Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C#C.[CH2:3]([Li])[CH2:4]CC.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>O1CCCC1>[OH:14][CH:13]([C:12]1[CH:15]=[CH:16][C:9]([F:8])=[CH:10][CH:11]=1)[C:3]#[CH:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: [Li]CCCC
Agent: C#C
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(F)cc1
Temperature: -72 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A 200 ml. volume of dry tetrahydrofuran was cooled to -60° C. in a dry ice/acetone bath and then acetylene gas was passed into the solvent until 8.0 g (0.307 mole) had dissolved. The resulting solution was then added to a second 200 ml. portion of dry tetrahydrofuran cooled to -70° C. in a flame-dried 1-liter three-necked, round bottomed reaction flask equipped with magnetic stirrer, addition funnel and nitrogen inlet tube to provide a dry nitrogen atmosphere. To this solution, there was then slowly added 99 ml. of a 2.22 molar solution of n-butyl lithium (0.22 mole) at such a rate that the internal temperature remained below -65° C. After the addition was complete, a solution consisting of 24.82 g (0.20 mole) of p-fluorobenzaldehyde dissolved in 80 ml. of tetrahydrofuran was added at such a rate that the internal temperature again remained below -65° C. The reaction mixture was then stirred at -72° C. for a period of 30 minutes and then allowed to warm up to +5° C. during another 30 minute period. The reaction was then quenched with 80 ml. of water, followed by the addition of anhydrous potassium carbonate to form a pasty mass and an organic supernatant liquid. The organic layer was decanted and combined with two subsequent ether washes of the potassium carbonate mass. The resulting orange solution was then dried over fresh anhydrous potassium carbonate for a period of approximately 16 hours (overnight) and subsequently distilled in vacuo to give 20.5 g (68%) of pure 1-hydroxy-1-(p-fluorophenyl)-2-propyne, b.p. 98°-101° C./8 mm. Hg. A second preparation gave a 92% yield of pure product (b.p. 104° C./9 mm. Hg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:31]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:30]2=[O:57])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH:31]([NH:49][C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[C:30]2=[O:57])=[O:27])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3S(=O)C2)cc1

Procedure:
A solution of 85% strength m-chloroperbenzoic acid (55.22 g) in methylene chloride (600 cc) is added dropwise, in the course of 2 hours, to a solution, cooled to -10° C., of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (or -3-ene) (mixture of the E and Z forms) (180.56 g) in methylene chloride (1.4 liters). The mixture is washed with a 5% strength solution of sodium bicarbonate (1.5 liters) and with water (2×1.5 liters), dried over sodium sulphate and concentrated at 20° C. under reduced pressure (20 mm Hg) to a volume of 300 cc. This solution is chromatographed on a column of Merck silica gel (0.05-0.2 mm) (3 kg) (diameter of the column: 9.2 cm, height: 145 cm). Elution is carried out successively with the following mixtures of cyclohexane/ethyl acetate: 80/20 (by volume) (15 liters) and 70/30 (by volume) (32 liters), 600 cc fractions being collected. Fractions 27 and 28 are collected and concentrated to dryness and this yields the Z form of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (5.56 g).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])(=[O:6])=[O:5])[CH2:2][CH3:3].[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1.[Cl-].[NH4+]>O.CN(C)C=O>[Cl:16][C:17]1[N:22]=[C:21]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: CCCS(=O)(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl

Procedure:
To a solution of 2-(Propane-1-sulfonyl)-phenylamine (3.69 g, 18.5 mmol) of N,N-dimethylformamide (40 mL), sodium hydride (1.48 g, 37 mmol) is added portionwise at 0° C. After stirring, 2,4,5-trichloropyrimidine (2.1 mL, 18.5 mmol) is added. The mixture is stirred at 0° C. for 30 minutes and is further stirred at room temperature for 7 hrs. After adding saturated aqueous ammonium chloride, the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane-ethyl acetate gradient) to afford the title compound as colorless solids.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:23]=[CH:22][C:14]([CH2:15][O:16][C:17](=[O:21])[C:18](Cl)=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH3:24][Si:25]([CH3:45])([CH3:44])[O:26][C@@H:27]([C@@H:29]1[C@@H:32]([CH:33]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:36])[CH3:34])[NH:31][C:30]1=[O:43])[CH3:28]>C(Cl)Cl>[CH3:44][Si:25]([CH3:24])([CH3:45])[O:26][C@@H:27]([C@@H:29]1[C@@H:32]([CH:33]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:36])[CH3:34])[N:31]([C:18](=[O:19])[C:17]([O:16][CH2:15][C:14]2[CH:22]=[CH:23][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)=[O:21])[C:30]1=[O:43])[CH3:28]
Reactant: CC(C(=S)c1ccccc1)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C
Reactant: O=C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(=S)c1ccccc1)[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N1C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: -30 °C
Reaction time: 0.58 h

