Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:12])[CH3:11].O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:12][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCNCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 4-chlorobenzaldehyde (1 eq.) in MeOH was added ethylamine 70% in water (10 eq.). The reaction was stirred for 15 h at 20° C. under argon then NaBH4 (2 eq.) was added. The reaction was stirred at 20° C. for 5 h. The reaction was quenched with water then acidified with aqueous HCl (2M). The aqueous layer was washed with EtOAc. The organic layer was discarded. Aqueous NaOH (2M) was then added to the aqueous layer until pH=10 and the crude was extracted twice with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford (4-chloro-benzyl)-ethyl-amine.
Reaction SMILES: [CH:1]1([N:7]([CH2:30][CH:31]([O:34][CH3:35])[O:32][CH3:33])[C:8](=[O:29])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:43]1[N:44]=[C:45]([CH3:49])[N:46]([CH3:48])[CH:47]=1>CO.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>[CH:1]1([N:7]([CH2:30][CH:31]([O:34][CH3:35])[O:32][CH3:33])[C:8](=[O:29])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:43]3[N:44]=[C:45]([CH3:49])[N:46]([CH3:48])[CH:47]=3)[CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(Br)cn1C
Reactant: COC(CN(C(=O)CCOCCc1cccc(B2OC(C)(C)C(C)(C)O2)c1)C1CCCCC1)OC
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: CO
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cn(C)c(C)n2)c1)C1CCCCC1)OC
Temperature: 120 °C

Procedure:
N-Cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethoxy)propanamide [Example 34 Step i)] (360 mg), potassium carbonate (203 mg), Pd(Ph3P)4 (42.5 mg) and 4-bromo-1,2-dimethyl-1H-imidazole (193 mg) in MeOH (3 mL) was loaded into a microwave vial, flushed with nitrogen and sealed. The reaction mixture was heated within a Discover microwave at 120° C. for 20 min. After cooling, the mixture was filtered and the filtrate was washed with DCM. Volatiles removed and the residue was purified on silica using 50%-100% EtOAc/iso hexane and then 5% MeOH/DCM to afford the subtitled compound (250 mg). MS [M+H-MeOH]+=426 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.61 and 7.59 (2×s, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.28-7.21 (m, 1H), 7.10-7.03 (m, 2H), 4.62 and 4.37 (2×t, J=5.1 Hz, 1H), 4.26-4.17 and 3.62-3.52 (2×m, 1H), 3.82-3.74 (m, 2H), 3.73-3.64 (m, 2H), 3.60 (s, 3H), 3.41 (s, 3H), 3.38 (s, 3H), 3.37 and 3.29 (2×d, J=4.7 Hz, 2H), 2.94-2.86 (m, 2H), 2.73-2.65 (m, 2H), 2.43 (s, 3H), 1.85-1.73 (m, 2H), 1.73-1.60 (m, 3H), 1.54-1.22 (m, 4H), 1.15-1.01 (m, 1H); a ˜2:1 mixture of rotamers is observed.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][O:12][C:11]2=[O:16])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>O1CCCC1.C(OC(C)C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[O:12][CH2:13][C:14]([NH:18][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C1COC(=O)N1CCc1ccc(Br)cc1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCc1ccc(Br)cc1
Yield: 90.2 %

