Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1.C(OCC)(=O)C>O1CCCC1>[O:36]=[C:30]([N:13]1[CH2:14][CH2:15][N:10]2[C:9](=[O:16])[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]2[CH2:12]1)[CH2:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: O=C1CCC(=O)O1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.15 g, 0.50 mmol) in tetrahydrofuran (10 mL) were added triethylamine (0.14 mL, 1.0 mmol) and succinic anhydride (55 mg, 0.55 mmol), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with 2 M hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate). The fractions were concentrated, and to the residue was added diethyl ether. The resulting crystals were collected by filtration and washed with diethyl ether to obtain the title compound (99 mg, yield 50%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[Na+].[I-:25]>CC(C)=O>[I:25][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 3-{[4-(3-Chloro-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one (45 mg, 0.137 mmol) and NaI (103 mg, 5 equiv.) in 1 mL acetone is heated at 80° C. overnight. The reaction mixture is cooled to room temperature and evaporated to dryness. The residue is dissolved in EtOAc and H2O. The organic layer is collected and dried over anhydrous Na2SO4, filtered, and concentrated to give the named compound as yellow solid (100%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[C:8]([CH3:16])[CH:7]=1>>[F:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[C:8]([CH3:16])[CH:7]=1
Reactant: Cc1cc(F)ccc1CC(=O)O
Reactant: O=[N+]([O-])O
Product: Cc1cc(F)c([N+](=O)[O-])cc1CC(=O)O
Temperature: 5 °C
Yield: 96.9 %

Procedure:
To stirring fuming HNO3 (90 wt %, 30.0 mL, 643 mmol) at −15° C. was added 4-fluoro-2-methylphenylacetic acid (15 g, 89.2 mmol) in portions such that the internal temperature remained below −10° C. After completing the addition the reaction was stirred with warming to 5° C. over 15 min. The mixture was poured onto ice (400 g), stirred vigorously until the ice had completely melted and the resulting solid was collected by filtration, rinsed well with H2O and dried on the filter to afford 2-(4-fluoro-2-methyl-5-nitrophenyl)acetic acid (18.43 g, 97% yield) as a pale yellow solid. 1H NMR (400 MHz, acetone-d6): δ 8.06 (d, J=7.6 Hz, 1H), 7.36 (d, J=12.0 Hz, 1H), 3.84 (s, 2H), 2.44 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:22]=1>>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:14])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCc1cccnc1
Product: CCCc1c(OCCCC(=O)NCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butanoic acid was allowed to react with 3-pyridine ethanamine according to procedure A and the product was purified by chromatography on silica gel to give 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[2(3-pyridinyl)ethyl]butanamide, the title compound, mp 94°-96° (from methylene chloride-ether) in 74% yield.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([Cl:1])[S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: Clc1nc2ccccc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Temperature: 5 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 2-chlorobenzothiazole (12.0 g, 70.7 mmol) in concentrated H2SO4 (60 mL) was added HNO3 (69% solution, 6 mL) dropwise at 0° C. for 20 min. The mixture was stirred at 5° C. for 3 h, poured into ice-water (150 mL). The precipitate was collected and washed with 5% sodium bicarbonate and water, dried in vacuo. 1H NMR analysis showed the mixture contained 78% 6-nitro-2-chlorobenzothiazole and 8% 5-nitro-2-chlorobenzothiazole. Recrystallization from ethanol gave 6-nitro-2-chlorobenzothiazole as white crystalline solid (11 g, 72%). 3.5 g of the solid was dissolved in refluxing ethanol-acetic acid (150: 15 mL), Iron powder was added in one portion. The mixture was refluxed for 1.5 h, filtered. The filtrate was concentrated in vacuo to half volume and neutralized with 10% NaOH to pH 7.5, extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated to give a residue, which was recrystallized from ethanol. Light purple crystals (2.5 g, 83%) were obtained. Mp 160-164° C.; TLC single spot at Rf 0.27 (30% EtOAc/hexane); 1HNMR (270 MHz, DMSO-d6) δ 7.58 (1H, d, J=9.0 Hz, 4-H), 7.03 (1H, d, J=2.0 Hz, 7-H), 6.77 (1H, dd, J=9.0, 2.0 Hz, 5-H), 5.55 (2H, s, NH2). The mother liquor from the recrystallization of nitration product was evaporated and subjected to iron powder reduction as described above. The crude product was purified with flash chromatography (ethyl acetate-DCM gradient elution) to give 2-chloro-benzothiazol-5-yl-amine as yellow solid. Mp 146-149° C.; TLC single spot at Rf 0.52 (10% EtOAc/DCM); 1HNMR (270 MHz, DMSO-d6) δ 7.63 (1H, d, J=8.6 Hz, 7-H), 7.05 (1H, d, J=2.3 Hz, 4-H), 6.78 (1H, dd, J=8.6, 2.3 Hz, 6-H), 5.40 (2H, s, NH2).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:18][CH2:17]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:25][CH2:24][CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]1)=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: CN1CCN(CCCN)CC1
Product: Cc1[nH]c2c(c1C(=O)NCCCN1CCN(C)CC1)CCCC2=O
Yield: 78.2 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 3-(4-methylpiperazin-1-yl)propan-1-amine 0.33 g (2.1 mmol) was reacted to give 0.26 g (78%) of the titled compound as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[O:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)=[O:5].[CH2:16]([Mg]Cl)[CH3:17]>C1COCC1>[CH3:14][S:11]([C:8]1[O:7][C:6]([C:4](=[O:5])[CH2:16][CH3:17])=[CH:10][CH:9]=1)(=[O:12])=[O:13]
Reactant: CON(C)C(=O)c1ccc(S(C)(=O)=O)o1
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(S(C)(=O)=O)o1
Reaction time: 18 h

