3[nH]cc(C[C@H]4CCCN4C(=O)OCc4ccccc4)c3c2)c1
Solvent: CCO
Product: NC(=O)c1cccc(-c2ccc3[nH]cc(C[C@H]4CCCN4)c3c2)c1
Yield: 77.7 %

Procedure:
3-(1-Benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-(3-carbamoylphenyl)-1H-indole (700 mg, 1.391 mmol) (see Preparation 40) in ethanol was reduced using catalytic hydrogenation, as described in Example 35. This gave the title compound as a white foam (345 mg). Found: C,71.16; H,6.98; N,12.34; C20H21N3O.H2O requires: C,71.19; H,6.87; N, 12.45.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9](O)=[O:10]>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:9]([Cl:3])=[O:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1Cl

Procedure:
In 100 ml of ethanol were dissolved 18 g of 1-bromo-n-decane and 9 g of 3-chloro-4-hydroxybenzoic acid, an aqueous solution of 40 g of sodium hydroxide in 100 ml of water was added to the above solution, and the mixture was heated and refluxed for 10 hours. Then the reacted solution was made weakly acidic by an addition of 1N hydrochloric acid and thrown in an enough quantity of water to precipitate the reaction product. The precipitate was recovered by filtration and recrystallized from ethanol to obtain 5 g of 3-chloro-4-decyloxybenzoic acid, then 15 g of thionyl chloride was added to 3 g of 3-chloro-4-decyloxybenzoic acid, and a reaction was carried out under reflux for 3 hours. The unreacted thionyl chloride was removed by distillation under a reduced pressure to obtain 3-chloro-4-decyloxybenzoic acid chloride quantitatively. Then the product was dissolved in a diethyl ether/THF (1/1) mixed solvent, 2.3 g of 4,4'-acetoxybiphenol and 2 g of triethylamine were added to the solution successively, and a reaction was carried out at room temperature with stirring overnight. The reacted solution was washed three times with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrogencarbonate and water, in this order, and the organic phase was dried with anhydrous sodium sulfate. The solvent was evaporated, the reaction product was recovered by the silica gel chromatography, then the reaction product was dissolved in 100 ml of a THF/methanol (9/1) mixed solvent, a 1N aqueous solution of lithium hydroxide was added to the resulting solution which was cooled with ice-cold water, and a reaction was carried out with stirring for 30 minutes. Then the reacted solution was made weakly acidic by addition of 1N hydrochloric acid, extracted with a diethyl ether/benzene (1/1) mixed solvent, and the extract was washed three times with 1N hydrochloric acid, a 1N aqueous solution of sodium hydrogencarbonate and water in this order. The organic phase was recovered and dried with anhydrous magnesium sulfate, and the organic solvent was evaporated to obtain a product. The product was recrystallized from an n-hexane/ethanol mixed solvent. The compound in which Z is fluorine can be similarly obtained by using 3-fluoro-4-hydroxybenzoic acid instead of 3-chloro-4-hydroxybenzoic acid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:23][C:21]1([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19][B:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:3]3[CH2:8][CH2:7][O:6][CH2:5][C:4]3=[O:9])=[CH:17][CH:16]=2)[O:22]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: O=C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(CN3CCOCC3=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
NaH (81 mg, 3 eq.) was added to a solution of morpholin-3-one in DCM. 2-(4-bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was added to the resulting solution and the reaction was stirred at room temperature for 16 hrs. DCM was evaporated, followed by addition of water. The solution was extracted with EtOAc. The organic layers were dried over MgSO4 and evaporated in vacuo to afford the title product used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[O:20][C:21](=[O:32])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][C:25]=1[CH3:31]>>[CH3:31][C:25]1[CH:26]=[C:27]([S:30][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[CH:28]=[CH:29][C:24]=1[O:23][CH2:22][C:21]([OH:32])=[O:20]
Reactant: COC(=O)COc1ccc(S)cc1C
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Product: Cc1cc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 3B and 2C. MS m/z 447 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.Cl.[CH3:13][O:14][C:15](=[O:19])[CH2:16][NH:17][CH3:18].C(N(CC)CC)C.[Na+].[Cl-]>CN(C)C=O>[N:4]1[C:3]([CH2:2][N:17]([CH3:18])[CH2:16][C:15]([O:14][CH3:13])=[O:19])=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: CNCC(=O)OC
Reactant: ClCc1cn2ccccc2n1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)Cc1cn2ccccc2n1
Yield: 25.9 %