Procedure:
The procedure described in Example 2 (step 2.2.) is repeated. Starting from 2.6 g (9.15 mmol) of 3-[2-(4-bromophenyl)ethyl]-1,3-oxazolidine-2,4-dione, prepared in Example 3 (step 3.1.), and 18.3 ml (36.6 mmol) of methylamine (2M) in tetrahydrofuran, and after the product has been taken up in diisopropyl ether, 2.6 g of pure product are obtained in the form of a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](B(O)O)=[CH:17][N:16]=1>>[C:9]1([C:6]2[N:5]=[CH:4][C:3]([CH2:2][C:18]3[C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=[N:16][CH:17]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1cnc(-c2ccccc2)nc1
Reactant: OB(O)c1cncc2ccccc12
Product: c1ccc(-c2ncc(Cc3cncc4ccccc34)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 64a (85 mg, 0.34 mmol) and isoquinolin-4-ylboronic acid (104 mg, 0.60 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. Orange solid. Yield: 68 mg, 67%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.40 (s, 2H), 7.44-7.51 (m, 3H), 7.61-7.67 (m, 1H), 7.67-7.74 (m, 1H), 7.87 (dd, J=8.4, 0.8 Hz, 1H), 8.02-8.06 (m, 1H), 8.37-8.42 (m, 2H), 8.49 (s, 1H), 8.66 (s, 2H), 9.24 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=30.9, 122.8, 127.4, 127.5, 127.9, 128.6, 128.6, 128.6, 130.4, 130.6, 131.0, 134.3, 137.2, 143.6, 152.7, 157.0, 163.1; (ESI): m/z=297.91 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:19]1[CH2:24][C@@H:23]([CH:25]2[CH2:27][O:26]2)[CH2:22][N:21]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1)=[O:17].[CH3:39][O-:40].[Na+].CO>CO>[OH:26][CH:25]([C@@H:23]1[CH2:24][C@H:19]([N:18]([C:16]([C:8]2[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[O:17])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:20][N:21]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:22]1)[CH2:27][O:40][CH3:39]
Reactant: C[O-]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C3CO3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: [Na+]
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(O)COC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 70 °C
Reaction time: 6 h

Procedure:
tert-Butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-oxirane-2-ylpiperidine-1-carboxylate (200 mg) was dissolved in methanol (5 ml), 28% sodium methylate-methanol solution was added, and the mixture was stirred at 70° C. for 6 hr. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (157 mg). MS (ESI+, m/e) 561(M+1)
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][CH2:22][C:23]([CH3:25])=[CH2:24])[C:10]1([CH3:37])[CH3:36])(C(C)(C)C)(C)C.C1C=CC=CC=1.[ClH:44]>C(O)C>[Cl:44][C:23]([CH2:22][CH2:21][CH2:20][C@H:19]([C@@H:18]1[C@:27]2([CH3:35])[C:15]([C:14]3[CH2:13][CH2:12][C@@H:11]4[C@:31]([C:30]=3[CH2:29][CH2:28]2)([CH3:34])[CH2:32][CH2:33][C@H:9]([OH:8])[C:10]4([CH3:37])[CH3:36])=[CH:16][CH2:17]1)[CH3:26])([CH3:25])[CH3:24]
Reactant: C=C(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: C[C@H](CCCC(C)(C)Cl)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
A mixture of 3β-(tert-butyldimethylsilyloxy)-4,4-dimethylcholesta-5,7,25-triene (50 mg), benzene (5 mL), ethanol (5 mL) and concentrated HCl (2 mL) was heated under reflux for 4 hours. The reaction was concentrated to half volume under reduced pressure and water (5 mL) was added. Extraction of the aqueous phase with dichloromethane and concentration under reduced pressure gave a residue, which was purified by flash chromatography. Recrystallisation from ethyl acetate:hexane gave the title compound as a white solid (35 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC)=O)=[C:13]([CH2:20]Br)[N:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)[C:11](=[O:33])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:34][NH:35][NH2:36]>O1CCOCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([N:12]2[C:13]3[CH2:20][N:35]([CH3:34])[NH:36][C:15](=[O:17])[C:14]=3[CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[NH:10][C:11]2=[O:33])=[CH:23][C:24]=1[C:29]([F:32])([F:31])[F:30]
Reactant: CCOC(=O)C1=C(CBr)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Reactant: CNN
Solvent: C1COCCO1
Product: CN1CC2=C(C(=O)N1)C(c1ccc(C#N)cc1)NC(=O)N2c1ccc(F)c(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
527 mg (1.0 mmol) of ethyl 4-(4-cyanophenyl)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-6-(bromomethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate were dissolved in 25 ml of dioxane, and 138 mg (3.0 mmol; 3 eq.) of methylhydrazine were added. The mixture was stirred at 120° C. for 1 h and then concentrated. The residue was purified directly by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave 270 mg (55% of theory) of the target compound.
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>ClCCl>[C:28]([NH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4])(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccc(CNC(=O)C(N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (RS)-2-amino-N-(4-cyano-benzyl)-2-phenyl-acetamide (0.1 g) in dichloromethane (5 ml) was cooled to 0° C. and treated with triethylamine (58 μl) and acetyl chloride (28 μl). The reaction mixture was stirred at rt for 1 hr, then diluted with dichloromethane, washed with 1N HCl and brine. The organic layer was dried over MgSO4, filtered and concentrated. The product was isolated by chromatography (silica gel, gradient dichloromethane=>dichloromethane/MeOH 9:1) to give (RS)-2-acetylamino-N-(4-cyano-benzyl)-2-phenyl-acetamide (98 mg). Off-white solid. MS 308.2 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][C:25]([C:23]([O:22][CH2:20][CH3:21])=[O:24])=[CH:26][CH:27]=4)=[CH:3][CH:4]=3)[O:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(-c2coc(-c3ccc(Br)cc3)n2)cc1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(C)cc4)co3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of Example 186B (140 mg, 0.45 mmol) in ethylene glycol dimethyl ether (7.0 mL) at room temperature was treated with tetrakis(triphenylphosphine)palladium (26 mg, 0.02 mmol), stirred for 5 minutes, treated with a solution of Example 186A (104 mg, 0.54 mmol) in ethanol (1.5 mL), stirred for 5 minutes, treated with 2M sodium carbonate (1.1 mL, 2.23 mmol), heated to reflux, and stirred for 4 hours. The reaction mixture was cooled to room temperature and concentrated. The concentrate was dissolved in water (20 mL) and extracted with diethyl ether (4×20 mL). The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 384 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.18-8.16 (m, 2H), 8.09-8.06 (m, 4H), 7.97-7.89 (m, 4H), 7.30-7.28 (m, 2H), 4.35 (q, 2H), 2.34 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28]>>[F:19][C:18]([F:21])([F:20])[C:11]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[N:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[CH:4][CH:5]=2)[N:10]=1
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Reactant: O=C1CCCCN1
Product: O=C1CCCCN1Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and 2-piperidinone using a similar procedure to that described for Description 15.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[N:3]1[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([CH2:9][N:3]4[C@H:2]([CH3:1])[CH2:6][CH2:5][S:4]4(=[O:7])=[O:8])=[CH:19][CH:18]=3)=[O:16])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COC(=O)c1ccc(CN2[C@H](C)CCS2(=O)=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4[C@H](C)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 78.3 %

