Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])([CH3:11])([CH3:10])[CH3:9].[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26](O)=[O:27].C(OP(C#N)(=O)OCC)C>CN(C=O)C.C(Cl)Cl>[C:8]([O:12][C:13](=[O:19])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:15][C:26](=[O:27])[CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: COCCOCC(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOCC(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
At 0°, 6.4 ml (45.7 mmol) of triethylamine are added to a solution of 5 g (23.9 mmol) of (L)-valine tert-butyl ester, 2.91 g (21.7 mmol) of 2-(methoxyethoxy)-acetic acid and 3.55 g (21.7 mmol) of cyanophosphonic acid diethyl ester in 30 ml of DMF and the mixture is then stirred overnight at RT. The reaction mixture is diluted with methylene chloride, washed in succession with 10% citric acid, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution and, after concentration by evaporation of the organic phase, yields 5.1 g of N-methoxyethoxyacetyl-(L)-valine tert-butyl ester, which is stirred for 1 h at RT in 22 ml of a (1:1) mixture of methylene chloride and TFA. Concentration by evaporation of the reaction solution yields the title compound in the form of a colourless oil. 1H-NMR (200 MHz, CDCl3): 10.0 (s, broad, 1H), 7.62 d, broad, 1H), 4.55 (m, 1H), 4.10 (s, 2H), 3.70 (m, 2H), 3.58 (m, 2H), 3.40 (s, 3H), 2.28 (m, 1H), 0.98 (d, J=7 Hz, 3H), 0.95 (d, J=7 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]([C:18]1[C:19]([CH2:50][CH2:51][CH3:52])=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]3[C:36](=[O:37])[C:35]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=4)([CH3:38])[NH:34][C:33]3=[O:49])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)([O:8]CC1C=CC(OC)=CC=1)[C:4]([F:7])([F:6])[F:5]>C(OCC)(=O)C.[C].[Pd]>[F:7][C:4]([F:5])([F:6])[C:3]([C:18]1[C:19]([CH2:50][CH2:51][CH3:52])=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]3[C:36](=[O:37])[C:35]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH:46]([CH3:47])[CH3:48])=[CH:43][CH:44]=4)([CH3:38])[NH:34][C:33]3=[O:49])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)([OH:8])[C:2]([F:53])([F:1])[F:54]
Reactant: CCCc1cc(N2CCN(CCN3C(=O)NC(C)(c4ccc(OC(C)C)cc4)C3=O)CC2)ncc1C(OCc1ccc(OC)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(N2CCN(CCN3C(=O)NC(C)(c4ccc(OC(C)C)cc4)C3=O)CC2)ncc1C(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.3 %

Procedure:
3-[2-(4-{5-[1,1,1,3,3,3-Hexafluoro-2-(4-methoxybenzyloxy)propan-2-yl]-4-propylpyridin-2-yl}piperazin-1-yl)ethyl]-5-[4-(1-methylethoxy)phenyl]-5-methylimidazolidine-2,4-dione (10 mg, 0.0131 mmol) was dissolved in ethyl acetate (2 mL), added palladium carbon (1.0 mg), and the mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The reaction solution was filtered through a pad of celite, and concentrated in vacuo. The title compound (7.3 mg (yield 86%)) was obtained as a yellow oil.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]1[C:10]#[N:11].O>C(O)(=O)C>[Br:1][C:7]1[CH:6]=[C:5]([C:10]#[N:11])[N:4]([CH3:3])[C:8]=1[CH3:9]
Reactant: Cc1ccc(C#N)n1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Br)cc(C#N)n1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of bromine (6.58 mL, 0.13 mol) in acetic acid (60 mL) is added dropwise, with the aid of a dropping funnel, to a solution of 1,5-dimethyl-1H-pyrrole-2-carbonitrile (15.0 g, 0.12 mol) in acetic acid (300 mL). The batch is stirred at ambient temperature for 24 hours. The reaction mixture is then poured into a beaker containing 300 mL of water. The solid formed is filtered off and rinsed with water. It is then dissolved in dichloromethane (300 mL) and the organic phase is washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to yield the expected product in the form of a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:15]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][C:10]=2[Cl:11])[NH:7][N:6]=[C:5]3[C:12]([OH:14])=[O:13])=[CH:20][CH:19]=1)(=[O:17])[CH3:16]
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2Cl)cc1
Yield: 35.7 %

