Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[CH3:20][N:21]([CH3:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:25]2[CH2:26][CH2:27][CH:22]([N:21]([CH3:28])[CH3:20])[CH2:23][CH2:24]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)[C@](O)(c2ccccc2)C2CCCC2)CC1
Reaction time: 12 h
Yield: 60 %

Procedure:
To a stirred solution of (R)-cyclopentylhydroxyphenyl acetic acid (5.00 g, 22.7 mmol) in DCM (200 mL, 3 mol) was added dimethylpiperidin-4-yl amine (2.91 g, 22.7 mmol). DIPEA (11.9 mL, 68.1 mmol) and HOBt (5.21 g, 34 mmol) were added, followed by EDCI (5.22 g, 27.2 mmol). The mixture was stirred for 12 hours, then washed with water (300 mL), a saturated aqueous NaCl solution (300 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. The crude material was purified via silica gel chromatography (10% MeOH/DCM w/1% NH3 (aq)) to afford 4.5 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C.[CH3:49][N:50]1[CH2:54][C@H:53]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@:52]2([CH2:65][CH2:64][CH2:63][NH:62][CH2:61]2)[C:51]1=[O:66].CN1C[C@@H](C2C=CC=CC=2)[C@@]2(CCCNC2)C1=O>CC#N.Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([N:62]1[CH2:63][CH2:64][CH2:65][C:52]2([C:51](=[O:66])[N:50]([CH3:49])[CH2:54][CH:53]2[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:61]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1C[C@H](c2ccccc2)[C@]2(CCCNC2)C1=O
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN1C[C@@H](c2ccccc2)[C@@]2(CCCNC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising (R)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid (Sigma-Aldrich) (1.052 g, 3.56 mmol) and ®T3P (50% in EtOAc) (4.16 ml, 7.12 mmol) in MeCN (20 mL) was treated dropwise with DIPEA (2.488 ml, 14.25 mmol). The resulting solution was stirred at room temperature for 30 minutes, then a racemic mixture of (4R,5S)-2-Methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one and (4S,5R)-2-Methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (Intermediate 1A) (1 g, 3.56 mmol) was added portionwise. The reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was diluted with 0.1M HCl (20 mL) and extracted with DCM (20 mL). The aqueous phase was further extracted with DCM (3×20 mL). The combined organic portions were washed with a saturated solution of sodium bicarbonate (20 mL), water (20 mL), dried (MgSO4), and concentrated in vacuo to afford the title compound. No purification was performed on the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN1C(=O)N(C)CCC1>[C:25]1([CH2:24][NH:31][C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Solvent: CN1CCCN(C)C1=O
Product: O=C(c1ccc(NCc2ccccc2)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 110 °C

Procedure:
A mixture of 0.16 g of 10-[(6-chloro-3-pyridinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.5 ml of benzylamine and 0.2 ml of N,N'-dimethylpropyleneurea is stirred and heated at 110° C. for 7 hours. After cooling to room temperature, the mixture is washed with hexane (3 times 10 ml). The residue is dissolved in water and made alkaline with 1N NaOH. The suspension is washed with H2O and extracted with ethyl acetate. The organic extract is washed with brine, dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated and the residue triturated with diethyl ether-hexane to give 0.20 g of white solid; mass spectrum (CI) 395 (M+H).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:15])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.C(N(C(C)C)C(C)C)C.[O:29]=[C:30]1[NH:35][C:34]2[CH:36]=[C:37]([S:40](Cl)(=[O:42])=[O:41])[CH:38]=[CH:39][C:33]=2[O:32][CH2:31]1>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:15][S:40]([C:37]3[CH:38]=[CH:39][C:33]4[O:32][CH2:31][C:30](=[O:29])[NH:35][C:34]=4[CH:36]=3)(=[O:42])=[O:41])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: O=C1COc2ccc(S(=O)(=O)Cl)cc2N1
Reactant: Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1COc2ccc(S(=O)(=O)Nc3cc(-c4cc5ccccc5s4)c4[nH]ncc4c3)cc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a mixture of 7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamine (Example #F.8.1, 32 mg, 0.12) and ethyl-diisopropylamine (0.032 mL, 0.18 mmol) in DMF (1 mL) at room temperature and under an inert atmosphere was added 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonyl chloride (33 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 2 hours then concentrated under reduced pressure. The crude material was purified by preparative HPLC (20% to 80% acetonitrile/0.05 M aqueous ammonium acetate, buffered to pH 4.5 over 30 min at 20 mL/min; Hyperprep C18, 300 Å, 8 μm, 250×21.1 mm column) to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid (7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-amide as a white solid (34 mg, 58%). LC/MS (Table 1, Method e) Rt 1.75 min; ESI−MS [M+H]+=475.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)N1CCOCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCOCC1
Temperature: 105 °C
Yield: 21 %

