Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][C:5]([CH2:15][NH2:16])([C:8]2[CH:9]=[N:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:16][CH2:15][C:5]1([C:8]2[CH:9]=[N:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3][C:2]([F:1])([F:17])[CH2:7][CH2:6]1)=[O:22]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1Cl
Yield: 38.2 %

Procedure:
A solution of C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine (38 mg, 0.157 mmol), 2,3-dichlorobenzoic acid (30 mg, 0.157 mmol), HOBt (25 mg, 0.185 mmol), EDCI.HCl (36 mg, 0.185 mmol) and DIPEA (48 mg, 0.345 mmol) in DMF (2 mL) was stirred at room temperature overnight. Water was added to the solution followed by extraction with EtOAc (3×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by Prep. HPLC to give the title compound (25 mg, yield: 38%). 1H NMR (CDCl3 300 MHz): δ ppm 8.18 (d, J=2.8 Hz, 1H), 7.89-7.80 (m, 1H), 7.50 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.33 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.28-7.18 (m, 1H), 6.98 (dd, J=8.8 Hz, 3.2 Hz, 1H), 5.85 (t, J=6.8 Hz, 1H), 3.64 (d, J=6.8 Hz, 2H), 2.36-2.00 (m, 6H), 1.87-1.65 (m, 2H). LCMS (MH+): m/z=417.1, tR (minutes, Method C)=1.11
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[N:19]=[CH:20][N:21]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:22]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:75][N:76]([CH3:87])[C:77](=[O:86])[O:78][C:79]1[CH:84]=[CH:83][CH:82]=[C:81]([NH2:85])[CH:80]=1>C(OC(C)C)(=O)C.CCOC(C)=O>[CH3:75][N:76]([CH3:87])[C:77]([O:78][C:79]1[CH:80]=[C:81]([NH:85][C:14]([C:11]2([CH2:17][C:18]3[N:19]=[CH:20][N:21]([C:23]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]2)=[O:15])[CH:82]=[CH:83][CH:84]=1)=[O:86]
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)C
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-((1-trityl-1H-imidazol-4-yl)methyl)piperidine-4-carboxylic acid from step B (270 mg, 0.6 mmol) in isopropyl acetate (5 mL) were added HATU (273 mg, 0.73 mmol) and N,N-diisopropylethylamine (205 μL, 1.2 mmol). The mixture was stirred for 5 min, and 3-aminophenyl dimethylcarbamate (108 mg, 0.6 mmol) was added. The resulting mixture was heated at 90° C. for 2 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (10-70% EtOAc:Hexanes) to afford the title compound (185 mg, 43%). MS (ES+) [M+H]+=714.2.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([O:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:21][C@@:20]3([CH3:30])[C@@H:12]([CH2:13][C@H:14]([CH3:32])[C@:15]3([OH:31])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:34])[CH:4]=[CH:5][C:6](=[O:33])[CH:7]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C1COCC1.CN(C1C=CN=CC=1)C>[F:1][C@:2]12[C@@H:22]([O:23][C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])[CH2:21][C@@:20]3([CH3:30])[C@@H:12]([CH2:13][C@H:14]([CH3:32])[C@:15]3([OH:31])[C:16](=[O:19])[CH2:17][O:18][C:35](=[O:37])[CH3:36])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:34])[CH:4]=[CH:5][C:6](=[O:33])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(=O)C(F)(F)F)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(=O)C(F)(F)F)C[C@@]21C
Temperature: 35 °C
Reaction time: 15 h
Yield: 92.8 %

Procedure:
To a solution of 1-3 (122.5 g) in THF (1 L) at RT was added DMAP (6.0 g, 49 mmol) and acetic anhydride (50.2 g, 491 mmol) and the mixture allowed to stir for 15 hours. The solvent was evaporated, and the residue diluted with 1 L of water. The precipitate was isolated by filtration and dried for 15 hrs in a warm (35° C.) vacuum oven to produce 123.4 g (94.7%) 1-4 as an off-white solid.
Reaction SMILES: COC(=O)[CH2:4][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].NC[CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44]>CCCCCCC.C(OCC)(=O)C>[CH3:46][O:45][C:43](=[O:44])[CH2:42][CH2:41][CH2:4][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]
Reactant: COC(=O)CCCN
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CCCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

