Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:48])(=[O:47])[CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:48])(=[O:47])[CH2:41][CH2:42][CH2:43][C:44]([O-:46])=[O:45]
Reactant: O=C(O)CCCC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C([O-])CCCC(=O)[O-]
Temperature: 5 °C

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of glutaric acid (0.15 g, 1.14 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and subsequently cooled to 5° C. and kept at this temperature overnight leading to precipitation. The precipitate was filtered and the filter cake was dried at 60° C. in a vacuum oven over 2 days to give Nilotinib glutarate form III.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:21][C:22]3[NH:26][N:25]=[N:24][N:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1nnn[nH]1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1nnn[nH]1
Yield: 83.7 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and aminotetrazole (50 mg, 0.59 mmol) to give 170 mg of the title compound (84%): mp 246°~247° C.; 1H NMR (270 MHz, DMSO-d6) δ12.12 (bs, 1H), 12.08 (s, 1H), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 5.19~5.28 (m, 1H), 3.01 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.84 (dm, 1H, J=17.1 Hz), 2.66~2.75 (m, 2H), 2.12 (dm, 1H, J=13.5 Hz), 1.83~1.97 (m, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[C:19]1([S:25]([C:28]2[S:32][C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:25]([C:28]2[S:32][C:31]([N:33]3[CH2:38][CH2:37][N:36]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:35][CH2:34]3)=[N:30][CH:29]=2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccc3)s2)CC1
Yield: 47 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-benzenesulfonyl-thiazol-2-yl)-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 47%). MS (m/e): 550.2 (M+H+, 100%), 567.2 (M+NH4+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][C:10]([O:12]CC)=[O:11])=O)=[CH:5][CH:4]=1.Cl.O[NH2:19]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]2[NH:19][O:12][C:10](=[O:11])[CH:9]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(=O)o[nH]2)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To 110 ml of acetic acid were added 16 g (72 mmol) of ethyl 4-methoxybenzoylacetate and 5 g (72 mmol) of hydroxyamine hydrochloride, followed by stirring at 100° C. for 2 hours. The resulting mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Crystals thus precipitated were collected by filtration, washed with water and then dried under reduced pressure, whereby the title compound was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([CH3:23])[CH2:6][N:7]([C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[NH4+].[Cl-]>C(O)C.[Fe]>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([CH3:23])[CH2:6][N:7]([C:13]1[C:18]([NH2:19])=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CN(c1nc(Cl)ncc1N)C1CCCC1

Procedure:
Reaction of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propionic acid ethyl ester with NH4Cl and iron powder in ethanol gave 3-[(5-Amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propionic acid ethyl ester
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:4].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([C:36]#[C:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:30]=[CH:29]2.[BH4-].[Na+]>ClCCl.O.CO>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][N:46]([CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][O:39][CH2:38]/[CH:37]=[CH:36]\[C:31]1[CH:30]=[CH:29][C:28]2[C:33](=[CH:34][CH:35]=[C:26]([O:25][CH3:24])[CH:27]=2)[CH:32]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: COc1ccc2cc(C#CCOCCCCCCNCc3ccccc3)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1ccc2cc(/C=C\COCCCCCCN(Cc3ccccc3)CC(O)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A solution of N-[5-(bromoacetyl)-2-(phenylmethoxy)phenyl]methanesulphonamide (0.96 g), N-[6-[3-(6-methoxy-2-naphthalenyl)-2-propynyloxy]hexyl]benzenemethanamine (1.38 g) and DEA (0.47 g) in dichloromethane (22 ml) was stirred at room temperature under nitrogen for 22 h, diluted with water (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic extracts were dried and evaporated in vacuo to give an oil. The oil was dissolved in methanol (20 ml) and dichloromethane (20 ml) and sodium borohydride (0.25 g) were added portionwise to the solution at 0° C. under nitrogen. The solution was stirred at room temperature for 1 h, cooled to 0° C. and a further portion of sodium borohydride (0.1 g) added. The solution was stirred at room temperature for 30 min and then carefully diluted with water (10 ml) and evaporated in vacuo. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The aqueous phase was re-extracted with dichloromethane (100 ml) and the combined organic fractions dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System C (100:2:1) gave the title compound as a colourless oil (0.77 g), t.l.c. (System C 98:2:1) Rf 0.23.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])C1C=CC=CC=1>[C].[Pd].CO>[OH:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)COCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)COCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.1 %

