Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]=O>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: Brc1ccccn1
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1cc2ccccc2n1-c1ccccn1
Yield: 30 %

Procedure:
A suspension of methyl 1H-indole-2-carboxylate (5.04 g), 2-bromopyridine (3.3 ml), potassium carbonate (7.9 g) and copper (II) oxide (3.9 g) in dry pyridine (80 ml) was heated under reflux for 48 hours. The solvent was removed in vacuo and dichloromethane added to the residue. After filtration the solvent was removed once again in vacuo and the resultant brown oil purified by column chromatography on silica eluting with diethyl ether in petroleum ether (bp 40°-60° C.). Methyl 1-(2-pyridyl)-1H-indole-2-carboxylate was obtained as a white solid: yield 4.74 g (65%). NMR (CDCl3) 3.7 (3H,s,CH3), 7.46 (8H,m,Ar--H), 8.60 (1H,m,Ar--H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:16]([O:18]C)=O)[S:14][CH:15]=2)=[O:9])[CH:3]=1.O.[NH2:21][NH2:22]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([C:16]([NH:21][NH2:22])=[O:18])[S:14][CH:15]=2)=[O:9])[CH:3]=1
Reactant: NN
Reactant: COC(=O)c1cc(NC(=O)c2cc(Br)ccn2)cs1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(NC(=O)c2cc(Br)ccn2)cs1
Yield: 101.9 %

Procedure:
The methyl 4-(4-bromopicolinamido)thiophene-2-carboxylate (2.7 g, 6.9 mmol) was dissolved in ethanol, hydrazine hydrate (1.4 mL, 28 mmol) was added and the reaction was refluxed overnight. The reaction mixture was concentrated, and the solids were suspended in acetonitrile and filtered to afford 2.4 g (70%) 4-bromo-N-(5-(hydrazinecarbonyl)thiophen-3-yl)picolinamide as a white solid. M+1=341.1
Reaction SMILES: [CH2:1]=[C:2]1[C:15](=[CH2:16])[CH:14]2[O:17][CH:3]1[C:4]1[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([OH:18])[C:11]=3[CH2:12][C:13]=12.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:18][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:13]1[CH:14]3[O:17][CH:3]([C:4]=1[CH2:5]2)[C:2](=[CH2:1])[C:15]3=[CH2:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: C=C1C(=C)C2OC1C1=C2Cc2c(O)cccc2C1
Product: C=C1C(=C)C2OC1C1=C2Cc2c(cccc2OCc2ccccc2)C1

Procedure:
By reacting the 1,2,3,4,9,10-hexahydro-2,3-dimethylene-1,4-epoxyanthracen-5-ol with benzyl bromide in place of methyl iodide in an analogous manner, there was obtained in good yield 1,2,3,4,9,10-hexahydro-5-benzyloxy-2,3-dimethylene-1,4-epoxyanthracene.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:28]CCC.CI>C1COCC1>[CH3:28][C:13]1[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:17][CH:16]=2
Reactant: [Li]CCCC
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole (1.6 g, 4.4 mmol, synthesized as described in Example 22A) in THF (10 mL), under N2, at −78° C., was added n-BuLi (2.5 M solution in hexanes, 2.15 mL, 5.37 mmol) dropwise. After stirring at −78° C. for 30 min, methyl iodide (0.94 g, 6.6 mmol) was added. After 30 min, the −78° C. bath was removed. The solution was warmed to rt. 5% HCl (10 mL) was then added and the mixture was partitioned between EtOAc and water. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (20-70% EtOAc-hexanes gradient) to afford the title compound (0.8 g, 77% yield): MS (ES) m/z 478 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:6]([CH3:27])([CH3:26])[CH2:7][O:8][C:9]=1[C:10]1[CH:24]=[C:23]([OH:25])[C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[O:29]=[O:30]>C(Cl)Cl>[C:1]([C:5]12[O:30][O:29][C:9]1([C:10]1[CH:24]=[C:23]([OH:25])[C:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:16][C:12]=3[CH:11]=1)[O:8][CH2:7][C:6]2([CH3:27])[CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1=C(c2cc(O)c3nc(-c4ccccc4)oc3c2)OCC1(C)C
Reactant: O=O
Agent: [Na]
Solvent: ClCCl
Product: CC(C)(C)C12OOC1(c1cc(O)c3nc(-c4ccccc4)oc3c1)OCC2(C)C
Yield: 85.1 %

