Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([CH2:17]O)[CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[S:7])(C)(C)C.[ClH:19]>C(O)C>[ClH:19].[ClH:19].[N:12]1[CH:13]=[CH:14][N:15]=[CH:16][C:11]=1[CH2:10][CH:9]1[CH2:17][S:7][C:6]([NH2:5])=[N:8]1
Reactant: CC(C)(C)NC(=S)NC(CO)Cc1cnccn1
Agent: Cl
Solvent: CCO
Product: NC1=NC(Cc2cnccn2)CS1

Procedure:
A solution of 7.2 g of N-(tert-butyl)-N′-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)ethyl]thiourea in 20 cm3 of 5N hydrochloric acid is heated at a temperature in the region of 110° C. for 20 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 55° C. and then taken up in ethanol and concentrated under the same conditions as above. The residue is chromatographed at atmospheric pressure on a column of silica gel (particle size 40-60 diameter 4 cm; height 30 cm), eluting with an acetic acid/water/ethyl acetate mixture (1/1/4 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions. The oil obtained is taken up in ethanol and the precipitate obtained is filtered off and then dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. to give 2.9 g of (4RS)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine dihydrochloride in the form of a brown solid melting at 190° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm) 3.23 (d, J=6 Hz: 2H); 3.43 (dd, J=11.5 and 5.5 Hz: 1H); 3.72 (dd, J=11.5 and 7.5 Hz: 1H); 4.74 (mt: 1H); 8.59 (broad s: 1H); 8.64 (broad s: 1H); 8.67 (broad s: 1H); 9.29 (unresolved complex: 1H); 9.77 (unresolved complex: 1H); 10.16 (broad s: 1H)].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Si]([C:16]([F:19])([F:18])[F:17])(C)(C)C.Cl>C1COCC1.[F-].[Cs+]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[C:16]([F:19])([F:18])[F:17])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1cc(C=O)ccc1F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cc(C(O)C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
2-Fluoro-5-formyl-benzonitrile (5 g, 33.5 mmol) and CsF (51 mg, 0.335 mmol) in THF (10 mL) were treated with TMSCF3 (4.77 g, 33.5 mmol) at room temperature for 2 hours. The reaction was then treated with 4 N HCl (5 mL) and stirred at room temperature for 30 min. The solvent was removed and the residue was partitioned between ether and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude material, purified by silica gel column (hexanes:ethyl acetate 3:1) to afford the title compound as colorless solid (4.5 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:19](=[O:40])[NH:20][C:21]3[S:22][C:23]([S:26][CH2:27][CH2:28][N:29]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:24][N:25]=3)[C:5]2=[CH:6][CH:7]=1.O.NN>C(O)C>[NH2:29][CH2:28][CH2:27][S:26][C:23]1[S:22][C:21]([NH:20][C:19]([N:8]2[C:5]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9]2)=[O:40])=[N:25][CH:24]=1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCN3C(=O)c4ccccc4C3=O)s1)c1ccc(Cl)cc12
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCN)s1)c1ccc(Cl)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
Methyl 5-chloro-1-((5-((2-(1,3-dioxoisoindolin-2-yl)ethyl)thio)thiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (56 mg, 0.094 mmol) was dissolved in ethanol (3 mL). Thereafter, hydrazine monohydrate (0.007 mL, 0.14 mmol) was added to the above obtained solution, and the thus obtained mixture was then stirred at 90° C. for 3 hours. Thereafter, insoluble matters were removed by filtration, and the reaction solution was then concentrated in vacuo. The obtained residue was purified by preparative thin-layer column chromatography (chloroform:saturated ammonium methanol=10:1) to obtain the captioned compound (20 mg, 46%) in the form of a white solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH2:50][OH:51])[CH2:48][OH:49].NCCN1CC[O:59][CH2:58]C1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:41][C:58]([NH:46][C:47]([CH2:50][OH:51])([CH3:52])[CH2:48][OH:49])=[O:59])=[CH:33][C:32]=3[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(N)(CO)CO
Reactant: NCCN1CCOCC1
Product: Cc1cc(OCCCNC(=O)NC(C)(CO)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 19 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and 4-(2-aminoethyl)-morpholine, respectively.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]([C:22]1[CH:26]=[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>ClCCl>[C:1]([NH:8][CH:9]([C:22]1[CH:26]=[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])[O:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCC(N)c1coc([Si](C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCC(NC(C)=O)c1coc([Si](C)(C)C)c1
Reaction time: 8 h