Procedure:
To a chilled (0° C.) solution of 5-methanesulfonyl-furan-2-carboxylic acid methoxy-methyl-amide (1.48 g, 6.36 mmol) in THF (30 mL) was added a 2 M solution of ethylmagnesium chloride in THF (7.0 mL, 14 mmol). The mixture was then slowly warmed to with stifling. After 18 hours, the mixture was quenched with saturated aqueous ammonium chloride (50 mL) and then diluted with ethyl acetate (50 mL). The aqueous phase was separated and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford 1-(5-methanesulfonyl-furan-2-yl)-propan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:61][N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:63]([C:60]1[S:59][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[N:62][CH:61]=1)(=[O:64])=[O:65])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1cnc(NC(C)=O)s1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (48 mg) was treated with 2-acetylamino-thiazole-5-sulfonyl chloride according to General Procedure E to give (S)-2-({(S)-7-(2-Acetylamino-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[O:30][CH3:31].[OH-].[Na+].Cl>C(O)C>[I:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]([O:30][CH3:31])[CH:8]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)COc1ccc(SCC=C(c2ccc(I)cc2)c2ccc(I)cc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(SCC=C(c2ccc(I)cc2)c2ccc(I)cc2)ccc1OCC(=O)O
Reaction time: 2 h

Procedure:
{4-[3,3-Bis-(4-iodo-phenyl)-allylsulfanyl]-2-methoxy-phenoxy}-acetic acid methyl ester (290 mg, 0.43 mmol) was dissolved in warm ethanol (30 ml). 1N NaOH (2 ml) was added at room temperature and the reaction mixture was stirred for 2 h after which it was evapo-rated. The residue was treated with 1N HCl (2.4 ml) and extracted with dichloromethane (3×25 ml). The combined organic phases were dried and evaporated to give the title compound in 275 mg (97%) yield.
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.[O:27]=[S:28]1(=[O:43])[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[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:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([N:31]6[CH2:30][CH2:29][S:28](=[O:43])(=[O:27])[CH2:33][CH2:32]6)=[CH:35][CH:36]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCS(=O)(=O)CC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(N2CCS(=O)(=O)CC2)cc1

Procedure:
The title compound, off-white solid (132 mg, 94%), MS (ISP) m/z=566.3 [(M+H)+], mp 282° 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-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH:21]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]([O:24]C)=[O:23].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH:21]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:22]([OH:24])=[O:23]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1cccnc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2sc3c(c2c(-c2cccnc2)c1C(OC(C)(C)C)C(=O)O)CCCC3
Temperature: 60 °C
Yield: 63.9 %

