Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:20]#[N:21])=[C:4](OC)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)#[N:2].O.[NH2:23][NH2:24].O>C(O)C>[NH2:2][C:1]1[C:3]([C:20]#[N:21])=[C:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)[NH:24][N:23]=1
Reactant: NN
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Solvent: O
Solvent: CCO
Product: N#Cc1c(N)n[nH]c1-c1ccc(Oc2ccccc2)cc1

Procedure:
1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (22.5 g) and 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[NH4+:14].[OH-]>CN(C)C=O.O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:14])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Br)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc([N+](=O)[O-])cc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
1.3 g (0.00526 mol) of 6-bromo-4-nitropyridine-2-carboxylic acid were dissolved in 10 ml of dimethylformamide, treated at 5° C. with 0.94 g (0.0058 mol) of 1,1-carbonyldiimidazole and subsequently stirred at room temperature for 3 hrs. Then, 40 ml of 25% NH4OH in water was added thereto and the mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned in water and dichloromethane and the organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. There were obtained 1.1 g (85%) of 6-bromo-4-nitropyridine-2-carboxamide as white crystals; m.p.: 179-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([Cl:15])=[O:6]
Reactant: COc1cccc(C)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1cccc(C)c1C(=O)Cl

Procedure:
2-Methoxy-6-methyl-benzoic acid (21.4 g, 0.129 mol) was refluxed for 3 hours in 230 mL thionyl chloride. Excess thionyl chloride was removed under reduced pressure. Co-evaporation of the residue with toluene gave 23.8 g of 2-methoxy-6-methyl-benzoyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)(=[O:3])[CH3:2].[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][C:23]=1[F:32]>>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][C:23]=1[F:32])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(C)(O)c1ccc(CN)c(F)c1
Reactant: CC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Product: CC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2F)c1

Procedure:
Prepared from 2-(3-Acetyl-phenoxy)-nicotinic acid and 2-(4-Aminomethyl-3-fluoro-phenyl)-propan-2-ol. mp 68-70° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:19]=2)=[CH:11][C:10]=1[Cl:27])C1C=CC=CC=1.B(F)(F)F.CCOCC.C(OCC)C>C(S)CCCCCCCCCCC>[Cl:27][C:10]1[CH:11]=[C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[N:19]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Clc1cc(-c2nc(CN3CCCCC3)co2)ccc1OCc1ccccc1
Agent: CCCCCCCCCCCCS
Agent: FB(F)F
Solvent: CCOCC
Product: Oc1ccc(-c2nc(CN3CCCCC3)co2)cc1Cl
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 1-({2-[4-(benzyloxy)-3-chlorophenyl]-1,3-oxazol-4-yl}methyl)piperidine i61 (0.3 g, 0.78 mmol, 1 eq) in dodecanethiol (5 ml) is added dropwise boron trifluoride diethyl etherate (1.59 ml, 12.54 mmol, 48 eq). The mixture is stirred at room temperature for 60 h. Diethyl ether is poured onto the mixture and the solid that precipitates is filtered off and recrystallized from diethyl ether to give 150 mg of 2-chloro-4-[4-(piperidin-1-ylmethyl)-1,3-oxazol-2-yl]phenol i66.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:26]=3)[CH2:21][CH2:20]2)=[O:14])[CH2:10][CH2:11]1
Reactant: O=C(O)C1(c2ccc(Cl)cc2Cl)CC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4Cl)CC3)CC2)c1

Procedure:
Example 41 was prepared from 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.49 (s, 1H), 7.44 (d, 1H, J=2.0 Hz), 7.35 (s, 1H), 7.28–7.19 (m, 3H), 6.92 (d, 1H, J=7.6 Hz), 5.69–5.62 (m, 1H), 3.26 (q, 2H, J=6.7 Hz), 2.89–2.82 (m, 2H), 2.54 (quintet, 1H, J=6.7 Hz), 2.47–2.37 (m, 1H), 2.32–2.26 (m, 3H), 1.97–1.88 (m, 2H), 1.79–1.69 (m, 4H), 1.66–1.56 (m, 4H), 1.24 (d, 6H, J=6.7 Hz), 1.05–1.01 (m, 1H); ESMS m/e: 516.2 (M+H)+; Anal. Calc. for C28H35Cl2N3O2.0.048 CHCl3: C, 64.51; H, 6.76; N, 8.05. Found: C, 64.51; H, 6.60; N, 8.15.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=2)[NH:31][C:30]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:55](Cl)([O:57]C(=O)OC(Cl)(Cl)Cl)Cl>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:47])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([N:38]=[C:55]=[O:57])[CH:36]=2)[NH:31][C:30]=1[C:39]1[CH:40]=[C:41]([CH3:46])[CH:42]=[C:43]([CH3:45])[CH:44]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:20])=[O:21])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N=C=O)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Reaction time: 0.33 h
Yield: 243.8 %

