Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([NH2:16])=O)=[CH:4]1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=[S:26])[NH2:16])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(N)=O)c2ccc(OC)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCn1cc(C(N)=S)c2ccc(OC)cc21
Yield: 71.4 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-carboxamide (120 mg, 0.55 mmol), Lawesson's reagent (240 mg, 0.6 mmol), and toluene (2 mL) are heated at 90° C. for 90 min. The reaction mixture is concentrated and purified by silica gel chromatography (EtOAc/CH2Cl2, 1/9) to yield 1-ethyl-6-methoxy-1H-indole-3-thiocarboxamide as a yellow solid (92 mg, 71%).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl.C(OCC)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:20]1[CH2:34][CH2:33][CH2:32][C@H:21]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 92.1 %

Procedure:
To a solution of Boc-D-Phe-OH (89.1 g, 336 mmol), Pro-OBn hydrochloride (81.2 g, 336 mmol), HOBT (50 g, 370 mmol) and N,N-diisopropylethylamine (176 mL, 1,008 mmol) at 0° C. in dichloromethane (600 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71 g, 370 mmol). After stirring for 18 hours, the mixture was diluted with diethyl ether (1 L) and washed sequentially three times with 1N citric acid (250 mL), once with water (250 mL), three times with saturated aqueous sodium bicarbonate (250 mL) and once with saturated aqueous sodium chloride (250 mL). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to yield 140 g (92.5%) of a pale yellow foam.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[OH:11][NH2:12]>C(O)C.C(OCC)(=O)C>[NH2:2][C:1](=[N:12][OH:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: NO
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(N)=NO
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
tert-Butyl cyanoacetate (1.0 g) was dissolved in ethanol (10 mL), and aqueous hydroxyamine solution (50%, 0.5 mL) was added dropwise under ice-cooling. After stirring at room temperature for 5 hr, the mixture was diluted with ethyl acetate, and washed with brine, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and ethyl acetate-hexane was added. The resulting precipitate was collected by filtration to give the object product (820 mg, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=Cc1cc(Br)cc(Cl)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOCC
Product: Clc1cc(Br)cc(CNC2CC2)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2,3-dichlorobenzaldehyde from the previous step (1 eq.), cyclopropylamine (1 eq.) and sodium cyanoborohydride (1.5 eq.) were combined in MeOH (0.2 M). At 0° C., acetic acid (3 eq.) was added dropwise and the reaction mixture was slowly warmed to RT over 16 h. The reaction mixture was then diluted with ether and quenched with 1N aq. NaHCO3. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→80:20 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: C([O:8][C:9](=[O:34])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.O[CH:36]1[CH2:41][C:40](=[O:42])[NH:39][C:37]1=[O:38].Cl.CN(CCCN=C=NCC)C>CO.CCOCC.[Pd]>[O:42]=[C:40]1[CH2:41][CH2:36][C:37](=[O:38])[N:39]1[O:34][C:9](=[O:8])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: O=C1CC(O)C(=O)N1
Reactant: CC(C)CC(C[PH](=O)OCCc1ccc(Cc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)CC(C[PH](=O)OCCc1ccc(Cc2ccccc2)cc1)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 86 %

