Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([O:13][C:14]([NH:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:8][C:20]1[N:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nccn1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Br)cn1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A solution of NBS (1.548 g, 8.70 mmol) in DMF (15 ml) was added slowly via addition funnel to a solution of ethyl 1-((tert-butoxycarbonyl)amino)-1H-imidazole-2-carboxylate (2.22 g, 8.70 mmol) in DMF (12 ml) at room temperature. The reaction was stirred at room temperature overnight. To the reaction was added a saturated solution of sodium bicarbonate until the yellow solution became a white suspension. The mixture was concentrated to dryness. The residue was partitioned between EtOAc and water. The organic phase was washed (brine), dried (Na2SO4) and concentrated to give a yellow viscous oil. The crude product was purified via silica gel column (Isco prep: 15-100% ethyl acetate/hexanes) to afford ethyl 4-bromo-1-((tert-butoxycarbonyl)amino)-1H-imidazole-2-carboxylate (1.52 g, 4.55 mmol, 52.3% yield) as a white solid. LCMS (Method B) m/z 334.1 [M+1], Br-pattern; 1H NMR (400 MHz, chloroform-d) δ 7.26 (s, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.51 (s, 9H), 1.42 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:35])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[C:31]([F:34])[C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].Br[CH:37]([CH3:42])[C:38]([O:40]C)=[O:39]>>[CH:27]1([NH:26][C:24]([C:23]2[CH:30]=[C:31]([F:34])[C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:1][CH2:42][CH2:37][C:38]([OH:40])=[O:39])([CH3:12])[CH3:13])[C:16]3=[O:35])[CH:22]=2)=[O:25])[CH2:28][CH2:29]1
Reactant: COC(=O)C(C)Br
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCN)c1=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCNCCC(=O)O)c1=O

Procedure:
of the title compound was prepared from 3-(3-(2-(2-(2-aminoethoxy)phenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide (Example 311) and methyl bromopropanoate using a similar method to that described for Example 312.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.C1C(=O)N([I:16])C(=O)C1>C(O)(=O)C>[I:16][C:7]1[C:2](=[O:1])[NH:3][CH:4]=[N:5][C:6]=1[CH3:8]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(O)ncn1
Solvent: CC(=O)O
Product: Cc1nc[nH]c(=O)c1I

Procedure:
To a stiffed solution of 70 g (0.64 mol) 4-hydroxy-6-methyl pyrimidine in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min The reaction is stiffed for to 30 h at RT until all starting material is consumed. The reaction mixture is diluted with water and the solid product is filtered off and washed with sodium thiosulfate solution to remove excess iodine. After drying, the desired product is obtained as a pale brown solid (90 g; 60%) which is used without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:7])[CH2:4][CH2:5][CH3:6].[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C)C=O>[Br:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][CH2:6][CH2:5][CH2:4][C:3]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7]
Reactant: BrCc1ccccc1Br
Reactant: CCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCCCc2ccccc2Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 136.4 %

Procedure:
One-hundred milligrams of sodium hydride (60% water-in-oil suspension) were added to a solution of 247 mg of ethyl 3-butyrylamino-4-nitrobenzoate in 10 ml of N,N-dimethylformamide in a nitrogen atmosphere at room temperature in some divided portions. The reaction suspension was stirred at the same temperature for 1 hour, and a solution of 244 mg of 2-bromobenzyl bromide in 2 ml of N,N-dimethylformamide was gradually added dropwise thereto over a period of 10 minutes. The reaction mixture was stirred at room temperature for 1 hour, and was poured in ice water. The oily substance precipitated was extracted with methylene chloride. The organic solvent layer was washed with water, dried, and then concentrated under reduced pressure. The residue was developed through silica-gel flash column chromatography, and was eluted with a mixture of 25% ethyl acetate and n-hexane to give 540 mg of yellow oil of ethyl 3-[N-(2-bromobenzyl)butyrylamino-4-nitrobenzoate.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][S:28]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:35](=[O:36])[C:34]5[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:39][CH:38]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (104 mg, 82%), MS (ISP) m/z=511.4 [(M+H)+], mp 236° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-methanesulfonyl-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([OH:21])[C:19]#[CH:20].C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:20]#[C:19][CH2:18][OH:21])=[CH:8][C:6]=2[N:7]=1
Reactant: C#CCO
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reaction time: 240 h