Procedure:
To a mixture of 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (200 mg, 0.73 mmol) and 4-acetylphenylboronic acid (131 mg, 0.80 mmol) in toluene (2 mL) and EtOH (1 mL) was added 2 N aqueous potassium carbonate solution (1.45 mL, 2.90 mmol). The resulting mixture was degassed with N2 for 10 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.036 mmol), and heated to reflux for 16 hours. The cooled reaction was quenched with saturated NH4Cl and the mixture was filtered. The filtrate was acidified with 1 N HCl to pH 5 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting crude material was purified by reverse phase chromatography (Biotage C18 column, 0-40% MeCN/water) to give the title compound (82 mg, 40% yield) as a solid. MS (ES+) 315.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.01 (d, J=8.39 Hz, 2H), 7.82 (s, 1H), 7.57 (d, J=8.20 Hz, 2H), 2.60 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[NH:22]2>>[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[N:22]2[CH2:7][C:4]1[S:3][C:2]([Cl:1])=[CH:6][CH:5]=1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1ccc(Cl)s1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(Cl)s2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-bromo-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 85-87° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.19-7.11 (m, 2H), 6.88-6.85 (m, 2H), 6.76 (d, J=3.8 Hz, 1H), 6.47 (s, 1H), 6.06 (s, 1H), 5.87 (d, J=5.8 Hz, 2H), 4.97 (ABq, 2H), 4.91 (d, J=9.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.9, 157.2, 156.9, 149.3, 143.3, 142.1, 136.3, 130.3, 129.8, 127.7, 126.3, 126.0, 120.2, 116.1, 107.9, 102.6, 101.6, 93.3, 77.2, 59.5, 39.4; MS (ES+) m/z 490.3 (M+1), 488.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH:12]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][CH2:12][C:11]1[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:10]=1[C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: NCc1ccccc1
Product: COc1ncc(Br)cc1-c1ccc(C(F)(F)F)cc1CNCc1ccccc1

Procedure:
2-(5-Bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzaldehyde and benzylamine were reacted as described in Example 17, Step 1 to provide benzyl-[2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:19]([CH3:30])[C:20]([CH2:22][NH:23]C(=O)C(C)(C)C)=[O:21])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C>C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH:9]=[CH:10][C:11]1=[N:23][CH2:22][C:20](=[O:21])[N:19]([CH3:30])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2
Reactant: CN(C(=O)CNC(=O)C(C)(C)C)c1ccccc1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1C(=O)CN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
65 mg (0.14 mmol) of (E)-N-[[N-[2-[3-(3,4-dichlorophenyl)acryloyl]phenyl]-N-methylcarbamoyl]methyl]pivalamide were dissolved in 5 ml of ethyl acetate saturated with hydrogen chloride and were stirred at room temperature for 30 minutes. The solvent was removed by evaporation and the residue dissolved in 5 ml of methanol and 40 mg (0.04 mmol) of triethylamine added. After 2 hours at room temperature the solvent was removed by evaporation and the residue chromatographed on silica gel using ethyl acetate/petrol 2:1 for the elution. There was obtained 33 mg of (E)-5-(3,4-dichlorostyryl)-1,3-dihydro-1-methyl-2H-benzo-1,4-diazepin-2-one as a pale yellow foam. MS: m/e 344.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[O:22]CC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[NH2:21][C:12]1[C:11]2[N:10]=[C:9]([OH:22])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: CCOc1nc2c(N)nc3cccnc3c2n1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1nc2cccnc2c2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
To a stirred suspension of 1-benzyl-2-ethoxy-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (1.3 g, 4 mmol) in dichloromethane (20 mL) was added boron tribromide (1M solution in dichloromethane, 10 mL, 10 mmol), and the reaction was stirred at room temperature. Additional aliquots of the boron tribromide solution (7.5 equivalents, 30 mmol total) were added to drive the reaction to completion. The reaction was concentrated under reduced pressure, and to it was added methanol (1 mL) followed by 6M HCl (100 mL). The reaction was heated at 50° C. for 2 hours, cooled in an ice bath, and adjusted to a basic pH by the addition of 6N NaOH. The product was extracted with dichloromethane and the organic layers were combined, dried (MgSO4), filtered, and evaporated to afford crude product. The product was purified by preparative HPLC (Analogix Separation System, and eluted with a gradient of 0-10% methanol in dichloromethane with 1% ammonium hydroxide) to provide a solid which was triturated with hot acetonitrile, filtered, and washed with ether to afford 4-amino-1-benzyl-1H-imidazo[4,5-c][1,5]naphthyridin-2-ol (196 mg) as a yellow solid, mp>250° C.; HRMS (ESI) calcd for C16H13N5O[M+H]+: 292.1198. found 292.1198.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][C@@H:5]2[C:7]([CH2:12][O:13][C:14](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:8][C@@H:9](C=C)[C@@H:4]2[O:3]1>CC1(C)OO1.CC(C)=O>[CH3:33][C:2]1([CH3:1])[O:3][C@@H:4]2[CH:9]=[CH:8][C@@H:7]([C@H:12]3[CH2:14][O:13]3)[C@@H:5]2[O:6]1
Reactant: C=C[C@@H]1C=C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Agent: CC1(C)OO1
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2[C@H]([C@H]3CO3)C=C[C@H]2O1
Temperature: -20 °C
Reaction time: 7 h

