Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][C:7]([NH2:9])=[O:8])([CH3:3])[CH3:2].[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14]N.N>>[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH:9][C:7](=[O:8])[CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CN(C)CCCN
Reactant: CC(C)OCCC(N)=O
Agent: N
Product: CC(C)OCCC(=O)NCCCN(C)C

Procedure:
131.2 g (1.0 mole) of 3-isopropoxypropionamide are heated with 1.07.3 g (1.05 mole) of 3-dimethylaminopropylamine for 6 hours in a temperature range of 145°-170° C. until the evolution of ammonia is complete. In the subsequent distillation in a high vacuum 198 g (0.92 mole=91.5% of the theoretical yield) of colorless liquid are obtained having a Bp0.1 of 128°-132° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)[C@@H:3]([OH:16])[CH2:4][N:5]([CH2:14][CH3:15])[NH:6][C:7]([O:9]C(C)(C)C)=O.[CH3:26][CH:27]([CH2:32]C)[CH2:28][C:29](O)=O.[CH3:34][C:35]1[CH:36]=[C:37]([C:44]([N:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH3:49])=[O:45])[CH:38]=[C:39]([CH:43]=1)[C:40]([OH:42])=O>>[F:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([F:25])[CH:21]=1)[CH2:17][C@H:2]([NH:1][C:40](=[O:42])[C:39]1[CH:43]=[C:35]([CH3:34])[CH:36]=[C:37]([C:44]([N:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH3:49])=[O:45])[CH:38]=1)[C@@H:3]([OH:16])[CH2:4][N:5]([CH2:14][CH3:15])[NH:6][C:7](=[O:9])[CH2:29][CH2:28][CH:27]([CH3:32])[CH3:26]
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Reactant: CCC(C)CC(=O)O
Reactant: CCN(C[C@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@@H](O)CN(CC)NC(=O)CCC(C)C)c1

Procedure:
Synthesized as described above from tert-butyl 2-((2S,3S)-3-amino-2-hydroxy-4-(3,5difluorophenyl)butyl)-2-ethylhydrazinecarboxylate, 3-methylpentanoic acid and 5-methyl-N,N-dipropyl-isophthalamic acid. MS (ESI+) for C33H48F2N4O4 m/z 603.3 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([O:16][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][C:12]=1[CH:13]=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc(Oc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(Oc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Phenoxy-2-hydroxybenzaldehyde (20 g, 94 mmol) and potassium carbonate (26.1 g, 188 mmol) are taken up in DMF (250 mL) and treated with benzyl bromide (16.1 g, 94 mmol). The mixture is stirred at room temperature overnight. The mixture is diluted with ethyl acetate and washed three times with saturated aqueous ammonium chloride, dried over magnesium sulfate and evaporated to give 2-benzyloxy-5-phenoxybenzaldehyde as a colorless solid. This is used without further purification.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10]C2=NC=1.Cl[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][C:33]=3[C:34]([F:37])([F:36])[F:35])[N:30]=[CH:29][CH:28]=[CH:27]4)O)=[CH:20][N:21]=2)[N:18]=1.C([Mg]Br)C.FC(F)(F)C1C=C2C(C=CC=N2)=CC=1C=O>C1COCC1>[CH3:2][N:6]1[CH:10]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([CH2:22][C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][C:33]=4[C:34]([F:37])([F:35])[F:36])[N:30]=[CH:29][CH:28]=[CH:27]5)=[CH:20][N:21]=3)[N:18]=2)[CH:8]=[N:7]1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: OC(c1cc2cccnc2cc1C(F)(F)F)c1cnc2ccc(Cl)nn12
Agent: CC[Mg]Br
Agent: O=Cc1cc2cccnc2cc1C(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3ncc(Cc4cc5cccnc5cc4C(F)(F)F)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(7-trifluoromethyl-quinolin-6-yl)-methanol 3-Bromo-6-chloro-imidazo[1,2-b]pyridazine (500 mg, 2.15 mmol) was dissolved THF (50 mL) and under nitrogen conditions, ethylmagnesium bromide solution (3 M, 0.860 mL) was added. The RM was stirred at rt for 30 min then a solution of 7-trifluoromethyl-quinoline-6-carbaldehyde (Intermediate G, 723 mg, 2.15 mmol) in THF was added. It was stirred at rt for 1 h. The solvent was removed and the residue was taken up with EtOAc and washed with water and brine. It was dried over Na2SO4 and the solvent was evaporated in vacuo. The residue was triturated with Et2O and the precipitate was filtered off. The title compound was obtained as a grey solid (tR 1.48 min (conditions 12), MH+=379).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][OH:9])[C:4]([O:6][CH3:7])=[O:5].[C:10]([O:14][C:15]([N:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:26](O)=[O:27])[C:20]=2[CH:19]=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)C(C)C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[OH:9][CH2:8][C@H:3]([NH:2][C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[CH:19]=[CH:18][N:17]2[C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[O:27])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](N)CO
Reactant: CC(C)(C)OC(=O)n1ccc2c(C(=O)O)cccc21
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)c1cccc2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.8 %

