Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:36](=[O:37])[C:35]([C:38]([O:40]CC)=[O:39])=[CH:34][C:9]2[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([O:32]C)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:12][C:8]=2[CH:7]=1)=[O:5])C>[OH-].[Na+].C(O)C>[C:4]([C:6]1[C:36](=[O:37])[C:35]([C:38]([OH:40])=[O:39])=[CH:34][C:9]2[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]([OH:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:12][C:8]=2[CH:7]=1)([OH:5])=[O:3]
Reactant: CCCCc1nc2cc(C(=O)OCC)c(=O)c(C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2cc(C(=O)O)c(=O)c(C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
An aliquot of the triester from Step (h) (300 mg) was hydrolyzed by stirring it in a mixture of 12 ml of 10% sodium hydroxide and 12 ml of ethanol for 6 h at 40° C. The azeotrope was distilled off, water (30 ml) was added and the resulting solution slowly acidified to pH 3 with HCl 2N. The resulting precipitated acid was isolated (mp 186, decomp.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[N:7][CH:8]=1.[F:15]F>C(#N)C>[F:15][N+:7]1[CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=[CH:5][C:6]=1[S:9]([O-:12])(=[O:11])=[O:10]
Reactant: FF
Reactant: O=S(=O)(O)c1ccc(C(F)(F)F)cn1
Solvent: CC#N
Product: O=S(=O)([O-])c1ccc(C(F)(F)F)c[n+]1F

Procedure:
To a mixture of 5-(trifluoromethyl)pyridine-2-sulfonic acid (227 mg, 1 mmol) and acetonitrile (60 ml) in a flask on a cooling bath kept at -10° C., a mixed gas of 10% fluorine/90% nitrogen was introduced at a flow rate of 15 ml/min. The total amount of the fluorine gas was 3.1 mmol. Thereafter, the nitrogen gas alone was introduced for 30 minutes. After the reaction mixture was concentrated, ethyl acetate was added to the residue. The precipitated crystal was recovered by filtration to obtain N-fluoro-5-(trifluoromethyl)pyridinium-2-sulfonate (212 mg, 0.86 mmol). Yield, 86%. Melting point, 190°-220° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH:9]([CH3:11])[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1cc(Br)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
A mixture of 32 g of 4-bromo-2-isopropylphenol, 25.7 g of benzyl bromide, 23 g of potassium carbonate and 300 ml of N,N-dimethylformamide was stirred at room temperature for 24 hours. The reaction solution was poured into ice-water, acidified by adding 10% hydrochloric acid and then extracted with 500 ml of diethyl ether. There, the ether layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 30 g of 4-bromo-2-isopropylphenyl benzyl ether (yield, 65%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:7]=1[F:31])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:38]>ClCCCl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([N:13]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:14][C:15]([F:23])([F:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:38])[C:7]=1[F:31])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)Cc1c(Cl)cnc(N(CC(F)(F)c2ccccn2)C(=O)OC(C)(C)C)c1F
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c(Cl)cnc(N(CC(F)(F)c2cccc[n+]2[O-])C(=O)OC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.8 g (1.7 mmol) ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-5-chloro-3-fluoro-4-pyridinyl)acetate 1-6 in 3 mL 1,2-dichloroethane was added 0.44 g (1.8 mmol, 70% by weight) m-chloroperoxybenzoic acid. The reaction mixture was stirred at room temperature 16 h, heated to 60° C. 2 h, cooled, diluted with 300 mL EtOAc, washed with 200 mL 0.1M NaOH, and 200 mL brine. Dried over Na2SO4, filtered, and concentrated. Purification by automated flash chromatography (40 g silica cartridge, linear gradient 1-10% MeOH/CH2Cl2 over 25 min, 40 mL/min flow rate) followed by repurification of the mixed fractions by traditional silica gel chromatography (2×15 cm silica gel, linear gradient 2-5% MeOH/CH2Cl2) afforded ethyl(2-{(tert-butoxycarbonyl)[2,2-difluoro-2-(1-oxido-2-pyridinyl)ethyl]amino}-5-chloro-3-fluoro-4-pyridinyl)acetate 1-7. 1H NMR (400 mHz, CDCl3) δ8.20 (s, 1H); 8.18 (br d, 1H, J=5 Hz); 7.57 (br dd, 1H, J=7.7 and 2 Hz); 7.31 (br m, 2H); 5.0 (br m, 2H); 4.19 (q, 2H, J=7.14 Hz); 3.82 (s, 2H); 1.28 (s, 9H); 1.25 (t, 3H, J=7.14 Hz). Mass spectrum (electrospray) M+H=490.1
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:61]([C:63]1[CH:64]=[CH:65][C:66]([O:69][C:70]2[CH:78]=[CH:77][C:73]([C:74](O)=[O:75])=[CH:72][CH:71]=2)=[N:67][CH:68]=1)#[N:62]>CN(C=O)C.O>[C:61]([C:63]1[CH:64]=[CH:65][C:66]([O:69][C:70]2[CH:78]=[CH:77][C:73]([C:74]([NH:17][CH2:18][C:19](=[O:20])[N:21]3[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]3)=[O:75])=[CH:72][CH:71]=2)=[N:67][CH:68]=1)#[N:62]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Oc2ccc(C(=O)NCC(=O)N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 57.3 %

