Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:16])[CH2:12][C:13]([OH:15])=O)[CH2:7][CH2:6]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:43]1([C:49]2[N:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11](=[O:16])[CH2:12][C:13]([NH:55][C:52]2[CH:53]=[N:54][C:49]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:50][CH:51]=2)=[O:15])[CH2:9][CH2:10]1
Reactant: Nc1ccc(-c2ccccc2)nc1
Reactant: O=C(O)CC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCC(Oc2ccccc2Cl)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a stirred solution of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid (0.08 g, 0.00027 mole) in DMF (3 mL) was added DMAP (0.049 g, 0.00040 mole), HOBt (0.043 g, 0.00032 mole) and EDCI.HCl (0.06 g, 0.00032 mole). After 2 minutes 6-phenyl-pyridin-3-ylamine (0.055 g, 0.00032 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.0642 g (53%) of 3-[4-(2-chloro-phenoxy)-piperidin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide. LC-MS purity: 450.15 (M+1)+, 99.25%, 1H NMR (DMSO-d6): δ 10.4 (s, 1H), 8.8 (s, 1H), 8.2 (dd, 1H), 8.1-8.0 (m, 2H), 8.0-7.9 (m, 1H), 7.5-7.2 (m, 6H), 7.0-6.9 (m, 1H), 4.8-4.7 (m, 1H), 3.8-3.7 (m, 2H), 3.7-3.6 (s, 2H), 3.6-3.5 (m, 2H), 2.1-1.5 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:7](N)([NH2:10])(=[O:9])=[O:8]>O1CCOCC1>[N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCCCC1

Procedure:
Piperidine (3.0 g) and sulfamide (5.93 g) in 1,4-dioxane (100 ml) were heated at reflux for 24 h. The solvent was evaporated under reduced pressure and the resulting solid suspended in CHCl3. The suspension was filtered and the filtrate concentrated in vacuo to afford the subtitle compound as a white solid. Yield: 3.85 g.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:11]2[N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:13]=3[N:12]=2)=[C:8]([OH:10])[CH:9]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:11]2[N:15]([CH2:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:13]=3[N:12]=2)=[C:8]([O:10][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[CH:9]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: Clc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a suspension of sodium hydride (16 mg, 0.4 mmol, 60%) in dry N,N-dimethylformamide (10 ml) at 25° C. was slowly added a solution of 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (0.10 g, 0.275 mmol) in dry N,N-dimethylformamide (5 ml), and was allowed to stir for 0.5 h. A solution of 1-bromomethyl-2-chloro-benzene (82 mg, 0.4 mmol; CAS Reg. No. 611-17-6) in N,N-dimethylformamide (5 ml) was then added drop wise to the above solution, and further stirred for 16 h at 25° C. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride. The solvents were removed under reduced pressure. The crude material dissolved in ethyl acetate, washed with water, and then with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (10-20% ethyl acetate/n-hexane) to afford the title compound as a colorless powder (38%). MS (Turbo Spray): m/z=501.2 (M+H).
Reaction SMILES: Cl.BrCCBr.C[Si](Cl)(C)C.I[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C1(C=CC(O)=CC=1)O.Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccn2)CC1
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
Zinc powder (10.50 g, 160.60 mmol) was added to 2M hydrochloric acid (25 mL) and the resulting suspension was stirred for 20 minutes. It was then filtered and washed with water (10 mL), ethanol (10 mL), diethyl ether (10 mL) and dried in a vacuum oven for 24 hours. The dried zinc was suspended in N,N-dimethylformamide (50 mL) and 1,2-dibromoethane (277 μL, 3.21 mmol) was added. The resulting suspension was warmed to 65° C. for 5 minutes and then allowed to cool to room temperature, after which time trimethylsilyl chloride (406 μL, 3.2 mmol) was added. The reaction was stirred at room temperature for 45 minutes and then a solution of tert-butyl 4-iodopiperidine-1-carboxylate (Synlett, 4, 379, 1998) (10 g, 32.1 mmol) and hydroquinone (177 mg, 0.05 mmol) in N,N-dimethylformamide (50 mL) was slowly added, followed by warming to 150° C. for 30 minutes. 2-bromopyridine (3.06 mL, 32.10 mmol) in N,N-dimethylformamide (20 mL) was then added, followed by 5 mol % of Pd2(dba)3 (1.44 g, 1.57 mmol), 10 mol % P-(2-furyl)3 (747 mg, 3.22 mmol) and the reaction was heated at 65° C. for 24 hours. The reaction mixture was filtered through Celite® and diluted with water (500 mL). It was then extracted with diethyl ether (2×250 ml). The organic layers were combined and washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using diethyl ether:pentane (50:50-100:0) as eluent afforded the product as a yellow oil, 1.9 g (23%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)OC1C=CC=CC=1)#[N:2].Cl.[NH:24]([C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)[NH2:25].C(N(CC)CC)C>C(O)(C)C.CN(C)C1C=CN=CC=1>[NH2:2][C:1]1[N:24]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[N:25]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[N:3]=1
Reactant: COc1ccc(N=C(NC#N)Oc2ccccc2)cc1OC
Reactant: N#Cc1ccc(NN)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc(N)n(-c3ccc(C#N)cc3)n2)cc1OC
Reaction time: 8 h
Yield: 7.5 %

