Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1I.[C:17]([Zn]C#N)#[N:18]>CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18]
Reactant: FC(F)(F)Cc1cnc2c(I)c(Cl)ccn12
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)ccn2c(CC(F)(F)F)cnc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 142.5 %

Procedure:
A 2.0-5.0 mL microwave vial was charged with 7-chloro-8-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (30 mg, 0.083 mmol) dissolved in DMF (832 μl). To that stirring solution was added dicyanozinc (5.86 mg, 0.050 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (28.8 mg, 0.025 mmol). The vial was sealed and degassed using sonication and ultra pure argon for 1 min. After which the vial was placed into a reaction block preheated to 120° C. After 5 hours, LCMS showed a good proportion of desired product by mass (m/z=260 [M+H]+Methanol/Water/Ammonium Acetate Phenomenex Luna C18, 30×2 mm, 3u ES+/−). The mixture was cooled to rt and diluted with sat'd sodium bicarbonate and EtOAc. The organic was washed with brine, dried with magnesium sulfate, concentrated under reduced pressure, and purified by flash chromatography: (4 g, equilibrated with none, loaded with DCM, initial waste: 0 mL, fraction size: 12 mL 16×100 mm, and eluted with EtOAc in hexanes 0% [20 mL], 0-100% [120 mL]). Collected fractions to give 7-chloro-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine-8-carbonitrile (18.5 mg, 86% yield) as a plaque white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.16 (d, J=7.3 Hz, 1H), 7.78 (s, 1H), 7.06 (d, J=7.3 Hz, 1H), 3.78 (q, J=9.8 Hz, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:16][C:17]1[C:22]([N:23]2[CH2:28][C@@H:27]3[CH2:29][C@H:24]2[CH2:25][NH:26]3)=[CH:21][CH:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:8][CH:2]([CH3:1])/[CH:3]=[CH:4]/[C:5]([N:26]1[CH2:25][C@@H:24]2[CH2:29][C@H:27]1[CH2:28][N:23]2[C:22]1[C:17]([CH3:16])=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7]
Reactant: Cc1ncccc1N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1N1C[C@@H]2C[C@H]1CN2C(=O)/C=C/C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
(E)-4-Methylpent-2-enoic acid (57 mg, 0.5 mmol) was dissolved in dichloromethane (2 ml), oxalyl chloride (42 μl, 0.5 mmol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of (1S,4S)-5-(2-methyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane hydrochloride (66 mg, 0.3 mmol) in DCM (2 ml). DIPEA (175 μl, 1 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 59 mg of a solid (0.21 mmol, 69%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)C.O.Br[CH2:18][CH2:19][CH2:20][OH:21]>O.ClCCl>[N:7]1([CH2:18][CH2:19][CH2:20][OH:21])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: OCCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: OCCCN1CCCCC1
Reaction time: 20 h

Procedure:
A solution of potassium carbonate (24.9 g) and piperidine (130 mL) in 1:1 ethanol-water (130 mL) was treated with 3-bromopropan-1-ol (25.0 g). The resulting mixture was stirred vigorously for 20 h. Dichloromethane (200 mL) and water (50 mL) were added and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic extracts were dried (magnesium sulfate) and evaporated in vacuo. Kugelrohr distillation of the residue (5-10 mm Hg, 120° C.) gave the title compound as a colorless oil (13.9 g).
Reaction SMILES: N(CCO)CCO.CCOCC.[CH2:13]([CH:15]([C:19]([CH3:21])=[O:20])[C:16]([OH:18])=[O:17])C.[N+]([O-])([O-])=O.[Ag+:26]>O>[CH3:13][CH:15]([C:19]([CH3:21])=[O:20])[C:16]([O-:18])=[O:17].[Ag+:26]
Reactant: CCC(C(C)=O)C(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: OCCNCCO
Solvent: CCOCC
Solvent: O
Product: CC(=O)C(C)C(=O)[O-]

Procedure:
Diethanolamine (4.4 g) was dissolved in water (5 mL), and this solution was added to the ether solution of α-ethylacetoacetic acid while cooling with ice. Next, a solution of silver nitrate (6.8 g) dissolved in water (8 mL) was added dropwise. The white precipitate that precipitated was filtered off, washed with ice water and then isopropanol, and dried, yielding silver α-methylacetoacetate as a white precipitate (yield 6.7 g). FIG. 6 shows the infrared absorption spectrum (IR) of the silver α-methylacetoacetate that was obtained. IR:1700 cm−1, 1547 cm−1.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([N:9]=[C:10]=[O:11])(=[O:8])[C:5]([CH3:7])=[CH2:6]>C(Cl)(Cl)Cl.ClCCCl>[C:4]([NH:9][C:10]([N:2]([CH3:3])[CH3:1])=[O:11])(=[O:8])[C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)C(=O)N=C=O
Reactant: CNC
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)N(C)C
Yield: 99.9 %

