Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CCOCC>[C:36]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:38])[CH3:37]
Reactant: COc1cc2c(cc1OC)C(CC(c1ccccc1)c1ccccc1)NCC2
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(CC(c1ccccc1)c1ccccc1)N(C(C)=O)CC2
Reaction time: 2 h
Yield: 96 %

Procedure:
A stirred solution of 1-(2,2-diphenyleth-1-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.8942 g, 5.0720 mmoles) in methylene chloride (15 mL) at 0° C. was treated with triethylamine (0.707 mL, 1.5 equiv.) and acetic anhydride (0.844 mL, 1.5 equiv.). After 2 hours at room temperature, The mixture was diluted with ether and washed with 1M sodium hydroxide (2×), water, and brine. The organic phase was dried over sodium sulfate and evaporated to give the product as a colorless foam (2.0178 g, 96%). 1H-NMR (CDCl3) δ (approx. 1.8:1 ratio of rotomers) 1.65 (rotomer A, s, 3H), 1.96 (rotomer B, s, 3H), 2.35 (rotomer B, m, 1H), 2.54 (rotomer A, m, 1H), 2.67 (rotomer A, m, 1H), 2.80 (rotomers A & B, m, 1H), 2.94 (rotomer A, m, 1H), 3.21 (rotomer A, m, 1H), 3.43 (rotomers A & B, m, 1H), 3.77 (rotomer B, s, 3H), 3.88 (rotomers A & B, s, 3H), 3.92 (rotomer A, s, 3H), 4.03 (rotomer A, m, 1H), 4.12 (rotomer B, t, 1H), 4.60 (rotomer B, m, 1H), 5.68 (rotomer A, m, 1H), 6.38 (rotomer B, s, 1H), 6.53 (rotomer A, s, 1H), 6.60 (rotomer B, s, 1H), 6.62 (rotomer A, s, 1H), 7.32 (rotomers A & B, m, 10H). Mass spec. 416.4 (MH)+. Anal. Calc. for C27H29NO3-2/3H2O: C-75.85, H-7.15, N-3.28. Found: C-75.89, H-7.03, N-3.24.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].[F:13][C:14]1([F:32])[CH2:19][CH2:18][C:17]([CH2:30][NH2:31])([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:1]([C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:31][CH2:30][C:17]1([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)[CH2:18][CH2:19][C:14]([F:13])([F:32])[CH2:15][CH2:16]1)=[O:8])#[N:2]
Reactant: Cc1c(C#N)cccc1C(=O)O
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: Cc1c(C#N)cccc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 3-cyano-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=438.2, tR (minutes, Method D)=0.75
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Br)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 611.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[N:4][C:5]2[N:6]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[CH:11]=2)[C:7]=1Cl.[C:20]1([CH3:28])[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.C1COCC1.[Li+].[Cl-].C1COCC1.Cl[C:42](=[O:47])[C:43]([O:45][CH3:46])=[O:44]>C1COCC1.CCOCC.[Cu]Br>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[CH:11]=[C:5]3[N:4]=[C:3]([CH3:19])[C:2]([C:42](=[O:47])[C:43]([O:45][CH3:46])=[O:44])=[C:7]([C:23]4[CH:24]=[CH:25][C:20]([CH3:28])=[CH:21][CH:22]=4)[N:6]3[N:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc2cc(-c3cccc(Cl)c3)nn2c(Cl)c1Br
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24.6 %

Procedure:
To a stirred mixture of 6-bromo-7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (0.179 g, 0.5 mmol) and copper(I) bromide (0.036 g, 0.250 mmol) in THF (3 mL) was added dropwise over 10 min a pre-mixed solution of 1M p-tolylmagnesiumbromide/THF (3.00 ml, 3.00 mmol) and 0.5M LiCl/THF (6.00 ml, 3.00 mmol) at rt. After 2.5 h, methyl 2-chloro-2-oxoacetate (0.552 ml, 6 mmol) was added at once and stirred overnight at rt. Then, the reaction was diluted with Et2O (50 mL), quenched with Na2CO3 (1 mL), washed with 10 mL each water and brine, dried (Na2SO4), filtered and concentrated to give orange paste which was purified by prep-HPLC to afford methyl 2-(2-(3-chlorophenyl)-5-methyl-7-(p-tolyl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.103 g, 0.123 mmol, 24.53% yield) as yellow solid which is contaminated with impurity. 1H NMR (500 MHz, CDCl3) δ: 7.95 (d, J=0.9 Hz, 1H), 7.81 (td, J=4.4, 1.5 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.40 (d, J=7.6 Hz, 2H), 7.38-7.36 (m, 2H), 6.99 (s, 1H), 3.39 (s, 3H), 2.71 (s, 3H), 2.71 (s, 3H). LCMS (M+H) calcd for C23H19ClFN3O3: 420.11. found: 420.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11]C(=O)C(F)(F)F)=[C:4]([CH:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[C:3]=1[F:23].O1CCOCC1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH2:11])=[C:4]([CH:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[C:3]=1[F:23]
Reactant: O=C(Nc1c([N+](=O)[O-])cc(Br)c(F)c1C1CCCO1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1c([N+](=O)[O-])cc(Br)c(F)c1C1CCCO1
Yield: 98.6 %

