Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:20])([C:16]([F:19])([F:18])[F:17])[C:13](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:13]([C:12]([F:20])([F:11])[C:16]([F:19])([F:18])[F:17])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)C(F)(F)c1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (2.01 g; 11.4 mmoles) and 2,2,3,3,3-pentafluoro-propionic acid (1.80 mL; 17.3 mmoles) were suspended in 6N HCl (10 mL; 60 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (60 mL) and with ethyl acetate (60 mL), then sodium bicarbonate (7.59 g; 90.3 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (30 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 100% CH2Cl2) to yield the title compound as a light tan solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH2:13]([Mg]Br)[CH3:14].B(F)(F)F>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1([NH2:6])[CH2:14][CH2:13]1
Reactant: N#Cc1ccccc1C(F)(F)F
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 214.2 %

Procedure:
To a cold solution of 2-(trifluoromethyl)benzonitrile (1.0 g, 0.58 mmol) in diethyl ether (20 mL) was added titanium isopropoxide (2.0 g, 0.70 mmol) at −70° C. and ethyl magnesium bromide (4.30 mL, 12.86 mmol). The reaction mass was stirred at RT for 2-3 h. Followed by addition of boron trifluoride solution (1.5 mL) and continued stirring for 2 h at RT. The reaction mass was quenched in 1N HCl and basified with NaOH solution. The obtained crude product was further purified by column chromatography on silica gel eluting with 1% EtOAC:DCM eluent to afford 0.250 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.82-0.84 (s, 2H), 0.91-0.93 (br s, 2H), 2.24 (br s, 2H), 7.41 (t, J=6.6 Hz, 1H), 7.58-7.67 (m, 3H).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]=1)(=[O:3])[CH3:2].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:25][N:26]([CH3:28])[CH:27]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[C:8]([O:11][CH3:12])=[CH:7][N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)[N:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(C)=O)c1=O
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)C=CN(C)C)c1=O
Temperature: 25 °C
Yield: 89 %

Procedure:
A solution of 3-acetyl-5-methoxy-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (1.39 g, 4.45 mmol) in N,N-dimethylformamide dimethyl acetal (15 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in AcOEt. The organic solution was washed with half-saturated brine, and the aqueous solution was extracted with AcOEt four times. The combined organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from AcOEt to give the title compound (1.46 g, 89% yield) as orange crystals: mp 176-178° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.91 (3H, s), 3.14 (3H, s), 3.96 (3H, s), 5.80 (1H, d, J=13.2 Hz), 7.61-7.68 (2H, m), 7.80 (1H, br s), 7.84-7.90 (2H, m), 7.96 (1H, s). Anal. Calcd for C17H16F3N3O3: C, 55.59; H, 4.39; N, 11.44. Found: C, 55.32; H, 4.51; N, 11.30.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:5].[OH-].[Li+]>C1COCC1>[C:7]1([NH:6][C:4](=[O:5])[C:3]([OH:17])=[O:2])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(=O)Nc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(=O)Nc1cccc2ccccc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To N-Naphthalen-1-yl-oxalamic acid methyl ester (0.14 g, 0.61 mmol) stirring in THF (2 mL) was added 2 mL of a 1N lithium hydroxide solution. The reaction was heated to 50° C. and stirred for 2 h. The resulting mixture was concentrated in vacuo to afford a yellow residue that was acidified with 1N HCL. The resulting mixture was extracted with DCM (3×50 mL), dried over MgSO4 and concentrated under vacuum to afford crude product. The crude material was purified by flash chromatography (0-20% MeOH:DCM, silica gel) to afford the desired product (0.128 g, 98%) as a thick oil. Expected mass=215. Observed mass=216.
Reaction SMILES: O[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C(F)(F)F)c(C#N)c(O)n1
Product: Cc1cc(C(F)(F)F)c(C#N)c(Cl)n1
Reaction time: 2 h
Yield: 90 %

