Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH:4]([C:11]([O:13]CC2C=C(OC)C(OC)=C(OC)C=2)=[O:12])[N:3]1[CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1>C(O)(C)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH:4]([C:11]([OH:13])=[O:12])[N:3]1[CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: COc1cc(COC(=O)C2Cc3sccc3C(=O)N2Cc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Solvent: CC(C)O
Product: COc1cc(CN2C(=O)c3ccsc3CC2C(=O)O)cc(OC)c1OC
Yield: 65 %

Procedure:
The compound is prepared by saponification of 4-oxo-6-(3,4,5-trimethoxy-benzyloxycarbonyl)-5-(3,4,5-trimethoxybenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (Example 15), to give beige crystals, M.p.=208° C. (isopropanol), Yield: 65%.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[C:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:19])=[CH:10][CH:9]=1.S(OC)(OC)(=O)=O.[H-].[Na+]>O.CO.C(OC)(C)(C)C.CN1C(=O)N(C)CCC1>[CH3:1][O:19]/[C:18](/[C:15]1[C:16]2[C:11](=[CH:10][CH:9]=[C:8]([Br:7])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)=[CH:20]/[C:21]([O:23][CH3:24])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CC(=O)c1cccc2ccc(Br)cc12
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)/C=C(/OC)c1cccc2ccc(Br)cc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
93 g (0.68 mol) of potassium carbonate are added to a stirred mixture of 189 g (0.61 mol) of methyl 7-bromo-1-naphthoylacetate and 500 ml of N,N'-dimethylpropyleneurea, and the mixture is stirred at 40° C. for 2 h. It is subsequently cooled to 0°-5° C., and a mixture of 85 g (0.68 mol) of dimethyl sulfate and 50 ml of N,N'-dimethylpropyleneurea is added dropwise. The mixture is then stirred at 40° C. for a further 2 h, and subsequently water and methyl tert-butyl ether are added. The aqueous phase is extracted once more with methyl tert-butyl ether, and the combined organic phases are dried over Na2SO4 and concentrated. The residue is taken up in 500 ml of N,N'-dimethylpropyleneurea, and 2.7 g (0.11 mol) of NaH are added. The mixture is stirred at room temperature for 15 h. Subsequently, 20 ml of methanol are added and the mixture is diluted with water and extracted with methyl tert-butyl ether. The organic phase is washed with water, dried over Na2SO4 and concentrated. The residue is recrystallized from methanol to give 102 g (52%) of methyl (E)-3-methoxy-3-(7-bromo-1-naphthyl)acrylate in the form of colorless crystals of melting point 111°-113° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:5]([N+:19]([O-])=O)[CH:4]=1.[H][H]>CC(O)=O.[Pd]>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:19]=[C:17]([NH2:18])[C:11]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])c(C2(C#N)CCCCC2)cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C1(CCCCC1)C(N)=N2
Temperature: 70 °C
Yield: 7.5 %

Procedure:
1-(4,5-Dimethoxy-2-nitrophenyl)cyclohexanecarbonitrile (0.251 g, 0.865 mmol), prepared in Step 2, in AcOH (6 mL) was treated with 10% Pd/C, fitted with hydrogen balloon and heated to 70° C. for 3 hours under hydrogen atmosphere. The catalyst was filtered off and washed with EtOH. The solvent was concentrated. Purification by reverse phase HPLC afforded 17 mg (8%) of 5′,6′-dimethoxyspiro[cyclohexane-1,3′-indol]-2′-amine 1H NMR (400 MHz, DMSO) δ 7.11 (s, 1H), 6.64 (s, 1H), 3.72 (s, 3H), 3.70 (s, 3H), 1.88-1.84 (m 4H), 1.82-1.66 (m, 4H), 1.22 (d, J=10.2 Hz, 2H). MS (ESI) m/z 261 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[C:18]([C:26]([OH:28])=[O:27])=[CH:19][N:20]2[CH:23]2[CH2:25][CH2:24]2)=[CH:15][C:14]=1[F:30])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[C:18]([C:26]([OH:28])=[O:27])=[CH:19][N:20]2[CH:23]2[CH2:24][CH2:25]2)=[CH:15][C:14]=1[F:30]
Reactant: CC(C)(C)OC(=O)NCCCNc1cc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCNc1cc2c(cc1F)c(=O)c(C(=O)O)cn2C1CC1
Yield: 135.8 %

