Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[NH:37]1[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]1>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:37]3[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: O[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC[C@@H](O)C3)ccc2n1CC1CCC(F)(F)CC1

Procedure:
Following the same procedure in Example 1, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (50 mg, 0.12 mmol), N,N-diisopropylethylamine (0.1 mL, 0.48 mmol) and (R)-(−)-3-pyrrolidinol hydrochloride (23 mg, 0.19 mmol) in (1 mL) methylene chloride. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 42 mg (61% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.43-1.52 (m, 2 H), 1.56 (s, 9 H), 1.60-1.69 (m, 3 H), 1.90-2.01 (m, 3 H), 2.09-2.21 (m, 1 H), 3.05-3.11 (m, 1 H), 3.20-3.25 (m, 2 H), 3.26-3.34 (m, 3 H), 4.13-4.18 (m, 1 H), 4.44 (d, J=7.62 Hz, 2 H), 7.81 (dd, J=8.79, 1.76 Hz, 1 H), 7.89-7.93 (m, 1 H), 8.04 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=455.2; Anal. Calc. for C22H31F2N3O3S+1.3 TFA+0.50H2O+0.2 CH3CN: C, 48.75; H, 5.46; N, 7.16. Found: C, 48.78; H, 5.48; N, 7.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][C:6]2=[O:13].[CH3:14][O-:15].[Na+].CO>>[CH3:14][O:15][C:6](=[O:13])[C:5]1[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:8]([OH:7])=[O:12]
Reactant: COc1ccc2c(c1)C(=O)OC2=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(OC)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-methoxy-isobenzofuran-1,3-dione (950 mg, 5.33 mmol) is added 0.5 M NaOMe in MeOH (16 mL, 18 mmol). The reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue subsequently quenched with 1M HCl aq (100 mL). The quenched reaction mixture is extracted with EtOAc (100 mL×2) and the combined organic layers are dried with Na2SO4 and filtered. The filtrate is concentrated under reduced to afford crude 4-methoxy-phthalic acid 2-methyl ester (850 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22]C(C)C)=[C:18]([O:26]C(C)C)[CH:17]=1)=[CH:13][C:12]([O:30][CH3:31])=[C:11]([O:32][CH3:33])[CH:10]=2)=[O:5])[CH3:2].O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:26])[CH:17]=1)=[CH:13][C:12]([O:30][CH3:31])=[C:11]([O:32][CH3:33])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC(C)C)c(OC(C)C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(O)c(O)c1
Reaction time: 6 h
Yield: 21 %

Procedure:
To a solution of 4-(3,4-diisopropoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (116.0 rag) in dichloromethane (2.5 ml), titanium tetrachloride (TICl4) (288 mg) was added at 0° C., followed by stirring at the same temperature for 6 hours. The reaction mixture was poured over water and extracted with chloroform. The chloroform layer was washed by sequential additions of a saturated aqueous sodium hydrogen carbonate solution and water and then dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (7:3, v/v) to yield 4-(3,4-dihydroxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (20.0 mg, 21%) having a melting point of 122° to 124° C.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[S:19][C:18]([S:20]([N:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)(=[O:22])=[O:21])=[CH:17][CH:16]=1>>[C:1]1([C:15]2[S:19][C:18]([S:20]([N:23]3[CH:27]=[CH:26][CH:25]=[CH:24]3)(=[O:21])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: O=S(=O)(c1ccc(-c2cccc3ccccc23)s1)n1cccc1
Yield: 87 %

Procedure:
N-[5-(1-napthyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 1-napthaleneboronic acid (353 mg, 2.05 mmol) and N-(5-bromothiophene-2-sulfonyl)pyrrole (600 mg, 2.05 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure sulfonamide in 87% yield as a pale yellow clear oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:11]=[CH:12][C:13](F)=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:8][N:9]=1.[NH2:30][NH2:31]>>[NH2:1][C@@H:2]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:17]=[C:14]3[C:13](=[CH:12][CH:11]=2)[NH:31][N:30]=[C:15]3[NH2:16])=[CH:8][N:9]=1
Reactant: NN
Reactant: N#Cc1cc(-c2cnc(NC[C@@H](N)Cc3ccc(C(F)(F)F)cc3)s2)ccc1F
Product: Nc1n[nH]c2ccc(-c3cnc(NC[C@@H](N)Cc4ccc(C(F)(F)F)cc4)s3)cc12
Temperature: 100 °C
Yield: 62 %

