Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1cc(CN)ccc1Br
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3-methyl-benzonitrile (commercially available) (15 g) in diethyl ether (150 ml) under an argon atmosphere was added a solution of lithium aluminum hydride in diethyl ether (1M) (150 ml) at ambient temperature. The reaction mixture was stirred at 40° C. for 2 hours. Then the reaction mixture was cooled to 0° C. and quenched by successive addition of water (10.5 ml), aqueous sodium hydroxide (20% w/v) (7.5 ml) and water (37.5 ml). The phases were separated. The organic phase was filtered through a plug of silica gel and the filtrate concentrated to give 4-bromo-3-methyl-benzylamine (15.11 g) as a yellow oil. 1H-NMR (400 MHz, CDCl3): 7.47 (d, 1H), 7.19 (s, 1H), 6.98 (d, 1H), 3.80 (s, 2H), 2.39 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([NH:18][C:19]([O:21]C(C)(C)C)=O)=[C:7]([NH:10][C:11](OC(C)(C)C)=[O:12])[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[CH2:1]([C:5]1[C:6]2[NH:18][C:19](=[O:21])[C:11](=[O:12])[NH:10][C:7]=2[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1csc(NC(=O)OC(C)(C)C)c1NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(=O)C(=O)OCC
Product: CC(C)Cc1csc2[nH]c(=O)c(=O)[nH]c12
Yield: 62.4 %

Procedure:
A mixture of di-t-butyl 4-isobutylthiophene-2,3-dicarbamate (3.70 g, 10 mmol), diethyl oxalate (30 ml, 220 mmol) and glacial acetic acid (30 ml) was refluxed for 20h. The mixture was concentrated and the residue was recrystallized from aqueous acetic acid to afford 1.4 g (62.5%) of the title compound. M.p.>270° C. 1H-NMR (DMSO-d6, δ): 0-9 (d, 6H), 1.75 (m, 1H), 2.45 (d, 2H), 6.75 (s, 1H), 11.9 (s, 1H), 12.2 (br.s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([OH:1])[CH:7]=1
Reactant: ClCCCBr
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCCl)cc1O
Temperature: 25 °C
Yield: 86.8 %

Procedure:
10 g (66 mmole) of 2',4'-dihydroxyacetophenone, 10 ml (101 mmole) of 1-bromo-3-chloropropane and 22.7 g (164 mmole) of anhydrous potassium carbonate in 250 ml of acetone were mixed and refluxed under heating for 16 hours. The mixture was cooled to room temperature, the solid insoluble was separated by filtration, and the filtrate was evaporated to dryness. The residue was dispersed in ethyl ether, filtered and dried to give 13.1 g (87%) of the product, melting point 74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[CH3:11].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc2cc[nH]c2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1Cl)NCC2
Temperature: 15 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
6-Chloro-5-methylindole (D9) (0.109 g, 0.66 mmol) was stirred at 15° C. in glacial acetic acid (3 ml), and sodium cyanoborohydride (0.125 g, 1.98 mmol) was added. The mixture was stirred at 15° C. for 2 h, diluted with water (40 ml), basified with solid NaOH, and extracted with ether. The extract was dried (Na2SO4) and evaporated to give the title compound (0.105 g, 95%) as a light yellow solid.
Reaction SMILES: C(OC(C1C(O)=C2C([Cl:15])=C(C3C=CC(F)=CC=3)N(C3C=CC(F)=CC=3)C2=CN=1)=O)C.[CH2:31]([O:33][C:34]([C:36]1[C:37]([OH:58])=[C:38]2[C:44]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:43][N:42]([C:51]3[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=3)[C:39]2=[CH:40][N:41]=1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([C:36]1[C:37]([OH:58])=[C:38]2[C:44]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:43][N:42]([C:51]3[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=3)[C:39]2=[C:40]([Cl:15])[N:41]=1)=[O:35])[CH3:32]
Reactant: CCOC(=O)c1ncc2c(c(-c3ccccc3)cn2-c2ccc(F)cc2)c1O
Reactant: CCOC(=O)c1ncc2c(c1O)c(Cl)c(-c1ccc(F)cc1)n2-c1ccc(F)cc1
Product: CCOC(=O)c1nc(Cl)c2c(c(-c3ccccc3)cn2-c2ccc(F)cc2)c1O