Procedure:
To 2-hydroxy-6-methyl-4-(trifluoromethyl)nicotinonitrile (1 g, 5 mmol) was added phosphoryl trichloride (15 mL). Then the mixture was heated to reflux and maintained at the same temperature with stirring for 2 hours. The resultant mixture was concentrated to give a residue and the residue was purified by chromatography (petroleum ether/ethyl acetate=1:1) to give 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (1 g, 90%). 1H NMR (300 MHz, CD3OD): δ 7.81 (s, 1H), 2.70 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH3:22]>>[OH:23][CH:20]([CH2:21][CH3:22])[CH2:19][NH:18][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12]
Reactant: CCC(O)CN
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Product: CCC(O)CNC(=O)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 54, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 1-aminobutan-2-ol (CAN 13552-21-1) as starting materials and isolated (65 mg, 32%) as colorless oil; MS (ESI, m/z): 305.5 (M+H+).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][CH:31]([CH3:33])[CH3:32]>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Product: CC(C)Cn1ccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 1-bromo-2-methylpropane. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.59-7.67 (m, 1H) 7.45-7.51 (m, 2H) 7.39-7.45 (m, 1H) 6.97-7.04 (m, 1H) 5.91-5.98 (m, 1H) 5.30-5.39 (m, 1H) 4.23-4.44 (m, 2H) 3.67 (s, 3H) 2.16-2.31 (m, 1H) 1.01 (s, 9H) 0.88-0.98 (m, 6H); LCMS (m/z) ES+=445 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+]>[Cu]>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 82 %

Procedure:
The same equipment and conditions as in example I were employed with the following charge: 20.4 grams (0.1 mole) iodobenzene, 27.4 grams (0.15 mole) diphenylamine, 16.8 grams (0.3 mole) potassium hydroxide flakes, 15.0 grams of copper powder and 30.0 milliliters of Soltrol® 170. The above-identified product was obtained as colorless crystals having a melting point of 125°-126° C. Yield 82%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[F:23])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=1[C:16]([F:19])([F:18])[F:17].Cl[C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[F:23])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:25]2[CH:26]=[C:27]3[N:34]([CH3:35])[CH2:33][CH2:32][N:28]3[C:29](=[O:31])[N:30]=2)=[CH:10][C:9]=1[C:16]([F:17])([F:18])[F:19]
Reactant: OCc1ccc(Oc2ccc(F)c(F)c2)c(C(F)(F)F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(F)c3)c(C(F)(F)F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (15.78 mg, 0.394 mmol), (4-(3,4-difluorophenoxy)-3-(trifluoromethyl)phenyl)methanol (80 mg, 0.263 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (48.8 mg, 0.263 mmol).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[C:52]([F:53])=[CH:51][C:48]([C:49]#[N:50])=[C:47]([F:54])[CH:46]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[C:52]([F:53])=[CH:51][C:48]([C:49]#[N:50])=[C:47]([F:54])[CH:46]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1cc(F)c(N)cc1F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3cc(F)c(C#N)cc3F)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-2,5-difluoro-benzonitrile according to procedure A followed by deprotection yielded the title compound as a white foam. MS (ESI): m/z=416.3 [M+H]+.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7](=O)([O:10]C)[O:8][CH3:9].[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][C:27](=[O:29])[CH2:28][CH:21]1[CH2:22][O:23][CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C=O)C>C1(C)C=CC=CC=1>[CH3:9][O:8][C:7]([CH:26]1[C:27](=[O:29])[CH2:28][CH:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])[CH:25]1[CH2:24][O:23][CH2:22]2)=[O:10]
Reactant: COC(=O)OC
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C1C(=O)CC2COCC1N2C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a suspension of t-BuOK (1.82 g, 16.26 mmol) in toluene (30 mL) was added dimethyl carbonate (0.98 g, 10.84 mmol). The mixture was heated at 90° C. for 5 mins, and then 7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (1.3 g, 5.4 mmol) was added. After the resulting mixture was stirred at 90° C. for 30 mins, the mixture was turned to brown gel, and then DMF (1.5 mL) was added to get a brown solution. The mixture was stirred at 90° C. for 3 hours. After it was cooled to room temperature, silica gel (25 g, 100200 mesh) was added and the solvent was concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc in PE 0%˜70%) to give 7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-6,9-dicarboxylic acid 9-tert-butyl ester 6-methyl ester (Compound AO) as light yellow oil (0.8 g, 49%). LC/MS: calc'd 300 (MH+), exp 300 (MH+); 1HNMR (400 MHz, CDCl3) δ 1.40-1.45 (m, 9H), 2.29-2.41 (m, 1H), 2.68-2.84 (m, 1H), 3.47-3.79 (m, 7H), 3.88-3.96 (m, 0.5H), 4.09-4.16 (m, 0.3H), 4.30-4.45 (m, 1H), 4.55-4.67 (m, 0.8H), 11.86 (s, 0.3H).
Reaction SMILES: [N:1]([CH:4]1[CH2:22][CH2:21][C:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[CH2:5]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[NH2:1][CH:4]1[CH2:22][CH2:21][C:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[CH2:5]1
Reactant: [N-]=[N+]=NC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NC1CCC2=C(C1)c1ccccc1Oc1ccccc12
Yield: 85 %

