Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][NH2:15])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1c[nH]c(-c2ccccc2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCc1c[nH]c(-c2ccccc2)n1
Temperature: 2.5 °C
Yield: 77.2 %

Procedure:
To a solution of 2-[3-(2-phenyl-1H-imidazol-4-yl)-propyl]-isoindole-1,3-dione (4.16 g) in ethanol (50 ml) was added hydrazine hydrate (3.18 g). The reaction mixture was stirred under reflux for 4 h, cooled down to 0-5° C., and the precipitate was filtered off. The filtrate was concentrated, and the oily residue was quenched with cooled 1 N NaOH solution (20 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and concentrated to dryness to obtain 3-(2-phenyl-1H-imidazol-4-yl)-propylamine (1.95 g) as a yellow foam, which was sufficiently pure to be used directly in the next step.
Reaction SMILES: [C:1]1([CH:7]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[C:1]1([CH:7]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[CH2:8][C:9]([NH2:24])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
To a stirred solution of 3-phenyl-3-(1-oxoisoindolin-2-yl)propionic acid (0.703 g, 2.50 mmol) in 15 mL of tetrahydrofuran under nitrogen was added carbonyldiimidazole (0.438 g, 2.70 mmol), and a few crystals of 4-N,N-dimethylaminopyridine [DMAP]. The reaction mixture was stirred for 1.5 hours and then 0.25 mL of 15 N ammonium hydroxide was added. After 20 minutes, the reaction mixture was concentrated in vacuo and the residue slurried in water. The resulting solid was isolated by filtration and dried in vacuo to afford 0.58 g (80%) of crude product as an off-white powder. The crude product was recrystallized from ethanol to afford 0.403 g (57%) of 3-phenyl-3-(1-oxoisoindolin-2-yl)-propionamide as white prisms: 1H NMR (DMSO-d6, 250 MHz) 7.8-7.2 (m, 10H), 6.92 (br s, 1H), 5.81 (overlapping dd, 1H) 4.59 (d, J=17.5 Hz, 1H), 4.16 (d, J=17.5 Hz, 1H), 3.1-2.8 (m, 2H); 13C NMR (DMSO-d6) 171.3, 167.0, 140.7, 132.2, 131.4, 128.6, 127.9, 127.5, 126.9, 123.5, 122.8, 51.5, 46.3, 37.9; Anal. Calcd for C17H16N2O2: Theory C, 72.84; H, 5.75; N, 9.99. Found: C, 72.46; H, 5.68; N, 9.91.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([CH:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:26]2=O)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:26]2[CH2:27][CH2:28][C:29]3[C:34]([C:25]=2[C:23](=[O:24])[C:22]2[CH:38]=[CH:39][C:19]([O:18][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:20][CH:21]=2)=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CCC(=O)C2C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(C(=O)c3ccc(OCc4ccccc4)cc3)c3ccc(OC)cc3CC2)cc1
Temperature: 45 °C

