Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][N:12]([CH2:16][C:17](OC)=[O:18])[C:11]2[N:21]([CH3:30])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:10]1=2.[C-]#[N:32].[K+].N>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]([NH2:32])=[O:18])[C:11]2[N:21]([CH3:30])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:10]1=2
Reactant: COC(=O)CN1CCSC(c2ccc(Cl)cc2Cl)c2c(-c3ccccn3)nn(C)c21
Reactant: [C-]#N
Agent: N
Agent: [K+]
Solvent: CO
Product: Cn1nc(-c2ccccn2)c2c1N(CC(N)=O)CCSC2c1ccc(Cl)cc1Cl
Temperature: 140 °C
Yield: 47.4 %

Procedure:
A mixture of methyl 2-[4-(2,4-dichlorophenyl)-1-methyl-3-(2-pyridyl)-6,7-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepin-8-yl]acetate (0.350 g, 0.76 mmol, Preparation #12 step A), KCN (0.050 g, 0.77 mmol), and ammonia (10 mL, 7 M in MeOH, 70 mmol) in methanol (10 mL) was heated, in a sealed flask, for about 50 min at about 140° C. in a microwave. After cooling to rt the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/methanol 95:5) to give 2-[4-(2,4-dichlorophenyl)-1-methyl-3-(2-pyridyl)-6,7-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepin-8-yl]acetamide (0.16 g, 0.36 mmol, 47%) as a beige solid: LC-MS (Table 1, Method b) Rt=5.49 min; m/z 448 (M+H)+.
Reaction SMILES: COC(=O)C[NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45](N)=[CH:44][CH:43]=1>CCCCCCC.C(OCC)(=O)C>[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([NH:5][C:6](=[O:37])[C:7]2[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[C:21]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH:33]4[CH2:35][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[CH:9][C:8]=2[Cl:36])=[CH:44][CH:43]=1
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Oc3ccncc3C(=O)N3CCN(C4CC4)c4ccccc43)cc2Cl)cc1

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 4-amino-benzoic acid methyl ester (commercially available, CAS RN 619-45-4) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light brown foam (29%). MS (ESI): m/z=617.136 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>O1CCCC1>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([NH:1][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[F:17])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=Cc1cnn2c(NC3CC3)cc(NC(=O)c3ccccc3F)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-amino-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (step b) (30 mg, 0.138 mmol) in 1.0 mL tetrahydrofuran, stirring under nitrogen, was added 2-fluoro benzoyl chloride (33 ul, 0.275 mmol) and DIPEA (28.8 ul). The reaction mixture was stirred at room temperature for one hour. The reaction was then partitioned between ethyl acetate and water, the organic layer was dried under sodium sulfate concentrated on high vacuum to yield N-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-2-fluorobenzamide. The crude product was further dissolved in 1.0 mL ethanol, added hydantoin (41.2 mg, 0.411 mmol) and pipperdine (40.0 ul). The reaction was heated to 80° C. for three hours. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol to yield 10 mg (40% yield, two steps) (Z)—N-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)-2-fluorobenzamide. LCMS (M+1=422)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][C:2]4=[O:7])=[N:14][CH:13]=3)=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: O=C1CCCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCCC4=O)nc3)CC2)c(C)c1
Yield: 20 %

Procedure:
Using piperidin-2-one (58 mg) and (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (200 mg) described in Preparation Example 127 and by the reaction and treatment in the same manner as in Example 1, the title compound (42 mg) was obtained.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:8]=1[O:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>O.CCO.[Fe]>[CH3:5][O:6][C:7]1[CH:19]=[C:18]([CH:17]=[CH:16][C:8]=1[O:9][C:10]1[N:11]=[CH:12][CH:13]=[CH:14][N:15]=1)[NH2:20]
Reactant: COc1cc([N+](=O)[O-])ccc1Oc1ncccn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1cc(N)ccc1Oc1ncccn1
Yield: 100 %

