Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][O:16]/[CH:17]=[CH:18]/[C:19](Cl)=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])/[CH:18]=[CH:17]/[O:16][CH3:15])=[CH:4][CH:3]=1
Reactant: CO/C=C/C(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO/C=C/C(=O)Nc1ccc(Br)cc1
Yield: 95.6 %

Procedure:
Combined 4-bromoaniline (285 mg, 1.659 mmol), CH2Cl2 (2.0 ml) and pyridine (0.25 ml, 3.09 mmol) and slowly added (E)-3-methoxyacryloyl chloride (200 mg, 1.659 mmol) and stirred at room temperature for 2 h. The resulting yellow solid was filtered off and washed with water. The solid was dried under vacuum to give the title compound (406 mg, 96%).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:27]([CH2:28][CH3:29])[CH2:26][CH2:25][C:24]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:23][C:22]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=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>[CH2:13]([O:12][CH2:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:18]2[CH:19]=[CH:20][C:21]3[N:27]([CH2:28][CH3:29])[CH2:26][CH2:25][C:24]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([CH2:39][N:40]([CH3:47])[CH:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[CH:37][CH:38]=4)=[O:31])=[CH:23][C:22]=3[CH:48]=2)=[CH:4][CH:5]=1)[CH3:14]
Reactant: CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCOCCOc1ccc(OB([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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-(2-ethoxyethoxy)phenyl borate (339 mg) and 7-bromo-1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (537 mg). To the solution was added potassium carbonate (357 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (50 mg), and the mixture was heated to reflux under argon atmosphere for 14 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (35 g, ethyl acetate→ethyl acetate ethanol=10:1→ethyl acetate:ethanol triethylamine=100:10:0.5) and recrystallized from ethyl acetate/IPE to give 7-[4-(2-ethoxyethoxy)phenyl]-1-ethyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 16) (332 mg, 53%) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: CC1Cc2cccc(Br)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1Cc2cccc(-c3ccccc3)c2C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
22.5 g (0.1 mol) of 7-bromo-2-methyl-1-indanone (2), 13.4 g (0.11 mol) of phenylboronic acid and 23.3 g (0.22 mol) of sodium carbonate were placed in 380 ml of dimethoxyethane and 120 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. 450 mg (2 mmol) of palladium acetate and 1.05 g (4 mmol) of triphenylphosphine (TPP) were added and the reaction mixture was stirred for 2 hours at 80° C. After addition of 300 ml of water, the mixture was extracted 3 times with 250 ml each time of diethyl ether, the ether phase was washed twice with 100 ml each time of water and dried over magnesium sulfate. Removal of the solvent gave 21.1 g of (15) as solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][NH2:20])[CH:5]=[C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[C:30](O)(=[O:33])[CH2:31][CH3:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CCOCC.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][NH:20][C:30](=[O:33])[CH2:31][CH3:32])[CH:5]=[C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])[C:7]=1[Cl:8]
Reactant: CCC(=O)O
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCN)cc(Cl)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(=O)NCCc1cc(Cl)c(Cl)c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a DMF (0.2 M) solution of 2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)-silyl]oxy}methyl)phenyl]ethanamine (1 eq.) from the previous step, Hunig's base (3 eq.) and propionic acid (1.1 eq.) was added portionwise O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.2 eq.). The resulting reaction solution was stirred at RT for 48 h. The now reddish solution was diluted with ether and washed sequentially with 1 N aq. NaOH, water and brine. The organic extract was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a brown oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 7:3 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: C[Li].[CH3:3][C:4]12[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:5]1=[N:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:11][C:12]=12.[Cl-].[NH4+].[CH2:25](OCC)C>O1CCCC1>[CH3:25][C@@:5]12[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22][C@:4]1([CH3:3])[C:12]1[CH:11]=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:8][C:7]=1[NH:6]2
