Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]1[N:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[S:16][CH:17]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:34]>C(Cl)Cl.C(OCC)C>[ClH:34].[ClH:34].[ClH:34].[NH2:7][C@H:8]([C:13]1[N:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[S:16][CH:17]=1)[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)OC(C)(C)C)cs2)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
1162 mg (2.46 mmol) ((S)—1-{2-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-carbamic acid tert-butyl ester was dissolved in methylene chloride (24.6 ml) and 2M HCl in diethyl ether (12.3 ml) was added at room temperature. A solid precipitated. The reaction was stirred at room temperature over night. The reaction was diluted with diethyl ether, stirred for 15 minutes and the solid was filtered off, washed with diethyl ether and dried to yield 1195 mg (100%) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride as a light yellow solid. MS ISP (m/e): 372.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.98 (s, 1H), 9.31 (s, 1H), 8.46 (br s, 3H), 7.93 (s, 1H), 7.66 (s, 1H), 7.47 (d, 1H), 7.31 (d, 1H), 7.13 (s, 1H), 4.27 (m, 1H), 3.90 (s, 3H), 2.35 (s, 3H), 1.94-1.83 (m, 1H), 1.80-1.69 (m, 1H), 1.52-1.39 (m, 1H), 0.90 (d, 3H), 0.86 (d, 3H).
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[S-:14][C:15]#[N:16].[NH4+].[OH-].[Na+]>CO>[Cl:3][C:4]1[C:10]([S:14][C:15]#[N:16])=[CH:9][C:7]([NH2:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: BrBr
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: N#CSc1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
A solution 8 ml of bromine 7.00 g in methanol was added dropwise to a suspension 8 ml of 4-chloro-2-nitroaniline 6.61 g (38.3 mmol) and ammonium thiocyanate 7.00 g (92.0 mmol) in methanol, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into ice water and alkalized with 4N sodium hydroxide, and the precipitated crystals were filtered. The crystals were washed with water and with ether and dried under reduced pressure, and 4-chloro-2-nitro-5-thiocyanatoaniline 7.88 g (89.6%) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([OH:17])[C:15]#[CH:16])[CH:5]=[C:4]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:3]1=2.I[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1>[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>[OH:17][CH:14]([C:6]1[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[C:3]2[C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[C:15]#[C:16][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1
Reactant: C#CC(O)c1cc(-c2ccc(C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: Cc1ccc(-c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 81 %

Procedure:
In a similar manner to that of Example 1g, by reacting 950 mg (2.9 mmol) of 1-(5,5,8,8-tetramethyl-4-p-tolyl-5,6,7,8-tetrahydro-2-naphthyl)prop-2-yn-1-ol with 595 mg (2.4 mmol) of 4-iodobenzoic acid in the presence of 47 mg of copper iodide and 54 mg of bis(triphenylphosphine)dichloropalladium. The desired product is obtained in the form of white crystals (m=1 g; yield=81%; m.p.=207° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(CN2CCOCC2)c1
Reaction time: 8 h

Procedure:
3-[5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-3-methyl-isoxazol-4-yl]-benzaldehyde (25 mg, 0.05 mmol) and morpholine (0.3 ml) were mixed with DCE (0.5 ml) in an microwave tube. Sodium triacetoxyborohydride (15 mg, 1.4 equiv) was added, the tube sealed, and nitrogen atmosphere introduced. After 1 hr more sodium triacetoxyborohydride (15 mg) was added and the reaction left stirring overnight. TLC analysis showed that the reaction had not gone to completion so a drop of acetic acid was added and the reaction again left stirring overnight after which the reaction was quenched with 1M NaHCO3 solution (7 ml) and extracted into EtOAc (5 ml). This was dried over MgSO4 and the solvent removed in vaccuo to provide 13 mg of the crude product as an off white powder which was taken over to the deprotection step.
Reaction SMILES: C([O:8][C:9](=[O:48])[C@H:10]([CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)[NH:11][C:12](=[O:37])[CH:13]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29]CC1C=CC=CC=1)[CH:14]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[OH:15])C1C=CC=CC=1>CO.[Pd]>[CH:16]1([CH:14]([OH:15])[CH:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[C:12]([NH:11][C@H:10]([C:9]([OH:48])=[O:8])[CH2:38][C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)=[O:37])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)C(Cc1ccccc1OCc1ccccc1)C(O)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(Cc1ccccc1O)C(O)C1CCCCC1
Reaction time: 3 h
Yield: 118.4 %

