Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=1[S:35]([CH3:38])(=[O:37])=[O:36])[C:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)(C)(C)C.[ClH:40]>O1CCOCC1.C(OC)(C)(C)C>[ClH:40].[NH2:7][CH:8]([C:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1)[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=1[S:35]([CH3:38])(=[O:37])=[O:36]
Reactant: CC(C)(C)OC(=O)NC(C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1S(C)(=O)=O
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {(4-cyano-2-methanesulfonyl-phenyl)-[6-oxo-2-(3-trifluoromethyl-phenylamino)-cyclohex-1-enyl]-methyl}-carbamic acid tert-butyl ester (INTERMEDIATE 16, 976 mg, 1.73 mmol) in 1,4-dioxane (2.0 mL) is added a solution of hydrogen chloride in 1,4-dioxane (4 M, 3.46 mL, 13.85 mmol) and the mixture is stirred at room temperature for 3 h. The reaction mixture is diluted with tert-butylmethylether and the precipitate is filtered off, washed with tert-butylmethylether and dried. Yield: 529 mg. ESI mass spectrum: [M+H]+=464; Retention time HPLC: 0.47 min (X012_S01).
Reaction SMILES: CC([Si](C)(C)[O:6][C@@H:7]1[CH2:11][N:10]([CH2:12][C:13]#[C:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9](=[O:21])[CH2:8]1)(C)C.Cl.[OH-].[K+]>>[OH:6][C@@H:7]1[CH2:11][N:10]([CH2:12][C:13]#[C:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9](=[O:21])[CH2:8]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)N(CC#CCN2CCCC2)C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C1C[C@H](O)CN1CC#CCN1CCCC1
Reaction time: 1 h
Yield: 8.4 %

Procedure:
A mixture of 7.2 g of (S)-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone and 75 ml of 1N methanolic hydrochloric acid was stirred for 1 hour, then cooled to 0° C. and basified to pH 8 with methanolic potassium hydroxide. The mixture was filtered and the filtrate evaporated. The residue was reevaporated from dichloromethane. The residual oil was purified by chromatography (alumina), giving 0.4 g of the desired product as a yellow oil, [α]D26 =-12° (dichloromethane).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>>[CH2:1]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
n-Octyl bromide (0.102 mol) is added to a solution of 4-(4-hydroxyphenyl)benzoic acid (0.102 mol) and 2.5 N sodium hydroxide (0.102 mol) and the mixture stirred at 70° C. for a period of 18 hours. The reaction mixture is allowed to cool and then acidified to pH 3 and partitioned between ethyl acetate and water. The organic phase is washed with water and brine and the solvent then removed to obtain the 4'-n-octyloxy-[1,1'-biphenyl]-4-ylcarboxylic acid, C21H23O3, M.W. 326.4
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18]>C1COCC1>[CH2:1]([S:8][C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccc1F
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1cc(Cl)ccc1SCc1ccccc1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
Benzyl mercaptan (0.61 mL, 5.20 mmol) was added dropwise over 10 min to a stirred suspension of sodium hydride (60% in oil, 230 mg, 5.75 mmol) in THF (10 mL) at ambient temperature under a nitrogen atmosphere. The white suspension was stirred for a further 1 h and then added dropwise to a stirred solution of 5-chloro-2-fluorobenzamide (900 mg, 5.20 mmol) in THF (10 mL), under nitrogen, over 10 min. The mixture was stirred at ambient temperature for 1 h, at 50° C. for 1 h and at reflux for 3 h and then quenched with water (200 mL). The product mixture was extracted with EtOAc (3×30 mL) and the combined extracts washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel with EtOAc:heptane (3:2, v/v) as eluent to give the title compound as a white solid (523 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4)nc23)CC1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a solution of 0.100 gm (0.43 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 3 mL 50% aqueous tetrahydrofuran were added 0.43 mL (0.86 mMol) benzoyl chloride and the resulting mixture was stirred at room temperature. After about 4 hours the reaction mixture was partitioned between dichloromethane and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of dichloromethane (2-10% methanol) containing 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 0.095 gm (66%) of the title compound. A portion was recrystallized from ethanol/water to provide an analytical sample.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=1)[CH2:15][N:16]1[C:20]2=[N:21][C:22]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)=[N:23][CH:24]=[C:19]2[CH:18]=[N:17]1)C1C=CC=CC=1>CO.[Pd]>[CH3:31][N:29]1[CH:30]=[C:26]([NH:25][C:22]2[N:21]=[C:20]3[N:16]([CH2:15][C:14]4[CH:13]=[C:12]([CH:34]=[CH:33][CH:32]=4)[O:11][CH2:10][CH2:9][OH:8])[N:17]=[CH:18][C:19]3=[CH:24][N:23]=2)[CH:27]=[N:28]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(OCCOCc5ccccc5)c4)c3n2)cn1
Agent: [Pd]
Solvent: CO
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(OCCO)c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-(2-(benzyloxy)ethoxy)benzyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (39 mg, 86 μmol) was dissolved in 2 mL methanol then palladium on carbon added under an inert atmosphere and the reaction mixture stirred overnight at rt under an hydrogen atmosphere. The reaction mixture was filtered through Celite and evaporated to afford the title compound after purification by preparative HPLC. 1H NMR (d6-DMSO) δ 9.85 (s, 1H), 8.92 (s, 1H), 8.11-7.97 (m, 2H), 7.56 (s, 1H), 7.23 (t, J=8.0 Hz, 1H), 6.95-6.74 (m, 3H), 5.52 (s, 2H), 4.81 (t, J=5.5 Hz, 1H), 3.90 (t, J=5.0 Hz, 2H), 3.83 (s, 3H), 3.65 (m, 2H); LC-MS method B, (ES+) 366.0, RT=6.64 min.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:21]([O:23]C)=[O:22])[CH2:8][CH2:7][N:6]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[Li+].[OH-].Cl>C1COCC1>[CH2:19]([O:18][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:9]([N:6]2[CH2:5][CH2:4][C:3]([O:2][CH3:1])([C:21]([OH:23])=[O:22])[CH2:8][CH2:7]2)[CH2:10][CH2:11]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)N1CCCC(N2CCC(OC)(C(=O)OC)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCC(N2CCC(OC)(C(=O)O)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.3 %

