Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18](F)=[C:19]([O:22][CH2:23]C)[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:26]#[N:27].[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH2:34][OH:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:35][CH2:34][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][O:28]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:27]=[CH:26][C:13]=1[C:14]#[N:15]
Reactant: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Reactant: OCC1CCCCO1
Product: COc1cc(Nc2c(C#N)cnc3cc(OCC4CCCCO4)c(OC)cc23)c(Cl)cc1Cl

Procedure:
Following the procedure used to prepare Example 15, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3-quinolinecarbonitrile (250 mg, 0.64 mmol) and tetrahydropyran-2-methanol provides 177 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-(tetrahydro-2H-pyran-2-ylmethoxy)-3-quinolinecarbonitrile, mp 193-196° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCOc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (5.0 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (63%); off white powder, mp 235° C.; MS: 420.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:21])[CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[N-:22]=[N+:23]=[N-:24].[Na+].CS(C)=O>O>[N:22]([CH2:9][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:21])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(Cl)c2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@@H](O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of toluene-4-sulfonic acid (S)-2-(3-chlorophenyl)-2-hydroxyethyl ester (16.34 g, 0.050 mol), sodium azide (6.50 g, 0.10 mol) and DMSO (50 mL) was stirred for 2 h at 80° C. Water (100 mL) was added, extracted with hexane-ether (1:1) mixture (2×150 mL). Combined extract was dried over Na2SO4, evaporated. The residue was separated on SiO2 (100 g), hexane-EtOAc, 0 to 20%. Colorless oil, 7.0 g, (0.035 mol, 71%).
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[S:19]1[CH:15]=[CH:16][CH:17]=[C:18]1[N:3]1[CH2:4][C@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[O:1][C:2]1=[O:13]
Reactant: Brc1cccs1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cccs1
Temperature: 25 °C
Yield: 47.6 %

Procedure:
(S)-Spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one (505 mg, 3.58 mmol), 5-bromothiophene (1.75 g, 10.74 mmol), copper (I) iodide (69 mg, 0.36 mmol) and potassium carbonate (495 mg, 3.58 mmol) were stirred at 120° C. overnight. After cooling to room temperature, the mixture was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound as a yellow solid (450 mg), m/zz 265 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.N.C(=O)=O.[Na]>C(O)C.C(O)(C)(C)C>[NH2:1][C:2]1[C:11]2[CH2:10][CH:9]=[CH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2ccccc12
Agent: N
Agent: O=C=O
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: CCO
Product: Nc1cccc2c1CC=CC2
Reaction time: 8 h
Yield: 97 %