Procedure:
A mixture of 2-chloro-6-iodo-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 19, prepared according to Example 12, (1.57 g), propargyl alcohol (288 μL), copper iodide (39 mg), bis(triphenylphosphine)palladium(II) chloride (146 mg), triethylamine (25 ml), and tetrahydrofuran (30 ml) were stirred under nitrogen for 10 days. The reaction mixture was then partitioned between chloroform and brine, the combined organics were then dried (MgSO4). The solvents were removed in vacuo. The crude product was then purified using flash chromatography to yield 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-yn-1-ol (1.2 g).
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:9].[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>O1CCCC1>[Br:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:3]1=[O:9]
Reactant: COc1ccc(CBr)cc1
Reactant: O=C1NCCCCC1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCCCC(Br)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution of 3-bromoazepan-2-one (1.398 g, 7.28 mmol) in tetrahydrofuran (10 ml), was added sodium hydride (0.48 g, 12.00 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour, and 1-(bromomethyl)-4-methoxybenzene (1.610 g, 8.01 mmol) was added. The mixture was warmed to room temperature over the span of 2 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to afford crude product, which was purified by chromatography on silica gel (ethyl acetate/hexanes=2/8) to afford 3-bromo-1-(4-methoxybenzyl)azepan-2-one (1.403 g, 4.49 mmol, 61.7% yield). MS ESI: [M+H]+ m/z 313.2.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.O.Cl.[NH:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1>C(O)(C)C>[C:12]1([C:9]2[C:8]3=[C:18]4[C:4](=[CH:5][CH:6]=[C:7]3[S:11][CH:10]=2)[NH:2][C:24]2[CH2:25][CH2:26][NH:21][CH2:22][C:23]4=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: c1ccc(-c2csc3ccc4[nH]c5c(c4c23)CNCC5)cc1

Procedure:
28 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride are dissolved in 300 ml of isopropanol and the solution is combined with 20 g of 4-piperidone hydrochloride monohydrate under an inert gas. After boiling the mixture for 3 hours, the solvent is evaporated off, the residue is taken up in isopropanol and the product is precipitated with the addition of isopropyl ether. The precipitate is filtered off and taken up in water; a layer of methylene chloride is introduced under the solution and the mixture is shaken with NaOH solution. The organic phase is separated off and worked up. Melting point: 228° C. (decomposition)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].O=[C:17]([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19]>ClCCCl>[CH3:21][O:20][C:18](=[O:19])[CH2:17][CH2:22][CH2:23][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH3:6]
Reactant: CCOC(=O)C(C)NCc1ccccc1
Reactant: CCC(=O)C(=O)OC
Solvent: ClCCCl
Product: CCOC(=O)C(C)N(CCCC(=O)OC)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Benzylamino-propionic acid ethyl ester (1.4 g, 6.7 mmol), methyl oxo-butanoate (1.7 g, 13.5 mmol), TEA (1.9 mL, 13.5 mmol) and NaBH(Oac)3 (2.9 g, 13.5 mmol) are taken up in 1,2-DCE (35 mL) and stirred at rt for 4 h. The reaction is partitioned between DCM and saturated aqueous NaHCO3. The organic layer is removed, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude residue is used without further purification. MS (ESI) m/z 308.3 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:20]=[O:21])[C:15]=2[O:16]COC)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][CH:13]=[C:14]([CH:20]=[O:21])[C:15]=2[OH:16])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1c(C=O)csc1-c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(-c2scc(C=O)c2O)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To 2-(4-t-butylphenyl)-3-methoxymethyloxy-4-formylthiophene (0.20 g, 0.66 mmol) in 1,4-dioxane (1.3 mL), 1 M hydrochloric acid (0.66 mL, 0.66 mmol) was added dropwise, and the reaction solution was stirred at 65° C. for 1 hour and at 80° C. for 1 hour. After addition of water, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (chloroform) to give the desired product as a reddish brown oil (0.12 g, yield 68%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1>O1CCOCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[CH:14]2)=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: c1ccc2[nH]cnc2c1
Solvent: C1COCCO1
Product: c1ccc2c(c1)ncn2CCc1c[nH]c2ccccc12

