Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])=[O:25]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:14](=[O:16])[NH:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reaction time: 1 h

Procedure:
53.6 g of carbobenzoxy-L-alanine are dissolved in 400 ml of dry tetrahydrofuran, the solution is treated dropwise with 30 g of thionyl chloride while cooling with ice and the mixture is stirred for 1 hour in the cold. A solution of 54 g (0.2 mol) of 2-amino-5-nitro-2'-chlorobenzophenone in 150 ml of dry tetrahydrofuran is subsequently added dropwise thereto rapidly, whereupon the mixture is stirred at room temperature for 24 hours. The solution obtained is concentrated, the residue is treated with ice and 10 percent sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried over sodium sulphate and evaporated. The residue is treated with dry ether, left to crystallize for 1 hour and then filtered while rinsing with ether/petroleum ether (1:1). After drying, there is obtained (S)-benzyl-[1-[[2-(o-chlorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl]carbamate of melting point 143°-145°; [α]25 D =18° (1 percent solution in methylene chloride).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=2[CH3:18])[CH:2]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:27]([Si:31](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28].N1C=CN=C1>ClCCl.O>[Si:31]([O:17][C:10]1[C:9]([CH3:18])=[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:13]([OH:14])=[C:12]([CH3:15])[C:11]=1[CH3:16])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1=C(C)C(=O)C(Cc2cccnc2)=C(C)C1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: Cc1c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)c(Cc2cccnc2)c1O
Reaction time: 1 h

Procedure:
6-(3-Pyridylmethyl)-2,3,5-trimethyl-1,4-benzoquinone (241 mg, 1 mmol) was dissolved in dichloromethane (5 ml). The solution was stirred for 1 hour with a solution containing sodium hydrosulfite (400 mg, 2.3 mmol) in water (5 ml). The dichloromethane layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 ml), and tert-butylchlorodiphenylsilane (550 mg, 2 mmol) was added. Then imidazole (136 mg, 2 mmol) was added under a stream of nitrogen. The reaction mixture was stirred at 43° C. for 16 hours and washed with water (5 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude 4-tert-butyldiphenylsilyloxy-6-(3-pyridylmethyl)-2,3,5-trimethylphenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:19])=[C:15](F)[CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:25][C:26]1([NH:30]C(=O)C(F)(F)F)[CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:28]4[CH2:29][C:26]([NH2:30])([CH3:25])[CH2:27]4)[CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC1(N)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Yield: 51.9 %

Procedure:
A mixture of 0.8 g (2.5 mmoles) of 1-(4-fluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.3 g (6 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 1 g of triethylamine is heated under reflux in 20 ml of pyridine for 3 hours. The mixture is evaporated, and extracted with methylene chloride. Filtration and evaporation yield 1.1 g of 1-(4-fluorophenyl)-6-fluoro-7-(3-trifluoroacetamido-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 146°-151° C., which is subsequently hydrolysed in a manner similar to that in example 41, to obtain 0.5 g (56%) of 1-(4-fluorophenyl)-6-fluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 270°-6° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[N:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[C:14]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:11])[CH3:10].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].O>COCCOC>[CH:20]([O:19][C:17]1[C:18]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:13]([O:12][CH:9]([CH3:10])[CH3:11])[C:14]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:15]([C:23]([F:24])([F:26])[F:25])[N:16]=1)([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1c(OC(C)C)cc(OC(C)C)nc1C(F)(F)F
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(OC(C)C)nc(C(F)(F)F)c(C(=O)OCC)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
To a -78° C. solution of 0.021 mol of LDA in DME (30 ml) was added a solution of 4.65 g (0.014 mol) of product of Example 6 in 20 ml of DME. The resulting solution was stirred for 10 minutes and treated with 2.7 ml (0.035 mol) of ethyl chloroformate. After stirring at -78° C. for 30 minutes the reaction mixture was warmed to room temperature in 30 minutes and poured into 50 ml of water. The mixture was extracted with ether. The ether extract was washed with 10% K2CO3, dried over CaSO4 and concentrated. The residue was first kugelrohr distilled at 0.15 torr (pot temperature 55° C.) to remove low boiling material (1.08 g), then distilled at 164°-173° C. (0.15 torr) to give 1.95 g (34.5%) of product as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li][CH2:15]CCC.CCCCCC.C([O:27][C:28](=O)[C:29]([F:32])([F:31])[F:30])C>C1COCC1>[CH3:7][C:4]1[N:3]([C:8]2[CH:12]=[C:11]([C:28]([OH:27])([CH3:15])[C:29]([F:32])([F:31])[F:30])[N:10]([CH3:13])[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1ccc(C)n1-c1ccn(C)n1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C(C)(O)C(F)(F)F)n(C)n1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (1.5 g, 8.6 mmol) in THF (100 mL) at −78° C., 2.5M nBuLi in Hexane (4.1 mL, 10.3 mmol) is added and stirred for 1.5 hours followed by the addition of trifluoro-acetic acid ethyl ester (1.5 g, 10.3 mmol). After 10 min the ice bath is removed and the reaction is allowed to reach room temperature. Then the reaction is cooled down to −78° C. again and methylmagnesium bromide (1.0 M solution in hexane, 8.6 mL) is added. After 5 min the ice bath is removed and the mixture is stirred at room temperature for 3 hour, poured into water, separated, and the water layer is extracted with DCM. The organic layers are combined and concentrated. The residue is purified by FCC to give the title compound. MS (ESI) m/z 288.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:15])[C:3]=1[C:4]#[N:5].[CH2:16](O)[CH2:17][CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/[N:45]=N/C(OC(C)C)=O)=O)C>>[NH2:45][C@@H:17]([CH3:18])[CH2:16][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[C:6]([F:15])[C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:14]1
Reactant: N#Cc1c(F)cc(-c2ccn[nH]2)cc1Cl
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1