Procedure:
To a solution of {2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}-[4-(4-amino(dimethanesulfonyl)phenyl)butyl]carbamic acid tert-butyl ester (120 mg in 8 mL dry methylene chloride) at 0° C. was added 0.040 mL pyridine followed by 18.2 mg triphosgene and the mixture stirred at low temperature. After 20 minutes, 0.025 mL triethylamine was added and after another 10 minutes the mixture was applied to a silica gel column for purification by flash chromatography (hexane:ethyl acetate, 2:3) to give the title compound (106 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])=[N:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.CC([O-])(C)C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:7][N:6]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(Cl)cn1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(N2CCOCC2)cn1
Temperature: 110 °C

Procedure:
2-[4-(5-chloropyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole (58 mg, 0.17 mmol), morpholine (18 μL, 0.21 mmol), Pd(OAc)2 (0.38 mg, 0.0017 mmol), 1,1′-biphenyl-2-yl[di(tert-butyl)]phosphine (1.0 mg, 0.0034 mmol), and NaOtBu (23 mg, 0.24 mmol) were combined in a sealable tube evacuated and backfilled with argon. Toluene (800 μL) was added and the mixture was degassed with a stream of argon for 5 min. The tube was sealed and the mixture was heated to 110° C. for 18 h. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford 2-[3-methoxy-4-(5-morpholin-4-ylpyridin-2-yl)phenyl]-1,3-benzoxazole as a yellow solid. The freebase was dissolved in Et2O/CH2Cl2 and treated with 1N HCl in Et2O. Resulting yellow solid was filtered and dried under high vacuum to afford the desired 2-[3-methoxy-4-(5-morpholin-4-ylpyridin-2-yl)phenyl]-1,3-benzoxazole hydrochloride as a yellow solid: 1H NMR (CD3OD, 300 MHz) δ 8.33–8.30 (d, 1H), 8.20–8.09 (m, 2H), 8.08–8.02 (m, 2H), 7.87–7.77 (m, 2H), 7.75–7.71 (m, 1H), 7.53–7.42 (m, 2H), 4.10 (s, 3H), 3.89 (t, 4H), 3.49–3.47 (t, 4H). MS (ESI) 388 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14](=[O:16])[CH3:15].B(Cl)(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:6]=[CH:5][C:4]=1[C:14](=[O:16])[CH3:15]
Reactant: COc1cc(OC(F)(F)F)ccc1C(C)=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC(=O)c1ccc(OC(F)(F)F)cc1O
Temperature: 0 °C
Yield: 96.8 %

Procedure:
A solution of 1-(2-methoxy-4-(trifluoromethoxy)phenyl)ethanone (17.8 g, 76.0 mmol) in CH2Cl2 (178 mL) was cooled to −25° C. and boron trichloride (91.0 mL of a 1.0 M solution in CH2Cl2, 91 mmol) was added dropwise keeping the internal temperature ≦−18° C. Following addition, analysis by LCMS indicated complete reaction. The reaction mixture was poured into ice (75 g) and partitioned. The organic layer was washed with water (50 mL), dried (Na2SO4), filtered, and concentrated to give 16.2 g (73.6 mmol, 97% yield) of the title compound. MS (DCI/NH3) m/z 238 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH2:5]O.BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[N:7]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[O:16][CH:5]=1)=[O:17]
Reactant: COC(=O)C(CO)NC(=O)c1cccc(Cl)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Product: COC(=O)c1coc(-c2cccc(Cl)c2)n1
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of 2-(3-chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 29.6 mmol) in CH2Cl2 at −20° C. was added dropwise De-oxofluor (7.2 g, 32.6 mmol). After stirring at this temperature for 30 min, BrCCl3 (3.6 g, 18.1 mmol) was added dropwise followed by DBU (2.79 g, 18.1 mmol). The mixture was then stirred at 2-3° C. for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate. The organic extract as then washed with brine and dried over Na2SO4 (anhydrous). Purification was performed by flash column chromatography on silica gel using ethyl acetate in hexanes as eluant to afford 2-(3-chloro-phenyl)-oxazole-4-carboxylic acid methyl ester (4.1 g, 59%) as a yellow solid.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@@H:15]3[CH2:14][CH2:13][C:12](=[O:19])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@@H:15]3[CH2:14][CH2:13][CH:12]([OH:19])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@@H]3[C@H]1CC2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(O)CC[C@@H]3[C@H]1CC2
Reaction time: 0.28 h

