Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]1[O:12][C@@H:11]([N:13]2[C:17]3[N:18]=[C:19]([NH2:23])[NH:20][C:21](=[O:22])[C:16]=3[S:15][C:14]2=[O:24])[C@@H:10](CC([O-])=O)[CH2:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].C([O-])([O-])=[O:30].[K+].[K+].CC(O)=O>CO>[NH2:23][C:19]1[NH:20][C:21](=[O:22])[C:16]2[S:15][C:14](=[O:24])[N:13]([C@@H:11]3[O:12][C@H:8]([C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH3:7])[CH2:9][C@H:10]3[OH:30])[C:17]=2[N:18]=1
Reactant: CC[C@H](OC(C)=O)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](OC(C)=O)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To a solution of [(2R,3R,5S)-5-[(1S)-1-acetoxypropyl]-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 6h, 210 mg, 0.5 mmol) in methanol (25 mL) was added K2CO3 (136 mg, 1 mmol). After being stirred at room temperature for 10 min, the reaction was adjusted to pH 7.0 by addition of HOAc (120 mg, 2 mmol), concentrated in vacuo and the residue was purified by preparative HPLC to afford 66.7 mg of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl]acetate (Example 6) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]2[O:11][C@:12]3([CH2:20][N:21]=2)[CH:17]2[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]2)[CH2:13]3)=[N:6][C:7]=1[F:8].C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]2[O:11][C@:12]3([CH2:20][N:21]=2)[CH:17]2[CH2:18][CH2:19][N+:14]([O-:30])([CH2:15][CH2:16]2)[CH2:13]3)=[N:6][C:7]=1[F:8]
Reactant: Fc1nc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ccc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3ccc(Br)c(F)n3)O1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To (R)—N-(5-bromo-6-fluoropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.064 g, 0.180 mmol) in CHCl3 (15 mL) was added m-CPBA (0.032 g, 0.186 mmol) at room temperature. The reaction stirred at room temperature for 3 hours. TLC showed lower spot and no starting material. The mixture was purified by chromatography (Biotage: 15-20% of 9:1 MeOH:NH4OH in CHCl3; ˜1.1 L) to yield the pure fractions. The fractions were combined and the solvent was removed to yield (S)-2-(5-bromo-6-fluoropyridin-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (0.045 g, 0.119 mmol, 65.9% yield) as a yellow powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.31-8.76 (m, 1H), 8.00 (br. s., 1H), 6.46-6.96 (m, 1H), 3.73 (d, J=11.0 Hz, 2H), 3.56 (br. s., 1H), 3.37 (br. s., 3H), 2.98-3.27 (m, 2H), 2.11 (br. s., 2H), 1.73-2.00 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:41]=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: OB(O)c1ccc(Oc2ccccc2F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3F)cc2)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv) in dioxane/H2O (7/3=V/V) (30 mL), [4-(2-fluorophenoxy)phenyl]boronic acid (500 mg, 2.16 mmol, 3.19 equiv), sodium carbonate (500 mg, 4.72 mmol, 6.99 equiv), and Pd(PPh3)4 (200 mg, 0.17 mmol, 0.26 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath and then concentrated under vacuum. The residue was loaded onto a silica gel column with dichloromethane/methanol (100:1) to give 0.2 g (59%) of tert-butyl (2S)-2-([4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)-pyrrolidine-1-carboxylate as a light yellow solid.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[OH:10][C@@H:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH2:13][CH2:12]1>CCO>[OH:3][NH:2][C:20]([C:15]1[C:14]2[CH2:13][CH2:12][C@H:11]([OH:10])[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[NH:21]
Reactant: N#Cc1cccc2c1CC[C@@H]2O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2c1CC[C@@H]2O
Reaction time: 16 h
Yield: 90 %

Procedure:
To hydroxylamine hydrochloride (0.87 g, 12.5 mmol) and sodium carbonate (1.32 g, 12.5 mmol) in EtOH (20 mL) was added (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile INT-2 (1.59 g, 10 mmol) in one portion and the solution was heated to reflux. After 16 h, the reaction was cooled and filtered to remove the solids. The EtOH was removed and the compound purified by chromatography (MeOH/DCM) to give 1.74 g (90%) of (S)-N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide INT-3 as a white foam. LCMS-ESI (m/z) calculated for C10H12N2O2: 192.1. found: 193.1 [M+H]+, tR=0.56 min. 1H NMR (400 MHz, MeOD) δ 10.30 (s, 1H), 9.97 (s, 1H), 7.72-7.58 (m, 1H), 7.46-7.37 (m, 2H), 5.22 (t, J=6.5, 1H), 3.17-3.03 (m, 1H), 2.99-2.83 (m, 1H), 2.49 (dddd, J=11.4, 8.0, 7.0, 4.4, 1H), 2.02-1.88 (m, 1H). (R)-N,1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide is made in an analogous fashion from (R)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27](Cl)[CH3:28])=[N:25][CH:26]=1>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=3)[CH3:28])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: C[C@@H](Cl)c1ccc(Cl)cn1
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ccc(Cl)cn2)nc2nc(N)sc12
Yield: 11.8 %