Procedure:
A solution of intermediate 12 (100 mg) in 10% TFA/DCM (1 mL) was stirred at room temperature for 2 h. The solvent was partially evaporated under reduced pressure. For five times the residual was diluted in DCM (2 mL) and concentrated under reduced pressure. Final solvent evaporation afforded the title compound (103.4 mg).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.C(OCC)(=[O:30])C.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][S:2]([C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:30]
Reactant: CCOC(C)=O
Reactant: CCCCCC(O)C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCC(O)C=CC1C=C(S(C)=O)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 17.6 mg of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone obtained in Example 34 in methanol (0.5 ml) was added a solution of 2KHSO5 ·KHSO4 ·K2SO4 (27.4 mg) in water (0.2 ml) at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the product was extracted into the organic layer. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to obtain 3 mg (yield 16%) of 2-methylsulfinyl-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: ClCCl.C(=O)(O)[O-].[Na+].[NH:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1.Cl[C:16]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17]>O>[OH:14][C@H:11]1[CH2:12][CH2:13][N:9]([C:16]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])[CH2:10]1
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)COC(=O)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of dichloromethane (5 mL) and water (5 mL) was added sodium bicarbonate (0.96 g, 11 mmol), followed by (3S)-pyrrolidin-3-ol (1.00 g, 11.5 mmol). Neopentyl chloroformate (1.71 mL, 11.5 mmol) was then added dropwise, and the resulting suspension was stirred at room temperature for 1.5 hours. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 4.50 (br s, 1H), 3.81-3.77 (m, 2H), 3.59-3.41 (m, 4H), 2.07-1.96 (m, 2H), 1.75-1.72 (m, 1H), 0.97 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][N:8]2[CH2:17][CH2:18][CH2:19][C:7]=12)=[O:5])C.[OH-].[Na+].C(#N)C.Cl>CO>[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:9][N:8]2[CH2:17][CH2:18][CH2:19][C:7]=12)([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2ccccc2)nn2c1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2)nn2c1CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 3-ethoxycarbonyl-2-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (2.1 g, 8.2 mmol) in MeOH (20 mL) add a solution of NaOH (15%, 40 mL) followed by acetonitrile (5 mL) and stirr at 50° C. for 3 hours. Cool the mixture to room temperature and add HCl (10%) until a pH of 3 is reached. Extract the mixture with EtOAc (3×100 mL) and wash with saturated aqueous sodium chloride (100 mL), dry (MgSO4), and concentrate in vacuo to give a yellow solid, 1.82 g, 97% yield, MS(ES+): m/z=229.1 (M+H)+
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[N:7]3[C:21]([CH3:24])=[N:22][N:23]=[C:6]3[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=2[N:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:20])[N:7]4[C:21]([CH3:24])=[N:22][N:23]=[C:6]4[N:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:4]=3[N:3]=[C:2]2[C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[CH:13][CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc(-c3nccs3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Yield: 78.4 %