Procedure:
2-[(4-Benzyl benzyl)methoxyphosphinoylmethyl]-4-methylpentanoic acid benzyl ester (650 mg, 1.36 mmole) was hydrogenated at 45 psi at room temperature in methanol (50 ml) over 5% palladium on barium sulfate (650 mg) for 1 hour. The catalyst was filtered off and washed with methanol. The filtrate was concentrated and traces of methanol removed by twice diluting the sample with methylene chloride and reconcentrating. The intermediate 2-[(4-benzyl benzyl)methoxyphosphinoylmethyl]-4-methylpentanoic acid was dissolved in dry dimethylformamide (14 ml) and hydroxysuccinimide (235 mg, 2.04 mmole) and dimethylaminopropylethylcarbodiimide hydrochloride (391 mg, 2.04 mmol) added. After stirring at room temperature for 20 hours the solution was diluted with ether (50 ml) and washed with 1N hydrochloric acid (50 ml, 2×25 ml) and saturated sodium bicarbonate solution (25 ml) and dried with magnesium sulfate. After filtration and concentration 566 mg (86%) of 2-[(4-Benzylbenzyl) methoxyphosphinoylmethyl]-4-methyl-pentanoic acid 2,5-dioxo-pyrrolidin-1-yl ester was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[CH3:27][O:28][CH:29]([O:47][CH3:48])[C:30]1[C:39]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][C:41]2=[O:46])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:6]([C:5]1[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][C:41]4=[O:46])=[C:30]([CH:29]([O:47][CH3:48])[O:28][CH3:27])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: COC(OC)c1nc2c(cc1N1CCOCC1=O)CCCN2
Reactant: O=C(n1cncn1)n1cncn1
Reactant: COCCNc1cc(N)ncc1C#N
Solvent: CN(C)C=O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(N4CCOCC4=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 683 mg, 3.56 mmol) in anhydrous DMF (6 ml) was added drop wise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (648 mg, 3.56 mmol) and DMF (6 ml) cooled at 0° C. After stirring for 1 h at 0° C. the reaction mixture was allowed to warm to room temperature and a solution of 4-(2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)morpholin-3-one (intermediate 333, 683 mg, 1.78 mmol) in DMF (6 ml) was added. The suspension was allowed to warm to room temperature, was continued to stir for 17 h and quenched by the addition of MeOH. The reaction mixture was diluted with water, filtered to remove solid impurities and the filter cake was washed with EtOAc. The filtrate was diluted with brine and EtOAc, phases were separated and the water phase was extracted with EtOAc (2×). The combined organic phases were washed with brine, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (containing 0.3% of aqueous NH3, 1-6%) in DCM. Fractions containing the product were combined, concentrated. The solid was precipitated from DCM and n-hexane, sonicated, filtered and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 0.83 min, ESI-MS 526.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.27 (s, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 6.88 (t, 1H), 5.34 (s, 1H), 4.23 (d, 2H), 4.10-3.84 (m, 4H), 3.71-3.24 (m, 15H), 2.92-2.82 (m, 2H), 1.98-1.87 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19].C1C(O)=CC=CC=1C>>[CH3:16][N:17]([CH3:20])[C:18]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[NH:19]
Reactant: Cc1cccc(N)c1-c1ccccc1
Reactant: CN(C)C#N
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: Cc1cccc(NC(=N)N(C)C)c1-c1ccccc1

Procedure:
A mixture of 2-amino-6-methylbiphenyl hydrochloride (2.98 g), N,N-dimethylcyanamide (1.46 g) and m-cresol (25 ml) was heated at 90°-95° C. for 6 hours to give N,N-dimethyl-N'-(6-methyl-2-biphenylyl)guanidine (m.p. 181°-182° C.) which was recrystallised from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH3:10])[CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:18][O:12][C:11](=[O:13])[C:9]([CH3:10])([CH3:14])[NH:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Nc1cc(Cl)ccc1[N+](=O)[O-])C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(C)(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of N-(5-chloro-2-nitrophenyl)-2-methylalanine (X, EXAMPLE 10, 22.3 g, DMF (260 ml), potassium carbonate (35.6 g), and iodomethane (26.9 ml) is stirred at 20°-25° for 16 hr. Aqueous workup (ether, water and saline washes, drying over magnesium sulfate) gives the title compound, mp 87°-89°; IR (Nujol) 3349, 2954, 2925, 1737, 1606, 1489, 1330, 1263, 1230, 1149 and 752 cm-1 ; NMR (CDCl3) 8.48, 8.15, 6.65, 6.54, 3.77 and 1.69 δ; MS (EI) 272 and 213 m/z.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]2[N+:20]([O-])=[CH:19][C:18]3[N:25]=[C:26]([CH2:32][O:33][CH3:34])[N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:17]=3[C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]=[C:19]([Cl:3])[C:18]3[N:25]=[C:26]([CH2:32][O:33][CH3:34])[N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:17]=3[C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1nc2c(Cl)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phosphorous oxychloride (1.78 g, 11.6 mmol) was added dropwise to a solution of 8-benzyloxy-1-(2-methylpropyl)-2-methoxymethyl-5-oxido-1H-imidazo[4,5-c]quinoline in 10 mL of DMF. After 1 hour, the reaction was poured onto 700 mL of ice and stirred overnight. Solid potassium carbonate was then added until the pH of the reached 10. After 30 minutes of stirring, the mixture was filtered. The resulting solid was washed with water and dried under a stream of air to give 3.75 g of 8-benzyloxy-4-chloro-1-(2-methylpropyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline as a yellow-tan solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH3:34][N:35]([CH3:41])[S:36]([CH:39]=[CH2:40])(=[O:38])=[O:37]>>[CH3:34][N:35]([CH3:41])[S:36]([CH2:39][CH2:40][N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)(=[O:38])=[O:37]
Reactant: C=CS(=O)(=O)N(C)C
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(=O)(=O)N(C)C)C3)ccc1-2
Yield: 75 %

