Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([F:17])[N:3]=1.ClC1C=C([C:25]2[N:29]3[CH:30]=[C:31]([NH:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]4)[CH:32]=[CH:33][C:28]3=[N:27][CH:26]=2)C=CN=1.BrC1N2C=C(NC3CCCC(O)C3)C=CC2=NC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:25]2[N:29]3[CH:30]=[C:31]([NH:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]4)[CH:32]=[CH:33][C:28]3=[N:27][CH:26]=2)[CH:5]=[C:4]([F:17])[N:3]=1
Reactant: OC1CCCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)C1
Reactant: CC1(C)OB(c2cc(F)nc(Cl)c2)OC1(C)C
Agent: OC1CCCC(Nc2ccc3ncc(Br)n3c2)C1
Product: OC1CCCC(Nc2ccc3ncc(-c4cc(F)nc(Cl)c4)n3c2)C1

Procedure:
The title compound is prepared from 2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and (1SR,3RS)-3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol [Intermediate R (step 1)] by a procedure analogous to [Intermediate J (step 2)]
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Br[CH:12]([CH3:20])[C:13]([O:15]C(C)(C)C)=[O:14]>>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([CH:12]([CH3:20])[C:13]([OH:15])=[O:14])[CH:3]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: CCOC(=O)c1cnn(C(C)C(=O)O)c1
Yield: 87.2 %

Procedure:
By a reaction in the same manner as in Example 10a and using ethyl 1H-pyrazole-4-carboxylate (1.40 g, 10.0 mmol) and tert-butyl 2-bromopropanate (3.14 g, 15.0 mmol), the title compound (1.85 g, 87%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1C=CC(F)=[C:6]([N+:11]([O-])=O)[CH:5]=1)C.C([N:18](CC)CC)C>>[N:3]1([CH2:4][CH2:5][CH2:6][NH2:11])[CH:14]=[CH:15][N:18]=[CH:1]1
Reactant: CCN(CC)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Product: NCCCn1ccnc1

Procedure:
A mixture of 8.8 g (0.041 mol) of diethyl(4-fluoro-3-nitrophenyl)amine obtained in the preceding stage, 17.0 g (0.136 mol) of 3-(imidazol-1-yl)propylamine (RN 5036-48-6) and 6.7 ml of triethylamine was heated at reflux with stirring for 2 hours.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:20])[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][C:9]=1[NH:16][C:17](=[O:20])[O:18][CH3:19]
Reactant: COC(=O)Nc1cc(O)c(Cl)cc1F
Reactant: BrC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 84.6 %

Procedure:
Cyclopentyl bromide (4.07 g, 27.3 mmol) was added to an acetonitrile solution (50 ml) containing methyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (5.00 g, 22,8 mmol) and potassium carbonate (1.80 g, 13.0 mmol), and the mixture was heated under reflux for 4 hours. After reaction, the reaction liquid was cooled to room temperature, 1 N hydrochloric acid (50 ml) was added thereto, and this was extracted with ethyl acetate (50 ml ×2). The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed by distillation under reduced pressure to obtain methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (5.56 g, 19.3 mmol). Yield: 84.8 %. m.p.: 120.0° to 123.0° C.
Reaction SMILES: Cl.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[C:11]([O:13][CH3:14])=[O:12].[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>N1C=CC=CC=1>[Br:15][C:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:2][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc2cccnc2[nH]1
Reactant: [Br-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1[nH]c2ncccc2c1Br
Temperature: 0 °C
Yield: 32.5 %

Procedure:
To a solution of 3.2 g of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride in 165 mL of pyridine is added dropwise, at 0° C. under an argon atmosphere, a solution of 5.04 g of pyridinium tribromide in 35 mL of pyridine. The reaction mixture is then stirred at 0° C., and then poured onto a mixture of 250 g of crushed ice and 750 ml of distilled water. The suspension is filtered and the solid is washed with twice 25 mL of distilled water and then dried in the open air. 0.87 g of methyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate is obtained in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCCC1>[CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:37])[NH2:14])=[CH:8]2
Reactant: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h
Yield: 199.4 %

Procedure:
A mixture of 7-(methyl{[2-(trifluoromethyl)phenyl]sulfonyl}amino)-1H-indole-2-carboxamide (2.6 g), Lawesson's reagent (1.3 g) and tetrahydrofuran (50 mL) was stirred at 60° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained oil was crystallized from toluene to give the title compound (2.65 g, yield: 100%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26]>C(O)C.Cl.Cl.NNC(N)=N>[ClH:26].[ClH:26].[C:21]([NH:24][N:25]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH2:1][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[N:25][NH:24][C:21](=[NH:22])[NH2:23])[CH:4]=1)(=[NH:23])[NH2:22]
Reactant: O=Cc1cccc(OCCOc2cccc(C=O)c2)c1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=Cc1cccc(OCCOc2cccc(C=NNC(=N)N)c2)c1
Yield: 78.5 %