Procedure:
To a solution of about 50 grams (0.24 mole) of p-methoxyphenylmagnesium bromide in tetrahydrofuran (THF) were added at room temperature 30.2 grams (0.08 mole) of 1-(p-benzyloxybenzoyl)-6-methoxy-2-tetralone dissolved in THF. Upon completion of the addition, the entire mixture was warmed to 45° C. Analysis of a sample of the mixture by thin-layer chromatography (TLC) showed the absence of starting material. The mixture then was poured into aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extract was washed, dried, and evaporated. The resulting residue was dissolved in benzene, and a catalytic amount of p-toluene- sulfonic acid was added. The mixture was stirred at room temperature until a TLC of the mixture indicated the absence of any carbinol intermediate. The mixture then was washed with water, dried, and concentrated. The residue was chromatographed over one kg. of alumina using 6 l. of benzene. The product was eluted with a mixture of 2 percent ethyl acetate in benzene. The product, 3-(4-methoxyphenyl)-4-(4-benzyloxybenzoyl)-7-methoxy-1,2-dihydronaphthalene was obtained as an oil.
Reaction SMILES: II.[CH2:3]1[O:14][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)[O:5][CH2:4]1.CO[CH:17]=[C:18]=[CH2:19].[Cl-]>C1COCC1.[Cu]Cl>[CH2:3]1[O:14][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:19][C:18]#[CH:17])[CH:8]=2)[O:5][CH2:4]1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: C=C=COC
Agent: Cl[Cu]
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: C#CCc1cccc(C2OCCO2)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Dry Mg (0.74 g) under dry N2 in a flask is covered with THF (10 ml) and a crystal of I2 added. 5 ml of a solution of 3-bromobenzaldehyde ethylene acetal (7.0 g) in THF (30 ml) is added and kept until it becomes warm, when it is cooled to 15°, and the remainder of the acetal solution added over 15 minutes, then stirred for an additional 1 hour. A mixture of methoxyallene (2.45 g), copper (1)chloride (0.30 g) and THF (30 ml) is cooled to -20°. The above Grignard solution (under moisture excluding conditions) is then added to this solution during 5 minutes, and allowed to warm to 20° C. with stirring over 30 minutes. Saturated aqueous ammnium chloride is added and the product is extracted with ether. The ether layer is washed with water, dried (MgSO4) and the residue distilled in vacuo. Yield 4.3 g (75%) 89°-96° (0.03 m Hg), nD20 1.5422.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH2:12]([NH2:18])[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([O:21][C:22]([C:24]1[C:25]([C:46]2[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=2)=[C:26]2[C:41](=[O:42])[N:40]3[CH2:43][CH2:44][CH2:45][N:39]3[C:27]2=[N:28][C:29]=1[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)=[O:23])[CH3:20].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][C:29]2[N:28]=[C:27]3[N:39]4[CH2:45][CH2:44][CH2:43][N:40]4[C:41](=[O:42])[C:26]3=[C:25]([C:46]3[CH:54]=[CH:53][C:49]([C:50]([NH:18][CH2:12][C:13]4[O:17][CH:16]=[CH:15][CH:14]=4)=[O:51])=[CH:48][CH:47]=3)[C:24]=2[C:22]([O:21][CH2:19][CH3:20])=[O:23])=[CH:33][CH:34]=1
Reactant: NCc1ccco1
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)c(=O)n1n2CCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)c(=O)n1n2CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.3 %

Procedure:
EDCI (31 mg, 0.16 mmol) was added to a solution of furfuryl amine (14 mg, 0.15 mmol), the product from Step E (71 mg, 0.15 mmol) and HOBT.H2O (20 mg, 0.15 mmol) in DMF (2.5 mL). The reaction was stirred 4 h at rt and then concentrated at reduced pressure. The remaining material was dissolved in CH2Cl2, washed with water, dried, filtered and concentrated. Chromatography on silica gel afforded the title compound as a yellow solid (30 mg, 0.05 mmol, 33%): 1H NMR (400 MHz, DMSO-d6) δ 9.06 (t, 1H, J=6), 7.89 (d, 2H, J=8), 7.56 (br s, 1H), 7.38 (d, 2H, J=8), 7.22 (br t, 2H J˜8), 7.07 (t, 2H, J=9), 6.37 (br s, 1H), 6.26 (d, 1H, J=3), 4.46 (d, 2H, J=6), 3.90 (m, 4H), 3.77 (t, 2H, J=7), 3.06 (m, 2H), 2.99 (m, 2H), 2.54 (quint., 2H, J=7), 0.78 (t, 3H, J=7) ppm; ESI-MS m/z 569 (M+H)+;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:12])[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1>CN(C=O)C.COC(OC)(C)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:10][O:11][C:13]([CH3:18])([CH3:14])[O:12]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCC(O)Cc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(Cc2ccc(Br)cc2)O1
Yield: 1994.1 %

