Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[CH2:9][CH:10]=O.[NH2:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:15]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O>CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:9]1[CH:10]=[N:13][C:14]2[C:15]([C:24]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[O:12]
Reactant: O=CCC(=O)c1ccccc1F
Reactant: Nc1c(C(=O)c2ccccc2)cccc1C(F)(F)F
Solvent: CC(=O)O
Product: O=C(c1ccccc1F)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Yield: 91.5 %

Procedure:
3-(2-Fluorophenyl)-3-oxopropionaldehyde (0.451 g, 2.70 mmol) and [2-amino-3-(trifluoromethyl)phenyl](phenyl)methanone (0.119 g, 0.448 mmol) in AcOH (5 mL) is treated with 0.1 mL of 1:20H2SO4/AcOH solution and heated at reflux for 20 min. The cooled reaction is quenched with water and extracted with ethyl acetate twice. The combined organic layers are washed with saturated aq sodium bicarbonate and dried over MgSO4. The product is purified by chromatography (5:95 ethyl acetate:hexane) to afford the title compound as a yellow solid (0.162 g, 91.5%). MS (ESI) m/z 396.1009; HRMS: calcd for C23H13F4NO+H, 396.10115; found (ESI, [M+H]+), 396.1009.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[C:31]([OH:38])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[C:31]=3[OH:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc(F)c1O
Product: Oc1c(F)cccc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3-fluoro-2-hydroxybenzaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 503; MS (ESI) m/z 501.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.[H][H]>[Pd].C(OCC)(=O)C>[Cl:8][C:7]1[N:6]=[C:5]([NH2:9])[C:4]([O:10][CH3:11])=[N:3][CH:2]=1
Reactant: [H][H]
Reactant: COc1nc(Br)c(Cl)nc1N
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ncc(Cl)nc1N
Yield: 82.2 %

Procedure:
A mixture of 5-bromo-6-chloro-3-methoxy-2-pyrazinamine (Example 125a) (0.6 g), triethylamine (0.72 mL), 10% palladium on carbon (0.05 g) and ethyl acetate (50 mL) were hydrogenated at 0.5 bar until reaction was complete as judged by hydrogen uptake. The reaction mixture was filtered and washed with water (25 mL), dried (MgSO4), filtered and evaporated to afford the sub-titled compound (0.33 g). Used Directly.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][C:35]([NH2:37])=[O:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][C:35](=[O:36])[NH2:37])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: NC(=O)CBr
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CC(N)=O)CC4)cn3)nc2n1C1CCCC1
Yield: 44.2 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and 2-bromo acetamide (95 mg, 0.690 mmol) gave 2-[5-(4-carbamoylmethyl piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (50 mg, 45%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.CCO.[C-:16]#[N:17].[K+]>O>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][C:16]#[N:17]
Reactant: Cc1cccc(CBr)c1[N+](=O)[O-]
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(CC#N)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 93.9 %

Procedure:
A round bottomed flask was charged with 6.51 g (0.028 mol) of 3-methyl-2nitrobenzyl bromide, 120 mL 1:1 EtOH:H2O, and 5.5 g KCN (0.084 mol). The reaction solution was heated to 60° C. for 2 h. The reaction was cooled and the volatiles removed in vacuo. The resulting solid was dissolved in 150 mL water and extracted with 300 mL ethyl acetate. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. This gave 4.63 g (92% yield) of the desired material as a slightly yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.45–7.41 (m, 2H), 7.33–7.31 (m,1H), 3.77 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O)[CH3:3].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[NH2:48][CH:49]([C:51]1[C:52](=[O:68])[NH:53][C:54]([CH2:57][C:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:61]=[CH:60][CH:59]=2)=[N:55][N:56]=1)[CH3:50]>>[OH:1][CH:2]([CH:4]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([NH:48][CH:49]([C:51]1[C:52](=[O:68])[NH:53][C:54]([CH2:57][C:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:61]=[CH:60][CH:59]=2)=[N:55][N:56]=1)[CH3:50])=[O:7])[CH3:3]
Reactant: CC(O)C(CCCc1ccccc1)C(=O)O
Reactant: CC(N)c1nnc(Cc2cccc3ccccc23)[nH]c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)C(CCCc1ccccc1)C(C)O)c1nnc(Cc2cccc3ccccc23)[nH]c1=O

