Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21](O)=[O:22].CCCP(=O)=O.C(N(C(C)C)C(C)C)C>O1CCCC1.C(OCC)(=O)C>[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21]([NH:15][C:13]1[CH:12]=[CH:11][N:10]2[CH:16]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[N:14]=1)=[O:22]
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)ccn1
Reaction time: 18 h
Yield: 17.8 %

Procedure:
A mixture of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (156 mg, 0.766 mmol, 1 eq.), 2-methylisonicotinic acid (116 mg, 0.842 mmol, 1.1 eq.), propylphosphonic anhydride in ethyl acetate 50% (1.13 ml, 1.91 mmol, 2.5 eq) and ethyldiisopropylamine (0.535 ml, 3.06 mmol, 4 eq) in tetrahydrofuran (10 ml) is stirred for 18 hours at roomtemperature. The solution is then refluxed for 4 hours. The mixture is diluted with ethyl acetate and washed with sat. aqueous sodium bicarbonate, with water, dried over magnesium sulfate and the solvent is removed in vacuo. Purification of the residue by chromatography on a 12 g RediSep silica cartridge using dichloromethane+5% methanol as eluent affords 2-methyl-N-(2-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-isonicotinamide (45 mg, 17.8%) as a yellow solid. MS: m/e=330.2 (M+H+)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]O)[N:9]=1)[CH3:3].Cl.[NH2:13][CH2:14][CH2:15][SH:16].Br>C(O)C>[CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:16][CH2:15][CH2:14][NH2:13])[N:9]=1)[CH3:3]
Reactant: CN(C)Cc1nc(CO)cs1
Reactant: NCCS
Agent: Br
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1nc(CSCCN)cs1
Temperature: 100 °C
Reaction time: 11 h

Procedure:
A reaction mixture was prepared from 18.8 g. of 2-dimethylaminomethyl-4-thiazolemethanol, 12.8 g. of 2-aminoethanethiol hydrochloride (cysteamine hydrocloride) and 160 ml. of 48% aqueous hydrobromic acid. The reaction mixture was stirred at about 100° C. for about 11 hours. The volatile constituents were removed in vacuo on a rotary evaporator. Water was added and the volatile constituents again removed by evaporation. The resulting residue, comprising 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide formed in the above reaction, was dissolved in ethanol. The ethanol was evaporated and the resulting residue again dissolved in ethanol. Evaporation of the ethanol yielded a hygroscopic residue which was recrystallized from a methanol-ethyl acetate solvent mixture. 2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide thus prepared had the following physical characteristics:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](O)=[O:20])[CH2:15][CH2:14]1)=[O:12].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:11]([O:10][CH3:9])=[O:12])[CH2:18][CH2:17]1)=[O:20]
Reactant: O=C1CCC(=O)N1O
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)ON2C(=O)CCC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-hydroxysuccinimide (6.18 g, 0.0537 mol) and trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (10.00 g, 0.05370 mol) in THF (100.00 mL) was charged with (N,N′-dicyclohexylcarbodiimide (11.08 g, 0.0537 mol) in THF (16 mL). This reaction was stirred at rt for an additional 16 h then stirred at 45° C. for 1 h. The reaction mixture was filtered while still warm through a fritted funnel. The cake was washed with 3 more portions of THF and the filtrate was concentrated in vacuo and was crystallized from i-PrOH (300 mL) and filtered through a fritted funnel resulting in 11.8 g, (78% yield) of the title compound as a white crystals. 1H NMR (400 MHz, CDCl3) δ ppm 1.45-1.69 (m, 4H), 2.07-2.16 (m, 2H), 2.18-2.28 (m, 2H), 2.29-2.39 (m, 1H), 2.59-2.71 (m, 1H) 2.84 (br. s., 4H) and 3.68 (s, 3H); MS (ES+): m/z 284.09 [MH+].
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[Br:16]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].[Na].C(=O)([O-])O>C(#N)C>[Br:16][C:8]1[C:3]([NH:2][CH3:1])=[N:4][CH:5]=[C:6]([C:9]([F:15])([F:14])[C:10]([F:11])([F:12])[F:13])[CH:7]=1
Reactant: CNc1ccc(C(F)(F)C(F)(F)F)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CNc1ncc(C(F)(F)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
To a mixture of methyl-(5-pentafluoroethyl-pyridine-2-yl)-amine (4.6 g) and acetonitrile (70 mL), N-bromosuccinimide (5.0 g) was added under ice-cooling, and stirred at room temperature for 8 hours. Into a mixture, saturated aqueous sodium thiosulfate solution and aqueous sodium, hydrogen carbonate solution were poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 6.3 g of (3-bromo-5-pentafluoroethyl-pyridine-2-yl)-methyl-amine.
Reaction SMILES: COC([NH:5][C:6]12[CH2:14][N:13](C(OC)=O)[CH2:12][CH:11]1[CH:10]=[CH:9][CH:8]=[CH:7]2)=O>O>[CH2:12]1[CH:11]2[C:6]([NH2:5])([CH:7]=[CH:8][CH:9]=[CH:10]2)[CH2:14][NH:13]1
Reactant: COC(=O)NC12C=CC=CC1CN(C(=O)OC)C2
Solvent: O
Product: NC12C=CC=CC1CNC2

