Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1>ClCCl.CO>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21]([C:22]1[CH:27]=[CH:26][C:25]2[N:28]([CH3:29])[C:11]([CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:30][C:24]=2[CH:23]=1)=[O:31]
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Yield: 22 %

Procedure:
Prepared analogously to Example 149a from 3-(4-cyanophenyl)propionic acid and 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide. Yield: 22% of theory; Rf value: 0.68 (silica gel; dichloromethane/methanol=19:1).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:14](I)=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Mg]Cl)(C)C.[Cl-].[Li+].[Cl:25][CH2:26][C:27](N(OC)C)=[O:28]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:14]([C:27](=[O:28])[CH2:26][Cl:25])=[CH:13][C:3]=1[CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(I)ccc1Br
Reactant: CON(C)C(=O)CCl
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(=O)CCl)ccc1Br
Temperature: 25 °C
Yield: 66.5 %

Procedure:
To a solution of (2-bromo-5-iodobenzyloxy)-(tert-butyl)dimethylsilane (8.7 g, 20.3 mmol) in tetrahydrofuran (135 mL) under argon at −20° C. was added i-propylmagnesium chloride-lithium chloride solution (1.3M in THF, 16.4 mL, 21.3 mmol). After stirring at this temperature for thirty minutes, a solution of 2-chloro-N-methoxy-N-methyl acetamide (3.4 g, 24.3 mmol) in tetrahydrofuran (5 mL) was added to the reaction via cannula. The reaction was stirred at −20° C. for one hour and then warmed to room temperature. After one hour at room temperature the reaction was diluted with ethyl acetate and the organics were washed with saturated aqueous NH4Cl solution, water and brine. The organic layer was dried (MgSO4) and concentrated, and the resulting residue was purified by flash chromatography to yield 1-(4-bromo-3-((tert-butyldimethylsilyloxy)methyl)phenyl)-2-chloroethanone (5.1 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18][C:19]1[C:20]([CH2:25][S:26][CH2:27][CH2:28][NH2:29])=[N:21][CH:22]=[CH:23][CH:24]=1.Cl>>[ClH:1].[Br:18][C:19]1[C:20]([CH2:25][S:26][CH2:27][CH2:28][NH:29][C:10]2[NH:9][C:8](=[O:15])[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=3)=[CH:12][N:11]=2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Reactant: NCCSCc1ncccc1Br
Agent: Cl
Product: O=c1[nH]c(NCCSCc2ncccc2Br)ncc1Cc1ccc(Cl)cc1

Procedure:
5-(4-Chlorobenzyl)-2-methylthio-4-pyrimidone (1.2 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)ethylamine (1.1 g) according to the procedure of Example 2. The reaction mixture was acidified with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue recrystallised from ethanol/water to give 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone monohydrochloride, m.p. 215°-218° (decomposes).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:13]([C:15]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32](F)=[CH:31][C:30]=3[C:36]([F:39])([F:38])[F:37])(=[O:28])=[O:27])[CH2:23][N:22]2[C:40]2[N:41]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:17][CH2:16]1)#[N:14].C(OC(C)=O)(C)C>CN(C)C(=O)C>[C:13]([C:15]1([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:31][C:30]=3[C:36]([F:37])([F:38])[F:39])(=[O:27])=[O:28])[CH2:23][N:22]2[C:40]2[N:41]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=3)[N:42]=[C:43]([CH3:45])[CH:44]=2)=[O:20])[CH2:16][CH2:17]1)#[N:14]
Reactant: OCC(F)(F)F
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(-c2ccc(C(F)(F)F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)OC(C)C
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(OCC(F)(F)F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 41.3 %

Procedure:
2,2,2-Trifluoroethanol (2.2 ul, 29 umol) and cesium carbonate (9 mg, 29 umol) were added to a solution of (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (15 mg, 24 umol; example 267c) in N,N-dimethylacetamide (0.2 ml) under an argon atmosphere. The mixture was stirred for 12 h at ambient temperature and for 5 h at 40° C. Ice water/0.1 N aqueous HCl solution 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc, the combined organic layers were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a yellow oil which was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to obtain the title compound (7 mg, 9.9 umol; 44%) as colorless oil. MS (ESI): m/z=710.1 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:21]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([Li])CCC>CCCCCC>[CH2:21]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:10](=[O:12])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:14][CH:13]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)c1ccc(OCC(=O)O)cc1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C)c1ccc(OCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Yield: 79.7 %

