Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[N:18]=[C:19]4[CH2:24][N:23](C(OCC5C=CC=CC=5)=O)[CH2:22][CH2:21][N:20]4[C:35]=3[CH3:36])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([SiH](C(C)C)C(C)C)(C)C.CCOCC>Br.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[N:18]=[C:19]4[CH2:24][NH:23][CH2:22][CH2:21][N:20]4[C:35]=3[CH3:36])[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: Cc1c(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)nc2n1CCN(C(=O)OCc1ccccc1)C2
Agent: Br
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1c(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)nc2n1CCNC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A solution of benzyl 2-(3-(3-chloro-4-isopropoxypheny)-1,2,4-oxadiazol-5-yl)-3-methy-5,6-dihydroimidazo[1,2-a] pyrazine-7(8H)-carboxylate (160 mg, 0.315 mmol) in 33% HBr solution in acetic acid (2.00 mL) containing triisopropylsilane (0.065 mL, 0.315 mmol)) was stirred at room temperature under nitrogen for 10 minutes. Ether (20 ml) was added to precipitate the product. The resulting solid was filtered off, treated with saturated bicarbonate solution (10 ml) and extracted with methylene chloride (2×10 ml). The combined organic layers were dried over sodium sulfate, filtered, concentrated to solids and dried under reduced pressure to yield 2-[3-(3-Chloro -4-isopropoxy-phenyl)-[1,2,4] oxadiazol-5-yl]-3-methyl-5,6,7,8-tetrahydro-imidazo [1,2-a] pyrazine (113 mg, 96%) as an off-white solid. LCMS (Table 1, Method a) Rl=3.14 min, m/z 374.24 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, 1H), 7.97 (d,d, 1H), 7.36 (d, 1H), 4.81 (m, 1H), 4.66 (s, 2H), 3.90 (s, 2H), 3.87 (t, 2H), 3.12 (t, 2H), 2.60 (s, 3H), 1.34 (d, 6H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:21][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1
Reactant: O=C(NC1CCN(CCO)CC1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(NC1CCN(CCCl)CC1)c1ccccc1

Procedure:
1 Gram of 1-(2-hydroxyethyl)-4-benzamidopiperidine suspended in 2 milliliters of dry benzene was treated with 0.62 gram of thionyl chloride. The stirred mixture was refluxed for 3 hours., then cooled and filtered to give the title compound as a light grey solid. Crystallisation from ethanol-ether of this hydrochloride gave 0.8 grams (62%) of pale yellow needles, melting point 238.5° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[Cl:9][C:10]1[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[C:14]([Cl:21])=[CH:13][C:11]=1[NH2:12].[OH-].[Na+]>O>[CH3:8][C:2]1[CH:1]=[C:6]([O:7][S:17]([C:15]2[CH:16]=[C:10]([Cl:9])[C:11]([NH2:12])=[CH:13][C:14]=2[Cl:21])(=[O:19])=[O:18])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(O)c1
Reactant: Nc1cc(Cl)c(S(=O)(=O)Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(OS(=O)(=O)c2cc(Cl)c(N)cc2Cl)c1
Reaction time: 0.5 h

Procedure:
110 g of m-cresol are dissolved in 1.5 liters of water at 60° C. and pH 10.5. 497 g of a 52.4% strength moist paste of 2,5-dichloro-aniline-4-sulphonic acid chloride are added in portions, over the course of 45 minutes, to this solution at 60° C. At the same time, the pH value is kept constant at between 10.0 and 10.5 by simultaneous dropwise addition of a total of 100 ml of a 45% strength sodium hydroxide solution. The mixture is then stirred for a further 30 minutes, after which the precipitate obtained is filtered off, washed until neutral and dried at 60° C. in a vacuum drying cabinet. 275 g of 4-amino-2,5-dichlorobenzenesulphonic acid 3-methyl-phenyl ester are obtained. ##STR7##
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][C:12]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:24][C:25]([CH:27]1[C:32](=[O:33])[CH:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][S:29][CH2:28]1)=[O:26])[CH:22]=[CH2:23]>C1CCCCC1.CCOC(C)=O>[CH2:21]([O:24][C:25]([C@@:27]1([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:20])=[C:12]([F:19])[CH:13]=2)[C:32](=[O:33])[CH:31]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30][S:29][CH2:28]1)=[O:26])[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)C1CSCC(NC(=O)OC(C)(C)C)C1=O
Reactant: O=C(Nc1ccc(CBr)cc1F)OCc1ccccc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)[C@]1(Cc2ccc(NC(=O)OCc3ccccc3)c(F)c2)CSCC(NC(=O)OC(C)(C)C)C1=O

