Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[NH2:11].[CH2:13]([O:20][CH2:21][C:22](Cl)=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)Cl>[CH2:13]([O:20][CH2:21][C:22]([NH:11][C:5]1[CH:6]=[CH:7][C:8]([Br:10])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:12])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccc1NC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl-2-amino-5-bromobenzoate (15 g, 62.6 mmol) in DCM (241 mL) at 0° C. was added benzyloxyacetyl chloride (12.5 mL, 75.1 mmol) followed by Et3N (20 mL, 144 mmol) dropwise. The resulting white suspension was stirred at room temperature for 3 hours. The mixture was then washed with saturated aqueous NH4Cl (200 mL) followed by water (200 mL). The organics were dried (Na2SO4), filtered and concentrated to dryness. The crude solid was triturated with MeOH (90 mL) and dried under vacuum to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.FC(F)(F)C([O-])=O>C(NC(C)C)(C)C>[CH2:16]([N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:5]2[CH2:4][N:3]([CH2:1][CH3:2])[CH2:15][CH2:14][C:6]1=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Agent: O=C([O-])C(F)(F)F
Solvent: CC(C)NC(C)C
Product: CCN1CCc2c(c3ccccc3n2Cc2ccccc2)C1
Yield: 34.4 %

Procedure:
Preparation of the title compound was carried out according to General Method 5. 2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example 5) (100 mg, 0.5 mmol), benzyl chloride (158 mg, 1.25 mmol) in diisopropylamine (2 mL) were heated at 80° C. for 12 h to obtain 50 mg of 5-benzyl-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: C([O:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:40])[CH2:30][C:31]2[CH:39]=[C:38]3[C:34]([CH:35]=[CH:36][NH:37]3)=[CH:33][CH:32]=2)[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)[O:16]2)[C:8]=1OC)(C)(C)C.B(Cl)(Cl)Cl>>[OH:23][B:15]1[C@@H:14]([NH:28][C:29](=[O:40])[CH2:30][C:31]2[CH:39]=[C:38]3[C:34]([CH:35]=[CH:36][NH:37]3)=[CH:33][CH:32]=2)[CH2:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([OH:5])=[O:43])[C:8]=2[O:16]1
Reactant: COc1c(CC(NC(=O)Cc2ccc3cc[nH]c3c2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: O=C(Cc1ccc2cc[nH]c2c1)N[C@H]1Cc2cccc(C(=O)O)c2OB1O

Procedure:
Prepared from 3-[2-(2-1H-Indol-6-yl-acetylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 365 (MH)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([F:14])[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[CH3:13].[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18]Cl.Cl.O.CCOCC>CN(C=O)C.CCOCC>[Br:3][C:4]1[CH:5]=[C:6]([F:14])[CH:7]=[C:8]2[C:12]=1[N:11]([CH2:18][C:17]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:16]=1[Cl:15])[CH:10]=[C:9]2[CH3:13]
Reactant: Cc1c[nH]c2c(Br)cc(F)cc12
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cn(Cc2ccc(Cl)cc2Cl)c2c(Br)cc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60% in oil, 526 mg, 13.15 mmol, 1.5 equiv.) was added to a solution of 7-bromo-5-fluoro-3-methyl-1H-indole, [which was prepared analogous to I-30, according to the method of Dobbs, A., J. Org. Chem., 66, 638-641 (2001)], (2 g, 8.77 mmol, 1 equiv.) in DMF (30 mL) at −10° C. Reaction mixture was warmed to rt and stirred for 30 min. A solution of 2,4-dichlorobenzyl chloride (2.06 g, 10.52 mmol, 1.2 equiv.) in DMF (10 mL) was added gradually over 2.5 min at −10° C. The reaction mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was poured into a stirred solution of 10% HCl/water/ether (1:1:2, 40 mL) mixture, and the aqueous layer was extracted with ether (2×10 mL). The combined organic layers were washed with water (3×75 mL), brine (75 mL), dried over MgSO4, filtered, and concentrated to afford crude product as brown solid. Ether (4 mL) was added to the crude product, cooled down to −78° C. and filtered to afford I-191 (2.49 g, 73%) as off-white solid. 1H-NMR (500 MHz, CDCl3) confirmed the structure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[NH2:7])[CH3:2].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[CH2:12]([O:11][C:10]1[CH:9]=[C:8]2[C:6](=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])[NH:7][CH:24]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2=[O:16])[CH3:13]
Reactant: CCOc1ccc(N)cc1OCC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2cc(OCC)c(OCC)cc2c1=O
Yield: 69 %