Procedure:
To estra-4,16-dien-3-one, (1) (87.2 mg, 0.340 mmol) in 1.7 mL of anh. ether was added lithium aluminum hydride (15.0 mg, 0.395 mmol) and the suspension was stirred 17 min. Reaction was then agitated 10 min. with 0.50 g of sodium sulfate decahydrate and filtered through Celite. The residue was washed with three 10 mL portions of ether and the combined filtrates were concentrated under reduced pressure. Preparative TLC (5% ethyl acetate/dichloro-methane on silica gel) gave crude product (50.0 mg) as a yellow resin. This could be rechromatographed until sufficiently pure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CC(N2CCOCC2)CCN1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCOCC3)CC2)cc1

Procedure:
The compound was prepared from 4-piperidin-4-yl-morpholine (Example 4) and 4-fluoro-nitrobenzene (Aldrich) following the procedure used in Example 1. MS (m+H)+: 292.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[O:4][N:3]=1.[H][H]>[Pt](=O)=O.C(O)C>[NH2:3][C:2]([CH3:1])=[CH:6][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=1)=[O:4]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)on1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(N)=CC(=O)c1ccc(C(F)(F)F)cc1

Procedure:
3-Methyl-5-[4-(trifluoromethyl)phenyl]isoxazole (1.8 g, 7.92 mmol) is introduced into 20 ml of ethanol, platinum(IV) oxide catalyst (180 mg) is added, and the mixture is then hydrogenated under atmospheric pressure hydrogen for 12 h. The catalyst is filtered off, and the filtrate is concentrated. 1.72 g (94% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH:30]([CH3:32])[CH3:31])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:33][CH3:34])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH:30]([CH3:31])[CH3:32])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:33][CH3:34]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)oc1C(C)C
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1C(C)C
Yield: 96.1 %

Procedure:
The same operation as in Example (95b) was performed using butyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-isopropyl-1,3-oxazole-4-carboxylate obtained in Example (111b) (0.45 g, 0.95 mmol), 10% Pd/C (0.2 g) and methanol (3 mL), to obtain 0.31 g of the title compound as a yellow oily substance (96%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11](OCC)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].C([Al+]CC(C)C)C(C)C.O.[Cl-].[Na+]>C1COCC1>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(N)sc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2ccc(CO)cc2s1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
50 g (0.225 mol) of ethyl 2-aminobenzothiazole-6-carboxylate are suspended in 1,000 ml of THF, cooled to -70° C., and 562.5 ml (0.675 mol) of diisobutylaluminum hydride (DIBAL, 20% strength in toluene, 1.2 molar) are slowly added dropwise under nitrogen. The reaction solution is stirred at -70° C. to -40° C. overnight and then without cooling for a further 3 hours. Then it is cooled to -70° C., 61.5 ml of water are added dropwise (vigorous exothermic reaction), and the mixture is allowed to reach room temperature. 305 ml of saturated sodium chloride solution are added, and the mixture is stirred at 20° C. for 1 hour. Precipitated aluminum hydroxide is filtered off with suction and washed with THF, and the filtrate is evaporated to dryness (36 g). The residue is dissolved in boiling ethanol, some insolubles are filtered off, and the filtrate is evaporated to dryness.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.P(Cl)(Cl)(Cl)=O>>[CH:4]1[N:3]=[CH:1][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: O=CNCc1ccccn1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccn2cncc2c1
Temperature: 25 °C

