Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:20][CH:21]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]([CH3:39])[C:22]1=[O:40].C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:7][C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([NH:20][CH:21]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]([CH3:39])[C:22]1=[O:40])=[O:19])([CH3:5])[CH3:6]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CN1C(=O)C(NC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21

Procedure:
The procedure of Example 77 was carried out in which Boc-D-phenylalanine was coupled to 3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one using dicyclohexylcarbodiimide. Following the identical work-up and purification procedure of Example 77 gave the analytical product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.[NH4+].[Cl-]>C1COCC1.CN(C=O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1
Reactant: OCc1ccc(Br)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(COCc2ccc(Br)cc2)cc1
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
A solution of 4-bromobenzyl alcohol (2.011 g, 10.7 mmol) in THF (42 mL) was added to a mixture of NaH (663 mg, 16.6 mmol, 60% in oil) in DMF (13 mL). The mixture was stirred for 1.5 h and 4-methoxybenzyl chloride (MPMCl, 2 mL, 14.8 mmol) was added. After 24 h, 100 mL saturated NH4Cl solution was added. The resulting mixture was extracted with ethyl acetate (3×60 mL) and the combined ethyl acetate solution was washed with water and brine. The solution was then dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (5% ethyl acetate/hexanes) gave 7-2 (2.43 g, 98%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([CH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O.[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>C(O)(=O)C.CCOCC>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:16]2[CH2:20][CH2:19][CH2:18][C:17]1=2
Reactant: CNCCCN
Reactant: O=C(CC1CCCC1=O)c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CNCCCn1c(-c2ccccc2)cc2c1CCC2

Procedure:
8.82 g (0.1 mole) of methylaminopropylamine are added to a solution of 20.35 g (0.1 mole) of 2-phenacylcyclopentanone in glacial acetic acid under nitrogen. After refluxing for 12 hours, water is added and the aqueous solution is washed with ether. The aqueous phase is basified with sodium carbonate and extracted with ether to give a reddish oil. The oil is dissolved in ether and is added to an ether solution of oxalic acid to give 1-(3-methylaminopropyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole oxalate, m.p. 184°-185° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:3][CH2:2]1.C1(CN2C3C=CC(S(CC4CCN(C(OC(C)(C)C)=O)CC4)(=O)=O)=CC=3N=C2CC(C)(C)C)CC1>>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CCN(C(=O)OC(C)(C)C)CC3)ccc2n1CC1CC1
Agent: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)ccc2n1CC1CC1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CCNCC3)ccc2n1CC1CC1

Procedure:
The title compound was prepared according to the procedure described in STEP D of Example 5 using tert-butyl 4-(1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)piperidine-1-carboxylate (STEP C) and tert-butyl 4-((1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)methyl)piperidine-1-carboxylate.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1.[CH:35]1(B(O)O)[CH2:37][CH2:36]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:35]1([C:2]2[CH:7]=[C:6]([C:8]([N:10]3[CH2:14][CH2:13][CH:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH2:11]3)=[O:9])[CH:5]=[CH:4][C:3]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH2:37][CH2:36]1
Reactant: OB(O)C1CC1
Reactant: O=C(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(I)c1)N1CCC(c2cccnc2)C1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C2CC2)c1)N1CCC(c2cccnc2)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Palladium acetate (8.00 mg, 0.036 mmol) was added to a solution of 4b (210 mg, 0.356 mmol), cyclopropylboronic acid (36.7 mg, 0.427 mmol), tricyclohexylphosphine (20.0 mg, 0.071 mmol) and potassium phosphate tribasic (227 mg, 1.07 mmol) in toluene:water (3.15 mL of an 20:1 mixture, respectively) at rt. The resulting solution was heated to 100° C. After approximately 24 h, the reaction was cooled to rt, diluted with EtOAc and filtered through a short column of Celite®, eluting with EtOAc. The resulting crude residue was purified by column chromatography on silica gel (gradient elution; 0%-1% methanol/EtOAc as eluent) to afford the title compound 4c. m/z (ES) 505 (MH)+.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:18][N:19]([CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1ccc2cc(OCC(O)CCl)ccc2[nH]1
Reactant: CNCc1ccccc1
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)CC(O)COc1ccc2[nH]c(=O)ccc2c1
Reaction time: 5 h
Yield: 37.1 %

