Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:32])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(C)c([N+](=O)[O-])cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2cc(C)c([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A solution of 2-(7-methyl-6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.5 g crude, 48% pure, 0.81 mmol) and Lawesson's reagent (0.656 g, 1.62 mmol) in toluene (30 mL) was heated at 120° C. for 20 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo to give the crude product, which was purified by chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) and further purified by preparative TLC (eluting with 20% EtOAc in petroleum ether) to give 2-(7-methyl-6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.130 g, 50%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.64 (s, 1H), 6.90 (s, 1H), 6.61 (s, 1H), 4.90 (q, J=15.6 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 2.54 (s, 3H), 1.65 (d, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[C:46]=1[O:55][CH3:56])=[CH:42][C:41]([Cl:57])=[CH:40][CH:39]=2>ClCCl>[C:15]([C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:13]=1[OH:14])[C:8]([NH:34][C:35]1[CH:36]=[N:37][C:38]2[C:43]([C:44]=1[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[C:46]=1[O:55][CH3:56])=[CH:42][C:41]([Cl:57])=[CH:40][CH:39]=2)=[O:10])([CH3:17])([CH3:16])[CH3:18]
Reactant: COc1ccc(-c2c(N)cnc3ccc(Cl)cc23)c(OC)c1OC
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(-c2c(NC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cnc3ccc(Cl)cc23)c(OC)c1OC
Temperature: 0 °C
Yield: 47.6 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzoic acid (220 mg) in dichloromethane (20 ml) was dropwise added dicyclohexylcarbodiimide (DCC) (180 mg) under stirring at 0° C. The mixture was stirred at 0° C. for 15 minutes. Then, 3-amino-6-chloro-4-(2,3,4-trimethoxyphenyl) quinoline (250 mg) was added to this mixture. The resultant mixture was stirred at 0° C. for an hour and at room temperature for two days. After the residue was filtered off, the filtrate was diluted with water and extracted with dichloromethane. The dichloromethane layer was washed with an aqueous sodium hydroxide solution, diluted with hydrochloric acid and water in this order and dried (MgSO4). The solvent was removed and the residue was purified by a silica gel column chromatography with hexane-ethyl acetate (3:1, V/V), and then crystallized from isopropyl ether to obtain 3-(3,5-di-tert-butyl-4-hydroxybenzamido)-6-chloro-4-(2,3,-4-trimethoxyphenyl) quinoline (199 mg, 47.6%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][NH:30][CH2:31][CH2:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=1.C(N(C(C)C)C(C)C)C>>[CH3:26][O:25][C:15]1[C:13]2[N:14]=[C:10]([NH:9][C:7]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:30]([CH3:29])[CH2:31][CH2:32][O:33][C:34](=[O:45])[C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([O:43][CH3:44])[CH:36]=4)=[CH:28][CH:27]=3)=[O:8])[S:11][C:12]=2[C:18]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: CNCCOC(=O)c1ccc(OC)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)OCCN(C)Cc2ccc(C(=O)Nc3nc4c(OC)ccc(N5CCOCC5)c4s3)cc2)cc1OC
Yield: 57 %

Procedure:
Conversion of 4-cloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (84 mg, 0.20 mmol) with 3,4-dimethoxybenzoic acid 2-methylamino-ethyl ester chlorohydrate (96 mg, 0.4 mmol) and N-ethyl diisopropylamine (0.14 ml, 0.80 mmol) using the general procedure C affords the product as light yellow solid in 57% yield. MS: m/e=621 (M+H+).
Reaction SMILES: CN(C=[N:5][C:6]1[CH:11]=[CH:10][N:9]([CH3:12])[C:8](=[O:13])[N:7]=1)C.CN>C(O)C>[CH3:12][N:9]1[CH:10]=[CH:11][C:6]([NH2:5])=[N:7][C:8]1=[O:13]
Reactant: CN(C)C=Nc1ccn(C)c(=O)n1
Agent: CN
Solvent: CCO
Product: Cn1ccc(N)nc1=O
Reaction time: 12 h