Procedure:
20 g of crude methyl 1-methoxycarbonylamino-8-azabicyclo[4.3.0]nona-2,4-diene-8-carboxylate are heated with 75 g (0.235 mol) of Ba(OH)2.8 H2O in 250 ml of water overnight under reflux. The BaCO3 is filtered off with suction, the filtrate is concentrated and the salt residues are boiled three times with 1,4-dioxane. The dioxane solutions are concentrated and the residue is distilled. Yield: 5 g (43.9% of theory based on Step D), boiling point: 65° C./0.2 mbar.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1
Reactant: OCc1ccc(Cl)c(OCc2ccc(F)cc2)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(OCc3ccc(F)cc3)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-3-[(4-fluorophenyl)methoxy]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.10 (2H, s), 5.18 (2H, s), 5.68 (1H, d, J=1.6 Hz), 6.97 (1H, dd, J=1.2 Hz, 8.0 Hz), 7.03-7.07 (3H, m), 7.39-7.43 (4H, m), 7.55 (1H, d, J=1.6 Hz), 8.04 (1H, s), 8.67 (1H, d, J=5.2 Hz). [M+H] Calc'd for C23H16ClFN4O2, 435. Found, 435.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[C:10]([N:17]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:9]=2)[CH2:4][CH2:3]1.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][N:42]=[C:41]2[NH2:47])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1>[CH2:30]([O:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][N:42]=[C:41]2[NH:47][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9][C:10]=1[N:17]([CH:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)[C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CN1CCN(c2ccc(C(=O)Cl)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Reactant: Nc1n[nH]c2ccc(OCc3ccccc3)cc12
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(OCc5ccccc5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Reaction time: 3 h
Yield: 75.1 %

