Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.N1C=CC=CC=1.[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:29]=1[C:30](Cl)=[O:31])[CH2:24][CH2:25][CH3:26]>O1CCOCC1.CC(C)=O>[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:29]=1[C:30]([NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=[O:31])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(CCN)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCCOc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(=O)OCC)cc1

Procedure:
To a solution of 12.2 g. ethyl 4-(2-aminoethyl)-phenylacetate hydrochloride in 40 ml dioxane and 40 ml acetone, there is added dropwise, after the addition of 8 ml pyridine, a solution of 12.3 g 2-butoxy-5-chlorobenzoyl chloride in 10 ml acetone. The reaction mixture is then stirred under reflux for 3 hours and thereafter evaporated in a vacuum. The residue is stirred with dilute hydrochloric acid and then with aqueous sodium bicarbonate solution, filtered with suction and washed with water. There are obtained 19 g of crude product which, after recrystallization from ethanol, with the addition of small amounts of water, gives ethyl 4-[2-(2-butoxy-5-chlorobenzamido)-ethyl]-phenylacetate; m.p. 80° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[CH2:22][O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>C(#N)C.C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:15]3[CH2:20][CH2:19][C:18]4([CH2:25][C:24]5[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=5[CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: c1ccc2c(c1)COC1(CCNCC1)C2
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)COC1(CCN(CCCOc3cccc4[nH]ccc34)CC1)C2

Procedure:
A solution of 1-chloro-3-(4-indolyloxy)propane, 1,4-dihydrospiro[3H-2-benzopyran-3,4'-piperidine] and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 62% overall yield. FDMS m/e=376 (M+ of free base).
Reaction SMILES: C(O[C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(C)C.[Cl:25]C1N=CC([C@@H](N)C)=CC=1>>[Cl:25][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(C)Oc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reactant: C[C@H](N)c1ccc(Cl)nc1
Product: C[C@H](NC(=O)[C@H]1C[C@@H]1c1ccccc1)c1ccc(Cl)nc1

Procedure:
Prepared analogously to Compound 1 using IM46 and commercially available (S)-1-(6-Chloro-pyridin-3-yl)-ethylamine (Aurora building blocks catalogue nr A06.81-4.555). Yield=1.40 g (71%), 1H-NMR (500 MHz, DMSO) δ 8.68 (d, 1H), 8.36 (s, 1H), 7.78 (d, 1H), 7.48 (d, 1H), 7.28 (m, 2H), 7.18 (m, 1H), 7.11 (d, 2H), 4.99 (m, 1H), 2.20 (m, 1H), 1.92 (m, 1H), 1.37 (m, 4H), 120 (m, 1H). LC-MS (m/z) 301.2 and 303.1 (MH+), tR=0.87 min (method B).
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][O:43][Si](C(C)(C)C)(C)C)[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>CO>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([C:13]([CH3:52])([CH3:51])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[C@H:41]([CH2:42][OH:43])[CH2:40][N:39]4[C@H:34]([CH2:35][O:36][CH2:37][CH2:38]4)[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccc(F)cc1Cl
Agent: Cl
Solvent: CO
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO)cc1-c1ccc(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(2-chloro-4-fluorophenyl)-6-[(7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin -8(1H)-yl]-3-pyridinyl}-N,2-dimethylpropanamide (D58, 22 mg, 0.027 mmol) was dissolved in dry MeOH (2 mL), cooled in an ice-salt bath to ˜0° C. before adding c.HCl solution (˜0.1 mL), slowly. The reaction mixture was stirred at ˜0° C. for 1 hour before warming up and stirring at R.T. for 2 hours. Placed directly onto a 2 g SCX column, washing with MeOH (2×5 mL) before eluting the compound off with NH3 in MeOH (4×5 mL). Solvent evaporated under reduced pressure to afford the title compound as an off white solid. (10mg)
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[C:12]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH2:21])([CH3:20])[CH3:19])(=[O:14])[CH3:13].C(N(C(C)C)CC)(C)C>ClCCl>[C:12]([C:15]1[CH:16]=[C:17]([C:18]([NH:21][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)([CH3:20])[CH3:19])[CH:22]=[CH:23][CH:24]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cccc(C(C)(C)N)c1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(C(C)(C)NC(=O)Oc2ccc(Cl)cc2)c1