Procedure:
3,3'-(ethylenedioxy)dibenzaldehyde (1.08 g), aminoguanidine hydrochloride (1.105 g), and aminoguanidine dihydrochloride (0.005 g) were heated in 96% ethanol (6.25 mL) for 18 hr under nitrogen. Cooling and filtration gave 1.428 g of 3,3'-(ethylenedioxy)dibenzaldehyde bis(amidinohydrazone) dihydrochloride, mp 264-6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8](COC)[C:7]=2[CH:6]=[C:5]([CH2:21][NH:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:4]=1.[ClH:29]>C(O)C>[ClH:29].[ClH:29].[ClH:29].[CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[NH:8][C:7]=2[CH:6]=[C:5]([CH2:21][NH:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:4]=1
Reactant: COCn1c(=O)c2c(c3c(OC)cc(CNN4CCOCC4)cc31)NCCC2
Agent: Cl
Solvent: CCO
Product: COc1cc(CNN2CCOCC2)cc2[nH]c(=O)c3c(c12)NCCC3
Temperature: 75 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
The compound (18 mg, 0.046 mmol) prepared in step 3 was dissolved in ethanol (1 ml), and added with 12 N aqueous solution of hydrochloric acid (1.5 ml). The reaction mixture was stirred at 75° C. for 2 hours. The solvent was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The precipitate was filtered, washed with ethyl acetate, and dried in vacuo to obtain the title compound (20.1 mg, yield: 96%, yellow solid).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[OH:16][C:17]1[C:30]2[C:29](=[O:31])[C:28]3[C:23](=[C:24]([O:32][CH3:33])[CH:25]=[CH:26][CH:27]=3)[O:22][C:21]=2[CH:20]=[C:19](O)[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:19]1[CH:18]=[C:17]([OH:16])[C:30]2[C:29](=[O:31])[C:28]3[C:23]([O:22][C:21]=2[CH:20]=1)=[C:24]([O:32][CH3:33])[CH:25]=[CH:26][CH:27]=3)(=[O:5])=[O:4]
Reactant: COc1cccc2c(=O)c3c(O)cc(O)cc3oc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc2c(=O)c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
Trifluoromethanesulfonic anhydride (3.1 mL, 18.43 mmol) was slowly added to a solution of 1,3-dihydroxy-5-methoxy-xanthen-9-one (3.32 g, 12.85 mmol) and pyridine (32.0 mL) in CH2Cl2 (130 mL) at 0° C. See, D. K. Ho et al., J. Org. Chem., 52, pp. 342-347 (1987). The reaction mixture then was allowed to slowly warm to RT and stirred for 16 h. The resulting orange mixture was concentrated to a brown oil, then dissolved in EtOAc (750 mL) and washed with 5% citric acid (3×100 mL), water (1×100 mL), and brine (1×100 mL). The organics were dried (MgSO4) and concentrated to yield 3.0 g (60%) of trifluoromethanesulfonic acid, 1-hydroxy-5-methoxy-9-oxo-9H-xanthen-3-yl ester as a light brown solid. Rf=0.65 (50% EtOAc/hexanes). 1H NMR (DMSO-d6, 400 MHz) δ: 12.89 (s, 1H), 7.74 (d, 1H), 7.60 (m, 1H), 7.50 (m, 1H), 7.42 (s, 1H), 7.04 (s, 1H), 3.97 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7](SC)[S:8][C:4]=2[CH:3]=1.[Br-].[CH2:14]([Zn+])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>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.CCOC(C)=O>[CH2:14]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:12]=[CH:11][C:5]=2[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CSc1nc2ccc(Br)cc2s1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Product: Brc1ccc2nc(Cc3ccccc3)sc2c1
Temperature: 60 °C
Yield: 28 %

