Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[SH:8].[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][C:19]=1[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[S:8][C:17]1[N:16]=[N:15][C:14]([Cl:13])=[C:19]([CH:20]([CH3:22])[CH3:21])[CH:18]=1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: OCCc1cc(Cl)c(S)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1cc(Sc2c(Cl)cc(CCO)cc2Cl)nnc1Cl
Temperature: 90 °C
Yield: 52.4 %

Procedure:
A solution of 2-(3,5-dichloro-4-mercapto-phenyl)-ethanol (73) (620 mg, 2.78 mmol) in dimethyl sulfoxide (25 mL) was treated with 3,6-dichloro-4-isopropyl-pyridazine (7) (530 mg, 2.78 mmol) and potassium carbonate (1.54 g, 11.12). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C., poured into a solution of water (200 mL) and a 1N aqueous hydrochloric acid solution (25 mL). The mixture was extracted with ethyl acetate (2×200 mL). The organics were then washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70:30 petroleum ether/ethyl acetate) afforded 2-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenyl]-ethanol (74) (550 mg, 52%) as a pale yellow oil; EI(+)-HRMS m/e calcd for C15H15Cl3N2OS (M+H)+ 377.0044, found 377.0043. Exact Mass=375.9971; Molecular weight=377.72
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[S:23][CH:24]=[C:25]([CH2:27]O)[N:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:25]4[N:26]=[C:22]([C:21]([F:30])([F:29])[F:20])[S:23][CH:24]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1csc(C(F)(F)F)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 12.5 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (63 mg), [2-(trifluoromethyl)-1,3-thiazol-4-yl]methanol (90 mg) and triphenylphosphine (193 mg) in tetrahydrofuran (6 ml) was added bis(2-methoxyethyl)azodicarboxylate (173 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (13 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8](O)=[O:9])=[C:5]([CH3:11])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[N:3]=1.[CH3:32][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])([CH3:35])[CH3:34].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[C:6]([CH2:7][C:8](=[O:9])[NH:39][S:36]([C:33]([CH3:35])([CH3:34])[CH3:32])(=[O:38])=[O:37])=[C:5]([CH3:11])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: Cc1nn(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c(C)c1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1nn(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)c(C)c1CC(=O)NS(=O)(=O)C(C)(C)C