Reactant: CCOCC
Reactant: CC(C)c1ccc2c(c1)C1(C)Cc3ccccc3C1=N2
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(c1)[C@@]1(C)Cc3ccccc3[C@@]1(C)N2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyllithium (1.4M in ether, 14.5 cm3, 12.4 mmol) in dry tetrahydrofuran (20 cm3), at -78° C., under nitrogen, in a flame dried flask, was added dropwise, over 1 hour, a solution of 9b,10-dihydro-9b-methyl-8-isopropylindeno-[1,2-b]indole (1.62 g, 6.20 mmol) in dry tetrahydrofuran (30 cm3). After addition, the mixture was stirred for a further 1/2 hour at -78° C. Saturated ammonium chloride solution (2 cm3) was then added and the mixture allowed to warm to room temperature. The reaction mixture was then portioned between diethyl ether (50 cm3) and saturated ammonium chloride solution (25 cm3), and the layers separated. The aqueous phase was extracted with diethyl ether (2×10 cm3) and the combined organic extracts were washed brine, dried (Na2SO4) and evaporated. The crude material thus obtained was purified by flash chromatography on silica gel eluting with 3-10% ethyl acetate/60°-80° petrol to yield a pale yellow gum. Yield: 0.77 g, 45%. 1H NMR (CDCl3) δ: 7.1-7.3 (4H, m), 6.98 (1H, d, J=1.8 Hz ), 6.82 (1H, dd, J=1.8 Hz and 7.9 Hz ), 6.47 (1H, d, J=7.9 Hz), 3.36 (1H, d, J=15.9 Hz), 3.06 (1H, d, J=15.9 Hz), 2.78 (1H, sept., J=6.8 Hz), 1.45 (3H, s), 1.34 (3H, s), 1.18 (6H, dd, J=1.3 Hz and 6.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][O:12][C:11](=[O:14])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1>O1CCCC1.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][O:12][C:11](=[O:14])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2=CC(=O)OC2)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1cccc(C2COC(=O)C2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(3-methoxy-phenyl)-5H-furan-2-one, (1.9 g, 10 mmol) in tetrahydrofuran (100 mL) and is added Raney nickel (7.6 g, 50% suspension in water) the mixture is stirred under hydrogen (ambient pressure) 18 h at room temperature. The mixture is filtered through Celite® and concentrated in vacuo to yield the title compound, 1.54 g (80%), as a white crystalline solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[Cl:40][C:41]1[CH:49]=[C:48]([C:50]#[C:51][CH2:52][O:53][CH3:54])[C:44]2[O:45][CH2:46][O:47][C:43]=2[C:42]=1[NH2:55]>CN(C=O)C.[Cl-].[NH4+]>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[N:20]=[CH:19][N:18]=[C:17]2[NH:55][C:42]1[C:43]2[O:47][CH2:46][O:45][C:44]=2[C:48]([C:50]#[C:51][CH2:52][O:53][CH3:54])=[CH:49][C:41]=1[Cl:40]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(C)CC4)c(OC)cc23)c2c1OCO2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.7 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.33 ml) in tetrahydrofuran (1.0 Mol/L, 1.33 mmol) was added to a solution of 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (0.212 g) and 5-chloro-7-(3-methoxyprop-1-ynyl)-1,3-benzodioxol-4-amine (0.16 g) in DMF (3 ml) cooled to 0° C. under a nitrogen atmosphere. The reaction mixture was stirred for 1.5 hours. The reaction mixture was diluted with a saturated solution of ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined and dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as the eluent to give the title compound as a light brown solid (0.22 g). NMR Spectrum: 1.93 (m, 2H), 2.12 (s, 3H), 2.22-2.50 (m, 10H), 3.36 (s, 3H), 3.93 (s, 3H), 4.17 (t, 2H), 4.35 (s, 2H), 6.14 (s, 2H), 7.14 (s, 1H), 7.15 (s, 1H), 7.80 (s, 1H), 8.29 (s, 1H), 9.49 (s, 1H); Mass Spectrum: M+H+ 554, M+H− 552.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][C:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH3:24])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][C:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[N:16]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[C:15]=2[CH3:24])[CH:6]=1)[CH3:2]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)c1ccc(OC)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC)c(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1