Procedure:
To the mixture of 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.22 mmol), 2-(tributylstannyl)-1,3-thiazole (122 mg, 0.33 mmol) in toluene (14 mL) was added tetrakis(triphenylphosphine)palladium(0) (12.6 mg, 0.011 mmol) under N2. The mixture was refluxed overnight. The reaction mixture was concentrated in vacuo. The crude residue was purified using preparative LCMS to yield the desired product (80 mg, 79%). LCMS calculated for C23H26N7O2S (M+H): 464.2. found 464.2.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]2[NH:26][C:27](=[O:29])[NH:28][C:24]=2[CH:23]=1>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:21][C:22]4[CH:31]=[CH:30][C:25]5[NH:26][C:27](=[O:29])[NH:28][C:24]=5[CH:23]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)cn1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5[nH]c(=O)[nH]c5c4)nn23)cn1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.2 mmol) was coupled with 5-amino-1,3-dihydro-benzimidazol-2-one (54 mg, 0.36 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 43 mg (44%) of tan powder. LC/MS: 374 (M+H); HPLC: 97% pure, RT=2.20 min; 1H NMR: (DMSO, δ) 10.49 (s, 1H), 10.39 (s, 1H), 9.20 (s, 1H), 8.88 (s, 1H), 8.83 (s, 1H), 8.47 (dd, J=8.4, 2.5, 1H), 7.25 (d, J=8.4, 1H), 7.21 (s, 1H), 7.10 (d, J=4.8, 1H), 6.95 (d, J=8.8, 1H), 6.87 (d, J=4.8, 1H), 6.79 (d, J=8.4, 1H), 3.86 (s, 3H).
Reaction SMILES: C(OC([N:8]([O:30]C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:28][CH3:29])=[CH:13][CH:12]=1)=O)(C)(C)C.Cl.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:26][C:24]1[C:23]([Cl:27])=[CH:22][C:21]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][OH:30])=[CH:16][CH:15]=3)[C:18]([CH2:28][CH3:29])=[N:19][C:20]=2[CH:25]=1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCNO)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-[4-(2-{(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino}ethyl)phenyl]-5,6-dichloro-2-ethyl-1H-benzimidazole (step 1, 174 mg, 0.3 mmol) and 2N hydrochloric acid (3 mL) in ethyl acetate (20 mL) was stirred at room temperature for 1 day. The reaction mixture was poured into water (100 mL), neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to afford 162 mg (quant.) of the title compound as a yellow oil: 1H-NMR (CDCl3) δ 10.35 (2H, br.s), 7.89 (1H, s), 7.46-7.50 (2H, m), 7.29 (2H, d, J=6.8 Hz), 7.17 (1H, s), 3.37 (2H, t, J=6.9 Hz), 3.12 (2H, t, J=6.9 Hz), 2.80 (2H, q, J=6.9 Hz), 1.34 (3H, m).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[C:8]([C:12]([O:14][CH2:15][C:16]([NH2:18])=[S:17])=[O:13])([CH3:11])([CH3:10])[CH3:9].ClCCl>C(O)C>[CH3:10][C:8]([CH3:11])([CH3:9])[C:12]([O:14][CH2:15][C:16]1[S:17][CH:2]=[C:3]([C:4]([OH:6])=[O:5])[N:18]=1)=[O:13]
Reactant: O=C(O)C(=O)CBr
Reactant: CC(C)(C)C(=O)OCC(N)=S
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)C(=O)OCc1nc(C(=O)O)cs1
Reaction time: 15 h

Procedure:
To a solution of bromopyruvic acid (0.37 g, 2.22 mmol) and 2-(tert-butylcarbonyloxy)thioacetamide (0.41 g, 2.22 mmol) in ethanol (20 ml) was added 4 A molecular sieves (2 g). After stirring for 15 h, 20 mL of dichloromethane was added. The mixture was stirred 5 min and filtered to give the product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)=[CH:4][CH:3]=1.[CH:28]([NH2:30])=[O:29]>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:30][CH:28]=[O:29])=[CH:26][CH:27]=1
Reactant: NC=O
Reactant: Cn1c(=O)cc(-c2ccccc2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Solvent: O=CO
Product: Cn1c(=O)cc(-c2ccccc2)c2cc(C(NC=O)c3ccc(Cl)cc3)ccc21
Temperature: 160 °C
Yield: 93 %

