Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)OCC[O:11]2)=[CH:6][CH:5]=1.C(O)C.Cl>O.[OH-].[Na+]>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][C:10](=[O:11])[C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[CH2:19][CH2:20]2)[OH:32])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(CCCC2(c3ccc(F)cc3)OCCO2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(CCCN1CCC(C(O)c2ccc(Cl)cc2)CC1)c1ccc(F)cc1

Procedure:
Sodium borohydride (0.4 g., 0.01 mole) was added in small portions to a stirring solution of 2.2 g. (0.0052 mole) of 2-(p-fluorophenyl)-2-{3-[4-(p-chlorobenzoyl)piperidino]propyl}-1,3-dioxolane in 20 ml. of absolute ethanol. The reaction mixture was stirred until gas evolution ceased and then dilute hydrochloric acid was added dropwise until an acidic solution was obtained. After stirring overnight the mixture was diluted with water and basified with dilute sodium hydroxide. The free base was extracted into chloroform, the chloroform solution was washed with water, dried over magnesium sulfate, filtered, and the filtrate concentrated under vacuum. The residual oil crystallized on trituration with isopropyl ether to give 1.2 g. (60%) of a light brown solid which melted at 143°-146° C. Recrystallization of the solid from benzene-isooctane gave 0.8 g. of a white powdery solid which melted at 146.5°-147° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:22]1([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccccc5)cn4)CC3)nc2)cc1

Procedure:
Under nitrogen, to a solution of the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (200 mg, 0.585 mmol) synthesized in Reference Example 1 in ethanol-toluene (2.0 mL-2.0 mL) were added phenylboronic acid (130.0 mg, 1.07 mmol), tetrakis(triphenylphosphine)palladium (56.0 mg, 0.050 mmol) and a 2.0 M aqueous potassium carbonate (0.5 mL, 1.0 mmol), and the resulting mixture was stirred at 80° C. for 3 hours. After cooling, the organic layer was collected and the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield crude crystals. The crude crystals were recrystallized from chloroform-hexane to yield the title compound as slightly yellow needles (melting point: 221.0–222.0° C.) (61.0 mg, yield: 31%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[CH:8]=[CH:7]2.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][C:2]([F:16])([F:15])[F:1])[CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cc(OC(F)(F)F)ccc2[nH]1
Product: FC(F)(F)Oc1ccc2nc(Cl)ccc2c1

Procedure:
The title compound may be prepared in a manner analogous to Example 3, Step C, from the 6-trifluoromethoxy-1H-quinolin-2-one of Step C, and phosphorous oxychloride.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][C:7]1=2)=[O:4].[ClH:26]>CO.O1CCOCC1>[ClH:26].[CH3:1][O:2][C:3]([CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][NH:16][CH2:17][CH2:18][C:7]1=2)=[O:4].[ClH:26]
Reactant: COC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)Cn1c2c(c3ccccc31)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 5-methoxycarbonylmethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (377 mg, 1.09 mmol) was dissolved in methanol (15 mL). 4N HCl in 1,4-dioxan (1.5 mL) was added and the mixture stirred at room temperature overnight. The solution was concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give 5-methoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride as an off white solid (314 mg, 100% assuming HCl salt).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[CH2:57]([C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][CH:65]=1)[NH2:62])[CH3:58]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:62][C:61]3[CH:63]=[CH:64][CH:65]=[C:59]([CH2:57][CH3:58])[CH:60]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: CCc1cccc(N)c1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 37.5 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and COMU (68 mg, 0.158 mmol) in 1.5 mL DMF was stirred at room temperature for 2 minutes, then 3-ethylaniline (0.127 mL, 0.90 mmol) added and the reaction continued for 4 hours at room temperature. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed eluting with portions of CHCl3, then 1:1 CHCl3:EtOAc, and then 5% MeOH/CHCl3. The obtained solid was then triturated with an EtOAc/hexane mixture to give the title compound as a light beige solid (21 mg, 38%). 1H NMR (DMSO-d6) δ: 10.08 (s, 1H), 8.13 (s, 1H), 7.61-7.64 (m, 1H), 7.57-7.61 (m, 1H), 7.49-7.52 (m, 1H), 7.32-7.40 (m, 2H), 7.18-7.29 (m, 2H), 6.93-6.98 (m, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 2.61 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H)
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:15][CH2:16][C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:25][C:17]([F:26])([C:18]([F:23])([F:24])[C:19]([F:20])([F:21])[F:22])[CH2:16][CH2:15][C:4]([CH2:3][C:2]([F:13])([F:1])[C:9]([F:10])([F:11])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)F
Reactant: FC(F)(F)C(F)(F)C(F)(F)CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 0.8 %