Temperature: 170 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methoxy-benzoic acid ethyl ester (0.175 g, 0.466 mmol) was combined with CuO (3.71 mg, 0.046 mmol), potassium carbonate (0.0805 g, 0.582 mmol) and 3-bromopyridine (0.229 mL, 2.33 mmol) in DMF (250 μL) and the reaction was heated to 170° C. overnight. After cooling the reaction was submitted to standard aqueous workup and the residue was purified by silica gel chromatography (0-100% (EtOAc:MeOH 98:2) in hexanes) to give the title compound.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]([O:20]C)=[O:19])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.[H][H].C(O)(=O)C>CO.[OH-].[Na+]>[C:18]([CH2:17][CH:6]([CH2:5][SH:4])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])([OH:20])=[O:19]
Reactant: [H][H]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
To a solution of the product from Example 81 (3.0 g.) in methanol (60 ml.), 1N sodium hydroxide (60 ml.) is added. After 4 hours, the solution is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle, and the desired material is eluted with water to yield 2.3 g. of the named product Rf : 0.2 (silica gel-benzene:acetic acid, 75:25).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([N+:38]([O-:40])=[O:39])[CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>C(#N)C>[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([N+:38]([O-:40])=[O:39])[CH:37]=1)[C:32]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:33])([O-:28])=[O:27]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)cc23)CC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-1-piperazinyl)-naphthalene (0.15 g, 0.622 mmol) and triethylamine (0.09 mL, 0.68 mmol) and 3,5-dinitrobenzoyl chloride (0.158 g, 0.684 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was purified using chromatography and recrystallization from acetonitrile to yield 0.17 g (63%) of the title compound: mp 254°-256° C. Analysis calculated for C22H21N5O5 : C, 60.68; H, 4.86; N, 16.08. Found: C, 60.59; H, 4.73; N, 15.88.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH2:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)(C)(C)C.[ClH:17]>O1CCOCC1>[ClH:17].[CH3:6][NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CN(CC1CCOCC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCC1CCOCC1

Procedure:
A solution of N-methyl-N-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (740 mg) in 4N hydrochloric acid in 1,4-dioxan (10 ml, ex Aldrich) was stirred at room temperature for 1 h. The dioxan was removed under reduced pressure and the residue triturated with ether. The solid was filtered onto a sinter, washed with ether and dried, to afford N-methyl-N-(tetrahydro-pyran-4-ylmethyl)-amine hydrochloride (460 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=O.[CH3:20][NH:21][NH2:22].O>C1(C)C=CC=CC=1>[CH3:20][N:21]1[N:22]=[C:5]([C:4]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:2]([Cl:1])[CH:3]=2)[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:10]
Reactant: CNN
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1nc(-c2ccc(Cl)c(Cl)c2)c2ccccc2c1=O
Yield: 84 %

Procedure:
To a solution of 2-(3,4-dichlorobenzoyl)benzoic acid (29.4 g, 0.1 mol) in toluene (100 mL) was added methyl hydrazine (5.8 mL). The mixture was brought to reflux for 3 hours, with the removal of water via a Dean Stark trap. The mixture was cooled, and the product was collected by filtration to afford 25.54 g (84%) of 2-Methyl-4-(3,4-dichlorophenyl)-1-(2H)-phthalazinone, m.p. 179°-181° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:2]3[N:7]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:5]=[CH:4][CH:3]=3)=[CH:20][N:21]=[C:22]2[N:27]=1
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccccn4)n3)cnc2n1
Yield: 33.7 %

Procedure:
6-Bromo-2,2′-bipyridine (0.35 g, 1.44 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.13 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-100%) and trituration with isohexane gave 6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2,2′-bipyridine (130 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.39-7.43 (2H, m), 7.85 (1H, d, J 8), 7.89-7.94 (1H, m), 7.99 (1H, dd, J 8 and 8), 8.31 (1H, d, J 8), 8.38 (1H, d, J 8), 8.56 (1H, s), 8.75-8.80 (1H, m), 10.53 (1H, d, J 7); m/z (ES+) 342 (M++H).