Reaction time: 2 h
Yield: 81 %

Procedure:
4-Chlorophenyl chloroformate (317 μL, 2.24 mmol) in dichloromethane (2 mL) was added to a mixture of 3-acetyl-α, α-dimethylbenzylamine 24 and diisopropylethylamine (390 μL, 2.24 mmol). The reaction mixture was stirred for 2 h. It was then diluted with dichloromethane, washed with 1 N HCl, and then brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate as eluent to give 25 (594 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 1.73 (s, 6H), 2.60 (s, 3H), 5.65 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 7.25 (d, J=6 Hz, 2H), 7.44 (t, J=8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 8.07 (1H, s); 13C NMR (DMSO-d, 100 MHz) δ 27.45, 29.79, 55.50, 124.23, 124.55, 127.31, 129.28, 129.55, 129.79, 130.39, 137.30, 148.70, 150.32, 152.97, 198.64; ESI-HRMS for C18H19NO3Cl (M+H)+ calcd. 332.1053. found 332.1059.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH3:19])[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:11]1[O:18][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:10]=1[CH3:19])[CH3:17]
Reactant: CCOC(=O)CC(=O)C(C)NC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1oc(-c2ccccc2)nc1C
Temperature: 90 °C
Yield: 48.1 %

Procedure:
To a crude mixture of ethyl 4-(benzoylamino)-3-oxopentanoate (0.6 g, 2.28 mmol) in DMF (4 mL) at rt, was added POCl3 (1.04 g, 6.84 mmol). The resulting solution was heated at 90° C. for 1 hour, then cooled down to rt, and poured into ice for 30 minutes. The aqueous solution was carefully added to a saturated aqueous solution of NaHCO3. Phases were separated with EtOAc and the combined organic extracts were dried over MgSO4 and solvent removed under reduced pressure. The crude material was purified on Biotage small column using a solvent gradient of 0 to 50% EtOAc/Hexane. This gave ethyl(4-methyl-2-phenyl-1,3-oxazol-5-yl)acetate (0.269 g 48% yield) as yellowish oil. ES-MS m/z 246.2 ((MH)+); HPLC RT (min.) 2.77; 1H NMR (CDCl3) δ 8.01-7.98 (m, 2H), 7.45-7.41 (m, 3H), 4.20 (q, 2H), 3.71 (s, 2H), 2.21 (s, 3H), 1.28 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Br:8])[CH:3]=1.[Li+].CC([N-]C(C)C)C.[CH2:17]1[CH2:25][O:24][C:23]2[C:19](=[C:20]([CH:26]=[O:27])[S:21][CH:22]=2)[O:18]1.CCOC(C)=O>C1COCC1.O>[Br:8][C:4]1[CH:3]=[C:2]([CH2:1][CH:26]([C:20]2[S:21][CH:22]=[C:23]3[O:24][CH2:25][CH2:17][O:18][C:19]=23)[OH:27])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1ccnc(Br)c1
Reactant: O=Cc1scc2c1OCCO2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OC(Cc1ccnc(Br)c1)c1scc2c1OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
4-Methyl-2-bromopyridine (450 mg, 2.62 mmol) was dissolved in anhyd THF (10 mL) and the resulting mixture was cooled to −78° C. LDA (1.76 mL, 1.8 M solution in THF, 3.17 mmol) was added dropwise and the resulting mixture was stirred for 1 h at the same temperature. A solution of 3,4-ethylenedioxythiophene-2-carboxaldehyde (500 mg, 2.94 mmol) in THF (20 mL) was added and the resulting mixture was stirred for 30 min at room temperature. AcOEt (120 mL) and water (120 mL) were added and the layers were separated. The organic layer was washed with water (2×150 mL), dried (Na2SO4) and the solvent was removed by rotary evaporation. Flash chromatography of the residue (silica gel, petroleum ether/AcOEt 1:1) afforded (9) as a yellow oil (850 mg, 2.48 mmol, 95%). 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J=5.0 Hz, 1H), 7.38 (s, 1H), 7.10 (d, J=5.0 Hz, 1H), 6.29 (s, 1H), 5.18 (t, J=6.7 Hz, 1H), 4.20-4.05 (m, 4H), 3.20-2.95 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([O:17]C)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:20][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:19])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.50 g, 4.10 mmol) in dichloromethane (80 mL) was treated dropwise with BBr3 (9.4 mL of a 1.0M solution in CH2Cl2, 9.4 mmol), and the mixture stirred overnight while warming to 20 C. The excess BBr3 was quenched with the dropwise addition of water, the mixture diluted with ether (200 mL), washed with Na2CO3 (100 mL) and brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.25 g of a white solid foam.
