Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([N+:31]([O-])=O)=[CH:26][N:25]=2)[C:5]1=[O:34])[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([NH2:31])=[CH:26][N:25]=2)[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ncc([N+](=O)[O-])cc2C)C1=O
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ncc(N)cc2C)C1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-5-nitropyridin-2-yl)piperidin-2-one (Example 113, Step A) (120 mg, 0.23 mmol) and tin(II) chloride dihydrate (260 mg, 1.1 mmol) were dissolved in 2.3 mL of ethyl acetate. The reaction apparatus was outfitted with a reflux condenser and was stirred at 90° C. for 4 hours. The reaction mixture was cooled to room temperature, quenched with 1M NaOH and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 90% EtOAc/Hex, gradient elution) provided the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:36][CH2:35][C:34]([O:33][CH3:32])=[O:37])=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COC(=O)CN
Reactant: COCc1cc(-c2nc(-c3cccc(C(=O)Cl)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Product: COCc1cc(-c2nc(-c3cccc(C(=O)NCC(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride was prepared following procedure described in example 116 starting from example 92. It was obtained as an oil (1070 mg, 96%). The title compound was prepared following procedure described in example 121 starting from 3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride and glycine methyl ester hydrochloride. The title compound was obtained as a pale yellow powder (97 mg, 86%). 1H NMR: (DMSO-d6, 300 MHz) δ 9.27 (m, 1H), 8.63 (m, 1H), 8.35 (m, 1H), 8.31 (m, 1H), 8.19 (dd, J=1.8 Hz, 7.9 Hz, 1H), 8.12 (m, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.39-7.26 (m, 3H), 7.15 (m, 1H), 4.23 (d, J=12.9 Hz, 1H), 4.17 (d, J=12.9 Hz, 1H), 4.07 (d, J=5.8 Hz, 1H), 3.68 (s, 3H), 3.25 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 472.2 (M+H)+ 470.2 (M−H)−. HPLC (Method A) Rt: 4.92 min (purity: 99.2%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([O:29]C)=[O:28])[C:20]=4[N:19]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([OH:29])=[O:28])[C:20]=4[N:19]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4c(C(=O)OC)cccc4[nH]3)C[C@H]2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4c(C(=O)O)cccc4[nH]3)C[C@H]2OC)nc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1H-benzimidazole-4-carboxylate obtained in Example (187d) (190 mg, 0.41 mmol) was dissolved in methanol (5 ml) and THF (5 ml). A 2 N aqueous lithium hydroxide solution (5 ml) was added, and the mixture was stirred at 50 to 70° C. for one hour. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid. The resulting solid was collected by filtration, washed with distilled water, and dried under reduced pressure at 45° C. to obtain the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[CH:26]=[C:25](F)[N:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:18]3[CH:26]=[C:25]([NH:35][CH2:34][C:33]4[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)[N:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COc1ccc(CN)cc1
Reactant: Fc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cn1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(OCc5ccccn5)c(Cl)c4)ncnc3cn2)cc1
Temperature: 70 °C
Reaction time: 118 h
Yield: 76.8 %

