Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:8]2[NH:13][N:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][C@H:21]([F:24])[CH2:20]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].C(C1N=C(NCC2C=CC(OC)=CC=2OC)C2NN=C(C#CCCCCl)C=2N=1)CCC.Cl.F[C@@H]1CCNC1>>[CH2:1]([C:5]1[N:6]=[C:7]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:8]2[NH:13][N:12]=[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][C@@H:21]([F:24])[CH2:20]3)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCN3CC[C@H](F)C3)c2n1
Agent: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCl)c2n1
Agent: Cl
Agent: F[C@@H]1CCNC1
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCN3CC[C@@H](F)C3)c2n1

Procedure:
Prepared similarly to Intermediate 25 from and 5-butyl-3-(5-chloropent-1-yn-1-yl)-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine and (R)-3-fluoropyrrolidine hydrochloride
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=3)[CH2:12][O:11][C:10]2=[O:24])=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH:27](OCC)(OCC)OCC>>[CH3:25][C:4]1[C:5]([N:9]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:19]=3)[CH2:12][O:11][C:10]2=[O:24])=[CH:6][C:7]2[N:8]=[CH:27][NH:1][C:2]=2[C:3]=1[CH3:26]
Reactant: CCCOc1ccc([C@H]2COC(=O)N2c2cc(N)c(N)c(C)c2C)cc1
Reactant: CCOC(OCC)OCC
Product: CCCOc1ccc([C@H]2COC(=O)N2c2cc3nc[nH]c3c(C)c2C)cc1

Procedure:
The (S)-3-(4,5-diamino-2,3-dimethylphenyl)-4-(4-propoxyphenyl)oxazolidin-2-one was dissolved in triethyl orthoformate and was refluxed for 30 minutes. After cooling the excess of triethyl orthoformate was removed under reduced pressure. The final product was purified via FPLC using a chloroform-methanol gradient (0→10%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5]([CH2:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:7])=[O:6].[H-].[Na+].CN(C)C(=O)C>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([C:12]2[CH:22]=[CH:23][C:9]([CH:8]3[CH2:2][CH2:3][CH2:4][S:5]3(=[O:7])=[O:6])=[CH:10][CH:11]=2)=[O:14])=[CH:16][CH:17]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CS(=O)(=O)CCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccc(Cl)cc1)c1ccc(C2CCCS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4-(3-bromopropyl)sulfonylmethyl-4'-chlorobenzophenone (2.5 g) and 60% sodium hydride (0.3 g) were added to N,N-dimethylacetamide (70 ml), and the mixture was stirred for 16 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the desired product as a slightly yellow viscous substance 1.0 g, yield: 50%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:12])[C:7]2(OCC[O:8]2)[CH2:6][S:5][CH2:4]1.C1COCC1.O>C(O)(=O)C>[OH:1][CH2:2][C:3]1([CH3:12])[CH2:4][S:5][CH2:6][C:7]1=[O:8]
Reactant: CC1(CO)CSCC12OCCO2
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(CO)CSCC1=O
Yield: 108.3 %