Procedure:
A mixture of 6-(4-chlorobenzoyl)-1-methyl-4-phenyl-2(1H)-quinolinone (24 g) in formamide (130 ml) and formic acid (100 ml) was stirred and heated at 160° C. for 12 hours. The mixture was poured into ice water and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The product was used without further purification, yielding 24.2 g (93%) of (±)-N-[(4-chlorophenyl)-(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)methyl]formamide (interm. 5-a).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:19][CH2:18]2)[CH:8]=[C:7]([F:28])[C:3]=1[C:4]([OH:6])=O.C(Cl)CCl.C1C=C[C:36]2N(O)N=[N:39][C:37]=2[CH:38]=1.CCN(C(C)C)C(C)C.C1(N)CC1>C(Cl)Cl>[CH:37]1([NH:39][C:4](=[O:6])[C:3]2[C:2]([F:1])=[CH:10][C:9]([O:11][CH2:12][CH2:13][C@@H:14]3[CH2:16][C@@H:15]3[CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:19][CH2:18]3)=[CH:8][C:7]=2[F:28])[CH2:38][CH2:36]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1c(F)cc(OCC[C@@H]2C[C@@H]2C2CCN(CC(F)(F)F)CC2)cc1F
Agent: NC1CC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CC1)c1c(F)cc(OCC[C@@H]2C[C@@H]2C2CCN(CC(F)(F)F)CC2)cc1F
Reaction time: 8 h

Procedure:
2,6-Difluoro-4-(2-{(1S,2R)-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]cyclopropyl}ethoxy)benzoic acid (40 mg, 0.098 mmol) in 0.5 mL of DCM was stirred with EDC (37.6 mg, 0.196 mmol), HOBt (30 mg, 0.196 mmol) and DIPEA (64 mg, 0.49 mmol) at RT for 15 min. Cyclopropylamine (11.2 mg, 0.196 mmol) was added. The reaction mixture was stirred overnight. Solvent was removed under vacuum. The residue was purified by mass directed RPHPLC. The product fraction was basified with 2 M sodium bicarbonate aq. solution. The product was extracted with EtOAc. The organic layer was dried with sodium sulfate and concentrated to yield Example 3. LCMS calc: 446.45; obs: 447.01 (M+1); Human GPR119 EC50: 5.28 nM.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].O.[NH2:18][C:19]1[N:28]=[C:27]([C:29]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[N:20]=1>C(O)C.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]>[NH2:18][C:19]1[N:28]=[C:27]([C:29]([N:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39]2)=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:2]3[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=3[CH:4]=[O:5])[CH:25]=2)[N:20]=1
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Reactant: O=Cc1ccc(F)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)ccc3C=O)ccc2n1
Temperature: 120 °C

Procedure:
244 mg of 2-bromo-4-fluorobenzaldehyde, 0.35 g of potassium carbonate, 4 μl of water and 98 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 500 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 12 ml of ethanol under argon. The mixture is heated at 120° C. for 4 h; then allowed to cool, during which a precipitate deposits. The precipitate is filtered off, taken up in 10 ml of ethyl acetate and washed 3 times with 10 ml of water each time. After drying over sodium sulfate, the mixture is filtered off and evaporated to dryness in vacuo; yield: 495 mg (91%) of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-4-fluorobenzaldehyde; HPLC retention time: 1.73 min;
Reaction SMILES: [C:1]([N:6]1[C@H:11]([C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[CH:13]=2)[CH2:10][O:9][CH2:8][C@@H:7]1/[CH:21]=[CH:22]/[C:23](OC)=O)(=[O:5])CC=C.C(N(CC)CC)C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.ClCCl>[F:18][C:16]1[CH:17]=[C:12]([C@@H:11]2[CH2:10][O:9][CH2:8][C@@H:7]3[CH:21]=[CH:22][CH2:23][C:1](=[O:5])[N:6]23)[CH:13]=[C:14]([F:20])[C:15]=1[F:19]
Reactant: C=CCC(=O)N1[C@@H](/C=C/C(=O)OC)COC[C@H]1c1cc(F)c(F)c(F)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC=C[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N12
Reaction time: 0.17 h
Yield: 26.3 %