Procedure:
According to Scheme 3 Step 2: A suspension of iron (4.45 mmol, 248 mg), acetic acid (1.07 mmol, 61 μL) and of 2-(2-methoxy-4-nitrophenoxy)pyrimidine (0.89 mmol, 220 mg) in water/EtOH (1:1, 7 mL) was stirred at 80° C. for 30 minutes. After evaporation of EtOH, the aqueous phase was basified with a saturated solution of NaHCO3 and was extracted with AcOEt. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield 3-methoxy-4-(pyrimidin-2-yloxy)aniline (0.89 mmol, 193 mg, 100%) as an oil. The product was used without further purification.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:15][CH2:16][CH:17]2[CH:21]3[O:22][C:23]([CH3:26])([CH3:25])[O:24][CH:20]3[CH:19]([N:27]3[CH:35]=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][C:32]=4[NH:36][C:37]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:38])[O:18]2)=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[C:10]([O:15][CH2:16][CH:17]2[CH:21]3[O:22][C:23]([CH3:26])([CH3:25])[O:24][CH:20]3[CH:19]([N:27]3[CH:35]=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][C:32]=4[NH:36][C:37]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:38])[O:18]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)OC2C(COc3ncccc3OCc3ccccc3)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)OC2C(COc3ncccc3O)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Reaction time: 5 h
Yield: 32.1 %

Procedure:
Dry argon was bubbled through a solution of 1-{9-[6-(3-Benzyloxy-pyridin-2-yloxymethyl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}-3-phenyl-urea (18 mg, 0.03 mmol, prepared as above) in methanol/ethyl acetate (1:1 v/v, 10 mL) at 23° C. for 10 min. Palladium on activated carbon (10%) was added and the suspension was degassed by argon for another 5 min. Hydrogen (H2) was conducted to the solution via a balloon, and the reaction proceeded for 5 h. The mixture was filtered and concentrated in vacuo to give the crude product. Preparative reverse-phase HPLC was used to obtain the pure compound (5 mg, 31% yield) as a white solid. MW calculated for C25H25N7O6 (MH+) 520. found 520 by LCMS.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH:20]([F:22])[F:21])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH:28]1[CH:33]=CC=C[CH:29]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH:20]([F:21])[F:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][CH2:33][C:28]#[CH:29])=[O:5]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Product: C#CCOC(=O)c1cc(-n2c(=O)cc(C)n(C(F)F)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A suspension of 2.00 g of 2-chloro-5-[3-difluoromethyl-3,6-dihydro-2,6-dioxo-4-methyl -1(2H)-pyrimidinyl]-4-fluorobenzoic acid and 2.05 g of thionyl chloride in 25 ml of benzene is heated at reflux temperature for 20 hours. The clear solution is evaporated to dryness under reduced pressure at 50° C., the residue is dissolved in 20 ml of methylene chloride and subsequently stirred at room temperature for 3.5 hours with 5 ml of propargyl alcohol and 0.55 g of pyridine. The reaction mixture is evaporated to dryness under reduced pressure, the residue is dissolved in 100 ml of ethyl acetate and the solution is extracted three times with 100 ml of water each time. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The resinous residue is purified by chromatography on a silica gel column using diethyl ether/n-hexane (1:1) as the eluent. There is obtained propargyl 2-chloro-5-[3-difluoromethyl-3,6-dihydro-2,6-dioxo-4 -methyl -1(2H)-pyrimidinyl]-4-fluorobenzoate, 1H-NMR (CDCl3, 400 MHz): 7.94 ppm (d, 1H), 7.71 ppm (t, 1H), 7.39 ppm (d, 1H), 5.83 ppm (s, 1H), 4.91 ppm (d, 2H), 2.52 ppm (t, 1H), 2.50 ppm (m, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11].[CH3:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.O.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:34]([CH3:33])=[CH:35][CH:36]=2)[C:17]=1[C:18]([OH:20])=[O:19])=[O:11]
Reactant: Cc1ccc(B(O)O)c2ccccc12
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)csc1NC(=O)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2csc(NC(=O)c3cc4ccccc4o3)c2C(=O)O)c2ccccc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
Tert-butyl 2-(benzofuran-2-carbonylamino)-4-(trifluoromethylsulfonyloxy)thiophene-3-carboxylate (7), (4-methyl-1-naphthyl)boronic acid (46), tetrakis(triphenylphosphine)palladium(0), and sodium carbonate were combined in 2:1:1 ethanol, toluene and water the biphasic mixture was stirred vigorously in sealed vial at 70° C. After 2 hours, the mixture was filtered through Celite and the Celite rinsed with methylene chloride. The organic fraction of the filtrate was washed with water, dried with sodium sulfate, filtered, concentrated, purified by preparative layer chromatography (10% ethyl acetate/Hexane) then treated with a 1:1 mixture of methylene chloride and trifluoroacetic acid. After 4 hours the mixture was concentrated in vacuo, and the residue triturated in methylene chloride, centrifuged, decanted and dried under high vacuum to give 47A as a white powder (12.0 mg, 26%). 1H NMR (500 MHz, DMSO d6) δ=12.80 (br, 1H), 12.60 (s, 1H), 8.04 (d, 1H), 7.88 (s, 1H), 7.87 (d, 1H), 7.74 (d, 1H), 7.57-7.52 (m, 3H), 7.46-740 (m, 2H), 7.37 (d 1H), 7.28 (d, 1H), 7.04 (s, 1H), 2.68 (s, 3H) ppm. ESI MS [M+H] 428.21.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-])=O)=[CH:11][CH:10]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(Cl)Cl.[Pd]>[CH2:6]([O:5][P:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[CH:11][CH:10]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)c1ccc(Oc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(Oc2ccccc2N)cc1
Reaction time: 15 h
Yield: 91.8 %

