Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](Cl)=[O:11])[CH:2]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH:22]=[N:23][NH2:24]>C1COCC1.CCN(CC)CC>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH:22]=[N:23][NH:24][C:10]([C:9]1[C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(Cl)c1cccnc1Oc1cccnc1
Reactant: NN=Cc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Oc1cccnc1
Yield: 55 %

Procedure:
To a stirred solution of 2-(pyridin-3-yloxy)-nicotinic acid (0.432 g, 2.0 mmol) in THF (15 mL) at 0° C. was added oxalylchloride (2 mL, 2M in CH2Cl2, 4.0 mmol) dropwise. The solution was stirred at room temperature for 3 h. The solvent was evaporated in vacuo to yield 2-(pyridin-3-yloxy)-nicotinoyl chloride as a solid. To a solution of 2-(pyridin-3-yloxy)-nicotinoyl chloride in 15 mL THF was added 3-trifluoromethyl-benzylidene-hydrazine (0.376 g, 2.0 mmol) in 5 mL THF and 1 mL Et3N at 0° C. The reaction mixture was refluxed for 6 h and the solvent was evaporated. The residue was purified by chromatography with EtOAc:hexanes, 1:2, yielding (0.425 g, 55%) of the title compound. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.90 (m, 2H), 7.78 (t, J=7.8 Hz, 1H), 7.41 (m, 2H), 6.43 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
A solution of methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (460 mg, 1 mmol) in THF (30 mL) was treated with a solution of lithium hydroxide (237 mg, 10 mmol) in water (10 mL) and stirred at ambient temperature for 16 h. The residue was dissolve in minimum amount of water and the pH was adjusted to 4 by the addition of aqueous hydrochloric acid (2M). The resulting solution was concentrated to dryness to afford 446 mg of the title compound. LC-MS m/z 452 (M+H)+, 0.77 min (ret time).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]2)[C:12]2[C:17]([CH3:18])=[CH:16][S:15][C:13]=2[N:14]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]2)[C:12]2[C:17]([CH3:18])=[CH:16][S:15][C:13]=2[N:14]=1
Reactant: COc1ccccc1-c1nc(N2CCN(C(=O)OCC(C)C)CC2)c2c(C)csc2n1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1csc2nc(-c3ccccc3O)nc(N3CCN(C(=O)OCC(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isobutyl 4-(2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.14 g, 0.32 mmol) in CH2Cl2 (2 mL) was cooled to −50° C., and a solution of BBr3 in CH2Cl2 (1 M, 0.96 mL, 0.96 mmol) was slowly added. After 1 h, additional BBr3 solution in CH2Cl2 (1 M, 0.96 mL, 0.96 mmol) was added to the reaction mixture. The reaction was allowed to gradually warm to room temperature over 2 h, and saturated aqueous NaHCO3 was slowly added. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give Isobutyl 4-(2-(2-hydroxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate. LC/MS: m/z 427.2 (M+H)+ at 4.39 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[S:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[S:35][C:34]([C:36]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10]3)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[O:37])=[CH:33][CH:32]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1ccc(Cl)s1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(Cl)s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 5-chlorothiophene-2-carboxylic acid (24 mg, 0.15 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[OH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O1CCCC1>[CH2:3]([O:4][C:5](=[O:7])[CH2:6][N:18]1[CH2:19][CH2:20][CH:15]([OH:14])[CH2:16][CH2:17]1)[CH3:2]
Reactant: CC(=O)OCCBr
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of bromoethylacetate, 3.3 mL (30.0 mmol) in 100 mL of tetrahydrofuran was added 4.2 g (30.0 mmol) of potassium carbonate and 3.0 mL (30.0 mmol) of 4-hydroxypiperidine. The reaction mixture stirred overnight at rt. and was concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and saturated aqueous NaHCO3. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give 4.65 g (83%) of the desired product as a tan oil. MS (ion spray) 188.0 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[C:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8](/[CH:9]=[CH:15]/[C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(-c2cccs2)c1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(C(=O)/C=C/c2cccc(-c3cccs3)c2)cc1
Yield: 71 %