Procedure:
1-Aminonaphthalene (79 g, 0.55 mol), ethanol (300 ml), t-butyl alcohol (50 ml), and NH3 (200-300 ml) were placed in a three-necked, round-bottomed flask equipped with a condenser cooled with dry ice. Sodium (30 g, 1.3 mol) was added in portions over a 4 hour period. Then another 50 ml t-butyl alcohol was added. After an hour, 100 ml absolute ethanol was added slowly. This mixture was stirred overnight and then quenched by careful addition of NH4Cl (50 g) and H2O (400 ml). The aqueous and organic layers were separated. The aqueous layer was extracted twice with ether. The ether extracts were combined with the organic layer, which was then extracted with H2O (2x) and sat. NaCl. The organic layer was dried over Na2SO4 and filtered through MgSO4. Following evaporation of ether and most of the t-butyl alcohol at 65° C., colorless 1-amino-5,8-dihydronaphthalene was obtained by vacuum distillation (mp 37°-39° C.; yield 97%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.[H-].[Na+].[CH3:14][SH:15].O>CN(C)C(=O)C>[CH3:10][C:7]1[CH2:8][CH2:9][C:4]([C:2]([CH3:11])([S:15][CH3:14])[CH3:1])([OH:3])[CH2:5][CH:6]=1
Reactant: CS
Reactant: CC1=CCC2(CC1)OC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CSC(C)(C)C1(O)CC=C(C)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of 15.2 g of 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene in 100 ml of N,N-dimethylacetamide was added 4.4 g of 60% sodium hydride. The mixture was cooled to 5°-10° C. and saturated with methyl mercaptan. Stirring was continued while heating the reaction mixture to 100° C. over a two and one-half hour period. After an additional hour at 100° C., the reaction mixture was poured into water and extracted twice with n-pentane. The combined extracts was washed with water, dried and Claisen-distilled to give 15.8 g of the desired product, b.p. 83°-85° C. (0.2 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9](S(C)=O)[N:8]=1.[N:32]1[CH:33]=[CH:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][C:36]=12.C(N(CC)CC)C.CN(C)C(=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[N:10]=[C:9]([N:38]2[CH2:39][CH2:40][N:35]3[CH:34]=[CH:33][N:32]=[C:36]3[CH2:37]2)[N:8]=1
Reactant: c1cn2c(n1)CNCC2
Reactant: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(S(C)=O)nc1N1CCC(O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of whole amount of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-methylsulfinylpyrimidine (prepared in the above (5)), 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 73 mg, triethylamine 0.083 ml and N,N-dimethylacetamide 4 ml is stirred at 110° C. for 4 hours. After cooling the reaction mixture is diluted with a 10% aqueous citric acid solution and washed with ethyl acetate. The organic layer is extracted with a 10% aqueous citric acid solution. The water layer is made basic with sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:methanol=100:1→50:1), and then crystallized from a mixture of ethyl acetate, methanol and isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless crystalline powder 20 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12](=[O:15])[CH2:13]Br)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C=O)C.[OH-].[K+]>O>[Cl:1][C:2]1[C:3]([N:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:15])[CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(CBr)Nc1c(Cl)cccc1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(Nc1ccccc1)c1c(Cl)cccc1C(=O)O
Yield: 66.7 %

