Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])=[N:11][C:10]=1[C:24](O)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH2:43]([O:50][C:51](=[O:54])[CH2:52][NH2:53])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH2:43]([O:50][C:51](=[O:54])[CH2:52][NH:53][C:24]([C:10]1[N:11]=[C:12]([C:19](=[O:23])[N:20]([CH3:21])[CH3:22])[C:13]2[C:18]([C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:25])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CN(C)C(=O)c1nc(C(=O)O)c(OCc2ccccc2)c2ccccc12
Reactant: NCC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1nc(C(=O)NCC(=O)OCc2ccccc2)c(OCc2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 4-benzyloxy-1-dimethylcarbamoyl-isoquinoline-3-carboxylic acid (210 mg, 0.6 mmol), NEt3 (175 μl, 1.25 mmol), and CH2Cl2 (12 ml) cooled with an ice bath was added ClCO2iBu (83 μl, 0.63 mmol) with stirring. After stirring for 15 min glycine benzyl ester hydrochloride (127 mg, 0.63 mmol) was added and the mixture was stirred for another 15 min before the ice bath was removed. Stirring was then continued at ambient temperature for additional 1.5 h. Subsequently; the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellowish gum. Purification by flash column chromatography on silica gel using hexanes:EtOAc=7:3 as the eluent gave the title compound as a slightly yellowish gum (211 mg); MS-(+)-ion: M+1=498.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][NH2:14].[C:25]([O:29][C:30]([NH:32][C:33](N1C=CC=N1)=[N:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:38]([O:37][C:35]([NH:34][C:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[N:14][CH2:13][CH2:12][N:11]([CH2:10][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)[CH:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:18][CH2:17][CH2:16]1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(=NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)NC(=O)OC(C)(C)C
Yield: 74 %

Procedure:
Using General Procedure B: Reaction of N-(tert-butoxycarbonyl)-2-amino-acetaldehyde (0.204 g, 1.28 mmol) and (1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.284 g, 1.02 mmol) with NaBH(OAc)3 (0.430 g, 2.03 mmol) in CH2Cl2 (10 mL) provided 0.71 g of a yellow foam. The foam was dissolved in THF (10 mL) and treated with 6N hydrochloric acid (10 mL). The resultant solution was stirred at room temperature overnight. The solution was neutralized with solid K2CO3 (5 g), diluted with water (5 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.205 g (64%) of N1-(1H-Benzimidazol-2-ylmethyl)-1-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine as a yellow solid. To a solution of N1-(1H-Benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine (0.205 g, 0.64 mmol) in dry THF (6 mL) was added N.N′-bis-(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (Tetrahedron Lett. 1993, 34, 3389.) (0.201 g, 0.64 mmol) and the resultant mixture was stirred at room temperature for 18 hours. The mixture was concentrated and the resultant oil was purified by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) and provided 0.267 g (74%) of N,N′-bis(tert-butoxycarbonyl)-N″-{2-[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-ethyl}-guanidine as a white foam.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[F:44][C:45]([F:57])([F:56])[C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH2:55])[CH2:53][CH3:54])=[CH:48][CH:47]=1.C(N(CC)CC)C>CN(C)C=O>[F:56][C:45]([F:44])([F:57])[C:46]1[N:51]=[CH:50][C:49]([C@H:52]([NH:55][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:53][CH3:54])=[CH:48][CH:47]=1
Reactant: CC[C@@H](N)c1ccc(C(F)(F)F)nc1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (50 mg, 0.180 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (27 mg, 0.197 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.197 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(6-trifluoromethyl-pyridin-3-yl)-propylamine hydrochloride (48 mg, 0.20 mmol) and triethylamine (55 mg, 0.54 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 45 mg (54%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide as white solid. LC/MS (method 5): Rt=4.12 min; m/z=465.35 (M+H+). 1H-NMR (400 MHz): δ (ppm)=8.76 (1H, s), 8.26 (1H, d), 8.01 (1H, d), 7.89 (1H, d), 7.24 (1H, s), 4.93-4.98 (2H, m), 4.84 (1H, d), 4.20-4.29 (2H, m), 3.92-3.99 (2H, m), 3.79-3.84 (1H, m), 3.69 (2H, bs), 2.07 (1H, m), 1.96 (1H, m), 1.77-1.89 (3H, m), 1.56 (1H, m), 1.19 (3H, d), 0.92 (3H, t).
Reaction SMILES: C1COCC1.C[O:7][C:8](=[O:31])[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[C:23]2[CH2:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][CH2:24]2)[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[OH-].[Na+]>C(O)C>[CH3:29][C:26]1([CH3:30])[CH2:25][CH2:24][C:23](=[C:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:12]2[CH:13]=[CH:14][C:9]([C:8]([OH:31])=[O:7])=[CH:10][CH:11]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(C(=C2CCC(C)(C)CC2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(C(=O)O)cc2)CC1
Temperature: 65 °C
Yield: 85.9 %