Procedure:
Grubbs catalyst 2nd generation (285 mg) was added to a solution of methyl (E)-3-[(3S,5R)-4-(3-butenoyl)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]acrylate (1.24 g) in dichloromethane (100 mL), and the reaction solution was heated under reflux in a nitrogen atmosphere for 1.5 hours. The reaction solution was returned to room temperature. Triethylamine (3 mL) was added to the reaction solution, which was then stirred for 10 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 250 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [O-:1]C#N.[Na+].[NH2:5][C:6]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)(=O)C.O>[Br:16][C:14]1[CH:13]=[CH:12][C:7]2[C:8](=[O:9])[O:10][C:11](=[O:1])[NH:5][C:6]=2[CH:15]=1
Reactant: N#C[O-]
Reactant: COC(=O)c1ccc(Br)cc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
87.0 g (1.33 mol) of sodium cyanate were added to 269.0 g (1.17 mol) of methyl 2-amino-4-bromobenzoate in 1.2 l of acetic acid with stirring at room temperature, and the mixture was subsequently stirred for a further 22 h. The reaction mixture was diluted with 1.5 l of water, and the residue was filtered off with suction. 0.42 l of sodium hydroxide solution (32%) was added to the solid, the mixture was diluted with 3.5 l of water and heated on a steam bath for 4 h. After cooling, the solid residue was filtered off with suction. Conventional work-up gave 205.2 g of 7-bromo-1H-benzo[d]-1,3-oxazine-2,4-dione; HPLC/MS (M+H)+=243 as solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:51]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][C:20]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[O:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:51])[C:8]=2[N:17]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCC(=O)N1CCOCC1

Procedure:
2-(Ethoxymethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinoline (5.1 g, 14 mmol) was treated with mCPBA (5.57 g, 24.2 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (5.14 g, 26.9 mmol) according to a modification of the method described in Part D of Example 8. The reaction was not washed with 10% aqueous sodium hydroxide prior to the addition of ammonium hydroxide. The crude product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol) and then triturated with ethyl acetate and isolated by filtration to provide 0.843 g of 2-(ethoxymethyl)-1-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-4-amine as off-white needles, mp 187-189° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[Br:12][C:13]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[C:33]#[N:34])=[CH:21][C:14]=1[O:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1)[C:17](=[O:18])[CH:16]([O:15][C:14]1[CH:21]=[C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[C:33]#[N:34])[CH:23]=[CH:24][C:13]=1[Br:12])[CH3:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccco1
Reactant: CC(Oc1cc(Oc2ccc(Br)cc2C#N)ccc1Br)C(=O)Cl
Solvent: ClCCl
Product: CCCCN(Cc1ccco1)C(=O)C(C)Oc1cc(Oc2ccc(Br)cc2C#N)ccc1Br
Temperature: -15 °C

Procedure:
N-Butyl-N-furfurylamine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-bromo-5-(2-cyano-4-bromophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. This residue is then purified by subjecting it to elution chromatography using mixtures of ethyl acetate and hexane with increasing concentrations of ethyl acetate as the eluant. The desired fractions determined by IR spectroscopy are then stripped of solvent to yield the desired product N-butyl-N-furfuryl-2-[2-bromo-5-(2-cyano-4-bromophenoxy)phenoxy]propionamide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16]C)=[O:15])=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2.[Li+].[OH-]>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:14]([OH:16])=[O:15])=[CH:4][C:5]([Br:13])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)c1cc(Br)c2c(c1N)N(C)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCCc2c(Br)cc(C(=O)O)c(N)c21
Temperature: 65 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (1.40 g, 4.68 mmol) in 2:1 THF/H2O (18 mL) at rt was added LiOH (224 mg, 9.36 mmol). The solution was warmed to 65° C. and stirred for 20 h. The resulting solution was cooled to rt and the THF was removed in vacuo. The aqueous residue remaining was acidified with 1 M aqueous HCl and the resulting tan solid that precipitated was collected by filtration and dried in vacuo to afford 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid in pure form.