Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][O:6][C:7]=1[CH2:8][N:9]1[C:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[S:17][C:13]=2[C:12](=[O:24])[N:11]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:10]1=[O:31].[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:29][CH2:30][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:7]6[O:6][CH:5]=[N:4][C:3]=6[CH3:2])[C:10]5=[O:31])[CH2:26][CH2:27]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: Cc1ncoc1Cn1c(=O)n(C2CCNCC2)c(=O)c2sc(-c3ccccc3)cc21
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ocnc5C)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(4-Methyl-1,3-oxazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (253 mg; compound B94) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (207 mg; compound C10) and HATU (257 mg) in DCM (7 ml) in the presence of DIPEA (0.27 ml) according to the procedure described in example 52 to afford the title compound after purification by preparative HPLC as a solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[C:45]([NH:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[NH:54][C:53]([C:58](O)=[O:59])=[CH:52]2)(=[O:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[C:45]([NH:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[NH:54][C:53]([C:58]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]3[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=3)[C:28]=1[F:44])=[O:59])=[CH:52]2)(=[O:47])[CH3:46]
Reactant: CC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
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: CC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
HATU (0.023 g, 0.062 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.013 g, 0.041 mmol), 5-(acetylamino)-1H-indole-2-carboxylic acid (0.009 g, 0.041 mmol) and DIPEA (0.011 mL, 0.062 mmol) in DMF (0.5 mL). The reaction mixture was stirred at RT overnight and was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was triturated with methanol to give the title compound (0.009 g, 43%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.50 (s, 1H), 9.74 (s, 1H), 8.95 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.40-7.49 (m, 3H), 7.32-7.40 (m, 1H), 7.28 (s, 1H), 7.15-7.24 (m, 1H), 7.06 (s, 1H), 4.53 (s, 2H), 1.98 (s, 3H). MS: m/z 511 (M+1).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH3:20][NH2:21]>C(O)C>[C:1]([NH:3][C:4]([NH:21][CH3:20])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=1)#[N:2]
Reactant: COc1cccnc1CSCCN=C(NC#N)SC
Reactant: CN
Solvent: CCO
Product: CNC(=NCCSCc1ncccc1OC)NC#N
Reaction time: 8 h

Procedure:
N-cyano-N'-[2-((3-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (1.9 g) in ethanol (10 ml) was treated with ethanolic methylamine (20 ml 33% solution) and the resultant clear solution was allowed to stand overnight. Excess of methylamine was removed by bubbling nitrogen through the solution and the crystalline precipitate was recrystallised from ethanol to yield the title product (1.2 g), m.p. 122°-123°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(NC(=O)CCl)cn2)nc(O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 16 (0.10 g, 0.42 mmol) in THF (5 mL), at 0° C. was added triethylamine (0.064 g, 0.63 mmol) and chloroacetylchloride (0.0715 g, 0.63 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(OCC)C>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]2=[O:23])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3ccccc32)CC1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2ccccc2N1C1CCNCC1
Yield: 150.4 %

Procedure:
4-(2-Oxo-2,3-dihydro-indol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 12.3 mmol) was set stirring in 30 mL of 1:1 TFA/CH2Cl2. After 45 min the solvent was evaporated under reduced pressure to give a clear purple oil. The oil was brought up in diethyl ether and cooled on ice to give a precipitate. The solid was filtered, washed with ether and air dried to give 4.0 g (100%) of the title compound as a TFA salt. 1H NMR (400 MHz, DMSO-d6): 8.6 (br s, 1H), 7.27 (m, 3H), 7.03 (m, 1H), 4.45 (m, 1H), 3.56 (s, 2H), 3.42 (m, 2H), 3.09 (m, 2H), 2.53 (m, 2H), 1.78 (m, 2H).
Reaction SMILES: [CH:1]1([NH:7][CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([S:20][CH2:21][C:22](O)=[O:23])[CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:8]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:22](=[O:23])[CH2:21][S:20][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:9])[CH:11]=1
Reactant: CCCCSCC(=O)O
Reactant: CC(NC1CCCCC1)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSCC(=O)N(C1CCCCC1)C(C)c1cccnc1

