Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:22]=[CH:21][N:13]3[C:14](=[O:20])[C:15]([CH2:18][OH:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:25]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:22]=[CH:21][N:13]3[C:14](=[O:20])[C:15]([CH2:18][O:19][CH3:25])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(CO)cnc2cc(C#Cc3cccc(F)c3)ccn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Reaction time: 0.25 h

Procedure:
To a solution of 8-((3-fluorophenyl)ethynyl)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (16 mg) in anhydrous THF (5 mL) was added NaH (16 mg, 60% in oil) in portions. After the reaction mixture was stirred for 15 min, MeI (0.05 mL) was added. The solution was stirred for 30 min. Then the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the desired product (11 mg), which was purified by preparative HPLC. MS (ESI): 309 (MH+); 1H NMR (300 MHz, CD3OD) δ 9.07-9.05 (d, J=6.81 Hz, 1H), 8.42 (s, 1H), 7.83 (s, 1H), 7.51-7.48 (m, 2H), 7.44-7.39 (m, 2H), 7.29-7.27 (m, 1H), 4.53 (s, 2H), 3.54-3.50 (d, J=7.02 Hz, 3H). mGluR5 PAM EC50: +++.
Reaction SMILES: Cl.Cl.[C@H:3]12[CH2:9][C@H:6]([NH:7][CH2:8]1)[CH2:5][N:4]2[CH2:10][C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][C:21]3[S:22][C:23]4[C:24]([N:29]=3)=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][C:14]=2[O:13][CH:12]=1.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:7]2[CH2:8][C@@H:3]3[CH2:9][C@H:6]2[CH2:5][N:4]3[CH2:10][C:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20][C:21]4[S:22][C:23]5[C:24]([N:29]=4)=[N:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:14]=3[O:13][CH:12]=2)=[CH:35][CH:34]=1
Reactant: c1cnc2nc(Oc3ccc4c(CN5C[C@@H]6C[C@H]5CN6)coc4c3)sc2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2coc3cc(Oc4nc5ncccc5s4)ccc23)cc1
Temperature: 25 °C
Yield: 17.3 %

Procedure:
A mixture of (1S,4S)-2-[3-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-benzofuran-6-yloxy]-thiazolo[4,5-b]pyridine dihydrochloride (50 mg, 0.11 mmol), 4-bromomethyl-benzoic acid methyl ester (28 mg, 0.12 mmol), and K2CO3 (38 mg, 0.28 mmol) in CH3CN (0.4 mL) was stirred at rt. Upon reaction completion, the mixture was concentrated, re-dissolved in DMF and purified by reverse phase HPLC to provide the title compound (10 mg, 16%). MS (ESI): mass calculated for C29H26N4O4S, 526.17; m/z found, 527.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.57 (dd, J=4.8, 1.6, 1H), 8.05-7.96 (m, 3H), 7.77 (d, J=8.5, 1H), 7.58 (dd, J=7.8, 4.3, 2H), 7.45 (d, J=8.3, 2H), 7.32-7.28 (m, 1H), 7.21 (dd, J=7.9, 4.8, 1H), 3.91 (s, 3H), 3.90-3.69 (m, 2H), 3.41-3.27 (m, 2H), 2.96-2.90 (m, 1H), 2.85-2.81 (m, 1H), 2.74-2.66 (m, 2H), 1.77 (s, 2H), 1.47 (s, 2H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[CH:20]1([NH:23][C:24](=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[C:27]([CH3:37])[CH:26]=2)[CH2:22][CH2:21]1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH:20]1([NH:23][C:24](=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][N:34]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]6[C:7](=[O:17])[NH:6][C:5]=5[CH:4]=4)[CH2:35][CH2:36]3)=[C:27]([CH3:37])[CH:26]=2)[CH2:22][CH2:21]1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cc(C(=O)NC2CC2)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCCN32)CC1
Temperature: 90 °C
Yield: 24.9 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol), N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (143 mg, 0.430 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143 mmol) were suspended in Propiononitrile (Volume: 1287 μl) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature and purified using HPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from MeCN (20 mL), filtered off, washed with water (2 mL) and dried in vacuum to afford (S)—N-cyclopropyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (50.7 mg, 0.107 mmol, 24.92% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49-0.59 (m, 2H) 0.60-0.71 (m, 2H) 1.33-1.57 (m, 3H) 1.64 (d, J=12.88 Hz, 1H) 1.85 (d, J=12.63 Hz, 1H) 2.04 (d, J=12.88 Hz, 1H) 2.25 (s, 3H) 2.42-2.56 (m, 4H) 2.60 (td, J=12.63, 2.78 Hz, 1H) 2.76-2.93 (m, 5H) 3.38 (s, 2H) 3.84 (dd, J=11.37, 2.78 Hz, 1H) 4.50 (d, J=13.14 Hz, 1H) 6.98 (d, J=2.02 Hz, 1H) 7.00 (d, J=8.34 Hz, 1H) 7.56-7.63 (m, 2H) 7.66 (d, J=2.02 Hz, 1H) 8.22 (d, J=4.29 Hz, 1H) 10.49 (s, 1H); [M+H] calc'd for C27H34N6O2, 475; found, 475.
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([OH:3])[OH:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:44][C:45]1([F:50])[CH2:49][CH2:48][NH:47][CH2:46]1>C(#N)C>[F:44][C:45]1([F:50])[CH2:49][CH2:48][N:47]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([B:1]([OH:2])[OH:3])=[CH:12][CH:11]=2)=[O:10])[CH2:46]1
Reactant: FC1(F)CCNC1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1ccc(B(O)O)cc1)N1CCC(F)(F)C1
Reaction time: 0.5 h
Yield: 0 %