Procedure:
A solution of 3-(4-bromo-phenyl)-propane-1,2-diol (1.41 g, 6.10 mmol) and p-toluenesulfonic acid (50 mg) in DMF (10 mL), 2,2-dimethoxypropane (10 mL) is stirred at rt for 2 h. The reaction mixture is diluted with sat. aq. NaHCO3 (150 mL) and extracted with diethyl ether (2×200 mL). The organic extracts are washed with water (200 mL), dried over MgSO4 and evaporated to give 4-(4-bromo-benzyl)-2,2-dimethyl-[1,3]dioxolane (1.57 g) as a pale brownish oil; LC-MS: tR=1.00 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1.C(N(CC)CC)C.[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[C:24]([C:25]([NH:39][CH:36]4[CH2:38][CH2:37]4)=[O:27])=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=2)[CH:7]=1
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Reactant: NC1CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-yl-amino]-nicotinic acid (40 mg, 0.10 mmol, 1 eq) in dry DMF (1 ml) was added triethylamine (15 μl, 0.11 mmol, 1.1 eq) followed by cyclopropylamine (70 μl, 0.10 mmol, 10 eq). To the suspension was added a solution of PyBrOP (56 mg, 0.21 mmol, 1.2 eq) in DMF (500 μl) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2×20 ml). The crude residue was purified by flash column chromatography (0-5% MeOH in CHCl3) to give 4-[2-(5-Chloro-2-fluorophenyl)-5,6,7,8-tetrahydroquinazolin-4-ylamino]-N-cyclopropyl nicotinamide, compound of formula (45), (15 mg, 34%) as a white solid.
Reaction SMILES: [CH3:1]Cl.[Cl:3][C:4]1[C:12]([Cl:13])=[C:11]2[C:7]([CH2:8][CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]2=[O:14])=[CH:6][C:5]=1[O:21][CH3:22].[Br-].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:3][C:4]1[C:12]([Cl:13])=[C:11]2[C:7]([CH2:8][C:9]([CH3:1])([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]2=[O:14])=[CH:6][C:5]=1[O:21][CH3:22]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Reactant: CCl
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A 35 ml glass pressure bottle, fitted with an efficient magnetic stirrer was charged with 25 ml of toluene. Methyl chloride (1.01 g, 20 mmole) were dissolved in the toluene and to this solution there were added 0.61 g (2 mmole) of 6,7-dichloro-5-methoxy-2-phenyl-1-indanone, 0.21 g (0.4 mole) of N-p-(trifluoromethylbenzyl) cinchoninium bromide and 5 ml of 50% aqueous sodium hydroxide. The reaction mixture was sealed with a screw cap and vigorously stirred for 18 hours at room temperature (22°-25° C.). The reaction mixture was then diluted with 25 ml of toluene and 15 ml of water. The aqueous layer was separated and the toluene layer was washed twice with 25 ml of 4N hydrochloric acid. An aliquot of the toluene solution was concentrated in vacuo to dryness on a rotary evaporator. An LC assay indicated a 98% yield while an NMR assay using the chiral shift reagent [tris-[3-heptafluoropropylhydroxymethylene)-d-camphorato]europium (III)] showed a (+):(-) isomer ratio of 95.3:4.7.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Br.[CH2:35]1[C:38]2([CH:42]([NH:43][C:44]3[C:45]4[N:46]([CH:53]=[C:54]([C:56]5[CH:57]=[N:58][N:59]([CH3:61])[CH:60]=5)[CH:55]=4)[N:47]=[CH:48][C:49]=3[C:50]([NH2:52])=[O:51])[CH2:41][NH:40][CH2:39]2)[CH2:37][CH2:36]1.[CH:62]1([C:65]([O-])=[O:66])[CH2:64][CH2:63]1>CN(C=O)C>[CH:62]1([C:65]([N:40]2[CH2:41][C@@H:42]([NH:43][C:44]3[C:45]4[N:46]([CH:53]=[C:54]([C:56]5[CH:57]=[N:58][N:59]([CH3:61])[CH:60]=5)[CH:55]=4)[N:47]=[CH:48][C:49]=3[C:50]([NH2:52])=[O:51])[C:38]3([CH2:37][CH2:36][CH2:35]3)[CH2:39]2)=[O:66])[CH2:64][CH2:63]1
Reactant: O=C([O-])C1CC1
Reactant: Cn1cc(-c2cc3c(NC4CNCC45CCC5)c(C(N)=O)cnn3c2)cn1
Agent: Br
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: Cn1cc(-c2cc3c(N[C@@H]4CN(C(=O)C5CC5)CC45CCC5)c(C(N)=O)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 200 uL aliquot of HATU (23.41 mg, 0.062 mmol) and diisopropylethylamine (21.51 μl, 0.123 mmol) were added to a 200 uL aliquot of 4-(6-azaspiro[3.4]octan-8-ylamino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide HBr (from Step 6, 15 mg, 0.041 mmol) and cyclopropane carboxylate (1.5 equiv.) in DMF. The reaction was stirred for 3 h at room temperature. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (3.9 mg). 1H NMR (500 MHz, METHANOL-d4/CDCl3) δ 8.11 (d, J=11.9 Hz, 1H), 7.80 (d, J=9.9 Hz, 1H), 7.78-7.71 (m, 2H), 6.91 (dd, J=14.1, 1.7 Hz, 1H), 4.83-4.75 (m, 1H), 4.13 (dd, J=10.4, 5.0 Hz, 1H), 4.07-3.99 (m, 1H), 3.96 (s, 1.5H), 3.94 (s, 1.5H), 3.98-3.76 (m, 2H), 2.37 (dd, J=11.1, 7.2 Hz, 1H), 2.28-1.95 (m, 5H), 1.12-0.70 (m, 4H)
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](Cl)=[O:7].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2[O:25][CH3:26].CCOCC>C(O)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2[O:25][CH3:26])=[O:7]
Reactant: COc1cc(C)nc2ccc(N)cc12
Reactant: O=C(Cl)C=Cc1ccccc1Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc(C)nc2ccc(NC(=O)C=Cc3ccccc3Cl)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chlorocinnamoyl chloride (prepared by treatment of 2-chlorocinnamic acid with oxalyl cloride and catalytic DMF in dichloromethane) (0.27 gm) in 1 mL acetic acid was added to a solution of 6-amino-4-methoxy-2-methyl-quinoline (0.25 g, 1.33 mmol) in glacial acetic acid (3 mL). A heavy precipitate formed, and the mixture was stirred for 1 h at room temperature. Ether (25 mL) was added and the solid was filtered, washed with ether, and dried by suction. The hydrochloride salt was suspended in warm water (25 mL) and ethanol (25 mL) and heated until dissolved. After cooling to room temperature, 5N sodium hydroxide was added to give a white precipitate that was filtered, and washed with water. Recrystallization from ethanol afforded the title compound; yield 0.27 g (58%); m.p. 228-229°; MS (FAB): m/z 353 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:26][C:27](=[O:38])[C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29].[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:33]([O:32][C:31]([NH:30][C@@H:28]([CH3:29])[C:27](=[O:38])[CH2:26][NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 73.4 %

