Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C@H:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][C:9]2[C:10]([CH2:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:36]=[O:37].CS(C)=O>C(O)C>[OH:37][CH2:36][C:2]1[N:1]([CH2:6][C@H:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][C:9]2[C:10]([CH2:20][S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2CS(=O)(=O)c1ccccc1
Reactant: C=O
Solvent: CS(C)=O
Solvent: CCO
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1CO)c1ccccc1)c2CS(=O)(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
A mixture of (S)-6-[2-(1H-imidazol-1-yl)-1-phenylethoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone (see example 3, 250 mg, 0.51 mmol), paraformaldehyde (1.5 g) and dimethylsulfoxide (6 mL) was stirred at 130° C. for 24 h. The mixture was diluted with ethanol (10 mL), filtered, concentrated, diluted with water (50 mL) and extracted with ethyl acetate (4×10 mL). The combined extracts were washed with water (3×10 mL), dried (brine, Na2SO4), and concentrated. The residue was purified by dry-flash column chromatography (SiO2, 2.5-22.5% 2-propanol-dichloromethane) to give (S)-6-{2-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1-phenylethoxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone as a white solid, 161 mg, 61% yield. NMR spectrum was consistent with structure. MS EI: M+* 517.1816 (M+* 517.1797).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20][O:21][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
360 mg (1.07 mmol) 3-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propan-1-ol in 3 ml CH2Cl2 were treated with 100 μl (1.29 mmol) methanesulfonic acid chloride and 450 μl (3.23 mmol) triethylamine at 0° C. The solution was stirred at RT for 2 h, diluted with CH2Cl2 and washed with 1N HCl and dried over Na2SO4. Evaporation gave 350 mg (79%) crude Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester, which was directly subjected to the following reaction.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:24]=[N:23][CH:22]=[C:21]3[C:16]=2[CH2:17][CH2:18][N:19]([C:25](OC(C)(C)C)=O)[CH2:20]3)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(O)(=O)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[C:16]3[CH2:17][CH2:18][N:19]([CH3:25])[CH2:20][C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(cncc2NC(=O)c2c(N)nn3cc(F)cnc23)C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCc2c(cncc2NC(=O)c2c(N)nn3cc(F)cnc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-butyl 5-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate was dissolved in MeOH (8 mL). Acetic acid (91.88 mg, 87.01 μL, 1.530 mmol), formaldehyde (37% solution in water, 99.33 mg, 91.13 μL, 1.224 mmol) and NaBH(OAc)3 (324.3 mg, 1.530 mmol) was sequentially added and the mixture was stirred for 1 hour at RT. The reaction mixture was partitioned between an aqueous saturated solution of NaHCO3 and DCM. The insoluble was filtered off and the combined organic extract was dried and concentrated in vacuo. The insoluble and the residue were combined and purified by fractionlynx to yield 2-amino-6-fluoro-N-(7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. MS (ES+) 342.2.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([F:42])=[CH:23][N:22]=1>>[F:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1F
Product: CNC(=O)CN1CCc2cc(Nc3ncc(F)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product was isolated as a pale yellow solid (0.044 g, 48%). MP: 82-124° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.29 (d, 1H, J=8.6 Hz), 8.16 (s, 1H), 7.93-7.90 (m, 1H), 7.40 (s, 1H), 7.36-7.29 (m, 1H), 7.22-7.18 (m, 1H), 6.63 (s, 1H), 6.56-6.53 (m, 1H) 6.53-6.48 (m, 1H), 3.93-3.84 (m, 10H), 3.17-3.09 (m, 6H), 2.92-2.82 (m, 7H), 2.74-2.65 (m, 4H). MS: 566.30 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.CO.I[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH3:29])[C:24](=[O:30])[CH:23]=[CH:22]2>ClCCl>[CH3:29][N:25]1[C:26]2[C:21](=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][NH:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][CH:6]=[CH:5]4)=[CH:28][CH:27]=2)[CH:22]=[CH:23][C:24]1=[O:30]
Reactant: Nc1ccc2ncccc2c1
Reactant: Cn1c(=O)ccc2cc(OCCCI)ccc21
Solvent: ClCCl
Solvent: CO
Product: Cn1c(=O)ccc2cc(OCCCNc3ccc4ncccc4c3)ccc21
Temperature: 60 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
6-Aminoquinoline (360 mg) was added to the methanol solution (10 ml) of 6-(3-iodopropoxy)-1-methyl-1H-quinolin-2-one (172 mg) and stirred at 60° C. for 17 hours. The reaction mixture was added to ice water, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound (86.4 mg) as a yellow amorphous solid.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:12]=3[F:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1C(=O)Cn1cncn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 53, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.02 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.56 (d, 2H), 7.47-7.37 (m, 1H), 7.27-7.15 (m, 4H), 7.10-6.92 (m, 7H), 5.24 (q, 2H), 4.55-4.49 (m, 1H), 3.88-3.80 (m, 1H), 3.39-3.30 (m, 1H), 2.84-2.65 (m, 3H), 2.02-1.92 (m, 1H). MS (EI) for C28H24F3N5O3. found 535.9 (MH+).
Reaction SMILES: CC(O)=O.[C:5]1([CH2:11][S:12][CH2:13][C@@H:14]([CH2:25][CH3:26])[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>Br.O>[C:5]1([CH2:11][S:12][CH2:13][C@@H:14]([CH2:25][CH3:26])[C:15]([OH:17])=[O:16])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC[C@H](CSCc1ccccc1)C(=O)OCc1ccccc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC[C@H](CSCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Glacial HOAc (120 ml) was added to a suspension of the product of step 8 (32.4 g, approx. 103 mmol) in 210 ml of 30-32% anhydrous HBr in glacial HOAc (approx. 1.03 mol) to complete the dissolution. The resulting solution was stirred at 70° C. for 6h and at 50° overnight. The reaction mixture was then cooled to r.t., diluted with H2O (750 mL) and extracted with CH2Cl2 (7×). The combined organic extracts were concentrated in vacuo. The residue was diluted with toluene (500 mL) and concentrated in vacuo 5 times to remove HOAc. The residue was dissolved in 1M aq KOH (750 mL), washed with CH2Cl2 (4×), acidified to pH 1 with concentrated HCl and extracted with CH2Cl2 (6×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford 17.6 g of the title compound as a pale yellow liquid which was used as such for the next step.
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](=[O:5])[CH3:4].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[C:16]1([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:3](=[O:5])[CH3:4])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc(NN=C(Cl)C(C)=O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NN=C(Sc2ccccc2)C(C)=O)cc1
Yield: 84.7 %