Procedure:
A solution of 6-(3-chloro-2-hydroxypropoxy)-carbostyril (5.05 g) and N-methylbenzylamine (6.0 g) in dimethylformamide (50 ml) is heated with stirring at 50°-60° C. for 5 hours. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (solvent; methanol:chloroform=1:100-1:25) and recrystallized from ethanol to give 6-[3-(N-methyl-N-benzylamino)-2-hydroxypropoxy]carbostyril (2.5 g), as white powder, m.p. 129°-132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[N:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl>[C:24]([NH:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[N:8][C:4]=2[CH:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)c1nc2cc(N)ccc2[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2[nH]c(C(=O)OC(C)(C)C)nc2c1
Yield: 92.3 %

Procedure:
A suspension of 1,1-dimethylethyl 5-amino-1H-benzimidazole-2-carboxylate (0.147 g, 0.630 mmol) in dichloromethane (5 mL) was cooled in an ice bath. Pyridine (0.076 mL, 0.945 mmol) and acetic anhydride (0.059 mL, 0.630 mmol) were added. The reaction mixture was filtered and the collected solid was washed with dichloromethane and dried under vacuum to give the title compound (0.160 g, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 13.06 (s, 1H), 10.05 (s, 1H), 8.14 (s, 1H), 7.61 (m, 1H), 7.24 (m, 1H), 2.04 (s, 3H), 1.55 (s, 9H). MS: m/z 276 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: COc1ccccc1I
Product: COc1ccccc1-n1ccc2cc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)ccc21

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2-methoxybenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 482.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH2:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1S
Reactant: O=C(NC(=Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CCO
Product: Nc1ccccc1SC(c1ccccc1)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 9.5 %

Procedure:
20 g of α-benzyloxycarbonylamino-β-phenylacrylic acid and 10 g of o-aminobenzenethiol were mixed with 40 ml of ethanol and the resulting mixture was heated under reflux for 20 hours. After cooling to room temperature, the precipitated crystalline component was separated by filtration and washed with ethanol to obtain 2.7 g of crystals. This product decomposed at 198° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:39]=[C:24]4[C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=5[O:37][CH3:38])=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:38][O:37][C:30]1[C:31]([O:35][CH3:36])=[CH:32][CH:33]=[CH:34][C:29]=1[C:25]1[C:24]2[N:23]([N:22]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][CH:16]=3)[N:39]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c1OC

Procedure:
[8-(2,3-Dimethoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine was prepared from 4-{4-[8-(2,3-dimethoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (0.264 g, 0.499 mmol) and trifluoroacetic acid (1 mL) in a manner analogous to Example 312 to give product (0.203 g, 95%). MP=94-97° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.52 (s, 1H), 8.78 (d, 1H), 7.52 (m, 3H), 7.15 (m, 6H), 3.87 (s, 3H), 3.59 (s, 3H), 3.05 (m, 2H), 2.55 (m, 4H), 1.62 (m, 2H), 1.45 (m, 2H). MS=430 (MH)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:25]=[S:26]1(=[O:33])[CH2:30][CH2:29][CH:28]([NH:31][NH2:32])[CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:32][NH:31][CH:28]3[CH2:29][CH2:30][S:26](=[O:33])(=[O:25])[CH2:27]3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: NNC1CCS(=O)(=O)C1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC1CCS(=O)(=O)C1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.5 g) in EtOAc (20.0 mL) was treated with 2-(1,1-dioxotetrahydrothiophen-3-yl)hydrazine (0.3 g, 1.2 eq.). The mixture was cooled to −60° C. and treated simultaneously with T3P (50% in EtOAc; 2.0 mL, 2 eq.) and DIPEA (1 mL, 4 eq.). The reaction mixture was stirred for 30 min at −60° C. before being concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.60 g of a solid residue. Purification by column chromatography (SiO2; elution with MeOH:CH2Cl2; desired compound eluted at 5% MeOH in CH2Cl2) afforded 100 mg (yield=15%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(tetrahydrothiophen-1-1-dioxide-3-yl)acrylohydrazide. 1H NMR (400 MHz, CD3OD) δ=9.57 (s, 1H), 8.64 (s, 2H), 8.10 (s, 1H), 7.34-7.36 (d, J=10.4 Hz, 1H), 5.89-5.92 (d, J=10.8 Hz, 1H), 4.01 (m, 1H), 3.04-3.26 (m, 4H), 2.27-2.34 (m, 2H). LCMS for C17H15F6N5O3S [M+H]+ 484.40. found 483.39 (RT 2.63 min, purity: 66.39%).
Reaction SMILES: [C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[O:29][C:21]1[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:20]=1[F:19])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Cl)c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.8 %