Procedure:
To a solution of N-[(2RS,3RS)-2-(2-benzyloxyphenylmethyl)-3-cyclohexyl-3-hydroxypropionyl]-L-tryptophan benzyl ester (150 mg) in methanol (3 ml) was added 10% palladium on carbon (45 mg) and the mixture was stirred under hydrogen atmosphere for 3 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give N-[(2RS,3RS)-3-cyclohexyl-3-hydroxy-2-(2-hydroxyphenylmethyl)propionyl]-L-tryptophan (128 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[C:13]1([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[CH2:21][OH:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O.CCCCCC>[Cl:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1-c1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(OCc2ccccc2-c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250 milliliter reaction flask equipped with a magnetic stirrer was added 10.04 grams (0.044 moles) of 3,4,5-trichloronitrobenzene, 8.16 grams (0.044 moles) of 2-phenylbenzyl alcohol, 1.29 grams (0.004 moles) of tetra-N-butylammonium bromide, 80 milliliters of toluene and aqueous sodium hydroxide (5.28 grams in 6.6 milliliters of water). The resulting mixture was stirred vigorously at ambient temperature overnight. The mixture was then diluted with water and filtered. The layers were separated and the organic layer was washed twice with water and finally once with a saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the mixture was concentrated under vacuum to give a red-orange oil which was stirred into hexane. Crystallization from the hexane and filtration afforded a yellow-orange powder having a melting point of 83.0° C.-84.5° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]([CH3:9])[CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:9][C@H:7]1[CH2:8][C@@H:3]([CH2:2][O:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:4][N:5]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6]1
Reactant: C[C@H]1C[C@@H](CO)CN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H](C)CN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To a stirred solution of (3R,5S)-tert-butyl 3-(hydroxymethyl)-5-methylpiperidine-1-carboxylate (0.783 g, 3.385 mmol) in DCM (5 mL) was added p-toluenesulfonyl chloride (0.968 g, 5.078 mmol) followed by DMAP (40 mg, 0.33 mmol) and DIPEA (1.18 mL, 6.77 mmol) at rt. The reaction mixture was stirred at rt for 3 h after which time water (5 mL) was added followed by stifling an additional 15 min. The resultant organic layer was washed with 0.1 N HCl (5 mL), brine (3 mL), dried over MgSO4, filtered and concentrated to dryness. The crude product was purified over silica gel (Biotage, eluting with 3:1 heptanes: EtOAc) to provide (3S,5R)-tert-butyl 3-methyl-5-((tosyloxy)methyl)piperidine-1-carboxylate (0.8602 g, 2.232 mmol, 65.9% yield).
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14]([O:16]C)=[O:15])=[O:7])=[C:4]([F:21])[CH:3]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14]([OH:16])=[O:15])=[O:7])=[C:4]([F:21])[CH:3]=1
Reactant: COC(=O)c1sccc1NC(=O)c1cc(F)c(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccsc1C(=O)O)c1cc(F)c(Cl)cc1F
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-[(4-chloro-2,5-difluorobenzoyl)amino]thiophene-2-carboxylate, MeOH, THF and 1M sodium hydroxide (NaOH) solution (aq) was stirred for two hours at 85° C. to give 3-[(4-chloro-2,5-difluorobenzoyl)amino]thiophene-2-carboxylic acid.
Reaction SMILES: [OH:1][CH:2]([C:4]1([CH3:26])[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:22][CH:23]([CH3:25])[CH3:24])=[C:8]2[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:3].O.C(=O)(O)[O-].[Na+:32].C>O1CCOCC1.[Pd]>[OH:1][CH:2]([C:4]1([CH3:26])[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:22][CH:23]([CH3:25])[CH3:24])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:32]
Reactant: CC(C)SC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C)(C(C)O)C2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)SC1=C(C(=O)[O-])N2C(=O)C(C)(C(C)O)C2C1
Reaction time: 1 h

Procedure:
Benzyl 6-(1-hydroxyethyl)-6-methyl-3-isopropylthio-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (25 mg) is dissolved in dioxane (2 ml) and the solution is treated with water (1 ml) containing sodium bicarbonate (6 mg) and 10% palladium on powdered charcoal (25 mg). The resulting mixture is hydrogenated at 40 psi for 1 hour. The catalyst is filtered off and washed with water (3 ml). The combined filtrate is extracted with ethylacetate (3×2 ml), concentrated in vacuo, and lyophilized to afford sodium 6-(1-hydroxyethyl)-6-methyl-3-isopropylthio-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]([C:26]([NH:28][C:29]1[C:30](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:31]([O:33][CH3:34])=[O:32])=O)C1C=CC=CC=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([O:33][CH3:34])=[O:32])=[O:19])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1NC(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1O
Product: COC(=O)c1ccccc1NC(=O)NS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Yield: 77.8 %