Procedure:
A mixture of ethyl (2-benzyloxyethoxy)acetate (0.50 g, 1.88 mmol), 10% palladium-carbon (0.05 g) and methanol (10 ml) was stirred under a hydrogen atmosphere at room temperature for 5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 0.29 g of ethyl (2-hydroxyethoxy)acetate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH:13]1([C:16]2[CH:17]=[C:18]([CH3:28])[C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:19]3[C:18]([CH3:28])=[CH:17][C:16]([CH:13]4[CH2:14][CH2:15]4)=[CH:21][N:20]=3)[CH2:23][CH2:24]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Yield: 95.4 %

Procedure:
Using 4-bromo-2-fluorobenzoyl chloride (2.5 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (2.7 g) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Preparation Example 108, the title compound (4.2 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1.Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(F)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Br)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.94 (s, br, 1H), 7.68–6.64 (m, 12H), 5.12–5.04 (m, 1H), 3.68–3.52 (m, br, 2H), 3.01–2.82 (br, 2H), 2.78–2.58 (m, br, 4H), 2.57–2.38 (m, br, 2H), 2.05–1.80 (m, br, 6H), 1.64–1.38 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 581.0 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17](=[S:19])[N:16]([CH3:20])[C:15]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)=[CH:10][CH:9]=1.Br[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(C)=O>[C:28]([NH:27][C:23]1[CH:22]=[C:21]([C:15]2[N:16]([CH3:20])[C:17]([S:19][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:18][C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=2)[CH:26]=[CH:25][N:24]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1cc(-c2c(-c3ccc(F)cc3)[nH]c(=S)n2C)ccn1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCSc1nc(-c2ccc(F)cc2)c(-c2ccnc(NC(C)=O)c2)n1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
K2CO3 (3.1 mmol/0.34 g) is added to undissolved N-{4-[5-(4-fluorophenyl)-3-methyl-2-thioxo-2H-imidazol-4-yl]pyridin-2-yl}acetamide (2.23 mmol/0.8 g), and the mixture is then suspended in 100 ml of absolute acetone. Ethyl 3-bromopropionate (2.3 mmol/0.422 g) are then added, and the mixture is stirred at room temperature for 24 h. The mixture is then heated under reflux for 3 h, the precipitate is filtered off and the filtrate is concentrated under reduced pressure using a rotary evaporator. The oily residue is separated on a column (mobile phase: CH2Cl2/EtOH, 9.5:0.5).
Reaction SMILES: [F:1][C:2]([F:42])([C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1)[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][O:22]C3CCCCO3)=[O:20])[C:12](=[O:34])[CH:11]=2)=[CH:6][CH:5]=1.Cl.CO>ClCCl.O1CCOCC1>[F:42][C:2]([F:1])([C@H:35]1[CH2:36][CH2:37][C@H:38]([OH:41])[CH2:39][CH2:40]1)[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][OH:22])=[O:20])[C:12](=[O:34])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: C[C@@](CCn1ccc(-c2ccc(OC(F)(F)[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: C[C@@](CCn1ccc(-c2ccc(OC(F)(F)[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 0.33 h