Procedure:
To 15 mL of methylene chloride were added 1.0 mg of TPP and 156 mg (0.43 mmol) of 4-t-butyl-5-(4-hydroxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [63]), and the mixture was externally irradiated with a 940 W sodium lamp in an oxygen atmosphere for 30 minutes, then concentrated. The concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ether =1:1) to obtain 25.3 mg of 5-t-butyl-1-(4-hydroxy-2-phenylbenzo[d]oxazol-6-yl)-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptane (Compound [64]) as colorless granular crystal. Yield 85.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([O:32]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>Cl.C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:19])([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[C:26]4[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=4)[CH:16]=3)[NH:11][C:10](=[O:32])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3cncn3C)c3cncn3C)ccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1)c1cncn1C
Yield: 214.7 %

Procedure:
A mixture of intermediate (7) (0.00141 mol) in HCl 3N (20 ml) and THF (5 ml) was stirred and refluxed overnight. The solvent was evaporated till dryness. The product was used without further purification, yielding 0.73 g (quant.) of 4-(3-chlorophenyl)-6-[hydroxybis(1-methyl-1H-imidazol-5-yl)methyl]-2(1H)-quinolinone hydrochloride (1:2).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7]Br.[CH2:11]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>CS(C)=O>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][CH2:7][N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:25][CH2:24]1
Reactant: c1ccc(CNCC2CCNCC2)cc1
Reactant: COC(CCCCBr)OC
Solvent: CO
Solvent: CS(C)=O
Product: COC(CCCCN1CCC(CNCc2ccccc2)CC1)OC
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from 5-bromopentanal dimethyl acetal and 4-[(benzylamino)methyl]piperidine using a similar method to that described for Example 8 (step 2). δ (250 MHz, d6 -DMSO) 1.26-2.14 (13H, m), 2.49 (2H, t, J=7.0 Hz), 2.63 (2H, d, J=6.6 Hz), 3.04-3.14 (2H, m), 3.49 (6H, s), 3.95 (2H, s), 4.61 (1H, t, J=5.7 Hz), 7.44-7.62 (5H, m), m/e (ES) 335 (M+1+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH2:20]3)=[C:15]([C:29]([F:32])([F:31])[F:30])[CH:14]=1)=[CH:9][C:8]([Br:33])=[CH:7][CH:6]=2.[H-].[Na+].Br[CH2:37][C:38](OCCCC)=[O:39]>CN(C=O)C>[Br:33][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:38](=[O:39])[CH2:37][N:12]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:20][CH2:21][CH:22]([C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:24]5)=[C:15]([C:29]([F:31])([F:30])[F:32])[CH:14]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: CCCCOC(=O)CBr
Reactant: COC(=O)C1CCN(c2ccc(Nc3c(N)cnc4ccc(Br)cc34)cc2C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc(N3CC(=O)Nc4cnc5ccc(Br)cc5c43)cc2C(F)(F)F)CC1
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
To a solution of compound 8.3 methyl 1-(4-(3-amino-6-bromoquinolin-4-ylamino)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (60 mg, 0.115 mmol, 1 equiv.) in anhydrous DMF (3 mL) at 0° C. was added sodium hydride (60%, 5.0 mg, 0.126 mmol, 1.1 equiv.). After the mixture solution was stirred for 15minutes, tent-Butyl bromoacetate (19 mL, 0.126 mmol, 1.1 equiv.) was added. The resulting mixture was stirred overnight at room temperature under argon. Upon quenching with water, the mixture was concentrated under vacuum, diluted with EtOAc (20 mL), and washed with water (20 mL) and brine (20 mL). The organic phase was dried over Na2SO4. After removal of solvent under vacuum, the resulting residue was purified via flash chromatography (CH2Cl2:MeOH=35:1) to afford the desired product 8.4 methyl 1-(4-(9-bromo-3-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperidine-4-carboxylate (61 mg; 94%). LC-MS (M+H): 563.15
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:19]([O:17][C:16](=[O:18])[C@H:9]([CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)C(=O)OCc1ccccc1
Yield: 95.5 %