Procedure:
To a solution of methyl 2-[2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.052 g; 0.122 mmol) in methanol (1.5 mL) was added a solution of sodium hydroxide 10 N (0.150 mL; 1.5 mmol) and the mixture was heated to 60° C. for 18 h. The volatiles were removed under reduced pressure and the residue was dissolved in water, the mixture was then acidified by adding 1N HCl until a precipitate was formed. The solid was filtered, washed with water and dried under reduced pressure to furnish 0.032 g (61%) of the title compound as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[CH:21]=[CH:22][CH:23]=2)[CH2:13]1.C([Sn]([C:45]#[N:46])(CCCC)CCCC)CCC>ClCCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:45]#[N:46])[CH2:13]1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: O=S(=O)(Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: N#Cc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Temperature: 80 °C
Yield: 7.6 %

Procedure:
A mixture of trifluoromethanesulfonic acid 3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}phenyl ester (51 mg, 0.11 mmol), tributyltin cyanide (142 mg, 0.45 mmol) and tetrakis(triphenylphosphine)palladium (189 mg, 0.164 mmol) in 1,2-dichloroethane (15 ml) was heated in a microwave reactor at 80° C. for 80 h. The solid precipitate was filtered off and the mixture was evaporated to dryness. The residue was redissolved in DCM, filtered and washed two times with 1 M HCl. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness. The crude product was purified by flash chromatography first using gradient of DCM and MeOH and then using gradient of heptane and EtOAc as eluent to give 2.8 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(F)c1
Yield: 85 %

Procedure:
To a solution of 3-fluorophenyl acetic acid (10.0 g, 64.9 mmol) in ethanol (300 mL), is added a catalytic amount of H2SO4 (98%, 1 mL) and the mixture reacted for 12 hours at 100° C. (LC-MS monitoring: complete conversion). The solvent is evaporated and the residue is partitioned between EtOAc and water; the organic layer is separated and dried over Na2SO4 in order to obtain 10.1 g of (I8) as a white solid (85% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>O1CCCC1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 130 mg of 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide in 5 mL of tetrahydrofuran are added dropwise 85 μL of 2-fluoro-5-(trifluoromethyl)phenyl isocyanate. The reaction mixture is then stirred for 16 hours at room temperature under an argon atmosphere and then concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica (eluent: 9/1 dichloromethane/methanol by volume). The fractions containing the expected product are concentrated under reduced pressure. 237 mg of 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=3)[N:27]=[CH:26][CH:25]=2)[O:21][C:20]1=[O:36].C(N(CC)CC)C.[O:44]=[C:45]1[CH2:50][O:49][C:48]2[CH:51]=[CH:52][C:53]([CH:55]=O)=[N:54][C:47]=2[NH:46]1.[BH4-].[Na+]>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH3:35][O:34][C:31]1[N:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[C:24]2[CH:22]1[O:21][C:20](=[O:36])[N:19]([CH2:18][CH2:17][CH2:16][NH:15][CH2:55][C:53]2[CH:52]=[CH:51][C:48]3[O:49][CH2:50][C:45](=[O:44])[NH:46][C:47]=3[N:54]=2)[CH2:23]1
Reactant: COc1ccc2nccc(C3CN(CCCN)C(=O)O3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [BH4-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2nccc(C3CN(CCCNCc4ccc5c(n4)NC(=O)CO5)C(=O)O3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To the dihydrochloride salt of 3-(3-Amino-propyl)-5-(6-methoxy-[1,5]naphthyridin-4-yl)-oxazolidin-2-one (previous patent) (0.47 g, 1.25 mmol) in CH2Cl2 (14 mL) and MeOH (3.5 mL) was added triethylamine (1.0 mL, 7.2 mmol) and the mixture was stirred at room temperature until all the solid went into solution. 3-Oxo-3,4-dihydro-2H pyrido[3,2,b][1,4]oxazine-6-carbaldehyde (SB-735368, 0.22 g, 1.23 mmol) was added and the reaction mixture was stirred for 15 hours. Sodium borohydride (0.0519, 1.35 mmol) was added followed by methanol (10 mL). After 30 minutes, the reaction mixture was diluted with chloroform and washed with saturated aqueous NaHCO3 solution, dried (MgSO4), filtered and concentrated. Flash chromatography on silica gel using a gradient of 0-10% MeOH/CHCl3 afforded the product as a white solid (0.36 g, 62%) 1H NMR (400 MHz, CDCl3): 0.8.79 (d, J=4.3 Hz, 1H); 8.26 (d, J=9.1 Hz, 1H); 7.70 (d, J=4.6 Hz, 1H); 7.18 (d, J=8.1 Hz, 1H); 7.17 (dd, J=9.0, 1.0 Hz, 1H); 6.87 (d, J=8.1 Hz, 1H); 6.31 (dd, J=9.0, 7.0 Hz, 1H); 4.64 (s, 2H); 4.35 (t, J=9.1 Hz, 1H); 4.04 (s, 3H); 3.72 (s, 2H); 3.47 (dd, J=8.8, 6.8 Hz, 1H); 3.41 (m, 2H); 2.63 (m, 2H); 1.75 (m, 2H). MS (ES) m/e 465 (M+H)+.
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[CH:32][CH:31]=3)=[O:28])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1COCC1.[OH-].[Na+].Cl>CO>[C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([C:27]([O:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=3)=[O:28])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(OC(=O)N2CCC(c3ccccc3)C(CN[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](NCC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To 232 mg of 4-(methoxycarbonyl)phenyl 3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidine-1-carboxylate were added 6.0 mL of THF, 3.0 mL of methanol, and 3.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. After neutralizing by addition of 3.0 mL of 1 M hydrochloric acid, the reaction mixture was concentrated under reduced pressure. To the residue was added water, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol). This was dissolved in a small amount of chloroform, and hexane was added thereto. Then, the precipitate was isolated by filtration, and dried under reduced pressure at 50° C. to obtain 66 mg of 4-({[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}oxy)benzoic acid as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:17]([C:27]#[N:28])[CH:16]=1)[C:3]([O:5]CC1C=CC=CC=1)=[O:4].Cl.[H][H]>[Pd].[C].C(O)(=O)C>[OH:1][CH:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:17]([C:27]#[N:28])[CH:16]=1)[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: N#Cc1cc(CCC(O)C(=O)OCc2ccccc2)ccc1C1CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1cc(CCC(O)C(=O)O)ccc1C1CCCCC1