Procedure:
In 50 ml of acetone, 3.2 g of 2-(2,2,3,3,3-pentafluoropropyl)malononitrile and 7.2 g of 5-iodo-1,1,1,2,2,3,3-heptafluoropentane were dissolved, 3.2 g of potassium carbonate was added and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture and the mixture was extracted with t-butyl methyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.05 g of 2-(3,3,4,4,5,5,5-heptafluoropentyl)-2-(2,2,3,3,3-pentafluoropropyl)malononitrile (hereinafter, referred to as the present compound (96)):
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=O)#[N:2].[OH-].[K+].[C-]#N.[K+].[N+:14]([C:17]1C=C[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)([O-])=O.[OH-].[Na+]>CN(C=O)C>[NH2:14][C:17]1[CH:18]=[CH:19][C:20]2[C:4](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:3]=1[C:1]#[N:2]
Reactant: O=[N+]([O-])c1ccc2ccccc2c1
Reactant: CCOC(=O)CC#N
Agent: [C-]#N
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
Ethyl cyanoacetate (111.0 g, 982 mmol) was added to a suspension of potassium hydroxide pellets (52.0 g, 789 mmol) and potassium cyanide (16.0 g, 246 mmol) in dry DMF (500 mL). This was stirred at ambient temperature for 30 minutes, then 85% 2-nitro naphthalene (40.0 g, 197 mmol) was added to the reaction mixture. After stirring at room temperature for 22 hours, the reaction was refluxed for 10 minutes, then 10% NaOH (300 mL) was added and refluxing was continued for an additional 2 hours. The resulting mixture was cooled and poured onto crushed ice and extracted with chloroform. The organic phase was washed with water followed with brine, then was dried (MgSo4), decolorized with activated carbon, and filtered through silica gel. The filtrate was concentrated and triturated first with ether and then with 1:1 ethyl acetate/hexane to give 23.0 g of 2-amino 1-naphthonitrile as a yellow solid. tert-Butyl nitrite (23.5 g, 205 mmol) was added dropwise to an ice-water cooled mixture of cupric chloride (20.3 g, 151 mmol) in a solution 2-amino-1-naphthonitrile (23.0 g, 137 mmol) in dry acetonitrile (250 mL). Gas evolution was controlled by the rate of addition of the tert-butyl nitrite. The resulting reaction mixture was stirred at 0° C. for 30 minutes, then at room temperature for 30 minutes. This was poured into cold, dilute aqueous HCl and the precipitate which formed was filtered, vacuum dried, and kugelrohr distilled (180° C., 3.5 torr) to give 15.5 g of white, crystalline 2-chloro-1-naphthonitrile, a 60% yield.
Reaction SMILES: NC1[C:7]([CH2:8][CH2:9][C:10]2[NH:19][C:13]3=[N:14][CH:15]=[C:16](Br)[CH:17]=[C:12]3[N:11]=2)=[C:6](C)[CH:5]=[CH:4]N=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:21][C:22]1[CH:23]=[C:24]([C:16]2[CH:17]=[C:12]3[N:11]=[C:10]([CH2:9][CH2:8][C:7]4[N:11]=[C:10]([NH2:19])[CH:9]=[C:5]([CH3:4])[CH:6]=4)[NH:19][C:13]3=[N:14][CH:15]=2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: Cc1ccnc(N)c1CCc1nc2cc(Br)cnc2[nH]1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4cc(Cl)cc(Cl)c4)cnc3[nH]2)c1
Yield: 61.7 %