Procedure:
(3aS,4R,6aR)-2,2-dimethyl-6-(trityloxymethyl)-4-vinyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (2-3) (7.0 g, 42.1 mmol, 1.0 equiv) was dissolved in a freshly prepared solution of DMDO in acetone (460 mL, 0.085 M, 0.9 equity), stirred at −20° C. for 7 hours and stored at −18° C. overnight. The reaction mixture was concentrated and purified via flash chromatography on a silica gel column (ethyl acetate/hexanes) to yield desired (3aS,4S,6aR)-2,2-dimethyl-4-((S)-oxiran-2-yl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole (2-4) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 5.92 (t, J=5.7 Hz, 1H); 5.75-5.71 (m, 1H); 5.17 (d, J=5.8 Hz, 1H); 4.70-4.57 (m, 1H); 2.98-2.89 (m, 2H); 2.77-2.72 (m, 1H); 2.55 (dt, J=4.8, 2.8 Hz, 1H); 1.41 (s, 3H); 1.35 (d, J=2.3 Hz, 3H).
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([CH3:9])([CH3:8])O)([CH3:3])[CH3:2].O=S(Cl)Cl.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]=[S:24]>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]1[N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]([CH3:9])([CH3:8])[S:24]1
Reactant: CC(C)NCC(C)(C)O
Reactant: S=C=Nc1cccc(Cl)c1Cl
Solvent: O=S(Cl)Cl
Product: CC(C)N1CC(C)(C)SC1=Nc1cccc(Cl)c1Cl

Procedure:
Isopropylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-Isopropyl-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3-isopropyl-5,5-dimethyl-1,3-thiazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[NH:10][C:11]([C:13]2[C:14]([OH:21])=[N:15][C:16]([CH2:19][OH:20])=[N:17][CH:18]=2)=[O:12])=[CH:5][CH:4]=1>C(Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:10][C:11]([C:13]2[C:14]([OH:21])=[N:15][C:16]([CH:19]=[O:20])=[N:17][CH:18]=2)=[O:12])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(NC(=O)c2cnc(CO)nc2O)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(C(NC(=O)c2cnc(C=O)nc2O)c2ccc(OC)cc2)cc1

Procedure:
A mixture of step B product, 2-17-c, (2.0 g, 5 mmol) and Dess-Martain reagent (2.4 g, 5.6 mmol) in DCM (60 mL) was stirred at the ambient temperature for 1 h. The reaction solution was evaporated under vacuum to give a residue, which was purified by column chromatography with the eluent DCM:MeOH=60:1 to afford the crude product, 2-17-d, (1.84 g, 84%) as a solid. LC-MS: (M+H3O)+ 416.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:38])(=[O:29])=[O:28])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:41][C:42](=[O:53])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH:51]=O)=[CH:45][CH:44]=1)C.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.FC(F)(F)C(O)=O.[OH-].[Na+].C(O)(=O)C>ClCCl.O.C1(C)C=CC=CC=1.C1COCC1>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:51][CH2:50][CH2:49][C:46]2[CH:47]=[CH:48][C:43]([C:42]([OH:53])=[O:41])=[CH:44][CH:45]=2)=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:38])(=[O:29])=[O:28])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Reactant: Cc1cccc(C)c1CS(=O)(=O)NCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(C)c1CS(=O)(=O)NCCc1c(CCCc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Temperature: -20 °C
Reaction time: 0.58 h
Yield: 81.4 %