Procedure:
The reaction of 392 mg of 1-chloro-1-[(4-methoxyphenyl) hydrazono]-2-propanone, 220 mg of thiophenol and 280 ul of triethylamine in 6 ml of ethanol as in Example 11 yielded 440 mg of 1-[(phenyl)thio]-1-[(4-methoxyphenyl)hydrazono]-2-propanone, mp 120°-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=O)=[C:5]2[OH:19].[C:20]([NH:33][NH2:34])(=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:34][NH:33][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:16])=[C:5]2[OH:19]
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(C)c1=O
Reactant: CCCCCCCCCCCC(=O)NN
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Cl)ccc2n(C)c1=O

Procedure:
Reagents: Comp 37 (0.36 mmols, 0.10 g); dodecanoyl hydrazine (0.39 mmols, 0.08 g). Yield: 0.143 g (90%), white solid, m.p.=156.5° C.-157.5° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12])=[N+:2]=[N-:3].[C:13]([O:17][CH3:18])(=[O:16])[C:14]#[CH:15]>>[F:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[CH2:4][N:1]1[CH:15]=[C:14]([C:13]([O:17][CH3:18])=[O:16])[N:3]=[N:2]1
Reactant: C#CC(=O)OC
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Product: COC(=O)c1cn(Cc2c(F)cccc2F)nn1

Procedure:
reacting 2-(azidomethyl)-1,3-difluorobenzene of formula III with methyl propiolate to obtain methyl 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylate of formula IV; and
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[NH:5]2.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: CC1Nc2cc(F)ccc2-n2cccc21
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)N2c3cc(F)ccc3-n3cccc3C2C)cc1