Procedure:
5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-2-fluorobenzonitrile (0.042 g, 0.100 mmol) was taken up in hydrazine (0.50 mL) in a microwave safe tube. The tube was sealed and heated in a Personal Chemistry microwave unit to 100° C. for 5 minutes. The hydrazine was then removed under reduced pressure, and the residue was purified by HPLC (95:5 to 70:30 water:MeCN over 45 minutes), affording 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-1H-indazol-3-amine (0.027 g, 0.062 mmol, 62% yield) as a yellow amorphous solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.75-7.71 (m, 1H), 7.67-7.60 (m, 2H), 7.51-7.45 (m, 3H), 7.34-7.25 (m, 2H), 3.64-3.48 (m, 2H), 3.42-3.34 (m, 1H), 3.09-3.00 (m, 1H), 2.89 (dd, J=13.8, 7.1 Hz, 1H), 1.95-1.91 (m, 1H). HRMS (M+H) for C25H27F3N6O2S calc. 433.14168, obs. 433.14225.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][NH:27]3)[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2].Br[CH2:31][C:32]1[O:33][C:34](=[O:38])[O:35][C:36]=1[CH3:37].C(=O)(O)[O-].[K+]>CN(C)C=O>[C:1]([C:3]1[C:4]([N:21]2[CH2:29][C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][C:32]3[O:33][C:34](=[O:38])[O:35][C:36]=3[CH3:37])[CH2:22]2)=[C:5]([F:20])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:14][CH2:15]1)[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8]2=[O:19])#[N:2]
Reactant: Cc1oc(=O)oc1CBr
Reactant: N#Cc1c(N2C[C@@H]3CCCN[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1CN1CCC[C@H]2CN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3C#N)C[C@H]21