Procedure:
To a solution of methyl (2S)-2-amino-3-hydroxypropanoate hydrochloride (1.25 g), 1-(tert-butoxycarbonyl)-1H-indole-4-carboxylic acid (2.10 g) and N-ethyl-N-isopropyl-2-propanamine (2.94 mL) in DMF (25.0 mL) was added dropwise DPPA (1.91 mL) at 0° C. and the mixture was stirred at ambient temperature for 3 days. The resulting mixture was diluted with water (50.0 mL) and extracted with EtOAc (75 mL). The organic layer was washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution. and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=99:1) to afford tert-butyl 4-({[(1S)-1-(hydroxymethyl)-2-methoxy-2-oxoethyl]amino}carbonyl)-1H-indole-1-carboxylate (2.12 g) as a colorless syrup.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:4]=[N:3]1.O=P(Cl)(Cl)Cl.CN([CH:24]=[O:25])C>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH:24]=[O:25])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:4]=[N:3]1
Reactant: CN(C)C=O
Reactant: CN1CCN(c2cnn(C)c(=O)c2)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(c2cnn(C)c(=O)c2C=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-methyl-5-(4-methylpiperazin-1-yl)pyridazin-3(2H)-one (416 mg, 2 mmol) in dry DMF (6.7 ml) was cooled to 5° C., then a solution of POCl3 (0.41 ml, 4.4 mmol) in dry DMF (1 ml) was added dropwise. The cooling bath was removed and the mixture was stirred at room temperature for 10 min. Then, the temperature was raised to 70° C. and stirring was continued for 75 min. After cooling, the volatile components were removed under reduced pressure and the residue was treated with crushed ice (15 g). The mixture was adjusted to pH 7-8 with aqueous NaOH. Then it was extracted with dichloromethane (4×40 ml) and the combined extracts were washed with water, dried (Na2SO4) and evaporated. Residual volatile material was removed at 10−2 mbar to leave an oily residue which slowly solidified on storage in a refrigerator.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:13])[CH2:10][C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:14](=S)=[S:15].[H-].[Na+].CI.[CH3:21][S:22]([CH3:24])=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[C:9]([C:10](=[C:21]([S:15][CH3:14])[S:22][CH3:24])[C:11]#[N:12])=[O:13]
Reactant: CS(C)=O
Reactant: N#CCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CSC(SC)=C(C#N)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To a solution of 3-(3,4-dichlorophenyl)-3-oxopropanenitrile (3.3 g, 15.4 mmol) and carbon disulfide (0.927 mL, 15.4 mmol) in DMSO (50 mL) under an atmosphere of argon at 15° C. was added sodium hydride (0.856 g, 033.9 mmol) with vigorous stirring. The reaction mixture was stirred at this temperature for 10 min and was allowed to warm to rt. To the reaction mixture was added methyl iodide (1.92 mL, 30.8 mmol) and the mixture was stirred at rt for 30 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 2-(3,4-dichlorobenzoyl)-3,3-bis(methylsulfanyl)acrylonitrile (2.9 g, 59%). LCMS: (FA) ES-318.1. 1H NMR (400 MHz, CDCl3) δ: 7.95 (d, 1H), 7.73 (dd, 1H), 7.56 (d, 1H), 2.82 (s, 3H) and 2.55 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:9][OH:10])[CH2:7][CH3:8].[Li+].CC([N-]C(C)C)C.[C:19]([O:26][CH2:27][CH3:28])(=[O:25])[C:20]([O:22]CC)=O>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:9][OH:10])[CH:7]([CH3:8])[C:20](=[O:22])[C:19]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=NO)c1ccco1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=NO)c1ccco1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
1-(Furan-2-yl)propan-1-one oxime (6.1 g, 43.9 mmol) was dissolved in 100 mL of THF and cooled to 0° C. LDA solution (55 mL, 110 mmol, 2M in heptane/THF/ethyl benzene) was added dropwise, and the reaction mixture was stirred at 0° C. for 1 hour and then warmed to room temperature. The mixture was then transferred to an addition funnel and added dropwise to a flask containing a pre-cooled mixture of diethyl oxalate (30 mL, 219 mmol) and THF (100 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and quenched with 150 mL of 10% hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with EtOAc. The aqueous layer was then neutralized with solid sodium bicarbonate and extracted further with CH2Cl2. The organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-40% EtOAc/hexanes) to give 10 g of the title compound. MS: (+) m/z 240.42 (M+1).