Procedure:
A mixture of 4-boronobenzoic acid (500 mg, 3.01 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (866 mg, 4.52 mmol) and 1-hydroxybenzotriazole (554 mg, 3.62 mmol) in acetonitrile (25 mL) was sonicated until it became a solution. N,N-Diisopropylethylamine (1.579 mL, 9.04 mmol) and 3,3-difluoropyrrolidine (484 mg, 4.52 mmol) were added. After 30 min at room temperature, the mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3×). The combined extracts were washed with brine, water, dried (Na2SO4) and concentrated. Reverse phase HPLC purification gave the expected product (0.250 mg, 33% yield). MS (ES+) m/z: 256 (M+H); LC retention time: 1.87 min (analytical HPLC Method A).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[F:14][C:15]1[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=1>ClCCl.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([NH:21][C:18]2[N:19]=[CH:20][C:15]([F:14])=[CH:16][N:17]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: Nc1ncc(F)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ncc(F)cn1)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.3 %

Procedure:
A suspension of 5-chloro-2,4-difluorobenzenesulfonyl chloride (1.99 g, 8.05 mmol) in dichloromethane (15 mL) was added portion-wise to a solution of 5-fluoro-pyrimidin-2-ylamine (1.00 g, 8.84 mmol) in pyridine (15 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature gradually and stirred for 16 hours. The reaction mixture was diluted with dichloromethane and partitioned with 1 N aqueous hydrogen chloride solution. The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with water, diluted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by automated silica gel column chromatography (100% chloroform to 10% methanol in chloroform gradient elution) to afford the title compound as a light yellow solid (0.32 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].Br[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[N:13]([CH3:15])[CH3:14]>>[CH3:14][N:13]([CH3:15])[C:12]1[CH:11]=[C:10]([CH:7]([C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])[OH:8])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ncsc1C=O
Reactant: CN(C)c1cccc(Br)c1
Product: Cc1ncsc1C(O)c1cccc(N(C)C)c1

