Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].C1CCN2C(=NCCC2)CC1>C1COCC1>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:25])[C:7]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:21])=[CH:18][CH:17]=3)=[C:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1ccc(-c2c(C(F)(F)F)oc3cc(O)ccc3c2=O)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-(7-hydroxy-4-oxo-2-(trifluoromethyl)-4H-chromen-3-yl)benzoic acid (synthesis is described in PCT/US2010/024035) (100 mg, 0.28 mmol) in THF (10 ml) was added CDI (139 mg, 0.86 mmol) at room temperature. The mixture was stirred for 2 hours. MeSO2NH2 (280 mg, 2.86 mmol) was added in one portion, followed by DBU (394 mg, 2.86 mmol). The mixture was stirred for 4 hours and partitioned between 1N HCl (30 ml) and ethyl acetate (100 ml). The organic phase was separated, washed with brine (50 ml), dried over Na2SO4 and concentrated to give the desired product contaminated with the acid starting material. The mixture was difficult to purify and the acid contaminant was converted into the methyl ester by treatment with SOCl2 (91 mg, 0.77 mmol) in MeOH (4 ml) at 0° C. When the addition was complete, the mixture was stirred for 3 days. The volatiles were removed under reduced pressure and the residue was purified by prep-HPLC to afford the desired product in Example 10 as a white powder (25 mg, 20.5%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:23])=[CH:11][C:12]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=1)=[O:7])#[N:2].N1C=CC=CC=1.[CH:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[C:10]([NH:23][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([CH:33]([CH3:34])[CH3:35])=[CH:37][CH:38]=2)=[CH:11][C:12]([O:15][Si:16]([CH3:21])([CH3:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2cccc(C#N)c2)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-4-(dimethyl-t-butylsiloxy)-1,2-benzenediamine (2.63 g, 7.17 mmol) and CH2Cl2 (45 mL) at 0° C. was added pyridine (0.65 mL, 8.0 mmol) followed by a solution of the 4-isopropyl benzoyl chloride (10.1 mmol) in CH2Cl2 (90 mL). The reaction was allowed to warm to room temperature and stirred for 10 m. The reaction was diluted with CH2Cl2 (200 mL) and washed with sat. aq. NH4Cl (2×50 mL). The organic layer was MgSO4 dried filtered, and concentrated. The residue was chromatographed (10% EtOAc/hexanes to 20% EtOAc/hexanes) to give the title compound as a solid (3.04 g, 83%); IR(CHCl3): 2962, 1656, 1610, 1513, 1473, 1295 cm−1; NMR(300 MHz, CDCl3): δ0.16 (s, 6H), 0.95 (s, 9H), 1.29 (s, 3H), 1.31 (s, 3H), 3.00 (m, 1H), 6.68 (d, 1H, J=9.0), 6.86 (s, 1H), 7.38 (d, 2H, J=8.1), 7.50 (d, 1H, J=9.0), 7.61 (m, 1H), 7.81 (d, 1H, J=6.3), 7.89 (d, 2H, J=7.1), 8.16 (d, 1H, J=9.3), 8.29 (s, 1H), 8.58 (br s, 1H), 9.40 (br s, 1H); MS(FD): 513.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([O:15][CH3:16])[CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH:13]([O:15][CH3:16])[CH2:12][N:11]([C:23]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:24])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCc1ccc(C2CNCC(OC)C2)cc1
Product: CCc1ccc(C2CC(OC)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
880 mg (4.0 mmol) of 3-(4-ethylphenyl)-5-methoxypiperidine and 780 mg (5.2 mmol, 1.3 eq.) of morpholine-4-carbonyl chloride were reacted according to General Method 3A. Yield: 896 mg (58% of theory)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH:20](B(O)O)=[CH2:21]>>[C:14]1([C@@H:12]([N:8]2[C:6]3=[N:7][C:2]([CH:20]=[CH2:21])=[CH:3][N:4]=[C:5]3[N:10]=[C:9]2[OH:11])[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](c1ccccc1)n1c(O)nc2ncc(Br)nc21
Reactant: C=CB(O)O
Product: C=Cc1cnc2nc(O)n([C@@H](C)c3ccccc3)c2n1
Temperature: 90 °C
Yield: 54 %

Procedure:
A scintillation vial equipped with a stirbar was charged with (S)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), vinyl boronic acid (2.2 equiv), and (DPPF)PdCl2 (0.10 equiv). The vial was fitted with a septum-lined cap and purged with nitrogen for 5-10 min. To this mixture was added dioxane (16.6 volume equivalents) and degassed 2N K2CO3 (4.2 volume equivalents) by syringe. The resulting mixture was heated to 90° C. overnight. The mixture was cooled to room temperature, diluted with 12 volume equivalents EtOAc, washed with twice with saturated aq. NaHCO3, and once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Biotage MPLC 5%-40% EtOAc/Hexanes) provided the title compound as an off-white solid (54%). LCMS m/z (APCI)=267.0 (M+H).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:17]I>CN(C)C=O.CCOCC.[Ag]=O>[C:1]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Reactant: CI