Procedure:
2-Chloro-6-fluoro-4-(1H-pyrazol-5-yl)benzonitrile (0.74 g, 3.3 mmol) was reacted with (S)-(−)-2-tert-butoxycarbonylamino)-1-propanol (0.88 g, 5.0 mmol) in the presence of triphenylphosphine and DIAD using the method of Example 99. After Boc-deprotection 0.45 g (49%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 0.95 (d, 3H), 3.17-3.28 (m, 1H), 4.01 (dd, 2H), 7.03 (d, 1H), 7.85-7.91 (m, 2H), 7.99 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[CH2:26]([N:22]([CH2:23][CH2:24][OH:25])[C:3]1[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1)[CH3:27]
Reactant: OB(O)c1cncnc1
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1Br
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(SC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 195.1) and pyrimidin-5-ylboronic acid to afford an off-white foam. HPLC (Condition 4) tR=5.43 min, UPLC-MS (Condition 3) tR=1.05 min, m/z=464.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=6.84 Hz, 3H) 3.14 (m, J=7.00, 7.00, 7.00 Hz, 2H) 3.32-3.52 (m, 4H) 4.61 (t, J=5.08 Hz, 1H) 7.69 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.60 Hz, 2H) 8.10 (d, J=2.35 Hz, 1H) 8.77 (d, J=1.95 Hz, 1H) 9.01 (s, 2H) 9.19 (s, 1H) 10.35 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH2:40])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH:40][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 603.0 [(M−H)−]; mp 268° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]=O)=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:22][OH:23].C([O-])(O)=O.[Na+]>C(O)C.O>[CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]=[N:22][OH:23])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(COc2ccc(C=O)nc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(COc2ccc(C=NO)nc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.8 %

Procedure:
To a solution of 5-(4-methanesulfonyl-benzyloxy)-pyridine-2-carbaldehyde (2.44 g, 8.4 mmol) in ethanol (1.5 mL) at 0° C. was added dropwise a solution of hydroxylamine hydrochloride (1.2 g) and NaHCO3 (1.6 g) in water (15 mL) and stirred at rt for 14 h. The reaction mixture was then filtered and the filtrate air-dried to yield 5-(4-methanesulfonyl-benzyloxy)-pyridine-2-carbaldehyde oxime (2.13 g, 83%) as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[NH:32][C:33](=O)[O:34]C1C=CC=CC=1.NC1C=NC=CN=1>>[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[NH:32][C:33]([N:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=3)[CH:10]=2)[CH2:4][CH2:3]1)=[O:34]
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cnccn1)Oc1ccccc1
Agent: Cl
Agent: Nc1cnccn1
Product: O=C(Nc1cnccn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1