Procedure:
To a sealed tube was added 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (900 mg, 1.91 mmol), ethanol (12 mL), piperidine (0.23 mL, 2.29 mmol) and 2-methyl-2-morpholino-propanal (0.49 mL, 2.86 mmol). The tube was sealed and heated to 105° C. for 24 hrs. The mixture was then cooled, concentrated and then dissolved in ethyl acetate (100 mL) and washed with 5% citric acid (100 ml) and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (column size 100 g. Solvent system 4%-8% MeOH/EtOAc) to obtain 245 mg (21% yield) of the title compound. MS (pos. ion) m/z: 611 (M+1).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([OH:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH3:31][O:32][CH2:33][CH2:34][C:35]([NH:37][NH2:38])=O>>[CH3:31][O:32][CH2:33][CH2:34][C:35]1[O:30][C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)=[N:38][N:37]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: COCCC(=O)NN
Product: COCCc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)o1

Procedure:
100 mg (0.15 mmol) of the compound from Example 108A and 36 mg (0.31 mmol) of 3-methoxypropanehydrazide were reacted according to the General Method 4. Yield: 5 mg (7% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 2-chloro-5-nitrobenzoic acid (5.0 g, 25.0 mmol) and dichloromethane (100 ml) was added oxalyl chloride (2.7 ml, 31.0 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 2 hours, the mixture was concentrated under reduced pressure to provide 2-chloro-5-nitro-benzoyl chloride.
Reaction SMILES: [O:1]=[C:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:22])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:28]([BH-](CC)CC)C.[Li+]>O1CCCC1>[OH:1][CH:2]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:3]=[CH:4]/[C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:22])[C:10]=1[O:11][C:12]1[CH:28]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCC(=O)/C=C/c1occc(=O)c1OCCCCCC(=O)OCC
Reactant: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(O)/C=C/c1occc(=O)c1Oc1cccc(C(=O)OCC)c1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution, cooled under nitrogen to -78°, of 0.200 g (0.53 mmol) of 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-4-pyrone in 2 ml of tetrahydrofuran was added dropwise keeping the internal temperature at -70° to -75°, 0.53 ml (0.53 mmole) of lithium triethylborohydride. After being stirred for an additional 30 min the cold reaction was quenched by the addition of 0.5 ml of 40% aqueous acetic acid and then partially concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed successively with aqueous sodium bicarbonate and brine solution. The organic solution was dried over magnesium sulfate and evaporated to give an oil. Chromatographic purification on silica gel eluting with ether furnished 0.131 g (65%) of 2-[(3RS)-3-hydroxy-trans-1-octenyl]-3-(5-carboethoxypenyloxy)-4-pyrone. NMR (CDCl3, 100 M Hz): δ0.90 (3H, t, J=4.5 Hz), 2.33 (2H, t, J=6 Hz), 4.13 (4H, m), 4.35 (1H, m).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:13]([C:15]([CH2:22][OH:23])([CH2:18][CH2:19][CH2:20][CH3:21])[CH:16]=[O:17])[CH3:14]>>[CH2:13]([C:15]([CH2:22][O:23][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:18][CH2:19][CH2:20][CH3:21])[CH:16]=[O:17])[CH3:14]
Reactant: CCCCC(C=O)(CC)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCC(C=O)(CC)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.4 %