Procedure:
A degassed mixture of 6-bromo-2-(methylthio)-1,3-benzothiazole (4.20 g, 16.14 mmol), tetrakis(triphenylphosphine)palladium(0) (186 mg, 0.161 mmol) and benzylzinc bromide (0.5 M in THF, 61.34 mL) was heated at 60° C. for 4 hrs. EtOAc (200 mL) was added and the organic layer was washed with saturated, aqueous NaHCO3 (3×150 mL), then water (3×150 mL). The organic layer was dried over MgSO4 and concentrated. The crude material was purified by ISCO® chromatography using 4% EtOAc in hexane to obtain the desired product (1.50 g, 28%). 1H NMR (400 MHz, acetone-d6) δ 8.20 (s, 1H), 7.88 (d, 1H), 7.62 (d, 1H), 7.44-7.30 (m, 5H), 4.44 (s, 2H); LC-MS m/z [M+H]+ 304.2 & 306.1, RT 4.02 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Methyl 2′-methyl-2-nitro-1,1′-biphenyl-4-carboxylate, prepared in step 1 (2.5 g, 9.2 mmol) was dissolved in dry THF (20 mL) and cooled to 0° C. To this solution was added lithium hydroxide (1.15 g, 27.6 mmol) in water (5 mL) and the mixture was stirred at RT for 4 h. The solvents were concentrated and the aqueous residue was washed with EtOAc. The aqueous layer was separated and acidified with 1.5N HCl to pH 2-3 and extracted with DCM. DCM was washed with water and dried over sodium sulphate and evaporated under reduced pressure to obtain the title compound as a yellow solid (1.6 g, 70%). 1H NMR: (DMSO-d6, 400 MHz) δ 13.67 (bs, 1H), 8.49 (s, 1H), 8.26-8.24 (d, 1H), 7.58-7.56 (m, 1H), 7.35-7.32 (m, 2H), 7.27-7.12 (d, 1H), 7.10 (d, 1H), 2.09-1.99 (s, 3H). LC/MS (Method A): 255.9 (M−H)−. HPLC (Method B) Rt 1.79 min (Purity: 99.16%).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH2:27](Br)[CH2:28][CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:30][CH:29]([CH3:31])[CH2:28][CH2:27][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([N+:7]([O-:9])=[O:8])[CH:18]=2)[C:14]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)=[CH:15]1
Reactant: CC(C)CCBr
Reactant: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CCn1cc(-c2ccc(C#N)cc2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Method L Add Cs2CO3 (1.0 g, 1.88 mmol) to a solution of 4-(6-Nitro-1H-indol-3-yl)-benzonitrile, 9, (100 mg, 0.37 mmol) and isopentyl bromide (0.1 mL, 0.75 mmol) in DMF (10 mL). Stir overnight at ambient temperature. Remove the DMF solvent to provide a solid and partition the solid between EtOAc and H2O, Sequentially wash the organic layer with H2O and brine then dry the organic layer over MgSO4. Filter and remove the solvent leaving a solid. Purify by silica gel column chromatography (0-100% EtOAc/hexanes gradient) and concentrated to dryness to afford 180 mg (95%) of the title compound. LRMS (API ES+)=334.3 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16]O)=[CH:8][CH:7]=1>>[Cl:3][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1
Reactant: OCCCCC(c1ccc(F)cc1)c1cccnc1
Reactant: O=S(Cl)Cl
Product: Fc1ccc(C(CCCCCl)c2cccnc2)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
64 Parts of thionyl chloride were added portionwise to 4 parts of ε-(4-fluorophenyl)-3-pyridinepentanol. Upon complete addition, stirring was continued for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The whole was treated with sodium carbonate. The product was extracted twice with methylbenzene. The combined extracts were washed with water, dried, filtered and evaporated, yielding 3.7 parts (100%) of 3-[5-chloro-1-(4-fluorophenyl)pentyl]pyridine as a residue (int. 57).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:16](=[O:18])[C:15]([C:19](O)=[O:20])=[CH:14][N:13]([CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[C:12]=2[N:11]=[CH:10]1.C(N(CC)CC)C.ClC(OCC)=O.C(=O)([O-])[O-].[BH4-].[Na+]>C1COCC1.C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:16](=[O:18])[C:15]([CH2:19][OH:20])=[CH:14][N:13]([CH:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[C:12]=2[N:11]=[CH:10]1
Reactant: CCCC(CCC)n1cc(C(=O)O)c(=O)c2c1ncn2-c1ccc(C)cc1C
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCC(CCC)n1cc(CO)c(=O)c2c1ncn2-c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 42.2 %