Procedure:
Acetic anhydride (0.1 ml) was added to a solution of 3-(1-aminotridecyl)-5-trimethylsilylfuran (89.8 mg, 0.27 mmol) and triethylamine (0.1 ml) in dichloromethane (1 ml) at room temperature. Stirring was continued overnight (14 hours) while the cooling bath attained room temperature. The residue, after solvent removal, was purified by preparative TLC (20×20 cm, 1000u; developed with 60% ethyl ether/hexane). The title amide was obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:14]([O:18]C(N1CCC(O)C1)=O)(C)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[NH2:39][C:40]1[CH:55]=[CH:54][CH:53]=[CH:52][C:41]=1[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=1)=[O:43].[N-]=C=O>C(Cl)Cl.C(N(CC)CC)C>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:14]([NH:39][C:40]2[CH:55]=[CH:54][CH:53]=[CH:52][C:41]=2[C:42]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=2)=[O:43])=[O:18])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)C1
Reaction time: 16 h
Yield: 35 %

Procedure:
A solution of 3-amino-1-tert-butoxycarbonylpyrrolidine (200 mg, 1.08 mmol; prepared from 1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine using a similar procedure to that described in Example 77-B) and triethylamine (0.38 mL) in methylene chloride (3.5 mL) was added dropwise to a solution of triphosgene (120 mg, 0.403 mmol) in methylene chloride (2 mL). After complete addition, a solution of 2-amino-N-(5-chloropyridin-2-yl)benzamide (242 mg, 0.983 mmol) and triethylamine (0.38 mL) in methylene chloride (3.5 mL) was added in one portion. After 16 h, the mixture was treated with an additional equivalent of the isocyanate. After 1 h, the mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was washed with 0.5 N HCl (2×), satd sodium bicarbonate (1×), water, brine, dried with sodium sulfate, and concentrated. The residue was purified by column chromatography (SiO2: 40 to 50% EtOAc in hexanes) affording 160 mg (35%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(OC([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:25]([NH:26][CH:27]([CH3:29])[CH3:28])=[CH:24][N:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)=O)C>ClCCl.[OH-].[Na+]>[CH3:29][CH:27]([NH:26][C:25]1[C:20]([N:17]2[CH2:16][CH2:15][NH:14][CH2:19][CH2:18]2)=[N:21][CH:22]=[N:23][CH:24]=1)[CH3:28]
Reactant: CC(C)Nc1cncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Nc1cncnc1N1CCNCC1

Procedure:
Trifluoroacetic acid (5 ml) is added to a solution of 1-[1,1-dimethylethoxy-carbonyl]-4-[5-(1-methylethylamino)-4-pyrimidinyl]piperazine (PREPARATION 29, 0.37 g) in dichloromethane (20 ml) at - 78°. The reaction is allowed to warm to 20°-25° overnight, and then diluted with excess aqueous sodium hydroxide solution (10%). The phases are separated. The aqueous phase is extracted twice again with dichloromethane. The combined organic extracts are washed with saline, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound, NMR (CDCl3) 1.25, 1.7, 3.01, 3.21, 3.45, 3.5, 7.86 and 8.34 δ.
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[N:3][N:4]=[C:5]([CH3:7])[CH3:6].[CH2:9]([Mg]Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C.O1CCCC1>[CH3:6][C:5]([NH:4][N:3]=[C:2]([CH3:8])[CH3:1])([CH3:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)=NN=C(C)C
Reactant: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)=NNC(C)(C)Cc1ccccc1
Temperature: 45 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
Acetone azine (1.50 g, 13.4 mmol) was dissolved in 10 mL of diethyl ether, mixed with 32 mL (19.2 mmol) of 0.6 M benzylmagnesium bromide in tetrahydrofuran and stirred at 45° C. for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride (100 ml), and the reaction solution was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (9:1 to 6:1) as the eluent to give 710 mg of the desired product as a pale yellow oil.
Reaction SMILES: [N+:1]([O-])(O)=O.[Cl:5][C:6]1[C:11]2[CH2:12][C:13]([CH3:16])([CH3:15])[O:14][C:10]=2[C:9]([C:17]([OH:19])=[O:18])=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[NH2:1][C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]2[O:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]=2[C:6]=1[Cl:5]
Reactant: CC1(C)Cc2c(Cl)ccc(C(=O)O)c2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)Cc2c(Cl)c(N)cc(C(=O)O)c2O1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 40 ml of nitric acid and 40 ml of sulfuric acid cooled to 5° C. by means of an external ice bath were added 10 g of 4-chloro-2,2-di-methyl-2,3-dihydro-7-benzofurancarboxylic acid over a period of 28 minutes. After stirring at 5° C. for 10 minutes, the mixture was added to ice with stirring. The resulting solid was collected by filtration and washed with water. After air drying, the residue was crystallized twice from ethyl acetate/hexane to provide 3.5 g of the desired subtitle intermediate, m.p. 260°-262° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:24])[C@@H:21]([CH3:23])[NH2:22].C([BH3-])#N.[Na+]>>[CH3:18][O:19][C:20](=[O:24])[C@@H:21]([CH3:23])[NH:22][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)[C@@H](C)NCc1ccc(-c2ccccc2C#N)cc1