Procedure:
To a solution of THF (2 mL) and ethanol (2 mL) containing 4-[(4,4-dimethyl-cyclohexylidene)-(4-hydroxy-phenyl)-methyl]-benzoic acid methyl ester (171) (0.16 g, 0.457 mmol) was added 1 N NaOH (4 mL). The reaction mixture was heated at 65° C. for 4 h. The reaction mixture was partially concentrated to remove the EtOH and THF. To the basic aqueous mixture was added 1 N HCl to pH ˜1 (according to litmus paper). The acidic aqueous solution was extracted with dichloromethane and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was triturated with dichloromethane, filtered, and dried to give 0.132 g (85%) of the title compound 172 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 6H), 1.32 (s, 4H), 2.12-2.19 (m, 4H), 6.66 (d, J=8.3 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.1 Hz, 2H), 7.83 (d, J=8 Hz, 2H), 9.33 (s, 1H), 12.74 (s, 1H). HRMS (ESI) Calcd for C22H23O3: 335.1647 (M−H)−. Found: 335.1640.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH3:19]>CO.[Cu]>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:19])[CH:7]=3)[CH2:9][CH2:10]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N
Reactant: Clc1cc(N2CCN(C3CCCC3)CC2)ccn1
Agent: [Cu]
Solvent: CO
Product: Nc1cc(N2CCN(C3CCCC3)CC2)ccn1
Temperature: 150 °C
Yield: 24 %

Procedure:
A mixture of 5.84 g (22 mmol) 1-(2-chloro-pyridin-4-yl)-4-cyclopentyl-piperazine, 0.8 g copper powder in 41 ml 7M ammonia in methanol was heated to 150° C. for 18 h. After evaporation to dryness the residue was purified on silica eluting with a gradient formed from dichloromethane/methanol and NEt3. The evaporation of the combined product fractions yielded 1.29 g (24%) of the title compound as yellowish solid. (m/e): 247.3 (MH+; 100%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12](=[C:13]([N+:25]([O-])=O)[C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1)[CH3:4].N1C2C(=CC=CC=2)C=CC=1>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:25][C:13]1[C:14](=[O:24])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12]=1[CH2:11][CH2:10][C@@H:9]1[C@@H:19]2[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@H:8]1[CH2:7][CH2:6][C@@H:5]2[CH:3]([CH2:2][OH:1])[CH3:4]
Reactant: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Product: CC(CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 24 h

Procedure:
A solution of 20-hydroxymethyl-4-nitropregn-4-en-3-one (2.01 g, 5.35 mM) in absolute ethanol (28 mL) is treated sequentially with Lindlar's catalyst (5% Pd on CaCO3 with 5.2% Pb, 0.81 g) and with quinoline (37 μl) and kept under hydrogen at between 40-55 p.s.i. for 24 hours. The mixture is then filtered through celite, and the filtrate is concentrated to a yellow solid which is purified by short path chromatography to give 4-amino-20-hydroxymethylpregn-4-en-3-one, m.p. 180°-185° C. (aqueous isopropanol).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([C:14]([CH2:27][CH3:28])([P:23]([OH:26])([OH:25])=[O:24])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1)[CH3:13].C(OCC)C>ClCCl>[CH2:27]([C:14]([CH2:12][CH3:13])([P:23]([OH:25])([OH:26])=[O:24])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)[CH3:28]
Reactant: CCC(CC)(c1ccc(CO)cc1)P(=O)(O)O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CC)(c1ccc(C=O)cc1)P(=O)(O)O
Reaction time: 1.5 h