Procedure:
To a stirred solution of (2R)-4-[4-{4-[difluoro(trans-4-hydroxycyclohexyl)methoxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (280 mg, 0.473 mM) in 2.3 mL of dichloromethane was added a solution of 4 M HCl in dioxane (0.120 mL, 0.473 mM). The reaction mixture was allowed to stir for 20 minutes before being treated with 0.5 mL of MeOH. Reaction was concentrated in vacuo and purified by reverse phase (Shimadzu) prep HPLC 35 mg, (14%). LCMS 529.1 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.30 (br. s., 2H) 1.40-1.54 (m, 2H) 1.64-1.74 (m, 3H) 1.99-2.14 (m, 4H) 2.31-2.42 (m, 1H) 2.51-2.67 (m, 1H) 3.09 (s, 3H) 3.45-3.62 (m, 1H) 3.87-4.02 (m, 1H) 4.23-4.34 (m, 1H) 6.70-6.75 (m, 1H) 6.78 (s, 1H) 7.21-7.33 (m, 2H) 7.65-7.74 (m, 3H)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:26][CH2:27][CH3:28])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:16]=2)=[N:7]1)[CH3:2].Br[C:30]1[CH:31]=[C:32]([NH:37][C:38](=[O:49])[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:40]=2)[CH:33]=[CH:34][C:35]=1[CH3:36].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:45]([C:41]1[CH:40]=[C:39]([CH:44]=[CH:43][CH:42]=1)[C:38]([NH:37][C:32]1[CH:31]=[CH:30][C:35]([CH3:36])=[C:34]([NH:11][C:10]2[N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:26][CH2:27][CH3:28])[N:7]=[C:8]([C:12]3[CH:13]=[N:14][N:15]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[CH:16]=3)[CH:9]=2)[CH:33]=1)=[O:49])([CH3:48])([CH3:46])[CH3:47]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C)c2)cc1Br
Reactant: CCOC(Cn1nc(-c2cnn(Cc3ccc(OC)cc3)c2)cc1N)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOC(Cn1nc(-c2cnn(Cc3ccc(OC)cc3)c2)cc1Nc1cc(NC(=O)c2cccc(C(C)(C)C)c2)ccc1C)OCC
Temperature: 150 °C

Procedure:
200 mg (0.44 mmol, purity 85%) of the compound from Example 2A and 199 mg (0.57 mmol) of the compound of Example 46A in 2.18 ml of 1,4-dioxane were degassed with argon. 9.9 mg (0.044 mmol) of palladium(II) acetate, 38.3 mg (0.066 mmol) of xantphos and 431 mg (1.32 mmol) of caesium carbonate were added and the mixture was heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 150° C. for 30 min. The reaction was then filtered through kieselguhr and the filtrate was concentrated. The residue was subjected to flash-chromatography on silica gel (mobile phase dichloromethane/ethyl acetate 1:1). The product fractions were concentrated under reduced pressure and the residue was dried. This gave 180 mg (63% of theory) of the title compound.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C2[N:28]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[NH2:28][C:19](=[O:21])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(N)=O
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a solution of N-Boc-O-benzyl-D-serine (510 mg, 1.72 mmol) and HOBt hydrate (317 mg, 2.07 mmol) in DMF (9 mL), EDC (432 mg, 2.25 mmol) was added. The mixture was stirred for 60 min. Then conc. NH4OH (0.600 mL, ˜8.40 mmol) was added. It was stirred for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-amino-3-(benzyloxy)-1-oxopropan-2-ylcarbamate (444 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:13]=2)=[CH:7][N:6]=1)(=[O:4])=[O:3]>C(O)C.O1CCCC1.[C].[Pd]>[CH3:1][S:2]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:13]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OC3CCOCC3)c2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OC3CCOCC3)c2)cn1
Temperature: 50 °C
Reaction time: 6 h
Yield: 100.7 %

Procedure:
To a solution of 2-(methylsulfonyl)-5-[4-nitro-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]pyridine (25.8 g) in ethanol (250 mL) and tetrahydrofuran (250 mL) was added 10% palladium carbon (3 g), and the mixture was stirred under hydrogen pressure of 0.5 MPa at 50° C. for 6 hr. Palladium carbon was removed, and the mixture was concentrated under reduced pressure to give the title compound (24 g, yield 100%) as a white powder.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:9]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][N:12]([CH:14]=[O:15])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[B-](F)(F)(F)F.C1CC=CCCC=C1.C1CC=CCCC=C1.[Rh].CC(C)=O>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:13][N:12]([CH:14]=[O:15])[CH2:11][CH2:10][N:9]1[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C1=CN(C=O)CCN1C(=O)C(F)(F)F
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: F[B-](F)(F)F
Solvent: C1=CCCC=CCC1
Solvent: CC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1CN(C=O)CCN1C(=O)C(F)(F)F
Reaction time: 11 h
Yield: 98.9 %