Procedure:
To a stirred solution of L-phenylalanyl-L-leucine, t-butyl ester (2.18 g, 6 mmol) in 10 ml of dimethylformamide (under argon) was added a solution of [(S)-3-chloro-1-methyl-2-oxopropyl]carbamic acid, 1,1-dimethylethyl ester (1.33 g, 6 mmol) in 20 ml of dimethylformamide, followed by sodium iodide (450 mg, 3 mmol) and sodium bicarbonate (504 mg, 6 mmol). The reaction mixture was allowed to stir for 15 hours, then the solvent was evaporated (<25C° C., vacuum pump). The yellow residue was taken up into ethyl acetate (250 ml) and washed with water (4×25 ml) and brine (25 ml), then dried (sodium sulfate) and evaporated to a yellow residue (3.44 g). Flash chromatography on silica gel (Merck, 230-400 mesh, 250 g) with hexane-ethyl acetate (1.25:1) yielded 2.29 g of a colorless oil. Rapid recrystallization from ethyl acetate-hexane afforded 1.61 g of a powdery white solid.
Reaction SMILES: [C:1](O)(=O)C.O.[CH:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C=O>[CH2:1]=[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[O:13]
Reactant: CC(=O)O
Reactant: CCCCCCC=O
Agent: C=O
Solvent: O
Product: C=C(C=O)CCCCC
Temperature: 50 °C