Procedure:
A solution of 3-chloro-2-(bromoacetamido) benzoic acid from Example 39 (4.6 g, 15.7 mmol), aniline (3.58 mL, 39.3 mmol) and DMF (45 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (400 mL) and 5% KOH (125 mL) and washed with CH2Cl2 (3×125 mL). The aqueous layer was acidified to pH 2 with 2 N HCl, cooled below room temperature and filtered. The filter cake was rinsed with cold water (50 mL) and dried under high vacuum at 45° C. to yield 3.19 g (67%) of the title compound as a tan solid; 1H NMR (DMSO-d6) δ 13.1 (broad s, 1H), 9.85 (s, 1H), 7.74 (d, J=7.6, 1H), 7.71 (d, J=8.0, 1H), 7.35 (t, J=7.6, 1H), 7.10 (t, J=7.6, 2H), 6.65-6.58 (m, 3H), 6.1 (broad s, 1H), 3.82 (s, 2H); 13C NMR (DMSO-d6) δ 169.62, 166.77, 148.33, 133.87, 132.70, 131.53, 130.93, 128.90, 128.82, 127.21, 116.59, 112.57, 47.16; MS (LSIMS, m/z) 305 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:59][CH3:60])=[C:31]([C:33]2[C:42]3[C:37](=[CH:38][C:39]([S:43](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:45])=[O:44])=[CH:40][CH:41]=3)[C:36](=[O:58])[NH:35][N:34]=2)[CH:32]=1>C1COCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([O:59][CH3:60])=[C:31]([C:33]2[C:42]3[C:37](=[CH:38][C:39]([S:43]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=4)[C:9]4[S:10][CH:11]=[CH:12][N:13]=4)(=[O:45])=[O:44])=[CH:40][CH:41]=3)[C:36](=[O:58])[NH:35][N:34]=2)[CH:32]=1
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4cc(Cl)ccc4OC)n[nH]c(=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A round-bottom flask was charged with N-(4-methoxybenzyl)thiazol-2-amine (63.5 mg, 0.288 mmol) and THF (1.60 mL) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a suspension. Lithium bis(trimethylsilyl)amide (1M in THF, 961 μl, 0.961 mmol) was added drop wise to give a light yellow solution. The mixture was stirred for 15 min. Then, a solution of perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (128 mg, 0.240 mmol) in THF (1.60 mL)) was added drop wise. LCMS after 1 h showed a complete conversion of SM to mainly product. The reaction was quenched with saturated aqueous ammonium chloride (0.5 mL) at −78° C. and then warmed to rt. The product was extracted with EtOAc. The organic layers was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 20-50% EtOAc/heptanes) to give 1-(5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydrophthalazine-6-sulfonamide (56 mg, 41.0% yield) as an off-white solid. m/z (ESI) 569.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[NH:19][N:18]=2)[N:3]=1.[CH:25]1([OH:29])[CH2:28][CH2:27][CH2:26]1>>[CH:25]1([O:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:5]=[C:4]([NH:16][C:17]3[CH:21]=[C:20]([CH:22]4[CH2:24][CH2:23]4)[NH:19][N:18]=3)[N:3]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(Cl)c2cc1OC
Reactant: OC1CCC1
Product: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(OC3CCC3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-cyclopropyl-1H-pyrazol-3-yl)-amine and cyclobutanol to give (1-Cyclobutoxy-6,7-dimethoxy-isoquinolin-3-yl)-(5-cyclopropyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 381(MH+).
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[N:7][C:8]=1[F:9].ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:43][C:44]1[CH:45]=[C:46]([NH:51][NH2:52])[CH:47]=[CH:48][C:49]=1[F:50]>>[Cl:43][C:44]1[CH:45]=[C:46]([N:51]2[C:10]([C:5]3[CH:6]=[N:7][C:8]([F:9])=[C:3]([Cl:2])[CH:4]=3)=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[N:52]2)[CH:47]=[CH:48][C:49]=1[F:50]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cnc(F)c(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cnc(F)c(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
240 mg (0.86 mmol) of the compound of Example 15A is reacted analogously to the synthesis of the compound of Example 20A with 253 mg (1.29 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 16 mg (5% of theory) of the title compound is obtained.
Reaction SMILES: I[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](=[S:24])([O-:23])=[O:22])=[CH:17][CH:16]=1.[K+]>C(O)C>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][CH:2]([S:24][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:3][CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)SC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 41.9 %

Procedure:
4-Iodo-piperidine-1-carboxylic acid, tert-butyl ester (1.3 g) and potassium toluene-4-thiosulfonate (1.0 g) were combined in ethanol (10 ml) with cis-dicyclohexane 18-crown-6 (10 mg) and heated under reflux for 12 h. After cooling the reaction mixture was partitioned between ethyl acetate and water, the organic layer was separated, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with iso-hexane/ethyl acetate 4:1 to 7:3), to yield the subtitle compound as an oil (0.65 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[SH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:21])([CH3:22])[C:15]=2[CH:23]=1
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCOS(C)(=O)=O)cc21
Reactant: Sc1ccccn1
Product: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCSc3ccccn3)cc21

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 2-mercapto-pyridine.
Reaction SMILES: C(OC([N:11]([O:28][CH:29]=[C:30]=[O:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:14]=1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=2[O:19][CH3:20])[CH2:12][NH:11][O:28][CH:29]=[C:30]=[O:31])[CH2:22][CH2:23]1
Reactant: [H][H]
Reactant: COc1ccc(CN(OC=C=O)C(=O)OCc2ccccc2)cc1N1CCN(C)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CNOC=C=O)cc1N1CCN(C)CC1
Yield: 109.8 %