Procedure:
The title compound was prepared from 4-methyl-5-thiazolecarbaldehyde and 3-bromo-N,N-dimethylaniline using the method of Example 32. M.p. 135°-138° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[F:45][CH:46]([F:51])[CH:47]1[CH2:50][NH:49][CH2:48]1.CN1CCOCC1>CN(C=O)C>[F:45][CH:46]([F:51])[CH:47]1[CH2:50][N:49]([C:13](=[O:15])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:17])[CH3:18])[CH2:48]1
Reactant: FC(F)C1CNC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](C(=O)N1CC(C(F)F)C1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). 3-(Difluoromethyl)azetidine (8.27 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-60% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (9.8 mg, 50%). 1H NMR (500 MHz, DMSO-d6) δ 0.78 (d, J=6.0 Hz, 3H), 0.94 (d, J=6.0 Hz, 3H), 2.31-2.39 (m, 1H), 2.99-3.15 (m, 1H), 3.77-4.35 (m, 4H), 4.82-5.11 (m, 3H), 6.10-6.41(m, 1H), 7.98 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 12.39 (s, 1H). [M+H] calc'd for C18H19F3N4O2, 381; found, 381.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:41]1=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:37])[C@H:26]([C:33]([OH:35])=O)[CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30].[NH2:53][C@H:54]([C:67]([O:69][CH2:70][CH:71]=[CH2:72])=[O:68])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:58][CH:57]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:25]([C:36]([O:38][CH2:39][CH:40]1[C:52]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42]2[C:41]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:37])[C@H:26]([C:33]([NH:53][C@H:54]([C:67]([O:69][CH2:70][CH:71]=[CH2:72])=[O:68])[CH2:55][C:56]1[CH:57]=[CH:58][C:59]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:60][CH:61]=1)=[O:35])[CH2:27][O:28][C:29]([CH3:30])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C=CCOC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 94.2 %

Procedure:
According to the general procedure for HBTU promoted coupling, 18.26 g Fmoc-Ser(tBu), 16.95 g HBTU, 11.95 g H-Tyr(tBu)-OAllyl and 26.10 ml DIPEA were reacted in a CYTOS® Lab System in anhydrous DMF at 45° C. and at a total flow rate of 32 ml/min at residence time of 1 min to yield 26.09 g crude material (yield based on HPLC: 96%) which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Cl)cc2C(C)(C)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(Cl)cc21
Yield: 66.9 %

Procedure:
1,1-Dimethylethyl N-((7-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (1.21 g, 3 mmol) was stirred in TFA (5 mL, 67 mmol) at room temperature for 20 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (650 mg). MS (m/e)=324.1 (M+H)+. Calculated for C15H14ClNO5 323.06.
Reaction SMILES: [Bi](Cl)(Cl)Cl.[I-].[Na+].[C:7](Cl)(=[O:9])[CH3:8].[CH2:11]([O:13][C:14]([C:16]1[C:17]2[C:32]([O:33][Si](C)(C)C)=[CH:31][CH2:30][CH2:29][CH2:28][C:18]=2[N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)=[O:15])[CH3:12]>C(Cl)Cl.CCOCC>[CH2:11]([O:13][C:14]([C:16]1[C:17]2[C:32](=[O:33])[CH:31]([C:7](=[O:9])[CH3:8])[CH2:30][CH2:29][CH2:28][C:18]=2[N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:20]=1)=[O:15])[CH3:12]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCCC2
Agent: Cl[Bi](Cl)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(C(C)=O)CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86 %