Procedure:
The title compound is synthesized according to General Procedure A. 100 mg of 2-[2-(2-amino-4-methylpyridin-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine in 5.0 ml dioxane, 903 μl Na2CO3 solution, 65 mg of 3,5-dichlorophenylboronic acid, 13 mg of PdCl2(PCy3)2, 120° C. for 64 h. During extraction with 20 ml of CH2Cl2/H2O the title compound starts precipitating in the organic layer. Subsequently, 37 mg of the pure title compound can be obtained as a colorless powder after filtration and lyophilization from 2.0 ml dioxane and 1.0 ml water. M.p. 224° C. ESI-MS: 398.3, 400.2, 402.3 (MH+; 100%, 65%, 13%). TLC: Rf=0.24 (dichloromethane/methanol 10:1).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([Br:28])=[CH:26][C:25](I)=[C:24]([N:30]([CH3:32])[CH3:31])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:35](B1OC(C)(C)C(C)(C)O1)([CH3:37])=[CH2:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[C:27]([Br:28])=[CH:26][C:25]([C:35]([CH3:37])=[CH2:36])=[C:24]([N:30]([CH3:32])[CH3:31])[N:23]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)c1nc([C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)c(Br)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(C)c1cc(Br)c([C@@H]2CC[C@H]3[C@@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)OC(=O)N23)nc1N(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-iodopyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (50 mg, 0.075 mmol) in DMF (1 mL) was added isopropenylboronic acid pinacol ester (13.9 mg, 0.083 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (1.84 mg, 2.26 mmol) and potassium carbonate (0.5 M in water, 0.30 mL, 0.151 mmol). The system was stirred at 50° C. overnight before cooling and partitioning with water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated before purifying by column chromatography to yield (1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[3-bromo-6-(dimethylamino)-5-(prop-1-en-2-yl)pyridin-2-yl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (19 mg, 0.033 mmol). MS ESI calc'd. for C24H23BrF6N3O2 [M+H]+ 580.1, found 580.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][C:9]2=[O:16])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:16])[CH:10]=[CH:11][C:12]([CH:14]=[O:15])=[CH:13]2)=[CH:6][CH:7]=1
Reactant: O=c1ccc(CO)cn1-c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=Cc1ccc(=O)n(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 100 mL round-bottomed flask was charged with 1-(4-fluorophenyl)-5-(hydroxymethyl)pyridin-2(1H)-one (0.420 g, 1.92 mmol) and 15 mL of CH2Cl2. To this was added Dess-Martin Periodinane (1.02 g, 2.39 mmol). After stirring at rt for 30 min, 15 mL of satd aq sodiumthiosulfate soln and 15 mL of satd aq sodium bicarbonate soln were added. The mixture was extracted with CH2Cl2 (3×30 mL) and the combined extracts were dried and concentrated. The residue was purified by MPLC to give 1-(4-fluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarbaldehyde.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]2[N:5]([C:9]([C:12]3[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:64](O)(=[O:67])[C:65]#[CH:66]>C(Cl)Cl>[CH:19]([O:18][C:16]1[CH:17]=[C:12]([C:9]2[N:5]3[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:64](=[O:67])[C:65]#[CH:66])[C:4]3=[N:11][CH:10]=2)[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:29])([F:30])[F:28])=[O:24])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: C#CC(=O)O
Reactant: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(-c2cnc3c(CN)cccn23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)NCc1cccn2c(-c3cc(NC(=O)NCC(F)(F)F)cc(OC(C)C)c3)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a solution of 1-(3-(8-(aminomethyl)imidazo[1,2-a]pyridin-3-yl)-5-isopropoxyphenyl)-3-(2,2,2-trifluoroethyl)urea (26 mg, 0.062 mmol) in DCM (3 ml) was added DIEA (0.075 ml, 0.432 mmol) and HATU (35.2 mg, 0.093 mmol) and finally propiolic acid (4.95 μl, 0.080 mmol). Reaction was stirred for 30 minutes at room temperature. Reaction was loaded directly onto silica column and purified by flash chromatography (0-10% CH2Cl2/MeOH) to give the title compound (19 mg, 0.040 mmol, 65.0% yield) as an off white solid. MS (ES+) C23H22F3N5O3 requires: 473. found: 474 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.92 (s, 1H), 8.47 (d, J=6.8 Hz, 1H), 7.74 (s, 1H), 7.17 (d, J=1.9 Hz, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 4.69-4.58 (m, 2H), 3.93 (dd, J=9.7, 6.4 Hz, 2H), 2.72-2.64 (m, 1H), 1.30-1.19 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][N:8](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9][C:5]=2[CH:4]=[N:3]1.Cl>>[CH3:1][N:2]1[C:6]2[CH2:7][NH:8][CH2:9][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Agent: Cl
Product: Cn1ncc2c1CNC2
Reaction time: 1.5 h

Procedure:
1-Methyl-5-trityl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (670 mg) obtained in Step A above was treated with 4N hydrochloric acid (4 mL). After 1.5 h, the reaction mixture was concentrated. The residue was purified on a Biotage Horizon® system (silica, gradient 10-19% methanol containing 10% concentrated ammonium hydroxide in dichloromethane) to yield 1-methyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole. LC-MS 124.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20]Br>>[C:1]([O:5][C:6](=[O:16])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:20][CH2:19][CH2:18][Br:17])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCBr
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](O)CC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](OCCCBr)CC1