Procedure:
4-N—(N,N-dimethyl-aminomethylene)-1-methylcytosine (1.0 g, 5.5 mmol) and ethanol solution (50 mL) containing 30% methylamine were added in 100 mL mad apple-type flask with a magnetic stirrer and the mixture was allowed to stir for 12 hr. The precipitated white solids were collected, and recrystallized in ethanol-water mixture. The object was obtained as white solids (0.61 g, yield, 88%). 1H NMR (400 MHz, DMSO-d6):3.31 (s, 3H), 5.59 (d, 1H), 6.91 (br, 2H), 7.54 (d, 1H) 13C NMR (100 MHz, DMSO-d6):δ6.6, 92.9, 146.6, 156.3, 166.1; MS (ES1+) calcd for C5H7N3O+(M+H+) 126.0662, found 126.0804.
Reaction SMILES: C(O[C:4]([C:6]1[NH:23][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:8]=2[CH:7]=1)=[O:5])C.[C-:24]#[N:25].[Na+].O>CN.C1COCC1>[CH3:24][NH:25][C:4]([C:6]1[NH:23][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:14][C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:8]=2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cc2c(N[C@H](C)c3ccccc3)ncnc2[nH]1
Reactant: [C-]#N
Agent: CN
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(N[C@H](C)c3ccccc3)ncnc2[nH]1

Procedure:
In a bomb tube, 155 mg (0.50 mmol) of 6-ethoxycarbonyl-4-[1(R)-phenyl-ethylamino]-7H-pyrrolo[2,3-d]pyrimidine and 2.5 mg (0.05 mmol) of NaCN in 4 ml of methylamine (33% in ethanol) are heated at 50° C. for 30 hours. The reaction mixture is dissolved in THF, 25 ml of water are added thereto and concentration by evaporation is carried out to a residual volume of =25 ml. The resulting crystals are filtered off and washed with water. Recrystallization from hot THF and ethyl acetate yields the title compound; HPLC: tRet (Grad20)=8.3; TLC-Rf =0.31 (CH2Cl2 /methanol [10:1]); FAB-MS: (M+H)+ =296.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCc1cccc(N)c1
Reaction time: 16 h
Yield: 86 %

Procedure:
A Parr hydrogenation vessel was charged with Part (1) compound (12.0 g, 54.3 mmol), concentrated HCl (15 mL, 0.15 mmol), 10% palladium on carbon (750 mg) and absolute ethanol (75 mL). The slurry was purged with nitrogen and agitated under an initial pressure of 45 psi of hydrogen gas. After 16 h, the flask was evacuated and the contents filtered through Celite and evaporated. The residue was dissolved in water and adjusted to pH 9 with solid sodium carbonate. The resulting mixture was extracted with dichloromethane (250 mL×2). The combined extracts were evaporated to give the title compound (8.7 g, 86%) as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[CH2:7]([C@@H:14]1[C@@H:22]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C@H:21]([CH3:28])[O:20][C:19](=[O:29])[C@@H:18]([NH:30][C:31](=[O:41])[C:32]2[C:37]([OH:38])=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][N:33]=2)[CH2:17][O:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:1]([O:4][CH2:5][O:38][C:37]1[C:32]([C:31](=[O:41])[NH:30][C@H:18]2[CH2:17][O:16][CH2:15][C@H:14]([CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C@@H:22]([O:23][CH2:24][CH:25]([CH3:26])[CH3:27])[C@H:21]([CH3:28])[O:20][C:19]2=[O:29])=[N:33][CH:34]=[CH:35][C:36]=1[O:39][CH3:40])(=[O:3])[CH3:2]
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3ccccc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3ccccc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1OCOC(C)=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
Bromomethyl acetate (48 uL, 0.49 mmol) was added to a suspension of N-((3S,7S,8R,9S)-7-benzyl-8-isobutoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (160 mg, 0.33 mmol), sodium iodide (NaI, 2.5 mg, 0.02 mmol) and sodium carbonate (Na2CO3; 56 mg, 0.53 mmol) in acetone (3 mL). The mixture was heated to 50° C. and stirred overnight. The suspension was diluted with acetone and filtered. The yellow solution was concentrated and purified by flash chromatography (50% EtOAc in hexanes) to furnish the product as a white foam (97 mg, 53%): IR (film) 3370, 3025, 2957, 2874, 1752, 1677 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=8.2 Hz, 1H), 8.27 (d, J=5.4 Hz, 1H), 7.34-7.23 (m, 2H), 7.20 (dd, J=7.2, 4.8 Hz, 3H), 6.95 (d, J=5.4 Hz, 1H), 5.80-5.64 (m, 2H), 5.13-4.92 (m, 2H), 4.02 (dd, J=11.7, 7.4 Hz, 1H), 3.90 (s, 3H), 3.54-3.28 (m, 5H), 3.14 (dd, J=11.7, 6.4 Hz, 2H), 2.40-2.23 (m, 1H), 2.06 (s, 3H), 2.01-1.82 (m, 2H), 1.50 (d, J=6.4 Hz, 3H), 0.93 (d, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.81, 170.31, 163.18, 160.20, 145.79, 143.93, 142.15, 140.02, 129.21 (2), 128.44 (2), 126.10, 109.69, 89.41, 84.58, 79.26, 75.74, 72.34, 72.16, 56.19, 51.81, 47.45, 35.09, 29.19, 20.88, 19.50 (2), 18.83; ESIMS m/z 560.36 ([M+H]+).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([CH2:14][O:15]CC3(C4C=CC(F)=CC=4)CCN(C)CC3)[N:5]=2)[CH2:3][CH2:2]1.BrC1N=C(C=O)C=C(C(F)(F)F)C=1>>[CH:1]1([C:4]2[N:5]=[C:6]([CH:14]=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CN1CCC(COCc2cc(C(F)(F)F)cc(C3CC3)n2)(c2ccc(F)cc2)CC1
Agent: O=Cc1cc(C(F)(F)F)cc(Br)n1
Product: O=Cc1cc(C(F)(F)F)cc(C2CC2)n1