Procedure:
The title compound was prepared by general method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (572 mg, 1.91 mmol) and 5-chloro-2-[(1R)-1-chloroethyl]pyridine (376 mg, 2.1 mmol). Purification by preparative HPLC yielded 99 mg (12% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: NC1CCOCC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Product: Cc1cc(F)ccc1-c1nc(NC2CCOCC2)nc2c1ccc(=O)n2-c1ccccc1C
Yield: 90 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 121 (150 mg, 0.35 mmol), and 4-aminotetrahydropyran (179 mg, 1.77 mmol) were reacted to give the crude material, which was purified as described in Example 198 to give the desired product 140 mg (90%). LC-MS: 445.4 (MH+, m/z), 2.27 (Rt, min).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>CO>[CH:22]1([N:25]=[C:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:5]([CH2:4][CH2:3][C@:2]23[CH3:1])[C@:15]2([CH3:21])[C:14]([CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16]2)=[CH:13][CH2:12]4)[CH2:24][CH2:23]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NC1CC1
Solvent: CO
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NC3CC3)CC[C@@H]12
Temperature: 25 °C

Procedure:
To a solution of 21 g of dehydroepiandrosterone in a mixture of 175 ml of cyclopropylamine and 150 ml of methanol was added 5 g of molecular sieves The reaction mixture was refluxed for 48 hours, cooled to room temperature, and filtered through magnesium sulfate. The magnesium sulfate was washed with ethyl acetate and the solvent was removed from the combined filtrates under reduced pressure to give 17-(cyclopropylimino)androst-5-en-3β-ol melting at about 187° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:12][C:10]2[N:11]=[C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]3[N:9]=2)=[O:27])=[CH:22][CH:21]=1
Reactant: COc1ccc(-c2ccccc2)c2nc(N)nn12
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COc1ccc(-c2ccccc2)c2nc(NC(=O)c3ccc(F)cc3)nn12

Procedure:
According to example 6, the title compound was synthesized from 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine and 4-fluoro-phenyl carboxylic acid chloride.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[H][H]>C(O)C.C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[S:1]1[C:5]([C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Reactant: [H][H]
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: c1ccccc1
Product: O=C(O)CCCCCC[C@H]1C(=O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)c1cc2ccccc2s1

Procedure:
(Z)-7-((1R,2R,3R)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoic acid (Example 7, 1 molar equivalent) is dissolved in a 3:2 mixture of ethanol and benzene (0.01 M) under a nitrogen atmosphere. Wilkinson's catalyst (30% by weight relative to starting material) is added and hydrogen gas is introduced. The hydrogen uptake is monitored and upon theoretical consumption, the solvents are removed under reduced pressure and the residue is dissolved in a minimal amount of ethyl acetate containing 1% acetic acid. The crude product is purified using a filtration column on silica gel, eluted with 0.4% acetic acid in ethyl acetate. A second flash silica column eluted with an isopropanol-hexanes-acetic acid solvent system affords the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:20]2=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)CC1(Nc2ccccc2N)CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)CC1(n2c(=O)[nH]c3ccccc32)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
A mixture of [1-(2-amino-phenylamino)-cyclohexyl]-acetic acid methyl ester (205 mg, 0.79 mmol) in THF (5 mL) was added 1,1′-carbonyldiimidazole (180 mg, 1.11 mmol). The solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The resulting residue was purified by CombiFlash with 50% EtOAc in Hexane as the eluent to afford the desired [1-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-cyclohexyl]-acetic acid methyl ester (194 mg, 86%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)OCC1.[H-].[Na+].[CH2:15](I)[CH3:16].Cl>CN(C=O)C.CC(C)=O>[CH2:15]([O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1)[CH3:16]
Reactant: CCI
Reactant: OCC1CCC2(CC1)OCCO2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOCC1CCC(=O)CC1
Temperature: 25 °C