Procedure:
To 13.6 g. of 2-formamidomethylpyridine in a round-bottom flask is added 25 ml. of phosphorous oxychloride. Following the exothermic reaction, the reaction mixture is cooled to room temperature, and quenched on crushed ice. The aqueous mixture is treated with sufficient 20% aqueous sodium hydroxide solution to provide a pH of 9-10, and the liberated product extracted into chloroform (3 × 300 ml.). The extracts are combined, dried over sodium sulfate and concentrated to a light brown oil, 14.0 g.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[C:9]([Cl:19])=[C:10]2[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]2=[N:12][CH:13]=1)(C)(C)C.[H-].[Na+].IC>CN(C=O)C>[Cl:19][C:9]1[C:8]([NH:7][CH3:6])=[CH:13][N:12]=[C:11]2[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:10]=12
Reactant: CCn1ncc2c(Cl)c(NC(=O)OC(C)(C)C)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1ncc2c(Cl)c(NC)cnc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a solution of (4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-carbamic acid tert-butyl ester (3.3 g, 11.1 mmol) in DMF (50 mL) at 0° C. was added NaH (0.694 g, 50% purity, 14.5 mmol). After 20 minutes, iodomethane (2.37 g, 16.7 mmol) was added and the temperature raised to RT. The reaction was quenched by addition of H2O and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4, and concentrated under vacuo to give a crude intermediate which was used directly in the next step without further purification. This residue as dissolved in CH2Cl2 (50 mL) and TFA (10 mL) was added. The reaction mixture was heated at 30° C. for 3 hours, diluted with CH2Cl2 (100 mL) and aqueous NaOH (1N) was added until pH reached 8. The organic phase was dried over Na2SO4, concentrated under vacuo to give the title product 2.24 g with high purity (no further purification needed) (96%) as a light yellow solid. ES-MS m/e: 211.2 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]([O:24][CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][C:29]([NH2:32])=[N:28]1)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:32][C:29]2[CH:30]=[CH:31][N:27]([CH2:26][CH2:25][O:24][CH3:21])[N:28]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Reactant: CC(C)OCCn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 9, 94 mg, 0.35 mmol) and 1-(2-isopropoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 101, 70 mg, 0.41 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.18 g, 0.41 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) dropwise and the resulting solution stirred at room temperature for 4 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (25 mL), a saturated sodium bicarbonate solution (25 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-12 g column, 50% ethyl acetate/hexane) to afford (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (110 mg, 75%) as an off white solid: [α]31D=−50.6°, (c=0.36, chloroform); HR-ES(+) m/e calcd for C24H32N4O3 [M+H]+ 425.2547, observed 425.2547; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-2.18 (m, 17H), 3.40-5.25 (m, 8H), 6.39 (d, J=2.11 Hz, 1H), 7.26-7.91 (m, 5H), 10.86 (s, 1H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1F
Yield: 57 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and 2-fluoro-phenylhydrazine according to the method described for Example 1 in 57% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=3[Cl:27])[C:14](=[O:29])[NH:13][C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44]Cl>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=3[Cl:27])[C:14](=[O:29])[N:13]([CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])[C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])cc2Cl)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])cc2Cl)cc1
Yield: 72.8 %

Procedure:
970 mg of (-)-cis-2-(4-methoxyphenyl)-3-(2-chloro-4-nitrobenzoyloxy)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 15 ml of acetone, and 690 mg of potassium carbonate and 375 mg of 2-(dimethylamino)ethyl chloride hydrochloride are added thereto. The mixture is refluxed for 6 hours under stirring. After the reaction, the mixture is evaporated under reduced pressure to remove solvent. Ethyl acetate is added to the residue, and the mixture is washed with water. The ethyl acetate solution is dried and evaporated under reduced pressure to remove solvent. The residue is dissolved in ethanol under heating, and the mixture is allowed to stand. Crystalline precipitates are collected by filtration and dried, whereby 810 mg of (+)-cis-2-(4-methoxyphenyl)-3-(2-chloro-4-nitrobenzoyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as pale yellow needles. Yield: 73%.