Procedure:
To N-cyano-N′-(3,4-dimethoxy-phenyl)-O-phenylisourea (0.215 g, 0.723 mmoles) in isopropanol (3 mL) was added 0.184 g (1.5 equivalents) of 4-Hydrazino-benzonitrile hydrochloride, followed by triethylamine 152 uL (1.5 equivalents) and catalytic (0.2 equivalents) 4-dimethylaminopyridine. The reaction was stirred overnight at 100 degrees Celsius. The reaction mixture was concentrated to dryness and purified by reverse phase column chromatography. The pure fractions were dried to provide 4-[5-amino-3-(3,4-dimethoxy-phenylamino)-[1,2,4]triazol-1-yl]-benzonitrile as tan solid (18.3 mg, 7.5% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:32][C:33](=[O:34])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-4-[4-(furan-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (81) and 2-bromoacetophenone according to General Procedure B. Yield 298 mg (34%), MP 134° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=7.2 Hz, 3H), 3.19 (m, 4H), 3.94 (m, 4H), 4.31 (q, J=7.2 Hz, 2H), 5.88 (s, 2H), 6.66 (dd, J=1.6, 3.2, Hz, 1H), 7.07 (d, J=3.6 Hz, 1H), 7.61 (m, 2H), 7.74 (m, 1H), 7.88 (d, J=1.2 Hz, 1H), 8.11 m, 2H), 8.20 (dd, J=2.8, 8.8 Hz, 1H), 8.64 (d, J=2.8 Hz, 1H); EIMS: 533 (M+1). Anal. (C28H25FN4O6) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH2:6][C:5]([CH2:9]I)([CH2:7]I)[CH2:4][C:3]=1[Br:11].C([BH3-])#N.[Na+]>CN(C)P(N(C)C)(N(C)C)=O.O>[Br:1][C:2]1[CH2:6][C:5]([CH3:9])([CH3:7])[CH2:4][C:3]=1[Br:11]
Reactant: BrC1=C(Br)CC(CI)(CI)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)CC(Br)=C(Br)C1
Yield: 70.1 %