Procedure:
618 mg (2.26 mmol) of 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and 613 mg (2.26 mmol) of methyl 2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 17 to obtain 792 mg (yield 78%) of methyl 2-{[(4-t-butoxycarbonyl-3-hydroxybenzenesulfonylamino)carbonyl]amino}benzoate. Properties: colorless amorphous, PMR (δ ppm, CDCl3): 1.60 (9H, s), 3.97 (3H, s), 7.09 (1H, t), 7.49-7.52 (2H, m), 7.65 (1H, d), 7.90 (1H, d), 8.01 (1H, dd), 8.33 (1H, d), 10.98 (1H, s), 11.18 (1H, s).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12].[Li+].[OH-]>CO.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The title compound 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinic acid (29) was prepared by the following procedure: To methyl 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinate (29I) (23 mg, 0.044 mmol) in MeOH (0.55 mL) and water (0.11 mL) was added an aqueous solution of LiOH (0.066 mL of 2.0 M, ˜0.13 mmol). The reaction mixture was stirred at rt for 15 hours, concentrated under reduced pressure to remove MeOH and diluted with water. The pH was adjusted to ˜4 with 2 M HCl, and the resulting precipitate was isolated by filtration and washed with water. The crude material was purified by column chromatography on silica gel eluting with a gradient of DCM:MeOH 98:2-92:8, to provide the desired product 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinic acid (29): MS (ESI(+)): m/z 507.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].ClCCl.Cl>CO.CCOCC>[CH3:1][N:2]([C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: C[C@H](c1ccccc1)N(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: C[C@H](c1ccccc1)N(C)C(=O)c1cnc(N2CCNCC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl 4-[5-[[methyl[(1R)-1-phenylethyl]amino]carbonyl]-2-thiazolyl]-1-piperazinecarboxylate (i.e. the product of Example 4, Step C) (0.75 g, 1.7 mmol) in 10 mL of methanol and 10 mL of dichloromethane was treated with 15 mL of 1 N HCl in ether. The reaction mixture was stirred at ambient temperature overnight, concentrated under reduced pressure, dissolved in water and brine, basified with 1. N aqueous NaOH solution and extracted with dichloromethane. The extract was dried over MgSO4 and concentrated under reduced pressure to give 0.48 g of the title compound as a yellow oil.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.Cl[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.O>[C:20]1([C:17]2[CH:18]=[CH:19][C:13]3[O:12][C:11]([N:4]4[CH:5]5[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]5)[CH2:2][CH2:3]4)=[N:15][C:14]=3[CH:16]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1nc2cc(-c3ccccc3)ccc2o1
Reactant: C1CN2CCC(CC2)N1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc3oc(N4CCN5CCC4CC5)nc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
1,4-Diazabicyclo[3.2.2]nonane (504 mg, 4.0 mmol) was added to a mixture of 2-chloro-5-phenylbenzoxazole (919 mg, 4.0 mmol), sodium tert-butoxide (423 mg, 4.4 mmol) and toluene (4 mL) at RT. The mixture was stirred at RT for 16 h and water (10 mL) and ethyl acetate (10 mL) were added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated and the residue was purified by chromatography (Biotage, 40S) eluting with 4% MeOH in CHCl3 with 20 drops of NH4OH per liter of eluent to afford 540 mg (42%) of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.60-7.56 (m, 3H), 7.42 (t, 2H, J=7.7 Hz), 7.33-7.20 (m, 3H), 4.51 (s, 1H), 3.92 (t, 2H, J=5.8 Hz), 3.17-2.97 (m, 6H), 2.20-2.07 (m, 2H), 1.84-1.75 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 162.2, 148.6, 144.3, 141.9, 137.9, 129.0, 127.5, 127.1, 119.8, 114.8, 108.8, 57.3, 50.4, 46.5, 44.4, 27.0; MS (Cl) m/z 320.1 (M+1). The hydrochloride salt was prepared by diluting the title compound in ethyl acetate and adding a 2.5 N HCl in ethyl acetate solution: mp>300° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:43][C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=1)=[O:27])#[N:2]
Reactant: COc1cccc(N)c1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of m-anisidine (0.182 ml, 1.62 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the objective product as a solid material.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][O:17][CH2:18][CH2:19]O)[C:7]2[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=2[CH2:5][CH2:4][S:3]1.[N+:21]([C:24]1C=[CH:28][C:27](S([O-])(=O)=O)=[CH:26][CH:25]=1)([O-])=O.N1CCCCC1>C1COCC1>[CH3:1][C:2]1([CH2:16][O:17][CH2:18][CH2:19][N:21]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[C:7]2[CH:8]=[C:9]([O:14][CH3:15])[C:10]([O:12][CH3:13])=[CH:11][C:6]=2[CH2:5][CH2:4][S:3]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Reactant: COc1cc2c(cc1OC)C(C)(COCCO)SCC2
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: COc1cc2c(cc1OC)C(C)(COCCN1CCCCC1)SCC2