Procedure:
The starting material can be obtained, for example, analogously to Example 1b): Reaction of 2.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 9.6 g of molecular sieve 5 A, 1.34 g of (D)-alanine methyl ester hydrochloride and 680 mg of sodium cyanoborohydride yields N-[(2'-cyanobiphenyl-4-yl)methyl]-(D)-alanine methyl ester after flash chromatography (N3). 1H-NMR (DMSO): 1.21 ppm (d, 3H), 3.63 ppm (s, 3H), 3.75 ppm (dd, 1H), 4.56 ppm (d, 2H), 4.58 ppm (d, 2H), 5.31 ppm (t, 1H), 7.4-8 ppm aromatics.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30](O)=[O:31])[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.O.[CH:53]([C:56]1[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=1[NH2:58])([CH3:55])[CH3:54].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(Cl)Cl>[CH:53]([C:56]1[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=1[NH:58][C:30](=[O:31])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)(=[O:12])=[O:13])[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=1)([CH3:55])[CH3:54]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Reactant: CC(C)c1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
3-[6-(4-t-Butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid (80 mg) was dissolved in dimethylformamide-methylene chloride (1:1, 6 ml). N-Hydroxybenzotriazole·H2O (42.2 mg), 2-isopropylaniline (133.2 mg), and 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide-HCl (32.6 mg) were added to the mixture. The reaction mixture was stirred overnight at room temperature. After the solvent was evaporated, ethyl acetate was added. The organic layer was successively washed with sat. aq. NaHCO3, 0.5N-HCl, and brine, was dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1), to thereby obtain 97.2 mg (yield: 100%) of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[C:27]1(C)C=CC=CC=1.C(OC(OCC)OCC)C>C(O)(C)C.[Pt]>[N:14]1([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=[CH:27]1
Reactant: O=C(NCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Reactant: Cc1ccccc1
Agent: [Pt]
Solvent: CCOC(OCC)OCC
Solvent: CC(C)O
Product: O=C(NCCCn1cnc2cnc3ccccc3c21)c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of N1-{3-[(3-nitroquinolin-4-yl)amino]propyl}benzamide (1.0 g, 2.8 mmol) in isopropyl alcohol (120 mL) was warmed to dissolve some of the material. A catalytic amount of platinum on carbon was added and the reaction mixture was placed under a hydrogen atmosphere at 50 psi (3.4×104 pascals) on a Parr apparatus. After 3 hours the reaction mixture was filtered to remove catalyst. The filtrate was concentrated under vacuum to provide crude N1-{3-[(3-aminoquinolin-4-yl)amino]propyl}benzamide as an oil. Toluene (100 mL) was added to the oil followed by the addition of triethylorthoformate (0.8 g, 5.6 mmol). The reaction mixture was heated on a steam bath overnight. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration to provide 0.53 g of N1-[3-(1H-imidazo[4,5-c]quinolin-1-yl)propyl]benzamide as an off white solid, m.p. 188-190° C. 1H NMR (500 MHz, DMSO-d6) δ8.67 (t, J=5.5 Hz, 1H), 8.50 (s, 1H), 8.37 (d, J=7.5 Hz, 1H), 8.17 (dd, J=8.0, 1.5 Hz, 1H), 7.87 (d, J=7.0 Hz, 2H), 7.71 (dt, J=7.5, 1.5 Hz, 1H), 7.56 (dt, J=7.5, 1.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.48 (t, J=7.0 Hz, 2H), 4.78 (t, J=7.0 Hz, 2H), 3.38 (q, J=6.0 Hz, 2H), 2.18 (quintet, J=7.0 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:53]=[C:52]3[C:48]=2[CH:49]=[N:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:47]4[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:58])=[O:59])[CH:53]=[C:52]5[C:48]=4[CH:49]=[N:50][NH:51]5)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc3[nH]ncc23)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc5[nH]ncc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 44.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (25 mg, 0.04 mmol) was treated with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-6-yl)methanesulfonamide (35 mg, 0.10 mmol), sodium carbonate (11 mg, 0.10 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.01 mmol) and 2 ml 1,2-dimethoxyethane and 1 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 13 mg (42% yield) of the title compound. Purity 98%.
Reaction SMILES: [Na].[C:2]([N:5]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:9]=2[NH:8][C:7](=[O:23])[CH2:6]1)(=[O:4])[NH2:3].[CH3:24]O>>[CH3:24][N:8]1[C:9]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:10]=2[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]([C:2](=[O:4])[NH2:3])[CH2:6][C:7]1=[O:23]
Reactant: NC(=O)N1CC(=O)Nc2ccc(Cl)cc2C1c1ccccc1
Reactant: CO
Agent: [Na]
Product: CN1C(=O)CN(C(N)=O)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 79.5 %