Procedure:
Was synthesized in the same manner as 2-cyclopropyl-6-(((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-4-(trifluoromethyl)pyridine starting from 6-bromo-4-(trifluoromethyl)picolinaldehyde. 1H-NMR (CDCl3, 400 MHz) δ 9.99 (s, 1H), 7.87 (s, 1H), 7.56 (s, 1H) 2.18 (m, 1H), 1.20 (m, 4H). LC: Tr=1.84 min, HPLC Method 1. Mass spec.: 216.37 (MH)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:21]1[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(-c2c(C(C)O)oc(=O)c3ccccc23)cn1
Yield: 37.7 %

Procedure:
The title compound was made in a similar way as that of the intermediate B1, using 4-bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.6 g, 2.23 mmol), 6-methoxypyridin-3-ylboronic acid (0.443 g, 2.90 mmol), Pd(PPh3)4 (0.206 g, 0.178 mmol) and Cs2CO3 (1.02 g, 3.1 mmol). The crude was purified via reverse phase chromatography on the Biotage 30 g C18 SNAP column (Phase A, water 95%, acetonitrile 4.9%, formic acid 0.1%; Phase B acetonitrile 99.9%, formic acid 0.1%) to afford the title compound (0.25 g, 38%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][C:7]1[CH:16]=[N:15][C:10]2=[N:11][CH:12]=[CH:13][N:14]=[C:9]2[CH:8]=1)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:14]1[CH:13]=[CH:12][N:11]=[C:10]2[N:15]=[CH:16][C:7]([CH2:6][CH2:5][CH:4]=[O:3])=[CH:8][C:9]=12
Reactant: CCOC(CCc1cnc2nccnc2c1)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=CCCc1cnc2nccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 7-(3,3-diethoxypropyl)-pyrido[2,3-b]pyrazine (522 mg in 20 mL chloroform) at 0° C. was added 20 mL of 50% aqueous trifluoroacetic acid and the mixture allowed to warm slowly to room temperature. After 30 minutes, the mixture was diluted with methylene chloride and the reaction quenched by the cautious addition of saturated sodium bicarbonate. The organics were concentrated in vacuo and purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:1; then methylene chloride:methanol, 95:5) to give the title compound (0.214 g).
Reaction SMILES: [NH:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[N+:21]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[OH-].[Li+].[H][H]>O.[Pd]>[NH2:21][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])[C:8]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]([OH:14])=[O:13]
Reactant: [H][H]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Pd]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccccc1