Procedure:
A reaction flask was charged with N-(4-bromo-3-fluoro-6-nitro-2-tetrahydrofuran-2-yl-phenyl)-2,2,2-trifluoro-acetamide (18) (242.3 g, 604.1 mmol), 1,4-dioxane (1.212 L), and aqueous 2 M sulfuric acid (362.4 mL, 724.9 mmol), and stirred at reflux for 5 days (HPLC showed 98% conversion). The reaction mixture was allowed to cool, diluted with EtOAc, neutralized with saturated aqueous NaHCO3, separated the layers, and re-extracted the aqueous phase with EtOAc (2×). The combined organic phase was washed with brine (2×), dried over MgSO4, filtered and concentrated in vacuo giving 19 as a greenish brown solid (181.7 g, 94% yield; 95% HPLC purity). The product was carried to the next step without further purification. LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 305.20 (3.63 min). 1H NMR (300 MHz, CDCl3) δ 8.35 (d, J=7.3 Hz, 1H), 7.45 (s, 2H), 5.23-5.16 (m, 1H), 4.23-4.14 (m, 1H), 3.93-3.84 (m, 1H), 2.31-1.96 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:14])[NH:10][NH:11][C:12]=1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(O)(=O)C>CN(C)C=O.O>[C:21]([N:11]1[C:12]([CH3:13])=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:14])[NH:10]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1[nH][nH]c(=O)c1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
4-Benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one (1.00 g) was suspended in N,N-dimethylformamide (5 mL) at room temperature. In addition, potassium carbonate (0.441 g) was added to the suspension, and the mixture was stirred for 30 minutes. Acetic anhydride (0.570 g) was added to the mixture in a dropwise manner at room temperature. The mixture was stirred at room temperature overnight and at 50° C. for 2 hours. In addition, the mixed solution of glacial acetic acid (0.191 g) and water (5.0 g) was added to the reaction mixture under stirring at room temperature. After confirming the precipitation of the crystals, water (25 g) was added to the mixture under stirring. The crystals were collected by filtration, washed with water and dried under reduced pressure to give a white solid of 1-acetyl-4-benzyl-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.92 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[F:15][C:16]([F:36])([F:35])[C:17]1[CH:34]=[CH:33][C:20]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30](=O)[CH3:31])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:30]([CH3:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:20]3[CH:33]=[CH:34][C:17]([C:16]([F:15])([F:35])[F:36])=[CH:18][CH:19]=3)=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 36, Step 2, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-propan-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[NH:9][O:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:19])[NH:9][O:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CONC(=O)NCc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Yield: 100.5 %

Procedure:
According to the procedure described in the synthesis method of Compound VI-9, tert-butyl 2-(3-(4-chlorobenzyl)ureidooxy)acetate (Compound V-6)(47.2 mg, 0.15 mmol) was reacted with 4N HCl/dioxane (2 ml) to obtain the title compound (39 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][O:8][C:7](=[O:15])[CH2:6]2.[CH3:16][C:17]1[N:18]=[CH:19][S:20][C:21]=1[CH2:22][CH2:23]O.CC1N(CCCO)C2C=CN=CC=2N=1>>[CH3:16][C:17]1[N:18]=[CH:19][S:20][C:21]=1[CH2:22][CH2:23][O:15][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9][O:8]1.[CH3:6][CH2:7][O:8][CH2:9][CH3:10]
Reactant: COc1cc2c(cc1OC)CC(=O)OC2
Reactant: Cc1ncsc1CCO
Agent: Cc1nc2cnccc2n1CCCO
Product: CCOCC
Product: COc1cc2c(cc1OC)CC(OCCc1scnc1C)OC2
Yield: 9 %