Procedure:
The title compound was prepared by condensing 3-(thiophen-2-yl)-benzaldehyde (Ex-42A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 238° C. (dec), 71% yield. 1H-NMR (DMSO-D6) δ 13.40 (bs, 1H), 8.29 (d, J=8 Hz, 2H), 8.22 (s, 1H), 8.13 (d, J=8 Hz, 2H), 8.04 (s, 1H), 7.87 (s, 1H), 7.83 (d, J=8 Hz, 1H), 7.73 (d, J=9 Hz, 1H), 7.69 (d, J=4 Hz, 1H), 7.63 (d, J=5 Hz, 1H), 7.52 (t, J=8 Hz, 1H), 7,20 (dd, J=4, 5 Hz, 1H). HRMS m/z=calc. 335.0742, found 335.0749.
Reaction SMILES: CI.[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:15]3[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=3[NH:9][C:8]=2[N:17]=1.[C:18]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:15]3[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=3[N:9]([CH3:18])[C:8]=2[N:17]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCc2[nH]c3nc(Br)ccc3c21
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c2c(c3ccc(Br)nc31)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
Methyl iodide (0.45 mL, 7.1 mmol) was added to a solution of 2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (1.6 g, 5.9 mmol) and Cs2CO3 (2.3 g, mmol) in DMF (21 mL) under N2 and stirred for 3 h at ambient temperature. The mixture was quenched with H2O (30 mL), upon which a solid precipitated out of solution. The solids were collected by filtration and washed with H2O (100 mL) to provide the title compound (1.47 g, 88%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=8.1 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 3.74 (s, 3H), 3.03 (t, J=6.0 Hz, 2H), 2.50-2.44 (m, 2H, overlap with H2O peak), 2.20-2.12 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 39.6 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.9 mg) was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Br:28])=[CH:24][C:25]=2[CH3:27])[N:20]=[CH:19][N:18]=1)C1C=CC=CC=1.B(Br)(Br)Br.O>C(Cl)Cl>[Br:28][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:16][C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[OH:8])=[N:18][CH:19]=[N:20]2)=[C:25]([CH3:27])[CH:24]=1
Reactant: Cc1cc(Br)cc2ncnc(Nc3ccc(F)cc3OCc3ccccc3)c12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)cc2ncnc(Nc3ccc(F)cc3O)c12
Temperature: 0 °C

Procedure:
A mixture of 10 g (22.8 mmol) of N-(2-benzyloxy-4-fluoro-phenyl)-7-bromo-5-methyl-quinazolin-4-amine (Intermediate V.1 step 1) and DCM is cooled to 0° C. and 34.2 ml (34.2 mmol) 1M BBr3 in DCM are added dropwise. After 6 h water is added carefully and the precipitate is filtered off, suspended in water and neutralized with 32% aq. ammonia solution. After 2 h the precipitate is filtered off and dried furnishing 2-[(7-bromo-5-methyl-quinazolin-4-yl)amino]-5-fluoro-phenol.
Reaction SMILES: C1(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2C=C[C:9]3[O:10]CC[O:13][C:8]=3C=2)C)CC1.Cl[C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:40]2[C:48]3[C:43](=[C:44]([CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)([CH:37]2[CH2:39][CH2:38]2)[CH3:36])=[CH:31][CH:30]=1>>[CH:37]1([C:35]([C:40]2[C:48]3[C:43](=[C:44]([CH2:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:45]=[CH:46][CH:47]=3)[NH:42][CH:41]=2)([C:32]2[CH:33]=[CH:34][C:29]3[O:10][CH2:9][CH2:8][O:13][C:30]=3[CH:31]=2)[CH3:36])[CH2:39][CH2:38]1
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Reactant: CSCc1cccc2c(C(C)(c3ccc4c(c3)OCCO4)C3CC3)c[nH]c12
Product: CC(c1ccc2c(c1)OCCO2)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 94 mg (0.25 mmol) of the compound from Example 188 in analogy to the synthesis of the compound from Example 209. 56 mg (55% of theory) of the target compound were obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C)c4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1cccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)c1