Procedure:
{3,5-Dimethyl-1-[4-(4-trifluoromethyl-benzoylamino)-benzyl]-1H-pyrazol-4-yl}-acetic acid (example 1.1, 250 mg, 0.58 mmol), 2-methylpropane-2-sulfonamide (95 mg, 0.70 mmol), 1,3-dicyclohexylcarbodiimid (143 mg, 0.70 mmol) and 4-dimethylaminopyridine (85 mg, 0.70 mmol) in 2.5 ml dichloromethane were stirred for 3 h at 30° C. The solvent was removed under reduced pressure and the residue was purified by MPLC (silica gel, CH2Cl2/methanol 95:5).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[CH2:31][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:33][CH3:34])[CH:7]=1)C.[OH-].[Li+]>CO.O>[CH2:38]([O:37][C:35]([N:32]([CH2:31][C:16]1[CH:17]=[C:18]([NH:21][C:22](=[O:30])[C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH:19]=[CH:20][C:15]=1[O:14][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([OH:45])=[O:3])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH2:33][CH3:34])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(Cc1cc(NC(=O)c2ccc(Cl)cc2)ccc1Oc1cc(CC(=O)O)ccc1OC)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a solution of {3-[2-[(benzyloxycarbonyl-ethyl-amino)-methyl]-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester (0.18 mmol) in MeOH and H2O was added lithium hydroxide (0.100 g, 2.4 mmol), and the reaction was stirred at 60° C. for 20 minutes. After work-up, the crude material was purified by preparative HPLC to give the title compound. M+H=603.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH3:34][C:35]1([CH3:53])[CH:44]([N:45]2[C:49]([CH:50]=O)=[CH:48][N:47]=[CH:46]2)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:52])[O:36]1>C1COCC1>[CH3:2][O:3][CH:4]=[CH:50][C:49]1[N:45]([CH:44]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37](=[O:52])[O:36][C:35]2([CH3:53])[CH3:34])[CH:46]=[N:47][CH:48]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=Cc1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of methoxymethyltriphenylphosphonium chloride (0.974 g, 2.84 mmol) in THF (10 mL) at −78° C. is added sodium hexamethyldisilazide (1M in THF, 3.0 mL, 3.09 mmol) and the mixture is stirred at −78° C. for 1 h. 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.10 g, 0.37 mmol) (Example 9a) in THF (0.2 mL) is then added at −78° C. and the mixture is stirred at ambient temperature overnight. It is then quenched with water and extracted with ethyl acetate. The organic phase is concentrated in vacuo. The residue is purified using by semi-preparative reverse phase HPLC to afford 4-[5-(2-methoxy-vinyl)-imidazole-1-yl]-3,3-dimethyl-isochroman-1-one; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (s, 3 H), 1.52 (s, 3 H), 3.75 (br. s, 3 H), 5.22 (s, 1 H), 5.31 (s, 1 H), 5.55 (br. s, 1 H), 6.82 (br. s, 1 H), 6.96 (br. s, 1 H), 7.16 (d, J=7.6 Hz, 1 H), 7.55 (td, J=7.6, 1.3 Hz, 1 H), 7.63 (td, J=7.6, 1.3 Hz, 1 H), 8.24 (dd, J=7.7, 1.4 Hz, 1 H).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)=[O:24])[N:18]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]
Reactant: CCOC(=O)N1CCNC[C@H]1C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NCC3CC3)n(-c3ccccc3)n2)C[C@H]1C
Reaction time: 16 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 6 ml DMF were added 28 μl DIPEA, 64 mg HATU and 29 mg (R)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 16 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 560 μl TFA. After stirring for 16 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 65 mg MS (ES+): m/e=696.
Reaction SMILES: [N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].[NH2:24][C@H:25]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH3:26]>>[N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:24][C@H:25]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH3:26])=[O:10])[CH3:7])=[O:4]
Reactant: CCNC(=O)[C@H](C)N
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Product: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
The condensation of Z-Pro-Ala with Ala-NH-Et by the procedure in Example 7 yields Z-Pro-Ala-Ala-NH-Et; m.p. 219°-220° C. from 2-propanol--AcOEt); (α)D20 =-36.2°; c=0.2 (dimethylformamide). This intermediate is successively converted, as described in Example 2, into (1) BOC-Asp(Obzl)-Pro-Ala-Ala-NH-Et, m.p. 133°-136° C. (AcOEt--petroleum ether), (α)D20 =-61.1°, c=0.2 (MeOH); (2) Asp(OBzl)-Pro-Ala-Ala-NH-Et.HCl, m.p. 189°-193° C. (MeOH--Et2O), and (3) Ac-Asp(OBzl(-Pro-Ala-Ala-NH-Et, m.p. 191°-193° C. (AcOEt--petroleum ether), (α)D20 =-68.5°, c=0.2 (MeOH). Hydrogenolysis of the latter product by the procedure in Example 1 yields the title compound, Nα -Acetylaspartyl-prolyl-alanyl-alanine ethylamide; m.p. 153°-155° C. (melting begins at 143° C.).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:5]=2[O:4][CH2:3]1.[H-].[Na+].I[CH3:29]>CN(C)C=O>[CH3:29][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)[C:5]=2[O:4][CH2:3][C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc3c2OCC(=O)N3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)COc2c(CC3CCN(C(=O)OC(C)(C)C)CC3)cccc21
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
A solution of tert-butyl 4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-ylmethyl)piperidine-1-carboxylate (0.6 g, 1.73 mmol) in anhydrous N,N-dimethylformamide (1 mL), was added dropwise to a stirred suspension of sodium hydride (60%) (0.08 g) in anhydrous N,N-dimethylformamide (12 mL) at 0° C. Stirring was continued for a further 20 mins. before iodomethane (0.5 g) in anhydrous N,N-dimethylformamide (1 mL) was added. The mixture was allowed to stir at room temperature for 4 hours. It was quenched with saturated ammonium chloride (20 mL) and extracted with diethyl ether (100 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo to give a crude oil. Silica gel chromatography eluting with ethyl acetate in hexane (10–20%) gave the title compound as a solid (0.6 g, 97%).
Reaction SMILES: CN(C=O)C.[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([S:17]([OH:20])(=O)=[O:18])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.C(Cl)(=O)C([Cl:24])=O>ClCCl>[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([S:17]([Cl:24])(=[O:20])=[O:18])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(=O)(O)c1ccc(N2CCCC2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(N2CCCC2)cc1
Temperature: 25 °C
Yield: 19 %