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30](O)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=1.CN1C=CN=C1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30]([NH:33][C:34]3[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Reactant: Cc1ncccc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cn1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ncccc1NC(=O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
(4bR,7R,8aR)-4b-benzyl-7-hydroxy-6-oxo-7-phenyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxylic acid (21 g, 49.2 mmol), 3-amino-2-picoline (5.8 g, 52.2 mmol) and 1-methylimidazole (20 mL, 246.2 mmol) were dissolved in anhydrous acetonitrile (105 mL). 1-Propanephosphonic acid cyclic anhydride (50 wt % in ethyl acetate) (47 mL, 78.8 mmol) was slowly added to control the mild exotherm. The mixture was stirred at 25° C. until the reaction was completed (less than an hour). Ethyl acetate (86 mL) was added to the mixture. The mixture was washed with water (4×100 mL). The organic phase was dried with MgSO4 and concentrated to dryness. The title product (22.3 g, 89% yield) was obtained as a light-yellow foam. 1H NMR (DMSO): δ 1.95 (m, 2H), 2.10 (m, 3H), 2.35 (s, 3H), 2.75 (m, 3H), 3.0 (d, 1H), 3.05 (m, 2H), 5.70 (s, 1H), 6.15 (d, 1H), 6.60 (m, 2H), 7.10 (m, 3H), 7.25 (m, 2H), 7.30 (m, 5H), 7.65 (d,
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:34][C:35]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:36]=1[C:37]([OH:39])=O.[S:45]1[C:49]([C:50]2[N:54]3[CH2:55][CH2:56][NH:57][CH2:58][C:53]3=[N:52][N:51]=2)=[N:48][CH:47]=[N:46]1>CN(C)C=O.C(OCC)C>[Cl:34][C:35]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:36]=1[C:37]([N:57]1[CH2:56][CH2:55][N:54]2[C:50]([C:49]3[S:45][N:46]=[CH:47][N:48]=3)=[N:51][N:52]=[C:53]2[CH2:58]1)=[O:39]
Reactant: c1nsc(-c2nnc3n2CCNC3)n1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
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: CCOCC
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1Cl)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
HATU (274 mg, 0.720 mmol) and DIPEA (0.252 ml, 1.441 mmol) were added to a colourless solution of 2,4-dichlorobenzoic acid (I38 mg, 0.720 mmol, commercially available) in N,N-dimethylformamide (DMF) (4.718 ml). The mixture was stirred at RT for 15 minutes. 3-(1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I115) (100 mg, 0.480 mmol) was added and the reaction mixture was stirred at RT for 18 h. The mixture was diluted in diethyl ether (100 mL) and washed with water (25 mL). The aqueous layer was extracted with diethyl ether (2×50 mL) and DCM (2×50 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product (brown liquid, 329.0 mg) was purified by flash chromatography (10 g SNAP, 0-100% ethyl acetate in hexane, 12 CV). The obtained oil residue was triturated with hexane. The product was diluted in DCM (100 mL) and washed with brine (3×25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained product was dried at 50° C. under vacuum 3 days to afford the desired product in 62.05 mg as a white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C1COCC1.N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:30]([C:20]45[CH2:29][CH:24]6[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]6)[CH2:27]4)[CH2:21]5)=[O:31])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a stirring solution of nitro amine 8 (0.240 g, 0.94 mmol) in dry THF-Pyridine (15 ml/0.400 ml), adamantane carbonyl chloride (0.280 g, 1.41 mmol) was added and the mixture stirred at room temperature for 3 h. The reaction was quenched by addition of water and the resulting yellow solid was filtered and passed through a SiO2 gel using EtOAc as a eluent to give 13 (0.265 g, 67%). 1H NMR (DMSO-d6, 500 MHz): δ 13.51 (1H, brs, NH), 9.60 (1H, brs, NH), 8.78 (1H, s), 8.45-8.40 (4H, m), 8.32 (1H, s), 2.00-1.60 (15H, m); EIMS m/z: 418.5 (M+1) and 416 (M−1).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63]/[C:64](/[NH2:67])=[N:65]/O)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]>CN(C=O)C>[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63][C:64]3[N:65]=[C:6]([C:3]4([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]4)[O:7][N:67]=3)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4(C(F)(F)F)CC4)n3)ccc1C)c(=O)n2C
Temperature: 100 °C