Procedure:
[4-(2-Nitrophenoxy)phenyl]phosphonic acid diethyl ester (140 mg, 0.4 mmol) was dissolved in methylene chloride and Pd/C 10% was added under N2. The compound was reduced with H2 in a Parr-apparatus at 207 kPa (30 psi) for 15 hours. The catalyst was filtered off and the organic phase was evaporated in vacuo. The remaining oil was purified on a silica gel column (eluent: methylene chloride/methanol (39.1)) to give the title compound as an oil (yield: 118 mg (92%)). 1H—NMR (CDCl3(in ppm: 1.32 (6H,t); 3.8 (2H,broad s); 4.1 (4H,q); 6.7 (1H,d.t.); 6.85 (1H,d.d.); 6.9 (1H,d.d.); 7.0 (3H,m); 7.7 (1H, d); 7.85 (1H,d). 13C—NMR (CDCl3) in ppm: 16.7 16.8; 62,4; 62,5; 116.5; 116.8; 117.2; 119.2; 119.9; 121.7; 123.8; 126.4; 134.2; 134.4; 139.5; 141.8; 161.6; 161.6.
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C@H:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=2)[CH:14]=[C:13]1C(OCC)=O)[CH3:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)C>[CH3:11][C@H:10]1[N:12]2[C:20]3[CH:19]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][C:15]=3[CH:14]=[C:13]2[C:6](=[O:5])[NH:8][CH2:9]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@H](C)CNC(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc2cc3n(c2c1)[C@H](C)CNC3=O
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of diethyl 1-{(2R)-1-[(tert-butoxycarbonyl)amino]propan-2-yl}-1H-indole-2,6-dicarboxylate (2.7 g, 6.4 mmol) in CH2Cl2 (10 mL) is added TFA (10 mL). The reaction mixture is stirred for 2 h and the solvent is removed under vacuum. To a solution of the residue in ethanol (30 mL) is added K2CO3 (4.5 g, 32.3 mmol) and the reaction mixture is stirred at room temperature for 16 h. The solvent is evaporated and the residue is taken up in water. To the mixture is added a small amount of diethyl ether followed by heptanes (100 mL). The suspension is filtered to afford the title compound (1.3 g, 57% for two steps) as a solid.
Reaction SMILES: [Na].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[N:4]=1.CCCC(C)C.[CH:16]([OH:19])([CH3:18])[CH3:17]>>[Br:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:19][CH:16]([CH3:18])[CH3:17])[N:4]=1
Reactant: CC(C)O
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Solvent: CCCC(C)C
Product: CC(C)Oc1cccc(Br)n1
Temperature: 80 °C

