Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][CH:3]([CH2:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C1C[O:39][CH2:38]C1>>[OH:1][N:2]([CH:3]([CH2:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[C:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH2:4][CH2:5][CH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH:38]=[O:39]
Reactant: C1CCOC1
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(C#Cc3cccs3)cn2)CC1
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(C#Cc3cccs3)cn2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
and a solution of 2-[4-(hydroxyamino)-5-({4-[5-(thien-2-ylethynyl)pyridin-2-yl]piperazin-1-yl}sulfonyl)pentyl]pyrimidine (84 mg, 0.16 mmol) in THF (8 mL) was then added. The reaction was brought to RT and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×5 mL). The residue was then dissolved in MeOH (10 mL) and heated to 40° C. for one hour. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtOAc) to give the title compound as an off-white foam (87 mg, 0.16 mmol, 54%).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[OH:25][CH2:26][C:27]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39](Br)[CH:40]=1)(=[O:34])=[O:33])([CH2:29][OH:30])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:31][S:32]([C:35]1[CH:36]=[N:37][CH:38]=[C:39]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)[CH:40]=1)(=[O:34])=[O:33])([CH2:29][OH:30])[CH3:28]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.4) (295 mg, 1.0 mmol) according to general procedure II. Obtained as a light-brown solid (240 mg, 40%). MS (ISP) 582.2 [(M+H)+]; mp 204-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[CH:13][C:14]#[N:15])[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.[OH-:23].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[CH:13][C:14](=[O:23])[NH2:15])[CH2:9][N:8]=[C:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: CN1C(=CC#N)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CN1C(=CC(N)=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 50 °C

Procedure:
15.2 g of the 7-chloro-1-methyl-2-cyanomethylene-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine obtained in Example 1 A are subsequently portion-wise introduced into 80 ml of concentrated sulfuric acid under stirring, and the resulting suspension is slowly heated up to a temperature of 50° C. until a clear solution is formed. Subsequently, the solution is maintained at a temperature of 50° C. for 1 hour. After cooling, the solution is worked-up by pouring it on ice, neutralizing the sulfuric acid with diluted potassium hydroxide solution and extracting the raw product with methylenechloride. The organic phase is separated, washed with water until neutral reaction of the washing-water, and dried over sodium sulfate. After filtration and evaporation of the solvent a residue is obtained which is re-crystallized from ethanol. 11 g of 7-chloro-1-methyl-2-carbamoylmethylene-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine, having a melting point of 179° to 181° C., are obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:8]=1.[CH:24]1([C:27]2[CH:28]=[C:29]([CH3:39])[C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[CH:28]=[C:29]([CH3:39])[C:30]([N:33]3[CH2:34][CH2:35][N:36]([C:11]([C:10]4[CH:15]=[CH:16][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:23])=[CH:8][C:9]=4[N:17]4[CH2:21][CH2:20][O:19][C:18]4=[O:22])=[O:13])[CH2:37][CH2:38]3)=[N:31][CH:32]=2)[CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1N1CCOC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCOC2=O)CC1
Yield: 9.5 %

Procedure:
Using methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-(2-oxooxazolidin-3-yl)benzoate (170 mg) described in Preparation Example 32 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (110 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (25 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[Cl:18][C:12](=[O:14])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(CC(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the compound (3.0 g) obtained in Example 206a in dichloromethane (50 mL) was cooled in an ice bath, and oxalyl chloride (3.93 g) and N,N-dimethylformamide (2 drops) were added. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[C:5]([CH3:16])=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]#[CH:18])[C:5]([CH3:16])=[C:6]([CH:7]=1)[NH2:8]
Reactant: C#Cc1cc(Cl)cc(NC(=O)OC(C)(C)C)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cc(Cl)cc(N)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
To a solution of 1,1-dimethylethyl (5-chloro-3-ethynyl-2-methylphenyl)carbamate (242 mg, 0.91 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (500 μl). The solution was stirred at ambient temperature for 1 hour. The solution was partitioned between saturated sodium bicarbonate and dichloromethane. The aqueous layer was extracted twice with dichloromethane. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford an orange oil which was purified by column chromatography (silica gel, 50% dichloromethane in hexane). The product was collected to afford 60 mg, 0.36 mmol (40%) of 5-chloro-3-ethynyl-2-methylaniline as a white solid. 1H NMR (400 MHz, CDCl3): 6.90 (d, 1H), 6.63 (d, 1H), 3.71 (br s, 2H), 3.24 (s, 1H), 2.23 (s, 3H); MS (EI) for C9H8ClN: 166 (MH+).