Procedure:
7-Fluoro-5-(4-methoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the product of Example 47 and p-anisoyl chloride according to the procedure of Example 106, Step 2. MS (ESI) m/z 337; Anal. Calcd for C20H17FN2O2: C, 71.42; H, 5.09; N, 8.33. Found: C, 70.89; H, 4.96; N, 8.01.
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][OH:6])[CH2:3][OH:4].C([Sn](=O)CCCC)CCC.CN1C=CN=C1.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C1(C)C=CC=CC=1.O>[C:29]1([CH3:30])[CH:31]=[CH:32][C:26]([S:23]([O:4][CH2:3][C:2](=[CH2:1])[CH2:5][OH:6])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(CO)CO
Agent: CCCC[Sn](=O)CCCC
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(CO)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
2-Methylene-1,3-propanediol (480 mg) and dibutyltinoxide (1,7 g) were dissolved in toluene (30 ml) and the resulting suspension was refluxed for 1 hour eliminating water with the help of a Dean-Stark apparatus. The flask was cooled down to room temperature and then, N-methyl-imidazol (797 ml) and tosyl chloride (1,56 g) were added. After 15 minutes stirring, the reaction crude was directly purified by column chromatography (hexane-ethyl acetate v/v from 7:1 to 1:1). The title compound (428 mg) was obtained as a white solid.
Reaction SMILES: [CH:1]1([C@H:4]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5](O)=[O:6])[CH2:3][CH2:2]1.CSC.B>C1COCC1>[CH:1]1([C@H:4]([NH:8][C@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: C[C@H](N[C@H](C(=O)O)C1CC1)c1ccccc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@H](N[C@H](CO)C1CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a solution of (S)-2-cyclopropyl-2-[(S)-1-phenylethylamino]acetic acid (400 g, 1.82 mol) in dry THF (5.2 L) at 0° C. was added borane dimethylsulfide (neat) (485 g, 6.39 mol) with vigorous stirring. The reaction mixture was stirred overnight at room temperature. Reaction progress was monitored by HPLC. Stirring was continued until the acid was consumed completely (18-20 h). Upon completion the reaction mixture was cooled to 0° C. and methanol (6 L) was added dropwise. The mixture was concentrated under vacuum and the residue was dissolved in chloroform (5 L). The organic layer was washed with 10% aqueous NaHCO3 solution (2×1 L) followed by brine, dried over Na2SO4, filtered and concentrated to afford a tan-yellow oil. The oil was distilled under reduced pressure to afford (S)-2-cyclopropyl-2-[(S)-1-phenylethylamino]ethanol (166 g, 44% yield) as a colorless oil: by 175-184° C., 0.1 mm Hg; [α]25D −52.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.91-3.86 (m, 1H), 3.67 (dd, JAB=10.6, JAX=3.8 Hz, 1H), 3.39 (dd, JBA=10.6, JBX=4.3 Hz, 1H), 2.40 (s br, 2H), 1.70-1.65 (m, 1H), 1.35 (d, J=6.6 Hz, 3H), 0.88-0.82 (m, 1H), 0.47-0.37 (m, 2H), 0.05-−0.06 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 146.8, 127.6, 126.2, 125.9, 63.0, 60.5, 54.4, 24.4, 13.3, 3.0, 1.5; LRMS (ESI) m/e 206.3 [(M+H)+, calcd for C13H20NO 206.2].
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22]C(=O)CC1C=CC=CC=1.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43]([OH:45])=O)[CH:38]=[C:39]([F:41])[CH:40]=1>>[F:41][C:39]1[CH:38]=[C:37]([CH2:42][C:43]([N:19]([C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C@@H:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20](=[O:33])[C@H:21]([CH2:32][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:7]=2)[NH2:22])=[O:45])[CH:36]=[C:35]([F:34])[CH:40]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: N[C@@H](Cc1ccccc1)C(=O)N(C(=O)Cc1cc(F)cc(F)c1)[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that N-[(2,3-cis)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-L-phenylalaninamide (105a) was used as the amine component and 3,5-difluorophenylacetic acid was used as the acid component to afford the title compound as a 1:1 mixture with the 2S,3S diastereomer (58 mg), white solid, m.p. 115-120° C. 1H NMR (300 MHz, d6-DMSO) δ 4.45 (m, 1H), 4.75 (m, 1H), 5.10 (m, 1H), 6.70 (m, 2H), 6.95-7.90 (m, 16H), 8.25 (two d, 1H, J=8 Hz), 10.5 (m, 1H). MS APCI, m/z=572 (M+1). LC/MS: 2.68 min.
Reaction SMILES: [OH-].[Na+].Cl[P:4]1(=[O:22])[O:9][CH:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]([CH3:21])([CH3:20])[CH2:6][O:5]1.Cl.CC[O:26]CC>O>[OH:26][P:4]1(=[O:22])[O:9][CH:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]([CH3:21])([CH3:20])[CH2:6][O:5]1
Reactant: CC1(C)COP(=O)(Cl)OC1c1cccc2ccccc12
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)COP(=O)(O)OC1c1cccc2ccccc12
Temperature: 100 °C
Reaction time: 0.58 h
Yield: 57.6 %