Procedure:
DIPEA (43 mg, 0.34 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt. (58 mg, 0.13 mmol) in DMF (1 mL). HOBT (18 mg, 0.13 mmol) and EDCI.HCl (26 mg, 0.13 mmol) were then added at room temperature. After 2 minutes, 4-(5-cyano-pyridin-2-yloxy)benzoic acid (30 mg, 0.11 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 34.4 mg (57.3% yield) of 4-(5-cyano-pyridin-2-yloxy)-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 85.6%, 1H NMR (CDCl3): δ 8.5 (ds, 1H), 8.0-7.9 (s, 3H), 7.8-7.5 (m, 4H), 7.5-7.4 (m, 1H), 7.0 (m, 2H), 4.5-3.5 (m, 8H), 3.5-3.0 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:24]([F:27])([F:26])[F:25])=[N:15][C:16]([C:17]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:10]2[CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[CH:19]1([C:17]([C:16]2[N:15]=[C:14]([C:24]([F:26])([F:25])[F:27])[N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=23)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)C3CCCC3)c2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(c1nc(C(F)(F)F)n2c1CNCC2)C1CCCC1

Procedure:
1-Cyclopentanecarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 28a (0.1 g, 0.258 mmol) was dissolved in a little ethyl acetate under stirring. A solution of 2.7 N hydrochloric acid in 5 mL of ethyl acetate was then added. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound cyclopentyl-(3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazin-1-yl)-methanone 28b, which was directly used in the next step.
Reaction SMILES: O.[NH2:2][NH2:3].Br[C:5]1[S:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][N:9]=1>C(O)C>[NH:2]([C:5]1[S:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][N:9]=1)[NH2:3]
Reactant: NN
Reactant: CC(C)(C)c1nnc(Br)s1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nnc(NN)s1
Yield: 79.6 %

Procedure:
Hydrazine hydrate (12.5 g) was added to a solution of 2-bromo-5-t-butyl-1,3,4-thiadiazole (22.1 g) in ethanol (100 ml), and the mixture was heated under reflux for 2 hours. The solvent was evaporated to give an oily solid which was crystallised from water to give 2-hydrazino-5-t-butyl-1,3,4-thiadiazole (13.7 g, 79%) as white needles, mp 111°-112° C.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([S:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].[CH2:25]([O:28][NH2:29])[CH:26]=[CH2:27]>O1CCCC1>[CH2:25]([O:28][N:29]=[C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([S:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:18]=2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH:26]=[CH2:27]
Reactant: CCCC(=O)C1=C(O)CC(c2ccc(C(=O)SCC)cc2)CC1=O
Reactant: C=CCON
Solvent: C1CCOC1
Product: C=CCON=C(CCC)C1=C(O)CC(c2ccc(C(=O)SCC)cc2)CC1=O
Reaction time: 15 h

