Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=[N:55][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCC1>CN(C=O)C>[CH:50]1([NH:55][C:30](=[O:31])[C:29]2[CH:33]=[C:34]([F:37])[C:35]([CH3:36])=[C:27]([C:10]3[C:11]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:12]=4[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:38][CH3:39])[N:9]=3)[CH:28]=2)[CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC3CCCC3)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and cyclopentanamine (8.15 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.2 mg, 56%). LC-MS m/z 607 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:22])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:30]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:22][C:34]([CH:30]2[CH2:33][CH2:32][CH2:31]2)=[O:35])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1)C1CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 0.2 g (0.66 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(pyrimidin-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.18 mL (1.32 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.082 g (0.69 mmol) of cyclobutanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for two hours at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.18 g (62%) as a white solid; mp=112-114° C.; MS (+) ESI m/z=386 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:3]=1[NH:4][S:5]([CH3:8])(=[O:7])=[O:6].C(N(CC)CC)C.[F:23][S:24]([C:27]1[CH:28]=C(S(Cl)(=O)=O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>O1CCCC1>[NH2:1][C:2]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:3]=1[N:4]([NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[S:5]([C:8]1[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([F:23])(=[O:25])=[O:26])[CH:28]=1)(=[O:7])=[O:6]
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=S(=O)(F)c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NN(c1ccc([N+](=O)[O-])cc1N)S(=O)(=O)c1cccc(S(=O)(=O)F)c1
Temperature: 5 °C
Yield: 166.2 %

Procedure:
2'-Amino-4'-nitromethanesulfonanilide (30.4 g; 0.13 mole) was dissolved in dry tetrahydrofuran (ca. 700 ml) and then triethylamine (13.1 g; 0.13 mole) was added and the solution was chilled to 5° C. While stirring and maintaining a temperature <10° C., While stirring and maintaining a temperature <10° C., m-fluorosulfonylbenzenesulfonyl chloride (33.8 g; 0.13 mole) was added dropwise. After the addition, the reaction was kept at the ice bath temperature for one hour and then stirring continued at room temperature for an additional hour. The reaction solution was poured into ice cold water (about 2 liters) while stirring and scratching vigorously. The product was filtered and dried to yield 50.6 g (85 percent) beige solid, m.p. 204° to 209° C. A small sample (1 g) was recrystallized from ethanol (150 ml) to yield a beige solid, m.p. 224° to 226° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].Br[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[CH2:13]([N:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]1=[O:9])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CBr
Reactant: COc1cc[nH]c(=O)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccn(CC(C)C)c(=O)c1C#N
Temperature: 50 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
A mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (15.00 g), 1-bromo-2-methylpropane (21.4 g), cesium carbonate (65.2 g) and dimethyl sulfoxide (150 mL) was stirred at 50° C. for 24 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ether to give the title compound (13.0 g).
Reaction SMILES: ClC1C=C(N(C)CC(O)=O)C=CC=1Cl.[Br:15][C:16]1[C:17]([Br:31])=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]([OH:29])=O)[C:20]=2[CH:30]=1.C1(C2C=CC=CC=2)C=CC(C(NC)CN2CCCC2)=CC=1.[C:53]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:58]=[CH:57][C:56]([CH:59]([NH:67][CH3:68])[CH2:60][N:61]2[CH2:66][CH2:65][O:64][CH2:63][CH2:62]2)=[CH:55][CH:54]=1>>[C:53]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:54]=[CH:55][C:56]([CH:59]([N:67]([CH3:68])[C:27](=[O:29])[CH2:26][N:21]2[C:20]3[CH:30]=[C:16]([Br:15])[C:17]([Br:31])=[CH:18][C:19]=3[O:24][CH2:23][C:22]2=[O:25])[CH2:60][N:61]2[CH2:62][CH2:63][O:64][CH2:65][CH2:66]2)=[CH:57][CH:58]=1
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)CN1C(=O)COc2cc(Br)c(Br)cc21
Agent: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Product: CN(C(=O)CN1C(=O)COc2cc(Br)c(Br)cc21)C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Yield: 58 %

Procedure:
The title compound was prepared according to the procedure described in example 11 replacing N-(3,4-dichlorophenyl)-N-methylglycine with (6,7-dibromo-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid, and [1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine with the product from step b) above to give the title compound (52 mg, 58%). MS (ES) m/e 643 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>CO.CCOCC>[ClH:29].[ClH:29].[N:11]1([C:14]2[CH:15]=[C:16]([C:20]3[NH:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nc4ccccc4[nH]3)c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: c1cc(-c2nc3ccccc3[nH]2)cc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-[3-(1H-benzoimidazol-2-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (1.80 g, 4.76 mmol) in MeOH (2 mL), 2M HCl in Et2O (8 mL) was added and the resulting mixture was stirred for 6 h at room temperature.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: CCOC(=O)CN=C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CNC(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and ethyl isocyanatoacetate as starting materials in 35% yield. LCMS for C29H33ClN7O4 (M+H)+: m/z=578.2.
Reaction SMILES: C(OC([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:7]1=[O:19])=O)C.O>[N+](C)([O-])=O>[CH:13]1([N:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:6][C:7]2=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1C(=O)CCN(C2CCCCC2)C1=O
Solvent: C[N+](=O)[O-]
Solvent: O
Product: O=C1CCN(C2CCCCC2)C(=O)C1