Procedure:
3,4-Diethoxyaniline (3.7 g) and diethyl ethoxymethylenemalonate (5.3 g) were reacted in the same manner as in Experimental Example 1 to obtain 6,7-diethoxy-3-ethoxycarbonyl-4(1H)-quinolone (4.3 g). The compound (3 g) was subjected to hydrolysis and decarboxylation in the same manner as in Experimental Example 2 to obtain 6,7-diethoxy-4(1H)-quinolone (compound 10, 1.9 g).
Reaction SMILES: I.[NH2:2][CH:3]([S:10][CH3:11])/[N:4]=[C:5](/N(C)C)\[CH3:6].Cl[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>ClCCl>[CH3:6][C:5]1[N:4]=[C:3]([S:10][CH3:11])[NH:2][C:13](=[O:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CSC(N)/N=C(\C)N(C)C
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(SC)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of (1E)-N′-[amino(methylthio)methyl]-N,N-dimethylethanimidamide hydrogen iodide salt (73.0 g, 0.26 mole) in dry dichloromethane (900 mL), was added ethyl 3-chloro-3-oxopropanoate (44 mL, 95% Lancaster, 0.34 mole) was added under a nitrogen atmosphere. The mixture was stirred for 4 h at room temperature, cooled to 0° C. then triethylamine (107 mL, 0.78 mole) was added. The reaction mixture was stirred overnight. The solvent was removed and H2O was added. The pH was adjusted to pH=5.0 with acetic acid and extracted with ethylacetate then evaporated and crystallized from the appropriate solvent (Ethylacetate-Hexanes mixture solvent, approximately 20% ethylacetate-Hexanes). This afforded ethyl 4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (36.5 g, 62% yield) after drying under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH:22]=O)=[O:14].C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:14])[NH:15][C:16]2[C:17]([CH:22]=1)=[CH:18][N:19]=[CH:20][CH:21]=2
Reactant: O=Cc1cnccc1NC(=O)Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1[nH]c2ccncc2cc1-c1c(Cl)cc([N+](=O)[O-])cc1Cl

Procedure:
2-(2,6-Dichloro-4-nitro-phenyl)-N-(3-formyl-pyridin-4-yl)-acetamide (3.0 g, 8.47 mmol) is dissolved in dry methanol (240 mL). Na2CO3 (1.80 g, 16.94 mmol) is added. The reaction is refluxed for 30 minutes, diluted by ethyl acetate (210 mL) and filtered. The solvents are evaporated to give crude product, which is recrystallized by ethyl acetate/hexanes to give 3-(2,6-dichloro-4-nitro-phenyl)-1H-[1,6]-naphthyridin-2-one as a slightly yellow solid (3.07 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)=[CH:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[NH:5][N:4]=1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)[CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: CNC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1cccc(C)n1
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNC(=O)CC(c1ccc2c(OC)n[nH]c2c1)c1cccc(C)n1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-N-methyl-3-(6-methyl-pyridin-2yl)-propionamide CCXLV was prepared from 3-(3-methoxy-1H-indazol-6-yl)-N-methyl-3-(6-methyl-pyridin-2yl)-acrylamide using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX (Example 4).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[S:23][C:24]([C:27](=[O:29])[CH3:28])=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)s1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)s1
Temperature: 78 °C
Yield: 64.7 %