Procedure:
In a similar manner to that described in Refernce example 29(a), a reaction was carried out using 4-isopropylphenoxyacetic acid (14.1 g), oxalyl chloride (15.8 ml), (R)-4-benzyloxazolidine-2-one (11.7 g) and a solution of n-butyl lithium in hexane (1.61N, 45.0 ml) and the reaction mixture was treated to afford the desired compound (18.6 g) as colorless crystals.
Reaction SMILES: C([N:4]1[CH2:8][CH:7]2[CH2:9][CH2:10][CH2:11][CH:6]2[C:5]1(C(OCC)=O)[C:12]([O:14]CC)=[O:13])(=O)C.CC(O)=O.[BrH:26]>>[BrH:26].[CH:5]1([C:12]([OH:14])=[O:13])[CH:6]2[CH2:11][CH2:10][CH2:9][CH:7]2[CH2:8][NH:4]1
Reactant: CCOC(=O)C1(C(=O)OCC)C2CCCC2CN1C(C)=O
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)C1NCC2CCCC21
Temperature: 120 °C

Procedure:
A solution of diethyl 2-acetylhexahydrocyclopenta[c]pyrrole-1,1(2H)-dicarboxylate prepared above in 48% aq. HBr and AcOH (4:1) was heated at 120° C. for 16 h. The reaction mixture was cooled, concentrated in vacuo and lyophilized to yield the title compound. MS (ESI) 156 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH:18]([CH:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[OH:27])[C:19]([O:21]C(C)(C)C)=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH:18]([CH:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[OH:27])[C:19]([OH:21])=[O:20])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1C(=O)OCc1ccccc1)C(O)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccccc1CC(C(=O)O)C(O)C1CCCCC1
Reaction time: 5 h
Yield: 40 %

Procedure:
t-Butyl 2-(2-benzyloxycarbonylphenylmethyl)-3-cyclohexyl-3-hydroxypropionate (100 mg) was dissolved in a solution of 10% trifluoroacetic acid in dichloromethane (1 ml) and the mixture was stirred for 5 hours. The solution was evaporated under reduced pressure and the residue was purified by chromatography [eluting with methanol-dichloromethane (1:19)] to give 2-(2-benzyloxycarbonyl-phenylmethyl)-3-cyclohexyl-3-hydroxypropionic acid (35 mg).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=4)[CH2:15]3)=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:28][CH:29]([F:34])[CH:30]1[CH2:33][NH:32][CH2:31]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:28][CH:29]([F:34])[CH:30]1[CH2:33][N:32]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:16]3[CH2:17][N:14]([C:12]([C:10]4[O:11][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[N:8][N:9]=4)=[O:13])[CH2:15]3)=[CH:26][CH:25]=2)[CH2:31]1
Reactant: FC(F)C1CNC1
Reactant: O=Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Oc2ccc(CN3CC(C(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.7 %

Procedure:
To a suspension of 68A (0.20 g, 0.57 mmol) in DCM (3 mL) was added 68C (0.25 g, 1.72 mmol) followed by DIPEA (0.30 mL, 1.72 mmol). Sodium triacetoxyborohydride (0.24 g, 1.15 mmol) was added. The mixture was stirred at RT for 5 h and then diluted with DCM. The solution was washed with an aqueous solution of NaHCO3 and then filtered through a phase separator. The solvent was removed by evaporation. The product was purified on a silica gel column using 1-4% methanol in DCM where the methanol contained 2M ammonia. The product was triturated from ether and after drying in the hood there was obtained 47 mg (19%) of 68 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.86 (m, 1H), 3.19 (m, 2H), 3.36 (m, 2H), 3.55 (s, 2H), 4.34 (dd, 1H), 4.64 (dd, 1H), 4.78 (dd, 1H), 5.07 (m, 1H), 5.11 (m, 1H), 5.99 (t, 1H), 6.74 (d, 2H), 7.22 (d, 2H), 7.54 (t, 2H), 7.59 (t, 1H), 8.16 (d, 2H), MS (APCI+) m/z 441 [M+H]+, LC purity: 90%. A sample of (3-(4-((3-(difluoromethyl)azetidin-1-yl)methyl)phenoxy)azetidin-1-yl)(5-phenyl-1,3,4-oxadiazol-2-yl)methanone was recrystallised from DCM/Et2O had m. p. 147° C. (purity 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([C:7]1[N:8]=[C:9](Cl)[C:10]2[N:11]([C:13](=[O:20])[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:15]=2)[CH:12]=1)([CH3:6])[CH3:5].[CH:23]([NH2:26])([CH3:25])[CH3:24]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:22])[C:4]([C:7]1[N:8]=[C:9]([NH:26][CH:23]([CH3:25])[CH3:24])[C:10]2[N:11]([C:13](=[O:20])[N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:15]=2)[CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(C)N
Reactant: COC(=O)C(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(Cl)n1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(NC(C)C)n1
Temperature: 25 °C