Procedure:
A solution of 0.23 g (1.2 mmol) of product from Step C, 4.8 ml THF, 4.8 ml H2O, and 7.2 ml acetic acid was heated at 70° C. for 96 hours. The cooled mixture was concentrated and the residue was dissolved in ethyl acetate (75 ml), washed with saturated sodium bicarbonate solution (15 ml), and brine, dried, filtered, and concentrated to give 0.19 g of an oil. The oil was flash chromatographed on silica gel eluting with chloroform to give 0.09 g (50%) of product as an oil; NMR (deuteriochloroform): δ 3.79 (dd, 1H), 3.58 (dd, 1H), 3.33 (d, 2H), 3.30 (d, 1H), 2.71 (d, 1H), 1.98 (t, 1H, --OH), 1.22 (S, 3H).
Reaction SMILES: C(OC(N1CCC(N[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[NH2:31][C@@H:32]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:33][C:34]([NH2:36])=[O:35]>>[C:34]([CH2:33][C@@H:32]([NH:31][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:35])[NH2:36]
Reactant: NC(=O)C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: NC(=O)C[C@@H](NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (3R)-3-amino-3-phenylpropanamide instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 406 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.22 (1H, s) 8.65 (1H, d, J=8.44 Hz) 8.01 (1H, d, J=5.42 Hz) 7.80 (1H, d, J=5.47 Hz) 7.47 (1H, d, J=5.52 Hz) 7.33-7.39 (3H, m) 7.26-7.32 (4H, m) 7.17-7.23 (1H, m) 6.86 (1H, br. s.) 6.80 (1H, d, J=5.86 Hz) 6.40 (1H, d, J=3.56 Hz) 5.44 (1H, q, J=7.24 Hz) 2.66-2.75 (1H, m) 2.57-2.65 (1H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH2:15][O:16][CH3:17])[C:13](=[O:18])[C:12]([CH3:20])([CH3:19])[C:11]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH2:15][O:16][CH3:17])[C@H:13]([OH:18])[C:12]([CH3:19])([CH3:20])[C:11]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 2-chloro-4-[5-(methoxymethyl)-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl]benzonitrile (170 mg) and lithium tri(sec-butyl)borohydride-THF solution (0.83 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as colorless crystals (yield: 142 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:44]1[CH:43]=[C:4]([CH:3]=[C:2]([F:1])[CH:45]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)=[N:7]1
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2ccn(Cc4cc(F)cc(F)c4)n2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4ccn(Cc5cc(F)cc(F)c5)n4)c3c2)cc1NS(C)(=O)=O
Yield: 49.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl) methane sulfonamide (53 mg, 0.0799 mmol) was hydrolyzed by lithium hydroxide (17 mg, 0.399 mmol) in THF/methanol/water (2/2/1 ml) to yield 20 mg of the titled compound. 1H NMR (DMSO-d6, 300 MHz): δ 11.8 (s, 1H), 9.00 (s, 1H), 8.538-8.530 (d, 1H), 8.45-8.44 (d, 1H), 7.89-7.88 (d, 2H), 7.55-7.54 (d, 1H), 7.50-7.46 (dd, 1H), 7.19-7.15 (m, 2H), 7.00-6.98 (m, 2H), 6.699-6.692 (d, 1H), 5.40 (s, 2H), 3.86 (s, 3H), 2.97 (s, 3H). MS: m/z=510.1 (M+1), HPLC: 96.47% in method B.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][C:25]2[N:36]([CH3:39])[N:37]=[CH:38][C:24]1=2.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:26][C:25]2[N:36]([CH3:39])[N:37]=[CH:38][C:24]1=2)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) were added tert-butyl 4-(aminooxy)-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate 137 (0.360 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 138 (0.42 g, 89%) as a white foam.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([O:22][C:23]4[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=4[F:33])(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([CH3:35])[CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]Cl>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:3]=[C:4]([CH3:35])[C:5]([N:9]3[C:18]4[C:13](=[CH:14][C:15]([S:19]([O:22][C:23]5[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=5[F:33])(=[O:21])=[O:20])=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]3=[O:34])=[CH:6][C:7]=2[F:8])=[CH:39][C:38]=1[CH3:46]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(-c2cc(C)c(-n3c(=O)ccc4cc(S(=O)(=O)Oc5c(F)c(F)c(F)c(F)c5F)ccc43)cc2F)ccc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-5-fluoro-2-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.20 g, 2.075 mmol), (4-chloro-3-methylphenyl)boronic acid (1.061 g, 6.23 mmol), copper(i) chloride (0.616 g, 6.23 mmol), cesium carbonate (2.70 g, 8.30 mmol), and bis(di-tert-butyl(4-ethylaminophenyl)phosphine)-dichloropalladium(ii) (0.036 g, 0.05 mmol). The flask was flushed with Ar (g), then Dioxane (10.38 ml) was added. The reaction was heated to 50° C. and stirred for one hour. The reaction was diluted with ethyl acetate and washed three times with water containing excess n-(2-hydroxyethyl)ethylenediaminetriacetic acid, trisodium salt hydrate. The organic layer was washed with water, washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 120 g, gradient elution 0-30% EtOAc:Heptane) to afford perfluorophenyl 1-(4′-chloro-2-fluoro-3′,5-dimethyl-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.01 g, 1.619 mmol, 78% yield) as an off-white solid. m/z (ESI) 624.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH2:23][CH:22]2[CH2:31][C:32]([O:34]CC)=[O:33]>>[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:30]=1[C:24]1([CH2:25][CH2:26][N:27]([C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[C:12]([F:15])([F:14])[F:13])[CH2:28][CH2:29]1)[CH2:23][CH:22]2[CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)Cc1ccc(Cl)cc1C(F)(F)F
Product: O=C(O)CC1CC2(CCN(C(=O)Cc3ccc(Cl)cc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 2-(4-chloro-2-(trifluoromethyl)phenyl)acetic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MS Method 1 tR=2.00, min, m/z=500.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl(2RS,3RS)-3-(3-fluorophenyl)-3-hydroxy-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (6.92 g, 16.5 mmol) in methanol (50 ml) was added 2N aqueous sodium hydroxide solution (16.5 ml, 33.0 mmol), and the mixture was stirred at room temperature for 2 hrs. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (4.28 g, 66%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([CH2:7]OS(C)(=O)=O)[CH2:4][CH2:3]1.[CH2:13]([NH:20][CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]([CH2:7][C@H:5]1[NH:6][C:2](=[O:1])[CH2:3][CH2:4]1)[CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)OC[C@@H]1CCC(=O)N1
Reactant: OCCNCc1ccccc1
Product: O=C1CC[C@@H](CN(CCO)Cc2ccccc2)N1
Temperature: 130 °C
Yield: 96.4 %