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (4.48 g, 20 mmol) and benzimidazole (4.72 g, 40 mmol) in abs. dioxane (50 ml) was stirred at 90° C. for 13 h. The solvent was then removed i. vac., CHCl3 (200 ml) was added to the residue and the mixture was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (40:1). Yield: 1.32 g (25%), pale brown solid
Reaction SMILES: [CH:1]([P:3](=[O:9])([CH:7]=[CH2:8])[CH:4]([CH3:6])[CH3:5])=[CH2:2].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH2:10]([N:17]1[CH2:8][CH2:7][P:3](=[O:9])([CH:4]([CH3:6])[CH3:5])[CH2:1][CH2:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CP(=O)(C=C)C(C)C
Reactant: NCc1ccccc1
Solvent: O
Product: CC(C)P1(=O)CCN(Cc2ccccc2)CC1
Temperature: 85 °C
Yield: 62.6 %

Procedure:
A 20 L four-necked round bottom flask fitted with an overhead stirrer and reflux condenser, flame dried and cooled in a stream of nitrogen, was charged with the product of Step 1 (250 g, 1734 mmol), THE (2500 mL), water (2500 mL) and benzyl amine (297.3 g, 2774 mmol). The reaction mixture was heated at 85° C. for 16 h. After completion, THF was removed under reduced pressure. The aqueous layer was extracted with ether to remove the excess of benzyl amine and later with dichloromethane (2×2500 mL). The combined dichloromethane layers were washed with brine (2×1000 mL), dried over sodium sulfate and concentrated to give 1-benzyl-4-(propan-2-yl)-1,4-azaphosphinane 4-oxide (273 g, 63%) as brown oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])=[N:5]2.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([NH:14][C:34]([NH:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=3)=[O:35])[CH:15]=[CH:16][CH:17]=1)=[N:5]2
Reactant: Nc1cccc(Oc2ccc3nccn3n2)c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nccn3n2)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (181 mg, 0.80 mmol) and triethylamine (0.040 mL, 0.29 mmol) in tetrahydrofuran (10 mL) was added 3-(trifluoromethyl)phenyl isocyanate (0.154 mL, 1.12 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and precipitated from methanol to give the title compound (205 mg, 62%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1.FS([C:22](C(O)=O)([F:24])[F:23])(=O)=O>[Cu]I.C(#N)C>[CH2:6]([CH:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8](=[O:11])[C:7]21[CH2:16][CH2:15][CH:14]([O:17][CH:22]([F:24])[F:23])[CH2:13][CH2:12]2)[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C1c2cc(Br)ccc2CC12CCC(O)CC2
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Product: O=C1c2cc(Br)ccc2C(Cc2ccccc2)C12CCC(OC(F)F)CC2
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
In a 25 mL round bottom flask was placed 6′-bromo-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (368 mg, 1.252 mmol) and it was azeotroped twice with acetonitrile (2 mL/each). CuI (24 mg, 0.126 mmol) was added followed by acetonitrile (2.5 mL). This solution was purged under a stream of N2 for 30 seconds. The solution was heated to 60° C. under a nitrogen atmosphere. After being 5 minutes at 60° C., FSO2CF2CO2H (136 mL, 1.316 mmol) was added dropwise. After 1 hour, the reaction was quenched with H2O (10 mL) and diluted with diethyl ether (10 mL). The phases were separated and the aqueous phase was back-extracted with diethyl ether (5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 40 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding benzyl 6′-bromo-4-(difluoromethoxy)spiro[cyclohexane-1,2′-inden]-1′(3′H)-one (137 mg, 0.398 mmol, 32% yield). M+H=344.9, 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, J=1.2 Hz, 1H), 7.69 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.26 (t, J=75.2 Hz, 1H), 4.20 (m, 1H), 2.98 (s, 2H), 2.14 (m, 2H), 1.80 (m, 2H), 1.65-1.52 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:33][NH:34][C@@H:35]([CH3:43])[C:36]([O:38]C(C)(C)C)=[O:37])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][CH2:25]1)[N:18]=2>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH2:33][NH:34][C@@H:35]([CH3:43])[C:36]([OH:38])=[O:37])[CH:12]=[CH:13][C:14]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: C[C@H](NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (1.0 mL, 12.98 mmol) was added to a solution of (S)-tert-butyl 2-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methylamino)propanoate (140.6 mg, 0.279 mmol) in DCM (2.1 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated in vacuo and the brown residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (10-100% CH3CN/water+0.1% TFA) to provide (S)-2-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methylamino)-propanoic acid as a light yellow solid. MS (ESI) m/z: Calculated: 447.1; Observed: 448.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.I[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: CC(C)CI
Reactant: OCCNCc1ccc(Cl)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(CCO)Cc1ccc(Cl)nc1
Yield: 80.6 %