Procedure:
A solution of 215 mg of 2-(2-tert-butyl-8-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionic acid methyl ester and 388 mg of isopropylamine in THF (5.0 mL) was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered, and concentrated to provide 2-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-2-methyl-propionic acid methyl ester as a light yellow solid. MS (M+H+)=350.4.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@@H:14]([NH:24]C(=O)OC(C)(C)C)[CH2:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)=[N:4][C:5]([N:8]2[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]2)=[CH:6][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:24][C@H:14]([C:3]1[N:4]=[C:5]([N:8]2[CH2:11][C:10]([CH3:12])([OH:13])[CH2:9]2)[CH:6]=[CH:7][C:2]=1[Br:1])[CH2:15][C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: CC1(O)CN(c2ccc(Br)c([C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(O)CN(c2ccc(Br)c([C@@H](N)Cc3cc(F)cc(F)c3)n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 42G (64 mg, 0.13 mmol) was dissolved in 2 mL of 20% TFA/methylene chloride. The reaction mixture was stirred at room temperature for 2 hours and then partitioned between EtOAc and saturated aq. NaHCO3. The organic layer was separated and concentrated to afford the title product. MS (m/z) 398.03[M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[NH2:16][C:17]1[CH:26]=[C:25]([OH:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[NH2:16][C:17]1[CH:26]=[C:25]([O:27][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=3)[O:11][C:2]([CH3:1])([CH3:15])[CH:3]2[OH:14])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Nc1cc(O)c2ccccc2n1
Product: CC1(C)Oc2ccc(C#N)cc2C(Oc2cc(N)nc3ccccc23)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 2-amino-quinolin-4-ol as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: CN(C=O)C.O[C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:8]=12.O=S(Cl)[Cl:22]>O>[Cl:22][C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:8]=12
Reactant: CSc1nc2ncc(C#N)c(O)c2s1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ncc(C#N)c(Cl)c2s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1f (34.6 g, 120 mmol), DMF-dimethyl acetal (34.0 mL, 240 mmol, 94% purity) and DMF (200 mL) were combined and heated to 80° C. for 90 minutes. The conversion to the cyclized intermediate, 7-hydroxy-2-methylsulfanyl-thiazolo[4,5-b]pyridine-6-carbonitrile was confirmed by LCMS (MS 298, MH+). The mixture was then cooled to 0° C. and SOCl2 was added dropwise (44 mL, 600 mmol). The reaction mixture was stirred for 2 hrs at ambient temperature. The mixture was then cooled back down to 0° C. and water (approximately 300 mL) was added dropwise. The resulting brown solid was collected by filtration and subsequently washed with water and MeOH to provide 7-chloro-2-methylsulfanyl-thiazolo[4,5-b]pyridine-6-carbonitrile Compound 1g (16.1 g) as a tan solid. 1H NMR (CDCl3) δ 8.82 (s, 1H), 2.91 (s, 3H). MS 242, 244 (MH+), 264, 266 (MNa+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>>[N:25]1[CH:30]=[CH:29][C:28]([C:31]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:32])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccncc1

Procedure:
Beginning with 0.015 gm (0.047 mmol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.011 mL (0.061 mMol) 4-pyridinecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].Cl[CH:17]([C:19]1[C:20]([CH3:35])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[CH3:18]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:17]([C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH3:18])=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1
Product: CCOC(=O)CCc1ccc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c(C)c1

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (example 73A]) was reacted with [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) to give [rac]-3-(3-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@H:12]3[CH2:15][C@@H:16]([OH:18])[CH2:17][N:11]3[C:10]2=[O:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C1C=CC=CN=1)C.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:29]([O:18][C@H:16]1[CH2:17][N:11]2[C:10](=[O:19])[N:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13](=[O:14])[C@@H:12]2[CH2:15]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1[C@@H]2C[C@@H](O)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C(O[C@@H]1C[C@H]2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)N2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (6R,7aS)-2-(3,5-dichlorophenyl)-6-hydroxytetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (1.2 g) (4 mmol) (Preparation 6), dimethylaminopyridine (50 mg) (0.1 eq.) and benzoic acid (0.49 g) (1 eq.) in 10 mL of dry DCM at 0° C. was added DCC (0.9 g) (1 eq.) in a minimal volume of DCM. The reaction mixture was stirred to RT overnight. After filtering off the insoluble material, the reaction mixture is washed with a dilute NaHCO3 aqueous solution, with dilute HCl solution, with water, dried over MgSO4, and evaporated under reduced pressure to afford to afford the titled compound as a viscous oil (1.54 g). 1H NMR (CDCl3): 8.05 (2H,d), 7.65 (1H,m), 7.5 (1H,d), 7.43 (2H,d), 7.38 (1H,m), 5.81 (1H,t), 4.62 (1H,dd), 4.23 (1H,dd), 3.56 (1H,d), 2.68 (1H,dd), 2.05–2.20 (1H,m).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1)=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][N:14]=2)=[O:12])=[O:29])[N:27]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C(NC[C@H]1NC[C@@H]2CCC[C@@H]21)c1nsc2ccccc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2nsc3ccccc23)c1