Procedure:
DMF (0.5 mL) was added to solution of 4-(pyrrolidin-1-yl)benzenesulfonic acid (7.3 g, 32.16 mmol) in dichloromethane (40 mL). Oxalyl chloride (10 g, 78.74 mmol) was then dropwise and the resulting solution was maintained at room temperature for 1 hour. The reaction mixture was then quenched by the addition of 40 mL of iced water. The resulting solution was extracted using dichloromethane (3×20 mL), and the organic layers were combined, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to afford 1.5 g (19%) of 4-(pyrrolidin-1-yl)benzene-1-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.78 (d, 2H), 6.55 (d, 2H), 3.41 (t, 4H), 2.03 (t, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:23](=[O:46])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[C:36]([CH2:37][O:38]C3CCCCO3)=[CH:35][N:34]=[N:33]2)[CH:27]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:38][CH2:37][C:36]1[N:32]([C:28]2[CH:27]=[C:26]([C:25]3[CH2:24][C:23](=[O:46])[NH:22][C:9]4[CH:10]=[C:11]([C:20]#[N:21])[C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[N:33]=[N:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc2c(cc1N1CCOCC1)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2

Procedure:
The title compound was prepared from (RS)-[4-cyano-5-morpholin-4-yl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M41) (0.36 g, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (152 mg, 61%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH3:11].[C:12]1([CH2:18][SH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:18]([S:19][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH3:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: SCc1ccccc1
Reactant: COc1c(Br)cc(F)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Br)cc(F)cc1SCc1ccccc1

Procedure:
1,3-Dibromo-5-fluoro-2-methoxy-benzene (14.2 g, 50 mmol), phenyl-methanethiol (5.86 ml, 50 mmol), Pd2dba3 (1.145 g, 1.25 mmol, 2.5 mol-%), Xantphos (1.447 g, 2.5 mmol, 5 mol-%) and DIPEA (17.5 ml, 100 mmol) were dissolved in 130 ml dry, degassed 1,4-dioxane and heated to reflux for 3 h. After cooling down the mixture was filtrated and evaporated. The remaining solid (22 g) is chromatographed on silica gel using n-heptane-MTBE as eluent. Yield: 12.42 g, 76%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][NH:13][CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:16][N:17]([CH3:24])[CH2:18]/[CH:19]=[CH:20]/[C:21](O)=[O:22].CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13]([C:21](=[O:22])/[CH:20]=[CH:19]/[CH2:18][N:17]([CH3:24])[CH3:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2sc3c(c12)CCNC3
Reactant: CN(C)C/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine (1000 mg, 4.0 mmol, 90% pure) in THF (20 mL) were added (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (730 mg, 4.4 mmol), EDCI (840 mg, 4.4 mmol), DMAP (97 mmol, 0.8 mmol) and diisopropylethylamine (120 mg, 8.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated to dryness under reduced pressure. The residue was purified by ISCO using a 20% ethyl acetate in methanol to obtain 1100 mg (82%) of the desired product. LCMS RT=1.51 min, [M+1]+=337.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9].[OH-].[Na+].[CH3:22]O>>[NH2:6][C@H:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:8]([O:10][CH3:22])=[O:9]
Reactant: CO
Reactant: COc1ccc(C[C@@H](N)C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@H](N)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
20 ml of sulphuric acid are added, dropwise, over a period of 30 minutes, to a solution containing 13 g (66.6 mmol) of (R)-2-amino-3-(4-methoxyphenyl)propionic acid in 150 ml of methanol. After stirring for 24 hours at ambient temperature, the reaction medium is basified to pH 8-9 by introducing 10N sodium hydroxide and a saturated solution of sodium hydrogen carbonate, followed by extraction with dichloromethane. The organic phase is dried over sodium sulphate, filtered and evaporated. 12.8 g in the form of a pale yellow oil are obtained with a yield of 92%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[FH:23].F.F.C(N(CC)CC)C>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]([F:23])([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Temperature: 120 °C
Reaction time: 6.5 h
Yield: 15.7 %