Procedure:
A mixture of 1.2 g (4.67 mmol) of N-(tert-butoxycarbonyl)-3-cyclopentyl-L-alanine, 540 mg (5 mmol) of benzyl alcohol, 675 mg (5 mmol) of 1-hydroxybenzotriazole, 1.152 g (6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.031 g (0.25 mmol) of 4-dimethylaminopyridine was stirred in 20 ml of dichloromethane for 1 hour and then a further 610 mg (5 mmol) of 4-dimethylaminopyridine were added. After 4 hours the solution was extracted with 2M hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated. The oil obtained was chromatographed on silica gel using ethyl acetate/ petrol (1:6) for the elution to give 1.55 g of N-(tert-butoxycarbonyl)-3-cyclopentyl-L-alanine benzyl ester as a colourless oil; MS: m/e 348 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16]S(C3C=C(C)OC=3C)(=O)=O)[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:29][C:30]1[S:31][C:32]([Cl:39])=[CH:33][C:34]=1[S:35](Cl)(=[O:37])=[O:36].FC1C=CC(OC)=C(C2C=CC(C(N)C)=CC=2)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:35]([C:34]3[CH:33]=[C:32]([Cl:39])[S:31][C:30]=3[Cl:29])(=[O:37])=[O:36])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(C)oc2C)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Agent: COc1ccc(F)cc1-c1ccc(C(C)N)cc1
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(Cl)sc2Cl)cc1

Procedure:
Prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) starting with 2,5-dichloro-3-thiophenesulfonyl chloride and 1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 7.40, 7.18 (a/b, 4H), 7.05-6.88 (m, 4H), 5.05 (d, 1H), 4.60 (m, 1H), 3.78 (s, 3H), 1.54 (d, 3H) ppm; MS (ESI) m/z: 482 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH3:15])[C:7]([CH2:16]Cl)=[CH:6]2.[CH2:18]([O:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24])[CH3:19]>>[CH2:18]([O:20][P:21]([CH2:16][C:7]1[C:8]([CH3:15])=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)([O:22][CH2:23][CH3:24])=[O:25])[CH3:19]
Reactant: COc1cc2cc(CCl)c(C)nc2cc1OC
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc2cc(OC)c(OC)cc2nc1C)OCC
Temperature: 160 °C

Procedure:
A mixture of 6,7-dimethoxy-3-chloromethyl-2-methylquinoline (2.48 g, 9.9 mmol) and triethylphosphite (6 ml) was heated at 160° C. for 4 h and cooled to room temperature. Excess triethylphosphite was removed by extraction with hexane and the remaining dark oil was purified by chromatography to give 3.50 g 3-(diethylphosphonomethyl)-6,7-dimethoxy-2-methylquinoline.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:28]C(=O)OC(C)(C)C)[CH2:12][NH:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:19]=2)=[CH:2]1.Cl>ClCCl.O1CCOCC1>[NH2:28][C@@H:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1cncc(/C=C/c2ccncc2)c1)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H](CNc1cncc(/C=C/c2ccncc2)c1)Cc1c[nH]c2ccccc12
Reaction time: 1 h