Procedure:
Following the procedure in Example 1, Step 6, 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (150 mg, 0.40 mmol, from Example 1, Step 5) and phenyl pyrazin-2-ylcarbamate (261 mg, 1.2 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from aminopyrazine) were used to provide the title compound (24 mg). MS (APCI 10V) AP+ 456.2, 376.2, 335.2, AP− 454.2, 435.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.43-2.50 (m, 2H) 2.56-2.62 (m, 2H) 3.54-3.61 (m, 2H) 3.64-3.70 (m, 2H) 6.46 (s, 1H) 6.98-7.05 (m, 2H) 7.10-7.17 (m, 2H) 7.40 (td, J=7.72, 0.67 Hz, 1H) 8.06-8.11 (m, 1H) 8.16 (d, J=2.68 Hz, 1H) 8.28 (dd, J=2.68, 1.54 Hz, 1H) 8.43 (ddd, J=2.56, 1.71, 0.85 Hz, 1H) 9.04 (d, J=1.56 Hz, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[N:16][CH:17]=1.[CH2:20]([Mg]Br)[CH2:21][CH2:22][CH2:23][CH3:24].BrCCCCC>C1COCC1>[OH:19][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:17][N:16]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=Cc1ccc(Oc2ccc3ccccc3n2)cn1
Reactant: CCCCC[Mg]Br
Solvent: C1CCOC1
Solvent: CCCCCBr
Product: CCCCCC(O)c1ccc(Oc2ccc3ccccc3n2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
To a cold (-30° C.) solution of 5-(2-quinolinyloxy)-2-pyridine carboxaldehyde (8 g, 0.032 mol) in dry THF (125 ml) was added a solution of pentylmagnesium bromide (prepared from 4.83 g (0.032 mol) of 1-bromopentane and 0.78 g (0.032 mol) of Mg turnings in THF (60 ml). After the addition of the Grignard reagent was complete (-45° C.), the solution was stirred at this temperature for 90 minutes, and allowed to slowly warm up to room temperature in about 2 hours. The reaction was quenched by adding a saturated solution of ammonium chloride. The clear organic layer was decanted, and most of the volatiles were removed. The residue was taken up in ethyl acetate, and then washed with water, brine, and dried over MgSO4. After removal of the ethyl acetate the crude residue (7.7 g) was purified by HPLC (silica gel; 25% ethyl acetate in hexane) to give 3.6 g (35%) of pure product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:21]1[S:22][C:23]2[C:29]([N+:30]([O-:32])=[O:31])=[C:28]([O:33][CH3:34])[CH:27]=[CH:26][C:24]=2[N:25]=1>O.COCCOC>[CH3:34][O:33][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[S:22][C:23]=2[C:29]=1[N+:30]([O-:32])=[O:31]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COc1ccc2nc(Br)sc2c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2nc(-c3ccc4ccccc4c3)sc2c1[N+](=O)[O-]
Temperature: 85.5 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
0.716 g (4.16 mmol; 1.1 equivalent) of 2-naphthalene boronic acid as well as a solution of 1.2 g (11.35 mmol; 3 equivalents) of sodium carbonate in 15 ml of water are added to a suspension of 1.09 g (3.78 mmol) of 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole and 131 mg (0.114 mmol; 0.03 equivalent) of palladium tetrakis-triphenylphosphine in 30 ml of 1,2-dimethoxyethane. The reaction mixture is maintained under stirring at 85.5° C. for 18 hours, then after concentration under reduced pressure, 100 ml of ethyl acetate is added to the medium which is then washed with twice 75 ml of a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulphate then the solvents are evaporated off under reduced pressure and the residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:2). 1.06 g (83% yield) of 6-methoxy-2-(2-naphthyl)-7-nitro-1,3-benzothiazole is obtained in the form of beige powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:18]=[C:17]3[N:28](C4CCCCO4)[N:29]=[C:30]([CH:31]4[CH2:33][CH2:32]4)[C:16]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.Cl>O1CCOCC1>[CH:31]1([C:30]2[C:16]3[C:17](=[N:18][C:19]([C:21]4[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=4)=[CH:20][C:15]=3[CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[NH:28][N:29]=2)[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(-c3ccc(O)cc3)nc3c2c(C2CC2)nn3C2CCCCO2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Oc1ccc(-c2cc(CN3CCNCC3)c3c(C4CC4)n[nH]c3n2)cc1
Reaction time: 16 h
Yield: 80.2 %

Procedure:
600 mg of 4-[3-cyclopropyl-6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester were dissolved in 6 ml of 1,4-dioxane and 2 ml of dichloromethane and treated with 4.8 ml of hydrochloric acid (4M in dry dioxane). After standing at rt for 16 h the volatiles were removed in vacuo. The residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient) and 315 mg (73%) of the title compound were obtained as hydrochloride.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1CCCNC1
Reactant: CCCCBr
Product: CCCCN1CCCC(C)C1