Procedure:
A mixture comprising 3.26 g of N-benzyloxycarbonyl-3-(4-methylpiperazin-1-yl)-carbonylmethoxy-4-methoxybenzylamine, 0.5 g of 5% palladium carbon and 70 ml of ethanol, was stirred at 60° C. for 6 hours in a hydrogen atmosphere and further at room temperature overnight. Palladium carbon was filtered off, and then the filtrate was distilled off under reduced pressure to obtain 2.45 g of the above-identified compound as slightly brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH:44]([CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH:44]([CH2:47][OH:48])[CH2:43][CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC(CO)CC5)n4c3)c3ccccc32)cc1

Procedure:
A solution of Intermediate 54d (210 mg, 0.261 mmol) and TBAF (1M in THF, 0.31 mL, 0.31 mmol) in THF (5 mL) was stirred at RT for 1.25 h. The mixture was diluted with water and extracted with DCM (3×15 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-16% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (134 mg, 79%). LCMS (Method 5): Rt 4.24 min, m/z 649.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.38-2.16 (9H, m), 2.36 (3H, s), 2.85-2.97 (2H, m), 3.28-3.49 (4H, m), 4.52 (1H, t, J 5.2), 4.78-4.85 (1H, m), 5.55 (1H, t, J 4.3), 6.32 (1H, s), 7.07 (1H, d, J 8.6), 7.15 (1H, dd, J 9.7, 2.1), 7.25-7.41 (8H, m), 7.60 (1H, d, J 9.7), 7.64 (1H, d, J 1.6), 8.04 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccccc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
p-Methoxyaniline (0.038 g, 0.308 mmol), triethylamine (0.031 g, 0.308 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.052 g, 0.308 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-benzyloxybenzoic acid (0.065 g, 0.154 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.066 g, 0.125 mmol, 81%).
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[CH:25]=[N:24][N:23]([CH3:26])[C:20]4=[N:21][CH:22]=3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO>[C:38]([O:37][C@@H:9]([C:10]1[C:28]([CH3:29])=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[CH:25]=[N:24][N:23]([CH3:26])[C:20]4=[N:21][CH:22]=3)[S:16][C:12]=2[C:11]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH2:8][OH:7])([CH3:41])([CH3:39])[CH3:40]
Reactant: Cc1cc2nc(-c3cnc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3cnc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 50 °C

Procedure:
To a solution of compound (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzo[d]thiazol-6-yl)ethyl pivalate (14 mg, 0.024 mmol) in THF (0.50 mL) and MeOH (0.50 mL) was added aqueous NaOH (0.10 mL of a 2 N solution). The reaction mixture was heated at 50° C. for 17 h, cooled, diluted with satd. aqueous NH4Cl and extracted with ethyl acetate. The organic layer was dried and concentrated to give the desired product which was used without any further purification. LCMS-ESI+: calc'd for C27H28ClN4O2S: 507.2 (M+H+); 507.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][NH:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:18][O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[CH2:29][N:9]([CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cccnc1CNCc1ncccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1C

Procedure:
Using General Procedure A: Reaction of bis-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester and DIPEA in CH3CN gave 2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.O>CS(C)=O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@@H:12]([F:14])[CH2:11][N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[CH:23][CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12
Reactant: BrCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ccccn3)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (2S,4R)-1-[2-(3-acetyl-5-hydroxy-indol-1-yl)-acetyl]-4-fluoro-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 579 (60.0 mg, 0.122 mmol) in DMSO (2.5 mL) was treated with cesium carbonate (160 mg, 0.490 mmol). After stirring at RT for 5 min, 2-(bromomethyl)pyridine (31.0 mg, 0.122 mmol) was added to the reaction mixture and stirring was continued at RT for 16 h. Water was then added to the mixture to form a solid precipitate which was filtered off, washed with water and dried in vacuo. Purification by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) afforded after lyophilization of the purified fractions the title compound as a white solid. MS (LC/MS): 580/581 [M+H]+; tR (HPLC conditions k): 3.00 min.