Procedure:
A 3-liter three-neck flask fitted with an overhead stirrer and condenser was charged with di-N-butyl amine (33 g, 0.25 mol) and acetic acid (31 g, 0.5 mol). Roughly 500 ml of 33% formaldehyde solution in water (178 g formaldehyde, 5.9 mol) was then added and the resulting solution was heated to 50° C. with stirring. After this temperature was reached heptanal (500 g, 4.3 mol) was fed in over about 1.5 h. A slight exotherm was noticed during the feed. Monitoring by GC showed the consumption of heptanal and the production of 2-methylene heptanal, finally reaching roughly 95% conversion after the addition was complete. The reaction mixture was allowed to cool to room temperature, poured into a separatory funnel, and washed once with 5% HCl solution. The organic layer was then washed once with saturated sodium carbonate, then taken directly on to the next step.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O1CCOCC1>[NH:12]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[NH2:13]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1ccc(C(=O)O)cn1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A suspension of 6-chloronicotinic acid (30.0 g, 189 mmol) in 1,4-dioxane (29.0 mL) was treated with hydrazine hydrate (134 mL, 1.51 mol) and heated to 90° C. overnight. The mixture was cooled to ambient temperature and then in ice for 30 min. Precipitate formation was induced by etching the side of the flask and the precipitate was filtered and re-suspended in EtOH (500 mL) with vigorous stirring. The resulting suspension was filtered. The precipitate was dissolved in water (300 mL) and HCl (6N) was added until pH=1. The pH was then adjusted to 5 with NaOH (50%, aq.) and the resulting suspension was stirred for 1 h. The solids were collected by filtration and dried in vacuum to give the title compound (16.65 g, 57.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.70 (d, 1H) 7.86 (dd, J=8.97, 2.15 Hz, 1H) 8.32 (br. s., 1H) 8.52 (d, J=1.77 Hz, 1H). MS m/z [M+H]+ 154.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[OH-].[K+].[CH3:14]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of 5-methoxyindole (1 g, 6.8 mmol) in 8 mL of DMF were added potassium hydroxide (0.92 g, 2.4 eq.) and methyl iodide (1 mL, 16 mmol). The resulting mixture was stirred at room temperature overnight. After removing volatile, the residue was diluted with EtOAc and washed with water (4×). The organic layer was dried and concentrated to afford 0.9 g (82%) 5-methoxy-1-methylindole. MS (EI): (M++1) 162.
Reaction SMILES: Cl.[CH:2]1([C:7]([NH2:9])=[NH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:11](=[CH2:14])[C:12]#[N:13]>>[CH:2]1([C:7]2[N:9]=[C:12]([NH2:13])[CH:11]=[CH:14][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)C1CCCC1
Agent: Cl
Product: Nc1ccnc(C2CCCC2)n1
Yield: 25.9 %

Procedure:
This material was obtained in analogy to example 2, step A] via the alternative preparation method from cyclopentanecarboxamidine hydrochloride (CAS 68284-02-6) (500 mg) and 2-chloroacrylonitrile (324 mg) to give 2-cyclopentyl-pyrimidin-4-ylamine as an amorphous glass (142 mg). MS (ESI): 164.6 (MH+). This material was contaminated with several side products that could not be identified.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[N:14])[C:6]=2[CH:15]=1.[C:17]1(=O)[O:22][C:20](=[O:21])[CH:19]2[CH2:23][CH2:24][CH:25]=[CH:26][CH:18]12.C(O)(=O)C>O>[C:13]([CH2:12][N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[C:20](=[O:21])[C:19]4[CH2:23][CH2:24][CH2:25][CH2:26][C:18]=4[C:17]3=[O:22])[C:3]([F:16])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])#[N:14]
Reactant: N#CCN1C(=O)COc2cc(F)c(N)cc21
Reactant: O=C1OC(=O)C2CCC=CC12
Solvent: CC(=O)O
Solvent: O
Product: N#CCN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 73.5 %

Procedure:
6-amino-4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (0.5 g), tetrahydrophthalic anhydride (0.38 g) and acetic acid (10 ml) were mixed with each other, then the mixture was refluxed under heating for 3 hours. After the liquor was allowed to cool, it was added to water (40 ml), and separating crystals were collected by filtration, and then the crystals were dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with a saturated solution of sodium bicarbonate, and water, in that order, and then dehydrated with anhydrous sodium sulfate, and subsequently concentrated. Separated crystals were washed with a small amount of ether to give the desired 2-[4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-on 6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.59 g). mp. 227°-229° C.
Reaction SMILES: [CH:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH2:26])=O)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[CH:1]1([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:26])=[CH:22][CH:23]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(N2CCN(CCC3CCc4ccccc43)CC2)cc1
Reaction time: 2 h

Procedure:
A mixture of 4-[2-(indan-1-yl)ethyl]-1-(4-carboxamido)phenylpiperazine (CXII, EXAMPLE 77, 0.7 g, 2 mmol), phosphorous oxychloride (0.93 ml, 10 mmol) in dimethylformamide (20 ml) is heated at 80° for 2 hr. The mixture is stirred for 2 hr and quenched with sodium hydroxide (20%) until the pH>13. The mixture is extracted with ethyl acetate (800 ml), and the organic phase is washed with saline, dried (magnesium sulfate), filtered and concentrated. The concentrate is purified by liquid chromatography on silica gel 60 (400 g), eluting with hexane/ethyl acetate (1/1). The appropriate fractions homogeneous by TLC are combined and concentrated to give the free base of title compound, which is converted into the hydrochloric acid salt and crystallized from hexane/ethyl acetate to give the title compound, mp 157-158°, NMR (CDCl6, TMS) 7.62-6.92 and 3.94-1.46 δ.