Procedure:
Pyridinium chlorochromate (110 mmol) in dichloromethane (150 mL) was rapidly stirred while 4-(diethyl phosphonomethyl)benzyl alcohol (73.6 mmol) in dichloromethane (15 mL) was rapidly added. After 1.5 hours, ethyl ether (200 mL) was added to the reaction mixture and the organic solution was decanted from the tarry residue. The residue was washed with 3×50 mL ethyl ether. The combined organic solution was filtered through Florisil chromatographic material and concentrated to a brown oil. The oil was then distilled to give the product as a clear oil (BP 150°-180° C. @0.002-0.005 mm Hq).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccc(F)c(Cl)c2)s1
Yield: 31 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and 3-chloro-4-fluorophenyl-boronic acid (10 mg, 0.06 mmol). The title compound was obtained in 31% yield (6.7 mg). MS (ESI+) calcd mass for C17H11ClFN5O2S2 435.002672, found 435.002662.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])C(F)(F)F.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1F)[C:33]#[N:34].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:37]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=2[F:29])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)=[O:15]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C(=O)c1ccc2c(c1)N(C)C(=O)CO2)c1cc(Oc2ccc(C#N)cc2F)ccc1Cl
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution of 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4, 100 mg) in N,N-dimethylacetamide (1.8 ml) were added 3,4-difluorobenzonitrile (41 mg) and cesium carbonate (235 mg). The mixture was heated under microwave conditions for 30 min to 120° C. After cooling to room temperature, water was added and the mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>1:1) to give 4-{4-chloro-3-[1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-oxo-ethyl]-phenoxy}-3-fluoro-benzonitrile (92 mg). In analogy to Example 1, step 3, this compound was reacted with trifluoromethyl trimethylsilane and tetramethylammonium fluoride to give the title compound (89 mg) as a colorless solid. MS (m/e)=535.1 [M+H+].
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([CH3:14])=[C:12](I)[C:11]([F:16])=[C:10]([O:17][CH3:18])[C:9]=1[NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])#[N:7].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>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.C(OCC)(=O)C>[C:6]([C:8]1[C:9]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:10]([O:17][CH3:18])[C:11]([F:16])=[C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]=1[CH3:14])#[N:7]
Reactant: OB(O)c1ccccc1
Reactant: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(F)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Temperature: 95 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (1.45 g, 1.26 mmol) was added to an N,N-dimethylformamide (50 ml) suspension of N-(2-cyano-5-fluoro-4-iodo-6-methoxy-3-methylphenyl)-2,2-dimethylpropionamide (I-69) (2.45 g, 6.28 mmol), phenylboronic acid (1.15 g, 9.42 mmol), potassium phosphate n-hydrate (74-78%, 3.60 g, 12.6 mmol), followed by stirring at 95° C. for 2 hours. The reaction liquid was cooled, then ethyl acetate (200 ml) was added, followed by washing with saturated brine (50 ml×3), drying over anhydrous magnesium sulfate, concentration under reduced pressure. The residue was purified twice by silica gel column chromatography (chloroform), (n-hexane:ethyl acetate=4:1) to obtain the entitled compound (2.06 g, 96%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:18][O:19][C:20]1[CH:46]=[CH:45][C:23]([CH2:24][N:25]2[CH2:29][CH:28]([CH2:30][CH2:31]OS(C3C=CC(C)=CC=3)(=O)=O)[N:27]([CH3:43])[C:26]2=[O:44])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:15])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:31][CH2:30][CH:28]2[CH2:29][N:25]([CH2:24][C:23]3[CH:45]=[CH:46][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[C:26](=[O:44])[N:27]2[CH3:43])=[CH:8][CH:7]=1
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)OC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)OC(C)C
Temperature: 55 °C
Yield: 84.8 %