Procedure:
N-[2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethyl-phenyl)-methanesulfonamide (300 g, 552 mmol), 4-(3-Oxo-propyl)-benzoic acid ethyl ester (250 g, 1.21 mol), triethylsilane (192 g, 1.66 mol), and dichloromethane (2.9 L) were combined, stirred, and cooled to −20° C. A solution of boron trifluoride etherate (55.0 g, 322 mmol) in dichloromethane (10 mL) was added to the reaction mixture over 9 min. After 35 min, trifluoroacetic acid (63 g, 553 mmol) was added to the reaction mixture. After 40 min, the reaction mixture was filtered cold through a celite pad into aqueous sodium bicarbonate (138 g/1.5 L). The organic layer was concentrated to 1.2 L g, then ethanol (1.5 L) was added. The solution was concentrated to 1.2 L. THF (450 mL) and a solution of aqueous sodium hydroxide (221 g, 2.76 mol) were added. The reaction mixture was then warmed to reflux for 30 min. The mixture was cooled to 50° C. Toluene (1.5 L), water (300 mL) and acetic acid (166 g, 2.76 mol) were added. The organic and aqueous phases were separated and the organic phase was concentrated to 1.2 L. Toluene (600 mL) was added and the mixture was concentrated to 1.2 L. The mixture was cooled to room temperature and stirred for 16 h. The solid was collected by filtration, washed with cold toluene (3×300 mL), and dried to give 317 g (81%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5](=[O:24])[CH2:6][CH:7]([OH:23])/[CH:8]=[CH:9]/[Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14].C(B(CC)CC)C.[BH4-].[Na+].OO>O1CCCC1.O.CCOCC.CO>[OH:24][CH:5]([CH2:6][CH:7]([OH:23])/[CH:8]=[CH:9]/[Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][C:3]([O:2][CH3:1])=[O:25]
Reactant: CCCC[Sn](/C=C/C(O)CC(=O)CC(=O)OC)(CCCC)CCCC
Agent: CCB(CC)CC
Agent: OO
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](/C=C/C(O)CC(O)CC(=O)OC)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A mixture of E-methyl-5-hydroxy-3-oxo-7-tributylstannyl-6-heptenoate (7.19 g) and 1M triethylborane in tetrahydrofuran (23.4 ml) in anhydrous tetrahydrofuran (40 ml) is stirred at 20°-25° C. for about 20 minutes. The mixture is cooled to -78° C., sodium borohydride (0.677 g) added, stirred for 10 minutes, methanol (15 ml) added over about 30 minutes maintaining temperature below -68° C. and stirred at -78° C. for about 2 hours. The mixture is allowed to warm to -60° C. and 30% hydrogen peroxide (35 ml) in water (86 ml) is added. The mixture is allowed to warm to room temperature while stirring for about 30 minutes, diluted with ether and the layers separated. The organic solution is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in 25% ethyl acetate in hexane to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:18][OH:19]>>[OH:19][CH2:18][C@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH2:20][CH2:21][CH3:22]
Reactant: CCC[C@@H](N)CO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CCC[C@H](CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2R)-2-amino-1-pentanol (CAN 80696-30-6) as starting materials and isolated (72 mg, 77%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 313.1311 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH:7](O)[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH2:6])[CH3:2].[Cl:16][C:17]1[C:22]([NH2:23])=[C:21](I)[CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][C:21]2[C:22](=[C:17]([Cl:16])[CH:18]=[CH:19][CH:20]=2)[NH:23][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:15])[CH3:2]
Reactant: C=C(C(=O)OCC)C(O)c1cccnc1
Reactant: Nc1c(Cl)cccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(c2cccnc2)Nc2c(Cl)cccc2C1
Temperature: 70 °C
Yield: 86.9 %