Procedure:
526 mg (2.37 mmol) of 2-(1-hydroxyethyl)-5-phenylpentanoic acid are reacted analogously to Example 39A with 320 mg (2.37 mmol) of 1-hydroxy-1H-benzotriazole, 408 mg (3.16 mmol) of N-ethyldiisopropylamine, 454 mg (6.350 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 500 mg (1.58 mmol) of 6-(1-aminoethyl)-3-(1-naphthylmethyl)-1,2,4-triazin-5(4H)-one to give 2-(1-hydroxyethyl)-N-{1-[3-(1-naphthylmethyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenylpentanamide.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[C:31]3[CH2:32][CH2:33][CH2:34][CH2:35][C:30]=3[S:29][C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]([NH2:28])=O)[N:23]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[C:31]3[CH2:32][CH2:33][CH2:34][CH2:35][C:30]=3[S:29][C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]#[N:28])[N:23]=1
Reactant: COc1ccc(CNc2nc(CCC(N)=O)nc3sc4c(c23)CCCC4)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(CCC#N)nc3sc4c(c23)CCCC4)cc1Cl
Reaction time: 1 h

Procedure:
1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 0°. 1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-2-yl]propionamide is then added. The mixture is stirred for one hour. After customary working up, 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]-benzothieno[2,3-d]pyrimidine-2-yl]propionitrile is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[C:13](OC(C)=C)(=[O:15])[CH3:14]>>[C:13]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[C:11]([Cl:12])[C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:9]1)(=[O:15])[CH3:14]
Reactant: Nc1ccc2c(c1Cl)CNCC2
Reactant: C=C(C)OC(C)=O
Product: CC(=O)N1CCc2ccc(N)c(Cl)c2C1

Procedure:
7-Amino-8-chloro-1,2,3,4-tetrahydroisoquinoline is treated with one molar equivalent of isopropenyl acetate by the procedure of Example 15 to give 2-acetyl-7-amino-8-chloro-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][CH:7]=1.[CH2:29]([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH2:31].[Cl-].[Li+]>CN(C)C=O.CCOCC.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>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:31][CH:30]=[CH2:29])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Yield: 92.2 %

Procedure:
Argon was passed through a solution of 7.0 g (0.0164 mol) of (S)-4-[[(trifluoromethyl)sulfonyl]oxy]-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]benzenepropanoic acid methyl ester, 5.7 g (0.0165 mol) of allyltributyl tin, and 1.42 g (0.04 mol) of lithium chloride in 50 mL of dimethylformamide for 10 minutes and 210 mg (0.0003 mol) of bis(triphenylphosphine)palladium dichloride was added. The bath temperature was raised to 90°-95° C. for 40 minutes and the mixture was allowed to cool. The mixture was diluted with ether and washed with water and saturated sodium chloride solution and dried over magnesium sulfate. The residue obtained after filtration and evaporation was purified by preparative liquid chromatography using silica gel cartridges on a Waters Prep 500 chromatograph, eluting with 10% ethyl acetate-hexane to give 4.83 g (92%) of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-(2-propenyl)benzenepropanoic acid methyl ester, mp 56°-59° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH:32]2[CH2:34][CH2:33]2)=[CH:26][CH:25]=1>>[CH:32]1([N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH2:34][CH2:33]1
Reactant: Fc1ccc(CNC2CC2)cc1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCN(Cc3ccc(F)cc3)C3CC3)cn2)c1
Yield: 9 %

Procedure:
The title compound was prepared in 9% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and N-[(4-fluorophenyl)methyl]cyclopropylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 0.16 (2H, m), 0.39 (2H, m), 1.82 (1H, m), 2.87 (2H, t, J=6.4 Hz), 3.74 (2H, s), 4.10 (2H, t, J=6.2 Hz), 7.09 (2H, t, J=8.9 Hz), 7.28 (2H, dd, J=7.1 Hz and 2.7 Hz), 7.51 (1H, d, J=4.5 Hz), 7.67 (2H, d, J=1.6 Hz), 8.25 (1H, s), 8.47 (1H, d, J=4.8 Hz). [M+H] Calc'd for C21H21FN4O2, 381. Found, 381.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[CH3:16])=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>COCCOC.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>[CH3:16][C:15]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:7]1[S:6][C:5]2=[N:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([C:32]([F:35])([F:34])[F:33])[C:28]([NH2:31])=[N:29][CH:30]=3)[N:9]2[N:8]=1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: Cc1ccncc1-c1nn2c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1ccncc1-c1nn2c(-c3cnc(N)c(C(F)(F)F)c3)cnc2s1
Temperature: 120 °C
Yield: 40.1 %