Procedure:
A suspension of 4-anilino-3-nitro-5-sulphamyl-benzoic acid (7 g) in water (80 ml) was adjusted to a pH of 9 by the addition of 2N sodium hydroxide or lithium hydroxide, and the resulting solution was hydrogenated at room temperature and 1.1 atmospheres hydrogen pressure after the addition of a palladium-on-carbon catalyst (0.3 g catalyst containing 10% Pd). After the hydrogen uptake had become negligible, the catalyst was removed by filtration, and the 3-amino-4-anilino-5-sulphamyl-benzoic acid was precipitated from the filtrate by addition of 4N hydrochloric acid until the pH was 2.5. After recrystallization from aqueous ethanol and drying in vacuo, the melting point was 251° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.S(Cl)([Cl:16])(=O)=O>CC(O)=O>[Cl:16][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][CH2:9]2
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc2c(c1)CCNC2
Solvent: CC(=O)O
Product: COc1ccc2c(c1Cl)CCNC2
Temperature: 25 °C

Procedure:
5.0 g (31 mmol) 6-Methoxy-1,2,3,4-tetrahydro-isoquinoline in 30 mL AcOH are cooled to 0° C. and 2.7 mL (34 mmol) sulfuryl chloride are added slowly. The resulting mixture is stirred at r.t. over night. The solvent is removed in vacuo and the residue is treated with toluene/ACN 1:1. The precipitate is filtered off and dried at 40° C. in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1.[C:20]([NH:27][CH2:28][CH2:29][C:30](O)=[O:31])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20]([NH:27][CH2:28][CH2:29][C:30]([NH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1)=[O:31])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: COC(=O)CC1Cc2ccc(N)cc2CN(C)C1=O
Product: COC(=O)CC1Cc2ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc2CN(C)C1=O
Yield: 87 %

Procedure:
Methyl (±)-8-amino-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate was coupled with Boc-β-alanine according to the procedure of Example 5(b). Purification by chromatography on silica gel gave the title compound (87%) as a light yellow foam: 1H NMR (CDCl3) δ8.20 (br s, 1H), 7.48 (s, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 5.27 (d, J=16.6 Hz, 1H), 3.92 (m, 3H), 3.80 (d, J=16.6 Hz, 1H), 3.70 (s, 3H), 3.01 (s, 3H), 2.90 (m, 5H), 2.48 (dd, J=16.8, 5.5 Hz, 1H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2=[N:7][N:8]([CH2:10][C:11](O)=O)[N:9]=[C:5]2[CH:4]=1.C([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=O.N1CCCCC1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2=[N:7][N:8]([CH:10]=[CH:11][C:27]3[CH:28]=[CH:29][C:24]([C:21]4[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=4)=[CH:25][CH:26]=3)[N:9]=[C:5]2[CH:4]=1
Reactant: COc1ccc2nn(CC(=O)O)nc2c1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc2nn(C=Cc3ccc(-c4ccccc4)cc3)nc2c1
Yield: 60.3 %

Procedure:
21 g of 5-methoxybenzotriazole-2-acetic acid, 20 g of 4-formyl-biphenyl and 5 ml of piperidine are melted at 165° to 175° C for 10 hours. 50 ml of dimethylformamide are then added and the product is allowed to crystallise. 20 g of 5-methoxy-2-[(p-phenyl)-styryl]-benzotriazole are obtained and after recrystallisation from methylglycol this melts at 176° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CC([O-])=O.[Na+].[N:32]#[C:33]Br.O>CO>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][N:14]([C:33]#[N:32])[CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: N#CBr
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C#N)CC2)c(C)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 78.9 %