Procedure:
In analogy to examples 1.4 and 1.5, trans-(4-Hydroxy-cyclohexyl)-methyl-carbamic acid tert-butyl ester was reacted with 1,3-dibromopropane to yield trans-[4-(3-Bromo-propoxy)-cyclohexyl]-methyl-carbamic acid tert-butyl ester which was reacted with N-allylmethylamine to yield trans-(4-[3-(Allyl-methyl-amino)-propoxy]-cyclohexyl)-methyl-carbamic acid tert-butyl ester as colorless oil, MS: 341 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:13])=[NH:12].[Cl:14][C:15]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:16]=1[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20]>>[NH2:22][CH2:21][C:18]1[C:19]([NH2:20])=[N:12][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[N:13][C:17]=1[C:16]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:15]=1[Cl:14]
Reactant: N=C(N)c1ccc2ccccc2c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: NCc1c(N)nc(-c2ccc3ccccc3c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=394.9 (M+H+), was prepared from naphthalene-2-carboxamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]([Cl:16])[CH2:8][C:9]([Cl:15])([Cl:14])[C:10]([Cl:13])([F:12])[F:11])=[O:5])C.Cl>>[Cl:16][CH:7]([CH2:8][C:9]([Cl:14])([Cl:15])[C:10]([Cl:13])([F:11])[F:12])[CH2:6][C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)CC(Cl)CC(Cl)(Cl)C(F)(F)Cl
Agent: Cl
Product: O=C(O)CC(Cl)CC(Cl)(Cl)C(F)(F)Cl

Procedure:
303.9 g of 2,4,4,5-tetrachloro-5,5-difluoropentane-1-carboxylic acid ethyl ester and 900 ml of a 22% aqueous hydrochloric acid are heated at 95°-100° C. for 20 hours. After cooling, the oily suspension obtained is purified, in the customary manner, by means of an ether extraction, bicarbonate extraction and ether extraction of the acidified bicarbonate solution. The yield is 206.9 g (75% of theory of 2,4,4,5-tetrachloro-5,5-difluoropentane-1-carboxylic acid in the form of a clear liquid, which boils at 107°-108° C./25 Pa.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21](Br)([F:23])[F:22].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][C:40]([CH:43]=O)=[CH:41][N:42]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O.[Zn]>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][C:40]([CH:43]=[C:21]([F:23])[F:22])=[CH:41][N:42]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C=O)s2)CC1
Reactant: FC(F)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C=C(F)F)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 6.73 mmol triphenylphosphine in 13 ml N,N-dimethylformamide was added 6.73 mmol dibromodifluoromethane and the mixture was stirred at room temperature for 1 h. 3.36 mmol 4-(5-formyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was added and the mixture was then cooled to 0° C. 6.73 mmol zinc dust was added in small portions and stirring continued for 10 min at 0° C. The mixture was then allowed to warm to room temperature and stirring continued for a further 2 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 19%). MS (m/e): 332.3 (M+H+, 10%), 276.0 ([M+2H−tBu]+, 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]([CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:5])[CH3:3].O=[C:22]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C([BH3-])#N.[Na+].[ClH:40]>O.C(O)C>[ClH:40].[CH2:26]([O:25][C:23]([CH:22]([NH:1][C@H:2]([C:4]([N:6]([CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:5])[CH3:3])[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N(CCC(=O)O)C1Cc2ccccc2C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CCC(=O)O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
L-Alanyl-N-(indan-2-yl)-β-alanine (2.0 g) is dissolved in a mixture of 20 ml of water and 100 ml of ethanol, 10 g of ethyl 2-oxo-4-phenylbutyrate is added, and a solution of 0.94 g of sodium cyanoborohydride in 20 ml of ethanol is added dropwise over 2 hours. The mixture is stirred at room temperature for 3 hours and then adjusted to pH 4.0 with 10% hydrochloric acid, and the ethanol is distilled off under reduced pressure. The residue is extracted with 200 ml of ethyl acetate, washed with water and dried, and the ethyl acetate is distilled off under reduced pressure. The residue is dissolved in 2 ml of 20% ethanolic hydrochloric acid, 100 ml of ethyl ether is added, and the mixture is allowed to stand at room temperature. Thus is obtained 1.2 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(indan-2-yl)-β-alanine hydrochloride as colorless amorphous powder.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1[C:19]2[CH:18]([C:20]([NH2:22])=O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH4+].[OH-]>>[CH:16]1[C:17]2[CH:18]([C:20]#[N:22])[C:19]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:11][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)C1c2ccccc2Oc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1c2ccccc2Oc2ccccc21
Yield: 87.1 %

Procedure:
POCl3 (25 mL) was added to crystalline 9H-Xanthene-9-carboxamide [26] (1.5 g, 6.65 mmol) while stirring. The solution was then heated at reflux (45 min), when TLC showed complete absence of starting material. The solution was then poured into a mixture of crushed ice and NH4OH with vigorous stirring. The solution was stirred (15 min) and excess of NH4OH was added to keep the solution alkaline. The solid formed was extracted with ether (3×50 ml). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an yellow oil which crystallized immediately. The product was purified by mplc using pet. ether: acetone (8:2) as eluent to give 1.2 g (87%) 9H-Xanthene-9-carbonitrile as colorless needles, mp 97-98° C. (EtOH).