Procedure:
Under nitrogen, a stirred solution of 3.7 g (7.3 mmol) of 1,2-dibromo-4,4-di(iodomethyl)cyclopentene (Step 7) and 1.3 g (20.6 mmol) of sodium cyanoborohydride in 15 mL of hexamethylphosphoramide (HMPA) was heated to 100° C. in an oil bath overnight. The reaction was cooled, diluted with 50 mL of water, and extracted 5 times with ethyl acetate/hexane (1:5). The combined extracts were washed 3 times with water, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) with hexane gave 1.3 g (70%) of 1,2-dibromo-4,4-dimethylcyclopentene (16 in Synthetic Scheme V) as a colorless oil: NMR (CDCl3) d 1.16 (s, 6H), 2.44 (s, 4H); MS (EI)m/e (rel intensity) 256 (24), 254 (63), 252(44), 175 (26), 173 (29), 94 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]=1[F:21].[CH3:22][N:23]1[CH2:28][CH2:27][O:26][C:25]2[CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=[N:32][C:24]1=2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:33]([C:30]3[CH:31]=[N:32][C:24]4[N:23]([CH3:22])[CH2:28][CH2:27][O:26][C:25]=4[CH:29]=3)=[O:34])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][C:3]=1[F:21]
Reactant: CN1CCOc2cc(C(=O)O)cnc21
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Product: CN1CCOc2cc(C(=O)Nc3cnc(OCC(F)(F)F)c(-c4ccc(Cl)c(F)c4)c3)cnc21

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3-fluoro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 81 a) and 3,4-dihydro-4-methyl-2H-pyrido[3,2-b]-1,4-oxazine-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 497.2(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:36]1[O:39][C@@H:37]1[CH3:38]>CO>[Cl:1][C:2]1[C:3]([NH:25][C@@H:26]2[C@@H:31]3[CH2:32][C@@H:28]([CH:29]=[CH:30]3)[C@@H:27]2[C:33]([NH2:35])=[O:34])=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=3[CH:19]3[CH2:20][CH2:21][N:22]([CH2:36][C@@H:37]([OH:39])[CH3:38])[CH2:23][CH2:24]3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[C@@H]1CO1
Reactant: COc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c(C2CCNCC2)c1
Solvent: CO
Product: COc1ccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)c(C2CCN(C[C@H](C)O)CC2)c1
Yield: 16.3 %

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(4-methoxy-2-piperidin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (Compound XXX) (60 mg, 0.1 mmol) was stirred with (R)-propylene oxide (8.0 mg, 1.0 mmol) in methanol (5 mL) in a sealed tube overnight. The reaction was concentrated and the product purified by reverse phase chromatography (Gilson). Desired fractions were collected, combined, and neutralized by partitioning between dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated, dried (magnesium sulfate) and concentrated to afford the title compound as a white solid 9 mg, 10%). 1H NMR (d-chloroform): 13.83 (br s, 1H), 7.89 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.07 (s, 1H), 6.97 (d, J=8 Hz, 1H), 6.32-6.28 (m, 3H), 5.62 (m, 1H), 5.22 (m, 2H), 3.95 (s, 3H), 3.87 (m, 1H), 3.70 (m, 1H), 3.15 (s, 1H), 3.07 (m, 1H), 2.93 (m, 2H), 2.74 (d, J=7 Hz, 1H), 2.36 (m, 4H), 1.99 (m, 3H), 1.76 (m, 3H), 1.28 (s, 1H), 1.18 (d, J=5 Hz, 3H). MS: 551.18 (M+H). HPLC retention time: 1.99 minutes (G Method).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=3[C:15](=O)[O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.Cl.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=3[CH2:15][O:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)c2cc(Cl)ccc21
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C1(CCN(Cc3ccccc3)CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of 1′-benzyl-6-chloro-3H-spiro[2-benzofuran-1,4′-piperidine]-3-one (1.1 g, 3.35 mmol) in THF (15 mL) was added 1 M solution of borane (Marxer, A; Rodriguez, H. R; McKenna, J. M; Tsai, H. M., J. Org. Chem., 1975, 40, 1427-1430) complex in THF (7 mL, 7.0 mmol) slowly at 0° C. After addition was complete, the reaction mixture was kept at room temperature for 30 minutes (min), then kept at reflux overnight, cooled to 0° C. and 6M aqueous hydrochloric acid (HCl) (3.5 mL) was added slowly. The reaction mixture was kept at reflux for 5 h, cooled to 0° C., pH of the reaction mixture was adjusted to 10 by addition of aqueous NaOH 6M and the whole was extracted with ethyl acetate. The organic layer was washed with H2O, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-30% ethyl acetate in petroleum ether) to give the sub-titled compound (900 mg).
Reaction SMILES: C1(O)C=CC=CC=1.[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]>O>[C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])=[CH2:9]
Reactant: CC(C)c1ccc(O)cc1
Solvent: O
Solvent: Oc1ccccc1
Product: C=C(C)c1ccc(O)cc1
Reaction time: 37 h