Procedure:
Using methyl (R)-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoate (79 mg) described in Preparation Example 42 and 1-(3,5-dimethylpyridin-2-yl)piperazine (53 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (96 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([OH:19])[CH:6]=1)[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29]O)[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([O:19][CH2:29][CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=2)[CH:6]=1)[CH3:2]
Reactant: OCCc1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(O)c1
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(OCCc2cccc(Cl)c2)c1

Procedure:
The compound of step 3 was coupled to 2-(3-chloro-phenyl)-ethanol in analogy to step 1 of example 1 to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: COC(C)(C)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(C)(C)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 56.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide (68 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-methoxy-2-methyl-propylamine (58 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 494.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.17 (t, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 3.64 (bs, 3H), 3.36 (d, 2H), 3.18 (s, 3H), 1.14 (d, 6H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]([C:20]2[CH:21]=[N:22][N:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH:24]=2)=[O:19])[CH:7]=[N:8][C:9]=1[C:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH:11]=1.[OH-].[Na+].[CH3:37]O>>[OH:16][CH:13]1[CH2:14][CH2:15][C:10]([C:9]2[N:8]=[CH:7][C:6]([NH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=4)[C:24]=3[CH3:37])=[O:19])=[CH:5][C:4]=2[CH3:3])=[CH:11][CH2:12]1
Reactant: CO
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2)cnc1C1=CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cc3)c2C)cnc1C1=CCC(O)CC1
Reaction time: 0.5 h