Procedure:
Bismuth (III) chloride (0.1 mmol) and sodium iodide (0.3 mmol) are transferred to a dried flask under nitrogen and 5 mL of a mixture of CH2Cl2/ether (9/1) is added by a syringe. This is followed by the addition of acetyl chloride (2.2 mmol) and the suspension is stirred for 5 min at RT. 4-trimethylsilanyloxy-7,8-dihydro-6H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2 mmol) in 5 mL of the same solvent mixture is added. After 2 hours at RT, the mixture is quenched with 20 mL saturated NaHCO3 solution and extracted several times with CH2Cl2. The organic layers are combined, dried over Na2SO4 and evaporated in vacuo yielding 5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester as an oil (86%). LRMS 363.4 found (M+1) 364.2 Step 3: In a sealed tube are 5-acetyl-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.1 mmol) and formamidine acetate (5.5 mmol) and 10 mL EtOH. The mixture is heated at 120° C. for 48 hours. The solvent is evaporated in vacuo and the residue is taken up in CH2Cl2 and washed two times with NaHCO3 (aq). The organic layer is dried over Na2SO4 and evaporated in vacuo and the residue chromatographed using 10% MeOH in CH2Cl2 as mobile phase to yield 7-Methyl-3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethyl ester (36%). LRMS 271.1 found (M+1) 272
Reaction SMILES: C(O)(=O)C.Cl.[O:6]1[CH2:10][CH2:9][CH:8]([NH:11][NH2:12])[CH2:7]1.[CH:13](=O)[C:14]([CH3:16])=[O:15].[Na+].[Cl-]>O>[O:6]1[CH2:10][CH2:9][CH:8]([NH:11][N:12]=[CH:13][C:14](=[O:15])[CH3:16])[CH2:7]1
Reactant: NNC1CCOC1
Reactant: CC(=O)C=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C=NNC1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
Acetic acid (1.7 mL) was slowly added to a solution of tetrahydrofuran-3-ylhydrazine hydrochloride (2.50 g, 18.0 mmol) (prepared as described by Bacon, E. R.; Singh, B.; and Lesher, G. Y. in U.S. Pat. No. 5,294,612) in water (30 mL). This mixture was then added dropwise to a solution of pyruvaldehyde (2.59 g, 2.34 mL, 14.4 mmol) in water (240 mL). The mixture was stirred overnight at room temperature. The mixture was poured into a seperatory funnel, NaCl was added and dissolved in the aqueous phase and then extracted with CH2Cl2 (6-times). The combined organic extracts were dried over Na2SO4, filtered and concentrated to provide crude material, which was purified by preadsorbing the oil on SiO2 followed by chromatography (Isco, 80 g RediSep column) eluting with a 0-80% EtOAc/heptane gradient over 80 minutes. Analysis of fractions resulted in isolation of 2-oxopropanal tetrahydrofuran-3-ylhydrazone (1.19 g, 53%).
Reaction SMILES: O1C2C=CC=CC=2C[C:3](=[O:11])N1.[C:12]([C:16]1[CH:44]=[CH:43][C:19]([C:20]([NH:22][C:23]2[CH:38]=[C:37](C(OC)=O)[CH:36]=[CH:35][C:24]=2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=2)=[O:26])=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].Cl.C1C[O:49][CH2:48]C1>>[C:12]([C:16]1[CH:44]=[CH:43][C:19]([C:20]([NH:22][C:23]2[CH:38]=[CH:37][C:36]([C:48]([O:11][CH3:3])=[O:49])=[CH:35][C:24]=2[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=2)=[O:26])=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1Cc2ccccc2ON1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: C1CCOC1
Agent: Cl
Product: COC(=O)c1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
Into 25 mL THF was dissolved 0.174 g (0.5 mmol) of the above benzoxazinone intermediate. The solution was cooled in an ice bath and placed under nitrogen atmosphere. To the mixture was added 1.5 mL (0.6 mmol) of a 0.4 M solution of the magnesium salt of 2-amino-5-chloropyridine (See Prep. D, Example 278). After 30 min, an additional 1.5 mL (0.6 mmol) of the magnesium salt was added. Stirring was continued for 15 min, and the reaction mixture was quinched with 100 mL cold dilute HCl. The mixture was extracted with 100 mL EtOAc, and the organic layer was washed with 100 mL cold dilute HCl, dried (MgSO4), and concentrated under vacuum. The crude product was chromatographed over silica (0 to 30% EtOAc in hexane gradient), giving 91 mg (39%) of title compound as a crystalline solid.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7](/[CH:12]=[CH:13]/[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:29]>>[ClH:29].[O:1]=[C:2]1[NH:11][C:10]2[N:9]=[CH:8][C:7](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To tert-butyl (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate (7.0 g, 25.5 mmole) was added 1:1 TFA/CH2Cl2 (100 mL). The reaction was stirred for 30 min, then was concentrated under vacuum. The residue was suspended in 4 N HCl/dioxane (100 mL), triturated, and concentrated to dryness. The resulting solid was triturated with Et2O, collected, and dried under vacuum to give the title compound (6.55 g, 100%) as a off-white solid: 1H NMR (400 MHz, d6-DMSO) δ 10.72 (s, 1 H), 8.35 (d, J=2.0 Hz, 1 H), 8.04 (s, 1 H), 7.54 (d, J=16.0 Hz, 1 H), 6.51 (d, J=16.0 Hz, 1 H), 2.91 (t, 2 H), 2.53 (t, 2 H); MS (ES) m/e 219.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][NH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(NCc2ccc(Cl)cc2Cl)c1
Yield: 42.8 %