Procedure:
Following the procedure for 320, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and ethenesulfonic acid dimethylamide were reacted. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 2% MeOH in DCM) to give 443 as a beige solid (117 mg, 75%). LCMS: RT=7.69 min, [M+H]+=503. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, d, J=8.17 Hz), 7.89 (1H, s), 7.08 (1H, dd, J=8.21, 1.86 Hz), 6.99-6.96 (1H, m), 5.92-5.83 (1H, m), 4.38 (2H, t, J=5.05 Hz), 3.77 (2H, t, J=6.90 Hz), 3.74-3.64 (1H, m), 3.39 (2H, t, J=5.06 Hz), 3.23 (2H, t, J=6.67 Hz), 3.00-2.92 (4H, m), 2.87 (6H, s), 1.60 (6H, d, J=6.64 Hz)
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][C:20]#[N:21].O>CN(C=O)C>[C:20]([CH2:19][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=2)[CH:6]=[C:7]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:21]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2ccc(I)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(I)cc2n1CC#N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 23.1 %

Procedure:
A solution of ethyl 6-iodoindole-2-carboxylate (7.0 g, 22 mmol) in DMF (25 mL) was added dropwise over 15 min to a stirred suspension of sodium hydride (60%, 1.36 g, 34 mmol) in DMF (50 mL) at 0° C. under Ar. The reaction was stirred at 0° C. for 45 min then chloroacetonitrile (2.85 mL, 45 mmol) was added in one portion. The reaction was then heated to 75° C. and stirred for one h. After allowing to cool to room temperature the mixture was poured into water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (1×200 ml), dried (magnesium sulfate), filtered and the solvent removed under vacuum to give the product (1.8 g, 23%). IR νmax (Nujol)/cm−1 2924, 2854, 1895, 1703, 1601, 1527, 1464, 1446, 1426, 1398, 1377, 1366, 1334, 1308, 1261, 1204, 1148, 1135, 1119, 1103, 1048, 1024, 989, 949, 904, 894, 871, 842, 833, 800, 786, 762, 736, 654, 612, 584 and 471; NMR δH (400 MHz; CDCl3) 7.79 (1H, s), 7.51 (1H, d, J 8.6 Hz), 7.42 (1H, d, J 8.6 Hz), 7.32 (1H, s), 5.54 (2H, s), 4.37 (2H, q, J 7 Hz), 1.39 (3H, t, J 7 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH2:26][Cl:27])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[NH2:25].[N:28]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[Cl:27][CH2:26][CH:3]([CH2:2][Cl:1])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[NH:25][N:28]=[C:11]2[S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OC(CCl)CCl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OC(CCl)CCl)cccc12
Temperature: 3 °C