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 methyl 4-aminobutyrate (commercially available, CAS RN 3251-07-8) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light brown foam (42%). MS (ESI): m/z=583.150 [M+H]+.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.[NH:28]1CCC[C@@H]1CO>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:28]
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: OC[C@H]1CCCN1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 168.1 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.350 g, 0.900 mmol, 1 eq, Example 56, Step D) was suspended in dioxane (20 mL) under Ar. (R)-2-Pyrrolidine methanol (0.272 g, 2.700 mmol, 3 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.200 g (57%) of the indole-amine was obtained as a white solid. This was converted to the .HCl salt. LC/MS (ESI+) 393 (M+1); Anal. Calcd for C24H28N2O3.1HCl.1.25H2O: C, 63.85; H, 7.03; N, 6.20; Found: C, 63.68; H, 6.81; N, 6.20.
Reaction SMILES: [CH:1]1([C@H:4]([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[C:12]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=3[CH3:26])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[CH:1]1([C@H:4]([NH:7][C:8]2[C:13]([NH2:14])=[C:12]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([O:24][CH3:25])=[CH:19][C:18]=3[CH3:26])[CH:11]=[CH:10][N:9]=2)[CH2:5][CH3:6])[CH2:3][CH2:2]1
Reactant: CC[C@@H](Nc1nccc(-c2cc(F)c(OC)cc2C)c1[N+](=O)[O-])C1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CC[C@@H](Nc1nccc(-c2cc(F)c(OC)cc2C)c1N)C1CC1
Yield: 96.9 %

Procedure:
(R)-(1-Cyclopropyl-propyl)-[4-(5-fluoro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-amine (0.17 g, 0.47 mmol) and Na2S2O4 (1.24 g, 7.10 mmol) were treated as in Part E of Example 9 to give 0.15 g (98%) crude (R)-N2-(1-Cyclopropyl-propyl)-4-(5-fluoro-4-methoxy-2-methyl-phenyl)-pyridine-2,3-diamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:13]=[C:14]([CH:18]([CH:25]2[CH2:27][CH2:26]2)[NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]([CH:18]([CH:25]2[CH2:27][CH2:26]2)[NH:19][S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])[CH:15]=[N:16][CH:17]=1
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccccc2Cl)c1)C1CC1
Temperature: 100 °C
Yield: 21.4 %

Procedure:
A mixture of 2-chlorophenylboronic acid (24 mg, 0.16 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (50 mg, 0.16 mmol), PdCl2(PPh3)2 (9 mg, 0.01 mmol) and Na2CO3 (2 M in water, 0.16 mL, 0.32 mmol) in DMF (1.5 mL) was heated at 100° C. for 2 h. After concentration, the residue was dissolved in DCM and filtered. The filtrates were concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-40%) to give the title compound (12 mg, 23%); ESI-MS m/z: 351 [M+1]+, 1H-NMR (MeOD, 400 MHz) δ 8.65 (1H, d, J=2.0 Hz), 8.55 (1H, d, J=2.0 Hz), 8.04 (1H, t, J=2.0 Hz), 7.61-7.58 (1H, m), 7.48-7.44 (3H, m), 4.29 (1H, d, J=8.8 Hz), 3.02-2.89 (2H, m), 1.34-1.28 (1H, m), 1.28 (1H, t, J=7.2 Hz), 0.80-0.75 (1H, m), 0.67-0.60 (2H, m), 0.51-0.47 (1H, m)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C1C(=O)N([Br:20])C(=O)C1.Cl.C(OCC)(=O)C>CC(C)=O>[Br:20][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:12]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Oc1ccc2cc(Br)ccc2c1Br