Procedure:
A solution of Example 11C (40 mg, 0.085 mmol) in dichloromethane (3.0 mL) at room temperature was treated with 4N HCl in dioxane (0.5 mL), stirred for 1 hour, and concentrated to provide the desired product as the hydrochloride salt (30 mg, 74%). MS (DCI/NH3) m/e 370 (M+H)+; 1H NMR (DMSO-d6) δ 11.09 (br s, 1H), 8.90 (d, J=5.8 Hz, 2H), 8.47 (br s, 2H), 8.33 (s, 1H), 8.22 (d, J=1.8 Hz, 1H), 8.14 (d, J=5.8 Hz, 2H), 7.98 (s, 1H), 7.94 (d, J=16.5 Hz, 1H), 7.86 (d, J=16.5 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.37 (d, J=4.5 Hz, 1H), 7.36 (s, 1H), 7.08 (m, 1H), 6.98 (m, 1H), 3.71 (m, 1H), 3.67 (m, 1H), 3.54 (m, 1H), 3.15 (m, 2H).
Reaction SMILES: C(OC([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][Br:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=O)C.[CH2:20]([O:22][C:23](C1C(C2C=CC(C)=CC=2)=CC=CC=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:20]([O:22][C:23]([C:7]1[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][Br:19])=[CH:16][CH:17]=2)=[CH:9][CH:10]=[CH:11][CH:6]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: CCOC(=O)c1ccccc1-c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-c1ccc(CBr)cc1
Yield: 99 %

Procedure:
4′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester was prepared in a similar fashion to 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester as described. 4′-Methyl-biphenyl-2-carboxylic acid ethyl ester (5.58 g, 23.22 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (4.96 g, 27.86 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.19 g, 1.16 mmol, 5 mol %). When complete, the reaction was worked up as described to give a yellow oil. The oil was purified by silica gel flash chromatography using 5% EtOAc in hexane as the mobile phase. Fractions containing the product were pooled and the solvent removed in vacuo to give 4′-bromomethyl-biphenyl-2-carboxylic acid ethyl ester (7.32 g, 99% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[S:14][C:13]([NH:15][C:16](=[O:18])[CH3:17])=[N:12][CH:11]=2)=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][C:27](N1C=CC=N1)=[N:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C)C=O>O1CCCC1>[C:16]([NH:15][C:13]1[S:14][C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH:27]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:26][C:24](=[O:25])[O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:3][CH:4]=2)=[CH:11][N:12]=1)(=[O:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(=O)Nc1ncc(CCc2ccc(N)cc2)s1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(CCc2ccc(NC(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)s1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 48.5 %

Procedure:
N-{5-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (100 mg), N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (119 mg), N,N-dimethylformamide (1 ml) and tetrahydrofuran (2 ml) were combined under nitrogen atmosphere. The reaction mixture was stirred at 50° C. for 5.5 hours. After cooled to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by preparative silica gel column chromatography with n-hexane/ethyl acetate (1:2) as an eluent to give di-tert-butyl {[(4-{2-[2-(acetylamino)-1,3-thiazol-5-yl]ethyl}phenyl)amino]methylidene}biscarbamate (93.9 mg) as a colorless solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:19]2[NH:20][C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)([C:24]([NH2:26])=[O:25])[CH2:22][O:23][C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[O:4]=[C:2]1[N:20]2[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)([C:24]([NH2:26])=[O:25])[CH2:22][O:23][C:18]3=[C:19]2[C:14](=[CH:15][CH:16]=[CH:17]3)[NH:13]1
Reactant: NC(=O)C1(c2ccccn2)COc2cccc(N)c2N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reaction time: 1 h
Yield: 192.9 %