Procedure:
The title compound was prepared in analogous manner as described for example 1c from (4-bromomethyl-2-fluoro-phenyl)-carbamic acid benzyl ester (37 g, 109 mmol) and 5-tert-butoxycarbonylamino-4-oxo-tetrahydro-thiopyran-3-carboxylic acid allyl ester (33 g, 105 mmol, example 1b) to yield a diastereomeric mixture of a yellow solid: TLC (cyclohexane-EtOAc 1:1) Rf=0.77; ESIMS [M+NH4]+=590; LCMS [M+NH4]+=590, RtI=1.60 min.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][NH2:7].C(=O)([O-])[O-].[Na+].[Na+].Br[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N+:25]([O-:27])=[O:26])[C:17](=O)[O:16]1.O>CN(C=O)C>[N+:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[CH:15]=[N:6][NH:7][C:17]2=[O:16])([O-:27])=[O:26]
Reactant: O=C1OC(Br)c2c1cccc2[N+](=O)[O-]
Reactant: NN
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]ncc2c([N+](=O)[O-])cccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.8 %

Procedure:
18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirred in 300 ml of DMF at 100° C. for 1 hour. Then, 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF is added, and it is stirred for another 4 hours at 100° C. It is added to water, extracted several times with ethyl acetate, and the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. After recrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazin-l-one is obtained as a solid.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:11](=[O:22])[CH:10]1[CH:23]([OH:29])[C:24]([O:26]CC)=[O:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.[OH-].[Na+]>>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:11](=[O:22])[CH:10]1[CH:23]([OH:29])[C:24]([OH:26])=[O:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)C1C(=O)N(c2ccc(C)cc2)CCN1C(=O)c1ccccc1
Agent: [Li]O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccccc3)C(C(O)C(=O)O)C2=O)cc1
Yield: 84.1 %

Procedure:
According to the Step 1-2 in synthetic method for EXAMPLE 1, compound 111-1 (128 mg) and LiOH—H2O (14.5 mg) were used instead of 1-1 (LP) and NaOH to obtain compound 111-2 (100 mg) as a beige amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:28]O)=[C:6]([NH:8][C:9]2([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH:7]=1.O=S(Cl)Cl.C([O-])([O-])=O.[K+].[K+].[N:40]1([C:46](=[O:48])[CH3:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl>[C:46]([N:40]1[CH2:45][CH2:44][N:43]([CH2:28][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[NH:8][C:9]2([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:19])[CH2:42][CH2:41]1)(=[O:48])[CH3:47]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)Nc1cc(Br)ccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(=O)N1CCN(Cc2ccc(Br)cc2NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 8.5 %