Procedure:
A mixture of 2-(2-chloro-1-chloromethyl-ethoxy)-6-(naphthalene-1-sulfonylmethyl)-phenylamine (4) (2 g, 4.77 mmoles) in THF and 4M HCl (15 ml) was stirred, under nitrogen, at 3° C., treated dropwise with a solution of sodium nitrite (0.34 g, 5 mmoles) in H2O (2 ml). The reaction mixture was poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum to afford the title compound as an off white solid (1.76 g, 4.05 mmoles), identified by HNMR analysis.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[OH-:6].[K+].Cl[C:9](Cl)(Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1>O>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:12]=[C:11]([CH2:10][C:9]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])[CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc(CC(Cl)(Cl)Cl)c1
Reactant: CCCCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CCCCOC(=O)Cc1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
To 200 ml. of butanol was added 40.3 g. of potassium hydroxide containing about 14% of water, and the mixture was stirred at ambient temperature to obtain a gelatinous mixture. To it was added 20 g. of 1,1,1-trichloro-2-(3-trifluoromethylphenyl)ethane, over about 5 minutes. The mixture was then heated to reflux and stirred at that temperature for 5 hours. It was then cooled and worked up as described in Example 1 above. The major product was distilled at 89°-97° under 0.5-0.7 torr to obtain 12.8 g. of the desired product. It was analyzed by vapor phase chromatography, using a 180-cm. column packed with Chrom G silica gel coated with 1.5% of OV-17 and 1.95% of OV-210, and found to be 94.0% pure.
Reaction SMILES: C([O:4][C:5]1[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[N:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)(C)C.B(Cl)(Cl)[Cl:22].CO>ClCCl>[ClH:22].[N:15]1([C:6]2[C:5]([OH:4])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[N:13]3)=[CH:8][N:7]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: ClB(Cl)Cl
Reactant: CC(C)Oc1c(N2CCOCC2)ncc2cccnc12
Solvent: CO
Solvent: ClCCl
Product: Cl
Product: Oc1c(N2CCOCC2)ncc2cccnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 8-isopropoxy-7-morpholin-4-yl-[1,6]naphthyridine (149 mg, 0.545 mmol) in dichloromethane (10 mL) at 0° C. was added BCl3 (1.5 mL of a 1 M solution in dichloromethane). The dark orange solution was left to stir at room temperature for 24 h. MeOH (10 mL) was added and the mixture concentrated. This process was repeated four times. Further washing of the remaining residue with diethyl ether (5 mL×2) provided 7-morpholin-4-yl-[1,6]naphthyridin-8-ol hydrochloride as a dark red solid (quantitative yield).—1H NMR (CD3OD): δ 9.09 (dd, J=1.5 and 5.1, 1H), 9.02 (s, 1H), 8.99 (dd, J=1.5 and 8.2, 1H), 7.79 (dd, J=5.1 and 8.2, 1H), 3.95 (m, 4H), 3.80(m, 4H).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](C4SC(C5C=CC=CC=5)=CN=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[O:64]1[C:68]([C:69]2[CH:78]=[CH:77][C:72](C(OC)=O)=[CH:71][CH:70]=2)=[CH:67][N:66]=[CH:65]1>>[CH3:38][CH:2]([CH3:1])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:25])[C:72]4[CH:71]=[CH:70][C:69]([C:68]5[O:64][CH:65]=[N:66][CH:67]=5)=[CH:78][CH:77]=4)=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Reactant: COC(=O)c1ccc(-c2cnco2)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(-c5cnco5)cc4)cc3)cc2C1=O
Yield: 58 %

Procedure:
The compound of example 621 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with commercially available methyl 4-(oxazol-5-yl)benzoate (Ryan Scientific, USA).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][O:28][C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(CBr)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](c2ccc(COc3ccc(C(F)(F)F)cc3)cc2)CC1

Procedure:
A mixture of 0.03 m of p-(trans-4-pentylcyclohexyl)-benzyl bromide (obtainable from p-(trans-4-pentylcyclohexyl)-benzoic acid), 0.03 m of p-(trifluoromethyl)-phenol, 0.03 m of potassium carbonate and 40 ml of DMF are warmed to 120° while stirring under the exclusion of air and, after cooling, worked up as usual. p-(Trifluoromethyl)-phenyl p-(trans-4-pentylcyclohexyl)benzyl ether is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1>CN(C=O)C>[Si:9]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of pyridin-4-ylmethanol (8.0 g, 73 mmol), tert-butyldimethylsilyl chloride (14.3 g, 95 mmol) and imidazole (12.9 g, 0.19 mol) in DMF (40 mL) was stirred overnight at room temperature. The reaction was poured onto water and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO4) and evaporated under reduced pressure to yield the title compound as yellow oil (7.5 g, 46%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(F)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.79 mmol) in methylene chloride (25 mL) was added dropwise 4-fluorobenzoyl chloride (89 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 130 mg (65%) of the title compound as white crystals: mp 189-190° C.; [α]21D -30° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 367 (11, M+).