Procedure:
To 0.14 g (0.29 mmol) of 1-(2,4-dimethylphenyl)-4-(heptan-4-yl)-7-oxo-4,7-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylic acid in 5 mL of THF was added 0.15 mL (1.1 mmol) of triethylamine and 0.10 mL (1.0 mmol) of ethyl chloroformate. The resulting yellow slurry was stirred at room temperature for 40 min. The crude carbonate solution was then added to 0.135 g (3.6 mmol) of sodium borohydride in 5 mL of ethanol at room temperature and the resulting mixture was stirred for 30 min. The reaction was concentrated in vacuo, diluted with water and extracted with chloroform. The combined extracts were washed with brine, dried over sodium sulfate, filtered and the resulting filtrate was concentrated in vacuo. The crude material thus obtained was purified by flash chromatography eluting with a 3% methanol/dichloromethane mixture to give 45 mg of the title compound as a white solid. Dirty fractions were combined, concentrated and purified to give an additional 23 mg of the title compound. The overall yield of the title compound was 68 mg (65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([OH:19])[CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:17][CH:16]([F:18])[C@H:15]([C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:3]=[C:2]([NH:1][C:27]3[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=3)[CH:7]=[C:6]([F:8])[CH:5]=2)=[CH:14][CH:13]=1)[OH:19]
Reactant: Nc1cc(F)cc(-c2ccc([C@H](O)C(F)F)cc2)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: O[C@@H](c1ccc(-c2cc(F)cc(Nc3nccc(C(F)(F)F)n3)c2)cc1)C(F)F
Temperature: 110 °C

Procedure:
Palladium(II) acetate (33.5 mg, 0.149 mmol) was added to a mixture of (1S)-1-(3′-amino-5′-fluorobiphenyl-4-yl)-2,2-difluoroethanol (222 mg, 0.747 mmol), cesium carbonate (487 mg, 1.494 mmol), and 2-chloro-4-(trifluoromethyl)pyrimidine (143 mg, 0.784 mmol) in degassed (by sparging with Argon) dioxane (8 mL). The mixture was heated to 110° C. for 5 hours. Upon cooling to room temperature, the reaction mixture was diluted with saturated aqueous NaHCO3, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/toluene) to afford (1S)-2,2-difluoro-1-(3′-fluoro-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-yl)ethanol. MS ESI calc'd. for C19H14F6N3O [M+H]+ 414, found 414. 1H NMR (500 MHz, Acetone-d6): δ 9.48 (s, 1H); 8.89 (d, J=4.9 Hz, 1H); 8.02 (d, J=2.1 Hz, 1H); 7.89 (dd, J=11.4, 2.4 Hz, 1H); 7.76 (d, J=8.0 Hz, 2H); 7.63 (d, J=8.0 Hz, 2H); 7.32 (d, J=4.9 Hz, 1H); 7.19-7.15 (m, 1H); 6.01 (td, J=55.9, 4.3 Hz, 1H); 5.37 (d, J=4.9 Hz, 1H); 5.00-4.93 (m, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[NH:16][C:15](=[O:24])[N:14]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:13]3=[O:30])[CH:9]=1)=[O:4].[OH-].[Na+]>CN(C)C=O>[CH3:29][S:26]([NH:25][N:14]1[C:13](=[O:30])[C:12]2[C:17](=[CH:18][C:19]([C:20]([F:21])([F:22])[F:23])=[C:10]([N:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[CH:7]3)[CH:11]=2)[NH:16][C:15]1=[O:24])(=[O:28])=[O:27]
Reactant: COC(=O)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-n3cnc(C(=O)O)c3)cc2c1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid methyl ester (150 mg, 0.335 mmol) in 10 ml dimethylformamide are added 1.7 ml of 1 M aqueous sodium hydroxide solution and stirred at room temperature for one hour and at 50° C. for two hours. After cooling to room temperature the solvent is evaporated in vacuo, the residue taken up in water, acidified with 5 ml of 1 M hydrochloric acid and extracted three times with 15 ml each of dichloromethane. The organic layer is dried over sodium sulfate, filtered and evaporated to give 126 mg (0.29 mmol, 87%) of amorphous 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid, ES-MS: m/z 434 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][C:9]1([CH3:20])[CH3:19])=O)(C)(C)C.I[CH2:22][CH3:23].[H-].[Na+].C(O)(C(F)(F)F)=O.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl.CCOC(C)=O.CCCCCC>[CH2:22]([CH:10]1[C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:8][C:9]1([CH3:19])[CH3:20])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C(=O)CC1(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCC1C(=O)c2ccccc2NC1(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.7 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (EXAMPLE 325) (0.10 g, 0.36 mmol) and iodoethane (0.50 mL, 6.3 mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 40 mg, 1.0 mmol) and the resulting mixture was stirred at rt for 15 h. The reaction was quenched with water (5 mL) and was extracted with EtOAc (2×15 mL). Removal of solvent and chromatography of the crude residue on a silica gel column using a 10% mixture of EtOAc and hexane as solvent afforded a mixture of products, which was treated with TFA (0.50 mL) in methylene chloride (1.0 mL) for 3 h. The reaction was neutralized to pH 10 by 5% NaOH and was extracted with EtOAc (2×20 mL). Chromatography (silica gel, EtOAc/hexane, 3/7) afforded 30 mg (41%) of (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone (30 mg, 0.15 mmol) as a colorless oil. The quinolinone (30 mg, 0.15 mmol) was treated with Et3SiH (1.0 mL) and BF3 -OEt2 (0.05 mL, 0.4 mmol) in CH2Cl2 (1.0 mL) at 100° C. for 15 h in a sealed tube. Purification of the crude product by chromatography (silica gel, EtOAc/hexane, 1/9) afforded 20 mg (71%)of (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethylquinoline. Data for (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 6.98 (d, J=7.5, 1 H), 6.96 (t, J=7.5, 1 H), 6.61 (t, J=7.5, 1 H), 6.44 (d, J=7.5, 1 H), 3.60 (s, 1 H), 2.90 (dd, J=16.7, 5.2, 1 H), 2.41 (dd, J=16.7, 10.7, 1 H), 1.68 (m, 1 H), 1.52 (m, 1 H), 1.23 (m, 1 H), 1.22 (s, 3 H), 1.05 (s, 3 H).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12]([O:16][C:17](=[O:40])[NH:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:27]([O-])=[CH:26][C:25]=2[N:24]=[C:23]1[CH2:36][CH2:37][CH2:38][CH3:39])([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+:42]>C(Cl)Cl>[C:12]([O:16][C:17](=[O:40])[NH:18][CH2:19][CH2:20][CH2:21][N:22]1[C:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=[C:26]([NH2:42])[C:25]=2[N:24]=[C:23]1[CH2:36][CH2:37][CH2:38][CH3:39])([CH3:15])([CH3:14])[CH3:13]
Reactant: [NH4+]
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
p-Toluenesulphonyl chloride (0.43 g) was added portionwise to a vigourously stirred mixture of the product from step (v) (0.9 g) in DCM (25 mL) and ammonium hydroxide solution (35%, 2.5 mL) at 0° C. The mixture was allowed to warm to rt over 2 h then partitioned between water/DCM, washed with saturated sodium bicarbonate solution, dried, filtered and the solvent evaporated. The solid product was triturated with diethylether to give the subtitle compound (0.6 g).
Reaction SMILES: [CH2:1]([N:5](CC(C)=C)[C:6]1[CH:11]=CC=C[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:16]1([CH3:23])[C:17](C)=[CH:18][CH:19]=[CH:20][CH:21]=1>[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:5]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][C:6]1([CH3:11])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C)CN(CCCC)c1ccccc1
Reactant: Cc1ccccc1C
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCCN1c2ccccc2CC1(C)C
Reaction time: 4.75 h