Procedure:
4-(4-Methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoyl chloride (10.04 mmol), in dry pyridine (100 mL), under a nitrogen atmosphere, cooled to 4° C., was treated with 5-benzyloxy-1H-indazol-3-ylamine (2 g, 8.37 mmol) in pyridine (35 mL) and stirred for 3 hours. The mixture was concentrated in vacuo. The residue was added to iced water (350 mL) and extracted with EtOAc (400 mL and 2×200 mL). The combined organic layers were dried over anhydrous sodium sulfate. After removal of the volatiles a brown solid was obtained that was taken in Et20 (200 mL), stirred 2 hours at room temperature, filtered and dried at 50° C. under vacuum to afford 4 g of title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1>C(O)C>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:19]=[C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[S:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc([N+](=O)[O-])c3)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc([N+](=O)[O-])c3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 155a (34 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (13 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 3H) 1.72-1.92 (m, 2 H) 2.02 (s, 3 H) 2.99 (t, J=7.54 Hz, 2 H) 5.32 (s, 2 H) 6.30 (d, J=6.99 Hz, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.19-7.25 (m, 1 H) 7.27 (d, J=2.57 Hz, 1 H) 7.38 (d, J=8.82 Hz, 1 H) 7.43 (d, J=8.46 Hz, 2 H) 7.72 (t, J=7.91 Hz, 1 H) 7.81 (d, J=8.82 Hz, 1 H) 7.91 (d, J=7.72 Hz, 1 H) 8.22 (d, J=8.82 Hz, 1 H) 8.32 (s, 1 H) 8.37 (d, J=7.35 Hz, 1 H) 8.97 (d, J=8.82 Hz, 1 H) 9.98 (s, 1 H) 11.01 (s, 1 H) 14.37 (s, 1 H); MS (ESI+) m/z 580(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[Cl:14]N1C(=O)CCC1=O>CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[Cl:14])=[O:4]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Product: COC(=O)c1ccc2[nH]cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
A mixture of 1.4 g (8 mmol) 1H-indole-5-carboxylic acid methyl ester and 1.28 g (9.6 mmol) N-chlorosuccinimid in 40 mL methanol was stirred at room temperature for 16 h. The mixture was evaporated to dryness and taken up in DCM washed with 1N NaHCO3 aq, dried with MgSO4, filtered and evaporated to dryness to yield 1.05 g (62%) of the title compound. MS(m/e): 210.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][CH2:13][C:14](OC)(OC)OC>>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:6][C:14]([CH2:13][Cl:12])=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccc(Br)cc1N
Reactant: COC(CCl)(OC)OC
Product: O=c1[nH]c(CCl)nc2cc(Br)ccc12

Procedure:
Reflux a solution of 2-amino-4-bromobenzamide (27 g, 0.13 mol; see Joshi and Chaudhari, (1987) Indian J. Chem., Sect. B, 26B(6):602-4) in 2-chloro-1,1,1-trimethoxyethane (50 mL) for 30 minutes, during which time a large precipitate appears. Evaporate the mixture fully and triturate with ether to collect 28 g of 7-bromo-2-chloromethyl-3H-quinazolin-4-one as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:25]3[CH:26]=[CH:27][C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:23][CH:24]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1

Procedure:
-Benzyl-5-[4-(tert-butyl)phenyl]-1H-indole was prepared by coupling 1-benzyl-5-bromo-1H-indole (1.44 g, 5.03 mmol), and 4-(tert-butyl)phenylboronic acid (1.08 g, 6.07 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.204 g, 0.250 mmol), and potassium-carbonate (1.39 g, 10.1 mmol) in dioxane (50 mL) and water (5 mL) following the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using 0-5% chloroform in hexane as an eluant yielded the title compound as an aqua solid (0.741 g, 43%), mp: 136-137° C. 1HNMR (200 MHz, DMSO-d6): δ 7.8 (s, 1H), 7.2-7.6 (m, 12H), 6.55 (d, 1H, J=2.6 Hz), 5.45 (s, 2H), and 1.3 ppm (s, 9H).
Reaction SMILES: [C:1]1(S([O-])(=O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Na+].C=O.[Cl-].[K+].CC(C1CC[C@H]2C(=CC[C@H]3[C@@](C(O)=O)(C)CCC[C@@]32C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[K+].[CH2:52](N(CC(O)=O)CC(O)=O)[CH2:53][N:54](CC(O)=O)[CH2:55][C:56](O)=O.S([O-])[O-].C=O.[Na+].[Na+].C=CC1C=CC=CC=1.N1(CCC=CC2C=CC=CC=2)CCCC1.C(NO)(C)C>O>[CH2:7]=[CH:6][C:5]1[CH:10]=[CH:1][CH:2]=[CH:3][CH:4]=1.[CH2:10]=[CH:1][CH:2]=[CH2:3].[N:54]1([CH2:6][CH2:7][CH:8]=[CH:9][C:10]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:55][CH2:56][CH2:52][CH2:53]1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: O=S(=O)([O-])c1cccc2ccccc12
Agent: C(=Cc1ccccc1)CCN1CCCC1
Agent: C=O
Agent: CC(C)C1=CC2=CC[C@@H]3[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1
Solvent: C=Cc1ccccc1
Solvent: O
Product: C=CC=C
Reaction time: 6.25 h