Procedure:
To a mixture 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl pivalate (250 mg, 0.94 mmol), 2-fluoro-4-nitrophenol (176 mg, 1.12 mmol, Aldrich) and K2CO3 (154 mg, 1.12 mmol) was added DMF (5 mL). The reaction was stirred at room temperature for 24 h. The reaction was quenched with water (5 mL) and CH2Cl2 (10 mL). The organic layer was separated, dried with sodium sulfate, concentrated in vacuo, and purified by silica gel flash chromatography (eluted with 1-25% EtOAc/CH2Cl2) to give the title compound (160 mg, 44%) as a white solid.
Reaction SMILES: ClCCl.[Si:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]1(O)[C:30]2[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[S:24][CH2:23][C:22]1([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH3:33])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C([BH3-])#N.[Na+]>[I-].[Zn+2].[I-].O>[Si:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][CH:21]1[C:30]2[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=2)[S:24][CH2:23][C:22]1([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH3:33])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[CH3:6]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
Dichloromethane (30 ml) was added to 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-4-hydroxy-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (946 mg, 1.66 mmol) obtained in Example 27, and then zinc iodide (795 mg, 2.49 mmol) and sodium cyanoborohydride (782 mg, 12.45 mmol) were added thereto. The reaction solution was stirred for 24 hours at room temperature and, after adding water, extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=9:1) to obtain 569 mg (yield: 62%, 3RS,4RS/3RS,4SR=5:1) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=2)[CH2:38][CH2:37]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:47][C:46]5[CH:45]=[CH:44][C:43]([CH2:42][N:39]6[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]6)=[CH:49][CH:48]=5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)cc2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 4-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride with yield 48 mg (37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (br. s., 4 H) 1.73 (br. s., 2 H) 1.98 (m, 2 H) 2.14 (s, 3 H) 2.17-2.45 (m, 8 H) 3.40 (s, 2 H) 3.94 (s, 3 H) 4.09 (t, J=12 Hz, 2 H) 4.84 (t, J=8.08 Hz, 1 H) 7.16-7.37 (m, 3 H) 7.66 (d, J=8.34 Hz, 2 H) 8.10 (s, 1 H) 8.19-8.39 (m, 2 H) 10.13 (s, 1 H). [M+H] calc'd for C33H39F3N8O3, 653; found 653.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]([CH3:31])=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl>>[CH3:32][N:17]([CH3:16])[CH2:18][CH2:19][CH2:20][N:21]([CH2:22][C:23]([CH3:31])=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6](=[O:8])[C:5]1[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CC(=Cc1ccccc1)CNCCCN(C)C
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: COc1cc(C(=O)N(CCCN(C)C)CC(C)=Cc2ccccc2)cc(OC)c1OC
Yield: 13 %