Procedure:
A mixture of (+)-methanesulfonic acid (S)-5-oxo-pyrrolidin-2-ylmethyl ester (500 mg, 2.59 mmol) and 2-(benzylamino)ethanol (1.56 g, 10.36 mmol) was heated at 130° C. in a microwave oven (Personal Chemistry Emrys™ Optimizer) for 40 minutes. The residue was partitioned between water and DCM, the organic phase was washed with brine, dried (Na2SO4) and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH from 95/5 to 90/10 respectively) to afford the title compound as yellow oil (620 mg, 96% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[CH2:3][S:4]([N:7](S(CC(C)C)(=O)=O)[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])[CH:15]=2)[N:10](C(OC(C)(C)C)=O)[N:9]=1)(=[O:6])=[O:5].FC(F)(F)C(O)=O>ClCCl>[C:23]([C:22]1[CH:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[NH:7][S:4]([CH2:3][CH:2]([CH3:43])[CH3:1])(=[O:6])=[O:5])[C:18]([C:27]#[N:28])=[C:19]([CH3:26])[NH:20][C:21]=1[CH3:25])#[N:24]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N(S(=O)(=O)CC(C)C)S(=O)(=O)CC(C)C)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NS(=O)(=O)CC(C)C)c3c2)C(C#N)=C(C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
120 mg (0.19 mmol) tert-butyl 3-{bis[(2-methylpropyl)sulfonyl]amino}-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 18A) were dissolved in dichloromethane (4 ml) and treated with 0.161 ml (2.1 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (4 ml), treated with 1 M aqueous lithium hydroxide solution (0.75 ml) and stirred at room temperature for 4 h. The mixture was then concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 13 mg (16% of th.) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[C:15](Cl)(=[O:17])[CH3:16].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15](=[O:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CNc1ccc(F)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN(C(C)=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((4-fluorophenyl)amino)acetate (1) (6.68 g, 33.9 mmol) in THF (84 mL) was added acetyl chloride (2.88 mL, 40.6 mmol) and the reaction was stirred overnight at room temperature. Water was added and the reaction was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield ethyl 2-(N-(4-fluorophenyl)acetamido)acetate (2) as an orange solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C1(C)C=CC=CC=1>[C:8]1(=[O:13])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12
Reactant: NCCCCCO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCCO
Yield: 74 %