Procedure:
In this experiment, an emulsion styrene/butadiene/pyrrolidinoethyl styrene (PES) terpolymer was prepared in a larger reactor. In the procedure utilized, 40.1 lbs. of soft water, 33 grams of sodium naphthalenesulfonate-formaldehyde dispersant (Daxad 14B from Hampshire Chemical Co., 47.5% active), 25.5 grams of potassium chloride, 767 grams of disproportionated rosin acid (potassium salt, 20% solution in water at pH 9.5), 2927 grams of C14-18 and C16-18 unsaturated mixed fatty acids (potassium salt, 10% solution in water at pH 9.5), and 5.82 grams of tripotassium phosphate were charged into a 10-gallon stainless steel reactor. Prior to charging to the reactor, the pH of the solution was adjusted to 10.2-10.8 with 20% potassium hydroxide. Next, 440 grams of soft water, 1.26 grams of ethylenediaminetetraacetic acid, ferric sodium complex (Akzo Nobel Chemicals Co.), and 7.75 grams of sodium formaldehyde sulfoxylate were added. Then, 3245 grams of styrene, 59.8 grams of PES (92% purity by GC), and 16.0 grams of tertiary dodecylmercaptan were added. The reactor was evacuated for 15 minutes, and 7700 grams of 1,3-butadiene was added. At 10° C., 10 grams of pinane hydroperoxide (55% active) was added. The emulsion polymerization was initiated at a temperature of 10° C. with the reactor being agitated at a speed of 250 rpm with two AFT blades. After 6.25 hours and about 65% conversion, the polymerization was shortstopped with a solution of 880 grams of soft water and 44 grams of isopropylhydroxylamine (15% active).
Reaction SMILES: N1(C2C=C[C:10]([NH:13][C:14]([C:16]3[NH:17][C:18]4[C:23](C(=O)C=3)=CC(OC)=CC=4Br)=O)=CC=2)CCOCC1.CN.[N:32]1([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]([C:47]3[CH:56]=[C:55]([NH:57][CH3:58])[C:54]4[C:49](=[C:50](Br)[CH:51]=[C:52]([O:59][CH3:60])[CH:53]=4)[N:48]=3)=[O:46])=[CH:40][CH:39]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[N:32]1([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]([C:47]3[CH:56]=[C:55]([NH:57][CH3:58])[C:54]4[C:49](=[C:50]([N:17]5[CH2:16][CH2:14][N:13]([CH3:10])[CH2:23][CH2:18]5)[CH:51]=[C:52]([O:59][CH3:60])[CH:53]=4)[N:48]=3)=[O:46])=[CH:40][CH:39]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CNc1cc(C(=O)Nc2ccc(N3CCOCC3)cc2)nc2c(Br)cc(OC)cc12
Reactant: COc1cc(Br)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Agent: CN
Product: CNc1cc(C(=O)Nc2ccc(N3CCOCC3)cc2)nc2c(N3CCN(C)CC3)cc(OC)cc12

Procedure:
The title compound was prepared from 8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (Reference Example 27b) according to the procedure described for Example 98 using N-methyl amine to prepare 8-bromo-4-methylamino-6-methoxy-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. A glassy orange solid was obtained. Mass Spec.: calc. for [C27H34N6O3+H]+ Theor. m/z=491; Obs.=491.5.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([NH:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: COC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccnc(OC)c1