Procedure:
A mixture of 5-Iodo-2-(4-methyl-pyridin-3-yl)-imidazo[2,1-b][1,3,4]thiadiazole (18 mg, 0.053 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (20 mg, 0.068 mmol, 1.3 eq), Pd(PPh3)2Cl2 (9 mg, 0.011 mmol, 0.2 eq) and sat aq K2CO3 (0.22 mL) in DME (0.5 mL) was heated under microwave irradiation at 120° C. for 30 min. On cooling, DCM was added and the mixture was washed with water. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM/MeOH 95:5) to afford the desired product (8 mg, 40%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=4.32 min, [M+H]+ m/z 377.1; 1H NMR (300 MHz, CDCl3) δ 8.80 (s, 1H), 8.70 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.31 (s, 1H), 7.56 (s, 1H), 7.28 (d, J=5.0 Hz, 1H), 5.39 (s, 2H), 2.63 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([SH:21])=[CH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(Cl)Cl.II>C(N(CC)CC)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:21][N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:12](=[O:13])[CH:11]=2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(C=C(S)c1ccc(C(=O)O)cc1)Nc1ccccc1
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(-c2cc(=O)n(-c3ccccc3)s2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
A mixture of 0.30 g (1.00 mmol)3-(4-carboxyphenyl)-3-mercapto-N-phenylpropenamide and 50 mL methylene chloride was stirred at room temperature. Added was 0.25 g (1.00 mmol) iodine followed by 0.2 mL (excess) triethylamine and the mixture stirred for one hour. Solvent was evaporated and 250 mL ethyl acetate added. The mixture was washed with three 100 mL portions of water. The organic layer was dried, filtered and solvent was evaporated from the filtrate. The resulting solid was triturated in absolute ethanol and filtered to dryness to provide 0.16 g (0.54 mmol, 54%)5-(4-carboxyphenyl)-N-phenyl-4-isothiazolin-3-one as a pale, yellow powder, mp=260-261° C. NMR (d6 -DMSO/TMS): 7.08 (s, 1H), 7.39-8.07 (m, 9H), 13.30 (bs, 1H). IR (KBr): 1678, 1652. Mass spectrum (CI): M/z=298.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.P(Cl)(Cl)([Cl:18])=O>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Cl:18])[C:6]([N+:12]([O-:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2ccc(Cl)nc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a suspension of 6-chloro-3-nitro-1,5-naphthyridin-4-ol (5 g, 22.1 mmol) in 15 mL of DMF, was added a solution of phosphorous oxychloride (2.7 mL, 28.8 mmol) in anhydrous DMF (10 mL) over 3 min. The mixture was stirred at room temperature overnight. The mixture was then poured onto crushed ice. The resulting precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford 2,8-dichloro-7-nitro-1,5-naphthyridine as yellow solid (4 g, yield 74.0%). MS (m/z): 244 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=3[CH:43]=2)=[CH:7][CH:6]=1.[F:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48](O)=[O:49].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[F:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=1)[C:48]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH:12]2[O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][N:34]([CH2:38][CH2:39][CH2:40][O:41][CH3:42])[C:33]=3[CH:43]=2)=[CH:9][CH:10]=1)=[O:49]
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCN)cc3)cc21
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCNC(=O)c4cccc(F)c4)cc3)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 0.375 g of benzyl 4-[4-(2-aminoethoxy)phenyl]-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate and 0.094 g of 3-fluorobenzoic acid in 6 ml of dichloromethane and 1.5 ml of N,N-dimethylformamide is admixed with 0.127 g of 3-dimethylaminopropyl ethyl carbodiimide hydrochloride and 0.167 g of 4-dimethylaminopyridine and stirred at room temperature over 18 hours. The reaction mixture is concentrated by evaporation and the residue partitioned between ethyl acetate and water. The organic phase is washed with 1N HCl, water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.39 (95:5 dichloromethane-methanol); Rt=5.25.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:30])[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=4)[CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.O>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:30])[CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=4)[CH2:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[CH:6][CH:5]=1
Reactant: COc1ccc2c(c1)N(C1CCN(CC(=O)c3ccc(F)cc3)CC1)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)N(C1CCN(CC(O)c3ccc(F)cc3)CC1)CCC2
Reaction time: 1 h

Procedure:
Sodium borohydride (73 mg) was added at 0° C. to a solution of 1-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline (400 mg) in methanol (10 ml). The resultant mixture was stirred at the same temperature for 1 hr and then at room temperature for 1 hr. After the completion of the reaction, water was added to the reaction solution followed by extraction with ethyl acetate. The resulting residue was purified by column chromatography (hexane/ethyl acetate system) to give 1-{1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline as an oil. This product was dissolved in ethanol and oxalic acid was added thereto. The resulting precipitate of salt was recrystallized form ethanol/ether to give the title compound (280 mg) (yield: 68%).
Reaction SMILES: [C-:1]#[N:2].[Na+].O.Cl[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1>C(O)C>[C:1]([CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1)#[N:2]
Reactant: [C-]#N
Reactant: C=Cc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=Cc1ccc(CC#N)cc1
Temperature: 65 °C