Procedure:
A mixture of compound 203 (3.07 g, 8.04 mmol) and 4-methoxybenzylamine (10.6 mL, 80.4 mmol) in dry DMSO (20 mL) was stirred under a nitrogen atmosphere at 70° C. (bath temperature) for 118 h. The mixture was then cooled and petroleum ether (200 mL) was added. It was stirred at room temperature for 15 min. The layers were allowed to separate and the petroleum ether layer was decanted. This procedure was repeated with more petroleum ether (200 ml). Water (200 mL) was added and the mixture was stirred at room temperature overnight (22 h). It was filtered and washed solid with water (5×30 mL), then with petroleum ether (3×30 mL). The sticky yellow/orange solid was stirred with acetone (150 mL) at room temperature for 20 min. Water (150 mL) was added slowly and stirred further at room temperature for 45 min. The fine solid was collected by suction-filtration, washed with water/acetone (1:1) (4×20 mL), petroleum ether (3×20 mL) and dried in vacuum over silica-gel/KOH to give pure N4-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (212) (3.08 g, 77%) as a yellow/orange solid, mp 182-184° C.; 1HNMR δ [(CD3)2SO] 9.60 (s, 1H), 8.72 (s, 1H), 8.64-8.56 (m, 1H), 8.33 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.88 (td, J=7.7, 1.8 Hz, 1H), 7.71 (dd, J=9.0, 2.6 Hz, 1H), 7.58 (d, J=7.7 Hz), 7.42-7.19 (m, 5H), 7.15 (s, 1H), 6.93-6.84 (m, 2H), 5.25 (s, 2H), 4.48 (d, J=6.3 Hz, 2H), 3.71 (s, 3H). Anal. Calcd for C27H23ClN6O2.0.6aCet011e: C, 64.80; H, 5.02; N, 15.74%. Found C, 64.47; H, 5.00; N, 15.95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[F:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](=O)[CH2:31]Br>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:31]=[C:30]([C:29]3[CH:34]=[CH:35][CH:36]=[C:27]([F:26])[CH:28]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1cccc(F)c1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3cccc(F)c3)nc2-c2ccc(Cl)cc2)cc1
Yield: 50.3 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (30 mL), 3-fluorophenacyl bromide (0.97 g, 4.48 mmol) was added. After heating the reaction mixture at 75–80° C. for 18 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl)-1H-imidazole (481 mg, 50%) as a white solid: mp 194–196° C. Anal. Calc'd. for C22H16N2SO2FCl: C, 61.90; H, 3.78; N, 6.56; S, 7.51. Found: C, 61.71; H, 3.59; N, 6.42; S, 7.69.
Reaction SMILES: Br[C:2]1[C:3]([CH3:36])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([CH2:20][O:21][CH3:22])[NH:16][C:15]=3[CH:14]=[C:13]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:37][N:38](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:37]([C:2]1[C:3]([CH3:36])=[C:4]([NH:8][C:9]([C:11]2[C:19]3[N:18]=[C:17]([CH2:20][O:21][CH3:22])[NH:16][C:15]=3[CH:14]=[C:13]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:34])([F:33])[F:35])=[O:25])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1)#[N:38]
Reactant: CN(C)C=O
Reactant: COCc1nc2c(C(=O)Nc3cccc(Br)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Agent: [C-]#N
Agent: [Zn+2]
Product: COCc1nc2c(C(=O)Nc3cccc(C#N)c3C)cc(NC(=O)c3ccccc3C(F)(F)F)cc2[nH]1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of N-(3-bromo-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (Example 38) (85 mg) in DMF (0.5 mL), was added zinc cyanide (60% content, 60 mg). After degassing, to the mixture was added tetrakis(triphenylphosphine) palladium (88 mg), and it was stirred at 100° C. for 24 hours. To the reaction mixture was added ice water, and it was extracted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on preparative thin-layer chromatography to obtain the titled compound (14 mg) as colorless powder.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12]COC)[CH:3]=1.[CH2:16]([S-:19])[CH2:17][CH3:18].[K+]>>[OH:12][C:4]1[CH:3]=[C:2]([S:19][CH2:16][CH2:17][CH3:18])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCOc1cc(F)ccc1C(=O)OC
Reactant: CCC[S-]
Agent: [K+]
Product: CCCSc1ccc(C(=O)OC)c(O)c1
Yield: 55 %

Procedure:
Using a procedure analogous to Example 66-A, methyl 4-fluoro-2-(methoxymethoxy)benzoate and potassium propanethiolate gave the title compound (6.1 g, 55%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[O:18][C:17](=[O:22])[C:16]([C:23]([OH:25])=O)=[CH:15]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12>CN(C=O)C>[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:16]3[C:17](=[O:22])[O:18][C:19]4[C:14]([CH:15]=3)=[CH:13][C:12]([O:11][CH3:10])=[CH:21][CH:20]=4)=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12
Reactant: COc1ccc2oc(=O)c(C(=O)O)cc2c1
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2oc(=O)c(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)cc2c1
Temperature: 25 °C
Yield: 83 %

Procedure:
DIEA (43.5 μL, 0.25 mmol) was added to 6-methoxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (95.0 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (475. mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 78.5 mg of product in 83% yield: LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(O)(/C=C/B1O[C:23](C)([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)C>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6](/[CH:25]=[CH:23]/[C:22]([CH3:28])([OH:21])[CH3:27])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(O)/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(O)/C=C/c1ccnc(Cl)n1
Temperature: 90 °C

Procedure:
To a solution of 2,4-dichloropyrimidine (71 mg, 0.476 mmol) in dioxane (4 mL) and sodium carbonate (2M in water, 0.25 mL, 0.5 mmol) were added (3E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol (100 mg, 0.476 mmol) and tetrakis triphenylphosphine palladium(0) (55 mg, 0.048 mmol). The solution was degassed by bubbling nitrogen gas and heated to 90° C. for 2 hr. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexanes) to afford (3E)-4-(2-chloropyrimidin-4-yl)-2-methylbut-3-en-2-ol as a colorless oil. MS ESI: [M+H]+ m/z 199.1. 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J=5.1, 1H) 7.24 (d, J=15.6, 1H) 7.12 (d, J=5.1, 1H) 6.60 (d, J=15.6, 1H); 1.22 (s, 6H).
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.[CH2:23](N)[CH2:24][CH2:25][CH2:26][CH2:27]CC.C(N(CC)CC)C>ClCCl>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: CCCCCCCN
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)OCc1ccc(OC(C)=O)c(OC)c1