Agent: O=[Ag]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 35.6 ml of benzylchloroformate in 200 ml of dichloromethane was added dropwise to a mixture of 10 g of (racemic)-3-pyrrolidinol, 48.3 ml of triethylamine and 725 ml of dichloromethane which was cooled to 0° C. The mixture was stirred for 48 hours at room temperature. The dichloromethane solution was extracted with 5% hydrochloric acid and 5% aqueous sodium bicarbonate. The acid and bicarbonate washes were combined, salted with sodium chloride and extracted with 2×750 ml of ethyl acetate. The combined organic extracts were dried and concentrated, giving 22.7 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol. A mixture of 2.5 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol, 2.0 ml of methyl iodide and 5.1 g of silver oxide in 50 ml of dimethylformamide was stirred at room temperature for 2 days. The mixture was diluted with ether and then filtered. The filtrate was concentrated to a small volume. The ether solution was washed with water, dried and concentrated to dryness in vacuo. The residue was purified by chromatography (silica gel) to give 2.4 g of (racemic)-N-carbobenzyloxy-3-methoxypyrrolidine as a pale yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.[CH2:24]([N:31]1[CH:40]=[C:39]([C:41]([NH:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[O:42])[C:38]2[C:33](=[CH:34][CH:35]=[C:36](Br)[CH:37]=2)[C:32]1=[O:50])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>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>[CH2:24]([N:31]1[CH:40]=[C:39]([C:41]([NH:43][CH2:44][CH2:45][N:46]([CH3:47])[CH3:48])=[O:42])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:10]3[CH:11]=[C:6]([C:5](=[O:23])[NH:4][CH:1]4[CH2:2][CH2:3]4)[CH:7]=[C:8]([F:22])[C:9]=3[CH3:21])[CH:37]=2)[C:32]1=[O:50])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)CCNC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(Br)cc12
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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+]
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C(=O)NCCN(C)C)c2c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a degassed mixture of N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.1 g) [prepared as described in WO 06110173], the product of step ii) (0.09 g) and potassium carbonate (0.06 g) in DMF (5 mL) under nitrogen, was added tetrakis(triphenylphosphine)palladium(0) (0.02 g) and the mixture stirred at 80° C. for 16 hours. The reaction mixture was concentrated to dryness and the crude product was purified (SiO2, elution with 90:10:0.1 dichloromethane: methanol: triethylamine) and by HPLC. The fractions containing product were concentrated to dryness and the residue crystallised from acetonitrile to afford the title compound as a solid (0.04 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccnc(O)c1
Reactant: Fc1cccc(F)c1CBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ccnc(OCc2c(F)cccc2F)c1
Yield: 61.7 %

Procedure:
A mixture of 5.00 g (24.2 mmol, 1.0 eq.) of 2,6-difluorobenzyl bromide [CAS No: 85118-00-9] and 3.16 g (29.0 mmol, 1.2 eq.) of 2-hydroxy-4-methylpyridine [CAS No: 13466-41-6] was dissolved in 50 ml of THF. The solution was admixed with 7.99 g (29.0 mmol, 1.2 eq.) of silver carbonate and the mixture was heated to reflux with exclusion of light overnight. Subsequently, the reaction mixture was filtered through kieselguhr and eluted with ethyl acetate, and the filtrate was concentrated. The crude product was purified by means of Biotage Isolera (100 g silica gel cartridge, cyclohexane/ethyl acetate gradient, 0% to 10% ethyl acetate). 3.51 g of the title compound were obtained (61% of theory).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.S(=O)(=O)(O)O.[Br:23]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:23][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[C:7]([NH2:12])=[N:8][CH:9]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)cc1OCc1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
32.6 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 138 mmol, 1 equivalent) were suspended in 552 ml of 10% strength sulphuric acid, and the mixture was cooled to 0° C. 8.5 ml of bromine (165 mmol, 1.2 equivalents) were dissolved in 85 ml of acetic acid and then, over a period of 90 min, added dropwise to the ice-cooled reaction solution. After the dropwise addition had ended, the mixture was stirred at 0° C. for 90 min and then diluted with 600 ml of ethyl acetate, and the aqueous phase was separated off. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried and concentrated. The residue was dissolved in dichloromethane and chromatographed on silica gel (petroleum ether/ethyl acetate gradient as mobile phase). This gave 24 g (55% of theory) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1Br)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)=[O:8]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1
Yield: 93 %

Procedure:
To a closed glass vessel equipped with a thermometer and a stirrer, there are charged 105.3 g (0.3 moles) of 3,3'-dinitro-4-bromo benzophenone, 5 g of 5% palladium/active carbon catalyst (available from Nihon-Engelhardt Co.) and 300 ml of dioxane. With the mixture being stirred at 70°-80° C., hydrogen is introduced into the vessel so that 40.5 l (1.81 moles) of hydrogen is absorbed in the mixture over about 8 hours. Then, after 33 g (0.33 moles) of 40% aqueous solution of caustic soda is added, hydrogen is further introduced at 70°-80° C. with the mixture being stirred so that an additional 7.2 l (0.32 moles) is absorbed during three hours. The reaction liquid is filtered at 70°-80° C. so as to remove the catalyst and then allowed to cool giving yellow needle-like crystals of 3,3'-diamino benzophenone. The crystals is filtered, washed with 30 ml of 50% aqueous solution of dioxane, and dried. Yield 93% (59.2 g). M.P. 149°-150° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH3:33])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[C:21]1[N:26]=[C:25]([CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:24]=[CH:23][CH:22]=1.[CH3:34][CH2:35][O:36][CH:37]=[C:38]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>O1CCCC1>[CH2:35]([O:36][CH:37]([CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:27]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([C:14]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[CH3:33])[N:26]=1)[C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH3:34]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCC(=O)Cc1cccc(-c2c(C)cc(C)cc2C)n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCC(=O)C(c1cccc(-c2c(C)cc(C)cc2C)n1)C(OCC)C(C(=O)OCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl amine (0.16 mL, 1.13 mmol) was dissolved in tetrahydrofuran (2 mL). n-Butyllithium (2.5M, 0.45 mL, 1.13 mmol) was added at 0° C. and the reaction stirred for 0.5 h. The solution was cooled to −78° C. and 1-(6-mesityl-pyridin-2-yl)-pentan-2-one (0.29 g, 1.0 mmol) was added. After 0.5 h, ethyl ethoxymethylene malonate (0.21 mL, 1.0 mmol) was added and the reaction was warmed to room temperature. The solution was quenched with water, extracted with ethyl acetate, dried, and concentrated. Flash chromatography (10%-20% ethyl acetate/hexanes) gave the title compound as a mixture of two isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].C([O-])([O-])=[O:22].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH2:12])=[O:22])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 4-[4-chloro-3-(trifluoromethyl)phenoxy]benzonitrile (Preparation 47, 48 g, 161 mmol) in DMSO (500 ml) was added K2CO3 (45 g, 323 mmol) followed by dropwise addition of a 30 wt % aqueous hydrogen peroxide solution (27 ml, 806 mmol) at 15° C. The reaction mixture was stirred for 1 hour at room temperature and the mixture was poured into water (500 ml) to afford a preciptate. The precipitated solid was collected by filtration, azeotroped with toluene, and dried over in vacuo to give 51 g of titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4]P(=O)(OC)OC.[H-].[Na+].[CH:17](=O)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[O:22]1[CH:21]=[CH:20][CH:19]=[C:18]1/[CH:17]=[CH:4]/[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[Br:1]
Reactant: O=Cc1ccco1
Reactant: COP(=O)(Cc1ccccc1Br)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1/C=C/c1ccco1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
A solution of dimethyl 2-bromobenzylphosphonate (10.35 g) in dry DMF (50 ml) was added dropwise at room temperature to a stirred suspension of sodium hydride (0.979 g) in dry DMF (100 ml) (effervescence). After 20 minutes, a solution of furfural (3.56 g) in dry DMF (50 ml) was added (exotherm) and the resulting mixture was stirred at room temperature for 4 hours, then diluted with water and extracted with ether. The extracts were washed with water, treated with magnesium sulphate and charcoal, filtered, concentrated under reduced pressure, and chromatographed using 40-60° C. petrol as eluant to give E-1-(2-furyl)-2-(2-bromophenyl)-ethylene (3.755 g), a pale yellow liquid (containing about 6% of the corresponding Z-isomer by GC).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([CH3:7])([CH3:6])[CH3:5])[CH3:3].C(=O)([O-])[O-].[K+].[K+].O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18](F)[CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[C:20]([NH:1][C@H:2]([CH3:3])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:21]=1
Reactant: C[C@@H](N)C(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](Nc1cc(Cl)ccc1[N+](=O)[O-])C(C)(C)C
Temperature: 75 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
Add 2-(R)-amino-3,3-dimethylbutane (20 mL, 0.148 mol), potassium carbonate (14.3 g, 0.104 mol) and water (50 mL) to a solution of 4-chloro-2-fluoronitrobenzene (13.3 g, 0.076 mol) in THF (450 mL) and stir at 75° C. for 3 h Cool to ambient temperature. Concentrate to ½ volume, dilute with ethyl acetate and wash with 1N HCl (4×100 mL), water, saturated sodium bicarbonate, saturated sodium chloride, dry with magnesium sulfate and concentrate to give the title compound as an orange solid (19.6 g, quant).
