Azzindani/Open_Reaction_Data huggingface dataset:
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[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][OH:66])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:57][CH:58]5[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][OH:66])[CH2:60][CH2:59]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(CCO)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized 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)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino piperidine 1-ethanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-2.07 (m, 12H) 2.38 (t, J=6.32 Hz, 2H) 2.89 (d, J=11.37 Hz, 2H) 3.27-3.34 (s, 3H) 3.49 (q, J=6.06 Hz, 2H) 3.65-3.83 (m, 1H) 3.93 (s, 2H) 3.97-4.14 (m, 2H) 4.37 (t, J=5.31 Hz, 1H) 4.76 (t, J=7.83 Hz, 1H) 7.48 (d, J=8.0 Hz, 1H), 7.49 (br. s., 1H) 7.96 (s, 1H) 8.12 (d, J=7.83 Hz, 1H)), 8.26 (s, 1H) 8.27 (d, J=8.0 Hz, 1H). [M+H] calculated for C28H37F2N7O4, 574. found 574.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2.[F:15][C:16]([Si](C)(C)C)([F:18])[F:17].C([O-])(=O)C.[Li+].Cl>CO.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])([CH3:13])[C:16]([F:18])([F:17])[F:15])[CH:6]=[CH:5]2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(O)(c1ccc2cc(Br)ccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a DMF (25 ml) solution of 1-(6-bromo-2-naphthyl)ethanone (2.5 g, 10.0 mmol, Tetrahedron Letters (2001), 42(2), 265-266), trifluoromethyltrimethylsilane (2.14 g, 15.1 mmol) and lithium acetate (33.1 mg, 0.5 mmol) were added and the mixture was stirred for 12 hrs at room temperature. Then, the reaction was partitioned with sodium acetate aqueous solution and ethylacetate. The organic layer was dried over sodium sulfate and filtered. Then, evaporation gave the crude residue which was treated with hydrogen chloride and methanol with stirring for 5 hrs. Then, evaporation gave the crude residue which was purified through silica gel column chromatography, eluting with hexane:ethyl acetate (5:1), to give the title compound as colorless oil in 83% yield. 1H NMR (300 MHz, CDCl3) 2.50 (1H, s), 7.58 (1H, d, J=8.8 Hz), 771-7.81 (3H, m), 8.04 (2H, d, J=8.9 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1.[NH2:20][CH2:21][CH2:22][NH:23][C:24]([NH:26][CH3:27])=[O:25]>C(O)(C)C>[OH:16][CH:14]([CH2:13][O:12][C:11]1[CH:17]=[CH:18][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH:2]([CH3:19])[CH3:1])=[CH:9][CH:10]=1)[CH2:15][NH:20][CH2:21][CH2:22][NH:23][C:24]([NH:26][CH3:27])=[O:25]
Reactant: CNC(=O)NCCN
Reactant: CC(C)COCCOc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: CNC(=O)NCCNCC(O)COc1ccc(OCCOCC(C)C)cc1

Procedure:
10.6 g of 3-(4-(2-(2-methylpropoxy)ethoxy)phenoxy)-1,2-epoxypropane and 14 g of N-2-aminoethyl-N'-methyl-urea was refluxed 40 h in isopropanol. The product crystallized when the heating was stopped. Recrystallized from isopropanol. Yield 8 g. M.p. 121° C. (base). The structure was determined using NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[O:37])O[C:33](=[O:34])[C:32]2=[CH:38][CH:39]=1>C(O)(=O)C>[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[O:37])[N:1]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:21]5[CH:22]=[CH:23][C:24]([N:27]6[C:36](=[O:37])[C:31]7=[CH:30][C:29]([F:28])=[CH:39][CH:38]=[C:32]7[C:33]6=[O:34])=[CH:25][CH:26]=5)[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:15]5[C:20]4=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:6][CH:7]=3)[C:33](=[O:34])[C:32]2=[CH:38][CH:39]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: Nc1ccc(C2(c3ccc(N)cc3)c3ccccc3-c3ccccc32)cc1
Solvent: CC(=O)O
Product: O=C1c2ccc(F)cc2C(=O)N1c1ccc(C2(c3ccc(N4C(=O)c5ccc(F)cc5C4=O)cc3)c3ccccc3-c3ccccc32)cc1