Procedure:
1-Oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (144 mg, 679 μmol), triethylamine (1.10 mL, 6.79 mmol) and triethylamine trihydrofluoride (2.85 mL, 20.4 mmol) were mixed in a sealed test tube. This mixture was stirred at 120° C. for 6.5 hours. The reaction mixture was cooled, and then quenched with a 2 N aqueous NaOH solution and extracted with ethyl acetate three times. The organic layers were combined, washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-AcOEt) to give 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (24.9 mg, 16%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:29])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([CH:27]=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([O:8][NH:9][C:10](=[O:29])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([CH2:27][NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Reactant: NC1CCCC1
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(CNC2CCCC2)co1)NOCc1ccccc1
Yield: 52.2 %

Procedure:
Method and purification as for preparation 157 using (3R)-N-(benzyloxy)-6-cyclohexyl-3-(4-formyl-1,3-oxazol-2-yl)hexanamide (preparation 156) (200 mg, 0.50 mmol) and cyclopentylamine (50 μl, 0.50 mmol) as starting materials to afford the title compound as a colourless oil (122 mg, 48%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[NH2:36][CH:37]1[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38]1>>[CH3:24][O:23][C:18]1[N:17]=[C:16]2[C:12]([C:10]3[N:9]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=4)(=[O:28])=[O:27])[C:5]4=[N:6][CH:7]=[CH:8][C:3]([CH2:2][NH:36][CH:37]5[CH2:38][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40]5)=[C:4]4[CH:11]=3)=[CH:13][N:14]([CH3:25])[C:15]2=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CN(C(=O)OC(C)(C)C)C4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 53.5 %

Procedure:
The product is prepared by following the procedure described in example 52c, starting with 0.3 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine and 0.253 g of 3-amino-1N-Boc-azetidine instead of the N-Boc-ethylenediamine used in example 52c. 0.203 g of tert-butyl 3-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}azetidine-1-carboxylate is obtained with the following characteristics:
Reaction SMILES: [C:1]1([C:7]2[C:8]([NH2:12])=[N:9][O:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:18]CC)(=[O:17])[C:14]([CH3:16])=O.[Li+].[OH-]>O1CCOCC1>[C:1]1([C:7]2[C:8]([NH:12][CH:14]([C:13]([OH:18])=[O:17])[CH3:16])=[N:9][O:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1nonc1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(Nc1nonc1-c1ccccc1)C(=O)O

Procedure:
Following General Procedure II-D and using 4-phenyl-furazan-3-ylamine (Maybridge) and ethyl pyruvate (Aldrich), the ethyl ester was prepared. Following General Procedure II-A, Method B (LiOH/H20/dioxane) and using the ethyl ester, the title compound was prepared.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:25]([CH:31]=O)=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:31][C:25]2[C:24]([CH3:23])=[CH:29][C:28]([CH3:30])=[CH:27][N:26]=2)[CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccn1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(C2CCN(C(=O)OC(C)(C)C)CC2)C(C)c2ccccn2)c(C)c1

Procedure:
Using General Procedure B: Reaction of 4-(1-Pyridin-2-yl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester and 3,5-dimethyl-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave 4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(1-pyridin-2-yl-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. Deprotection with TFA using General Procedure F gave (3,5-dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(1-pyridin-2-yl-ethyl)-amine as a pale yellow oil.