Procedure:
To a solution of dimethylamine (0.45 g; 10 mmol) in chloroform (20 ml), a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (20 ml) was dropwise added under nitrogen stream while cooling with ice. After completion of the addition, chloroform and 1,2-dichloroethane were evaporated under reduced pressure to give 1-methacryloyl-3,3-dimethylurea (1.56 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[OH:20][CH:21]([CH3:29])[C:22](=[CH2:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(CCCC)CCCC)CCC>[Pd+2]>[C:21]([CH:22]([CH2:28][C:7]1[CH:6]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)[C:4]([F:19])=[CH:3][C:2]=1[Cl:1])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:20])[CH3:29]
Reactant: Cc1nn(-c2cc(I)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: C=C(C(=O)OCC)C(C)O
Agent: [Pd+2]
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C(Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl)C(C)=O
Yield: 48.9 %

Procedure:
This compound was prepared in the manner of Example 6, with 1.03 grams (0.0025 mole--1.0 equiv.) of 1-(4-chloro-2-fluoro-5-iodophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, 0.365 gram (0.0025 mole--1.0 equiv.) of ethyl 3-hydroxy-2-methylenebutanoate, 1.6 grams (0.0084 mole--3.36 equiv.) of tributylamine, and 0.062 gram (0.000029 mole--0.01 equiv.) of 5% palladium(II) on carbon as reagents. A yield of 0.52 gram of 98% pure ethyl α-acetyl-2-chloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoate (49.6% yield) was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][O:9][C:8]=2[CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH3-]C#[N:16].[Na+]>CO>[C:1]1([C:7]2[CH:11]=[CH:10][O:9][C:8]=2[CH2:12][NH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1occc1-c1ccccc1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: NCc1occc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.1 %

Procedure:
Stir a solution of 3-phenylfuran-2-carbaldehyde (401 mg, 2.33 mmol) and NH4OAc (1.79 g, 23.30 mmol) in methanol (8 mL) at room temperature under nitrogen. Add NaCNBH3 (102 mg, 1.63 mmol). After stirring at room temperature for 24 hours, concentrate the mixture, dilute with water (2 mL), basify with 1N sodium hydroxide, and extract with diethyl ether (4×10 mL). Dry the combined organic phases (magnesium sulfate), filter and concentrate. Perform flash chromatography on silica gel eluting with 9:1 ethyl acetate/MeOH to afford 37 mg of the title compound as a yellow solid. 1H NMR (CDCl3) δ 7.19-7.41 (m, 6H), 6.49 (d, J=2 Hz, 1H), 3.95(s, 2H), 1.80 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH2:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[C:27]([CH3:32])[N:26]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:24][C:25]1[N:30]=[C:29]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([NH:14][C:12]([C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[C:4]([CH3:23])[CH:3]=[C:2]4[NH2:1])=[O:13])=[CH:16][CH:17]=2)[CH:28]=[C:27]([CH3:32])[N:26]=1
Reactant: Cc1cc(N)c2cc(C(=O)Nc3ccc(CN)cc3)ccc2n1
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NCc2ccc(NC(=O)c3ccc4nc(C)cc(N)c4c3)cc2)nc(N)n1
Yield: 82.2 %