Procedure:
20.6 g (67.0 mmol) of 4-formyl-1-trifluoroacetyl-1,4,5,6-tetrahydropyrazine-2-carboxylic acid tert-butylamide, 26.2 mg (64.5 μmol) of bis(1,5-cyclooctadiene)rhodium(I) tetraflouroborate and 41.8 mg (77 μmol) of 1-[1(R)-(di-tert-butylphospino)ethyl]-2-(S)-(diphenylphosphino)-ferrocene were placed in a 160 ml autoclave under argon (S/C=1000). 70 ml of acetone (degassed) was added and hydrogenation was carried out for 11 hours at 100° C. under a hydrogen pressure of 13-10 bar. After distillation of the solvent, 20.5 g (99%) of the title compound was obtained in the form of a crystalline solid. After cleavage of the protecting groups, the enantioselectivity of the hydrogenation was determined by GC analysis, giving an ee of 96.4 percent. The melting point of the title compound was: 172.0° to 173.0° C. Other data concerning the title compound was:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:45]=[C:46]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[CH2:47][NH:48][C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)=[O:50]>CN(C=O)C.O>[F:21][C:11]([F:10])([F:22])[C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:66]2[CH2:65][CH2:64][N:63]([C:46](=[O:45])[CH2:47][NH:48][C:49]([C:51]3[CH:56]=[CH:55][C:54]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)=[CH:53][CH:52]=3)=[O:50])[CH2:68][CH2:67]2)=[O:18])=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(C(F)(F)F)cc2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 4-trifluoromethyl-benzoic acid (48.9 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 33 mg (25.9% yield) of biphenyl-4-carboxylicacid {2-[4-(4-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.96%, 1H NMR: (DMSO) δ 8.65 (t, 1H), 8.0 (d, 2H), 7.9-7.7 (m, 6H), 7.7-7.64 (d, 2H), 7.56-7.46 (t, 2H), 7.46-7.38 (t, 1H) 4.2 (s, 3H), 3.6 (d, 7H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[Cl:14][C:15]1[C:23]2[C:19](=[CH:20][N:21]([CH3:24])[N:22]=2)[C:18]([CH:25]=O)=[CH:17][CH:16]=1>O1CCCC1.[Cl-].[NH4+]>[Cl:14][C:15]1[C:23]2[C:19](=[CH:20][N:21]([CH3:24])[N:22]=2)[C:18](/[CH:25]=[CH:3]/[C:1]#[N:2])=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cn1cc2c(C=O)ccc(Cl)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1cc2c(/C=C/C#N)ccc(Cl)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (1.62 mL, 10.02 mmol) in tetrahydrofuran (70 mL) was added 60% sodium hydride (370 mg, 9.25 mmol) under ice-cooling, and the mixture was stirred at 0° C. for 30 min. To the mixture was added a solution of 7-chloro-2-methyl-2H-indazole-4-carbaldehyde (1.50 g, 7.71 mmol) in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=15/85→40/60) to give the title compound (1.45 g, yield 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Yield: 95 %

Procedure:
The title compound was prepared from 4-methoxy-benzene sulfonyl chloride and 1H-indole, according to Method A, described above. Yield 95%; mp 124-126° C.; 1H NMR (CDCl3) δ 7.90-7.93 (dd, J=8 Hz, 1H), 7.74 (d, J=9 Hz, 2H), 7.43-7.49 (m, 2H), 7.14-7.27 (m, 2H), 6.79 (d, J=9 Hz, 2H), 6.56-6.58 (dd, J=4 Hz, 1H), 3.41 (s, 3H); 13C NMR (CDCl3) δ 164.1, 135.2, 131.2, 130.1, 129.5, 126.7, 124.9, 123.6, 121.8, 114.8, 113.9, 109.3, 56.0; MS (AP+) m/z288.05 (M++1).