Procedure:
At room temperature, 3-(5-Bromo-2-hydroxymethyl-phenylamino)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (100 mg, 0.137 mmol) was dissolved in 2 ml dried CH2Cl2. Then SOCl2 (49 mg, 0.333 mmol) was added slowly. After stirred for about half an hour, K2CO3 (84 mg, 0.612 mmol) and 1-piperazin-1-yl-ethanone (32 mg, 0.245 mmol) were added. This solution was stirred for about 2 h, then the solution was concentrated and the crude product was purified by Prep-HPLC to obtain 7 mg white solid rac-3-[2-(4-Acetyl-piperazin-1-ylmethyl)-5-bromo-phenylamino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.CN1C(=O)N(C)CCC1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:21]=1.CI>C1COCC1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:2])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:21]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(CCC(=O)OC(C)(C)C)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(CC(C)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
An oven dried flask was charged with THF (40 mL) under nitrogen and cooled to −78° C. and 2M LDA in THF (7.62 mL, 15.23 mmol) was added dropwise followed by DMPU (8 mL, 6.09 mmol). Tert-butyl 3-(4-methoxyphenyl)propanoate (1.44 g, 6.09 mmol) was added by cannula in THF (4×5 mL), and the reaction was stirred at −78° C. for 1 hr. Methyl iodide (1.143 mL, 18.28 mmol) was added dropwise, and the reaction was stirred 30 minutes at −78° C. and then warmed to room temperature for 1 hr. The reaction was then quenched with water (40 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 1N HCl (2×30 mL) and brine (2×30 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 60% ethyl acetate/hexanes) afforded of tert-butyl 3-(4-methoxyphenyl)-2-methylpropanoate. 1H NMR (CDCl3, 500 MHz) δ 7.09 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.5 Hz, 2H), 3.78 (s, 3H), 2.89 (multiplet, 1H), 2.57 (multiplet, 2H), 1.38 (s, 9H), 1.10 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.[C:17]([NH:24][C@@H:25]([C:27](O)=[O:28])[CH3:26])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:20]([O:19][C:17]([NH:24][C@H:25]([CH3:26])[C:27]([NH:6][CH:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])=[O:28])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H](N)CO
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of L-Serine methyl ester hydrochloride (5.0 g, 32.0 mmol), in CH2Cl2 (150 mL) at 0° C., were added Et3N (4.88 mL, 35.2 mmol), Boc-D-Alanine (6.06 g, 32 mmol), and DCC (7.26 g, 35.2 mmol) sequentially. The reaction was allowed to warm to room temperature and stirred overnight. All the solvent was evaporated and the residue was triturated with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated under low pressure and chromatographed on silica gel (70% ethyl acetate/30% chloroform) to yield 86% of methyl 2-((R)-2-(tert-butoxycarbonylamino)propanamido)-3-hydroxypropanoate.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:12])[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][CH:6]=1.S(=O)(=O)(O)O>C(Cl)Cl.O>[OH:11][C:10]1[CH:9]=[C:8]2[C:7](=[CH:6][C:5]=1[CH3:12])[C:10](=[O:11])[CH2:9][CH2:8]2
Reactant: Cc1ccccc1O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(cc1O)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a stirred suspension of aluminum chloride (3.0 g, 22.2 mmol) and o-cresol (2.0 g, 18.5 mmol) in methylene chloride (10 mL) was added 4-chloropropionyl chloride (2.0 mL, 20.4 mmol). After stirring overnight at rt, the reaction was quenched by the addition of methanol followed by 2N hydrochloric acid. The product was extracted in methylene chloride (3×30 mL), dried over magnesium sulfate and concentrated in vacuo to give a colorless oil. This oil was treated with concentrated sulfuric acid (10 mL) at 90° C. for 1 h, diluted with water (50 mL) and the product extracted into methylene chloride (3×30 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 33% ethyl acetate/hexanes gave 0.47 g of the title compound: 1H NMR (500 MHz, CDCl3): δ 7.56 (s, 1H), 6.81 (s, 1H), 5.36 (s, 1H, OH), 3.04 (t, J=5.9 Hz, 2H), 2.65 (t, J=5.8 Hz, 2H), 2.28 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.Cl[CH2:23][C:24]([NH:26][C:27]1[CH:28]=[CH:29][C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[CH:36]=1)=[O:25]>C(O)C>[OH:21][C@@H:13]([CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:23][C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]3[S:34][C:33]([CH3:35])=[N:32][C:31]=3[CH:36]=2)=[O:25])[CH2:19][CH2:20]1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: Cc1nc2cc(NC(=O)CCl)ccc2s1
Solvent: CCO
Product: Cc1nc2cc(NC(=O)CN3CCN(C[C@@H](O)COc4ccc5sc(C)nc5c4)CC3)ccc2s1

Procedure:
A mixture of (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol (0.2 g, 0.65 mmol) and 2-chloro-N-(2-methylbenzothiazol-5-yl)acetamide (0.155 g, 0.65 mmol) in ethanol was allowed to stir at reflux for 24 hours. The solvent was removed under reduced pressure and the residue was purified using preparative thin layer chromatography, to afford 2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2-methylbenzothiazol-5-yl)acetamide.
Reaction SMILES: FC1C=CC(B(O)O)=CC=1.[CH:11]1([C:14]([CH:18]2[CH2:20][CH2:19]2)([OH:17])[C:15]#[CH:16])[CH2:13][CH2:12]1.[N:21]([CH2:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1)=[N+:22]=[N-:23]>>[N:21]([CH2:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1)=[N+:22]=[N-:23].[CH:11]1([C:14]([CH:18]2[CH2:20][CH2:19]2)([OH:17])[C:15]2[N:23]=[N:22][N:21]([CH2:24][C:25]3[CH:34]=[C:33]4[C:28]([C:29]([C:36]5[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=5)=[CH:30][C:31](=[O:35])[O:32]4)=[CH:27][CH:26]=3)[CH:16]=2)[CH2:13][CH2:12]1
Reactant: C#CC(O)(C1CC1)C1CC1
Agent: OB(O)c1ccc(F)cc1
Agent: [N-]=[N+]=NCc1ccc2c(-c3ccc(F)cc3)cc(=O)oc2c1
Product: O=c1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C(O)(C4CC4)C4CC4)nn3)cc2o1