Procedure:
A solution of 0.71 ml of triethylamine and 1.1 g of p-nitrobenzyloxyoxalyl chloride in 10 ml of methylene chloride was added to a solution of 0.9 g of (3S,4S)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(1RS)-1-(phenylthiocarbonyl)ethyl]-2-azetidinone in 10 ml of methylene chloride, cooled to about -30° C., and the mixture was stirred for 35 minutes at the same temperature. The reaction mixture was worked up and purified in the same manner as in Preparation 1(3), giving (3S,4S)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(1RS)-1-(phenylthiocarbonyl)ethyl]-1-(p-nitrobenzyloxyoxalyl)-2-azetidinone as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]([F:10])([F:9])[F:8])=[CH:5][CH:6]=1.[Br:11]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:11][CH2:1][C:2]1[O:3][C:4]([C:7]([F:10])([F:9])[F:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(F)(F)F)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1ccc(CBr)o1
Yield: 78.6 %

Procedure:
To a solution of 2-methyl-5-(trifluoromethyl)furan (4 g, 26.6 mmol) in chloroform (60 ml) were added N-bromosuccinimide (5.2 g, 29.3 mmol) and 2,2′-azobis(isobutyronitrile) (220 mg, 1.33 mmol). The reaction solution was heated under reflux for 15 min. The reaction solution was cooled, poured into water (200 ml) and was extracted with chloroform. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 2-(bromomethyl)-5-(trifluoromethyl)furan (4.79 g, 78%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:24]1[N:25]=[CH:26][C:27]([C:30]([N:32]([CH2:34][CH3:35])[CH3:33])=[O:31])=[N:28][CH:29]=1>C(#N)C.C(OC(=O)C)C>[CH2:34]([N:32]([CH3:33])[C:30]([C:27]1[N:28]=[CH:29][C:24]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[N:25][CH:26]=1)=[O:31])[CH3:35]
Reactant: CCN(C)C(=O)c1cnc(Cl)cn1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)CC)cn2)c2cc(C)oc2c1
Temperature: 100 °C

Procedure:
Ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1c: 2.25 g, 10.22 mmol), potassium carbonate (2.1 g, 15.3 mmol), 5-chloro-N-ethyl-N-methylpyrazine-2-carboxamide (SM-4: 2.04 g, 10.2 mmol) were mixed in acetonitrile (30 ml). The mixture was heated at 100° C. over night, after which time, the reaction mixture was diluted with ethylacetate (50 ml) and filtered. The organic layer was concentrated and purified by column chromatography on silica gel eluting with ethylacetate in heptanes 20-100% to afford ethyl 4-(5-(ethyl(methyl)carbamoyl)pyrazin-2-yloxy)-2-methylbenzofuran-6-carboxylate (I-7a: (3.9 g, 99.5%) as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][F:27]>CC(N(C)C)=O>[F:27][CH2:26][CH2:25][C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:12]
Reactant: FCCBr
Reactant: CCOC(=O)C1Cc2cc(OC)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C1(CCF)Cc2cc(OC)ccc2C1=O
Temperature: 65 °C
Reaction time: 20 h

Procedure:
To a mixture of ethyl 5-methoxy-1-oxoindane-2-carboxylate (crude product from the preceding two reactions, ˜190 mmol), K2CO3 (53.8 g, 389 mmol) and KI (64.7 g, 390 mmol) in anhydrous dimethylacetamide (792 mL) was added 1-bromo-2-fluoroethane (18.4 mL, 247 mmol) and the mixture was stirred and heated at 65° C. After 20 hours, analysis of an aliquot by NMR showed the reaction to be complete. After cooling to room temperature, most of the dimethylacetamide was removed by evaporation at reduced pressure. The residue was partitioned between EtOAc and water and the organic phase was washed with water (4 times) and brine and dried over Na2SO4. Filtration and removal of the solvent under reduced pressure gave crude ethyl 2-(2-fluoroethyl)-5-methoxy-1-oxoindane-2-carboxylate which was used in the next step without purification.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([CH3:19])[N:3]=1.[C-:20]#[N:21].[Na+].O.C(OCC)(=O)C>C(#N)C>[CH3:19][C:4]1[N:3]=[C:2]([C:20]#[N:21])[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[N:5]=1
Reactant: [C-]#N
Reactant: Cc1nc(F)c(C(F)(F)F)c(C(F)(F)C(F)(F)F)n1
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C#N)c(C(F)(F)F)c(C(F)(F)C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
5.0 g (16.8 mmol) of 4-fluoro-2-methyl-6-(pentafluoroethyl)-5-(trifluoromethyl)pyrimidine are dissolved in 40 ml of acetonitrile. 986 mg (20.1 mmol) of sodium cyanide are added and the reaction mixture is stirred for 18 hours at 50° C. A further 493 mg (10.7 mmol) of sodium cyanide are added and the reaction mixture is stirred under reflux for three hours. After adding 100 ml of water and 100 ml of ethyl acetate, the organic phase is separated off. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed twice with water and with a saturated sodium chloride solution, then dried over sodium sulphate, filtered and the solvent is removed on a rotary evaporator. This gives 4.71 g of 2-methyl-6-(pentafluoroethyl)-5-(trifluoromethyl)pyrimidine-4-carbonitrile (92%) as a dark oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:6])[CH:2]=[CH2:3].[NH2:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([N:16]2[C:22](=[O:23])[C:21]3[C:20](=[CH:28][C:27]([Cl:29])=[CH:26][CH:25]=3)[NH:19][C:17]2=[O:18])(=[O:15])=[O:14])=[CH:11][CH:12]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: C=CCOC(=O)c1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 37.6 %