Reaction SMILES: Cl.[NH:2]1[CH2:16][CH2:15][CH2:14][C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C.[O:41]=[C:42]([CH2:46][CH2:47][CH3:48])[C:43](O)=[O:44]>ClCCl>[O:41]=[C:42]([CH2:46][CH2:47][CH3:48])[C:43]([N:2]1[CH2:16][CH2:15][CH2:14][C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])=[O:44]
Reactant: CCCC(=O)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
8.8 g benzyl prolinate hydrochloride, 9.78 g dicyclohexylcarbodiimide and 6.12 g diisopropylethylamine were reacted together in 50 mL dichloromethane at 0°. 5.51 g 2-oxopentanoic acid in 10 mL dichloromethane was added dropwise at 0°. The pH of the reaction was adjusted to between 8 and 9 with diisopropylethylamine. The reaction mixture was stirred for four hours at 0°, then room temperature overnight. The next day, the reaction mixture was filtered, concentrated to dryness, and partitioned between ethyl acetate and water. The organic layer was washed with 5% sodium bisulfate, 5% sodium bicarbonate, and saturated sodium chloride solutions, and dried with magnesium sulfate. The organic layer was concentrated to give a yellow oil. The oil was then passed through a silica gel column and eluted with ethyl acetate/hexane (4:6) and ethyl acetate/hexane (1:1). Benzyl N-(2-oxopentanoyl)prolinate, [α]D25 -56.9, was isolated.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.Cl.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1.C(N(C(C)C)C(C)C)C.FC(F)(F)C(O)=O.CN([CH:36]=[C:37]([N:43]1[CH:47]=[C:46]([C:48]#[N:49])[N:45]=[CH:44]1)[C:38](OCC)=[O:39])C>O>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:8]2[C:38](=[O:39])[C:37]([N:43]3[CH:47]=[C:46]([C:48]#[N:49])[N:45]=[CH:44]3)=[CH:36][NH:9]2)[CH:7]=1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Reactant: NNc1cc(Cl)ncn1
Reactant: C1CCONC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCCCO4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 200 mg (1.4 mmol) of the compound from Example 11A, 205 mg (1.7 mmol) of 1,2-oxazinane hydrochloride [Bhat et al., J. Chem. Soc. Perkin Trans. 2 2000, 7, 1435-1446] and 289 μl (215 mg, 1.7 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine in 3 ml of water is stirred at 100° C. for 1.5 h. Following the addition of 59 μl (49 mg, 0.4 mmol) of trifluoroacetic acid and 324 mg (1.4 mmol) of the compound from Example 6A, the reaction mixture is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 199 mg (39% of theory)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:9][S:10]([O:8][CH2:7][CH2:6][C:4]1[CH:5]=[N:1][N:2]([S:10]([CH3:9])(=[O:12])=[O:11])[CH:3]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cn[nH]c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cnn(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(1H-pyrazol-4-yl)ethanol (50 mg, 0.45 mmol) in dichloromethane (3 mL) at 0° C. was added methanesulfonyl chloride (0.104 mL, 1.39 mmol) followed by N,N-diisopropylethylamine (0.312 mL, 1.78 mmol) dropwise. The ice bath was removed and the mixture warmed to ambient temperature and stirred for 1 h. The solvent was removed in vacuo and the residue purified by column chromatography (silica gel Biotage 25S) eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give the title compound as a colorless solid. LC/MS 269.2 (M+1).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[CH:26])=[CH:19][C:16]=1[CH:17]=[O:18])([O-:14])=[O:13].[Cl-].[NH4+]>C1COCC1>[N+:12]([C:15]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]#[CH:26])=[CH:19][C:16]=1[CH:17]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[OH:18])([O-:14])=[O:13]
Reactant: Brc1ccc(C2CC2)cc1