Procedure:
In a 500 μl 4-opening flask equipped with a stirring bar, 49.01 g of sodium cyanide was mixed with 70.07 g of water and 50.96 g of ethanol. Then, the temperature of the flask was elevated to 60° C. and the sodium cyanide was completely dissolved. To said solution, 87.50 g of 4-chloromethylstyrene was slowly added and it was reacted for 3 hours while stirring and maintaining the reaction temperature within 60-70° C. When the reaction terminated, said solution was cooled to 40° C., and 100 g of diethylether was added and the diethylether layer was separated. The separated organic layer was extracted with 300 g of water three times, and the water layer was extracted with 50 g of diethylether and was combined with said organic layer. The separated obtained organic layer was dried with magnesium sulfate for one day, and then the organic solvent was removed using an evaporator to obtain the product 4-cyanomethylstyrene. The yield of the product was 80%, and the product was a deep purple color.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH2:11]([O:13][C:14](=[O:25])[C:15](=[CH:21]OCC)[C:16](OCC)=[O:17])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O>[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([N:1]2[C:16]([OH:17])=[C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:25])[CH:21]=[N:2]2)[CH:8]=1)#[N:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N#Cc1ccnc(NN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2cc(C#N)ccn2)c1O
Temperature: 100 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carbonitrile (5.36 g, 40 mmol, PREPARATION 2), diethyl(ethoxymethylidene)propanedioate (8.64 g, 40 mmol) and K2CO3 (10.76 g, 80 mmol) in H2O (100 mL) was stirred at 100° C. for 4 h. The reaction mixture was cooled to rt and filtered to afford the title compound (2.5 g, 24%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.19 (3H, t, J=7.2 Hz), 4.02 (2H, q, J=7.2 Hz), 7.38 (1H, dd, J=4.8, 1.6 Hz), 7.53 (1H, s), 8.53 (1H, d, J=5.2 Hz), 8.79 (1H, s). [M+H] Calc'd for C12H10N4O3, 259; Found, 259.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH3:10].[C-:11]#[N:12].[K+].O.[I-].[K+]>CC(=O)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:11]#[N:12])=[C:4]([CH3:10])[CH:5]=1
Reactant: [C-]#N
Reactant: Cc1cc(F)ccc1CCl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(F)ccc1CC#N
Yield: 87.2 %

Procedure:
A mixture of 16 parts of 1-(chloromethyl)-4-fluoro-2-methylbenzene, 7.8 parts of a solution of potassium cyanide in a small amount of water, 0.1 parts of potassium iodide and 240 parts of 2-propanone is stirred and refluxed for 22 hours. The reaction mixture is cooled and filtered. The filtrate is evaported. The residue is taken up in water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated, yielding 13 parts (87.2%) of 4-fluoro-2-methylbenzeneacetonitrile as a residue.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[CH3:12][N:13](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[C:10]2[S:9][N:8]=[N:7][C:6]=2[CH:5]=[C:4]([C:12]#[N:13])[CH:3]=1
Reactant: Brc1cc(I)cc2nnsc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(Br)c2snnc2c1
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of 7-bromo-5-iodo-1,2,3-benzothiadiazole (22 mg, 0.0645 mmol), zinc cyanide (7.58 mg, 0.0645 mmol), Pd(PPh3)4 (7.46 mg, 0.00645 mmol) and DMF (2 mL) was heated to 60° C. for 4 h. The solution was extracted with EtOAc (50 mL), and the organic fraction was washed with saturated aqueous sodium bicarbonate solution (3×50 mL). The organic fraction was adsorbed onto silica gel and purified by ISCO chromatography (3 to 5% EtOAc:heptane) to afford 14 mg (90%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J=1.0 Hz, 1 H), 8.92 (d, J=1.3 Hz, 1 H).
Reaction SMILES: CS[C:3]1[S:7][C:6]([C:8]#[N:9])=[C:5]2[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:4]=12.[CH3:15][NH:16][CH3:17]>C1COCC1>[CH3:15][N:16]([CH3:17])[C:3]1[S:7][C:6]([C:8]#[N:9])=[C:5]2[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[C:4]=12
Reactant: CSc1sc(C#N)c2c1C(=O)CCC2
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1sc(C#N)c2c1C(=O)CCC2
Yield: 45 %

Procedure:
A solution of 3-methylsulfanyl-4-oxo-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonitrile (0.446 g) and dimethylamine (excess) in THF were heated in a sealed tube at 80° C. for 10 days. Aqueous work up and chromatographic purification afforded 0.2 g of 3-dimethylamino-4-oxo-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonitrile (45%).