Procedure:
TFA (5 mL) was added to a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(2-methoxypyridin-4-yl)propanoate (2.4 g, 7.7 mmol) in CH2Cl2 (10 mL) at 0° C. with stirring. The mixture was stirred for 1 h and then concentrated to dryness. The residue was azeotroped three times with EtOAc (10 mL for each portion) to remove residual TFA to afford crude (S)-methyl 2-amino-3-(2-methoxypyridin-4-yl)propanoate as its TFA salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[C:20]#[N:21]>CN(C)C=O.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=2[C:20]#[N:21])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1OCc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
4-Chloro-2-methylphenol (0.12 g, 0.83 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.2 g, 0.83 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried to yield 155 mg of 2-(4-chloro-2-methylphenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.[N+](C1C=C[C:26]([N:29](C)[C:30](=O)[O-:31])=CC=1)([O-])=O>CN(C)C=O>[CH3:26][NH:29][C:30](=[O:31])[NH:1][CH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1
Reactant: NCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: CN(C(=O)[O-])c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CNC(=O)NCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
A mixture of 1 g of 8-aminomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one and 1.8 g of 4-nitrophenyl-N-methylcarbamate in 40 ml of dimethylformamide is stirred for 18 hours at a temperature in the region of 20° C. The reaction mixture is filtered and washed with 5 ml of dimethylformamide. The solid is taken up in 25 ml of dimethylformamide and the suspension is heated at 100° C. for 30 minutes. The insoluble material is filtered and washed with 5 ml of dimethylformamide and then with 20 ml of acetone. After drying under reduced pressure (1 mbar) at 60° C., 1.2 g of 8-(3-methylureido)methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a yellow solid, the melting point of which is greater than 260° C. (Analysis; % Calculated C: 62.13, H: 4.89, N: 22.64; % Found C: 62.0, H: 4.5, N: 22.6).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH:12]=O)=[O:11])[CH3:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:19][CH2:20][NH2:21].COC1C=C(C=CC=1OC)CCN=C(OC)C(C1C=CC=CC=1)=O.[BH4-].[Na+].[ClH:53]>C(O)C>[ClH:53].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:19][CH2:20][NH:21][CH2:12][CH:10]([OH:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CCOc1ccccc1C(=O)C=O
Agent: COC(=NCCc1ccc(OC)c(OC)c1)C(=O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Solvent: CCO
Product: CCOc1ccccc1C(O)CNCCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.1 g of 2-ethoxyphenylglyoxal (crude oil) are dissolved in 20 ml of ethanol, and 1.85 g of 3,4-dimethoxyphenethylamine are added thereto. The solution is stirred at room temperature for 30 minutes, whereby a solution containing α-(3,4-dimethoxyphenethylimino)-2-methoxyacetophenone is obtained. 0.6 g of sodium borohydride is added gradually to said solution under ice-cooling, and the mixture is stirred at room temperature for one hour. The reaction mixture is evaporated to remove solvent. Water is added to the thus obtained residue. Then, the aqueous mixture is extracted with chloroform. The extract is washed with water, dried and then evaporated to remove solvent. The oily residue thus obtained is treated with hydrochloric acid and recrystallized from a mixture of isopropanol and ether. 3.1 g of α-(3,4-dimethoxyphenethylaminomethyl)-2-ethoxybenzylalcohol hydrochloride are obtained. M.p. 169°-170° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:5][C:6]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([OH:20])=O)=[CH:11][CH:10]=1.CN(C(ON1N=[N:46][C:41]2[CH:42]=CC=N[C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>ClCCl.CN(C=O)C>[CH:41]([NH:46][C:18]([CH:16]1[CH2:17][CH:15]1[C:12]1[CH:13]=[CH:14][C:9]([NH:8][CH2:7][C:6]2[S:5][C:4]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=3)=[N:3][C:2]=2[CH3:1])=[CH:10][CH:11]=1)=[O:20])([CH3:42])[CH3:40]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CNc1ccc(C2CC2C(=O)NC(C)C)cc1
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
To a mixture of (+)-(trans)-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylic acid (III-3c) (0.12 g, 0.28 mmol) in dichloromethane (2 mL) and DMF (1 mL) was added HATU (0.16 g, 0.42 mmol). The mixture was stirred for 15 min followed by addition of isopropylamine (0.02 g, 0.33 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a yellow ppt which was filtered and dried under high vacuum to give the title compound as a yellow powder (0.08 g, 61%). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 6.59 (d, J=8.4 Hz, 2H), 5.49 (d, J=7.9 Hz, 1H), 4.44 (s, 2H), 4.13-4.08 (m, 1H), 2.49 (s, 3H), 2.40-2.37 (m, 1H), 1.56-1.51 (m, 1H), 1.44-1.39 (m, 1H), 1.26-1.10 (m, 7H). ES-MS m/z 474.2 (MH+).