Procedure:
5-Acetyl-thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.245 g, 3.077 mmol) and ethyl formate (0.739 mL, 9.23 mmol) were dissolved in anhydrous ethanol (6.16 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (5.75 mL, 15.38 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 5-Acetyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.864 g, 1.99 mmol, 65%).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:23]=3)[CH2:18][CH2:17][N:16]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:10][CH:9]=1.[C:40](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:40][N:3]1[N:2]=[N:1][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH:15]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:23]=4)[CH2:18][CH2:17][N:16]3[C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:10][CH:9]=2)=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(/C=C/c3nn[nH]n3)cc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc(/C=C/c2ccc(CC3c4ccc(OCc5ccccc5)cc4CCN3c3ccc(F)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.6 %

Procedure:
To a solution containing 1-{[4-((1E)-2-(2H-1,2,3,4,-tetrazol-5-yl)vinyl)phenyl]methyl}-2-(4-fluorophenyl)-6-(phenylmethoxy)-1,2,3,4,-tetrahydroisoquinoline (430 mg, 0.831 mmol) in dimethyl formamide (12 mL) was added cesium carbonate (812 mg, 2.493 mmol) and methyl iodide (0.06 mL, 1.0 mmol). The mixture was allowed to stir at ambient temperature for 18 hours. The solvent was removed and the resulting oil was extracted with ethyl acetate and distilled water. The organic layer was dried over sodium sulfate, filtered and concentrated to afford a brown oil. The brown oil was purified by column chromatography (SiO2, 30% ethyl acetate/hexanes), to afford the title compound (100 mg, 23% yield): ES-MS (m/z) 532 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([C:23]([NH:25][O:26]C4CCCCO4)=[O:24])=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])=[CH:2]1.Cl>CO>[OH:26][NH:25][C:23]([C:17]1[CH:16]=[C:15]2[C:20]([CH2:21][CH2:22][N:13]([C:11](=[O:12])[CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:14]2)=[CH:19][CH:18]=1)=[O:24]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)Cc1c[nH]c3ccccc13)CC2
Agent: Cl
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CN(C(=O)Cc1c[nH]c3ccccc13)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of 180 mg 2-(1H-indol-3-ylacetyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 6 ml methanol and 6 ml 0.1 N aqueous hydrochloric acid are stirred at ambient temperature overnight. The reaction mixture is evaporated and the residue is dissolved in a mixture of acetonitrile and water and lyophilized. 92 mg of the title compound are obtained. MH+=350.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](O)[CH3:9])[C:3]=1[OH:11]>CO.[Pd]>[CH2:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[OH:11])[CH3:9]
Reactant: CC(O)c1cccc(F)c1O
Agent: [Pd]
Solvent: CO
Product: CCc1cccc(F)c1O
Reaction time: 6 h

Procedure:
A mixture of 2-fluoro-6-(1-hydroxy-ethyl)-phenol (1.7 g, 10.9 mmol) and 10 wt % Pd/C (0.85 g, Degussa type) in MeOH (30 mL) was stirred under a balloon of H2 for 6 hours. The reaction mixture was filtered through a pad of celite washing with EtOAc. The filtrate was concentrated to a yellow oil (1.35 g, 87%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.6 Hz, 3 H), 2.68 (q, J=7.3 Hz, 2 H), 5.12 (s, 1 H), 6.76 (m, 1 H), 6.92 (m, 2 H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:24])[CH2:4][CH2:3]1.[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.C([BH3-])#N.[Na+]>>[O:24]=[C:11]1[N:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:36][C:34]3[CH:33]=[CH:32][C:29]4[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=4[N:35]=3)[CH2:3][CH2:4]2)[C:15]2[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: COC(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)c1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Yield: 13 %

Procedure:
Methyl 4-[2-(4-aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (Intermediate 84), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 13% yield.
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=2[N:10]=1)(=O)=O.Cl.[CH3:23][NH:24][CH3:25].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[CH3:23][N:24]([CH3:25])[C:5]1[N:6]=[CH:7][C:8]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)ncc2C1
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 130 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of tert-butyl 2-(methylsulfonyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (2.8 g, 8.95 mmol, 1.0 eq.), dimethylamine HCl (1.09 g, 13.42 mmol, 1.5 eq.) and DIPEA (4.37 ml, 25.56 mmol, 4.0 eq.) in NMP (6.5 ml) was stirred for 1 hour at 130° C. in a microwave. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2×150 ml). The combined org. phases were washed with sat. NaCl solution (200 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 18% ethyl acetate in hexane). Yield: 78% (1.95 g, 7.01 mmol)
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>COCCOC>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=2[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)=[CH:40][CH:39]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3Br)cc1)n2C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Yield: 85.1 %