Procedure:
1.10 g (4.15 mmol) of 4-allyloxycarbonylbenzene-sulfonylisocyanate and 712 mg (4.15 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 657 mg of the above-identified compound (yield 37.6%). Properties: colorless crystal, Melting point: 130°-132° C., PMR (δppm, DMSO-d6): 4.59 (2H,d), 5.18 (1H,d), 5.27 (1H,d), 5.87-5.94 (1H,m), 7.13 (1H,s), 7.22 (1H,d), 7.62-7.70 (2H,m), 7.86 (1H,d), 8.09 (2H,d), 11.63 (1H,br).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH2:12]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:11][NH:12][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(Cl)nc1
Reaction time: 3 h

Procedure:
26.2 of crude 6-chloro-nicotinic acid chloride are introduced in portions into a solution of 25 ml of anhydrous methylamine in a mixture of 150 ml of dioxane and 50 ml of toluene whilst cooling at 0° C. to -5° C., and the mixture is then stirred for 3 hours longer, without further cooling. The reaction mixture is evaporated in vacuo, the residue is stirred with 100 ml of water and the undissolved material is filtered off and dried, giving crude 6-chloro-nicotinic acid N-methylamide of melting point 150°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)[S:10][C:11]=2[C:12]([O:14]CC)=[O:13])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)[S:10][C:11]=2[C:12]([OH:14])=[O:13])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc(-c2ccnc(Cl)c2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of ethyl 4-(4-chlorobenzyl)-2-(2-chloropyridin-4-yl)thiazole-5-carboxylate (199 mg, 0.506 mmol) in THF (2.84 mL) and water (1.42 mL) was added 1.0 M LiOH (0.658 mL, 0.658 mmol) and the resulting solution was stirred at room temperature overnight. The mixture was acidified to pH=4 with 1 N HCl. The precipitated solids were filtered, washed with water and dried to give 179 mg of the title compound as an a white solid. (96% yield). LC/MS (FA) ES+ 365, 367.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=2)[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: N#CCCc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCc1cccc(Nc2nc(Cl)ncc2Cl)c1

Procedure:
3-(3-Amino-phenyl)-propionitrile (0.110 g, 0.000752 mol), 2,4,5-Trichloro-pyrimidine (0.152 g, 0.000828 mol), Potassium carbonate (0.125 g, 0.90 mmol), and DMF (1.0 mL, 0.014 mol) were heated at 85° C. for 90 min. The reaction mixture was diluted with H2O, extracted with CH2Cl2×3, dried over MgSO4, filtered, and concentrated under reduced pressure. Title compound isolated as a white solid. MP=111-112. HPLC purity: 95% LCMS: 295.10 (M+H) 1H-NMR (CDCl3, 400 MHz) δ 8.21 (d, J=0.8 Hz, 1H), 7.53-7.56 (m, 2H), 7.38 (dd, J=7.6 Hz, 7.8 Hz, 1H), 7.31 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.00 (dd, J=7.0 Hz, 7.3 Hz, 2H), 2.67 (dd, J=7.4 Hz, 7.2 Hz, 2H).
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([F:22])=[C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])[N:19]=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:16]1[N:17]=[CH:18][N:19]=[C:20]([NH:23][C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])[C:21]=1[F:22]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc(NC(=O)C2CC2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc(NC(=O)C2CC2)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl N-tert-butoxycarbonyl-N-[6-(cyclopropanecarbonylamino)-5-fluoro-pyrimidin-4-yl]carbamate (4, 0.89 g, 2.25 mmol) in dichloromethane (20 mL), trifluoroacetic acid (20 mL, 2.25 mmol) was added at 0° C. and stirred the reaction mass at room temperature for 16 h. After completion the reaction, trifluoroacetic acid was distilled and the crude compound was basified with liquid ammonia. The solid precipitated out was filtered and dried to afford N-(6-amino-5-fluoro-pyrimidin-4-yl)cyclopropanecarboxamide (5) as off white solid. Yield: 0.4 g, 90%; MS (ESI) m/z 197.06 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.99 (s, 1H), 7.16 (s, 2H), 7.04 (s, 1H), 2.06 (m, 1H), 0.82-0.78 (m, 4H).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([S:33]([CH3:32])(=[O:35])=[O:34])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CCCN1CCCOc1cnc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1
Agent: [H-]
Agent: [Na+]
Product: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Yield: 52 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{5-[3-((S)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 11), sodium hydride and methanesulfonyl chloride, to give the desired product as a light yellow oil (52%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:26])=[CH:4][C:5]([F:25])=[C:6]([CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:8].[Br:27][C:28]1[CH:33]=[CH:32][N:31]2[C:34]([C:37](NC3C=C(C(=O)NCCOC(C)(C)C)C=CC=3F)=[O:38])=[CH:35][N:36]=[C:30]2[CH:29]=1>>[Br:27][C:28]1[CH:33]=[CH:32][N:31]2[C:34]([C:37]([NH:1][C:2]3[CH:24]=[C:6]([C:7](=[O:8])[NH:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:5]([F:25])=[CH:4][C:3]=3[CH3:26])=[O:38])=[CH:35][N:36]=[C:30]2[CH:29]=1
Reactant: CC(C)(C)OCCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: Cc1cc(F)c(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1N
Product: Cc1cc(F)c(C(=O)NCc2ccccc2N2CCN(C)CC2)cc1NC(=O)c1cnc2cc(Br)ccn12