Procedure:
O-2-(4-Methylthiazol-5-yl)ethyl-6,7-dimethoxyisochroman-3-ol ether was prepared by the procedure of Example 2 employing 6,7-dimethoxyisochroman-3-one in lieu of undecanoic-gamma-lactone and 2-(4-methylthiazol-5-yl)ethanol in lieu of 3-(2-methylimidazo[4,5-c]pyrid-1-yl)propanol.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[CH2:7][CH3:8].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:16]([N:14]1[CH:10]([O:9][CH2:6][CH2:7][CH3:8])[CH2:11][CH2:12][C:13]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCOC1CCC(=O)N1C(=O)c1ccccc1
Yield: 57.9 %

Procedure:
18.6 cm3 of a 1.5M solution of n-butyllithium in hexane is added to a solution of 4 g of 5-(1-propyloxy) pyrrolidin-2-one in tetrahydrofuran at -60° C., while maintaining the temperature between -55° C. and -60° C. After agitation for 15 minutes at -60° C. a solution of 3.93 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added at this temperature. After allowing the mixture to return to ambient temperature, the solvent is evaporated under reduced pressure. The residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 4 g of the expected product is obtained. b.p. =200° C. under 0.1 mbar.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=4)[CH2:16][NH:15][CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cccc(-c2noc(C3CNCC(c4ccc(C(F)(F)F)cc4)C3)n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.82 g (1.67 mmol) of the compound from Example 185A was initially charged in 13 ml of dichloromethane, and 1.3 ml (1.90 g, 16.78 mmol) of trifluoroacetic acid were added at RT. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 0.65 g (99% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:15]=[C:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[CH:17]1([N:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[C:14]([CH3:23])=[N:15]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: COCCN
Product: CCOc1cc(NCCOC)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 37 %

Procedure:
The same reaction procedure as in Example 16 was performed, except that the compound obtained in Example 116 was used in place of the compound obtained in Example 15, and methoxyethylamine was used in place of N-methylpiperazine. In this manner, 55 mg (37%) of the captioned compound was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CN(C=O)C.CCOCC>[F:10][C:9]([F:11])([F:12])[C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([NH:1][S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH2:7][CH2:6]1)([OH:17])[C:13]([F:14])([F:15])[F:16]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1CCC(C(O)(C(F)(F)F)C(F)(F)F)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=S(=O)(NC1CCC(C(O)(C(F)(F)F)C(F)(F)F)CC1)c1ccccc1
Reaction time: 1 h
Yield: 72 %

Procedure:
A solution of 100 mg (0.37 mmol) of the acetate salt of 2-(4-amino-cyclohexyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 5 mL of DMF was treated with 0.2 mL (1.16 mmol) of DIPEA and 0.144 mL (1.1 mmol) of benzenesulfonyl chloride. The mixture was stirred for 1 hr and distributed between a diluted aqueous solution of HCl and Et2O. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. Column chromatography on silica gel with EtOAc/heptane 1:1 gave 90 mg (72%) of N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide as a pink solid, MS: 404 (M−H)−.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([CH2:23][N:24]([CH3:26])[CH3:25])[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[NH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>CN(C=O)C.O1CCOCC1.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>[CH3:25][N:24]([CH2:23][C:21]1[N:20]=[N:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:33]4[CH:34]=[CH:35][C:30]([C:28]([NH2:27])=[O:29])=[CH:31][CH:32]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH:22]=1)[CH3:26]
Reactant: CN(C)Cc1cn(-c2ccc(Nc3ncc(Br)n4ccnc34)cc2)nn1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN(C)Cc1cn(-c2ccc(Nc3ncc(-c4ccc(C(N)=O)cc4)n4ccnc34)cc2)nn1
Yield: 6.8 %