Reaction SMILES: C(OC(OCC)C1C=CC=C2C=1SC1C(C=O)=CC=CC=1N2C)C.CSCS(C)=O.[ClH:31].C([N+](C)(C)C)C1C=CC=CC=1.C(C1C=CC=C2C=1SC1C(CC(OC)=O)=CC=CC=1N2C)=O.C([O-])(=O)C.[Na+].Cl.NO.[N:73](=[CH:75][C:76]1[CH:89]=[CH:88][CH:87]=[C:86]2[C:77]=1[S:78][C:79]1[C:80]([CH2:91][C:92]([O:94][CH3:95])=[O:93])=[CH:81][CH:82]=[CH:83][C:84]=1[N:85]2[CH3:90])O>O1CCCC1.CO.Cl.[Pd].O>[ClH:31].[NH2:73][CH2:75][C:76]1[CH:89]=[CH:88][CH:87]=[C:86]2[C:77]=1[S:78][C:79]1[C:80]([CH2:91][C:92]([O:94][CH3:95])=[O:93])=[CH:81][CH:82]=[CH:83][C:84]=1[N:85]2[CH3:90]
Reactant: COC(=O)Cc1cccc2c1Sc1c(C=NO)cccc1N2C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CCOC(OCC)c1cccc2c1Sc1c(C=O)cccc1N2C
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc2c1Sc1c(CN)cccc1N2C

Procedure:
A solution of 500 mg (1.46 mmol) of 6-diethoxymethyl-10-methyl-phenothiazine-4-carbaldehyde in 5 ml of tetrahydrofuran can be converted analogously to that described in Example 1.1.1.d with 0.22 g (1.75 mmol) of methyl (methylthiomethyl) sulphoxide, 0.14 ml of TRITON B (benzyltrimethylammonium hydrochloride) solution (35% in methanol) and hydrolysis into methyl 6-formyl-10-methyl-phenothiazine-4-acetate. This compound can be converted analogously to that described in Example 1.1.1.e in methanol, water and tetrahydrofuran using sodium acetate and hydroxylamine hydrochloride into methyl 6-[(hydroximino)methyl]-10-methyl-phenothiazine-4-acetate. This compound can be hydrogenated over palladium/charcoal in methanol and methanolic hydrochloric acid (20%) analogously to that described in Example 1.1.1.f, whereby there is obtained methyl 6-aminomethyl-10-methyl-phenothiazine-4-acetate hydrochloride which can be converted analogously to that described in Example 1.1.2 in dioxan and 1N sodium hydroxide solution using di-tert-butyl dicarbonate into methyl 6-[(1-tert-butylformamido)methyl]-10-methyl-phenothiazine-4-acetate. The product obtained can be hydrolyzed with 1N potassium hydroxide solution in methanol analogously to that described in Example 1.1.3 to give (6-tert-butoxycarbonyl-aminomethyl-10-methyl-phenothiazin-4-yl)-acetic acid prepared according to Example 2.1.1.g.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[CH:10][C:11](C4C=CC=CC=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[F:28][CH:29]([F:48])[O:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]=1[O:46][CH3:47]>>[CH:1]1([N:4]2[C:8]3[C:9]([O:19][C@@H:20]([C@H:22]4[CH2:26][NH:25][C:24](=[O:27])[CH2:23]4)[CH3:21])=[CH:10][C:11]([C:34]4[CH:35]=[CH:36][C:31]([O:30][CH:29]([F:28])[F:48])=[C:32]([O:46][CH3:47])[CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC(F)F
Reactant: C[C@@H](Oc1cc(-c2ccccc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: COc1cc(-c2cc(O[C@H](C)[C@H]3CNC(=O)C3)c3c(c2)ncn3C2CC2)ccc1OC(F)F