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([B:16]1[O:20][C@H]2C[C@H]3C[C@@H]([C@@]2(C)[O:17]1)C3(C)C)[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[O:5].C(O)CCCCCC.B([O-])OCC(C)C>CO>[F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([B:16]([OH:20])[OH:17])[CH2:12][CH:13]([CH3:14])[CH3:15])=[O:9])=[O:5]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)c1cccc(F)c1F)B1O[C@H]2C[C@H]3C[C@H](C3(C)C)[C@@]2(C)O1
Agent: CC(C)COB[O-]
Solvent: CCCCCCCO
Solvent: CO
Product: CC(C)C[C@H](NC(=O)CNC(=O)c1cccc(F)c1F)B(O)O
Reaction time: 8 h

Procedure:
To a solution of 2,3-difluoro-N-[2-({(1R)-3-methyl-1-[(3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (0.536 g, 1.2 mmol) in methanol/1N HCl (1:1) (1.5 mL) were added heptanol (1 mL) and isobutyl boronate (0.207 g, 2.0 mmol). The reaction mixture was allowed to stir overnight. The heptanol layer was separated and the methanol/HCl layer was concentrated. The crude product was purified by reverse phase HPLC to give [(1R)-1-({[(2,3-difluorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1>CO.[Pd]>[NH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][C:4]2=[N:3][O:2][CH3:1])=[CH:9][CH:10]=1
Reactant: CON=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CON=C1CCCc2ccc(N)cc21
Yield: 95.9 %

Procedure:
1-Methoxyimino-7-nitro-tetralin (252 mg, 1.14 mmol) was treated with 10% Pd-C (25 mg) in MeOH (5 mL) and hydrogenated at 1 atm for 2 h. The mixture was filtered through Celite to give a yellowish solid (208 mg, 96% yield).
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH:17]2[CH2:20][N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:18]2)=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([O:39][C@H:40]3[CH2:44][CH2:43][O:42][CH2:41]3)=[CH:35][CH:34]=2)O1>>[CH3:15][C@@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:5]2[N:4]=[C:3]([O:16][CH:17]3[CH2:20][N:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:18]3)[C:2]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C@H:40]4[CH2:44][CH2:43][O:42][CH2:41]4)=[CH:35][CH:34]=3)=[CH:7][N:6]=2)[CH2:10][CH2:11]1
Reactant: CS(=O)(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Reactant: CC1(C)OB(c2ccc(O[C@H]3CCOC3)cc2)OC1(C)C
Product: CS(=O)(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(O[C@H]3CCOC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 3, 5-bromo-N-(cis-4-methylcyclohexyl)-4-(1-(methylsulfonyl)azetidin-3-yloxy)pyrimidin-2-amine was reacted with (S)-4,4,5,5-tetramethyl-2-(4-(tetrahydrofuran-3-yloxy)phenyl)-1,3,2-dioxaborolane to provide the title compound (105 mg, 46% yield). 1H NMR (CDCl3, 400 MHz) 8.12 (s, 1H), 7.38 (m, 2H), 6.91 (m, 2H), 5.34 (m, 1H), 5.20 (sb, 1H), 4.95 (m, 1H), 4.31 (m, 2H), 4.09-3.92 (m, 6H), 2.90 (s, 3H), 2.22 (m, 2H), 1.80-1.57 (m, 6H), 1.23 (m, 2H), 0.94 (d, 3H). MS (ESI) m/z: Calc. 502.2 (M+). Found: 503.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:31]([O:33][C:34](=[O:39])[C:35]([NH:37]O)=[NH:36])[CH3:32]>CN(C=O)C.O>[CH2:31]([O:33][C:34]([C:35]1[N:37]=[C:12]([C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[O:14][N:36]=1)=[O:39])[CH3:32]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CCOC(=O)C(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1noc(-c2ccncc2Nc2ccc(I)cc2F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A reaction mixture of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid (1000 mg, 2.79 mmol, 1.00 eq), and Di-imidazol-1-yl-methanone ((543 mg, 3.35 mmol, 1.20 eq) in DMF was stirred for 4 hrs at RT under argon. Then hydroxyamino-imino-acetic acid ethyl ester (612 mg, 4.19 mmol, 1.5 eq.) was added and the reaction mixture was stirred overnight, and then diluted with water. A yellow precipitate was formed that was filtered to afford the product (785 mg). [5.46 min; 455 (M+1)]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]1[CH:18]2[CH:13]([CH2:14]CCC2)[CH2:12][CH2:11][CH2:10]1.C1(C(Cl)(Cl)Cl)C=CC=CC=1>>[C:13]1([C:14]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:18]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1ccccc1O