Procedure:
The title compound was prepared from 5-amino-2-fluoro-4-methyl-N-(2-(4-methylpiperazin-1-yl)benzyl)benzamide (step 3) analogously to 7-bromo-N-(5-(2-tert-butoxyethylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (Intermediate 2a step 2);
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:22]3[CH:36]=[CH:35][C:25]([C:26]([O:28]CC[Si](C)(C)C)=[O:27])=[CH:24][CH:23]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2.CC1C(C)C=C(C2C=CC(C)=CC=2)C2C=C(C(OC3C=CC(C(OCC[Si](C)(C)C)=O)=CC=3)=O)C=CC1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1([CH3:37])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:35][CH:36]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Oc4ccc(C(=O)OCC[Si](C)(C)C)cc4)cc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(C2=CC(C)C(C)c3ccc(C(=O)Oc4ccc(C(=O)OCC[Si](C)(C)C)cc4)cc32)cc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Oc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 110.0 mg (0.213 mmol) 2-trimethylsilylethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]oxy]benzoate (Compound 38) and 167.3 mg of tetrabutylammonium flouride (0.640 mmol, 0.64 ml of a 1M solution in THF) in 2.0 ml THF was stirred at room temperature for 22 hours. Ethyl acetate was added and the resulting solution washed with H2O and saturated aqueous NaCl then dried over MgSO4. Removal of the solvents under reduced pressure and washing of the residual solid with EtOAc and CH3CN afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.10 (2H, d, J=8.8 Hz), 8.06 (1H, dd, J=2.0, 8.1 Hz), 7.82 (1H, d, J=1.9 Hz), 7.64 (1H, d, J=8.1 Hz), 7.35 (2H, d, J=8.6 Hz), 7.25 (4H, m), 6.08 (1H, t, J=4.7 Hz), 2.42 (2H, d, J=4.7 Hz), 2.35 (3H, s), 1.39 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](O)([C:25]([F:28])([F:27])[F:26])[CH2:10][C:11]([C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:24])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.Cl.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:25]([F:28])([F:26])[F:27])=[CH:10][C:11]([C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:24])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Temperature: 30 °C
Reaction time: 3 h
Yield: 102 %

Procedure:
0.96 g of ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoate, 2.0 g of toluene, 0.43 g of acetic anhydride, 26 mg of 4-dimethylaminopyridine and 0.43 g of triethylamine were fed and the mixture was stirred for 3 hours at 30° C. 2 ml of iced water, 2 drops of concentrated hydrochloric acid and 5 ml of toluene were added to the reaction solution, and separated. The organic phase was washed with water, and the solvent was distilled off under reduced pressure to obtain 0.94 g of ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoate as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[C:24]([CH3:35])[NH:23][C:22]=1[CH:36]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:36][C:22]4[NH:23][C:24]([CH3:35])=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (74.8 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 102 mg (80%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.27 (br s, 1H, NH), 11.66 (br s, 1H, NH), 9.12 (br s, 1H), 8.29 (s, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.31-7.36 (m, 2H), 3.43 (m, 4H, 2×CH2), 2.30 (s, 3H, CH3), 2.27 (m, 4H, 2×CH2), 2.18 (s, 3H, CH3), 2.12 (s, 3H, CH3). MS 510 [M++1].