Procedure:
Sodium (0.50 g, 21.7 mmol) was dissolved in isopropanol (50 ml) under an atmosphere of nitrogen with warming at 80° C., then allowed to cool to ambient temperature. 2,6-Dibromopyridine (10.0 g, 41.4 mmol) was added and the solution heated to 90° C. After 5 h the cooled reaction mixture was partitioned between diethyl ether (150 ml) and water (100 ml). Diethyl ether extracts were washed with water and saturated brine then dried over magnesium sulphate, filtered and evaporated in vacuo to give a semi-solid. Addition of isohexane, filtration and concentration in vacuo gave a residue that was purified by chromatography on silica gel eluting with dichloromethane to give 2-bromo-6-isopropoxypyridine (2.1 g) as a colourless liquid: δH (400 MHz, CDCl3) 1.33 (6H, d, J 6), 5.28 (1H, quin, J 6), 6.60 (1H, d, J 8), 7.00 (1H, d, J 7), 7.38 (1H, dd, J 7 and 8); m/z (ES+) 214/216 (M++H).
Reaction SMILES: C(O[C:6]([N:8](C)[NH:9][C:10](=[O:54])[C@H:11]([N:19]([C:21](=[O:53])[C@H:22]([N:34]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[CH3:35])[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH3:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:42]1[C:41]2[CH:40]([CH2:39][O:38][C:36](=[O:37])[N:34]([CH3:35])[C@@H:22]([C:21](=[O:53])[N:19]([CH3:20])[C@@H:11]([C:10]([NH:9][NH:8][CH3:6])=[O:54])[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[CH:45]=[CH:44][CH:43]=1
Reactant: CN(NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a solution of N'-[(2R)-2-(N-((2R)-2-[N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-methylamino]-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionyl]-N-methylhydrazinecarboxylic acid tert-butyl ester (0.27 g, 0.36 mmol) in methylene chloride (2 ml) at 0° C. was added trifluoroacetic acid (2 ml) and the mixture was stirred for 90 min. Then methylene chloride (50 ml) and saturated sodium bicarbonate (5 ml) was added and the mixture was titrated with solid sodium bicarbonate until pH=7. The water layer was separated and extracted with methylene chloride (20 ml) and the combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.18 g (78%) of N-methyl-N-((1R)-1-(N-methyl-N-[(1R)-1-(N'-methylhydrazinocarbonyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid ((9H-fluoren-9-yl)methyl) ester as white amorphous powder.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8]1.CN([CH:21]=[O:22])C.O>C1COCC1>[CH3:6][N:7]1[C:11]([CH:21]=[O:22])=[N:10][C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:8]1
Reactant: Cn1cnc(-c2ccccc2)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2)nc1C=O
Temperature: -40 °C
Yield: 86.4 %

Procedure:
BuLi (10.6 mL, 1.6 M in hexane, 17.0 mmol) was added dropwise to at solution of 1-methyl-3-phenyl-1H-1,2,4-triazole (2.7 g, 17.0 mmol) in THF (85 mL) at −78° C. The mixture was warmed to −40° C. over 15 min and recooled to −78° C. DMF (1.32 mL, 17 mmol) was added dropwise and the mixture was warmed to ambient temperature over 2 h. Water was added to the mixture and it was extracted with EtOAc (3×). The organics were combined, washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (EtOAc, hexanes) yielded 2.75 g of Intermediate 386.1 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.22 (s, 3H) 7.34-7.56 (m, 3H) 8.10 (dd, J=7.58, 1.71 Hz, 2H) 10.03 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH2:14][C:15]([OH:17])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:18]C(N)=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[C:9](=[O:10])[NH:18][C:15](=[O:17])[CH2:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(N)=O
Reactant: CC(C)(C)c1ccc(C(=O)O)c(CC(=O)O)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc2c(c1)CC(=O)NC2=O
Temperature: 25 °C
Yield: 42 %