Procedure:
A stirred mixture of 2.0 grams (0.007 mole) of 2-{[(6-chloro(3-pyridyl))methyl]amino}ethan-1-ol (known compound), 1.29 gram (0.007 mole) of 1-iodo-2-methylpropane and 0.9 gram (0.007 mole) if diisopropylethylamine in 50 mL of acetonitrile was heated at reflux for 16 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, eluting with a mixture of diethyl ether and hexanes. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.37 grams of 2-{[(6-chloro(3-pyridyl))methyl](2-methylpropyl)amino}ethan-1-ol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:32]=[O:33])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH2:32][OH:33])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=C(CO)NC(C)=C(C(=O)OCc2ccccc2)C1c1ccccc1[N+](=O)[O-]

Procedure:
To a suspended solution of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (1.2 g) in ethanol (20 ml) was added sodium borohydride (60.6 mg) under ice-cooling and stirred, and further stirred for an hour at 0° C. and another an hour at 3° C. The reaction mixture was added with water and the resultant mixture was adjusted to pH 6 to 7 with 2 N hydrochloric acid, and the solvent was distilled off. The residue was extracted with ethyl acetate and washed with water and dried. After removal of the solvent, the resultant oil (1.3 g) was purified by column chromatography on silica gel with an eluent (a mixture of ten parts of benzene and one part of ethyl acetate by volume) to give an oil which was immediately crystallized. The resultant crystals were recrystallized from a mixture of diethyl ether and n-hexane and dissolved in benzene. The benzene solution was subjected to azeotropic process five times to give pure crystals of benzyl 2-methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate, m.p. 51° to 57° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:7]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)CCO
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN(C)CCOC(=O)c1ccccc1

Procedure:
In accordance with the procedure of Example 10, 89.1 g of 2-dimethylaminoethanol and 140.5 g of benzoyl chloride are reacted in altogether 300 ml of CHCl3. The reaction mixture is neutralised with 210 ml of 20% NaOH. Yield: 187.7 g (97.1%) of analytically pure product (analysis by gas chromatography) with a boiling point of 127° C./9 torr.
Reaction SMILES: [CH2:1]([C@@H:3]1[N:8]([C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)[CH3:2]>[Pd].CO>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([N:8]2[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:4][C@@H:3]2[CH2:1][CH3:2])=[CH:14][CH:13]=1
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
A 100-mL single-neck round-bottomed flask was purged with nitrogen and charged with 161a (0.7 g, 2.08 mmol), 10% palladium on carbon (50% wet, 208 mg), and methanol (40 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 6 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 161b (568 mg, 89%). MS: [M+H]+ 306
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([NH2:1])[CH:3]=1
Reactant: CO
Reactant: Nc1cc(C(=O)O)ccc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)c(N)c1
Temperature: 65 °C
Yield: 95 %

Procedure:
To a solution of 3-amino-4-hydroxybenzoic acid (10 g, 0.65 mol) in methanol (1.5 L) was added thionylchloride (233 g, 1.96 mol) drop-wise at 5-10° C. with stirring and allowed to reflux at 65° C. for 16 h. Excess methanol and thionylchloride was distilled off and crude dissolved in ethylacetate (500 mL). The organic layer was washed with 5% aqueous NaHCO3 solution, water, brine and dried. The solvent was removed under vacuum to give methyl-3-amino-4-hydroxybenzoate (105 g, 95%).