Procedure:
A degassed mixture of 2-[(hydroxy)(pyridin-3-yl)methyl]acrylic acid ethyl ester (8.2 g, 39.6 mmol), 6-chloro-2-iodoaniline (10.0 g, 39.5 mmol), triethylamine (9 mL, 122 mmol) and palladium(II) acetate (300 mg) in acetonitrile (80 mL) was heated at 70° C. overnight. The mixture was cooled to room temperature and partitioned between ethyl acetate (200 mL) and water (100 mL). The aqueous layer was separated and the organic layer was washed with brine (50 mL), filtered, dried (phase separator) and concentrated in vacuo to give a crude solid. This was washed with a minimum of ice-cold diethyl ether to yield 8-chloro-2-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (10.8 g, 87%) as a white solid. δH (CDCl3) 8.73 (m, 2H), 8.04 (m, 1H), 7.66 (dd, J 7.9, 5.5 Hz, 1H), 7.18 (m, 1H), 7.05 (m, 1H), 6.94 (m, 1H), 6.29 (s, 1H), 3.99 (m, 4H), 1.04 (t, J 7.1 Hz, 3H). LCMS (ES+) 315.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][NH:5]2.N[C@@H:17](C)CO>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH2:15][CH3:17])[CH2:6][NH:5]2
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Reactant: C[C@H](N)CO
Product: CC[C@H]1CNc2cc(Br)ccc2N1C(C)=O

Procedure:
(S)-1-(6-bromo-2-ethyl-3,4-dihydroquinoxaline-1(2H)-yl)ethan-1-one was synthesized according to the procedure outlined for (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone substituting (S)-2-aminobutan-1-ol for (S)-2-aminopropan-1-ol in the initial step. MS (ESI, pos. ion) m/z 241, 243 [M−42 (acyl)]+.
Reaction SMILES: CC1C=CC(CNC2C(N)=CC=CC=2)=CC=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[N:28]=[C:27]2[CH2:35][CH:36]2[CH2:41][CH2:40][N:39](CC3C=CC=CC=3)[CH2:38][CH2:37]2)=[CH:21][CH:20]=1.[H][H]>[Pd].CO>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:26]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[N:28]=[C:27]2[CH2:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: COc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3cccnc32)cc1
Agent: [Pd]
Agent: Cc1ccc(CNc2ccccc2N)cc1
Solvent: CO
Product: COc1ccc(Cn2c(CC3CCNCC3)nc3cccnc32)cc1
Yield: 89 %

Procedure:
A mixture of 41 parts of 3-[(4-methoxyphenyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-3H-imidazo[4,5-b]-pyridine and 480 parts of methanol was hydrogenated at normal pressure and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 30 parts (89%) of 3-[(4-methoxyphenyl)methyl]-2-(4-piperidinylmethyl)-3H-imidazo[4,5-b]pyridine (37). In a similar manner there were also prepared:
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[CH3:11][NH:12][C:13]([C:15]1[C:20]([NH2:21])=[N:19][CH:18]=[C:17]([Br:22])[N:16]=1)=[O:14]>C(OC(=O)C)(=O)C>[Br:22][C:17]1[N:16]=[C:15]2[C:20](=[N:19][CH:18]=1)[N:21]=[CH:11][N:12]([CH3:1])[C:13]2=[O:14]
Reactant: CNC(=O)c1nc(Br)cnc1N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: Cn1cnc2ncc(Br)nc2c1=O
Temperature: 25 °C
Yield: 89 %

Procedure:
To a mixture of triethyl orthoformate (70 mL) and acetic anhydride (70 mL) was added 3-amino-6-bromo-pyrazine-2-carboxylic acid methylamide (12.7 g, 55 mmol; see Example 16 (b) above) with stirring. The resulting solution was heated at reflux for 2 hours and allowed to cool to room temperature. The precipitate that formed was collected, washed with ethyl acetate, and dried to afford 6-bromo-3-methyl-3H-pteridin-4-one as a white solid (11.8 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ3.54 (s, 3H), 8.70 (s, 1H), 9.15 (s, 1 H); 13C NMR (100 MHz, DMSO-d6) δ34.03, 133.28, 137.82, 152.39, 152.70, 153.33, 159.19.