Procedure:
An amount of 1.5 g (6.35 mmol) of 4-tert-butyl-2-(carboxymethyl)benzoic acid and urea (763 mg, 12.7 mmol) were heated neat at 145-148° C. for 1.5 hours. The mixture is cooled to room temperature and 200 mL of chloroform is added and washed 3× with water, dried over sodium sulfate and evaporated. The crude product is purified by column chromatography 4% methanol methylene chloride to give 580 mg (41% yield) of the product as a brown solid. MS (ESI) m/z 218.2 (M+1).
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:27])[CH:20]=2)[N:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([OH:3])=[O:2].Cl[C:29]1[N:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([OH:33])=[O:32]>>[C:1]([C@@H:4]([NH:13][C:14]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:27])[CH:20]=2)[N:15]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:29]2[C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=[CH:36][N:37]=2)=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(O)c1cccnc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ncccc2C(=O)O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 96, 2-[1-carboxy-2-(4-hydroxy-phenyl)-ethylamino]-6-chloro-quinoline-3-carboxylic acid is reacted with 2-chloronicotinic acid to provide the title compound in a form of diammonia salt after chromatography on silica (aq. ammonia containing eluent).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]O.[C:20]1(=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[NH:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1.O.C(#N)C>[O:30]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[N:21]1[CH2:5][CH:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:2]([F:19])([F:18])[F:1]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(NC(CO)CC(F)(F)F)OCc1ccccc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(CN1C(=O)c2ccccc2C1=O)CC(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.58 g of rac-benzyl (4,4,4-trifluoro-1-hydroxybutan-2-yl)carbamate (Example 145A, 5.70 mmol, 1 equivalent), 0.84 g of 1H-isoindole-1,3(2H)-dione (phthalimide, 5.70 mmol, 1 equivalents) and 2.24 g of triphenylphosphine (8.54 mmol, 1.5 equivalents) were dissolved in 28 ml of THF, and 1.84 g of di-tert-butyl(E)-diazene-1,2-dicarboxylate (DIAD, 8.54 mmol, 1.5 equivalents) were added at RT. The mixture was stirred at RT for 30 min and a water/acetonitrile mixture was then added. Purification by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA) gave 1.92 g (79% of theory) of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[CH:14][C:13]=2[C:17]=1[CH2:18][CH2:19][CH2:20][NH2:21].ClC1C(CCCN)=CC2OC=CC=2C=1.N1C=CC=CC=1>C1COCC1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[CH:14][C:13]=2[C:17]=1[CH2:18][CH2:19][CH2:20][NH:21][C:1](=[O:3])[CH3:2]
Reactant: NCCCc1c(Cl)ccc2occc12
Reactant: CC(=O)OC(C)=O
Agent: NCCCc1cc2occc2cc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)NCCCc1c(Cl)ccc2occc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetic anhydride (1.95 ml) was added dropwise to a solution of 3-(5-chloro-benzofuran-4-yl)-propylamine mixture with 3-(5-chloro-benzofuran-6-yl)-propylamine (2.86 g) and pyridine (2.2 ml) in dry THF (70 ml) at 0° under nitrogen. The mixture was stirred at room temperature for 3 h, then evaporated to dryness in vacuo . The residue was purified by HPLC (CN-PK5-10530 column). Eluting with 5% isopropanol/heptane gave the title compound as a colourless solid (1.37 g) mp 82-83° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)=[O:11].OC1C=C(C(=O)/C=C/C2C=CC=CC=2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:10](=[O:11])[CH2:9]1
Reactant: O=C(/C=C/c1ccccc1F)c1cccc(O)c1
Agent: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Product: O=C1CC(c2ccccc2F)c2ccc(O)cc21
Reaction time: 16 h
Yield: 83 %

Procedure:
The procedure of Step 2 of Example 1 was repeated except for using (E)-3-(2-fluorophenyl)-1-(3-hydroxyphenyl)prop-2-en-1-one obtained in Step 1 as a starting material instead of (E)-1-(3-hydroxyphenyl)-3-phenylprop-2-en-1-one, being stirred for 16 h to obtain the title compound (83%).