Procedure:
Into 20 ml og tetrahydrofuran was dissolved 2 g of 2-butyryl-5-[4-(ethylthio)carbonylphenyl]-3-hydroxy-2-cyclohexen-1-one and to the solution was added 0.8 g of allyloxyamine. The mixture was kept for 15 hours at room temperature and the solvent was distilled off from it under reduced pressure. Then, the residue was recrystallized with mixture of benzene-ligroin and 0.8 g of colorless objective crystals having a melting point of 72°-75° C. was obtained.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[Se:17][CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Li]CCCC.[CH:26](N1CCOCC1)=[O:27]>C(OCC)C.CC(OC)(C)C.Cl>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[Se:17][C:18]([CH:26]=[O:27])=[CH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(c2ccc(-c3ccc[se]3)cc2)CC1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: CCCC1CCC(c2ccc(-c3ccc(C=O)[se]3)cc2)CC1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
1.48 g (4.47 mmol) of 2-[4-(4-propylcyclohexyl)phenyl]selenophene are initially introduced in 15 ml of diethyl ether, and 4.4 ml (7.0 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 15 min and subsequently cooled to −78° C. 1.4 ml (14.0 mmol) of N-formylmorpholine are added in one portion, and the mixture is warmed to RT and stirred for 24 h. The batch is diluted with MTBE, and 1 N hydrochloric acid is added. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is recrystallised from n-heptane. 5-[4-(4-Propylcyclohexyl)phenyl]selenophene-2-carbaldehyde is obtained as a red solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:9][C:10]#[N:11])[CH:5]=[CH:4][N:3]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+].CNCCNC.[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C.[I+].[Cu+]>[C:10]([CH2:9][C@H:8]([NH:12][C:13]([C:15]1[C:16]2[CH:23]=[N:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:17]=2[CH:18]=[N:19][CH:20]=1)=[O:14])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:7]=1)#[N:11]
Reactant: N#CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(Br)c1
Reactant: CS(=O)[O-]
Agent: [Cu+]
Agent: CNCCNC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cc([C@H](CC#N)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-bromo-pyridin-4-yl)-2-cyano-ethyl]-amide (122 mg, 0.262 mmol), sodium methanesulfinate (53.5 mg, 0.524 mmol) and copper (I) iodine (99.8 mg, 0.524 mmol) in DMSO (2.5 mL) was evacuated and purged with argon three times and warmed at 130° C. After 45 minutes, the reaction was cooled to room temperature and N,N′-dimethylethylenediamine (112 μL, 1.05 mmol) was added. The mixture stirred for 30 minutes and was then diluted with ethyl acetate (20 mL), stirred for 15 minutes, and saturated aqueous ammonium chloride (20 mL) was added. The mixture was sonicated for 30 minutes, and was then diluted with ethyl acetate (100 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-8% methanol in CH2Cl2. The solid was further purified by HPLC using a C18 column and a gradient of 5-95% acetonitrile+0.1% TFA and water+0.1% TFA to afford the title compound. MS m/z 465.68 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[C:23]#[N:24]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([C:23]#[N:24])[CH:25]=[CH:26][C:27]=1[F:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)c(Br)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cc(C#N)ccc1F

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-bromo-4-fluorobenzonitrile (ABCR), the title compound was obtained as a beige solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc
Reaction SMILES: [NH2:1][C@@H:2]([C:14]([NH:16][C@@H:17]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1.[NH:32]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:33]([C:38](O)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36].O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C.O>[NH:32]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[C@H:33]([C:38]([NH:1][C@@H:2]([C:14]([NH:16][C@@H:17]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1)=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCC[C@@H](NC(=O)[C@H](N)Cc1ccc2ccccc2c1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCC[C@@H](NC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
To a solution of H-DNal-DNle-OBzl (180 mg, prepared in (2)) in dichloromethane (5 ml) were added Boc-Leu-OH.H2O (180 mg), HOBT.H2O (70 mg) and EDCI.HCl (99 mg) successively under ice cooling. After being stirred at room temperature for 14 h, the mixture was diluted with ethyl acetate, washed with sat. aq. NaHCO3, 10% aq. citric acid, water and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by dry column flash chromatography (Merck, Kieselgel 60) with ethyl acetate/hexane=1/2 for elution to give Boc-Leu-DNal-DNle-OBzl (239 mg). A solution of the tripeptide derivative (87 mg) in 95% ethanol (10 ml) was hydrogenated over 10% Pd/C (21 mg) at an atmospheric pressure of hydrogen for 1 h. After removal of the catalyst by filtration, the filtrate was concentrated in vacuo to give Compound 16 (74 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)cc1F
Yield: 58.1 %

Procedure:
Using 0.21 g of 2,4-difluorobenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.17 g of 2-(2,4-difluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (70)).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].BrN1C(=[O:19])CCC1=O.BrC1C2C=CC=C([N+]([O-])=O)C=2OC=1.C(N(CC)CC)C>CS(C)=O.F[B-](F)(F)F.[Ag+]>[N+:1]([C:4]1[C:12]2[O:11][CH2:10][C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1cccc2c1OCC2
Agent: [Ag+]
Agent: F[B-](F)(F)F
Agent: O=[N+]([O-])c1cccc2c(Br)coc12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1COc2c1cccc2[N+](=O)[O-]