Procedure:
6-Bromo-2-naphthol (500 mg, 2.242 mmol, 1 eq) and NBS (558.7 mg, 3.319 mmol, 1.4 eq) are stirred at RT in 4.4 ml of acetone and 22 μl of 1 N HCl for 15 min. Ethyl acetate is added, and this organic phase is washed three times with 1 N HCl. After drying over magnesium sulfate, filtering and concentrating in vacuum on a rotary evaporator, the desired product is obtained in quantitative yield (677 mg).
Reaction SMILES: C(OC(=O)C([N:12]1[CH2:19][CH:18]2[CH2:20][CH:14]([C:15]3[N:16]([C:21](=[O:31])[C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=3)[CH2:17]2)[CH2:13]1)=CC(OCC)=O)C.FC(F)(F)C(O)=O>C(#N)C>[OH:30][C:22]1[C:21](=[O:31])[N:16]2[CH2:17][CH:18]3[CH2:20][CH:14]([C:15]2=[N:24][C:23]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:13][NH:12][CH2:19]3
Reactant: CCOC(=O)C=C(C(=O)OCC)N1CC2CC(C1)c1nc(C(=O)OCC)c(O)c(=O)n1C2
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CNCC2C1
Temperature: 23 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To diethyl-2-(2-(ethoxycarbonyl)-3-hydroxy-4-oxo-7,8,10,11-tetrahydro-4H-7,11-methanopyrimido[1,2-a][1,5]diazocin-9(6H)-yl)-2-butenedioate (0.300 g, 0.673 mmol) in acetonitrile (15 mL) was added trifluoroacetic acid (1 mL) at 23° C. The reaction mixture was stirred at 23° C. for 6 hours. CH3CN and trifluoroacetic acid were then removed in vacuo and the crude material was redissolved in toluene and dried again (2×30 mL) to afford 234 mg (90% yield) of the title trifluoroacetic salt. LCMS (+ESI, M+H+) m/z: 280.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:25]3[CH2:24][CH2:23][N:22]([C:26]4[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21][CH2:20][C:19]=3[N:18]=[C:17]([CH:36]([CH3:38])[CH3:37])[N:16]=2)=[CH:10][CH:9]=1)([CH3:7])[C:3](OC)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:7][C:2]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:25]3[CH2:24][CH2:23][N:22]([C:26]4[C:31]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21][CH2:20][C:19]=3[N:18]=[C:17]([CH:36]([CH3:38])[CH3:37])[N:16]=2)=[CH:10][CH:9]=1)([CH3:1])[CH2:3][OH:4]
Reactant: COC(=O)C(C)(C)c1ccc(Nc2nc(C(C)C)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(Nc3ccc(C(C)(C)CO)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a solution of methyl 2-methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate (Example 174, 73 mg, 0.14 mmol) in THF was added LiAlH4 (14.2 mg, 0.374 mmol). After stirring at rt for 4 h, the reaction mixture was quenched with satd. aq. Na2SO4. The reaction mixture was then filtered through a plug of diatomaceous earth and concentrated. The crude residue was purified (FCC) to give the title compound (45.4 mg, 66%). MS (ESI): mass calcd. for C27H32F3N5O, 499.26; m/z found, 500.3 [M+H]+. 1H NMR (CDCl3): 8.41-8.39 (m, 1H), 7.89 (dd, J=7.8, 1.8 Hz, 1H), 7.70-7.66 (m, 2H), 7.40-7.36 (m, 2H), 6.98-6.94 (m, 1H), 6.51 (s, 1H), 3.70-3.60 (m, 6H), 3.26-3.20 (m, 2H), 3.08-3.00 (m, 1H), 2.98-2.94 (m, 2H), 1.37 (s, 6H), 1.34 (d, 6.9 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1>[Ni].CO>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=c1ccc2ccc(C=CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Agent: [Ni]
Solvent: CO
Product: O=c1ccc2ccc(CCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Yield: 67.9 %