Procedure:
A mixture of N-butyl-N-(2-methylprop-2-eneyl)aniline (9.6 parts), zinc chloride (6.12 parts) and xylene (20 parts) was heated under reflux with vigorous stirring for 4.75 hours. The cooled mixture was filtered and the organic phase evaporated to leave 1-butyl-2,2-dimethylindoline (5.3 parts).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][OH:8])[NH:4][N:3]=1.CCO/[CH:12]=[C:13](/[CH:15]=O)\[CH3:14]>C(O)(=O)C>[CH3:15][C:13]1[CH:12]=[N:1][C:2]2[N:3]([N:4]=[C:5]([CH2:7][OH:8])[N:6]=2)[CH:14]=1
Reactant: Nc1n[nH]c(CO)n1
Reactant: CCO/C=C(\C)C=O
Solvent: CC(=O)O
Product: Cc1cnc2nc(CO)nn2c1
Temperature: 80 °C

Procedure:
To a solution of (3-amino-1H-1,2,4-triazol-5-yl)methanol (16.6 g, 87.6 mmol) in acetic cid was added 3-ethoxymethacrolein (10.0 g, 87.6 mmol), and the mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction, the product crystallized out of solution. The collected product was a white solid (14.0 g, 92%). 1H NMR (300 MHz, DMSO-D6) δ: 2.38 (m, 3 H) 4.63 (m, 2 H) 5.52 (m, 1 H) 8.75 (m, 1 H) 9.21 (m, 1 H). MS (APCI, M+H+): 163.1, 165.1.