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.OP(O)(O)=O>ClCCl>[C:1]1([C:7]2([C:16]3[CH:17]=[CH:18][C:13]([OH:19])=[CH:14][CH:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: Oc1ccccc1
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: ClCCl
Product: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-Phenyl-1-cyclohexene (1 g, 6.3 mmol), phenol (1.5 g, 15.9 mmol) and BF3.H3PO4 (0.05 mL) were mixed and shaken at 80° C. overnight. Dichloromethane (30 mL) was added and the organic phase was washed with saturated NaHCO3 (aq.) (2×10 mL), dried (Na2SO4) and concentrated. The title compound was crystallised from a mixture of methanol and water. Yield: 1040 mg. 1H NMR (400 MHz, CDCl3): δ 7.28-7.25 (m, 4H), 7.16-7.10 (m, 3H), 6.75-6.70 (m, 2H), 4.51 (br. s, 1H), 2.28-2.22 (m, 4H), 1.60-1.52 (m, 4H), 1.52-1.45 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 153.25, 149.15, 141.22, 128.63, 128.39, 127.29, 125.55, 115.21, 45.89, 37.50, 26.63, 23.14. LC-MS purity (UV/MS): 100/100%, Rt 5.07 min, M−1: 251.62.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:39]([N:42]=[C:43]=[O:44])[CH2:40][CH3:41]>C1COCC1>[CH2:39]([NH:42][C:43]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:23])([F:25])[F:24])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)=[O:44])[CH2:40][CH3:41]
Reactant: CCCN=C=O
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride (100 mg, 0.204 mmol) and triethylamine (57 μL, 0.408 mmol) in 5 mL THF at 0° C. was added n-propylisocyanate (21.6 mg, 0.255 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to yield 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid propylamide (83 mg, 81%). ES-MS calcd for C25H26F3N5O3 (m/e) 501.51, obsd 502.1 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:28]C2CC2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]([CH3:43])[C:38](=[O:44])[CH2:37][CH2:36]2.C[Si](Cl)(C)C>C(O)CCC>[NH2:28][C:4]1[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH:32][C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[N:39]([CH3:43])[C:38](=[O:44])[CH2:37][CH2:36]3)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: CN1C(=O)CCc2cc(N)ccc21
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CN1C(=O)CCc2cc(Nc3nc(N)c4c(-c5ccc(F)cc5)c[nH]c4n3)ccc21

Procedure:
A solution of 2-chloro-N-cyclopropyl-5-(4-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (76 mg, 0.17 mmol), 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (60 mg, 0.34 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (2 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound. MS 403.4 (M+H); UV 205.3, 293.4 nm.
Reaction SMILES: [OH:1][C:2]([CH3:17])([CH3:16])[CH:3]([NH:8][C:9](=[O:15])OC(C)(C)C)[C:4](=[O:7])[NH:5][CH3:6].FC(F)(F)C(O)=O.[CH:25]1([C:28]2[C:29]([O:37][C@@H:38]([CH3:43])[C:39]([F:42])([F:41])[F:40])=[CH:30][C:31](C(O)=O)=[N:32][CH:33]=2)[CH2:27][CH2:26]1>ClCCl>[CH:25]1([C:28]2[C:29]([O:37][C@@H:38]([CH3:43])[C:39]([F:42])([F:40])[F:41])=[CH:30][C:31]([C:9]([NH:8][CH:3]([C:2]([OH:1])([CH3:16])[CH3:17])[C:4]([NH:5][CH3:6])=[O:7])=[O:15])=[N:32][CH:33]=2)[CH2:27][CH2:26]1
Reactant: CNC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)O
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C(NC(=O)c1cc(O[C@@H](C)C(F)(F)F)c(C2CC2)cn1)C(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[2-hydroxy-2-methyl-1-(methylcarbamoyl)propyl]carbamate (example 236a, 760 mg, 1.94 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (3.00 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated down to dryness and the crude residue was dissolved in toluene. Volatiles were removed in vacuo to afford a white solid which was dried in HV overnight to yield the crude amine (680 mg) as a trifluroacetate salt which was used without any purification. The crude amine salt was used to synthesize the title compound in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) as starting materials and the title compound was isolated (76 mg, 59%); MS (ESI, m/z): 404.6 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([Cl:10])=[CH:5][C:4]=1[CH2:11]Br.[C:13]1([C:19]([NH2:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:10][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][C:7]=1[F:9])[CH2:2][N:32]([C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:11]2
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1cc(CBr)c(CBr)cc1Cl
Product: Fc1cc2c(cc1Cl)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2(b) from 1,2-Bis-bromomethyl-4-chloro-5-fluoro-benzene and triphenylmethylamine. Brown oil.