Procedure:
(3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (0.16 g, 0.45 mmol) was dissolved in MeOH (4 mL) and cooled to 0° C. NaOAc (112 mg, 1.4 mmol) and CNBr (68 mg, 0.64 mmol) were added and the solution was slowly warmed to room temperature and stirred for 6 hours. H2O (15 mL) was added and the solution was extracted with CH2Cl2 (3×30 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure to afford 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carbonitrile (134 mg, 79%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:31]=[CH:30][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N+:24]=4[O-:29])[S:22][C:15]=23)=[C:11]([F:32])[CH:10]=1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.[C:43]1([CH2:49][C:50]([N:52]=[C:53]=[S:54])=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[F:32][C:11]1[CH:10]=[C:9]([NH:8][C:53]([NH:52][C:50](=[O:51])[CH2:49][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[S:54])[CH:31]=[CH:30][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N+:24]=3[O-:29])[S:22][C:15]=12
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc[n+]4[O-])sc23)c(F)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cccc[n+]4[O-])sc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A mixture of 432 (243 mg, 0.53 mmol) in 3:1 mixture of DCM/TFA (8 mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure. The resultant solid was dissolved in 1:1 mixture of EtOH/toluene (10 mL) and treated with 2-phenylacetyl isothiocyanate (140 mg, 0.8 mmol). The reaction mixture was stirred for 1 hour at room temperature and concentrated. The residue was purified by flash chromatography using the gradient 0-20% MeOH in EtOAc as an eluent yielding 430 (101 mg, 36% yield). MeOH-d4/CDCl3 (1:1) 8.5 (d, 1H, J=5.4 Hz), 8.38 (m, 3H), 8.0 (d, 1H, 11.9 Hz), 7.62 (t, 1H, J=7.7 Hz), 7.45 (m, 2H), 7.2-7.4 (m, 6H), 6.64 (5.1 Hz), 3.75 (s, 2H). LCMS: (M+H) 531.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24](C#N)[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:30][O:31]C1C=C(C2N=C(OS(C(F)(F)F)(=O)=O)C=C3C=2N=CC=C3)C=CC=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:31][CH3:30])[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: COc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Product: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(OC)c3)n2)CC1

Procedure:
This compound is prepared in an analogous way to compound 4-[8-(3-Cyano-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester from trifluoromethanesulfonic acid 8-(3-methoxy-phenyl)-[1,7]naphthyridin-6-yl ester. Purification is by chromatography followed by trituration with ether to yield a white solid. MS (AP+) 391.0
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[CH:10][C:4]=1[NH2:1]
Reactant: Nc1ccc(SCCCCl)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(SCCCCl)cc1N

Procedure:
6 G of 2nitro-4-(3-chloropropylthio)aniline is treated in 120 ml. methanol and 120 ml. of water with 30 g. of sodium hydrosulfite (Na2S2O4) on the steam bath for about 5 minutes. The reaction mixture is concentrated under vacuum and extracted well with chloroform. Evaporation of the dried extract affords 1,2-diamino-4-(3-chloropropylthio)benzene.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.Br[CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](Cl)=[O:31].[Na+].[Cl-]>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([N:15]2[CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]2=[O:31])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Reactant: CC(C)(CCBr)CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CCN(C2c3cc4nonc4cc3OC(C)(C)C2O)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To 654 mg of (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole dissolved in 10 mL of ethyl acetate were added 337 mg of triethylamine and dropwise added 696 mg of 5-bromo-3,3-dimethylvaleryl chloride at the room temperature over a 10-minute period, followed by stirring at the room temperature for one hour. The reaction mixture was added with 20 ml of saturated aqueous NaCl solution, and extracted twice with ethyl acetate (each 20 mL). After the extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 66 g of dimethylformamide and was dropwise added with 2.7 g of 20% tetraethylammonium hydroxide solution over 20 minutes under ice-cooling. Under ice-cooling, the mixture was reacted for 30 min. and then, the solvent was distilled off under reduced pressure and was added with 20 mL of saturated aqueous NaCl solution and extracted thrice with methylchloride (each 20 mL). After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure The residue was subjected to a silica gel column chromatography (ethyl acetate:n-hexane=1:1, Rf=0.5) to obtain 598 mg of the intended compound as colorless crystals.