Procedure:
Prepared in analogy to that of 3-chloro-1,2-bis-(4-fluoro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester from 1-(4-Fluoro-phenyl)-4-hydroxy-3-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester. The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=11.82 (s, 1H), 7.7-7.1 (m, 10H), 4.51 (q, 2H, J=6.8 Hz), 1.46 (t, 3H, J=6.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH:9]=2)=[CH:4][CH:3]=1.I[C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C1O[CH2:58][CH2:57]OCCOCCOCCOCCOC1>[Cu].ClC1C=CC=CC=1Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:31]1([CH3:35])[CH:32]=[CH:33][CH:34]=[C:29]([N:1]([C:22]2[CH:23]=[C:57]([CH3:58])[CH:9]=[CH:10][CH:21]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]([C:21]4[CH:26]=[CH:25][C:24]([N:27]([C:29]5[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=5)[C:29]5[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=5)=[CH:23][CH:22]=4)[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([N:20]([C:7]5[CH:6]=[C:5]([CH3:8])[CH:4]=[CH:3][CH:2]=5)[C:16]5[CH:15]=[C:14]([CH3:12])[CH:19]=[CH:18][CH:17]=5)=[CH:16][CH:15]=4)[CH:13]=3)=[CH:4][CH:3]=2)[CH:30]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Cc1cccc(I)c1
Agent: [Cu]
Agent: Nc1ccc(-c2cc(-c3ccc(N)cc3)cc(-c3ccc(N)cc3)c2)cc1
Agent: O=C([O-])[O-]
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(N(c2ccc(-c3cc(-c4ccc(N(c5cccc(C)c5)c5cccc(C)c5)cc4)cc(-c4ccc(N(c5cccc(C)c5)c5cccc(C)c5)cc4)c3)cc2)c2cccc(C)c2)c1

Procedure:
1,3,5-tris(4-aminophenyl)benzene was prepared as described above in the preparation of compound 1. A mixture of 3 g of 1,3,5-tris(4-aminophenyl)-benzene, 22.2 g of m-iodotoluene, 5.9 g of potassium carbonate, 0.2 g of 18-crown-6 crown ether, 2.2 g of copper bronze and 40 ml of orthodichlorobenzene was flushed with argon and then the whole apparatus placed under vacuum. The mixture was then refluxed under argon for 120 hours. The reaction mixture was then filtered hot and the filtrate evaporated to dryness. High boiling point petroleum ether was then added and the product crystallized slowly in a deep freeze. It was then filtered off, dissolved in dichloromethane, precipitated with methanol and the precipitate, after drying, purified by preparative chromatographically using a 7:1 mixture of dichloromethane and n-hexane as the eluent. The 1,3,5-tris-(4-di-m -tolylaminophenyl)benzene produced had a melting point of 269.6° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([C:19](=[O:21])[NH2:20])[N:18]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[S:15][C:16]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([C:19]([NH2:20])=[O:21])[N:18]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2nc(C(N)=O)c(Nc3ccccn3)s2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1nc(N2CCC[C@@H](N)C2)sc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
To a suspension of {1-[4-carbamoyl-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid tert-butyl ester (prepared as described in example 1) (359 mg, 0.86 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL, 130 mmol) to form a yellow solution. The mixture was stirred at ambient temperature for 30 minutes then evaporated to dryness in vacuo. The residue was taken up in dichloromethane (25 mL) and washed with saturated aqueous sodium hydrogen carbonate (100 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (5×20 mL) until no further yellow color was extracted in to the organic layer. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give 2-((R)-3-amino-piperidin-1-yl)-5-(pyridin-2-ylamino)-thiazole-4-carboxylic acid amide as a yellow solid (280 mg).
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[C:9]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][C:10]1=[O:21])[CH2:7][CH3:8])[CH:2]=[CH2:3].[OH-:22].[Na+]>CC(C)=O.O>[CH2:1]([O:4][N:5]=[C:6]([C:9]1[C:14](=[O:15])[CH2:13][C:12]2([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:11][C:10]=1[O:21][C:6](=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: [OH-]
Reactant: C=CCONC(CC)=C1C(=O)CC2(CCCCC2)CC1=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC2(CCCCC2)CC1=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(1-allyloxyaminopropylidene)spirobicyclohexane-3,5-dione (1.5 g) in acetone (30 ml), sodium hydroxide (0.2 g) in water (1 ml) was added at room temperature and then benzoylochloride (0.7 g) was added. After stirring for 5 hr, the reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo and oily substance (0.8 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[F:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2cc(Br)ccc2N1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1CCc2cc(-c3cccc(F)c3)ccc2N1
Temperature: 86 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (1a) (226 mg, 1.00 mmol) and 3-fluorophenylboronic acid (210 mg, 1.50 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (415 mg, 3.00 mmol) and water (2.0 mL). The reaction mixture was stirred for 5 minutes under an atmosphere of dry N2, and PdCl2(PPh3)2 (35 mg, 0.05 mmol) was added. The resulting mixture was heated at 86° C. for 5 hours, cooled, diluted with ethyl acetate (20 mL), filtered through a layer of celite which was washed with ethyl acetate (60 mL), the filtrate transferred to a separation funnel, and washed with 2 N potassium carbonate (20 mL), followed by 30% ammonium chloride (40 mL), then brine (50 mL). The solvent was removed from the organic layer under reduced pressure, to provide a pale yellow solid. To this crude product was added methanol (2 mL), the mixture sonicated, filtered, washed with cold methanol (3.0 mL), and dried under reduced pressure, to afford 6-(3-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one, the compound of Formula (I) in which R1 is hydrogen, as a white solid; MS m/z 242.1 (M+H), anal HPLC >97% in purity. 1H NMR (400 MHz; dmso-D6) δ 10.21 (s, 1H); 7.58 (d, J=2.1 Hz, 1H); 7.42-7.55 (m, 4H); 7.15 (m, 1H); 6.96 (d, J=8.2 Hz, 1H); 3.42 (t, J=7.6 Hz, 2H); 2.97 (t, J=7.6 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: c1ccsc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: O
Product: Brc1ccc(-c2cccs2)cc1
Temperature: 85 °C
Yield: 98 %