Procedure:
7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-pent-1-enyl}-1H-[1,8]naphthyridin-2-one (160 mg, 0.361 mmol) was hydrogenated using Raney Nickel (0.2 g) in MeOH for 42 h. The reaction was filtered and concentrated. Purification by liquid chromatography (5% MeOH/CH2Cl2 with 1% NH4OH) gave the title compound as a white foam (109 mg, 0.245 mmol, 68%), which was further purified by HPLC to remove a small amount of over-reduced side-product. MS: APCI: M−1: 443.1 (Exact Mass: 444.15).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:36][C:37]1[C:38](=[O:55])[C:39]([C:49]2[N:53]([CH3:54])[N:52]=[CH:51][CH:50]=2)=[N:40][N:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:42]=1.[CH3:56][N:57]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:59]=[C:58]1[CH2:66][CH2:67][CH2:68]O>C1(C)C=CC=CC=1>[CH3:56][N:57]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:59]=[C:58]1[CH2:66][CH2:67][CH2:68][O:36][C:37]1[C:38](=[O:55])[C:39]([C:49]2[N:53]([CH3:54])[N:52]=[CH:51][CH:50]=2)=[N:40][N:41]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:42]=1
Reactant: Cn1nccc1-c1nn(-c2ccccc2)cc(O)c1=O
Reactant: Cn1c(CCCO)nc2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1nccc1-c1nn(-c2ccccc2)cc(OCCCc2nc3ccccc3n2C)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
Toluene (20 mL) was added to di-tert-butyl diazene-1,2-dicarboxylate (345 mg), and triphenylphosphine (459 mg) and the mixture was stirred at room temperature for 10 min. Then, 5-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)-1-phenylpyridazin-4(1H)-one (268 mg), and further, 3-(1-methyl-1H-benzimidazol-2-yl)propan-1-ol (285 mg) were added, and the mixture was stirred at room temperature for 64 hr. The crystals precipitated from the reaction mixture were collected by filtration, washed successively with toluene, methanol, and diisopropyl ether, and dried to give the title compound (217 mg).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4](O)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][OH:5]
Reactant: NC(CC(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(CCO)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a suspension of 3-amino-3-phenylpropanoic acid (2.0 g, 12.1 mmol) in dry THF (45 mL) cooled to 0° C. under N2 was added portionwise over 20 minutes solid LiAlH4 (920 mg, 24.2 mmol). Stirring was continued at room temperature for 24 h. after which time solid Na2SO4.10H2O was added with stirring until only a heavy white precipitate was present. The organic layer was diluted with ether and filtered through Celite® and the concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and extracted with 1N HCl (3×40 mL). The aqueous layers were combined and basified to pH ˜12 with 5M NaOH. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic phases dried (Na2SO4) and concentrated in vacuo to separate the product which was used without further purification (0.9 g, 49%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=1)[C:8](O)=[O:9])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=1)[C:8]([Cl:20])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(OC(C)C)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)Oc1cc(OC(C)C)cc(C(=O)Cl)c1
Temperature: 25 °C

Procedure:
Diisopropoxybenzoic acid (compound F, 10 g, 41 mmol) was dissolved in benzene (100 mL) in a 500 mL round bottom flask. Thionyl chloride (12.2 mL, 168 mmol) was added and the reaction heated at reflux for 1 hour. The mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was redissolved in dichloromethane and concentrated again to give 3,5-diisopropoxybenzoyl chloride. In a separate 200 mL flask, N,O-dimethylhydroxylamine-HCl (4.0 g, 42 mmol) was suspended in 80 mL dichloromethane at 0° C. Triethylamine (12.4 mL, 88 mmol) was added slowly, followed by crude 3,5-diisopropoxybenzoyl chloride. The reaction flask was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with water and extracted with three portions of dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the resulting brown oil by column chromatography (30% acetone/hexane) gave the Weinreb amide (compound G) as a yellow oil in 60% yield from 3,5-dihydroxybenzoic acid: Rf 0.33 (30:70 acetone/hexane); IR (cm−1): 2977, 1647, 1590, 1441, 1374, 1184, 1155, 1113, 1037, 964; 1H NMR (250 MHz, C6D6): δ 1.06 (dd, J=2.5, 5.9 Hz, 12H), 3.00 (s, 3H), 3.05 (s, 3H), 4.19 (qn, J=6.2 Hz, 2H), 6.69 (t, J=2.5 Hz, 1H), 7.10 (d, J=2.5 Hz, 2H); 13C NMR (63 MHz, C6D6): 21.9 (4C), 33.4, 60.4, 69.8 (2C), 106.6, 108.1 (2C), 137.0, 159.3 (2C), 169.8.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][C:19]=4[O:18][CH2:17]3)[O:26][CH2:25][CH2:24][CH2:23]5)[C:9]2=[O:29])C=CC=CC=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:19]=3[O:18][CH2:17]2)[O:26][CH2:25][CH2:24][CH2:23]4)[C:9]1=[O:29]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCCO3
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCCO3
Yield: 64.6 %