Procedure:
The first N-substitution of 3-methylpiperidine was carried out using butyl bromide as an N-alkylating agent to form 1-butyl-3-methylpiperidine. An equimolar amount of butyl bromide was added dropwise to a solution of 3-methylpiperidine in methanol keeping the temperature at 20° C. by an ice-water bath. The mixture was hydrolyzed with potassium carbonate, extracted with ether, and dried over Na2SO4. The solution was fractionally distilled at reduced pressure and the fraction with by 195° C. was collected. 1H-NMR (300 MHz, CDCl3) δ 0.82 (d, 3H), 0.90 (t, 3H), 1.30 (m, 2H), 1.48 (m, 2H), 1.65 (m, 5H), 2.24 (m, 2H), 2.82 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:19][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11](=[O:27])[C:10]=2[CH:28]=1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CC(O)=O>[CH2:30]([N:16]1[CH2:17][CH2:18][C:13]2([N:12]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11](=[O:27])[C:10]3[CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=[CH:8][C:9]=3[O:19]2)[CH2:14][CH2:15]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(Cc1ccccc1)C1(CCNCC1)O2
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)N(Cc1ccccc1)C1(CCN(Cc3ccccc3)CC1)O2
Yield: 95 %

Procedure:
(E)-3-{1′-Benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester was obtained by reacting (E)-3-{3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (485 mg, 1.13 mmol, Intermediate 6) with benzyl bromide, according to the procedure described in Example 2, Step A, giving a white solid (544 mg, quantitative). The methyl ester (500 mg, 1.03 mmol) was hydrolyzed with HCl 20% and AcOH following the procedure described Example 55, Step B, giving (E)-3-{1′-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid as a white solid (500 mg, 95%). The resulting product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (228 mg, 40%). Finally, removal of the THP protecting group (177 mg, 0.312 mmol) following the procedure described in Example 1, Step C gave (E)-3-{1′-benzyl-3,4-dihydro-3-benzyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-N-hydroxy-acrylamide (150 mg, trifluoroacetate salt) after purification by preparative HPLC.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@@H:25]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:26]([OH:28])=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)[Br:37]>ClCCl.O>[BrH:37].[OH:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH:24][C@@H:25]([CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])(=[O:22])=[O:23])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N2CCN(c3ccc(S(=O)(=O)N[C@@H](Cc4ccccc4)C(=O)O)cc3)CC2)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Br
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(N2CCN(c3cccc(O)c3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of (S)-2-{4-[4-(3-methoxy-phenyl)-piperazin-1-yl]-benzenesulfonylamino}-3-phenyl-propionic acid (0.103 g, 0.000208 mol) in dichloro-methane (2 mL) at -78° C. under nitrogen was added dropwise a 1.0 M solution of boron tribromide in dichloromethane (1.0 mL, 0.0010 mol). The mixture was stirred for 15 minutes at -78° C. and then allowed to warm to +3° C. After 6 hours, the reaction mixture was diluted with water. The resulting suspension was stirred overnight. The solids were filtered off, washed with additional water, and dried in vacuo to give the title compound as an off-white solid; yield 0.069 g (69%), mp=229-230° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH2:5][CH2:6][CH2:7][N:8]=1.CC(C)([O-])C.[K+].[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][NH:35][C:36](=[O:49])[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45](OC)=[O:46])=[CH:39][CH:38]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>CN(C=O)C>[CH2:15]([O:22][C:23]([NH:25][C@@H:26]([CH2:34][NH:35][C:36](=[O:49])[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45](=[O:46])[NH:2][C:3]2[NH:8][CH2:7][CH2:6][CH2:5][N:4]=2)=[CH:39][CH:38]=1)[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC1=NCCCN1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.25 g (9.2 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride and 1.03 g (9.2 mmol) of potassium tert-butoxide were dissolved in 3 ml of absol. DMF and the mixture was stirred at RT for 30 min. 740 mg (1.53 mmol) of tert-butyl (2S)-2-benzyioxycarbonylamino-3-(4-(2-methoxycarbonylethyl)benzoylamino)propionate (Example 3c) in 1 ml of DMF were then added and the mixture was stirred at RT for 4h. It was adjusted to pH 4 using glacial acetic acid, the solvent was stripped off in vacuo, and the residue was chromatographed on silica gel (dichloromethane/methanol/glacial acetic acid/water (9/110.1/0.1)).