Procedure:
(1,4-Dioxa-spiro[4.5]dec-8-yl)-methanol (from Example 33, 765 mg, 4.44 mmol) in DMF (3 mL) at 0° C. was treated with NaH (Aldrich, 60% in mineral oil, 355 mg, 8.88 mmol) followed by EtI (Aldrich, 0.7 mL, 8.88 mmol). The resulting solution was slowly warmed to room temperature for 2 hours and heated at 60° C. for additional 30 min. The solution was then partitioned between ethyl acetate and saturated NH4Cl. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, which was treated with 1N HCl (2 mL) and acetone (6 mL) at room temperature for 2 hours. The solvent was removed and the solution was then partitioned between ethyl acetate and saturated NaHCO3. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, purified by silica gel column (hexanes:ethyl acetate 5:1) to afford the title compound as colorless solid.
Reaction SMILES: C1(C[N:8]2[C:12](=[O:13])[CH:11]([CH2:14][CH2:15][CH3:16])[N:10]([CH3:17])[S:9]2(=[O:19])=[O:18])C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:17][N:10]1[S:9](=[O:19])(=[O:18])[NH:8][C:12](=[O:13])[CH:11]1[CH2:14][CH2:15][CH3:16]
Reactant: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCC1C(=O)NS(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 2-phenylmethyl-5-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (4.15 g ), 10% Pd/C (2.0 g), and ammonium formate (8.0 g) and methanol was stirred overnight at room temperature. The solvent was removed and the crude product was purified by flash chromatography to afford 2.3 g (80.9%) of 5-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =propyl; R2 =H; R3 =CH3).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[OH:30][C@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[CH2:28][NH:27][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(C(=O)O)cc3)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(C(=O)O)cc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acid (which was obtained in Example 233) and N-[5-((1R)-2amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35–1.50 (m, 2 H), 1.75–2.00 (m, 2 H), 2.50–2.95 (m, 5 H), 2.92 (s, 3 H), 3.45–3.60 (m, 2 H), 4.60–4.70 (m, 1 H), 6.77 (d, J=9.3 Hz, 2 H), 6.80–6.90 (m, 3 H), 7.02 (dd, J=8.4, 1.8 Hz, 1 H), 7.20 (d, J=1.8 Hz, 1 H), 7.60 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2 H); MS (ES) m/z: 603.2 (M−H)−; HRMS Calcd. for C27H31N4O8S2 (M−H)−: 603.1588. Found: 603.1572.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:8]([OH:10])=[O:9])[CH3:7].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:9][C:8](=[O:10])[C@H:6]([CH3:7])[NH2:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Solvent: O=S(Cl)Cl
Product: C[C@H](N)C(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 67 %

Procedure:
Thionylchloride (9.8 ml, 135 mmol, 1.2 eqv) was added dropwise during 15 min. to benzyl alcohol (210 ml) stirred under nitrogen and cooled to −10° C. Alanine (10.0 g, 112 mmol, 1.0 eqv) was added in portions during 10 min. The reaction mixture was heated overnight at 60-70° C. The reaction mixture was evaporated in vacuo and the residue was dissolved in water (150 ml). The pH was adjusted to 1-2 by addition of 4N HCl (aq.) and the aqueous phase was extracted with dichloromethane (2×200 ml). The organic phase was washed with hydrochloric acid (pH 1, 1×50 ml). The aqueous phases were collected, alkalinized (to pH 9-10) by addition of 2N NaOH (aq.) and subsequently extracted with dichloromethane (2×200 ml and 1×100 ml—alkaline extract). The alkaline extract was dried (Na2SO4), filtered and evaporated under reduced pressure affording 13.39 g (67%) of the title compound as a colorless oil. The product was characterized as its hydrochloride: The product (0.50 g, 2.8 mmol) was dissolved in ether (5 ml) and HCl in ether (2 ml) was added. The precipitate was collected by filtration and washed with ether (2×5 ml) yielding 0.57 g (95%) of white crystalline alanine benzyl ester hydrochloride. 1H-NMR (D2O/TMS): δ 1.48 (unresolved d, 3H, Me); 4.15 (unresolved q, 1H, CH); 5.20 (s, 2H, CH2); 7.38 (br s, 5H, Ph). 13C-NMR (D2O/TMS): δ 14.7 (Me); 48.4 (CH); 68.1 (CH2); 128.1, 128.5, 134.3 (Ph); 170.1 (C═O). MS(FAB+) m/z (%): 180 (100, M-HCl+H). Anal. Calcd. for C10H14,ClNO2: C, 55.69; H, 6.54; N, 6.49. Found: C, 55.60; H, 6.56; N, 6.40.
Reaction SMILES: [NH:1]1[CH:7]([CH2:8][C:9]([OH:11])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].Cl.Cl.[CH3:14][C:15]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>CS(C)=O>[O:3]=[C:2]1[NH:1][CH:7]([CH2:8][C:9]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([CH3:14])[CH:24]=3)=[CH:33][CH:32]=2)=[O:11])[C:5](=[O:6])[NH:4]1
Reactant: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Reactant: O=C(O)CC1NC(=O)NC1=O
Agent: Cl
Solvent: CS(C)=O
Product: Cc1cc(COc2ccc(NC(=O)CC3NC(=O)NC3=O)cc2)c2ccccc2n1