Procedure:
To a cold (10° C.) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30° C. The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HCl and extracted with methlyene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo to give 24.4 g of brown oil.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[O:1][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]2)[N:17]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2noc(-c3cccs3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
To a cold (0° C.) solution of tert-butyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (8 g, 32.7 mmol) in anhydrous DCM (150 mL) was added thiophene-2-carbonyl chloride (4.8 g, 32.7 mmol) followed by DIEA (7.2 mL, 39.2 mmol). The reaction mixture was stirred at RT for 12 hours and then filtered. The filtrate was evaporated and the residue was refluxed in pyridine (100 mL) for 3 hours. The solvent was removed under vacuum and the residue was dissolved in DCM. The organic layer was washed with a 10% aq. solution of sodium bicarbonate, water, brine and dried. The solvent was concentrated and the residue was purified by chromatography (Pet. Ether/EtOAc 7/3) to give 2.2 g (20%) of The title compound as a solid. TLC-Pet ether/EtOAc (9/1): Rf=0.75. HPLC purity>97%.
Reaction SMILES: [CH:1](=O)[CH3:2].ClC(Cl)C.[C:8]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([C:24]4[N:25]=[C:26]([CH2:34][CH:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[N:27]5[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=45)=[CH:19][CH:20]=3)[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:38]1[CH2:39][CH2:40][CH:35]([CH2:34][C:26]2[N:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]3=[C:24]([C:18]3[CH:17]=[C:16]4[C:21]([CH:22]=[CH:23][C:14]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)=[N:15]4)=[CH:20][CH:19]=3)[N:25]=2)[CH2:36][CH2:37]1)[CH3:2]
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetaldehyde (6.76 mg, 0.15 mmol) in dichloroethane (5 mL, 2 equiv) was added to 1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine (100.00 mg, 0.23 mmol) and sodium triacetoxyborohydride (65.0 mg, 306.8 mmol). The reaction mixture was stirred at rt overnight. The crude product was purified by a 5 g Jones silica gel (dry loaded with silica, wetted with 100% CH2Cl2, eluted with 100% CH2Cl2 h 3% (7N NH3) in MeOH/CH2Cl2→6% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product. 1H NMR (400 MHz, METHANOL-D) δ 8.38 (1H, d, J=8.66), 8.25 (1H, s), 8.08 (2H, dd, J=1.64 Hz, J=1.08), 8.00 (2H, m), 7.79 (1H, dd, J=2.06, J=1.70), 7.51 (1H, d, J=5.15), 7.44 (3H, m), 7.00 (1H, d, J=5.12), 3.06 (2H, d, J=10.88), 2.97 (2H, d, J=7.08), 2.54 (2H, d, J=5.80), 2.18 (2H, m), 1.98 (1H, m), 1.75 (2H, d, J=13.12), 1.43 (2H, m), 1.07 (3H, t); MS (ES+): m/z 435.12/436.10 (15/5) [MH+]; HPLC: tR=1.71 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:17][CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH2:10]2)[C:5]([Cl:25])=[CH:4][N:3]=1.Cl.[CH3:27][N:28]1[CH:32]=[C:31]([NH2:33])[CH:30]=[N:29]1.C(N(C(C)C)C(C)C)C>CCCCO>[Cl:25][C:5]1[C:6]([NH:8][CH:9]2[CH2:17][CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH2:10]2)=[N:7][C:2]([NH:33][C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4CN(C(=O)OC(C)(C)C)CC4C3)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydro-1H-isoindole-2(3H)-carboxylate (767.3 mg, 1.98 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (411.5 mg, 3.08 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (792.9 g, 6.14 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography ((EtOAc/PE (v/v)=1/1) to give the title compound as a pale yellow solid (493 mg, 55.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH:13][NH2:14])=[O:12])=[CH:5][CH:4]=1.[N+:15]([C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>CO>[N+:15]([C:18]1[O:22][C:21]([CH:23]=[N:14][NH:13][C:11](=[O:12])[CH:10]=[CH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: COc1ccc(C=CC(=O)NN)cn1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CO
Product: COc1ccc(C=CC(=O)NN=Cc2ccc([N+](=O)[O-])o2)cn1

Procedure:
To a solution, heated to 50°-60° C., of 0.9 g (4.66 mmol) of 3-(6-methoxy-3-pyridyl)-2-propenoic acid hydrazide in 50 ml of methanol, 0.66g (4.7 mmol) of 5-nitrofuran-2-carbaldehyde is added.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH:29]=3)[CH2:22][CH2:23]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)ccc1F