Procedure:
Sodium hydroxide (29.4 g, 0.735 mol) was dissolved in water (300 ml). To the solution was added 2-chloro-5,5-dimethyl-4-(1-naphthyl)-1,3,2-dioxaphosphorinane 2-oxide (76.1 g, 0.245 mol) little by little, with stirring and heating at 100° C. The addition was completed for 35 min, and the solution was further stirred for 20 min. The reaction solution was cooled to 55° C., which resulted in precipitation of a large amount of crystals. Under stirring, concentrated hydrochloric acid (73 ml) was added to the mixture to adjust the mixture to acidic, and the mixture solidified and turned into powder by leaving it for about 1 hr. To the powder was added ether (100 ml), and the mixture was stirred and filtered. The obtained crystals were washed alternately with water and ether and dried to give the title compound as pale ocher crystals having the melting point of 216 to 217° C. (41.23 g, yield 57.6%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.[CH3:18]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:18])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(Br)cc1
Reactant: CO
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)/C=C/c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of (2E)-3-(4-bromophenyl)prop-2-enoic acid (4.5 g, 0.020 mol) in MeOH (20 mL), sulfuryl dichloride (2.7 g, 0.023 mol) was added dropwise at 0° C. The resulting solution was heated to reflux for 1 h. The reaction mixture was allowed to cool to rt and concentrated to dryness under reduced pressure to yield a residue, which was subjected to flash column chromatography on silica gel (5-10% EtOAc/petroleum ether) to afford compound 66c as a colorless oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C10H9BrO2: 241.1 (M). found: 241.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>CCCCCC>[CH2:12]([N:16]([CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(N=C=O)c(C)c1
Reactant: CCCCNCCCC
Solvent: CCCCCC
Product: CCCCN(CCCC)C(=O)Nc1ccc(C)cc1C

Procedure:
A solution of 4.89 g. of 2,4-dimethylphenylisocyanate in 100 ml. of hexane is added to a solution of 3.48 g. of di(n-butyl)amine in 150 ml. of hexane and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield 1,1-di-(n-butyl)-3-(2,4-dimethylphenyl)urea, m.p. 48°-50° C.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13]
Reactant: BrCCCBr
Reactant: O=C1Nc2cccc3c2C1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2cccc3c2C1(CCCBr)CCC3
Temperature: 60 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
2a, 3,4,5-Tetrahydrobenz [cd]indole-2(1H) -one (1.0 g, 5.8 mmol) was dissolved in anhydrous N,N-dimethylformamide (40 ml). Thereto was added sodium hydride (230 mg, 5.8 mmol), and the resulting solution was stirred at 60° C. for 1 hour. The reaction solution was mixed with 1,3-dibromopropane (1.8 ml, 17 mmol) and again stirred for 2 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and water. The reaction product was extracted with ethyl acetate, washed with saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 150 mg of the title compound (0.51 mmol, 8.8% in yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[N:13]([O-])=O.[Na+].C(OCC)C.[F:22][B-:23]([F:26])([F:25])[F:24].[H+]>>[F:22][B-:23]([F:26])([F:25])[F:24].[C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([N+:1]#[N:13])=[C:3]([CH3:12])[CH:4]=1)(=[O:11])[CH3:10]
Reactant: O=N[O-]
Reactant: CC(=O)Nc1cc(C)c(N)cn1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)Nc1cc(C)c([N+]#N)cn1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
The N1-(5-amino-4-methyl-2-pyridyl)acetamide (8.00 g, 48.4 mmol) obtained in (B) was dissolved in tetrafluoroboric acid (160 ml) and slowly added dropwise with an aqueous solution (40 ml) of sodium nitrite (3.51 g, 50.8 mmol) at −20° C. under nitrogen atmosphere. The reaction mixture was further stirred at −10° C. for 1 hour and added with diethyl ether (800 ml), and the deposited white solid was collected by filtration and washed with diethyl ether to obtain the title compound (14.7 g, quantitative).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:29]([NH2:32])[CH2:30][NH2:31]>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:31][CH2:30][CH2:29][NH2:32])[CH:7]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: NCCN
Reactant: Fc1cc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)ccn1
Product: NCCNc1cc(-c2n[nH]c3cnc(-c4cccnc4)cc23)ccn1
Yield: 64 %

Procedure:
Following the procedure of Example 143, 3-(2-fluoropyridin-4-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 1,2-ethylenediamine were reacted and purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 32 mg (64%) of 159. ESI MS m/z 332.1 (M+1). 1H NMR (400 MHz, DMSO): 9.38 (s, 1H), 9.23 (s, 1H), 8.60 (d, J=11.0 Hz, 2H), 8.53 (d, J=7.1 Hz, 1H), 8.10 (s, 1H), 7.54 (s, 1H), 7.25 (d, J=11.9 Hz, 2H), 6.67 (s, 1H), 2.78 (s, 2H)