Procedure:
Ethyl 4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.136 g, 0.39 mmol) was dissolved in THF (5 mL) at rt and 1M LiOH sol. (0.4 mL) was added. The reaction mixture was stirred at rt for 2 days. The pH was carefully adjusted to pH 6 by addition of concentrated hydrochloric acid, the solvents were removed in vacuo, to give 1-[1-(ethoxycarbonyl)azepan-4-yl]-4-methoxypiperidine-4-carboxylic acid (0.131 g), Intermediate 8, as a yellow oil which was used directly without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([CH2:23][CH2:24][CH3:25])=[CH:20][CH2:21][CH3:22])=[C:13]([CH3:26])[N:12]=1)[CH3:2]>CO.[Pd]>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[C:13]([CH3:26])[N:12]=1)[CH3:10]
Reactant: CCC=C(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC

Procedure:
A solution of 2-(2,6-diethylphenyl)-4-methoxy-6-methyl-5-(1-propylbutenyl)pyrimidine (100 mg) in MeOH is hydrogenated over Pd—C at 50 psi for 18 h. The catalyst is removed by filtration and the filtrate is concentrated to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 7.24-7.29 (m, 1H), 7.13 (d, J=8 Hz, 2H), 3.91 (s, 3H), 2.51 (s,3H), 2.41 (q, J=7.5 Hz, 4H), 2.38-2.45 (m, 8H), 1.58-1.82 (m, 3H), 1.14-1.44 (m, 2H), 1.08 (q, J=7.5, 6.6 Hz, 6H) 0.89 (t, J=7.5 Hz, 6H); LC-MS found 355 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][C:12](=[O:14])[CH3:13])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2].[CH3:15]I.[H-].[Na+]>CS(C)=O>[C:1]([C:3]1[C:4]([N:11]([CH3:15])[C:12](=[O:14])[CH3:13])=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2]
Reactant: CSc1ncc(C#N)c(NC(C)=O)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ncc(C#N)c(N(C)C(C)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-acetamide (562 mg, 2.70 mmol) and methyl iodide (1.7 mL, 27.0 mmol) in anhydrous DMSO (14 mL) was added NaH (60% wt. dispersion in mineral oil, 130 mg, 3.23 mmol) at 0° C. The reaction mixture was stirred at RT for 16 h and was then quenched by adding water (50 mL). The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (from 0 to >33% EtOAc/hexane in 5 min.) to afford 431 mg (72% yield) of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-N-methyl-acetamide as an off-white solid. MS=223 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH2:24]([O:26][C:27]([C:29]1[CH:30]=[N:31][NH:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[CH:30]=[N:31][N:32]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])=[CH:18][CH:19]=2)[CH:33]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)cc2)c1