Yield: 47.8 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((1-cyclopropyl-5-phenyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one:, using instead 2-(4-(difluoromethoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (123.6 mg, 0.412 mmol) as a starting material to afford 60.0 mg (47.8%) of (R)-4-((R)-1-((1-cyclopropyl-5-(4-(difluoromethoxy)-3-methoxyphenyl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (GS0697836). 1H NMR (300 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.58 (s, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.37 (d, J=1.8, 1H), 7.26-7.19 (m, 2H), 7.06 (t, J=8.4 Hz, 1H). 7.06 (t, J=75 Hz, 1H), 7.05 (s, 1H), 4.88-4.82 (m, 1H), 3.92 (s, 3H), 3.72-3.65 (m, 1H), 3.38 (t, J=9.3 Hz, 1H), 3.18 (dd, J=6.3, 6.9 Hz, 1H), 2.83-2.76 (m, 1H), 2.39-2.21 (m, 2H), 1.30 (d, J=6 Hz, 3H), 1.15-0.99 (m, 4H), LCMS-ESI+ (m/z): [M+H]+ calcd for C24H25F2N3O4:457.18; found 458.17.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]1.O>CS(C)=O>[O:9]1[C:10]2([CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)[CH2:2]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC2(CC1)CO2
Yield: 240.8 %

Procedure:
to a stirred solution of trimethylsulfoxonium iodide (56.1 g, 255 mmol) in anhydrous DMSO (150 ml) was added a mixture of NaH (18.5 gram 1.5 equiv., 60% in mineral oil) under a nitrogen atmosphere. The mixture was stirred at 65° C. for 1 hour, whereafter compound 2 (32 g, 150 mmol) was added as a solution in DMSO (10 ml). The mixture was refluxed overnight under a nitrogen atmosphere. The solution was allowed to reach room temperature, water was added and the mixture was extracted with diethyl ether (3×200 ml). The combined organic layer was washed with H2O, with brine and dried over Na2SO4. The Et2O was evaporated to yield 82.1 gram (32 g, 95%) compound 3. 1H-NMR (300 MHz, CDCl3): δ (ppm)=1.45 (s, 9H, BOC); 1.50-2.10 (m, 6H), 2.60-2.70 (m, 2H), 3.5-3.60 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:11]([O:13]CC)=[O:12])=[N:5][CH:6]=[C:7]([O:9][CH3:10])[N:8]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[C:4]([C:11]([OH:13])=[O:12])=[N:5][CH:6]=[C:7]([O:9][CH3:10])[N:8]=1
Reactant: CCOC(=O)c1ncc(OC)nc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cnc(C(=O)O)c(OC)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.9 %

Procedure:
To a solution of ethyl 3,5-dimethoxypyrazine-2-carboxylate (0.314 g, 1.48 mmol) in MeOH (5 mL) at room temperature was added potassium hydroxide (0.135 g, 2.41 mmol). The reaction mixture was stirred at RT for 17 h, quenched with 5 M HCl (0.48 mL), and diluted with EtOAc. The solid was removed by filtration and the filtrate was concentrated. Purification by flash column chromatography on silica gel (10% MeOH in DCM) gave 3,5-dimethoxypyrazine-2-carboxylic acid (0.261 g, 1.42 mmol, 96% yield) as a white solid. LC/MS (ESI+) m/z=185.1 (M+H)+.
Reaction SMILES: C(OC(=O)C[C:8]1([C:17]([OH:19])=[O:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)(C)(C)C.Cl>CCOC(C)=O>[C:17]([CH2:8][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]1[C:17]([OH:19])=[O:18])([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)O)Cc2ccccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)CC1c2ccccc2CC1C(=O)O
Reaction time: 1 h

Procedure:
A solution of 2-(2-tert-butoxy-2-oxoethyl)indane-2-carboxylic acid from Step B (1.50 g, 5.43 mmol) in EtOAc (100 mL) was saturated with HCl (g) and aged at ambient temperature for 1 h, then concentrated to dryness in vacuo to give the title compound. MS: m/z=284 (M+Na+CH3CN).