Procedure:
A solution of 1′-(diphenylmethyl)-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one (0.61 g, 1.32 mmol) and triethylsilane (0.67 mL, 4.2 mmol) in trifluoroacetic acid (4.5 mL) was stirred at reflux under nitrogen for 2.5 h. Once cooled, the reaction was diluted with water (40 mL) and extracted with ethyl acetate (3×25 mL). The combined organic solution was washed with brine (50 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved into 10% diethyl ether in dichloromethane (5 mL) and, after standing at ambient temperature, yielded a colorless precipitate. This material was collected by filtration and washed with hexanes. Drying in air provided 6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one (0.25 g, 63%) as a colorless solid. An additional portion (0.14 g, 37%) of product was also recovered by concentrating the filtrate and triturating the residual solid with hexanes: mp 216-220° C. (hexanes); 1H NMR (300 MHz, DMSO-d6) δ10.58 (s, 1H), 7.23 (ddd, J=7.8, 7.5, 0.9 Hz, 1H), 7.08 (d, J=7.2 Hz, 1H), 6.98-6.91 (m, 2H), 6.36 (s, 1H), 6.31 (s, 1H), 4.74 (d, J=9.0 Hz, 1H), 4.61 (d, J=9.0 Hz, 1H), 4.05 (dd, J=5.1, 4.8 Hz, 2H), 2.61-2.45 (m, 2H), 1.84-1.77 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ178.6, 159.5, 155.4, 141.8, 132.9, 128.6, 123.8, 123.6, 122.3, 121.4, 114.8, 109.7, 97.9, 79.5, 66.0, 57.3, 23.9, 21.7; MS (ES+) m/z 294.1 (M+1).
Reaction SMILES: O[C:2]1([CH3:11])[CH:6]([CH2:7][CH:8]=[CH2:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[Cl-].[Na+].[OH2:14]>>[CH2:7]([C:6]1[C:5](=[O:10])[CH2:4][CH:3]([OH:14])[C:2]=1[CH3:11])[CH:8]=[CH2:9]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: O
Agent: [Cl-]
Agent: [Na+]
Product: C=CCC1=C(C)C(O)CC1=O

Procedure:
In an autoclave, 4-hydroxy-4-methyl-5-allyl-2-cyclopentenone (20 g) and water (400 ml) were charged, and the resultant mixture was stirred at 180° C. for 6 hours in a nitrogen atmosphere. After cooling, sodium chloride (50 g) was added to the reaction mixture, and the resulting mixture was extracted with methyl isobutyl ketone. The extract was concentrated under reduced pressure to give 2-allyl-3-methyl-4-hydroxy-2-cyclopentenone (19 g). Yield, 95%. M.P. 130°-132° C./1.2 mmHg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:15])=[N:12][O:13][N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl.O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([NH2:15])=[N:12][O:13][N:14]=2)=[CH:8][CH:9]=1
Reactant: Nc1nonc1-c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nonc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
4-(4-Nitrophenyl)-1,2,5-oxadiazol-3-amine (0.500 g, 2.42 mmol), tin dichloride (1.61 g, 8.49 mmol), and water (0.306 mL, 17.0 mmol) were combined in ethyl acetate (20 mL) in a round bottom flask, and the mixture was stirred at room temperature overnight. The solvent was removed and methylene chloride was added, and the mixture was washed three times with aqueous NaOH. The organic phase was dried over MgSO4, filtered, and concentrated to afford the title compound as a yellow solid (400 mg, 94%).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]([Cl:23])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[ClH:23].[C:15]([N:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: O=C(N=c1ccn(-c2ccccc2)nc1)c1ccccc1
Yield: 37 %

Procedure:
6.0 (28.9 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 50 ml of benzoyl chloride were kept at 120° C. for 10 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was washed with acetone and recrystallized from isopropanol. 3.3 g (37% of theory) of 4-benzoylimino-1,4-dihydro-1-phenylpyridazine hydrochloride were isolated as pale beige crystals of melting point 225°-226° C. (decomposition).