Procedure:
Treatment of (±)-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.90 g, 2.27 mmol) with sodium azide (0.44 g, 6.84 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (10%, 0.060 g) generally according to the procedure described for Example 1 afforded 0.444 g (71%) of (±)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >210° C. (dec); Anal. calcd. for C16H17NOHCl.0.2H2O: C, 68.79; H, 6.64; N, 5.01. Found: C, 68.54; H, 6.57; N, 4.9.
Reaction SMILES: C[O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)\[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>CO>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12](/[C:7](/[CH2:8][CH2:9][CH2:10][CH3:11])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:20])=[O:2])=[CH:17][CH:16]=1
Reactant: CCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reaction time: 2.5 h

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4-nonadienoic acid methyl ester (8g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 2.5 hours the reaction was worked up in the normal manner and the crude product crystallized from 2-propanol-hexane to give 6.2 g of (E,E)-5-(4-methoxyphenyl)-2,4-nonadienoic acid, mp 138°-139.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])CCC.[I:31]I>O1CCCC1.CCCCCC>[I:31][C:12]1[N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[C:15]2[N:16]=[CH:17][N:18]=[C:19]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:14]=2[CH:13]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccnc4)ncnc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cccnc4)ncnc32)cc1
Reaction time: 1.5 h
Yield: 19.1 %

Procedure:
To a solution of 7-[(4-methylphenyl)sulfonyl]4-pyridin-3-yl-7H-pyrrolo[2,3-d]pyrimidine [1 g, Reference Example 2] in tetrahydrofuran (20 mL) at −78° C. was added drop wise a solution of butyl lithium in hexane (2 mL, 1.6M) under inert atmosphere. The solution was stirred at that temperature for 1.5 hour and iodine (796 mg) was added. The reaction mixture was stirred at −78° C. for another 1 hour and allowed to reach room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium sulfite solution. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a gradient of ethyl acetate and cyclohexane (50:50, to 100, v/v) to give the title compound (260 mg) as an amorphous solid. MS: 477 [MH]+. LCMS (Method B) RT=3.26 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](O)([CH3:11])C.O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:9][CH:11]=[CH2:14])[C:2]=1[CH3:1]
Reactant: Cc1cccc(C(C)(C)O)c1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCc1cccc(C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
2-(2,3-Dimethylphenyl)propan-2-ol, compound of formula (XXIV), prepared according to either example 1 or example 2, (1.10 g, 6.70 mmol), was dissolved in benzene (20 mL), and p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol) was added. The mixture was stirred at room temperature for 3 h. Silica gel (200 mg) was added, and stirring was continued for ca. 16 hours, and then the reaction mixture was refluxed for 30 min. After cooling to room temperature, the mixture was filtered, washed with aqueous K2CO3 solution, conventionally dried, and concentrated under reduced pressure, to yield 0.90 g (92%) of the title compound. 1H NMR: 2.02 (m, 3H), 2.21 (s, 3H), 2.28 (s, 3H), 4.82 (m, 1H), 5.17 (m, 1H), 6.97 (m, 1H), 7.05 (m, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH3:14])(O)[CH3:7])=[CH:2]1.Cl.C(OCC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH3:14])=[CH2:7])=[CH:2]1
Reactant: Cc1ncoc1C(C)(O)c1ccoc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C=C(c1ccoc1)c1ocnc1C
Reaction time: 0.17 h