Procedure:
1-Cyclohexyl-2,4-dioxo-piperidine-3-carboxylic acid ethyl ester (3.1 g, 11.6 mmol) was heated with water (0.25 ml, 13.9 mmol) in nitromethane (30 ml) at 95° C. for 1 hour. The solution was concentrated to give an off-white solid weighing 2.3 g (93%). A sample was recrystallised from toluene.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:20]([NH:24][CH2:25][C:26]#[N:27])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([N:24]([CH2:25][C:26]#[N:27])[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCNCC#N
Reactant: O=C(O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Product: CCCCN(CC#N)C(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared from 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoic acid (which was obtained in Example 150) (0.37 g, 1.4 mmol) and (n-butylamino)acetonitrile (0.48 g, 4.2 mmol) according to the procedure shown for Example 154 to give 0.52 g of an amber gum; MS (ES) m/z: 358.3 (MH+); HRMS (ES) Calcd. for C20H28N3O3 (MH+): 358.2125. Found: 358.2120.
Reaction SMILES: [BH4-].[Na+].Br[C:4]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>CN(C)C(=O)C.O.O.O.O.O.O.[Co](Cl)Cl>[CH:5]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH:4]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)C1CC1(Br)C(=O)OC(C)(C)C
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)C1CC1C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
Sodium borohydride (35.7 mg, 0.944 mmol) was added to and dissolved in N,N-dimethylacetamide (1.5 mL) at room temperature, followed by addition of an N,N-dimethylacetamide solution (1.0 mL) of di-tert-butyl 1-bromocyclopropane-1,2-dicarboxylate (cis/trans=11/89) (hereinafter the compound will be referred to as “compound (4c)”) (202 mg, 0.629 mmol) at 10° C. Without manipulating the temperature of the reaction, cobalt chloride hexahydrate (0.7 mg, 0.003 mmol) was added to the resultant solution. After completion of addition, the resultant mixture was stirred at 10° C. for 15 minutes. After completion of reaction, the entirety of the reaction mixture was diluted with an HPLC mobile phase to 20 mL, to thereby yield a solution containing 152.4 mg (yield: 100%) of the title compound. Yield was determined by means of high performance liquid chromatography (HPLC) (the same shall apply hereinafter).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][C:24]1[CH:25]=[C:26]([N:30]([CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Br:20][CH2:23][C:24]1[CH:25]=[C:26]([N:30]([CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(CO)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(CBr)c1
Reaction time: 0.25 h

Procedure:
Resin-supported triphenylphosphine (1.6 g, 3 mmol per gram resin) was dispersed on dichloromethane. At 0° C., bromine (0.850 g, 5.3 mmol) solution was added dropwise to the resin. And the mixture was stirred for 15 min, followed by dropping a solution of N-(3-hydroxymethylphenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (0.930 g, 3 mmol). After 1 h, the resin was filtered and washed with CHCl3. Evaporation afforded the title compound. 1H NMR:, 8.81 (s,1H), 8.68 (d,1H, J=5.4 Hz), 8.47 (d,1H,J=8.3 Hz), 7.91 (m,1H), 7.26-7.39 (m,1H), 5.16 (s,2H), 4.40 (s,2H), 3.12 (q,2H,J=7.3 Hz), 1.40 (t,3H,J=7.3 Hz). MS calcd. 370.0; MS (M+1) 371.1.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][CH2:8][CH:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][C:26]([OH:28])=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:38]1([S:44]([NH2:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[CH2:6][O:7][CH2:8][CH:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][C:26]([NH:47][S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])=[O:28])[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)COCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(COCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer was introduced (2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-ethoxy)-acetic acid (compound 235 prepared at example 1.4.2; 2.7 g, 4.54 mmoles) dissolved in CH2Cl2 (25 ml). Benzenesulphonamide (1.07 g, 6.8 mmoles), DMAP (10 mg, 0.45 mmoles) and EDCI (0.96 g, 5 mmoles) were added to the solution and the reaction mixture was stirred at room temperature for 48 hours. The organic solution was washed with HCl 0.1N and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/NH3: 95/5/0.2 v/v/v) to afford the monohydrate of N-[(2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-ethoxy)-acetyl]-benzenesulfonamide (compound 306; 1.5 g, 50%) as a beige solid.
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:11][C:10]2=[O:29])=[CH:6][CH:5]=1)([OH:3])=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[N:32]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[CH2:13][N:12]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)[CH2:11][C:10]3=[O:29])=[CH:30][CH:31]=2)=[O:3])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)cc1)N1CCCC1
Reaction time: 8 h