Procedure:
Commercially available (+/−)hydantoin-5-acetic acid (100 mg, 0.63 mmol) and 4-[(2-methyl-4-quinolinyl)methoxy]-aniline bis-HCl salt (213 mg, 0.63 mmol) were warmed in 1 mL dry DMSO and coupled using GENERAL COUPLING METHOD A. Purified on silica gel using 5% MeOH in EtOAc to give 116 mg (46%) of a white waxy solid. MS found:(M+H)+=406.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Br:17])[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>CN(C)C=O.O>[Br:17][C:4]1[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=[C:2]([C:30]2[CH:29]=[N:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[CH:3]=1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(Br)c2s1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cncc(OC)c3)cc(Br)c2s1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
A stirred mixture of 1-(5,7-dibromo-benzothiazol-2-yl-3-ethyl urea (300 mg, 0.79 mmol), sodium carbonate (167 mg, 1.58 mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloro-palladium(II) (45 mg, 0.05 mmol), 3-methoxy-5-pyridineboronic acid pinacol ester (186 mg, 0.79 mmol) in dimethyl formamide (8 ml) and water (2 ml), was purged with nitrogen for 5 min and heated at 100° C. for 1 h. The reaction mixture was concentrated in vacuo then partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0 to 5% methanol in ethyl acetate to give 1-[7-Bromo-5-(5-methoxy-pyridin-3-yl)-benzothiazol-2-yl]-3-ethyl-urea 1 as a white solid (49 mg, 15%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CO>[C:13]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][OH:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)(=[O:15])[CH3:14]
Reactant: OCc1ccc2c(c1)CCCN2
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N1CCCc2cc(CO)ccc21
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (314 mg) in methanol (4 ml) was dropwise added acetic anhydride (589 mg) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed in vacuo, and ethyl acetate and saturated sodium bicarbonate solution were added to the residue. The organic layer was washed with water and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate=1:2, v/v) to give 1-acetyl-6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (227 mg).
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>CC(N(C)C)=O>[O:22]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][N:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(CN1C(=O)c2ccccc2Nc2ncccc21)c1ccccc1
Temperature: 0 °C
Yield: 24.4 %

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (5.0 g, 1 eq.) was suspended in dimethylacetamide (DMA) (50 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (2.07 g, 2.2 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and 2-bromo-1-phenylethanone (7.04 g, 1.5 eq.) was added. The reaction was stirred at room temperature before the addition of a further quantity of 2-bromo-1-phenylethanone (9 g, 2 eq.). The reaction was quenched after 2 hours at room temperature (the reaction did not proceed to completion). The reaction was poured onto 200 mL water and extracted with dichloromethane (3×75 mL). The organic extracts were combined, washed with water (2×100 mL), brine (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (0-5% methanol in dichloromethane) gave 5-(2-oxo-2-phenylethyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.9 g, 24%) as a red solid. LCMS: 330 [M+H].
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.[CH:16]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+]>C(O)(=O)C>[CH:16]1([O:21][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OC2CCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To 30 ml of N,N-dimethylformamide, 1.00 g (6.4 mmol) of 6-chloronicotinic acid and 1.72 g (20 mmol) of cyclopentanol were dissolved, followed by adding 0.80 g (20 mmol) of 60% sodium hydride, stirring at room temperature for 1 hour and heating under refluxing for 3 hours. The reaction liquid was then poured in 100 ml of ice water and acetic acid was added to make pH 5. The crystal precipitated was filtered, washed with cold water and hexane, and dried to obtain 1.06 g (yield: 80%) of 6-cyclopentyloxynicotinic acid.