Procedure:
Schema 3 illustrates an alternative method of producing the above benzofuranyl-3-on-7-yl uracils by the oxidation of a 2,3-dihydro-4,6-optionally disubstituted-7-nitrobenzofuran (Compound III in Schema 1). The 2,3-dihydro-7-nitrobenzofuran is treated with N-bromosuccinimide while being irradiated with light. The product of this reaction, a 3-bromo-7-nitrobenzofuran (VIII), is then reacted with silver tetrafluoroborate in dimethyl sulfoxide in the presence of triethylamine, yielding the corresponding 2,3-dihydro-7-nitrobenzofuran- 3-one (IX). This compound may be used in place of compound III in Schema I to produce the corresponding 3-(2,3-dihydrobenzofuran-3-on-7-yl)-1-alkyl-6-haloalkyluracil.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[CH:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][CH2:29][S:30][CH3:31].CN1C(=O)CCC1>O>[CH3:31][S:30][CH2:29][CH2:28][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[N:12][N:11]2[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[N:10]=1
Reactant: CCCSc1nccc(-n2ncc3c(O)cccc32)n1
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCSc1nccc(-n2ncc3c(OCCSC)cccc32)n1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
1-(2-Propylsulfanyl-pyrimidin-4-yl)-1H-indazol-4-ol (600 mg), potassium carbonate (1.104 g) and 1-chloro-2-methylsulfanyl-ethane 401.9 mg) were added to NMP (6 mL), and the mixture was heated to 80° C. for three hours. The mixture was cooled, diluted with water and filtered. The collected solid was washed with water and dried under reduced pressure to give 705 mg of 4-(2-Methylsulfanyl-ethoxy)-1-(2-propylsulfanyl-pyrimidin-4-yl)-1H-indazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[N:5]2[CH:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[S:32][CH:31]=[N:30][CH:29]=1)CCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[N:5]4[CH:20]=[CH:21][N:22]=[C:4]4[CH:3]=[C:2]([C:28]4[S:32][CH:31]=[N:30][CH:29]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1
Reactant: N#CCC(C1CC1)n1cc(-c2nc(Cl)cc3nccn23)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#CCC(C1CC1)n1cc(-c2nc(-c3cncs3)cc3nccn23)cn1
Temperature: 100 °C
Yield: 78.1 %

Procedure:
To a flask charged with 3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-cyclopropylpropanenitrile (Preparation M; 0.020 g, 0.064 mmol), 5-(tributylstannyl)thiazole (0.029 g, 0.077 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.0061 g, 0.013 mmol), and tris(dibenzylideneacetone)dipalladium (0.0059 g, 0.0064 mmol), evacuated and backfilled with argon, was added 1.5 mL of dioxane. Argon was bubbled through the reaction for 5 minutes and the flask was sealed and heated to 100° C. for 3 hours. The reaction mixture was loaded onto a silica gel column pre-wetted and eluted with ethyl acetate containing 0.5% ammonium hydroxide to afford the title compound (0.018 g, 0.050 mmol, 78% yield). MS (apci) m/z=362.1 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)#[N:27]>CN(C=O)C>[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)#[N:27]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1C#N

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide and 2-cyanophenylboronic acid (CAS RN 138642-62-3) and using DMF as solvent for the reaction. Off-white solid (21%). MS (ESI): m/z=450.0 [M+H]+.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C@H:9]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:28]=[CH:27][C:21]4[CH:22]=[CH:23][C:24](=[O:26])[O:25][C:20]=4[CH:19]=3)[O:8][C:7]=2[CH:29]=1.[CH:30](N(C(C)C)CC)(C)[CH3:31].ICC>CN(C=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C@H:9]([CH2:12][N:13]([CH2:30][CH3:31])[CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:28]=[CH:27][C:21]4[CH:22]=[CH:23][C:24](=[O:26])[O:25][C:20]=4[CH:19]=3)[O:8][C:7]=2[CH:29]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1ccc2ccc(OCCCNC[C@H]3COc4ccc(O)cc4O3)cc2o1
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN(CCCOc1ccc2ccc(=O)oc2c1)C[C@H]1COc2ccc(O)cc2O1
Temperature: 60 °C

Procedure:
(S)-7-[3-[[(2,3-Dihydro-7-hydroxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (0.89 g, 2.13 mmole), diisopropylethylamine (0.80 ml, 4.59 mmole) and iodoethane (0.24 ml, 3.0 mmole) were combined in DMF and heated at 60° C. for 15 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 75 ml of dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue (1.82 g) was column chromatographed on 75 g of silica gel using first 0.5% methanol/dichloromethane and then 2% methanol/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the free base redissolved in methanol. 2.8 ml of 4N isopropanolic HCl was added, the mixture was brought to a boil on a hot plate and the solvent gradually replaced with isopropanol. Upon cooling, 0.66 g of the title compound precipitated as a yellow solid, monohydrochloride, quarter hydrate, m.p. 204°-207° C.