Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)=[CH:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)=[CH:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of methyl 2-chloro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoate (Step 3, 1.10 g, 2.56 mmol) in tetrahydrofuran (7.0 mL) and methanol (5.0 mL) was added a solution of lithium hydroxide (0.245 g, 10.2 mmol) in water (3.0 mL). The mixture was stirred at room temperature for 2 h. and concentrated under reduced pressure to a volume of about 3 mL. The residue was diluted with water (3 mL), and adjusted with 1N HCl to pH of about 4-5. The precipitate was filtered out, washed several times with water and dried in air overnight. The precipitate was then triturated sequentially with ether and dichloromethane (DCM)-Hexane (1:1). The desired product (638 mg, 60%) was obtained. LCMS (M+H)+: m/z=415.9/417.9.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=CC=1Cl.[Cl-].[Al+3].[Cl-].[Cl-].[Br:19][C:20]1[CH:30]=[C:24]2[C:25]([O:27][C:28](=[O:29])[C:23]2=[CH:22][CH:21]=1)=[O:26]>O.C(OCC)(=O)C>[C:25]([C:24]1[CH:30]=[C:20]([Br:19])[CH:21]=[CH:22][C:23]=1[C:28]([OH:29])=[O:27])(=[O:26])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
A mixture of benzene (2.94 ml), o-dichlorobenzene (20 ml) and aluminum chloride (5.87 g) was cooled to 5° C. and 5-bromophthalic anhydride (5.0 g) was added by small portions while maintaining the temperature of the mixture below 10° C. The mixture was stirred at around 25° C. for 1 h and then at 80° C. for 1 h. The reaction mixture was cooled to around 5° C. and ethyl acetate (40 ml) was added dropwise. Water (20 ml) was added dropwise below 40° C. The organic layer was separated and 4N hydrochloric acid (20 ml) was added. The mixture was stirred until the precipitated solid was dissolved. The organic layer was separated and washed with water (20 ml). The solvent was evaporated and toluene (30 ml) and ethyl acetate (3 ml) were added to the residue, which was followed by heating to 80° C. The obtained solution was cooled to 25° C. over 30 min and the precipitated crystals were collected by filtration. The crystals were dissolved in a mixture of toluene (30 ml) and ethyl acetate (1.5 ml) by heating and the obtained solution was cooled to 25° C. and then to 5° C. The precipitated crystals were collected by filtration and washed with toluene, to give the title compound (2.81 g, yield 41.8%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[O:6][CH:7]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C(OCC)(=O)C>C(OCC)(=O)C.C(O)C>[CH:8]([C:5]1[O:6][CH:7]=[C:3]([CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[N:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1nc(CCl)co1
Reactant: CCOP(OCC)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1coc(C(C)C)n1)OCC
Temperature: 160 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
A mixture of 4-chloromethyl-2-isopropyl-1,3-oxazole (1.12 g) and triethyl phosphite (2.57 g) was stirred at 160° C. for 16 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v), ethyl acetate, then ethyl acetate-ethanol (10:1, v/v) to give diethyl [(2-isopropyl-1,3-oxazol-4-yl)methyl]phosphonate as a colorless oil (1.67 g, yield 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl.O>C(O)C>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][NH2:5]
Reactant: Cc1cccc(C)c1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(C)c1CN
Reaction time: 3.5 h

Procedure:
To a stirred solution of N-(2,6-Dimethylbenzyl)phthalimide (Step B, 7.77 g, 29.3 mmol) in ethanol (80 ml) was added hydrazine monohydrate (2.16 ml, 44.52 mmol) and the reaction mixture was refluxed for 3.5 hours. To this reaction mixture was added c HCl to bring pH to 1 and refluxing continued for another 3.5 hours, water was added and reaction mixture was filtered, the filtrate was concentrated and pH was adjusted to 10 with 2 N NaOH. The residue was taken in methylene chloride and washed with brine, dried over Na2SO4, filtered and concentrated to give an oil which was used without further purification.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[O:16][CH3:17].C([Li])CCC.[B:23](OC)([O:26]C)[O:24]C.[Cl-].[NH4+]>C(OCC)(=O)C.C1COCC1>[CH:12]1([O:11][CH2:10][C:5]2[CH:6]=[C:7]([O:8][CH3:9])[C:2]([B:23]([OH:26])[OH:24])=[C:3]([O:16][CH3:17])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: COB(OC)OC
Reactant: COc1cc(COC2CCC2)cc(OC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(COC2CCC2)cc(OC)c1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a mixture of 2-bromo-5-[(cyclobutyloxy)methyl]-1,3-dimethoxybenzene (2.39 g, 7.94 mmol) and THF (20 mL) was added n-butyllithium (2.73M n-hexane solution: 3.49 mL, 9.53 mmol) at −78° C. (internal temperature), and the mixture was stirred for one hour. To the mixture was added trimethyl borate (1.07 mL, 9.53 mmol) and the mixture was gradually warmed to room temperature while stirring. Thereafter, a saturated aqueous solution of ammonium chloride was added to the mixture while cooling on ice, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. To the residue, heptane (30 mL) was added, the precipitated solid was filtered and then dried under reduced pressure to obtain the title compound (905 mg, 3.40 mmol).