Procedure:
A mixture of 9,9-bis(4-aminophenyl)fluorene (17.4 g, 50 mmol), 4-fluorophthalic anhydride (18.3 g, 110 mmol), and 250 ml of acetic acid was stirred and heated under reflux for five hours and then stirred at ambient temperature overnight. A colorless precipitate formed which was filtered, washed twice with 150 ml of ethanol, washed twice with 100 ml of hexane, suction-dried for two hours, and then dried in a vacuum oven at 120° C. for 16 hours. The title compound was isolated as a colorless powder (29.2 g, 90.6% yield) that had melting point of 323.5°-326° C. and a 1H NMR spectrum (DMSO-d6) corresponding to δ8.02 (m, 4H), 7.86 (dd, 2H), 7.72 (m, 2H), 7.60 (d, 2H), 7.46 (t, 2H), and 7.35 (m, 10H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:20]#[C:21][CH:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[OH:23])[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][CH2:9][C:10]1([C:20]#[C:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:23])[CH2:11][CH2:12][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:18][CH2:19]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(O)C#CC2(COCc3ccccc3)CCC3(CC2)OCCO3)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C(=O)C#CC2(COCc3ccccc3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.4 %

Procedure:
To a solution of 3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)propyn-1-ol (Reference Example 88) (585 mg, 1.44 mmol) in dichloromethane (7.2 mL), manganese dioxide (625 mg, 7.19 mmol) was added, and the obtained solution was stirred at room temperature for 13 hours. The reaction solution was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (540 mg, 1.33 mmol, 93%) as a colorless oily compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2.[SH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2
Reactant: O=C1CCc2cc(OCCCCCBr)ccc2N1
Reactant: Sc1ccccn1
Product: O=C1CCc2cc(OCCCCCSc3ccccn3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(5-bromo-pentoxy)-3,4-dihydro-carbostyril and 2-mercapto-pyridine.
Reaction SMILES: Cl.[Si]([O:9][C@H:10]1[C:19](=[O:20])[C:18]2[CH:17]=[CH:16][N:15]3[CH:21]=[C:22]([CH3:24])[N:23]=[C:14]3[C:13]=2[NH:12][C@@H:11]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.[OH-].[Na+]>CO>[OH:9][C@H:10]1[C:19](=[O:20])[C:18]2[CH:17]=[CH:16][N:15]3[CH:21]=[C:22]([CH3:24])[N:23]=[C:14]3[C:13]=2[NH:12][C@@H:11]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O[Si](C)(C)C(C)(C)C)C3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)C3=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
30 ml of concentrated hydrochloric acid are added dropwise at room temperature in the course of 20 minutes to 29.8 g (73.1 mmol) of (8R,9R)-8-(tert-butyldimethylsilanyloxy)-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one, dissolved in 30 ml of methanol. The mixture is stirred for a further 30 minutes at room temperature. The methanol is stripped off and the pH of the remaining solution is adjusted to 10 using 2M sodium hydroxide solution. The mixture is extracted three times with 30 ml of dichloromethane each time, the combined dichloromethane phases are washed once with 30 ml of water and the organic phase is dried over magnesium sulfate. The drying agent is filtered off, the filtrate is concentrated and the residue is brought to crystallization using diethyl ether. The crystallizate is filtered off with suction and dried in vacuo at 50° C. 12.2 g (57% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]2[O:14][CH:15]=[CH:16][C:3]=12.[CH:17]1([C@H:23]([NH2:25])[CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[K+]>CN1CCCC1=O>[CH:17]1([C@H:23]([NH:25][C:2]2[N:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:4]3[O:14][CH:15]=[CH:16][C:3]=23)[CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Clc1nnc(-c2ccccc2)c2occc12
Reactant: C[C@@H](N)C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1nnc(-c2ccccc2)c2occc12)C1CCCCC1
Temperature: 140 °C
Reaction time: 6 h
Yield: 43.8 %

Procedure:
0.10 g of 4-chloro-7-phenyl-furano[2,3-d]pyridazine and 0.165 g of (R)-1-cyclohexylethylamine was dissolved in 1 ml of N-methylpyrrolidone, and the solution was stirred at 140° C. for 6 hours. After cooling the solution, an aqueous 5% KOH solution was added thereto, and the solution was extracted with chloroform. By purifying the extract by silica gel chromatography, 0.061 g of (R)-4-(1-cyclohexylethylamino)-7-phenyl-furano[2,3-d]pyridazine was obtained.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[OH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:13][CH:14]=1
Reactant: COC(=O)Nc1ccccc1-c1ccc(COC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Nc1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
The crude 4-(tetrahydropyranyloxy)methyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl (250 mg) dissolved in 4 mL of methanol was treated with 1 mL of 10% methanolic p-toluenesulfonic acid. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was made basic by the addition of saturated aqueous sodium bicarbonate, then diluted with ethyl acetate. The organic layer was washed with water (2×), dried over magnesium sulfate and evaporated under vacuum. The residue was purified by preparative thin layer chromatography on silica gel, eluting with methylene chloride/methanol (100:3) to give 137 mg of the product. FAB-MS (Li+ spike): calculated for C15H15NO3 (257); found 264 (M+Li). 1H NMR (200 MHz, CDCl3): 3.51 (s, 3H), 4.75 (s, 2H), 6.62 (br s, 1H), 7.14 (dd, 2H), 7.34 (dd, 1H), 7.4 (dd, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[CH2:7][C:6]=2[C:5]([C:13]#[N:14])=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[N:15]=[N:16][NH:17][N:14]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C#N)ccc(N)c2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nn[nH]n3)ccc(N)c2C1=O
Temperature: 120 °C
Yield: 38.9 %