Procedure:
N-[1-(3-pyridyl)ethyl]-N-cyclohexyl-α-(n-butylthio)acetamide was prepared by the method of Example 2 by reacting 5.0 g. of N-cyclohexyl-[1-(3-pyridyl)ethyl]amine with 3.6 g. of α-(n-butylthio)acetic acid and 5.0 g. of N,N'-dicyclohexylcarbodiimide in 200 ml. of dichloromethane. Oil.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:3]1=[O:27].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>O1CCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[C:3]2=[O:27])=[O:37])=[CH:31][CH:30]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-pyrroidinecarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperatufe. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 264°-266° C.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C#N)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (300 mg, 0.76 mmol) is coupled to 4-bromobenzonitrile (167 mg, 0.92 mmol) using Method B to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.[Cl-]>ClCCl>[CH3:14][Si:15]([CH3:17])([CH3:16])[C:18]#[C:19][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C#C[Si](C)(C)C)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1 g 5-bromo-1,2,3-trimethoxybenzene, 1.14 mL of trimethylsilylacetylene, 1.4 mL of diisopropylethylamine (DIPEA) and 290 mg of triphenylphosphinpalladium(II) chloride and 39 mg Cu(I)iodide were placed in a dried flask under argon. The mixture was stirred for 1 h at 80° C., after cooling diluted with dichloromethane (DCM) and filtered through a plug of silica. The filtrate was extracted with aqueous ammonia, saturated brine and concentrated. The residue was purified via flash chromatography (SiO2: cyclohexane→cyclohexane/ethylacetate 9:1) to give trimethyl((3,4,5-trimethoxyphenyl)ethynyl)silane.
Reaction SMILES: [CH:1]1([C:5](=[O:20])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[O:30]>C1COCC1>[CH2:33]([O:32][C:28](=[O:31])[CH:29]([OH:30])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:11][CH:12]=1)[C:5]([CH:1]1[CH2:2][CH2:3][CH2:4]1)=[O:20])[CH3:34]
Reactant: CCOC(=O)C=O
Reactant: O=C(Cc1ccc(OC2CCCCC2)cc1)C1CCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)C(C(=O)C1CCC1)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
To a stirred solution of 1-cyclobutyl-2-(4-cyclohexyloxy-phenyl)-ethanone (3.60 mmol, 0.98 g) and triethylamine (3.60 mmol, 0.51 mL) in THF (2.0 mL) was added a solution of ethyl glyoxylate (50% in toluene, 18.0 mmol, 3.82 mL) and continued stirring for 12 h at room temperature. After removal of volatiles under reduced pressure, the crude product was pre-absorbed onto 10 g SiO2 followed by purification on a 24 g SiO2 cartridge using a 0-30% ethyl acetate/hexanes gradient to give 4-cyclobutyl-3-(4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-butyric acid ethyl ester (0.42 g).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12]([CH:15]=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:22][C:23]#[N:24]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21](/[C:22](=[CH:15]/[C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)/[C:23]#[N:24])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: O=Cc1cc2ccccc2c2ccccc12
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc3ccccc3c3ccccc23)cc1OC
Yield: 63 %

Procedure:
Phenanthrene-9-aldehyde (250 mg) was condensed with 3,4-dimethoxybenzyl cyanide (214 mg) through Method A (production step 2), to thereby yield the target product (yield: 278 mg, 63%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:25]1C=NC=CC=1C>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:25])=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1ccncc1Br
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cnccc2C)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 3-Bromo-4-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=340.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[C:10]([C:15]1[C:16]([CH2:23][CH2:24]O)=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1)=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[C:10]([C:15]1[C:16]([CH2:23][CH2:24][Br:27])=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1)=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CCO)c(C2=CC3CCC2N3C(=O)OC(C)(C)C)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CCBr)c(C2=CC3CCC2N3C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
To a stirred solution of 7-tert-butoxycarbonyl-2-[4-(2-hydroxyethyl)-2-methoxy-5-pyridinyl]-7-azabicyclo[2.2.1]hept-2-ene (390 mg, 1.13 mmol) in dry CH2Cl2 (20 mL) under N2 was added CBr4 (745 mg, 2.25 mmol). The mixture was stirred at room temperature for 10 min, and then a solution of PPh3 (590 mg, 2.25 mmol) in dry CH2Cl2 (5 mL) was slowly added. After that the reaction mixture was stirred at room temperature for 2 h and quenched by water, and then diluted with CH2Cl2. The organic layer was separated and washed with brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography with hexane/EtOAc (6:1) to afford 7-tert-butoxycarbonyl-2-[4-(2-bromoethyl)-2-methoxy-5-pyridinyl]-7-azabicyclo[2.2.1]hept-2-ene as a syrup (400 mg, 87%). 1H NMR (CDCl3) δ 7.95 (br s, 1H), 6.66 (s, 1H), 6.23 (br s, 1H), 4.86 (d, 1H, J=3.6 Hz), 4.81 (br s, 1H), 3.94 (s, 3H), 3.59-3.46 (m, 2H), 3.42-3.12 (m, 2H), 2.09-1.92 (m, 2H), 1.45 (s, 9H), 1.36-1.20 (m, 2H); 13C NMR (CDCl3) δ 163.83, 155.35, 148.55, 146.16, 144.63, 132.04, 123.16, 111.15, 80.16, 63.16, 61.35, 53.44, 35.97, 30.76, 28.20, 25.96 and 25.32, 24.55 and 23.62.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)([O-:3])=[O:2].[CH3:21][OH:22].[CH2:23]=[O:24].C(N(CC)CC)C>C(OCC)(=O)C.O>[N+:1]([C:4]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:12]=1)([CH2:23][OH:24])[CH2:21][OH:22])([O-:3])=[O:2]
Reactant: CCCCCCCCc1ccc(CCC[N+](=O)[O-])cc1
Reactant: C=O
Reactant: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCc1ccc(CCC(CO)(CO)[N+](=O)[O-])cc1
Temperature: 27.5 °C