Procedure:
In this example, the procedure employed in Example 1 was repeated by passage of the mixture of air, phenol, water, and para-isopropylphenol over the pretreated catalyst, this time at a temperature of about 400°-480° C. for 37 hours. A total of 23 cuts were taken yielding a total volume of about 330 ml product whose conversions to the para-isopropenylphenol were between about 25-30%.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH:19](O)[CH2:20][O:21][C:22]3[C:27]4[C:28](=[O:37])[CH:29]=[C:30]([C:32]([O:34]CC)=[O:33])[O:31][C:26]=4[CH:25]=[CH:24][CH:23]=3)[C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])C.S(Cl)([Cl:41])=O>ClCCCl>[Cl:41][CH:19]([CH2:20][O:21][C:22]1[C:27]2[C:28](=[O:37])[CH:29]=[C:30]([C:32]([OH:34])=[O:33])[O:31][C:26]=2[CH:25]=[CH:24][CH:23]=1)[CH2:18][O:17][C:13]1[C:9]2[C:10](=[O:12])[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[O:7][C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc4oc(C(=O)OCC)cc(=O)c34)cccc2o1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(O)c1cc(=O)c2c(OCC(Cl)COc3cccc4oc(C(=O)O)cc(=O)c34)cccc2o1

Procedure:
A mixture of 24.5 parts of 5,5'-[(2-hydroxytrimethylene)dioxy]bis [4-oxo-4H-1-benzopyran-2-carboxylic acid] diethyl ester and 47.6 parts of thionyl chloride in 40 parts of dry 1,2-dichloroethane was refluxed for 16 hours. The solvent was then evaporated, the residue was triturated with petrol and the resulting solid was crystallized from ethanol to give 15.6 parts of 5,5'-[(2-chlorotrimethylene)dioxy]bis[4-oxo-4H-1-benzopyran-2-carboxylic acid], diethyl ester as white crystals m.p. 144°-144.5° C.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH3:25][C:24]([CH3:27])([CH3:26])[C@H:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:20](=[O:21])[NH:22][CH3:23]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: CNC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and (S)-2-amino-3,3,N-trimethyl-butyramide (CAN 89226-12-0, 106.7 mg, 0.64 mmol) as starting materials, and isolated (45 mg, 29.4%) as off white solid, LC-MS (UV peak area, ESI) 100%, 361.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1N
Reactant: CCOC(=O)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CNc1cc(I)c(Cl)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
To a solution of 4-chloro-5-iodo-2-methoxybenzenamine (6 g, 21.2 mmol) in MeOH (50 mL) at room temperature, AcOH (3 drops) and ethyl glyoxalate (5.6 g, 27.5 mmol, 50% in toluene) were added. The mixture was stirred at room temperature for 2 h and then sodium cyanoborohydride (5.32 g, 84.8 mmol) was added to the mixture. The resulting mixture was stirred at 50° C. for 16 h. The mixture was allowed to cool to room temperature, and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product (8.6 g).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36]1[C:40]2([CH2:45][CH2:44][CH2:43][CH:42]([CH2:46][OH:47])[CH2:41]2)[CH2:39][CH2:38][CH2:37]1.Br[C:49]1[N:54]=[CH:53][C:52]([CH:55]=[O:56])=[CH:51][CH:50]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:36]1[C:40]2([CH2:45][CH2:44][CH2:43][CH:42]([CH2:46][O:47][C:49]3[N:54]=[CH:53][C:52]([CH:55]=[O:56])=[CH:51][CH:50]=3)[CH2:41]2)[CH2:39][CH2:38][CH2:37]1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OCC1CCCC2(CCCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC2CCCC3(CCCC3)C2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
To a mixture of palladium(II) acetate (135 mg), 2-(di-tert-butylphosphino)-1,1′-binaphthyl (478 mg) and cesium carbonate (3.9 g) was added toluene (15 mL), followed by stirring under argon atmosphere at room temperature for 10 minutes. To this reaction mixture were added spiro[4.5]dec-7-yl-methanol (1.0 g) obtained in Step 1 and 6-bromopyridine-3-carboxaldehyde (1.1 g), followed by stirring the mixture at 90° C. for 1.5 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:49 to 1:9) to give 6-(spiro[4.5]dec-7-ylmethoxy)-pyridine-3-carboxaldehyde (0.313 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]CC)=[O:35])[C:28]([CH3:39])=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[C:28]([CH3:39])=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1nc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2nc1C(=O)O
Temperature: 90 °C
Yield: 97.2 %