Procedure:
3.7 g of 2-azido-1,2,3,4-tetrahydro-tribenzo(b,d,f)-oxepine are added to a suspension of 3 g of lithiumaluminiumhydride in 100 ml of dry ether. The mixture is refluxed for one hour. After the mixture has been cooled down, 12 ml of water are added carefully after which the mixture is stirred for some time. The suspension is filtered and after that the filtrate is dried and evaporated to dryness. The residue is converted with maleic acid into the maleate. Melting point of the maleate: 198°-202° C. Yield 85%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[Br-].[CH2:13]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:14][CH3:15].C([Li])CCC.CCCCCC>>[CH2:7]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=1)[CH:13]=[CH:14][CH3:15]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC=CCc1cccc([N+](=O)[O-])c1
Yield: 96.7 %

Procedure:
Treatment of 3-nitrobenzaldehyde (8.2 g) with propyltriphenyl phosphonium bromide (25 g) and n-butyllithium in hexane (64.9 mmol), as described in Example 1a, gave 3-(2-butenyl)nitrobenzene (9.3 g), δ (360 MHz, CDCl3) 1.1 (3H, t, CH3), 2.4 (2H, m, CH2CH3). 5.8 (1H, m, =CH--CH2), 6.3 (1H, m, CH=CH2), 7.2 to 8.0 (4H, m, ArH). Treatment of the above 3-(2-butenyl)nitrobenzene (9.3 g) with hydrogen and palladium on carbon (10%, 0.93 g) as described in Example 1a, gave 3-butylaniline (7.0 g), δ (60 MHz, CDCl2) 0.9 (3H, t, CH3), 1.4 (4H, m, CH2CH2CH3), 2.5 (2H, t, ARCH2), 3.4 (2H, bs, NH2 ) and 6.2 to 7.0 (4H, m, ArH).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[C:21]([NH2:33])=[N:22][CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH:25]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=O.[NH3:34]>CO>[NH2:33][C:21]1[C:20]([C:7]2[S:6][C:5]([C:3]([NH2:34])=[O:2])=[C:9]([O:10][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH3:12])[CH:8]=2)=[CH:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[CH:23][N:22]=1
Reactant: N
Reactant: COC(=O)c1sc(-c2cc(-c3cccc(Cl)c3)cnc2N)cc1OC(C)c1ccccc1Cl
Solvent: CO
Product: CC(Oc1cc(-c2cc(-c3cccc(Cl)c3)cnc2N)sc1C(N)=O)c1ccccc1Cl
Temperature: 100 °C
Yield: 54 %