Reactant: C#CCOc1ccc([N+](=O)[O-])c(C=O)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCOc1ccc([N+](=O)[O-])c(C(O)c2ccc(C3CC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 407 mg (16.7 mmol) magnesium turnings in 5 ml anhydrous THF is treated with a solution of 1-bromo-4-cyclopropyl-benzene in 20 ml THF at such a rate to maintain gentle reflux. Stirring is continued for another ½ h after complete addition. The resulting Grignard reagent is then slowly added to a solution of 2-nitro-5-propargyloxy-benzaldehyde in 30 ml THF at −75° C. The reaction is kept between −75° C. and −65° C. throughout the addition, followed by slow warming to rt. The mixture is then poured into saturated aqueous ammonium chloride solution and extracted with diethyl ether. Purification of the crude product by flash chromatography (hexane/dichloromethane) yields a yellow brown oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:16][NH:17][C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>CS(C)=O.CC(=O)OCC>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([N:17]([CH3:16])[C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2=[N:10][N:9]=1
Reactant: CN[C@@H](C)c1ccccc1
Reactant: COC(=O)c1cc(Cl)nn2c(C)nnc12
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N(C)[C@@H](C)c2ccccc2)nn2c(C)nnc12
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
A mixture of compound methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (2.0 g, 8.85 mmol) and (S)-N-methyl-1-phenylethanamine (2.39 g, 17.7 mmol) in anhydrous DMSO (20 mL) was stirred for 30 min at 130° C. under microwave condition. After cooled to room temperature, the mixture was diluted with EA (100 mL) and washed with H2O (100 mL*3). The organic layer was dried over Na2SO4, concentrated in vacuum and purified by flash column chromatography (silica-gel, DCM: MeOH=10:1) to give product (S)-methyl 3-methyl-6-(methyl (1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate as a yellow oil (400 mg, 14.5%). LRMS (M+H+) m/z: calcd 326; found 326.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[CH:23]([N:26]([CH:29]([CH3:31])C)[CH2:27]C)([CH3:25])C.C(Cl)(Cl)=[O:33].N1CCCC1>C1COCC1.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([F:22])[CH:18]=[CH:19][CH:20]=5)[N:15]([C:27]([N:26]5[CH2:23][CH2:25][CH2:31][CH2:29]5)=[O:33])[CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: Fc1cccc2c1NCc1c(-c3noc(C4CC4)n3)ncn1-2
Solvent: O
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: O=C(N1CCCC1)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2cccc(F)c21
Reaction time: 3 h

Procedure:
To 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-6-fluoro-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXIII, EXAMPLE 103, 0.418 g) in THF (15 ml) is added diisopropylethylamine (0.245 ml) followed by phosgene (1.2M in toluene, 1.76 ml). The reaction is stirred for 3 hr, after which pyrrolidine (0.23 ml) and diisopropylethylamine (0.25 ml) are added. The reaction is stirred for 1 hr, then treated with several ml of water and concentrated. The residue is partitioned between dichloromethane, aqueous sodium bicarbonate, and saline. The phases are separated, the organic phase is dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel (150 ml) eluting with methanol/dichloromethane (2/98). The appropriate fractions are pooled and concentrated to give the product which is recrystallized from dichloromethane and hexane to give the title compound, mp 220.5°-221.5°; MS m/z at 394; IR (mineral oil) 1500, 1392, 1662, 1221, 793 and 1613 cm-1 ; NMR (CDCl3), 1.35, 1.86, 2.26, 3.33, 5.10, 7.08, 7.21, 7.37 and 8.11 δ.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:18][CH:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: CN1CCC(O)CC1
Reactant: N#Cc1cnc(N)cc1F
Product: CN1CCC(Oc2cc(N)ncc2C#N)CC1

Procedure:
From intermediate 21 and 1-methylpiperidin-4-ol, reacted in an analogous manner to the preparation of intermediate 45. (UPLC-MS 3) tR 0.30 min; ESI-MS 233.2 [M+H]+.