Procedure:
Sodium borohydride (19 mg) was added to a solution of N-[5-methyl-6-(4-oxocyclohex-1-en-1-yl)pyridin-3-yl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide (114 mg) in methanol (15 ml) under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. After the reaction, 1N aqueous solution of sodium hydroxide was added and the organic solvent was evaporated. The precipitated solid was washed with water, filtered and dried at 60° C. under current of air to give the titled compound (110 mg) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:25][C:9]2[C:10](=[O:24])[NH:11][C:12]3[C:13]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:15]=[CH:16][C:17]=3[C:8]=2[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[O:24]=[C:10]1[C:9]2[O:25][C:6]([CH:4]=[O:3])=[CH:7][C:8]=2[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:12]=2[NH:11]1
Reactant: CCOC(=O)c1cc2c(o1)c(=O)[nH]c1c(N3CCCCC3)cccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1cc2c(o1)c(=O)[nH]c1c(N3CCCCC3)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carboxylic acid ethyl ester (iv) in DCM at 0° C. is treated with diisobutylaluminum hydride (“DIBAL-H”) and is allowed to warm to room temperature. The reaction is quenched with a saturated solution of sodium potassium tartrate and partitioned. The organic layer is dried over MgSO4, filtered and treated with manganese dioxide (“MnO2”). After stirring for 16 h at room temperature, the reaction is filtered and is concentrated to give 4-oxo-6-piperidin-1-yl-4,5-dihydro-furo[2,3-c]quinoline-2-carbaldehyde (v).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]1([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[CH2:5]2.C([O-])([O-])=O.[Na+].[Na+].Cl.[NH2:26][OH:27]>C(O)C.O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]1([CH2:17][CH2:16][C:15](=[N:26][OH:27])[CH2:14][CH2:13]1)[CH2:5]2
Reactant: NO
Reactant: O=C1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1Nc2ncc(Br)cc2CC12CCC(=NO)CC2
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
To a stirred solution of 6′-bromo-1′H-spiro[cyclohexane-1,3′-[1,8]naphthyridine]-2′,4(4′H)-dione (P) (0.35 g, 1.13 mmol) in ethanol/water (18 mL/2 mL) were added Na2CO3 (0.6 g, 5.68 mmol) and hydroxylamine hydrochloride (0.39 g, 5.68 mmol) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 4 h. Then the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get the desired compound as an off-white solid (200 mg, 95%); 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.28 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 7.88 (d, J=2.0 Hz, 1H), 2.99 (s, 2H), 2.30-2.16 (m, 4H), 1.84-1.66 (m, 2H), 1.50-1.38 (m, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=1)([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[Br:1][C:17]1[C:12]([CH:9]([CH3:11])[CH3:10])=[N:13][C:14]([NH2:18])=[N:15][CH:16]=1
Reactant: CC(C)c1ccnc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(C)c1nc(N)ncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.6 %

Procedure:
N-Bromosuccinimide (0.5 g, 2.8 mmol) was added to a solution of 4-isopropylpyrimidin-2-amine (0.39 g, 2.81 mmol) in chloroform. The resultant yellow solution was stirred at ambient temperature for 1 h and concentrated in vacuo. The residue was purified by column chromatography (3-10% 9:1 methanol:ammonium hydroxide in chloroform) to afford 5-bromo-4-isopropylpyrimidin-2-amine (0.69 g, 3.18 mmol, 113%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (1 H, s), 6.75 (2 H, s), 3.10-3.23 (1 H, m), 1.14 (6 H, d, J=6.80 Hz). MS (LC/MS) R.T.=2.58; [M]+=216.09.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]2[C:19]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:18][N:17]=[C:16]2[CH2:26][O:27][CH3:28])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[OH:29]OS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:1][C:2]1[C:3]([N:15]2[C:19]([C:20]3[CH:21]=[N+:22]([O-:29])[CH:23]=[CH:24][CH:25]=3)=[N:18][N:17]=[C:16]2[CH2:26][O:27][CH3:28])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2
Reactant: O=S([O-])OO
Reactant: COCc1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COCc1nnc(-c2ccc[n+]([O-])c2)n1-c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 60 h
Yield: 85.8 %

Procedure:
(−)-6,7-Dichloro-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,3(1H,4H)-quinoxalinedione (see Preparation 1) (412.2 g, 0.98 mol) and OXONE (trade mark) (1.44 kg, 2.3 mol) were slurried in water (4.13 L) and the mixture stirred at ambient temperature for 60 hours. Saturated aqueous sodium thiosulphate solution (2.2 L) was added and the slurry stirred for 1 hour before being filtered under reduced pressure. The filter cake was slurried at ambient temperature for 4 hours in 1:1, by volume, isopropyl alcohol: dichloromethane (111 L) and the solid collected by filtration. The filtrate was vaporated under reduced pressure to give the title compound as a colourless solid (366 g).