Procedure:
A solution of 0.01 moles of benzyl α-hydroxy-γ-(3-cyano-4-cyclohexylphenyl)butyrate dissolved in 100 ml. of acetic acid and containing 0.01 mole of hydrogen chloride is shaken with hydrogen over a 5% Pd carbon catalyst until 0.01 moles of hydrogen is absorbed. The catalyst is then filtered and the solution is evaporated to dryness and crystallized to obtain α-hydroxy-γ-(3-cyano-4-cyclohexylphenyl)butyric acid.
Reaction SMILES: [C:1](#[N:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].N[NH:10][C:11]([NH2:13])=[S:12].O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH2:2]([C:1]1[S:12][C:11]([NH2:13])=[N:10][N:8]=1)[CH2:3][CH2:4][CH2:5][C:6]1[S:12][C:11]([NH2:13])=[N:10][N:7]=1
Reactant: N#CCCCCC#N
Reactant: NNC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(CCCCc2nnc(N)s2)s1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
A mixture of adiponitrile (8.00 g, 73.98 mmol) and thiosemicarbazide (13.48 g, 147.96 mmol) in trifluoroacetic acid (TFA) (75 mL) was heated at 80° C. for 17 hours. The reaction was cooled to room temperature and poured into a mixture of ice and water. Sodium hydroxide pellets were added to the mixture until it was basic (pH 14). The white precipitate was collected by suction filtration, rinsed with water and dried to provide 5,5′-(butane-1,4-diyl)-bis(1,3,4-thiadiazol-2-amine) (1001, 13.07 g). 1H NMR (300 MHz, DMSO-d6) δ 7.00 (s, 4H), 2.84 (bs, 4H), 1.68 (bs, 4H).