Procedure:
100 mg (0.25 mmol) of 8-cyano-1-cyclopropyl-7-((1S,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 59 mg (0.30 mmol) of 4-bromomethyl-5-methyl-1,3-dioxol-2-one and 30 mg of potassium bicarbonate are heated at 140° C. in 2 ml of dimethylformamide for 30 minutes. The reaction solution is concentrated in vacuo, the residue is taken up in methylene chloride and the mixture is washed with water. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The resulting residue is stirred with water, filtered off with suction and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[Cl:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (3.32 g), 2-chloro-4-nitrophenol (2.36 g) and triphenylphosphine (5.11 g) in dichloromethane (60 ml) was added dropwise diethyl azodicarboxylate (3.1 ml) in an ice bath and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=5/2 as an eluant to give the desired compound (3.90 g, yield 76%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C.O>C1COCC1>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:7][N:6]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 5-bromo-2-methoxy-pyridine (1.453 g, 7.73 mmol) in THF (50 mL) at −78° C. under N2 was added n-BuLi (3.4 mL, 2.5 M in hexanes, 8.5 mmol) dropwise. The mixture was stirred at −78° C. for 30 minutes, then 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.4 mL, 11.60 mmol) was added. The reaction mixture was warmed to room temperature for 1 hour, then poured into water and extracted with EtOAc. The combined extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to give 2A (1.221 g, 67.5%) as a colorless oil.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[I:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([NH:55][CH:56]2[CH2:58][CH2:57]2)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([N:55]([CH:56]2[CH2:57][CH2:58]2)[C:28](=[O:30])[C:27]2[CH:26]=[CH:25][C:24]([I:23])=[CH:32][CH:31]=2)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: O=C(O)c1ccc(I)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2ccc(I)cc2)C2CC2)CC1
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (2.67 g) is added to a solution of 4-iodo-benzoic acid (2.06 g) and ethyldiisopropylamine (2.88 mL) in N,N-dimethylformamide (15 mL) at room temperature. The solution is stirred for 10 min prior to the addition of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (2.00 g). The resulting mixture stirred at room temperature overnight. The mixture is concentrated in vacuo and the residue is mixed with water and ethyl acetate. The organic phase is separated, washed with water and aqueous NaHCO3 solution, dried, and the solvent is evaporated. The crude product is used for the next reaction step without further purification. LC (method 5): tR=2.32 min; Mass spectrum (ESI+): m/z=471 [M+H]+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12]C)=[O:11])=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[CH:5]=1>CO.O1CCCC1>[Cl:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:18]=2)[CH:5]=1
Reactant: COC(=O)COc1ccc(Cl)cc1Oc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2OCC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1M Sodium hydroxide solution (0.5 m) was added to a solution of the product from step (iii) (0.197 g) in methanol (1 ml) and tetrahydrofuran (3 ml) and stirred at RT for 16 h. The solvent was evaporated under reduced pressure and the residue partitioned between DCM/2M hydrochloric acid. The organics were dried, evaporated under reduced pressure and the residue recrystallised from DCM-isohexane, yield 0.108 g.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][CH:17]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][N:18]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:43]1[CH:44]=[CH:45][CH:46]=[C:41]([O:15][CH2:16][CH:17]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:20][CH2:19][N:18]2[C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH:42]=1
Reactant: Oc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(COc2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of diisopropylazodicarboxylate (2.67 mL, 13.5 mmol) in THF (25 mL) was added dropwise over 1 h to a solution of 4-tert-butyl 1-benzyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (4.52 g, 12.9 mmol), 3-hydroxypyridine (1.35 g, 14.2 mmol) and triphenylphosphine (3.55 g, 13.5 mmol) in THF (75 mL) at 15° C. After complete addition, the reaction mixture was allowed to warm to rt and stir overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (10 to 40% EtOAc in Hexanes gradient). This gave 0.9055 g (16%) of the title compound. Rf=0.35 in 80% EtOAc/Hexanes; LC-MS: RT=9.85 min; [M+H]+=428.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH:16]([NH2:18])[CH3:17].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[S:29](Cl)(=[O:31])=[O:30].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[S:29]([NH:18][CH:16]([C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH3:17])(=[O:30])=[O:31]
Reactant: CC(N)c1cc(F)ccc1-c1ccc(F)cc1F
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(C)c2cc(F)ccc2-c2ccc(F)cc2F)c(OC)c1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A stirred solution of 1-(2′,4,4′-trifluoro-1,1′-biphenyl-2-yl)ethylamine (0.71 g, 2.84 mmol) in dichloromethane (5 mL) was treated with 2,4-dimethoxybenzenesulfonyl chloride (0.71 g, 3.0 mmol), and N,N-diisopropylethylamine (0.77 g, 6.0 mmol). The reaction was stirred at room temperature for twelve hours, and the solvent was evaporated in vacuo to a crude oil. The crude oil was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of between 5% and 50% methyl tert-butyl ether in hexane at a flow rate of 40 mL/min to afford, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from ethyl acetate-hexane yielded the title compound (0.93 g, 2.07 mmol, 73%) as a homogeneous, colorless, crystalline solid, m.p. 192-194° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][NH:18][C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:39](Br)[C:40]#[CH:41]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH2:41][C:40]#[CH:39])[C:19]([CH3:21])([CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCN1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c2=O)C1(C)C
Temperature: 45 °C

Procedure:
A mixture of 3-(benzyloxy)-N-(4-fluorobenzyl)-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide (prepared as described in Example 3, Step 1) (1 eq.), K2CO3 (2 eq.), propargyl bromide (2.5 eq.) in DMF was heated at 45° C. overnight and then cooled at room temperature. The solvent was removed under reduced pressure and the residue was taken up in EtOAc and washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield the titled acetylene. MS (ES) C27H27FN4O3 requires 474. Found: 475 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[CH:13][C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: Cc1nc2ccccc2s1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(Cl)c(C=Cc2nc3ccccc3s2)c1
Yield: 70 %