Procedure:
7-(Azidomethyl)-4-(4-fluorophenyl)-2H-chromen-2-one was prepared using the general procedure described in example 1, steps 3-7, but substituting 4-fluorobenzeneboronic acid in place of 3-fluorobenzeneboronic acid. The title compound was prepared using 1,1-dicyclopropylprop-2-yn-1-ol and 7-(azidomethyl)-4-(4-fluorophenyl)-2H-chromen-2-one using the general cycloaddition procedure described in example 12. 1H NMR (400 MHz, acetone-d6): 1H NMR (400 MHz, acetone-d6): 7.95 (s, 1H), 7.7-7.65 (m, 1H), 7.52 (d, 1H), 7.40-7.35 (m, 3H), 7.30 (d, 1H), 6.40 (s, 1H), 5.80 (s, 2H), 3.72 (s, 1H), 1.45-1.35 (m, 2H), 0.55-0.45 (m, 4H), 0.45-0.35 (m, 2H), 0.30-0.20 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:9][C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CCN(C(C)C)C(C)C.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.C(Cl)Cl>[CH2:26]([O:33][C:34]([NH:1][CH2:2][C@@H:3]1[CH2:9][C:6]2([CH2:7][CH2:8]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1CN
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2(CC2)C[C@H]1CNC(=O)OCc1ccccc1

Procedure:
To a solution of (S)-tert-butyl 6-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate (prepared according to WO2011006960; 136 mg, 0.6 mmol) in acetonitrile (1.5 ml), DIPEA (156 μl, 0.9 mmol) and benzylchloroformate (100 μl, 0.7 mmol) were added. After 1 h at RT the reaction was diluted with DCM (20 ml) and washed with an aqueous satd. solution of NH4Cl; organics were evaporated to obtain an oil, which was purified on silica gel column (Cyclohexane/AcOEt from 9/1 to 7/3). Yield 168 mg, transparent oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]2[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:13]([CH2:14][C:15]=1[C:16]1[S:20][C:19]([CH2:21][O:22][CH2:23][CH2:24][OH:25])=[N:18][CH:17]=1)[CH2:12][N:11]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:10]2)=[O:7])C>CCO>[C:37]([O:36][C:34]([N:11]1[CH2:10][CH:9]2[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:13]([CH2:14][C:15]([C:16]3[S:20][C:19]([CH2:21][O:22][CH2:23][CH2:24][OH:25])=[N:18][CH:17]=3)=[C:8]2[C:6]([OH:7])=[O:5])[CH2:12]1)=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CCOC(=O)C1=C(c2cnc(COCCO)s2)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CC(c3cnc(COCCO)s3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Aq. 1M NaOH (1.0 mL) was added to a sol. of the compound C5 (50 mg, 0.090 mmol) in EtOH (1.0 mL). The resulting mixture was stirred at 70° C. for 1 h, cooled to rt and the solvent removed in vacuo. The crude mixture was partitioned between Et2O and aq. sat. NH4Cl. The aq. layer was extracted once more with Et2O, then acidified to pH= 4-5, and extracted again with Et2O. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the title compound (26.4 mg, 56%), which was not further purified. LC-MS: tR=0.82 min, ES+: 526.41.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:19]=4)=[CH:16][N:17]=[C:11]3[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl.O.[OH-].[Na+]>CCO>[C:24]1([C:20]2[CH:19]=[C:18]([C:15]3[N:12]4[CH:13]=[CH:14][C:9]([C:8]5[C:3]([OH:2])=[N:4][CH:5]=[CH:6][CH:7]=5)=[CH:10][C:11]4=[N:17][CH:16]=3)[CH:23]=[CH:22][N:21]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ncccc1-c1ccn2c(-c3ccnc(-c4ccccc4)c3)cnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1ncccc1-c1ccn2c(-c3ccnc(-c4ccccc4)c3)cnc2c1