Procedure:
A yellow solution of VII (87 mg, 0.255 mmol), n-heptylamine (31 mg, 1.05×0.255 mmol) and triethylamine (26 mg, 36 μL, 0.255 mmol) in 3 mL of dichloromethane was stirred at room temperature overnight. The reaction was worked up as described for 7. The product was purified by preparative thick layer chromatography using dichloromethane/diisopropyl ether, 9:1, v/v, as the developing solvent. The result was 58 mg (67%) of 6 as a clear oil: Rf=0.53 (dichloromethane/acetone, 97:3, v/v); 1HNMR (CDCl3) δ 6.98 (d, 3J=8.0 Hz, 1H), 6.94 (s, 1H), 6.91 (d, 3J=8.0 Hz, 1H), 4.98 (s, 2H), 4.73 (bs 1H, NH), 3.81 (s, 3H), 3.18-3.14 (m, 2H), 2.29 (s, 3H), 1.50-1.43 (m, 2H), 1.31-1.19 (m, 8H) and 0.85 (t, 3J=7.0 Hz, 3H). Exact mass (FAB+) calculated for C18H27NO5 [M+] 337.1889. found 337.1895.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=O)[C:7]=1[Cl:8])=[O:4].[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=1[C:20]([OH:22])=[O:21]>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:10]([C:11]2[CH:19]=[CH:18][CH:17]=[C:13]3[C:14]([O:22][C:20](=[O:21])[C:12]=23)=[O:16])[C:6](=[O:5])[C:7]=1[Cl:8])=[O:4]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Solvent: C1COCCO1
Product: O=C1OC(=O)c2c1cccc2N1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 130 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
20 g (0.12 mol) of 2,3-dichloromaleic anhydride are added to a solution of 18.1 g (0.1 mol) of 3-aminophthalic acid in 90 ml of dioxane. The reaction mixture is stirred at 20°-30° C., whereupon a clear solution is produced over the course of approx. 30 minutes. The dioxane is then distilled off in vacuo (20 mm Hg) and the oil which remains is warmed to 130° C. After 3 hours, the crystalline mass is cooled to 50° C. and mixed with 100 ml of ethyl acetate. The reaction product is filtered off at 10° C. and dried in vacuo at 80° C. 18.1 g (58% of theory) of crystalline 3-(2',3'-dichloromaleinimidyl)-phthalic anhydride are obtained, melting at 229°-230° C. after recrystallisation from anhydrous acetic acid.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OC)=O.[F:14][CH:15]1[C:22](=O)[CH2:21][CH:20]2[N:24](C(OCC3C=CC=CC=3)=O)[CH:16]1[CH2:17][O:18][CH2:19]2>O1CCCC1>[F:14][CH:15]1[CH:22]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:21][CH:20]2[NH:24][CH:16]1[CH2:17][O:18][CH2:19]2
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=C1CC2COCC(C1F)N2C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC1CC2COCC(N2)C1F
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of NaH (273 mg, 11.4 mmol) in tetrahydrofuran (30 mL) at 0° C. was added dropwise a solution of methyl 2-dimethoxyphosphorylacetate (2.1 g, 11.4 mmol) in tetrahydrofuran (10 mL). The reaction was stirred at 70° C. for 1 hour and then cooled to 0° C. again. To the reaction mixture was added a solution of benzyl 6-fluoro-7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 100c (1.7 g, 5.7 mmol) in tetrahydrofuran (8 mL). The reaction was allowed to warm up to room temperature and stirred 2 hours. After being quenched with 1 N HCl, the solvent was evaporated under reduced pressure. Ethyl acetate (20 mL) was added. The mixture was washed with water, brine, dried over Na2SO4 and evaporated to dryness. The crude mixture was purified on silica gel, eluted with 0 to 20% EtOAc in hexanes, to give the desired product benzyl (7Z/E)-6-fluoro-7-(2-methoxy-2-oxo-ethylidene)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 100d (1.8 g, 89%). MS: calc'd (MH+) 350, measured (MH+) 350.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11](Cl)=[O:12].[CH2:22]([NH:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:23]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([N:24]([CH2:22][CH3:23])[CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:12]
Reactant: CCCCCCC(C)NCC
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCC(C)N(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
Triethylamine (2.02 g, 20 mmol) was added to a mixture of the compound of Example b (2.47 g, 10 mmol) and N-ethyl-N-(1-methylhept-1-yl)amine (3.15 g, 20 mmol) in toluene (25 mL). The reaction was stirred 2.5 h at ambient temperature, then was partitioned between ethyl acetate and dilute citric acid. The organic phase was washed twice with sat aq NaHCO31 followed with brine, then was dried (MgSO4), concentrated, and kugelrohr distilled under vacuum. The fraction which distilled at 157° C. was collected to afford 1.16 g of the title compound as an amber oil, a 38% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH:8]([CH3:10])[CH2:7][C:6]=1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][O:23][CH3:24])=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH3:10])[CH2:7][CH:6]1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][O:23][CH3:24])=[O:4]
Reactant: COCOc1ccc(OCOC)c(C2=C(C(=O)OC)CC(C)C2)c1
Agent: [Pd]
Solvent: CO
Product: COCOc1ccc(OCOC)c(C2CC(C)CC2C(=O)OC)c1
Yield: 100 %