Reactant: C1CCC2CCCCC2C1
Solvent: ClC(Cl)(Cl)c1ccccc1
Product: c1ccc(-c2nc3ccccc3o2)cc1

Procedure:
16.4 g (0.15 mol) of 2-aminophenol (A) was refluxed together with 75 ml of decaline in the apparatus described under (a). 29.3 g (0.15 mol) of benzotrichloride (B) was added drop by drop over a period of 15 minutes, and the mixture was heated for another 3 hours with gentle refluxing. Then it was suction filtered while hot and concentrated by evaporation under dry. One half was chromatographed through Al2O3 : 7 g of Compound I, melting point 99°-100° C (41% of the theory). Of the remaining half, one gram was sublimed at 140° C and 0.2 mm Hg; 0.8 g of Compound I, melting point 100°-103° C (44% of the theory).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4](I)[CH:3]=1.[C:17]([CH:19]1[CH2:22][CH2:21][CH2:20]1)#[CH:18]>CCN(CC)CC.C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([C:18]#[C:17][CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Reactant: C#CC1CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C#CC1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To the solution of tert-butyl 6-chloro-4-iodopyridin-3-ylcarbamate (7.0 g, 19.8 mmol) in Et3N (100 mL) was added the solution of ethynylcyclobutane in THF (prepared in step a), Pd(PPh3)2Cl2 (1.8 g, 2.1 mmol) and CuI (400 mg, 2.1 mmol). The reaction mixture was stirred at 25° C. for 16 h. The mixture was diluted with water and extracted with dichloromethane (3×100 mL). The extract was washed with brine, dried, concentrated in vacuo and purified by chromatography on silica gel (5-10% ethyl acetate in petroleum ether as eluant) to afford tert-butyl 6-chloro-4-(cyclobutylethynyl)pyridin-3-ylcarbamate (3.6 g, 60% yield). 1H NMR (300 MHz, CDCl3) δ: 9.11 (br, s, 1H), 7.22 (s 1H), 6.97 (s, 1H), 3.39-3.25 (m, 1H), 2.48-1.98 (m, 6H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=3)C)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[CH3:28]N1CCOCC1.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.[NH2:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57]>CN1CCCC1=O>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:27])[C:8]2[CH:14]=[C:13]([C:15]([CH3:28])=[CH:16][C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH:52][C@H:53]([C:61]([O:63][CH2:64][CH3:65])=[O:62])[CH2:54][CH2:55][C:56]([O:58][CH2:59][CH3:60])=[O:57])=[O:25])=[CH:20][CH:19]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(O)c2cc(C=C(C)c3ccc(C(=O)O)cc3)cnc2n1
Reactant: CN1CCOCC1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=C(C)c2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g of 2-acetamido-4-hydroxy-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine in 50 mL of N-methylpyrrolidinone containing 0.18 g of N-methylmorpholine was added 0.22 g of phenyl N-phenylphosphoramidochloridate in a single portion. After stirring the mixture at room temperature for 1 hour, 0.20 g of diethyl L-glutamate was added. The reaction mixture was stirred overnight, the solvent was removed under reduced pressure and the residue was triturated with chloroform. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to preparative thin layer chromatography on silica gel using a 5% methanol in chloroform mixture as the eluent. This gave 74.6 mg (25%) of the title compound as a pale yellowish solid; NMR (CDCl3, 250 MHz) d 1.22(t, 3H, J=7.1 Hz), 1.30(t, 3H J=7.1 Hz), 2.11-2.57(m, 10H), 4.14(q, 2H, J=7.1 Hz), 4.24(q, 2H, J=7.1 Hz), 4.75-4.83(m, 1H), 6.86(brs, 1H), 7.18(brs, 1H), 7.57(d, 2H, J= 8.42 Hz), 7.84(d, 2H, J=8.42 Hz), 8.50(d, 1H, J=2.01 Hz), 8.96(brs, 1H), 10.34(brs, 1H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C@H:14]1[C:23](O)=[O:24].[CH3:26][C@:27]12[C@@H:35]([CH3:36])[C@H:31]([NH:32][CH2:33][CH2:34]1)[CH2:30][C:29]1[C:37]([OH:41])=[CH:38][CH:39]=[CH:40][C:28]2=1>ClCCl>[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C@H:14]1[C:23]([N:32]1[CH2:33][CH2:34][C@:27]2([CH3:26])[C@@H:35]([CH3:36])[C@H:31]1[CH2:30][C:40]1[CH:39]=[CH:38][C:37]([OH:41])=[CH:29][C:28]=12)=[O:24]
Reactant: O=C(O)[C@@H]1COc2ccccc2O1
Reactant: C[C@H]1[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H]1[C@H]2Cc3ccc(O)cc3[C@]1(C)CCN2C(=O)[C@@H]1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbonyldiimidazole (0.47 g) is added to a solution of (S)-2,3-dihydro-benzo[1,4]dioxine-2-carboxylic acid (0.63 g) in dichloromethane (6 mL). The resulting solution is stirred at room temperature for 1 h before (2R,6R,11R)-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-ol is added. The solution is further stirred at room temperature overnight. Then, dichloromethane (30 mL) is added and the resulting solution is washed with water. After drying (Na2SO4), the solvent is evaporated to give the product as a white foam-like solid.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][C:6](=[O:8])[O:5][CH2:4]2)[CH2:2]1.CN(C)C(=O)C.[CH3:15][O-:16].[Na+].[Cl-].[NH4+]>CO.O>[CH3:15][O:16][C:6](=[O:8])[CH2:7][C:3]1([CH2:4][OH:5])[CH2:1][CH2:2]1
Reactant: O=C1CC2(CC2)CO1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)CC1(CO)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To a stirred solution of crude 5-oxa-spiro[2.4]heptan-6-one (2.24 g, ca. 20 mmol; prepared according to the method of EP 0 678 515 A1 (herein incorporated by reference in its entirety for all purposes): impurity is N,N-dimethyl acetamide) in anhydrous methanol (40 mL) in water bath, was added sodium methoxide (1.296 g, 24 mmol). After 15 min, ammonium chloride (2 g) was added and the mixture was stirred at room temperature for 30 min. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:1)) to afford 5.8 g (47%) of (1-hydroxymethyl-cyclopropyl)-acetic acid methyl ester as a colorless oil. 1H-NMR (200 MHz, CDCl3) δ 0.47-0.61 (4H, m), 2.44 (2H, s), 2.55 (1H, t, J=5.6 Hz), 3.48 (2H, d, J=5.6 Hz), 3.69 (3H, s).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[N:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19]([OH:21])=O)=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH:22]1[N:26]=[CH:25][N:24]([C:27](N2C=NC=C2)=O)[CH:23]=1.CN(C)CCN>CN(C=O)C>[CH3:25][N:24]([CH3:27])[CH2:23][CH2:22][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[CH:1]=[CH:2][N:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:21]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cccc2nc3ccc4cnccc4c3nc12
Agent: CN(C)CCN
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4cnccc4c3nc12