Procedure:
prepared by reaction of benzo[d]isothiazole-3-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][O:23][CH2:24][CH2:25]OC>CN(C=O)C.O>[CH3:22][O:23][CH2:24][CH2:25][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: COCCOCCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reaction time: 1 h
Yield: 154.8 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.8 g, 4.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), and 1-(chloromethoxy)-2-methoxyethane (0.59 mL, 5.2 mmol) in DMF (14 mL) was heated in a microwave at 90° C. for 1 hr. After the initial heating, additional 1-(chloromethoxy)-2-methoxyethane (0.59 mL) and cesium carbonate (2 g) was added. Heating was repeated for an additional 1 hr. The crude reaction mixtures were then diluted with water (250 mL) and extracted with ethyl acetate (3×50 mL). The title compound was purified by silica gel column using DCM/EtOAc/MeOH (8/1.5/0.5) as eluent to give 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.6 g) as a light yellow oil. ESI-MS:m/z 283.2 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[S:9][C:10]([C:13]([NH2:15])=[O:14])=[CH:11][N:12]=2)=[CH:5][CH:4]=1)=O.[CH2:18]([NH2:23])[CH2:19][CH:20]([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[CH3:21][CH:20]([CH3:22])[CH2:19][CH2:18][NH:23][CH2:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[S:9][C:10]([C:13]([NH2:15])=[O:14])=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: CC(C)CCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Oc2ncc(C(N)=O)s2)cc1
Reaction time: 8 h

Procedure:
Place 2-(4-formylphenoxy)thiazole-5-carboxamide (0.187 g, 0.755 mmol), isoamylamine (0.072 g, 0.831 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.8 mL), cap and stir overnight. Add NaBH4 (0.029 g, 0.755 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes to give the title compound: TOF MS ES+ 320.1 (M+H)+, HRMS calcd for C16H22N3O2S 320.1432 (M+H)+, found 320.1428, time 0.32 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min. 20-95% over 18], tR=9.7 min, 96.9% purity.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[O:17][CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH3:21])[CH:10]=[C:9]1[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])=O)(C)(C)C.[ClH:38]>CCO>[ClH:38].[C:32]1([S:29]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH2:18][CH2:19][NH:20][CH3:21])(=[O:31])=[O:30])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(CCOc1cccc2cc(S(=O)(=O)c3ccccc3)n(C(=O)OC(C)(C)C)c12)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CNCCOc1cccc2cc(S(=O)(=O)c3ccccc3)[nH]c12
Temperature: 100 °C

Procedure:
2-Benzenesulfonyl-7-[2-(tert-butoxycarbonyl-methyl-amino)-ethoxy]-indole-1-carboxylic acid tert-butyl ester (0.230 g., 0.43 mmol) from the above step was dissolved in 5 mL EtOH. To this solution was added 1 mL of 2M ethanolic hydrogen chloride solution. The reaction mixture was heated at 100° C. for 35 minutes. Upon cooling to ambient temperature, a fine white precipitate was observed. After filtration and drying in vacuo at 60° C., [2-(2-Benzenesulfonyl-1H-indol-7-yloxy)-ethyl]-methyl-amine hydrochloride was obtained as 0.140 g. white crystals. MS: 329 (M−H)−, mp=289.4–291.6° C.
Reaction SMILES: [Sn](Cl)Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.[OH-].[Na+]>CCO>[NH2:12][C:7]1[CH:6]=[C:5]([F:4])[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(F)ccc1O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Tin(II) chloride (12.1 g, 63.6 mmol) was added to a solution of 4-fluoro-2-nitrophenol (2.00 g, 12.7 mmol) in EtOH (45 mL), and the reaction mixture was heated to 70° C. After 2 h, the reaction mixture was allowed to cool to rt and was poured onto ice (˜200 mL). After warming to rt, the pH was adjusted to ˜9 with 2 N aqueous NaOH, and the mixture was filtered. The filtrate was extracted with EtOAc (3×), and the combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 1.21 g (75%) of the title compound. LC-MS: RT=4.48 min., [M+H]+=128.0.