Procedure:
0.303 g (1.773 mmol) of 2-(chloromethyl)imidazo[1,2-a]pyridine were dissolved in 15 ml of dimethylformamide with magnetic stirring and then 0.253 g (1.773 mmol) of sarcosine methylester hydrochloride and 0.741 ml (5.32 mmol) of triethylamine were added. The mixture was stirred at r.t. for 16 h, and then treated with 30 ml of a saturated NaCl aqueous solution. The aqueous phase was concentrated in vacuo. The residue was triturated in 75 ml of isopropanol, the salts were removed by filtration and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol, 95/5, v/v). 0.107 g (yield=26%) of methyl 2-((imidazo[1,2-a]pyridin-2-ylmethyl)(methyl)amino)acetate were obtained as a pale yellow oil. LC-MS: m/z=234 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.49 (d, J=6.8 Hz, 1H), 7.79 (s, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.18 (ddd, J=9.0, 6.7, 1.2 Hz, 1H), 6.84 (td, J=6.7, 1.1 Hz, 1H), 3.76 (s, 2H), 3.61 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: Cl[CH:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[CH2:22](N(CC)CC)[CH3:23]>O1CCCC1>[CH2:22]([C:6]1[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([CH:3]=[CH:2][C:18]([O:20][CH3:21])=[O:19])[CH:14]=[CH:13][C:7]=1[C:8]([OH:10])=[O:9])[CH3:23]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1ccc(CC(Cl)C(=O)OC)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)ccc(C=CC(=O)OC)c1[N+](=O)[O-]

Procedure:
The solution of 3.20 g of ethyl 4-(2-chloro-2-methoxycarbonylethyl)-3-nitrobenzoate in 130 ml of tetrahydrofuran is admixed with 6.46 ml of triethylamine and stirred at reflux over 18 hours. The reaction mixture is cooled, poured onto water (300 ml) and extracted with tert-butyl methyl ether (2×300 ml). The organic phases are washed successively with water (2×300 ml) and brine (150 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The crude title compound is obtained as a slightly yellowish solid from the residue. Rf=0.30 (1:2 EtOAc-heptane). Rt=4.50.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][CH:8]=1)[CH3:2].[CH2:32]=O>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:32])[CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][CH:8]=1)[CH3:2]
Reactant: C=O
Reactant: CCOC(=O)COc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: 60 °C
Yield: 86 %

Procedure:
A solution of (4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester (0.09 g, 0.2 mmol) in dioxane (1 mL) was treated with 1N NaH2PO3 solution (1 ml) and a 37% aqueous solution of formaldehyde (1 ml). The mixture was heated to 60° C. for 7.5 h. Additional dioxane (1 ml) was added and heated for 11.5 h. The mixture was extracted with aqueous saturated NaHCO3 solution/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 0.08 g (86%) of (4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester as yellow waxy solid, MS: 465 (MH+).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:27]([C:30]1[N:34]2[CH2:35][C@H:36]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:49]=3[F:55])[CH2:37][CH2:38][C@@H:39]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:33]2=[N:32][CH:31]=1)(=[O:29])[CH3:28]>O1CCCC1>[F:55][C:49]1[C:50]([F:54])=[CH:51][CH:52]=[CH:53][C:48]=1[C@H:36]1[CH2:35][N:34]2[C:30]([C:27]([OH:29])([CH3:28])[C:2]([F:4])([F:3])[F:1])=[CH:31][N:32]=[C:33]2[C@H:39]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:38][CH2:37]1
Reactant: CC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(C)(O)C(F)(F)F)cnc21
Reaction time: 0.08 h
Yield: 31.3 %

Procedure:
(Trifluoromethyl)trimethylsilane (0.273 mL, 1.85 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran; 74 μL, 0.074 mmol) were sequentially added to a solution of tert-butyl (6S,9R)-3-acetyl-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (150 mg, 0.37 mmol) in tetrahydrofuran (1 mL). After 5 min, additional (trifluoromethyl)trimethylsilane (100 μL, 0.678 mmol) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran; 25 μL, 0.025 mmol) were added. After 30 min, the reaction mixture was quenched with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with water, saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (55 mg). MS 476.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nc3c([N+](=O)[O-])cccc3o2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc3c(N)cccc3o2)CC1
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl 4-((4-nitrobenzo[d]oxazol-2-yl)methyl)piperazine-1-carboxylate (5.97 g, 16.6 mmol, 1.0 equiv) in MeOH (49 mL) was added Pd/C (10% Pd, wet, 2.99 g). The resulting suspension was fixed with a hydrogen balloon and sparged with hydrogen while stirring was maintained. After 1 h, the mixture was filtered through a pad of celite and concentrated in vacuo to provide the title compound as an off-white solid (5.0 g, 91%).