Procedure:
A mixture of 2-[[1-methyl-6,7-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-1-yl]methoxy]ethanol-4-nitrobenzenesulfonate and piperidine is stirred at room temperature in THF. The mixture is then partitioned between methylene chloride and aqueous sodium carbonate. The title compound is isolated by chromatography and is crystallized.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]=[O:21].[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[N:23]>C/C(/O)=C/C(C)=O.[C-]#[O+].[C-]#[O+].[Rh].O1CCCC1>[C:22]([CH:24]([CH2:20][OH:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])#[N:23]
Reactant: C=O
Reactant: CCOC(=O)CC#N
Agent: [Rh]
Agent: CC(=O)/C=C(/C)O
Agent: [C-]#[O+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)CO
Reaction time: 0.17 h
Yield: 64 %

Procedure:
A reactor was charged with 0.26 g (1 mmol) of acetylacetonatodicarbonylrhodium, 0.52 g (2 mmol) of triphenylphosphine, and 200 ml of tetrahydrofuran (THF). The mixture was stirred for 10 minutes in a nitrogen atmosphere. After the dropwise addition of 10.54 g (130 mmol) of a 37% formaldehyde aqueous solution and 11.31 g (100 mmol) of ethyl 2-cyanoacetate, the mixture was reacted at 25° C. for 16 hours with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate (=10/1)) to obtain 9.16 g of ethyl 2-cyano-3-hydroxypropanoate shown by the following formula (M-18′) (yield: 64%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:49]=[CH:50][CH:51]=1)[CH2:29][N:30]1[CH2:48][CH2:47][C:33]2([O:38][CH2:37][CH2:36][N:35]([C:39]([C:41]3[S:42][C:43]([CH3:46])=[CH:44][CH:45]=3)=[O:40])[CH2:34]2)[CH2:32][CH2:31]1.FC(F)(F)C(O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:46][C:43]1[S:42][C:41]([C:39]([N:35]2[CH2:34][C:33]3([CH2:47][CH2:48][N:30]([CH2:29][C:28]4[CH:27]=[C:26]([CH2:25][CH:24]=[O:23])[CH:51]=[CH:50][CH:49]=4)[CH2:31][CH2:32]3)[O:38][CH2:37][CH2:36]2)=[O:40])=[CH:45][CH:44]=1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)C2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cccc(CC=O)c4)CC3)C2)s1
Reaction time: 0.5 h

Procedure:
Dess-Martin periodinane (0.16 g) was added to a stirred solution of (9-(3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-methylthiophen-2-yl)methanone (0.13 g) (example 9, step c) and trifluoroacetic acid (0.036 g) in DCM (4 mL) under nitrogen. After 0.5 h, saturated sodium thiosulphate solution (5 mL) and saturated sodium bicarbonate solution (5 mL) were added and the reaction mixture extracted twice with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound. Yield 0.13 g. Used directly.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O-:14])=[O:13])[CH:6]=[C:7]([CH:11]=1)[C:8]([O-:10])=[O:9])#[CH:2].[K+].[K+]>O>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])#[CH:2]
Reactant: C#Cc1cc(C(=O)[O-])cc(C(=O)[O-])c1
Agent: [K+]
Solvent: O
Product: C#Cc1cc(C(=O)O)cc(C(=O)O)c1
Yield: 99.5 %

Procedure:
Dipotassium 5-ethynylisophthalate in an amount of 5 g (0.019 moles) was dissolved into 20 ml of ion-exchanged water and insoluble substances were removed by filtration with a 5C filter paper. To the obtained filtrate, a 5 moles/liter hydrochloric acid was added under stirring until the pH became 1. The formed solid substance was separated by filtration, washed with ion-exchanged water and filtered. The filtration and the washing were repeated twice. The obtained solid substance was dried at 50° C. under a reduced pressure and 3.6 g of 5-ethynylisophthalic acid was obtained (the yield: 99.5%).