Procedure:
The solution of 27 mg (0.05 mmol) 4-{[(4-amino-2-methyl-6-quinolinyl)carbonyl]amino}benzylamine, 15 mg (0.1 mmol) 2-amino-4-chloro-6-methylpyrimidine, and 0.05 ml (0.3 mmol) diisopropyl ethylamine in 1 ml DMF was stirred at 120° C. for 5 h. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 17 mg (51%) of the title compound. MS 414.3 (M+1)+, 1H-NMR (DMSO-d6) δ 2.19 (s, 3H), 2.60 (s, 3H), 4.56 (d, 2H), 5.94 (s, 1H), 6.65 (s, 1H), 7.33 (d, 2H), 7.75 (d, 2H), 7.88 (d, 1H), 8.35 (d, 1H), 8.97 (s, 1H), 8.96-9.01 (m, 2H), 10.51 (s, 1H), 12.30 (br. 1H), 13.60 (br. 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:3]=3)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile (example 49a) was treated with 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, light brown powder; MS: [M+H]+=449.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:34][CH3:35])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:33])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[S:26][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:24][CH:23]=2)[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.Cl[C:46](=[O:51])[C:47]([O:49][CH3:50])=[O:48]>ClCCl.C(OCC)(=O)C>[CH3:35][O:34][CH:3]([O:2][CH3:1])[CH2:4][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:33])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[S:26][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:24][CH:23]=2)[CH2:17][CH2:16]1)[C:46](=[O:51])[C:47]([O:49][CH3:50])=[O:48]
Reactant: COC(CNc1ccccc1C(=O)CCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1)OC
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(=O)N(CC(OC)OC)c1ccccc1C(=O)CCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound prepared in Example 323 (555 mg) in dichloromethane (7.0 mL) at 0° C. was added diisopropylethylamine (0.59 mL) followed by methyl 2-chloro-2-oxoacetate (0.16 mL). The reaction was allowed to warm to room temperature and then stirred for 2 hours. The solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 80% ethyl acetate/hexane with 3% (9:1 methanol/concentrated ammonium hydroxide)) to furnish the title compound (392 mg) with the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[C:23]([C:25]1[CH:29]=[CH:28][S:27][C:26]=1[C:30]1[O:35]C(C)(C)[O:33][C:32](=O)[CH:31]=1)#[N:24]>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:32](=[O:33])[CH2:31][C:30]([C:26]1[S:27][CH:28]=[CH:29][C:25]=1[C:23]#[N:24])=[O:35])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2sccc2C#N)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1sccc1C#N
Yield: 93 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and 6-(3-cyano-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J3) (280 mg, 1.19 mmol) according to the general procedure K. Obtained as a light yellow solid (446 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([S:12][CH:13]1[N:16](/[C:17](=[C:21](\[O:23][CH3:24])/[CH3:22])/[C:18](O)=[O:19])[C:15](=[O:25])[CH:14]1[NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:11])=[O:10].C(Cl)(=O)C([Cl:40])=O>CN(C)C=O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([S:12][CH:13]1[N:16](/[C:17](=[C:21](\[O:23][CH3:24])/[CH3:22])/[C:18]([Cl:40])=[O:19])[C:15](=[O:25])[CH:14]1[NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:11])=[O:10]
Reactant: CO/C(C)=C(/C(=O)O)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CO/C(C)=C(/C(=O)Cl)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
One drop of dimethylformamide in dioxane is added to a solution of 54 mg (0.1 mM) of 2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid in 0.5 ml of a 10% strength solution of oxalyl chloride in dioxane, whereupon an evolution of gas occurs immediately. The mixture is stirred for 2 hours at room temperature and the solvent and the excess oxalyl chloride are evaporated off in vacuo. The residue is dried in a high vacuum and gives 2-[4-(o-methoxybenzenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid chloride in the form of aslightly orange-coloured foam, IR spectrum (CH2Cl2): 5.60, 5.90 and 8.70μ.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (0.65 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.44 g, 2.20 mmol) according to the general procedure IVb. Obtained as a white solid (0.66 g, 73%). MS (EI) 446.0 [(M)+]; mp 134° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:12]2[C:11](=[O:13])[NH:10][C@@H:9]3[CH2:14][NH:15][CH2:16][C@H:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:19]([C:21]1[CH:30]=[CH:29][CH:28]=[C:27](C(F)(F)F)[C:22]=1C(OC)=O)=O.C(=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.C([O-])(O)=O.[Na+]>[CH2:19]([N:15]1[CH2:16][C@@H:8]2[C@H:9]([NH:10][C:11](=[O:13])[C:12]3[C:3]([C:2]([F:1])([F:17])[F:18])=[CH:4][CH:5]=[CH:6][C:7]=32)[CH2:14]1)[C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:22]=1
Reactant: COC(=O)c1c(C=O)cccc1C(F)(F)F
Reactant: O=C1N[C@@H]2CNC[C@H]2c2cccc(C(F)(F)F)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C1N[C@@H]2CN(Cc3ccccc3)C[C@H]2c2cccc(C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of (±)-trans-6-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one, the free base of Example 10, (161 mg, 0.63 mmol) in 4 mL of 1,2-dichloroethane was added benzaldehyde (0.076 mL, 0.76 mmol), sodium triacetoxyborohydride (267 mg, 1.26 mmol) and 3 drops of glacial acetic acid. The mixture was allowed to stir at ambient temperature for 3 h. The reaction was diluted with sat'd aq NaHCO3 and extracted with ethyl acetate. The organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford 180 mg (83%) of the title compound which was sufficiently pure to be used without purification. LRMS (ESI): 347.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=O)[CH:9]=[CH:10][CH:11]=1)=[O:4].[CH2:18]([NH2:21])[C:19]#[CH:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[F:16][C:2]([F:1])([F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13](=[O:15])[NH:21][CH2:18][C:19]#[CH:20])[CH:7]=1)=[O:4]
Reactant: O=C(O)Cc1cccc(NC(=O)C(F)(F)F)c1
Reactant: C#CCN
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: CC#N
Product: C#CCNC(=O)Cc1cccc(NC(=O)C(F)(F)F)c1
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To the mixture of 2-(3-(2,2,2-trifluoroacetamido)phenyl)acetic acid (2.96 g, 12 mmol), propargylamine (0.97 ml, 15 mmol), HATU (4.5 g, 12 mmol) in acetonitrile (50 ml), added DIPEA (5.2 ml, 30 mmol) slowly. Stirring was kept 2 hours at room temperature. Removed solvent, extracted with EtOAc, washed with 1N HCl, water and brine, dried over sodium sulfate. Concentrated to get 1.42 g 2,2,2-trifluoro-N-(3-(2-oxo-2-(prop-2-ynylamino)ethyl)phenyl)acetamide as white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[C:23]([CH3:24])=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35](=[N:37]O)[NH2:36])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(C1C=CC(S(N)(=O)=O)=CC=1)#N.CCN(C(C)C)C(C)C>>[CH3:7][O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[N:16]=[CH:17][C:18]([C:19]2[O:21][N:37]=[C:35]([C:32]3[CH:31]=[CH:30][C:29]([S:26]([NH2:25])(=[O:27])=[O:28])=[CH:34][CH:33]=3)[N:36]=2)=[CH:22][C:23]=1[CH3:24]
Reactant: NC(=NO)c1ccc(S(N)(=O)=O)cc1
Reactant: COCC1CCCN1c1ncc(C(=O)O)cc1C
Agent: N#Cc1ccc(S(N)(=O)=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CCCN1c1ncc(-c2nc(-c3ccc(S(N)(=O)=O)cc3)no2)cc1C