Procedure:
A solution of 12.4 g (67 mmol) of 2-chloro-5-nitrobenzaldehyde and 10.0 g (67 mmol) of freshly distilled 2-methylbenzothiazole in 60 ml of acetic anhydride was refluxed for 5 h. The precipitated yellow solid was collected by filtration and recrystallized from toluene to afford 14.9 g (70%) of 2-(2'-chloro-5'-nitrostyryl)benzothiazole (IIIa); mp 188°-189° C., UV λmaxEtOH nm (ε) 214(16808), 332.5(28445); 1H-NMR δTMSCDCl3 (ppm) 8.58 (d, J=2.7 Hz, 1H), 8.16-7.26 (complex pattern, 8H); 13C--NMRTMS δTMSDMSO-d6 (ppm) 165.0, 154.0, 147.1, 140.2, 135.3, 134.9, 131.1, 130.7, 127.3, 126.7, 126.0, 124.0, 123.6, 121.6, 121.0; IR νmaxKbr (cm-1) 1521.8, 1455.4, 1342.4, 1116.3, 1046.3, 951.3, 873.34, 826.1, 724.1, 737.4, 728.3. Anal. Calcd. for C15H9CiN2O2 : C, 56.87, H, 2.86, N, 8.84; Found: C, 56.84; H, 2.86, N, 8.73.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([O:34][CH2:35][CH3:36])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[S:20][C:21]=2[CH3:22])=[CH:9][C:8]=1[CH3:33])C.[Li+].[OH-]>>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:19]2[S:20][C:21]([CH3:22])=[C:17]([CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:34][CH2:35][CH3:36])[C:4]([OH:37])=[O:3])=[C:8]([CH3:33])[CH:9]=3)[N:18]=2)=[CH:28][CH:27]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(OCCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-(4-{3-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-propoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-(4-{3-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-propoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid as colorless liquid.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2].[CH2:31]([C:36]1[CH:37]=[N:38]C(Br)=[N:40][CH:41]=1)[CH2:32][CH2:33][CH2:34][CH3:35]>>[C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:40]=[CH:41][C:36]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:37][N:38]=4)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(C#N)c(F)c3)nc2)CC1
Reactant: CCCCCc1cnc(Br)nc1
Product: CCCCCc1cnc(N2CCC(c3ccc(COc4ccc(C#N)c(F)c4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-(4-cyano-3-fluorophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 13) (33 mg, 0.08 mmol) and 5-pentyl-2-bromopyrimidine (27 μL, 0.16 mmol) following a procedure analogous to that in Example 48 as a white crystal (24 mg, yield 65%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[OH:22][N:23]=[C:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.FC(F)(F)C([O-])=O.CS(C)=O>C(O)(C)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:26]4[CH2:27][CH2:28][C:24](=[N:23][OH:22])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: ON=C1CCNC1
Agent: O=C([O-])C(F)(F)F
Solvent: CC(C)O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(=NO)C3)c(F)c(F)c2c1=O
Yield: 44.6 %

Procedure:
The reaction was conducted at room temperature for 3 hours in the same manner as in Example 3 except that 300 mg (1 mmol) of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 535 mg (2.5 mmol) of 3-hydroxyiminopyrrolidine-trifluoroacetate were used as starting materials and 5 ml of dimethyl sulfoxide was used as the solvent for reaction. 7 ml of isopropanol was added to the reaction mixture, and the precipitate thereby formed was collected by filtration and recrystallized from a mixture of 6 ml of dimethyl sulfoxide and 6 ml of isopropanol to give 170 mg of the desired product as pale yellow powder.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:15]=2[F:27])[CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=1)=[O:38]>C(#N)C>[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:15]=2[F:27])[CH2:10][N:9]([CH2:36][C:37](=[O:38])[NH:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@H]1CNC[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H]1CN(CC(=O)Nc2ccc(Cl)cn2)C[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
(3R,4R)-4-[2-Fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-3-carboxylic acid ethyl ester hydrochloride (0.315 g; synthesis described in EP04101265.9 example 28 step 3) is suspended in acetonitrile (10 ml) and K2CO3 (0.425 g) is added as solid. 2-Bromo-N-(5-chloro-2-pyridinyl)-acetamide (0.23 g) is added and the reaction mixture is stirred at 25° C. for 18 h. After that the mixture is heated for 3 h to 80° C., cooled to 25° C. and filtered. The filtrate is evaporated to dryness followed by flash chromatography over silica gel using DCM/MeOH/NH3 as eluent to yield 0.203 g (46.3%) (3R,4R)-1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarba-moyl]-pyrrolidine-3-carboxylic acid ethyl ester. White solid. MS 542.3 [M+H+].