Procedure:
To a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (9 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (31 μL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A58). MS m/z 456.6 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C#CCCCO)ccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cc(CCCCCO)ccc21
Yield: 98.6 %

Procedure:
2.8 g (9.3 mmol) 5-(5-Hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 60 ml MeOH were subjected to hydrogenation with 10%Pd/C to yield 2.8 g (quantitative) 5-(5-Hydroxy-pentyl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless viscous oil, MS: 305 (M).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](=[O:14])([O-])[O-].[Na+].[Na+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>C(Cl)(Cl)Cl.[Pd]>[CH3:2][N:3]1[C@H:4]2[C@@:17]([CH3:21])([C:17]3[CH:21]=[CH:9][C:8]([C:2]4[NH:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)=[CH:7][C:18]=3[CH2:19][CH2:5]2)[CH2:18][CH2:19][C:11]1=[O:14]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4nc5ccccc5[nH]4)cc3CC[C@@H]12
Reaction time: 16 h
Yield: 25 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (187 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium (0) (23 mg, 0.02 mmol), 2-chlorobenzimidazole (104 mg, 0.68 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. An additional 23 mg of the palladium reagent was added, and let stir an additional 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-5% methanol/ethyl acetate eluent gradient) to give 57 mg (25%) of the title compound as an amorphous foam. mp 183°-186°. FDMS: m/e=345.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:19])[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]1=[O:18].[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].CCN(C(C)C)C(C)C>CN(C=O)C>[O:17]=[C:16]1[CH:15]=[CH:14][C:13](=[O:18])[N:12]1[CH2:11][CH2:10][C:9]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:19]
Reactant: NCCCCCCCC(=O)O
Reactant: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCCCCCNC(=O)CCN1C(=O)C=CC1=O
Temperature: 25 °C

Procedure:
3-(2,5-Dioxo-2,5-dihydropyrrol-1-yl)propionic acid 2,5-dioxopyrrolidin-1-yl ester (787 mg, crude) was dissolved in DMF (15 ml). 8-Aminooctanoic acid (350 mg) and DIPEA (0.45 ml) was added. The mixture was stirred under nitrogen at room temperature over night. The mixture was concentrated. The residue was dissolved in EtOAc and extracted with 0.1 N HCl (2×). The phase separation was not easy. The organic layer was washed with brine (2×), dried (Na2SO4) and concentrated to give a white solid. LC-MS, M/z: 311.34 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
20.0 G. (0.148 moles) of 4-isopropylaniline is added with stirring to 75 ml. of acetic anhydride at from 20° to 45° C. The reaction mixture is stirred at 35° C. for 1 hour. 11 Ml. of fuming nitric acid (specific gravity 1.5) is added at a temperature of from 25° to 35° C. over a period of 20 minutes and stirred for 3 hours. The acid mixture is added to a mixture of 180 ml. of water, 45 ml. of concentrated sulfuric acid and 142 ml. of ethanol with stirring. The reaction mixture is stirred overnight at room temperature, refluxed for 2 hours, neutralized with saturated sodium carbonate solution and extracted with chloroform. The chloroform layer is dried and evaporated in vacuo affording 35 g. of a dark orange oil which is used as is in the next step.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[F:15][C:16]([F:51])([F:50])[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]2[O:26][CH:27]=[C:28]([CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][N:42]4[CH:46]=[CH:45][N:44]=[C:43]4[CH2:47][CH2:48][NH2:49])=[CH:34][CH:33]=3)[N:29]=2)=[CH:19][CH:18]=1.O>C1COCC1>[F:51][C:16]([F:50])([F:15])[C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]2[O:26][CH:27]=[C:28]([CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][N:42]4[CH:46]=[CH:45][N:44]=[C:43]4[CH2:47][CH2:48][NH:49][C:8](=[O:10])[CH3:9])=[CH:34][CH:33]=3)[N:29]=2)=[CH:19][CH:18]=1
Reactant: NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (137 μl) and acetic anhydride (74.0 μl) were added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethylamine (200 mg) in THF at 0° C., and the mixture was stirred at 0° C. for 1.5 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; dichloromethane to dichloromethane:methanol=20:1) and recrystallized from ethyl acetate-hexane to give the titled compound (123 mg) as colorless needle crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH3:12]>>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([NH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: N
Reactant: FC(F)(F)c1cccnc1Cl
Product: Nc1ncccc1C(F)(F)F
Temperature: 175 °C
Reaction time: 72 h

Procedure:
10 g of 2-chloro-3-trifluoromethylpyridine was dissolved in 100 mL of 25% aqueous ammonia, and stirred in a sealed-tube at 175° C. for 3 days. The reaction mixture was cooled back to room temperature, and was extracted with diethyl ether. The organic layer was washed with water and with saturated brine in the subsequent order, and then dried over anhydrous sodium sulfate. After filtering the insolubles, the filtrate was concentrated under reduced pressure to obtain 8.73 g of 3-(trifluoromethyl)-2-pyridinamine [34-1] as a white solid.