Procedure:
A mixture of 7-Amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindole-4-carbonitrile (Compound 181B, 25.0 mg, 0.134 mmol), sodium azide (104 mg, 1.60 mmol) and ammonium chloride (85.7 mg, 1.60 mmol) in DMF (6 mL) were mixed and heated in microwave at 120° C. for 9 hours. The crude mixture was filtered and directly purified by MDP to obtain the title compound (12.0 mg, 39% yield). MS (ES+): m/z 231.23 (100) [MH+]; HPLC: tR=0.59 min (UPLC, analytical).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[O:3]1.[OH-].[K+].[F:21][C:22]1[C:27]([CH:28]=[O:29])=[C:26]([F:30])[CH:25]=[CH:24][C:23]=1[NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33]>CO>[F:21][C:22]1[C:27]([CH:28]([OH:29])[C:17]2[C:11]3[C:12](=[N:13][CH:14]=[C:9]([B:4]4[O:3][C:2]([CH3:18])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]4)[CH:10]=3)[NH:15][CH:16]=2)=[C:26]([F:30])[CH:25]=[CH:24][C:23]=1[NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F

Procedure:
In a round bottom flask, 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (27, 0.400 g, 1.64 mmol) is combined with 10 mL of methanol and potassium hydroxide (0.256 g, 4.56 mmol). Propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (28, 0.400 g, 1.52 mmol) is added and the reaction is stirred at room temperature for 3 hours, with additional potassium hydroxide added up to 7 equivalents. The reaction is concentrated under vacuum, the solid added to water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of 10-100% ethyl acetate (with 2.5% acetic acid) in hexanes. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=508.37.
Reaction SMILES: CC1(C)[O:9][CH:8]2[C@H:4]([C@@H:5]([CH2:19][I:20])[O:6][C@H:7]2[N:10]2[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[C:12]([F:18])=[CH:11]2)[O:3]1>FC(F)(F)C(O)=O.O>[I:20][CH2:19][C@H:5]1[O:6][C@@H:7]([N:10]2[CH:11]=[C:12]([F:18])[C:13]([NH2:17])=[N:14][C:15]2=[O:16])[C@H:8]([OH:9])[C@@H:4]1[OH:3]
Reactant: CC1(C)OC2[C@@H](O1)[C@@H](CI)O[C@H]2n1cc(F)c(N)nc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nc(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F

Procedure:
A solution of 5'-deoxy-5'-iodo-2',3'-O-isopropylidene-5-fluorocytidine (20 g) in trifluoroacetic acid/water (9:1, 100 ml) was stored at room temperature for 70 min. The solution was evaporated to dryness, co-evaporated with ethanol (2 × 200 ml) and dissolved in ethyl acetate (200 ml). Triethylamine was added to neutrality, and after storage overnight the crystals were collected and dried. Yield = 16.8 g (93%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][CH:26]=1)=[O:22]>>[CH2:1]([NH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]1([C:15]([NH:19][C@@H:20]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[CH:46][CH:45]=2)[C:21]([N:23]([CH2:35][CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27][CH:26]=2)=[O:22])=[O:17])[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1ccnc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: O=C(NCc1ccccc1)NCC1(C(=O)O)CC1
Product: CCOC(CN(Cc1ccnc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)C1(CNC(=O)NCc2ccccc2)CC1)OCC
Yield: 71.8 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 1-((3-benzylureido)methyl)cyclopropanecarboxylic acid (Compound VI-1) (174 mg, 0.35 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(quinolin-4-ylmethyl)propanamide (Compound IV-4) (173 mg, 0.7 mmol) and the obtained residue was purified by Purif silica gel column chromatography (eluent: n-hexane:ethylacetate=50:50 to 0:100) to obtain the title compound (182 mg, 72%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH3:36])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH3:36])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 70 °C
Yield: 48 %