Procedure:
Ethyl 2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (49 g) obtained in Example 4, 4-chlorophenylboronic acid (18 g) and tetrakis-(triphenylphosphine)palladium (10 g) were suspended in 1,2-dimethoxyethane (600 ml). Saturated aqueous sodium hydrogencarbonate solution (300 ml) was added and the mixture was refluxed under-heating for 2 hr. Chloroform was added to the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, chloroform:ethyl acetate=97:3). Ethyl acetate and diisopropyl ether were added to the resulting oil for crystallization and the resulting crystals were collected by filtration to give the title compound (44 g, yield 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CO.C(N(CC)CC)C.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>CCOC(C)=O>[F:20][C:21]([F:28])([F:27])[C:22]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:23]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(NC(=O)C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
A solution of p-aminobenzoic acid in MeOH (500 mg, 3.65 mmol) was treated with 1.0 eq triethylamine (3.65 mmol, 509 μl) followed by 1.1 eq trifluoroacetic acid, ethyl ester (4.015 mmol, 478 μl). The solution was stirred overnight. The solution was diluted with EtOAc, washed with 5% KHSO4, followed by brine. The solution was dried over MgSO4 and solvent was removed by evaporation. The residue was purified by recrystallization in EtOAc/Hexane to afford eggshell-colored glossy plates (265 mg (31%), C9H6F3NO3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18](N(OC)C)=[O:19])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2.[CH3:24][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18](=[O:19])[CH3:24])=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2cccnc2c1-c1ccccc1F
Solvent: C1CCOC1
Product: CC(=O)c1ccc2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8-(2-fluorophenyl)-N-methoxy-N-methylquinoline-7-carboxamide (63 mg, 0.20 mmol) in tetrahydrofuran (0.5 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (0.87 mL, 1.2 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was used directly in next step. LCMS calculated for C17H13FNO(M+H)+: m/z=266.1; found: 266.0.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]([CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36]O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][CH2:27][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCCOCCOCCCOc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCOCCOCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
Triphenylphosphine (2.01 g) in dry dichloromethane (16 ml) was added dropwise over 20 min to a stirred solution of 3-[2-(3-phenoxypropoxy)ethoxy]-1-propanol (1.5 g), and carbon tetrabromide (2.54 g) in dry dichloromethane (27 ml) at 0° C. under nitrogen. The solution was allowed to warm to room temperature and stirred under nitrogen for 4 h. The solution was purified by FCC eluting with System F (4:1) to give the title compound (1.75 g) as a colourless oil. T.l.c. (System F 1:1) Rf 0.55
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:29])[NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:29])[N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: CC1Cc2c(F)cccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1Cc2c(F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 52.5 %

Procedure:
The product is prepared by following the procedure described in example 1c using 0.22 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 116 mg of (−)-4-fluoro-2-methyl-2,3-dihydro-1H-indole [reference example 8c, step 6c] and 0.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 123 μl of pyridine and 3.5 ml of N,N-dimethylformamide. 0.15 g of (+)-2-{2-[4-fluoro-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one is thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.I[CH3:12]>>[CH3:12][NH:6][C:5]1[CH:7]=[CH:8][C:9]2[O:10][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CI
Product: CNc1ccc2c(c1)OCO2
Yield: 18 %

Procedure:
The title compound was prepared from 3,4-(methylenedioxy)aniline and iodomethane by the procedure described in example 2 in 18% yield. 1H NMR (CDCl3): 6.67 (d, J=8.3, 1H), 6.25 (d, J=2.2, 1H), 6.04 (dd, J=2.2, 8.3, 1H), 5.85 (s, 2H), 3.50 (br s, 1H), 2.79 (s, 3H).