Procedure:
10 g (96.9 mmo)of 5-amino-l-pentanol was dissolved in 300 ml of toluene and refluxed together with 17.2 g (116 mmol) of phthalic anhydride at 120° C. for 24 hours. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography (eluent; chloroform) to give 16.6 g of 5-phthalimido-1-pentanol in a yield of 74%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([O:18][CH3:19])[CH:9]=2)[C:5]([CH3:20])=[CH:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O1CCOCC1>[O:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:2]3[N:7]=[C:6]([C:8]4[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([O:18][CH3:19])[CH:9]=4)[C:5]([CH3:20])=[CH:4][N:3]=3)=[CH:32][CH:33]=2)[CH2:25][CH2:26]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)ncc2C)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2C)cc1OC
Temperature: 25 °C
Yield: 32.8 %

Procedure:
To a solution of methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-2-methoxybenzoate (165 mg, 0.56 mmol) in 1,4-dioxane (5 mL) was added 4-morpholinoaniline (96 mg, 0.54 mmol) and p-toluenesulfonic acid monohydrate (97 mg, 0.51 mmol). The reaction was heated at reflux for 40 h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice more with ethyl acetate and the combined organic fractions were washed twice with 5% aqueous citric acid, water, brine then dried (sodium sulfate) filtered and concentrated to afford the crude product. Trituration with methanol provided methyl 4-(2-(4-morpholinophenylamino)-5-methylpyrimidin-4-yl)-2-methoxybenzoate as a yellow solid (77 mg, 32%); 1H NMR (300 MHz, d6-DMSO) δ 9.36 (s, 1H), 8.38 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.0 Hz, 2H), 7.38 (s, 1H), 7.27 (d, J=8.1 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 3.72 (m, 4H), 3.01 (m, 411), 2.12 (s, 3H); LC-ESI-MS (method B): rt 6.7 min.; m/z 435.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]1([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([CH2:14][O:15][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OCC1CCCC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(OCC2CCCC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and cyclopentylmethanol by the method of Example 10 (b).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].[CH3:21][C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:26][C:22]=2[CH3:21])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 7 c], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester (example 47 c]) was reacted with 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 g], to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless oil, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.C[O:29][C:30](=O)[CH2:31][C@H:32]1[CH2:36][CH2:35][C@H:34]([O:37][CH3:38])[CH2:33]1>>[CH3:38][O:37][C@H:34]1[CH2:35][CH2:36][C@H:32]([CH2:31][C:30]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH:6]=[CH:5][S:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:29])[CH2:33]1
Reactant: COC(=O)C[C@H]1CC[C@H](OC)C1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5sccc45)CC3)CC2)C1

Procedure:
The title compound was prepared in analogy to example 2 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (100 mg, 0.22 mmol) and racemic trans-(3-methoxy-cyclopentyl)-acetic acid methyl ester [WO 2009/019174] (46 mg, 0.27 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (61 mg, 57%), MS (ISP) m/z=485.4 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([NH2:22])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([NH:22][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(N)c3O2)cc1
Reactant: Cc1ccc(Br)cc1C
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Nc4ccc(C)c(C)c4)c3O2)cc1
Yield: 40.1 %

Procedure:
Treatment of (±)-(7-amino-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.96 g, 3.0 mmol) with 4-bromo-1,2-dimethylbenzene (0.558 g, 3.0 mmol), generally according to the procedure described for Intermediate 202 provided 0.51 g (38%) (±)-{7-[(3,4-dimethylphenyl)amino]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow solid. mp 88-90° C.