Procedure:
Experimental condition analogous to Example 13 were used with 3,4,5-trimethoxy benzoic acid, 0.65 g (3 mmol), and N,N-Dimethyl-N′-(2-methyl-3-phenyl-ally)-propane-1,3-diamine, 0.6 g (2.5 mmol) and O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate 1.5 g (5 mmol) to give 130 mg of a white solid as a HCl salt. Yield: 13%.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[OH:50][CH2:51][CH2:52][CH2:53][CH2:54][N:55]1[CH:59]=[C:58]([C:60]2[CH:65]=[CH:64][C:63]([NH:66][C:67]3[C:72]([C:73]([F:76])([F:75])[F:74])=[CH:71][N:70]=[C:69]([NH:77][C:78]4[CH:92]=[CH:91][C:81]([CH2:82][P:83](=[O:90])([O:87]CC)[O:84][CH2:85][CH3:86])=[CH:80][C:79]=4[O:93][CH3:94])[N:68]=3)=[C:62]([C:95](=[O:98])[NH:96][CH3:97])[CH:61]=2)[CH:57]=[N:56]1>>[OH:50][CH2:51][CH2:52][CH2:53][CH2:54][N:55]1[CH:59]=[C:58]([C:60]2[CH:65]=[CH:64][C:63]([NH:66][C:67]3[C:72]([C:73]([F:74])([F:75])[F:76])=[CH:71][N:70]=[C:69]([NH:77][C:78]4[CH:92]=[CH:91][C:81]([CH2:82][P:83](=[O:87])([OH:90])[O:84][CH2:85][CH3:86])=[CH:80][C:79]=4[O:93][CH3:94])[N:68]=3)=[C:62]([C:95](=[O:98])[NH:96][CH3:97])[CH:61]=2)[CH:57]=[N:56]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCCO)c4)cc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCCO)c4)cc3C(=O)NC)n2)c(OC)c1
Yield: 96.7 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({4-[1-(4-hydroxybutyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 14B, 63.6 mg, 0.09 mmol) to afford 59 mg of the title compound (96%). 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=8.6 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.91 (d, J=0.5 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.83 (d, J=2.3 Hz, 1H), 7.65 (dd, J=2.15, 8.72 Hz, 1H), 7.06 (t, J=1.9 Hz, 1H), 6.80 (dd, J=1.9, 8.2 Hz, 1H), 4.23 (t, J=6.9 Hz, 2H), 3.90 (s, 3H), 3.83 (quin, J=7.0 Hz, 2H), 3.56-3.62 (m, 2H), 2.93-3.00 (m, 2H), 2.91 (s, 3H), 1.92-2.02 (m, 2H), 1.50-1.60 (m, 2H), 1.14 (t, J=7.1 Hz, 3H). MS (ESI): m/z 678.79 [M+H]+. UPLC: tR=1.02 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:31]1[C:35]2=[N:36][CH:37]=[CH:38][C:39]([CH2:40][NH2:41])=[C:34]2[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:41][CH2:40][C:39]4[CH:38]=[CH:37][N:36]=[C:35]5[NH:31][CH2:32][CH2:33][C:34]=45)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccnc2c1CCN2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)ccc2C(C)(C)C1

Procedure:
A mixture of 7-[(2-fluoro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.187 g), C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine HCl salt (0.098 g, step B), DIEA (1.0 mL) and IpOH (1.5 mL) was subjected to a Microwave condition (170° C., 1000 s). Solvent was removed and the residue was purified by chromatography through silica gel (70 g, 1-4% MeOH/CH2Cl2 with 1% NH4OH, stepwise gradient) to afford 7-({2-[(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-amino]-pyridine-3-carbonyl}-amino)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as cream color solid. MS: (ES+) 529 (M+H). Calc'd. for C30H36N6O3—528.65.
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.[OH-].[K+].CS(C)=O>C(O)C>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 71 %

Procedure:
0.728 g (2 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 0.730 g (13 mmole) of KOH in solution in 10 ml of ethyl alcohol were heated to reflux for 1 hour. After addition of 2 ml of DMSO, the reaction mixture was heated to 120° and the excess of ethyl alcohol distilled therefrom. The resulting mixture was then heated at 110° for 12 hours, then treated as indicated hereinabove to afford 0.29 g (71% yield) of the desired compound.