Procedure:
0.16 g. (6.85 mmoles) of metallic sodium are dissolved in 2 ml. of absolute methanol, and a suspension of 0.9 g. (2.86 mmoles) of 4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 50 ml. of absolute methanol is added to the solution at room temperature, with stirring. The suspension is stirred at room temperature for 30 minutes, and then evaporated under reduced pressure. The oily residue is dissolved in 9 ml. of dimethyl formamide, and 0.48 ml. of methyl iodide are added to the stirred solution at room temperature. The mixture is stirred for additional 2 hours, then diluted with 50 ml. of water and extracted with 3 × 10 ml. of chloroform. The chloroform extracts are combined, dried over sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure, to obtain 0.85 g. of a residue, which is recrystallized from ethanol. 0.75 g. (79.5 %) of 1-methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained; m.p.: 217°-220° C.
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[CH2:17]([O:16][C:14]([C@@H:13]1[CH2:12][C@@H:11]2[C@@H:9]([CH2:10]2)[NH:8]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)[C@@H]1C[C@H]2C[C@H]2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 3-benzyl ester 2-tert-butyl ester (3.27 g, 9.79 mmol) in CH2Cl2 (50 mL) was added was added TFA (7.54 mL, 98 mmol). The reaction mixture was stirred overnight at RT and subsequently concentrated under reduced pressure to give the desired material as a yellow oil. MS (UPLC): 218.1 [M+H]+; tR (HPLC conditions b): 1.24 min.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C:29]1([C:33](O)=[O:34])[CH2:32][CH2:31][CH2:30]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33]([C:29]5([OH:28])[CH2:32][CH2:31][CH2:30]5)=[O:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C1(O)CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1(O)CCC1

Procedure:
The title compound, white solid (81 mg, 76%), MS (ISP) m/z=429.4 [(M+H)+], mp 177.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 1-hydroxy-cyclobutane-carboxylic acid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[S:10]1[CH:14]=[CH:13]C(C=O)=[CH:11]1.Cl.[CH3:18][CH2:19][O:20]CC>>[S:10]1[CH:14]=[CH:13][C:1]([C:2]2([CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]2)[CH2:18][CH2:19][OH:20])=[CH:11]1
Reactant: BrCc1ccccc1
Reactant: CCOCC
Reactant: O=Cc1ccsc1
Agent: Cl
Agent: [Mg]
Product: OCCC1(c2ccsc2)C=CC=CC1
Temperature: -10 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
Benzyl bromide (25.65 g, 150 mmol) was added dropwise over 8 h to a suspension of magnesium (3.6 g, 150 mmol) in ether (75 ml) dissolved in ether (30 ml). The resulting mixture was cooled to -10° C. 3-thiophenecarboxaldehyde in ether (45 ml) over 30 min was then added and the resultant reaction mixture was stirred at room temperature for 6 h. This was cooled to 0° C. and the reaction mixture was decomposed by addition of 0.1N HCl. The ether layer was separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers was dried over MgSO4 and filtered. Removal of the solvent gave 1-(3-thienyl)phenethyl alcohol (16 g, 78% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: CN1CCN(C(=O)c2ccc(Br)cc2)CC1

Procedure:
1-(4-bromobenzoyl)-4-methylpiperazine was prepared according to the general procedure in Example 4 Step 1 using 4-bromobenzoyl chloride (1 g, 4.56 mmol) and 1-methylpiperazine (0.532 mL, 4.78 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:8]1[O:10][CH2:9]1>>[CH2:1]([N:4]([CH:9]([OH:10])[CH3:8])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C1CO1
Reactant: C=CCNCC=C
Product: C=CCN(CC=C)C(C)O

Procedure:
Diallylamine was reacted with ethylene oxide to give diallylaminoethanol and this was reacted with thionyl chloride to give an aqueous solution of diallylaminoethyl chloride in accordance with the method disclosed by J. B. Wright et al., J. Amer. Chem. Soc., 72, pp. 3556-3559, 1950.