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl.O>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:17][CH:16]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: O=C(O)c1ccc(CCc2ccccc2)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(CCc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
4-Phenethylbenzoic acid (30 mg, 0.13 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (103 mg, 0.27 mmol) was dissolved in dichloromethane (20 mL), and then added triethylamine (2 mL) was added. After the mixture were stirred at 25° C. for 0.5 hour, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (20 mg, 0.13 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (15 ml) was added. And the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-phenethylbenzamide (10 mg, 21%). LRMS (M+H+) m/z: calcd 360.18. found 360. HPLC purity (214 nm): 94%. 1H NMR (300 MHz, CD3OD): δ 7.67 (d, J=8.7 Hz, 2H), 7.24-7.12 (m, 7H), 6.10 (s, 1H), 4.48 (s, 2H), 2.95-2.91 (m, 4H), 2.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.Cl.Cl.[OH:89][CH2:90][CH2:91][N:92]1[CH2:97][CH2:96][N:95]([CH2:98][C:99](O)=[O:100])[CH2:94][CH2:93]1>>[OH:89][CH2:90][CH2:91][N:92]1[CH2:97][CH2:96][N:95]([CH2:98][C:99]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:22])([CH3:23])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:100])[CH2:94][CH2:93]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)CN1CCN(CCO)CC1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCN(CCO)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except [4-(2-hydroxy-ethyl)-piperazine-1-yl]-acetic acid dihydrochloride was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 700.6 (M+H)+, 2.03 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.96 (s, 1H), 5.30 (dd, J=1.7, 6.0 Hz, 1H), 4.76 (s, 1H), 4.66 (s, 1H), 3.93-3.89 (m, 2H), 3.42 (br. s., 2H), 3.30-3.25 (m, 2H), 3.22 (d, J=4.6 Hz, 2H), 2.97 (br. s., 3H), 2.68-2.60 (m, 1H), 2.55-2.47 (m, 1H), 2.44 (dd, J=8.2, 12.5 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.91-1.77 (m, 2H), 1.75 (br. s., 1H), 1.72 (s, 3H), 1.72-1.68 (m, 1H), 1.62-1.31 (m, 11H), 1.30-1.24 (m, 1H), 1.15 (d, J=13.1 Hz, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1C=O.O.O1CCC[CH2:24]1>>[N:14]1[CH:15]=[CH:16][C:17]([CH:24]=[CH:5][C:3]#[N:4])=[CH:18][CH:19]=1
Reactant: O=Cc1ccccn1
Reactant: C1CCOC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#CC=Cc1ccncc1
Reaction time: 1 h

Procedure:
Sodium hydride (ca. 60%, 1.0 g, 28.1 mmol) was dissolved in tetrahydrofuran (10 ml), and a solution of diethyl cyanomethylphosphonate (4.7 g, 26.8 mmol) in tetrahydrofuran (5 ml) was added under ice cooling condition. The mixture was stirred for 1 hr. Successively, a solution of 2-pyridinecarbaldehyde (2.7 g, 25.0 mmol) in tetrahydrofuran (5 ml) was added to the mixture, and the mixture was stirred at 0° C. to room temperature for 3 hrs. The reaction mixture was combined with water under ice cooling condition, concentrated under reduced pressure to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (100 g) column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected and concentrated to give the titled compound (a mixture of E-form and Z-form, 2.5 g, 77%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[N:8][CH:9]([CH3:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C(N(CC)CC)C.[CH:30]([Cl:33])([Cl:32])[Cl:31]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])[N:8]([C:4]([O:3][CH2:1][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:5])[C:9]([CH3:13])=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)C1=C(C)NC(C)N=C1c1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(C)N=C(C)N(C(=O)OCC(Cl)(Cl)Cl)C1c1ccccc1[N+](=O)[O-]
Yield: 45 %

Procedure:
1.0 g (3.3 millimole) of 5-Ethoxycarbonyl-2,6-dimethyl-4-(2-nitrophenyl)dihydropyrimidine was dissolved in 20 ml of chloroform and 2 ml of triethyl amine (14.3 millimole) was added to the solution with stirring and then 0.9 ml (6.54 millimole) of 2,2,2-trichloroethoxychloroformate was added dropwise. After stirring for one hour, the reaction mixture was concentrated under reduced pressure and the residue was purified on silica gel by column chromatography (eluant: methylene chloride) to obtain 0.71 g (45% yield) of title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=2)[CH2:17][CH:16]1[CH3:34].C1CCN2C(=NCCC2)CC1.[CH3:46][O:47][C:48](=[O:51])[CH2:49]Br.[NH4+].[Cl-]>CN(C=O)C.CCOCC>[CH3:46][O:47][C:48](=[O:51])[CH2:49][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[O:6][C:2]([CH3:1])=[C:3]([CH2:14][N:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:32])([F:31])[F:30])=[CH:21][CH:22]=4)[CH2:17][CH:16]3[CH3:34])[N:4]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)CBr
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CN1c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2CC1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2nc(CN3c4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4CC3C)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 40 mg (0.083 mmol) of 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-phenol (example 99) in 0.5 mL of DMF was treated with 0.01 mL of DBU and 0.01 mL (0.1 mmol) of methylbromoacetate. The mixture was stirred overnight at RT and distributed between Et2O and a saturated aqueous solution of NH4Cl. Drying of the combined organic phases, evaporation of the solvent and chromatography on silica gel with n-heptane/EtOAc 1:1 gave (4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-2,3-dihydro-indol-1-ylmethyl]-oxazol-2-yl}-phenoxy)-acetic acid methyl ester, off-white foam, MS: 559 (MH+).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=N)[NH:10]1>CO>[NH:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:6]2[S:5][C:4](=[O:7])[NH:3][C:2]2=[NH:1])[NH:10]1
Reactant: N=C1CSC(=O)N1
Reactant: N=C1NC(=N)c2ccccc21
Solvent: CO
Product: N=C1NC(=O)SC1=C1NC(=N)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3.5 parts of 4-imino-2-thiazolidinone, 4.4 parts of 1,3-diiminoisoindoline and 100 parts of methanol was stirred under an atmosphere of nitrogen at room temperature for 3 hours and then at reflux temperature for 2 hours. The reaction mixture was cooled to 25° C. and the solid therein was collected by filtration, washed with fresh methanol and dried in vacuo at 50° C. to obtain 5.4 parts of 1-imino-3-(2-oxo-4-imino-5-thiazolidinylidene)isoindoline as a yellow powder melting at 346°-348° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:38])[NH:28][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)([CH3:31])[CH3:30])[CH:22]=4)=[C:17]([N+:39]([O-])=O)[C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1>C(O)C.CC(O)=O.CCOC(C)=O.[Fe]>[NH2:39][C:17]1[C:11]2[C:12]([C:13]([NH:15][CH3:16])=[O:14])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:9][C:10]=2[CH:20]=[CH:19][C:18]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:38])[NH:28][C:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:31])[CH3:30])[CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)c([N+](=O)[O-])c12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)c(N)c12
Reaction time: 1 h
Yield: 59 %

Procedure:
Iron (25 mg, 0.453 mmol) was added to a stirring solution of 2-(4-fluorophenyl)-N-methyl-4-nitro-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (50 mg, 0.091 mmol) in ethanol (1 mL) and AcOH (1 mL) at rt. It was placed in a reaction block set to 100° C. It was allowed to stir for 1 hr. The mixture was allowed to cool and was diluted with EtOAc and washed with 1M HCl, followed by 1N NaOH and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and triturated with Et2O to give the titled compound (28 mg, 56%). 1H NMR (300 MHz, CD3OD) δ ppm 7.83-7.89 (1H, m), 7.73-7.81 (3H, m), 7.52-7.64 (2H, m), 7.42-7.49 (2H, m), 7.10-7.35 (6H, m), 6.98 (1H, d, J=8.42 Hz), 2.87 (3H, s), 1.76 (6H, s). LC-MS retention time: 2.33 min; m/z (MH+): 522. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=14.17 min, purity=97%; Column: Waters XBridge phenyl column 4.6×150 mm, 3.5 μm, Rt=12.84 min, purity=98%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20](F)=[C:19]([C:24]#[N:25])[CH:18]=2)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:37][NH2:38]>[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:20](=[CH:21][CH:22]=2)[NH:38][N:37]=[C:24]3[NH2:25])[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc(F)c(C#N)c2)c1)Cc1c[nH]c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc3[nH]nc(N)c3c2)c1)Cc1c[nH]c2ccccc12
Yield: 84 %

Procedure:
A mixture of Example 97B (120 mg, 0.25 mmol) and 98% hydrazine (5 mL) was heated to reflux for 5 hours, poured over ice, diluted with brine, extracted with ethyl acetate, dried over MgSO4, and concentrated. Purification by flash chromatography (7% MeOH/CH2Cl2) provided the desired product (103 mg, 84%).
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].[OH-].[K+]>CS(C)=O.O>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][O:9][N:8]=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)CCCl
Reactant: ON=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCON=C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of diphenyl-methanone oxime (2 g, 10 mmol) and (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.5 g, 10.4 mmol) in DMSO (20 ml) was added powdered potassium hydroxide (800 mg, 14.3 mmol) and the reaction mixture stirred overnight. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed thoroughly with water and brine, then dried over anhydrous sodium sulphate and filtered. Concentration of the organic layer under reduced pressure gave diphenyl-methanone O-(2-dimethylaminoethyl)-oxime (700 mg, 26%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](O)=[CH:10]2)=[CH:5][CH:4]=1.OS([O-])=O.[Na+].[OH-].[NH4+:20]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([NH2:20])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc2ccc(O)cc2c1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2ccc(N)cc2c1
Temperature: 25 °C
Yield: 70 %

Procedure:
The solution of 7-methoxynaphthalen-2-ol (6.5 g, 37.31 mmol) and NaHSO3 (11.6 g, 111.54 mmol) in ammonium hydroxide (100 ml) was stirred for 2 days at 140° C. in a sealed tube and then cooled to room temperature. The solids were collected by filtration to afford 7-methoxynaphthalen-2-amine as an off-white solid (4.5 g, 70%). (ES, m/z): [M+H]+ 174.1; 1H NMR (300 MHz, CDCl3): δ 7.57 (d, J=8.7 Hz, 2H), 6.97-6.87 (m, 3H), 6.79 (dd, J=8.7, 2.1 Hz, 1H), 3.90 (s, 3H), 3.84 (br s, 2H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][C@H:16]1[CH2:21][O:20][CH2:19][C@H:18]([CH3:22])[NH:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:15][C@@H:16]1[N:17]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[C@@H:18]([CH3:22])[CH2:19][O:20][CH2:21]1
Reactant: C[C@H]1COC[C@H](C)N1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2oc(N3[C@@H](C)COC[C@@H]3C)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.6 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (620 mg, 2.96 mmol) and (3S,5S)-3,5-dimethylmorpholine (341 mg, 2.96 mmol) and potassium carbonate (1.0 g, 7.4 mmol), in DMF (15 mL), was stirred in a 35° C. oil bath. After 17 h, the reaction mixture was cooled to ambient temperature, diluted with H2O (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. Methyl 2-((3 S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxylate (770 mg, 89%) was obtained as an amber oil. 1H NMR consistent.