Procedure:
1-(3-Nitropropyl)-4-octylbenzene (37 g) and methanol (190 mL) are charged into a round bottom flask and stirred at 25-30° C. Paraformaldehyde (37 g) and triethylamine (38.52 g) are charged into the flask and the reaction mixture is heated to a reflux temperature (about 68° C.). The reaction mixture is maintained at the same temperature for about 2 hours and is cooled to a temperature of 25-30° C. The reaction mixture is evaporated under reduced pressure at a temperature of about 45° C. to obtain crude compound. Water (190 mL) and ethyl acetate (190 mL) are charged to the crude compound, stirred, and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (190 mL) and the organic layer is combined with the initial organic layer. The combined organic layer is washed with water (190 mL) followed by brine solution (190 mL), dried over sodium sulphate, and evaporated under reduced pressure. Hexane (370 mL) is charged at 28° C. and the reaction mass is stirred at the same temperature for about 1 hour. The solid obtained is collected by filtration, washed with hexane (37 mL), and dried at 28° C. for about 3 hours to give 20.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH:15]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC1C=CC(N2CCN(C(=O)C(NC(=O)OC(C)(C)C)CC3C=CC=CC=3)CC2)=CC=1>>[ClH:1].[NH2:20][CH:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1)=[O:28]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCN(c2ccc(F)cc2)CC1
Product: CC(C)CC(N)C(=O)N1CCN(c2ccc(Cl)cc2)CC1
Product: Cl
Yield: 65.3 %

Procedure:
Using 1,1-dimethylethyl 2-(4-(4-chlorophenyl)-1-piperazinyl)-2-oxo-1-(2-methylpropyl)ethylcarbamate in lieu of 1,1-dimethylethyl 2-(4-(4-fluorophenyl)-1-piperazinyl)-2-oxo-1-(phenylmethyl)ethylcarbamate, the procedure of Reference Example 13 was otherwise repeated to provide 1-(2-amino-4-methyl-1-oxopentyl)-4-(4-chlorophenyl)piperazine hydrochloride (1.50 g, 65.3%) as white crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([F:45])=[CH:4][C:5]2[C:10]3[C:11]4[C:42](=[O:43])[NH:41][C:40](=[O:44])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:35][C@@H:34]7[CH2:36][O:37][C@@H:32]([CH2:33]7)[C@H:23]6[O:24]CC6C=CC=CC=6)[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:38])=[C:16]([F:39])[CH:15]=5>[OH-].[OH-].[Pd+2].C1COCC1>[F:1][C:2]1[C:3]([F:45])=[CH:4][C:5]2[C:10]3[C:11]4[C:42](=[O:43])[NH:41][C:40](=[O:44])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:35][C@@H:34]7[CH2:36][O:37][C@@H:32]([CH2:33]7)[C@H:23]6[OH:24])[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:38])=[C:16]([F:39])[CH:15]=5
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@@H]2CO[C@@H](C2)[C@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@@H]2CO[C@@H](C2)[C@H]1O
Yield: 58.8 %