Procedure:
5-[2-Amino-5-(3-chloro-phenyl)-pyridin-3-yl]-3-[1-(2-chloro-phenyl)-ethoxy]-thiophene-2-carboxylic acid methyl ester (57 mg, 0.11 mmol, 1.0 Eq.) was suspended in 7M NH3 in MeOH (10 mL) and heated to 100° C. in a pressure tube for 3 days. The reaction was allowed to cool to ambient temperature, the solvent was removed in vacuo and the product purified by column chromatography (ISCO Companion™, 12 g column, 0-10% MeOH/DCM). The solvent was removed in vacuo and the compound was partitioned between DCM (10 mL) and water (10 mL). The organic layer was extracted with DCM (2×7 mL), dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid (20 mg, 0.08 mmol, 54%); 1H NMR (400 MHz, d-6 DMSO) δ 1.71 (3H, d), 6.04 (1H, q), 6.30 (2H, br s), 7.05 (1H, s), 7.12 (1 h, br s), 7.33-7.36 (2H, m), 7.40-7.48 (3H, m), 7.58-7.63 (2H, m), 7.70-7.72 (1H, br m), 8.35 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([O:28]C)=[O:27])[CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1>Cl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:21][CH2:22][C@H:23]([C:26]([OH:28])=[O:27])[CH2:24][CH2:25]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Agent: Cl
Product: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 37% HCl (30 mL) and methyl trans-4-(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (500.0 mg, 1.28 mmol) was stirred for 18 h at rt. The reaction mixture was then concentrated in vacuo, and the residue washed with diethyl ether (3×10 mL) and ethyl acetate (2×10 mL), then with ice-cold acetonitrile (10 mL) to afford 0.3 g of the desired product. 1H NMR (d6-DMSO, 400 MHz): δ 12.15 (br s, 1H), 11.69 (s, 1H), 8.45 (br s, 2H), 7.97 (d, J=6.4 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.50 (dd, J=8.0, 0.4 Hz, 1H), 7.19 (m, 1H), 7.13 (d, J=6.0 Hz, 1H), 7.06 (m, 1H), 6.83 (d, J=1.6 Hz, 1H), 3.27 (td, J=11.6, 3.2, 3.2 Hz, 1H), 2.33 (td, J=10.8, 3.2, 3.2 Hz, 1H), 2.05 (m, 4H), 1.73 (m, 2H) and 1.58 (mz, 2H). MS (ES+): m/z 376.05 [MH+].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9](O)[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:15]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCC(O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a stirred solution of the N-t-butyloxycarbonyl-aminopropanol (15.0 g, 65.6 mmol) in dichloromethane (260 mL) at 0° C. was slowly added Dess-Martin periodinane reagent (47.3 g, 111 mmol). The mixture was allowed to gradually warm to ambient temperature and stirred overnight. It was then partitioned between diethyl ether (600 ml) and 1N sodium hydroxide (300 mL) and shaken vigorously. The organic layer was dried and evaporated. The residue was chromatographed on silica, eluting with 25% ethyl acetate/hexane to afford the product as a thin, colorless oil (4.20 g, 28%). 1H NMR (300 MHz, CDCl3) δ 9.63 (s, 1 H), 5.17 (br s, 1 H), 3.30 (q, 2 H), 2.60 (t, 2 H), 1.33 (s, 9 H).
Reaction SMILES: [CH2:1]([N:4]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:20](=[O:42])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])=[NH:30])=[CH:25][CH:24]=3)[CH2:13][C@:14]([CH2:16][C:17]([OH:19])=O)([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3].[NH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH2:46]([O:45][C:43](=[O:44])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:20](=[O:42])[NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:31][C:32]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[NH:30])=[CH:27][CH:28]=3)[CH2:13][C@@:14]([CH3:15])([CH2:16][C:17](=[O:19])[NH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:8]2=[N:7][CH:6]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Nc1ccccc1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)O
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)Nc1ccccc1
Yield: 56.6 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 18 g, intermediate 39a (20 mg, 0.028 mmol) was coupled with aniline (3.39 mg, 0.036 mmol) to provide 12.4 mg (57%) of intermediate 40a. MS (ESI) 782.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([F:33])[CH:26]=1>>[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])=[C:27]([F:33])[CH:26]=1
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)c1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 4-bromomethyl-3-fluoro-benzoic acid methyl ester analogous to Example 1 to afford 4-{[(4-chloro-benzenesulfonyl)-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester: MS: m/e=504.9 (MH+), 522.1(MNH4+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26])=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=[O:6].[BH4-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)CCCCc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccc(CCCCCO)cc2)nc1)c1ccc(Cl)c(Cl)c1

Procedure:
To a solution of ethyl 5-{4-[5-(3,4-dichloro-benzoylamino)pyridin-2-yloxy]phenyl}pentanoate (8.79 g, 18.0 mmol) in THF (140 mL) was added sodium borohydride (3.14 g, 144 mmol), and the resulting solution was refluxed for 3 hours under a nitrogen atmosphere. The resulting reaction solution was cooled with ice, and treated with 1 N hydrochloric acid. The resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2), to thereby yield 7.07 g of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH2:18])=[N:14][NH:15]2)=[CH:11][CH:10]=1>N1C=CC=CC=1>[F:20][C:8]([F:7])([F:19])[C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH:18][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])=[N:14][NH:15]2)=[CH:11][CH:10]=1
Reactant: Nc1n[nH]c2cc(C(F)(F)F)ccc12
Reactant: C/C=C/C(=O)Cl
Solvent: c1ccncc1
Product: CC=CC(=O)Nc1n[nH]c2cc(C(F)(F)F)ccc12
Reaction time: 17 h

Procedure:
0.23 cm3 of crotonyl chloride is added to 500 mg of 6-trifluoro methyl-1H-indazole-3-amine, prepared as described in patent U.S. Pat. No. 3,133,081, in 10 cm3 of pyridine, cooled to about 10° C. The temperature is allowed to return to about 19° C. over 17 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 25 cm3 of tetrahydrofuran, 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 25 cm3 of distilled water. The combined organic phases are dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume) and collecting 30 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 30 cm3 of diisopropyl ether and then filtered off on a sinter funnel. After drying (90 Pa; 45° C.), 41 mg of N-[6-(trifluoromethyl)-1H-indazol-3-yl]-2-butenamide (E form) are obtained in the form of a white solid melting at 208° C.