Procedure:
Example 110 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.31–8.12 (m, 1H), 7.44–7.15 (m, 5H), 7.12–6.94 (m, 1H), 6.75–6.61 (br, 1H), 6.61–6.46 (br, 1H), 3.35–3.12 (m, 4H), 2.70–2.47 (m, 3H), 2.46–2.35 (m, 2H), 2.35–2.21 (m, 2H), 1.92–1.67 (m, 8H), 1.54 (s, 6H), 1.02 (t, 3H, J=7.2 Hz); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: C([CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:7]=1[C:8]([OH:10])=O)(O)=O.[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[I:15][C:12]1[CH:13]=[CH:14][C:6]2[O:5][CH:4]=[C:8]([O:10][C:16](=[O:18])[CH3:17])[C:7]=2[CH:11]=1
Reactant: O=C(O)COc1ccc(I)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Oc1coc2ccc(I)cc12
Temperature: 140 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
Place 2-carboxymethoxy-5-iodo-benzoic acid (Preparation 21a; 7 g, 21 mmol) acetic anhydride (35 ml), sodium acetate (4 g), and acetic acid (5 mL) into a 50 mL round bottom flask. Heat the resulting mixture at 140° C. under stirring for 5 h and cool to room temperature. Add water (12 mL) into the mixture gradually maintaining the temperature below 60° C. and continue to stir for 18 h. Dilute with water (200 mL) and collect the resulting precipitate via vacuum filtration. Wash the solid with water and dry to give the final product (6 g, 95%). MS (electrospray, m/z) 303 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][C:16]#[N:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH2:19]>C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[CH2:15][C:16]([NH2:17])=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(CC#N)c1ccc(N2CCN(C)CC2)cc1
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(CC(N)=O)c1ccc(N2CCN(C)CC2)cc1
Temperature: 90 °C
Yield: 74 %

Procedure:
A suspension of 3-(4-(4-methylpiperazin-1-yl)phenyl)butanenitrile (450 mg, 1.85 mmol) and poly phosphoric acid (4.5 g) was heated at 90° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with cold water and basified with saturated sodium bicarbonate solution. The aqueous layer was extracted with DCM, washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 360 mg (74%) of 3-(4-(4-methylpiperazin-1-yl)phenyl)butanamide as light yellow color solid.
Reaction SMILES: Br[C:2](Br)([F:4])[F:3].CN(P(N(C)C)N(C)C)C.O=[C:17]([CH3:25])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(OCC)C>O1CCCC1>[F:3][C:2]([F:4])=[C:17]([CH3:25])[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: FC(F)(Br)Br
Reactant: COC(=O)CCCC(C)=O
Agent: CN(C)P(N(C)C)N(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCCC(C)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Reaction was carried out under nitrogen atmosphere. To 650 ml of tetrahydrofuran, 80 g (0.38 mol) of dibromodifluoromethane was dissolved, followed by drop-wisely adding 121 g (0.74 mol) of tris(dimethylamino)phosphine at −10° C. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature for 1 hour, followed by further drop-wisely adding 24.9 g (0.17 mol) of methyl 5-oxohexanoate dissolved in 250 ml of tetrahydrofuran, at −20° C. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature overnight. To this mixture, diethyl ether was added, followed by washing with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (diethyl ether:hexane=1:4) to obtain 27 g (yield: 88%) of methyl 6,6-difluoro-5-methyl-5-hexenoate.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=2)=[CH:58][C:57]=1[CH3:69])[CH3:54]>CN(C=O)C>[CH2:53]([O:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:63]=2)=[CH:58][C:57]=1[CH3:69])[CH3:54]
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1C
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
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: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 52.5 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.020 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.37 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 53% yield: LCMS (ESI) m/z 484 (MH+).
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18]1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18]1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: c1ccc(C2CCNC2)nc1
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Product: CCCC[C@@H](C(=O)N1CCC(c2ccccn2)C1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 2-pyrrolidin-3-yl-pyridine A-5 according to General Procedure B.