Procedure:
Dimethyl 2-aminoterephthalate (10.45 g), 2,4-dichlorobenzyl chloride (11.74 g), potassium iodide (8.33 g) and potassium carbonate (13.82 g) in a mixed solvent of toluene (50 ml) and water (30 ml) were heated under reflux for 20 hr. After cooling, toluene (50 ml) was added and the precipitated yellow crystals were collected by filtration. The crystals were washed with water and toluene and dried to give the objective compound (7.87 g). The mother liquor was concentrated and crystallized from ethyl acetate to give the second crystals (4.43 g).
Reaction SMILES: [CH3:1][C:2](O)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12](#[N:14])[CH3:13].S(=O)(=O)(O)[OH:16].[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]([NH:14][C:12](=[O:16])[CH3:13])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC#N
Reactant: CC(C)(O)Cc1ccccc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)NC(C)(C)Cc1ccccc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a mixture of 2-methyl-1-phenyl-2-propanol (1.5 g, 10 mmol) and acetonitrile (3 mL) in acetic acid (15 mL) was added concentrated sulfuric acid (3 mL) dropwise at room temperature. The mixture was stirred at 65° C. for 3 hours and then poured into ice-water (ca. 200 mL). The aqueous solution was basified with saturated aqueous sodium hydroxide until pH>11. The suspension was stirred for further 0.5 hour, and then the precipitated solid was filtered and washed with water. The white solid was air-dried to give N-(2-methyl-1-phenylpropan-2-yl)acetamide (1.5 g, 78% yield), which was used for the next step without further purification.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[NH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].O[N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=N1.CN(C)CCCCN=C=NCC.CN1CCOCC1>ClCCl.O>[C:25]1([C:23]2[N:34]=[C:35]([CH:40]3[CH2:39][CH2:38][CH2:37][CH2:36][NH:32]3)[NH:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:4]([O:3][C:1]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=[O:19])[NH:21][CH2:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: NCC(=O)c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)C1CCCCN1C(=O)OCc1ccccc1)c1ccccc1
Product: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Temperature: 0 °C

Procedure:
(S)-1-(Carbobenzyloxy)-2-piperidinecarboxylic acid (15.8 g, 60 mmol), 2-amino-1phenyl-ethanone hydrochloride (10.30 g, 60 mmol), and HOBT (1-hydroxybenzo-triazole) (16.20 g, 120 mmol) were mixed in dichloromethane (400 mL). The stirring mixture was cooled to 0° C. and then (4-dimethylamino-butyl)-ethyl-carbodiimide (14.90 g, 78 mmol) and NMM (N-methyl-morpholine) (7.27 g, 72 mmol) were added. The reaction mixture was then warmed to room temperature. After 16 hours the reaction mixture was treated with water, and the resulting solid was filtered. The organic phase from the filtrate was separated and washed consecutively with saturated NaHCO3, 2N citric acid, and saturated NaHCO3 once again, then dried over MgSO4, filtered, and concentrated to yield the title product 2-(2-oxo-2-phenyl-ethylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester as a yellow oil, which was used without further purification.
Reaction SMILES: C([NH:9][C:10]([NH:12][C@H:13]1[CH2:18][C@H:17]2[CH2:19][C@@H:14]1[CH2:15][C:16]2([F:21])[F:20])=[S:11])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>CO.O>[F:21][C:16]1([F:20])[CH2:15][C@H:14]2[CH2:19][C@@H:17]1[CH2:18][C@@H:13]2[NH:12][C:10]([NH2:9])=[S:11]
Reactant: O=C(NC(=S)N[C@H]1C[C@H]2C[C@@H]1CC2(F)F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)N[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-benzoyl-3-((1R,2S,4R)-5,5-difluorobicyclo-[2.2.1]heptan-2-yl)thiourea (˜1.80 mmol) and potassium carbonate (1.49 g, 10.8 mmol) in methanol (5.0 mL), water (2.5 mL), and tetrahydrofuran (2.5 mL) was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and water. The organic portion was washed with brine, conc. in vacuo, and purified by flash column chromatography (0 to 65% of ethyl acetate in hexanes) to give the title compound as a white solid. MS m/z: 207.0 (M+H)+.