Procedure:
23 mg (0.053 mmol) of 1-(4-carboxybenzyl)-4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 5 ml of dichloromethane. 6 mg (0.079 mmol) of pyrrolidine, 13 mg (0.079 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.022 ml (0.159 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([CH2:18][O:19][C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26]Br>>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1cccc(F)c1CBr
Reactant: CC(=O)OCc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Product: CC(=O)OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 118.4 %

Procedure:
2-(2,6-Difluorophenyl)4-acetoxymethylbenzimidazole (Example 101) (3.55 g, 11.74 mmol) and 2,6-difluorobenzylbromide (3.40 g, 16.4 mmol, 140 M%) were reacted. The crude product was purified using flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether, yielding white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetoxymethylbenzimidazole (5.94 g, 13.9 mmol, 76% yield). M.p. 126-127° C. 1HNMR (300 MHz, CD2Cl2): δ7.54 (m, 1H, H4′), 7.48 (m, 1H, H6), 7.33-7.27 (m, 2H, H5,7), 7.25 (m, 1H, H″), 7.08 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.54 (s, 2H, CH2PhF2), 5.36 )s, 2H, CH2O), 2.08 (s, 3H, OAc).
Reaction SMILES: [OH-].[NH4+:2].Cl[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5]>>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])[NH2:2]
Reactant: [NH4+]
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Agent: [OH-]
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(N)=O)cc2)CC1

Procedure:
Ammonium hydroxide (large excess) was added to the product from Example 1C (8.43 g. 27.3 mmol) at room temperature. White solids precipitated out and were collected by filtration and washed with water to afford the title compound (7.9 g, 100%) as a white solid which was taken on to the next step-without further purification. MS (DCI) m/z 290.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([F:8])([F:7])[F:6].O.[NH2:11][NH2:12]>CO>[F:6][C:5]([F:8])([F:7])[CH2:4][C:3]([NH:11][NH2:12])=[O:2]
Reactant: NN
Reactant: COC(=O)CC(F)(F)F
Solvent: CO
Solvent: O
Product: NNC(=O)CC(F)(F)F
Yield: 57.8 %

Procedure:
A solution of 3,3,3-trifluoro-propionic acid methyl ester (24.6 g, 173 mmol) in methanol (173 mL) was treated with hydrazine hydrate (8.4 mL, 173 mmol). The resulting mixture was then heated under reflux for 16 h and filtered. The filtrate was adsorbed on silica, evaporated and chromatographed (SiO2, dichloromethane:methanol=95:5 to 90:10). The title compound (14.2 g, 58%) was obtained as a white solid. MS: m/e=142.1 [M]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[C:6]([NH2:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>C1C=CC=CC=1.O>[CH2:2]([NH:14][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-Bromobutane (1.51 g, 0.011 mol) in benzene (10 ml) was slowly added to a refluxing mixture of benzamide (1.21 g, 0.01 mol), 50% aqueous sodium hydroxide solution (10 ml) and 1 mmol of the catalyst (Table 3). After the addition of has been completed, refluxing is continued for 4 hours. The reaction mixture was then cooled to room temperature and diluted with water (20 ml). The organic phase is separated, washed with water (3×10 ml) until neutral, dried over magnesium sulphate and evaporated to give pure N-n-butylbenzamide. Yields are given in Table 3.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH:31]=[N:30][CH:29]=[CH:28]3)[CH:21]=1>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:31]1[C:32]2[C:27](=[CH:26][C:25]([C:22]3[CH:21]=[C:20]([C:10]#[C:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:24][N:23]=3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: Ic1cc(-c2ccc3cnccc3c2)no1
Reactant: C#C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C#Cc1cc(-c2ccc3cnccc3c2)no1)Cc1ccccc1
Temperature: 65 °C
Yield: 50.6 %

Procedure:
To a solution of (S)-tert-butyl 1-phenylbut-3-yn-2-ylcarbamate (0.16 g, 0.65 mmol) in 6 mL of Et3N in a sealable tube were added 6-(5-iodoisoxazol-3-yl)isoquinoline (0.18 g, 0.54 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.019 g, 0.027 mmol), and copper(I) iodide (0.016 g, 0.082 mmol). The tube was sealed and heated to 65° C. for 12 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel, affording tert-butyl(S)-4-(3-(isoquinolin-6-yl)isoxazol-5-yl)-1-phenylbut-3-yn-2-ylcarbamate (0.12 g, 50% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.30 (s, 1H), 8.63-8.57 (m, 1H), 8.20-8.17 (m, 1H), 8.09-8.03 (m, 2H), 7.73-7.69 (m, 1H), 7.39-7.27 (m, 5H), 6.81 (s, 1H), 5.05-4.94 (m, 1H), 4.86-4.74 (m, 1H), 3.17-3.03 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCC1CCCCO1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 2-(3-bromopropyl)tetrahydro-2H-pyran.