Procedure:
7-(2-Methoxy-pyridin-3-yl)-3-(2-phenyl-pyridin-4-y1)-imidazo[1,2-a]pyridine (Ex. 1.100) (1 eq, 0.38 mmol, 145 mg) is dissolved in EtOH (0.5 ml) and HCl (37% in H2O, 0.04 eq, 0.015 mmol, 0.5 ml) is added. The reaction is heated at reflux for 3 h and is cooled down to rt before H2O is added. The pH is adjusted to 7 with the addition of NaOH (4N) and the suspension is filtered. The solid is washed with a mixture H2O/EtOH 4:1 and dried in vacuo to afford 3-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridin-7-yl]-pyridin-2-ol as a light yellow oil; [M+H]+=365
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]([S:24](=[O:34])(=[O:33])[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][Si:56]([CH3:61])([CH3:60])[CH2:57][CH2:58]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[N:8]([S:24]([N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:58][CH2:57][Si:56]([CH3:61])([CH3:60])[CH3:55])(=[O:33])=[O:34])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CN(c1ccc(I)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN(c1ccc(I)cc1OCc1ccccc1)S(=O)(=O)N(CC[Si](C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.83 h

Procedure:
To a solution of N-(t-butoxycarbonylsulfamoyl)-N-(2-benzyloxy-4-iodophenyl)glycine tert-butyl ester (3.49 g, 5.6 mmol) in toluene (224 mL) is added triphenylphosphine (2.22 g, 8.47 mmol) and 2-trimethylsilanylethanol (992 mg, 8.38 mmol). DIAD (1.6 mL, 8.13 mmol) is then added dropwise over 10 min. After it is stirred for 50 min., toluene is remove under reduced pressure. After 18 h, 20% EtOAc/hexane is added (50 mL in 4 increments) to form a precipitate. The solid is filtered out and the filtrate is then concentrated. The residue is then purified by column chromatography to give the title compound as a white foam.
Reaction SMILES: C[Si](C)(C)[O-:3].[Na+].[Br:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:10](F)[CH:9]=1>C1COCC1>[Br:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:10]([OH:3])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(Br)cc1O
Temperature: 25 °C
Yield: 205.8 %

Procedure:
A solution of 2 M sodium trimethylsilanolate (15.6, 31.1 mmol) in THF was added dropwise to 4-bromo-2,5-difluoronitrobenzene (2.47 g, 10.4 mmol) under a nitrogen atmosphere. A bright red suspension was formed, and the mixture was refluxed for 27 hours. The mixture was cooled to room temperature and concentrated. Water (6 mL) was added, and the solution was acidified with a 10% HCl solution, extracted with DCM (70 mL×2). The organic layers were combined and concentrated to give 5-bromo-4-fluoro-2-nitrophenol (5.05 g, 2.06%). MS m/z: 236(M+1). 1H NMR (400 MHz, CD3OD) δ ppm 7.48 (d, J=5.87 Hz, 1H), 7.95 (d, J=8.41 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=O)[CH3:15])[CH:9]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[C:14](=[C:21]2/[C:20](=[O:22])[NH:19][C:18](=[O:23])[S:17]/2)/[CH3:15])[CH:9]=1
Reactant: O=C1CSC(=O)N1
Reactant: CC(=O)c1cccc(-c2ccccc2Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: C/C(=C1/SC(=O)NC1=O)c1cccc(-c2ccccc2Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 1-(2′-chloro-1,1′-biphenyl-3-yl)ethanone (145 mg, 0.63 mmol) and 2,4-thiazolidinedione (67 mg, 0.57 mmol) in xylene (1.9 mL), sodium acetate (38 mg, 0.28 mmol) and acetic anhydride (53 μL, 0.57 mmol) were added and the solution was heated in a sealed tube for 16 h. It was then cooled to rt, partitioned between ethyl acetate and water, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. Finally filtered, concentrated and purified by chromatography. (hexanes:ethyl acetate; 4:1) to give the product as a solid.