Procedure:
A mixture of 2,3,9,10-tetrafluoro-12-(2-O-benzyl-3,6-anhydro-4-deoxy-β-D-glucopyranosyl)-6,7,12,13-tetrahydro(5H)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (0.034 g, 0.055 mmol) and 20% Pd(OH)2/C (0.048 g) in 5 mL of freshly distilled THF was hydrogenated (balloon pressure) at room temperature for 5 days. The resulting mixture was filtered through a bed of Celite and the cake was washed with THF and then with methanol. The filtrate was evaporated and the residue was chromatographed (Sephadex LH-20/methanol) to give the title compound (0.017 g, 59%) as a yellow solid: 1H NMR (THF-d8, 400 MHz) δ 11.15 (br s, 1H), 10.17 (br s, 1H), 9.19 (dd, J=11.1, 8.5 Hz, 1H), 9.09 (dd, J=11.2, 8.3 Hz, 1H), 7.81 (dd, J=11.6, 6.7 Hz, 1H), 7.51 (dd, 10.5, 6.7 Hz, 1H), 6.21 (d, J=7.3 Hz, 1H), 5.37 (br s, 1H), 4.89 (s, 1H), 4.57 (m, 2H), 4.27 (d, J=9.7 Hz, 1H), 3.85 (d, J=9.1 Hz, 1H), 3.09 (d, J=13.4 Hz, 1H), 2.09 (dd, J=13.1, 6.0 Hz, 1H); MS (ESI−) m/e 524 (M−H)−; HPLC: 99.0% (270 nm).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[C:27](Cl)(=[O:31])[O:28][CH2:29][CH3:30].C(N(CC)CC)C.[OH-].[Na+]>N1C=CC=CC=1.O1CCCC1>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:27](=[O:31])[O:28][CH2:29][CH3:30])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)Cl
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc(-c2nc3c(c(C4CCCCC4)nn3C)c(=O)[nH]2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a 6 ml tetrahydrofuran suspension of 100 mg (0.283 mmol) of the compound obtained in Example 44, 48 μl (0.50 mmol) of ethyl chlorocarbonate and 98 μl (0.707 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 3 hours. Further, 48 μl (0.50 mmol) of ethyl chlorocarbonate and 1 ml of pyridine were added, and the mixture was stirred at room temperature for 18 hours. Then, a 1M aqueous solution of sodium hydroxide was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1˜2/1) to obtain 68 mg (57%) of the captioned compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@@H:19]([NH2:21])[CH3:20])[CH3:2].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:21][C@H:19]([C:4]2[N:3]([CH2:1][CH3:2])[C:7]3[C:8]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)=[C:9]([F:12])[CH:10]=[CH:11][C:6]=3[N:5]=2)[CH3:20])[N:26]=[CH:25][N:24]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCn1c([C@H](C)Nc2ncnc(N)c2C#N)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 80 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A mixture of (S)-1-(1-ethyl-6-fluoro-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.203 g, 0.715 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.11 g, 0.715 mmol) and DIPEA (0.65 mL, 3.58 mmol) in IPA (5 mL) was stirred at 80° C. in a sealed microwave tube for 16 hours. After cooling, the mixture was concentrated in vacuo and the residue was purified chromatography, (Si—PPC, gradient 0-5% MeOH in DCM), to give 410 as a solid (0.095 g, 33%). LCMS (Method K): RT 3.03 min [M+H]+ 403. 1H NMR (DMSO-d6, 400 MHz): δ 8.71-8.67 (1H, m), 7.96 (1H, s), 7.92 (1H, td, J=7.8, 1.9 Hz), 7.73 (1H, d, J=7.7 Hz), 7.70-7.62 (2H, m), 7.47 (1H, ddd, J=7.7, 5.0, 1.1 Hz), 7.25 (2H, br s), 7.12 (1H, dd, J=10.4, 8.8 Hz), 5.60 (1H, quin, J=7.2 Hz), 3.80-3.67 (2H, m), 1.55 (3H, d, J=6.8 Hz), 0.69 (3H, t, J=7.1 Hz)
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7]C)=[O:5])#[N:2].C[O-].[Na+].Cl[CH2:13][C:14](=[O:16])[CH3:15]>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[CH2:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C#N)CC(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled (0° C.) solution of ethyl cyanoacetate (6.58 g, 58.1 mmol) in MeOH (20 mL) was slowly added a solution of NaOMe (25% w/v; 58.1 mmol). After 10 min, chloroacetone (5 mL; 62.8 mmol) was slowly added. After 4 h, the solvent was removed. The brown oil was diluted the EtOAc (100 mL) and washed with H2O (100 mL). The organic fraction was dried, filtered, and concentrated to a brown oil (7.79 g; 79%). The oil was a mixture of methyl/ethyl ester products (9/1), and was used without further purification. 1H NMR (200 MHz, CDCl3): δ 1.26 (t, J=7.1 Hz), 2.44 (s, 3H), 3.02 (dd, 1H, J=15.0, 7.0 Hz), 3.42 (dd, 1H, J=15.0, 7.1 Hz), 3.62 (s, 3H), 3.91 (dd, 1H, J=7.2, 7.0 Hz), 4.24 (q, J=7.2 Hz).