Procedure:
To a suspension of 10% palladium on carbon (0.5 g) in methanol (40 mL) add a solution of 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopent-1-enecarboxylic acid methyl ester 8a (2.4 g, 7.1 mmol) in methanol (10 mL). Place the mixture under hydrogen (60 psi) at 40° C. for twelve hours. Purge the reaction with nitrogen and filter through celite. Concentrate the filtrate in vacuo to yield 2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentanecarboxylic acid methyl ester (2.47 g, 7.1 mmol, 100%) as a clear oil. 1H NMR (δ, 400 MHz, CDCl3): 6.98 (d, 1H, J=8.8 Hz), 6.85 (d, 1H, J=8.8), 6.81 (dd, 1H, J=3.2, 8.8 Hz), 5.15 (s, 2H), 5.10 (d, 1H, J=6.6 Hz), 5.07 (d, J=6.6 Hz), 3.77-3.67 (m, 1H), 3.51 (s, 3H), 3.46 (s, 3H), 3.38-3.31 (m, 1H), 3.15 (s, 3H), 2.19-2.03 (m, 2H), 1.96-1.68 (m, 3H), 1.19 (d, 3H, J=6.2 Hz). HRMS calcd. 339.1808; found (electrospray, M+1) 339.1818.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[S:15][C:16]=1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:31][C:32]1[CH:39]=[C:38](F)[CH:37]=[CH:36][C:33]=1[C:34]#[N:35]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[S:15][C:16]=1[CH2:17][O:18][C:38]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([Cl:31])[CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: OCc1sc(-c2ccc(C(F)(F)F)nc2)nc1CCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)nc3)nc2CCCOCc2ccccc2)cc1Cl
Temperature: 25 °C
Yield: 33.4 %

Procedure:
1.44 g [4-(3-Benzyloxy-propyl)-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol were dissolved in 15 ml dimethylformamide. 231 mg sodium hydride (95%) were added and the reaction mixture stirred at room temperature. After thirty minutes 549 mg 2-chloro-4-fluorobenzonitrile were added and the reaction mixture stirred at room temperature for one hour. Then the reaction was quenched by the addition of 20 ml water and extracted three times with portions of 50 ml methyltertbutylether. The combined organic phases were dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 641 mg 4-[4-(3-Benzyloxy-propyl)-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-ylmethoxy]-2-chloro-benzonitrile as yellow lyophilisate.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:29][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][NH:31][CH3:30])[O:14][C:15]=2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Product: CNCC1Cc2ccc(Cl)c(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.056 g, 73%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.1 g, 0.23 mmol) and methylamine (0.24 g, 7.8 mmol). mp 155-157° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])=[CH:6][CH:5]=1)([O-])=O.N.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])=[CH:8][CH:9]=1
Reactant: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: Nc1ccc(-n2ccc(=O)[nH]c2=O)cc1

Procedure:
To a solution of 1.4 g 1-(4-Nitro-phenyl)-1H-pyrimidine-2,4-dione in 120 mL MeOH, 15 g Raney Nickel (washed three times with MeOH) were introduced under a nitrogen atmosphere. Then 15 mL of a 7 M solution of NH3 in MeOH were added. The nitrogen atmosphere was replaced by a hydrogen atmosphere and the mixture was hydrogenated under normal pressure at RT. After 2 h the reaction mixture was filtered through a pad of celite. The solvents were removed under reduced pressure and the residue was subjected to the next reaction step without further purification. Yield: 502 mg.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:17]I>>[CH3:17][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1=[O:1]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Product: CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O

Procedure:
(S)-tert-butyl 1-methyl-2-oxoazepan-3-ylcarbamate was prepared from (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (Example 8) and methyl iodide according to the general procedure of Example 9. The crude product was purified by column chromatography, eluting with 50% ethyl acetate/hexanes, to provide compound (2e) in 48% yield.