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(4-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-amine (63 mg, 0.152 mmol), 4-(aminocarbonyl)phenylboronic acid (50.3 mg, 0.305 mmol) 1.5 M Na2CO3 (0.813 mL, 1.22 mmol) and Pd(PPh3)4 (44.0 mg, 0.0381 mmol) in (2:1) DMF-dioxane (1.8 mL). Purification of the crude material by Isolute FlashSilicaII Cartridge chromatography eluting with 95:5 DCM:NH3 (7M in MeOH) followed by reverse phase preparative HPLC, affords the title compound as a white solid (4.7 mg, 7%). LCMS: Rt 1.92 min (96%) m/z (APCI) 455 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.24 (6H, s), 3.61 (2H, s), 7.51 (1H, br s), 7.64 (1H, s), 7.80 (1H, s), 7.85-7.91 (4H, m), 8.08-8.12 (3H, m), 8.16 (1H, br s), 8.36 (2H, d), 8.66 (1H, s), 10.09 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][C:10]1([CH3:15])[O:14][CH2:13][CH2:12][O:11]1)[CH3:2].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C1COCC1.CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[CH2:7][CH2:8][CH2:9][C:10]1([CH3:15])[O:14][CH2:13][CH2:12][O:11]1)[CH3:2]
Reactant: CCOC(=O)CNCCCC1(C)OCCO1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN(CCCC1(C)OCCO1)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of 2-4 (24 g, 0.104 mol) in 100 mL THF were added a trace of DMAP, 20 drops of triethylamine, and BOC2O (23.8 g, 0.109 mol). After 4 h, evaporative removal of the solvent gave 2-5 as a colorless oil. TLC Rf =0.38 (silica, 30% ethyl acetate/hexane). 1H NMR (300 MHz, CDCl3, mixture of rotamers) δ 4.22 (m, 3H), 3.93 (m, 4H), 3.27 (m, 2H), 1.63 (m, 4H), 1.51 (s, 3H), 1.47 (s, 3H), 1.42 (s, 3H), 1.31 (s, 3H), 1.28 (m, 4H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:17]/[N+:14]([O-:16])=[O:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCOc1ccc(/C=C/[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 13 h
Yield: 75.7 %

Procedure:
A mixture of 4-butoxy-benzaldehyde (4.72 g, 26.5 mmol) described in Manufacturing Example 67-1-1, nitromethane (2.85 mL, 53 mmol), ammonium acetate (3.06 g, 39.8 mmol) and acetic acid (40 mL) was stirred for 13 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (4.44 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH2:11][CH2:12][OH:13])=[CH:9][N:8]([C@@H:14]3[O:29][C@H:28]([CH2:30][O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=4[Cl:40])[C@@H:17]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[C@@:15]3([CH3:41])[OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:62]1[C:66](=[O:67])[C:65]2=[CH:68][CH:69]=[CH:70][CH:71]=[C:64]2[C:63]1=[O:72].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([CH2:11][CH2:12][O:13][N:62]3[C:63](=[O:72])[C:64]4=[CH:71][CH:70]=[CH:69][CH:68]=[C:65]4[C:66]3=[O:67])=[CH:9][N:8]([C@@H:14]3[O:29][C@H:28]([CH2:30][O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=4[Cl:40])[C@@H:17]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[C@@:15]3([CH3:41])[OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(CCO)c2c(Cl)ncnc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(CCON2C(=O)c3ccccc3C2=O)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of the compound 2.6 (359.0 mg, 0.54 mmol) in THF (10 mL) were added triphenylphosphine (215.0 mg, 0.82 mmol) and N-hydroxyphthalimide (132.0 mg, 0.0.81 mmol) followed by diethylazodicarboxylate (DEAD) (153 μL, 0.88 mmol), and the solution was stirred overnight at room temperature. The reaction mixture was diluted by adding 10 mL of CH2Cl2 and 10 mL of water. The aqueous layer was extracted three times with CH2Cl2, dried over Na2SO4, filtered and evaporated. The product was purified by flash column chromatography using 15-20% EtOAc in hexanes as eluent gave the desired compound 2.7 (369 mg, 85%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[C:6]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2c(Cl)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2c(Cl)cccc2C1=O
Yield: 81 %

Procedure:
A solution of 14.0 g of 4-chloro-1-indanone, 17.3 ml of 3-buten-2-ol and 140 mg of p-toluenesulfonic acid in 140 ml of 2,2-dimethoxy-propane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). 15.2 g (81%) of (RS)-2-(2-buten-1-yl)-4-chloro-1-indanone were obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][NH:12][CH3:13].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:12]([CH3:13])[CH3:11])=[O:10])=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(Br)cn1

Procedure:
To a solution of 5-bromopyridine-2-carboxylic acid (1.5 g, 7.4 mmol), dimethyl amine (1.3 gm, 16 mmol), diisopropylethyl amine (excess) in DMF (10 mL) was added a solution of HATU in DMF (5 mL). After stirring the reaction for 14 hours at room temperature, the solvent was removed under reduced vacuum. The residue was taken up in ethyl acetate, washed with 1 N HCl (2×), brine (2×), 1 N NaOH (2×), brine (3×), dried over MgSO4, and concentrated. The crude was product was used in subsequent steps without further purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:29][CH:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1ccccc1F
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccccc1F

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(2-fluoro-phenyl)-C-phenyl-methylamine (CA [55095-24-4]).