Procedure:
A 1 N solution of sodium hydroxide (150.5 μL, 150.5 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-methyl-2-quinolinecarboxylate (43.3 mg, 75.2 μmol) in tetrahydrofuran and methanol (1:1, 1.5 mL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (150.5 μL), water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 40.0 mg (97%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-methyl-2-quinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.44 (br s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 8.08-8.00 (m, 2H), 7.72 (s, 1H), 7.70 (s, 1H), 7.64 (d, J=8 Hz, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.93 (d, J=9 Hz, 2H), 4.89 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 2.57 (s, 3H), 1.34 (d, J=7 Hz, 6H). HRMS C30H24Cl2N2O4 m/z 547.1191 (M+H)+Cal; 547.1196 (M+H)+Obs.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:9]1=[O:32].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH:33]([C:13]1[N:12]=[C:11]2[N:10]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:9](=[O:32])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[CH2:17][C:16]2=[CH:15][N:14]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1cccc3ccccc13)C(=O)N(c1ccccc1Br)C2
Reactant: Nc1ccccc1
Product: O=C1N(c2ccccc2Br)Cc2cnc(Nc3ccccc3)nc2N1c1cccc2ccccc12
Temperature: 120 °C
Yield: 63.8 %

Procedure:
A mixture of 160 mg (0.3 mmol) of 3-(2-bromophenyl)-3,4-dihydro-7-methanesulfonyl-1-(1-naphthyl)pyrimido[4,5-d]pyrimidin-2(1H)-one and 200 μl (2.2 mmol) of aniline was heated at 120° C. for 2 hours. The residue was partitioned between ethyl acetate (10 ml) and 2M hydrochloric acid (10 ml) and the ethyl acetate layer separated then washed with saturated aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate, filtered and evaporated to give 100 mg (67%) of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-(1-naphthyl)pyrimido[4,5-d]pyrimidin-2(1H)-one as an orange solid of melting point 120-125° C. [Mass spectrum (ESI) MH+ =522].
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:22]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCCN(Cc3ccccc3)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CN2CCCC(N3CCNCC3)C2)cc1
Reaction time: 5 h
Yield: 95.2 %

Procedure:
30 g of TFA are added to a solution of 9.2 g of the compound obtained in step 4.1, in 85 ml of DCM. The medium is stirred at AT for 5 h, and then concentrated. The crude obtained is taken up in DCM and then washed 4 times with a 2M sodium hydroxide solution. The organic phase is washed with a saturated NaCl solution. After drying over MgSO4, the organic phase is concentrated, to give 6.32 g of the expected product.