Procedure:
As shown in the following Reaction 8,130 mg (0.6 mmol) of 4-bromophenyl boronic acid was melted in 15 mL of thiophene, and 500 mg (3.22 mmol, 3 eq) of manganese(III) acetate dihydrate was added thereto, and then the reaction solution was refluxed for 1 hour at temperature of 85° C. Next, the reaction solution was filtered with hexane using a funnel charged with silica gel, and dehydrated with magnesium sulfate and distilled under reduced pressure. The compound distilled under reduced pressure was purified with a column chromatography (mobile phase: n-hexane) to obtain 140 mg of 2-(4-bromo-phenyl)-thiophene with a yield of 98%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 7.50 (m, 4H), 7.25 (d, 2H), 7.07 (t, 1H)].
Reaction SMILES: Cl.CN.[C:4]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([CH2:16][CH3:17])[CH2:10]1)([O:6][CH2:7][CH3:8])=[O:5].[OH-].[K+].[C:20]([BH3-])#[N:21].[Na+]>CO>[C:4]([N:9]1[CH2:14][CH2:13][CH:12]([NH:21][CH3:20])[CH:11]([CH2:16][CH3:17])[CH2:10]1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)N1CCC(=O)C(CC)C1
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCOC(=O)N1CCC(NC)C(CC)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methylamine hydrochloride (17 g, 252 mmol) was added to the stirred solution of 1-carbethoxy-3-ethyl-4-piperidone (10 g, 50 mmol) in methanol (150 ml) followed by 14.1 g (252 mmol) KOH. Stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (4.72 g, 75 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 12 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to give crude 1-carbethoxy-4-methylamino-3-ethylpiperidine. The obtained crude 1-carbethoxy-4-methylamino-3-ethylpiperidine was suspended in 7 M NaOH solution (50 ml), stirred at 110° C. for 230 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to dryness to afford 4-methylamino-3-ethyl-piperidine. Yield 3.5 g (50%), C8H18N2, m/z 142 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:23]([C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([S:31]([N:12]2[C:8]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:11]2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)#[N:24]
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(C#N)c2)c1)C(=O)OC(C)(C)C

Procedure:
By an operation similar to that in Reference Example 32 and using tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (305 mg), and 3-cyanobenzenesulfonyl chloride (318 mg), the title compound was obtained as a colorless oil (yield 447 mg, 95%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.O>COCCOC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: OB(O)c1ccccc1Cl
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)c1ccnc(-c2ccccc2Cl)c1
Temperature: 110 °C
Yield: 89.1 %