Procedure:
Oxalyl chloride (122 mL; 1.44 mmol), Intermediate 29 (120 mg; 0.48 mmol), 4-(aminosulfonyl)-N′-hydroxybenzenecarboximidamide, prepared as described in WO 2006/013104 A1 from 4-cyanobenzene-1-sulfonamide (ABCR; CD10716), (103 mg; 0.48 mmol, 1 eq.) and DIEA (248 mL; 1.44 mmol) were reacted according to the procedure described for Example 38. Purification by column chromatography (from cHex/EtOAc, 50/50 to EtOAc) followed by recrystallisation from DCM/n-pentane afforded the title compound as a yellow solid. LC/MS (Method A): 430.3 (M+H)+. HPLC (Method A) Rt 2.80 min (purity 93.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[S:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[S:19])[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: Cc1ccc(C(=S)CBr)cc1
Product: CCOC(=O)n1c(C(=S)c2ccc(C)cc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-4′-methylthioacetophenone (Cutler et al., J. Am. Chem. Soc., 1952, 74, 5475). 1H-NMR (CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 7.67 (2H, d, J=8.4 Hz), 7.53 (1H, d, J=8.4 Hz), 7.31-7.23 (3H, m), 5.75 (2H, br s), 3.82 (2H, q, J=7.0 Hz), 2.51 (3H, s), 0.89 (3H, t, J=7.0 Hz)
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[CH3:15])=[CH:5][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:18])=[O:17].CCN(C(C)C)C(C)C.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:38]([NH:37][CH2:35][CH3:36])=[O:39])=[N:11][C:10]=2[CH3:15])=[CH:5][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:17])=[O:18]
Reactant: CCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(Cl)c(S(=O)(=O)N2CCN(C)CC2)c1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(Cl)c(S(=O)(=O)N3CCN(C)CC3)c2)s1
Temperature: 120 °C

Procedure:
A stirred solution of 5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-ylamine hydrobromide (174d) (0.1 g, 0.26 mmol) in DMF (1 ml) at room temperature is treated with DIPEA (0.07 g, 0.52 mmol) and ethyl isocyanate (0.025 ml, 0.33 mmol). The reaction mixture is heated to 120° C. for 1 hour and then allowed to cool to room temperature. Purification by preparative LC-MS affords the titled compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCc1ccncc1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Brc1cnc2ccc(NCc3ccncc3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and pyridin-4-ylmethanamine according to general procedure 1 providing the intermediate (94 mg, 84%) as a yellow solid: Rf=0.28 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 8.45-8.46 (m, 2H), 7.60 (d, J=9.7 Hz, 1H), 7.51-7.50 (m, 2H), 7.39 (s, 1H), 6.79 (d, J=9.7 Hz, 1H), 4.61 (s, 2H); ES-MS: (M+H)=304, 306 m/z.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:45])[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36](C)(C)[O:37][SiH2]C(C)(C)C)[CH:30]=1)[CH2:26][CH3:27])([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:45])[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([CH2:36][OH:37])[CH:30]=1)[CH2:26][CH3:27])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCN(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(Cc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
TBAF (1M in THF, 3.03 mL, 3.03 mmol) was added dropwise to a sol. of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-ethyl-carbamic acid tert-butyl ester (628 mg, 1.52 mmol) in THF (14.9 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc was added, and the mixture was washed with aq. sat. NH4Cl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 19:1) yielded the title compound (300 mg, 66%). LC-MS: tR=0.98 min; ES+: 300.28.