Procedure:
Triphosgene (20 mg, 0.07 mmol) was added to a solution of 5-amino-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide (40 mg, 0.2 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (60 μL, 0.3 mmol) at room temperature. The reaction was stirred for 1 h and then partitioned between ethyl acetate and water. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (0.040 g. 80%). LCMS calculated for C15H13N4O3 (M+H)+: m/z=297.1. found: 297.1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:14]([C:17]1[CH:18]([C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=2)[NH:19][C:20](=[S:34])[N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:22]=1[CH3:23])(=[O:16])[CH3:15]>CN(C=O)C>[C:14]([C:17]1[CH:18]([C:35]2[CH:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=2)[N:19]=[C:20]([S:34][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[C:22]=1[CH3:23])(=[O:16])[CH3:15]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCSC1=NC(c2ccc(C#N)cc2)C(C(C)=O)=C(C)N1c1cccc(C(F)(F)F)c1
Reaction time: 15 h

Procedure:
To a solution of 2-bromoethyl acetate (37.6 mg, 0.23 mmol) in 500 μl DMF are added potassium carbonate (82.9 mg, 0.6 mmol) and 4-{5-acetyl-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}benzonitrile (Example 1; 62.3 mg, 0.15 mmol). The reaction mixture is shaken for 15 hours, filtered and purified by preparative HPLC (column: Nucleosil 100-5 C 18 Nautilus 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% formic acid; flow rate: 25 ml/min; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 550 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [C:1]([C:3]1[C:12]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[C:6]([OH:13])=[CH:5][CH:4]=1)#[N:2].[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][CH:16]2[O:18][CH2:17]2)=[C:7]2[O:8][CH2:9][CH2:10][O:11][C:12]=12)#[N:2]
Reactant: N#Cc1ccc(O)c2c1OCCO2
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OCC2CO2)c2c1OCCO2

Procedure:
A mixture of 31 g of 5-cyano-8-hydroxy-1,4-benzodioxane (VII) (Code number 770583), 38.35 g of epibromohydrin and 133 g of potassium carbonate in 300 ml of acetonitrile was brought to reflux for 12 hours. The mixture was filtered, the product then crystallized in the filtrate, it was filtered out and recrystallized in acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:35][CH2:36][O:37][C:38]([F:41])([F:40])[F:39])(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:35][CH2:36][O:37][C:38]([F:41])([F:40])[F:39])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Product: COc1cn(C(CCOC(F)(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
416 mg (1.00 mmol) of tert-butyl {4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate in the presence of 1.20 ml (1.20 mmol, 1.2 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 393 mg (1.50 mmol, 1.5 eq.) of 2-(trifluoromethoxy)ethyl trifluoromethanesulphonate were reacted according to General Method 7B. Yield: 327 mg (62% of theory)
Reaction SMILES: [CH:1]([N:4]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:5](=[O:23])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=1[CH3:20])([CH3:3])[CH3:2].[C:32]1([NH:38][N:39]=[C:40]([C:44](Cl)=[O:45])[C:41](Cl)=[O:42])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[O:45]=[C:44]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[O:23])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[CH3:20])[C:41](=[O:42])[C:40]1=[N:39][NH:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)C(=NNc1ccccc1)C(=O)Cl
Reactant: COc1ccc(N(C(=O)CNc2ccccc2Nc2c(C)nn(C)c2C)C(C)C)cc1
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)Cn2c(=O)c(=NNc3ccccc3)c(=O)n(-c3c(C)nn(C)c3C)c3ccccc32)C(C)C)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 192.2 %

Procedure:
A solution of N-Isopropyl-N-(4-methoxy-phenyl)-2-[2-(1,3,5-trimethyl-1H-pyrazol-ylamino)-phenylamino]-acetamide (3.0 g, 7.1 mmol) in THF (70 mL) and a solution of 2-(phenyl-hydrazono)-propanedioyl dichloride (1.75 g, 7.1 mmol) in THF (70 mL) were simultaneously added to THF (35 mL) cooled to 0° C. The solution stirred at RT for 15 h and was subsequently concentrated in vacuo to yield the title compound (8.1 g) which was used without further purification.