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyridine (4 g, 22.0 mmol), 2-chlorophenylboronic acid (5.04 g, 24.2 mmol), Ba(OH)2 (12.5 g, 66.1 mmol) and Pd(PPh2)2Cl2 (464 mg, 0.66 mmol) in DME (140 mL)/water (35 mL) was heated at 110° C. for 1 h. The solids were filtered off and the mother liquor were concentrated to around 80 mL and extracted with EtOAc. The organic layer was washed with brine, then water, dried (MgSO4), filtered and concentrated. Purification by column chromatography (1/1 Petroleum ether/EtOAc) gave the Suzuki adduct (5.05 g, 89%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH:15]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:15][CH2:14][N:9]4[C:7]5=[N:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=[C:6]5[CH:12]=[CH:11][C:10]4=[O:13])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2n1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A suspension of [3-(methyloxy)-6-oxopyrido[2,3-b]pyrazin-5(6H)-yl]acetaldehyde (185 mg 0.84 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h) (283 mg, 0.84 mmol) in chloroform (10 mL) and methanol (1.5 mL) was stirred at room temperature under argon for 1 h before addition of sodium triacetoxyborohydride (515 mg, 2.52 mmol). The reaction was stirred at rt overnight. A saturated solution of sodium bicarbonate (20 mL) was added to the reaction and the aqueous phase was extracted with 10% MeOH/DCM (3×50 mL).The combined organic phases were dried (MgSO4), filtered and evaporated and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford 252 mg of the title compound (60%).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:36].[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: CN(C)CCCl
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCN(C)C)cc4)cc3)n(C)c(=O)c12
Temperature: 80 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
2-[4-(4-Hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (306 mg), 2-dimethylaminoethyl chloride hydrochloride (218 mg), and potassium carbonate (316 mg) were dissolved in DMF (5 ml) and the solution was stirred at 80° C. for 20 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration to provide the title compound as colorless solid (193 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=O.N1C=CC=CC=1.[NH2:18][OH:19].O>CCO>[Cl:11][C:6]1[CH:5]=[C:4]([C:2](=[N:18][OH:19])[CH3:1])[CH:9]=[CH:8][C:7]=1[Cl:10]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NO
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccc(Cl)c(Cl)c1
Temperature: 90 °C

Procedure:
A mixture of 3,4-dichloroacetophenone (1.0 eq), pyridine (5.0 eq) and hydroxylamine (5.0 eq) in EtOH (10 vol) was heated to a temperature of 90° C. for 80 minutes. To the cooled reaction mixture was added water (40 vol) and the precipitated solid was filtered, washed with water (2×10 vol) and dried to give 1-(3,4-dichloro-phenyl)-ethanone oxime.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][CH:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]1.ClC1C(C(F)(F)F)=CC=CC=1C(NC(C1(N(C)C)CCCC1)C1C=CC=CC=1)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:20][N:19]([CH3:21])[C:14]1([CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:12][C:4](=[O:5])[C:3]2[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:11])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: Cc1cccc(C)c1C(=O)Cl
Agent: CN(C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of 2,6-dimethylbenzoyl chloride (1.7 g, 10.1 mmol) in DCM (10 ml) was added dropwise to a mixture of {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (2.0 g, 9.2 mmol), and triethylamine (1.4 ml, 10.0 mmol) in DCM (40 ml) and stirred at room temperature for 2 h. The mixture was washed with saturated aqueous sodium hydrogen carbonate, the organic layer was separated through a phase separation cartridge and then evaporated to a white solid. Chromatography with eluent 50-100% ethyl acetate/pentane, then 0-10% methanol/ethyl acetate afforded the title product as a white solid (3.1 g, 97%). 1H NMR (CDCl3) δ: 0.85-1.00 (1H, m), 1.30-1.55 (3H, m), 1.60-1.75 (2H, m), 1.78-1.90 (2H, m), 2.21 (6H, s), 2.31 (6H, s), 5.19 (1H, d, J=6 Hz), 6.79 (1H, br d), 7.02 (2H, d, J=8 Hz), 7.16 (1H, t, J=8 Hz), 7.20-7.35 (3H, m), 7.43 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 351 (MH+). C23H30N2O requires 350. Ret. time 2.0 min. The white solid product was converted to the HCl salt using 1M HCl/diethylether to afford the salt as a white solid on evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][O:14][CH3:15].CC([O-])=O.[K+].[NH2:21]O.Cl.O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:21])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: NO
Reactant: COCCOc1cc(C=O)ccc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1cc(C#N)ccc1OC
Temperature: 130 °C
Yield: 89.3 %

Procedure:
To a solution of 4-methoxy-3-(2-methoxyethoxy)benzaldehyde (10 g) in AcOH (80 mL) was added KOAc (9.5 g) and NH2OH.HCl (6.7 g). The resulting mixture was heated at 130° C. for 18 h under N2 atmospheres. After reaction finished, the mixture was poured into water (400 mL). The solid was collected, washed with water (100 mL) and air-dried to give 4-methoxy-3-(2-methoxyethoxy)benzonitrile (8.8 g) as a light yellow solid.