Procedure:
3-(4-Hydroxy-phenyl)-2-isopropoxy-propionic acid methyl ester (1.7 g, 7.3 mmol), Toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (3.4 g, 8.0 mmol), and Cs2CO3 (3.6 g, 11 mmol) were combined in 10 mL of DMF and heated at 55° C. for 18 h. After cooling, the mixture is diluted with 100 mL of water and extracted with 3×20 mL of ethyl acetate. The organics were dried, concentrated, and the residue is purified by flash chromatography using 7/3 ethyl actate/hexanes to give 3.0 g (86%) of the title compound as an oil. NMR
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([OH:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])C>CS(C)=O.[Cl-].[Na+].O>[Cl:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][C:8]2([OH:19])[C:6]([OH:7])=[O:5])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1(O)CCCc2ccc(Cl)cc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)C1(O)CCCc2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
NaOH (10M, 1 mL) was added to a solution of 7-chloro-1-hydroxytetraline-1-carboxylic acid, ethyl ester (0.8 g; 3.1 mmol; from step (iii) above) in DMSO (20 mL), and the mixture was heated to 100° C. for 3 hours. The resultant mixture was diluted with crushed ice (40 g) and brine (40 mL), and the mixture was extracted with EtOAc. The aqueous layer was acidified to pH 2 with 2M HCl and extracted with EtOAc (2×40 mL). The combined organic layer was dried (Na2SO4) and concentrated. Yield 0.22 mg (30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14]([OH:16])=O.[C:17]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14]([N:25]1[CH2:26][CH2:27][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24]1)=[O:16]
Reactant: COc1ccccc1-c1oncc1C(=O)O
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-c1oncc1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-(2-methoxyphenyl)-isoxazole-4-carboxylic acid (50.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1479.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[S:14](Cl)(=[O:16])=[O:15])#[N:6]>C(OCC)C>[C:5]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[S:14]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:16])=[O:15])#[N:6]
Reactant: N#Cc1c(F)cccc1S(=O)(=O)Cl
Reactant: CC(C)N
Solvent: CCOCC
Product: CC(C)NS(=O)(=O)c1cccc(F)c1C#N
Reaction time: 1 h

Procedure:
To a solution of 5.2 ml of isopropylamine in 50 ml of diethyl ether cooled in an ice bath, a solution of 4.4 g of 2-cyano-3-fluorobenzenesulphonylchloride in 50 ml of diethylether was added dropwise while stirring; reaction temperature approx. 5° C. After leaving to stand at room temperature for one hour, the reaction mixture was washed twice with ice water, dried on anhydrous Na2SO4, filtered and evaporated to dryness. The desired product was obtained in a yield of 4.16 g; melting-point 97°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COc1ccc(C(C)=O)cc1
Product: COc1ccc(C(=O)C=Cc2ccc(Cl)cc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and commercial 4-methoxyacetophenone, 3-(4-chlorophenyl)-1-(4-methoxyphenyl)-prop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>O1CCCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-]>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ncco2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C., stirred solution of oxazole (190 μL, 3.8 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (2.6 mL of a 1.6 M solution in hexanes, 4.2 mmol). After 30 min, zinc chloride (11.5 mL of a 1.0 M solution in diethyl ether, 11.5 mmol) is added. The reaction mixture is warmed to 0° C. and methyl 4-iodobenzoate (1 g, 3.8 mmol) and palladium(0)tetrakis(triphenylphosphine) (530 mg, 0.4 mmol) are added. The reaction mixture is heated at 70° C. for 20 h under argon, cooled to room temperature, and then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (3:1 hexanes/ethyl acetate) yields the title compound. 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 4H), 8.07-8.05 (m, 1H), 7.36-7.35 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1cnc2c(N)nc3cccnc3c21
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cnc2c(N)nc3c(c21)NCCC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.46 g) in trifluoroacetic acid (10 mL). The reaction mixture was reduced on a Parr apparatus under 45 psi (3.15 Kg/cm2) hydrogen pressure for 4 hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under vacuum. The residue was combined with aqueous sodium bicarbonate then a small amount of 10% sodium hydroxide was added. The resulting precipitate was extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate then concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluting with 5% methanol in dichloromethane containing 0.5% ammonium hydroxide). The eluant was concentrated under vacuum. The residue was recrystallized from ethyl acetate to provide 6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a solid, m.p. 222-226° C. Analysis: Calculated for C13H19N5: % C, 63.65; % H, 7.81; % N, 28.55; Found: % C, 63.07; % H, 7.51; % N, 28.00.