Reaction SMILES: [C@H]1(NC([C@@H]2CC3C(=CC(OS(C(F)(F)F)(=O)=O)=CC=3)CN2C(OC(C)(C)C)=O)=O)C2C(=CC=CC=2)CCC1.[N+:39]([C:42]1[CH:51]=[C:50]2[C:45]([CH2:46][C@@H:47]([C:52]([NH:54][C@H:55]3[C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[CH2:58][CH2:57][CH2:56]3)=[O:53])[NH:48][CH2:49]2)=[CH:44][CH:43]=1)([O-:41])=[O:40].[C:65]([O:69][C:70]([NH:72][C@@H:73]([C:77]([CH3:80])([CH3:79])[CH3:78])[C:74](O)=[O:75])=[O:71])([CH3:68])([CH3:67])[CH3:66]>>[CH3:78][C:77]([CH3:80])([CH3:79])[C@H:73]([NH:72][C:70](=[O:71])[O:69][C:65]([CH3:68])([CH3:67])[CH3:66])[C:74]([N:48]1[C@H:47]([C:52](=[O:53])[NH:54][C@H:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[CH2:58][CH2:57][CH2:56]2)[CH2:46][C:45]2[C:50](=[CH:51][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=2)[CH2:49]1)=[O:75]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1Cc2ccc([N+](=O)[O-])cc2CN1
Agent: CC(C)(C)OC(=O)N1Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Yield: 97.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound D, (S)-7-nitro-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (1.69 g, 4.81 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (1.22 g, 5.29 mmol) were converted to the title compound (2.65 g, 98%). MS (ESI+) m/z 565.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1.N1C=CC=CC=1.[C:45](Cl)(=[O:47])[CH3:46]>ClCCl>[ClH:1].[Cl:1][C:2]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:17][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([NH:16][C:45](=[O:47])[CH3:46])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Product: Cl
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
To 3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethylamino]-propoxy}-phenylamine (80.0 mg, 0.15 mmol) dissolved in anhydrous dichloromethane (1 mL) was added pyridine (18 uL, 0.22 mmol) and acetyl chloride (12.7 uL, 0.18 mmol) at room temperature. The reaction was maintained for 60 hours after which the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 5 to 95% over 15 min, UV detection at 214 nm and 254 nm) and the resulting residue after solvent removal was treated with aqueous 6N HCl (0.5 mL) and acetonitrile (2 mL). The solvent was removed under reduced pressure to give 41.4 mg (0.07 mmol, 47%) of the title compound as a colorless oil. MS (ESI) 581.0
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][C:11]([CH3:13])=O.O>C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:11](=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([CH3:13])[CH3:10]
Reactant: CC(C)=O
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)C(C(=O)OC)=C(C)C
Reaction time: 24 h

Procedure:
A solution of 51 grams (0.39 mol) of dimethyl malonate, 30 grams of acetone, and 2.5 grams of zinc chloride in 50 mL of acetic anhydride was refluxed with stirring for 24 hours. The solution was poured into ice and water, then extracted with 200 mL of dichloromethane. The organic phase was washed 2×150 mL water, dried over sodium sulfate and concentrated to a brown oil. After two distillations the 41 gram fraction collected at 25°-34° C. (0.1 mm Hg) gave satisfactory analytical for dimethyl isopropylidenemalonate.