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.146 g 0.5 mmol), 4-chloro-7-ethoxy-6-methoxyquinazoline from Example 6B Step 1 (0.12 g, 0.5 mmol), and Cs2CO3 (0.161 mg, 0.5 mmol) in isopropanol (10 mL) was heated at 70° C. for 7 hours. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with EtOAc/hexane as eluant to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-ylthio)phenyl]urea as solid (0.118 g, 48%). 1H NMR (300 MHz, CDCl3) δ 9.3 (br, 1H), 8.74 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.62 (d, 1H), 7.37 (m, 3H), 7.25 (1H), 5.91 (s, 1H), 4.29 (q, 2H), 4.06 (s, 3H), 1.58 (t, 3H), 1.32 (s, 9H); LC-MS (ESI) m/z 494 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]3[C:24]4[NH:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]=4[CH2:15][CH2:14][N:13]3[C:25]3[N:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=4)=[CH:27][N:26]=3)=[CH:6][C:5]=2[O:4]1.CN(C=[O:45])C>>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([C:28]2[CH:29]=[N:30][C:25]([N:13]3[CH2:14][C:15]4[C:16](=[O:45])[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=5[NH:23][C:24]=4[CH:12]3[C:7]3[CH:8]=[CH:9][C:10]4[O:11][CH2:3][O:4][C:5]=4[CH:6]=3)=[N:26][CH:27]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: COc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1OC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2cnc(N3Cc4c([nH]c5ccccc5c4=O)C3c3ccc4c(c3)OCO4)nc2)cc1OC

Procedure:
Sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol) and 1-(3,4-methylenedioxyphenyl)-2-[5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl]-2,3,4,9-tetrahydro-1H-β-carboline (218 mg, 0.43 mmol) (prepared as in Example 13) in DMF (10 mL, anhydrous) were stirred at room temperature for 30 min. Dry air was then bubbled through the solution for 16 h. Ethyl acetate (100 mL) and saturated NaHCO3 were added, the organic phase was washed with water, brine, and dried with MgSO4. Solvent was evaporated and the residue purified by chromatography (silica gel, ethyl acetate) to yield the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]([OH:26])[CH3:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1COCC1.C(OC(C)C)(C)C>>[C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:26])[CH3:25]
Reactant: CC(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 311, the title compound was synthesized using 6-bromo-3-(1-hydroxyethyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one. Crystals (THF-diisopropyl ether).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)[C:3]=1[C:4]#[N:5].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=2[C:4]#[N:5])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: Cc1cn(-c2cccc(F)c2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2cccc(F)c2C#N)c1CN(C)C
Yield: 46 %

Procedure:
As described for example 84b, 2-fluoro-6-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 7 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 97:3) afforded the title compound as a light yellow solid (yield: 46%). 1H-NMR (400 MHz, DMSO): δ=1.94 (s, 6H), 2.17 (s, 3H), 3.23 (s, 2H), 7.61-7.67 (m, 2H), 7.86 (s, 1H), 7.86-7.96 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH:14]([CH3:27])[CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH:14]([CH3:27])[CH2:15][N:16]3[C:17](=[O:26])[C:18]4[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:21])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CC(Br)CN1C(=O)c2ccccc2C1=O
Reactant: c1cc(N2CCNCC2)ccn1
Product: CC(CN1C(=O)c2ccccc2C1=O)N1CCN(c2ccncc2)CC1

Procedure:
The title compound was prepared from 1-pyridin-4-yl-piperazine [Org. Lett. 4 (2002) 737-740] and N-(2-bromopropyl)-phthalimide according to the method described in Reference Example 1/a.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:33]1([N:30]2[CH2:29][CH2:28][CH:27]([S:24]([CH2:23][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]5[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=5)=[O:12])=[CH:21][CH:22]=4)[O:6][C:2]=3[CH3:1])(=[O:25])=[O:26])[CH2:32][CH2:31]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide (300 mg, 0.66 mmol, 1.00 equiv), cyclohexanone (98 mg, 1.00 mmol, 1.51 equiv) and acetic acid (120 mg, 2.00 mmol, 3.03 equiv) in 1,2-dichloroethane (10 mL) was stirred for 4 h at room temperature. To this was added sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified on a silica gel column with water/acetonitrile (95/5-20/80) to give 350 mg (99%) of 4-[4-[(1-cyclohexylpiperidine-4-sulfonyl)methyl]-5-methyl-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS (ES, m/z): 537 [M+H]+; 1HNMR (300 MHz, CD3OD, ppm) δ 8.60 (s, 1H), 8.47 (d, 1H), 8.11 (d, 2H), 8.00 (d, 2H), 7.89 (d, 1H), 7.47-7.43 (m, 1H), 4.65 (s, 2H), 4.40 (s, 2H), 3.14 (d, 3H), 2.50 (d, 3H), 2.41-2.33 (m, 3H), 2.25 (d, 2H), 1.92-1.83 (m, 6H), 1.67 (d, 1H), 1.29-1.09 (m, 5H).