Temperature: 55 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of pyrido[4,3-α]phenazine-11-carboxylic acid (II.3) (0.11 g, 0.38 mmol) and CDI (0.12 g, 0.76 mmol) in DMF (5 mL) was heated and stirred at 50-60° C. for 2 h. N,N-Dimethylethylenediamine (0.5 mL, excess) was then added, and the mixture was stirred at room temperature for 2 h. The DMF was removed under reduced pressure, and the residue was diluted with water. The resulting precipitate was collected and crystallized from CH2Cl2/hexane to give pyrido[4,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (0.11 g, 84%): mp 213-215° C.; 1H NMR [CDCl3] δ 2.48 [s, 6 H, N(CH3)2], 2.75 [t, J=5.7 Hz, 2 H, CH2N(CH3)2], 3.89 (q, J=5.5 Hz, 2 H, CH2NH), 8.03-8.14 (m, 3 H, 3xArH), 8.42 (dd, J=8.4, 1.5 Hz, 1 H, ArH), 9.00 (d, J=5.5 Hz, 1 H, H-1 or H-2), 9.07 (dd, J=7.2, 1.5 Hz, 1 H, H-10), 9.34 (s, 1 H, H-4), 9.36 (d, J=5.5 Hz, 1 H, H-1 or H-2), 10.66 (br, 1 H, CONH).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:27][CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH2:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([CH2:24][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[CH:6]=[CH:7]2)[CH2:26][CH2:27]1)=[O:32])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(Cn2ccc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To 6-fluoroindole (1.35 g, 10.0 mmol) in N,N-dimethylformamide (100 mL) was added a 60% mineral oil dispersion of sodium hydride (0.44 g, 11 mmol). The mixture was stirred at room temperature under nitrogen for 30 min, then 4-tosyloxymethyl-N-carbobenzyloxypiperidine (4.0 g, 10 mmol) added and the mixture heated at 70° C. under nitrogen for 16 hours. The solvent was removed in vacuum and replaced with methylene chloride (350 mL). The solution was washed with 250 mL portions of 2N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine and dried over sodium sulfate. Filtration, concentration in vacuum and column chromatography on silica gel with methylene chloride as eluent gave 3.7 g of 4-(6-fluoro-indol-1-ylmethyl)-piperidine-1-carboxylic acid benzyl ester. This material was dissolved in ethyl acetate (100 mL), 10% Pd on carbon (0.50 g) and cyclohexene (3.2 g, 40 mmol) added, and the mixture refluxed under nitrogen for 2 hours. Filtration through celite, followed by concentration in vacuum gave 2.1 g of the title compound as a white solid. 1H-NMR (CDCl3) doublet of doublets 7.5 δ (1 H); doublet 7.0 δ (1 H); doublet of doublets 6.95 δ (1 H); triplet of doublets 6.82 δ (1 H); doublet 6.42 δ (1 H); doublet 3.9 δ (2 H); doublet 3.02 δ (1 H); triplet 2.5 δ (2 H); doublet 1.5 δ (2 H); multiplet 1.2 δ (2 H).
Reaction SMILES: [C:1]1([C@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17]>>[CH2:19]([C@H:15]1[S:11][C:10]([NH:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])[CH3:20]
Reactant: CCC(Br)C(=O)O
Reactant: C[C@H](CNC(N)=S)c1ccccc1
Product: CC[C@H]1SC(NC[C@@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2S)-2-phenylpropyl]thiourea and 2-bromo-butyric acid according to Method D3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].Br[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH2:33][O:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]2([CH2:33][O:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: COCC1(c2ccc(Br)cc2)CCOCC1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COCC1(c2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)CCOCC1
Yield: 74.2 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (78 mg) was reacted with tetrahydro-4-(4-bromophenyl)-4-(methoxymethyl)-2H-pyran (88 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(tetrahydro-4-(methoxymethyl)-2H-pyran-4-yl)phenyl]pent-4-enoic acid methyl ester (97 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.