Procedure:
1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethanol (900 mg) in dry chloroform was treated with 1M anhydrous hydrogen chloride in diethylether (1.1 equivalents). After 10 minutes at room temperature, aqueous sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The material thus obtained was purified by flash chromatography to give the title compound as an almost colourless liquid.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([CH2:37][N+:38]#[C-:39])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2[O:26][CH:39]=[N:38][CH:37]=2)[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(-c3cnco3)c2)cc1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
A mixture of 1-trityl-1H-imidazole-4-carbaldehyde (25.0 g, 73.9 mmol), TosMIC (14.42 g, 73.9 mmol) and K2CO3 (10.21 g, 73.9 mmol) in MeOH (750 mL) was heated to reflux for 3 h. The mixture was then allowed to cool to RT, diluted with H2O, and extracted with AcOEt. The combined org. layers were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane/AcOEt 100:0 to 0:100) gave the title compound (14.6 g). UPLC (2 min) rt 1.415 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[I:17]I>CCCCCC.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([I:17])=[CH:8][C:6]=2[N:7]=1
Reactant: II
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Following the procedures in U.S. Pat. No. 6,492,383, 2.5 M of n-Butylithium (9.4 mL, 22.48 mmol) in hexane solution was added to a mixture of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine 4 (3.0 g, 11.74 mmol) in 60 mL of THF at −78° C. The reaction mixture was allowed to warm to −40° C. and stirred for 30 min. A solution of iodine (6.0 g, 23.48 mmol) in 10 mL of THF was added dropwise. After the addition was completed. The reaction mixture was brought to room temperature and stirred for 2 h. The mixture was quenched by diluting with dichloromethane and extracting with H2O (2×100 mL). The organic layer was washed with Na2S2O3 (2×100 mL), H2O (2×100 mL), dried over MgSO4, filtered and evaporated to afford 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (3.4 g, 75%).
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16](#[N:18])[CH3:17]>>[CH:1]1([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:11]([OH:12])[CH2:17][C:16]#[N:18])[CH:13]=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1cccc(OCC2CCCC2)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCC2CCCC2)c1

Procedure:
Aldol condensation with acetonitrile and 3-(cyclopentylmethoxy)benzaldehyde gave 3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxypropanenitrile as a colorless oil. Yield (0.4 g, 38%): 1H NMR (400 MHz, CDCl3) δ 7.22-7.28 (m, 1H), 6.88-6.94 (m, 2H), 6.82-6.88 (m, 1H), 4.95 (t, J=6.4 Hz, 1H), 3.81 (d, J=6.4 Hz, 2H), 2.83 (brs, 1H), 2.71 (d, J=6.4 Hz, 2H), 2.33 (dddd, J=7.2 Hz, 1H), 1.76-1.88 (m, 2H), 1.50-1.68 (m, 4H), 1.28-1.40 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([N:14]2[CH2:18][C@@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:15]2[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[F:41])=[O:13])=[CH:6][C:5]=1[F:42].O[Li].O>C1COCC1.O>[Cl:40][C:36]1[C:35]([F:41])=[C:34]([C@@H:15]2[C@:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:17]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][N:14]2[C:12]([NH:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([F:42])[CH:6]=2)=[O:13])[CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCc2ccc(C(=O)O)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a mixture of rac-4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-methyl)-2-fluoro-benzoic acid methyl ester (53.0 mg, 0.0838 mmol) in THF (6 mL) was added a solution of LiOH.H2O (Aldrich, 26 mg, 0.615 mmol) in water (3 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-({[(2S,3S,4S)-2-(3-Chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid (38.9 mg, 75%). HRMS (ES+) m/z Calcd C31H28Cl2F3N3O3+H (M+H): 618.1533; Found: 618.1532
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2]1.C=O.[BH3-][C:16]#N.[Na+].FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[CH3:16][N:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2]1
Reactant: c1cncc(O[C@@H]2CCNC2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CC[C@@H](Oc2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To 164 mg (1 mmol) of 3-(3-(R)-pyrrolidinyloxy)-pyridine were added 300 mg (10 mmol) of paraformaldehyde, 314 mg (5 mmol) of NaCNBH3, and 5 mL of dry THF at room temperature. To the suspension was added 2 mL of trifluoroacetic acid dropwise. The suspension was allowed to stir at room temperature overnight. Next day, to the suspension was slowly added a mixture containing 20 mL of 4N NaOH and ice-chips. The mixture was then extracted with ethyl acetate (2×40 mL). The combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (15:1, CHCl3:MeOH) to obtain 9 mg (5%) of a clear oil: 1H NMR (300 MHz, CD3OD) δ 8.19 (1H, d, J=1.7 Hz), 8.12 (1H, m). 7.38 (2H, m), 4.99 (1H, m), 2.94-2.80 (3H, m), 2.52-1.93 (3H, m), 2.40 (3H, s); Mass spectrum (ESI) m/z 179.4 (M+H+).