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (840 mg) described in Preparation Example 108 and 1H-pyrazole-4-carboxylic acid ethyl ester (320 mg) and by the reaction and treatment in the same manner as in Example 1, 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-1H-pyrazole-4-carboxylic acid ethyl ester was obtained. Using this compound and 1-methylpiperazine (230 μL) and by the reaction and treatment in the same manner as in Example 109, the title compound (88 mg) was obtained.
Reaction SMILES: [CH3:1][SiH:2]([CH3:14])[NH:3][CH2:4][CH:5]=[CH:6]CC1C=CC=CC=1.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:21]([N:3]1[CH2:4][CH2:5][CH2:6][Si:2]1([CH3:14])[CH3:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[SiH](C)NCC=CCc1ccccc1
Reactant: Cc1ccccc1
Product: C[Si]1(C)CCCN1Cc1ccccc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Into a glass tube with an outside diameter of 10 mm and a length of 10 cm were introduced 5 mg ((1,5-cyclooctadiene)RhCl)2 and 2 mL of a mixture of 1 part N-dimethylsilyl-N-benzylallylamine and 2 parts toluene, and the tube was sealed. After this had been left quiescent for 30 minutes at room temperature, the conversion of N-dimethylsilyl-N-benzylallylamine was 100 weight %. 1-Benzyl-2,2-dimethyl-1-aza-2-silacyclopentane was obtained in a yield of 96%. No production of 1-benzyl-2,2,3-trimethyl-1-aza-2-silacyclobutane was observed.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][O:33][NH2:34]>CS(C)=O>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[N:34][O:33][CH3:32])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CON
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=NOC)c4)cc23)CC1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3.0 mL) was added O-methylhydroxylamine (57 mg, 0.684 mmol). The reaction was stirred overnight. Additional O-methylhydroxylamine (0.342 mmol) was added to the reaction mixture and stirred for 48 h. The solvent was then concentrated and purified by Gilson Preparatory HPLC to give 29.8 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)imino]methyl}phenyl)-1H-indole-7-carboxamide (56%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C)C=O>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 22 %

Procedure:
DIEA (0.046 mL, 0.27 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.050 g, 0.24 mmol) and HATU (0.101 g, 0.27 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-imidazo[1,2-a]pyridin-2-yl-phenylamine (0.051 g, 0.24 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.021 g of 1541A in a 22% yield: LCMS (ESI) m/z 398 (MH+).
Reaction SMILES: BrC1C=CC=CC=1[N+]([O-])=O.C([N:18]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])[CH2:19]1)C1C=CC=CC=1>>[N+:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH:20]1[CH2:21][CH2:22][NH:18][CH2:19]1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccccc1C1CCN(Cc2ccccc2)C1
Agent: O=[N+]([O-])c1ccccc1Br
Product: O=[N+]([O-])c1ccccc1C1CCNC1
Yield: 27 %

Procedure:
Synthesized from 1-bromo-2-nitrobenzene according to an analogous synthetic method to Preparation Example 103, 1-benzyl-3-(2-nitrophenyl)pyrrolidine (1.0 g) was used according to an analogous synthetic method to Preparation Example 104 to provide 3-(2-nitrophenyl)pyrrolidine (184 mg). Synthesized from 3-(2-nitrophenyl)pyrrolidine and 3-bromoanisole according to an analogous synthetic method to Example 116 described below, 1-(3-methoxyphenyl)-3-(2-nitrophenyl)pyrrolidine (141 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (126 mg).
Reaction SMILES: B(Br)(Br)Br.[Br:5][CH2:6][C:7]1[C:8]2[CH:23]=[C:22]([O:24]C)[C:21]([O:26]C)=[CH:20][C:9]=2[S:10][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].CO>ClCCl>[Br:5][CH2:6][C:7]1[C:8]2[CH:23]=[C:22]([OH:24])[C:21]([OH:26])=[CH:20][C:9]=2[S:10][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(CBr)c2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(c1sc2cc(O)c(O)cc2c1CBr)N1CCOCC1
Reaction time: 1 h

Procedure:
A solution of 1 N boron tribromide in dichloromethane (3.4 ml) was added to a solution of (3-bromomethyl-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone) (0.46 g) in dichloromethane (10 ml) at −20° C. Stirring was continued at 0° C. for one hour. Methanol was added and the mixture was evaporated to dryness. To the residue 5% Na2SO3 solution (5 ml) was added, the mixture acidified and the precipitate filtered.
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][NH:27][C:28]=1[Sn](CCCC)(CCCC)CCCC>CS(C)=O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:21]([C:28]2[NH:27][N:26]=[CH:25][C:24]=2[F:23])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1
Temperature: 100 °C

Procedure:
Pd(Ph3P)4 (17.33 mg, 0.015 mmol) was added to solution of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 4.2, 133 mg, 0.3 mmol) and 4-fluoro-5-(tributylstannyl)-1H-pyrazole (101 mg, 0.270 mmol) in DMSO (1 mL) in a vial under an argon atmosphere. The vial was sealed and the RM mixture was heated at 100° C. for 18 h. After cooling to RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, n-heptane/EtOAc from 10% to 50% EtOAc) to afford the title compound as an off-white powder. HPLC (Condition 4) tR=5.5 min, UPLC-MS (Condition 3) tR=1.05 min, m/z=399.2 [M−H]−.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([OH:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:17][CH:13]2[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCN(C(=O)OCc3ccccc3)C2)CC1
Reaction time: 8 h
Yield: 58.7 %

Procedure:
(S)-3-Hydroxy-piperidine-1-carboxylic acid benzyl ester (2.34 g, 8.6 mmol) was dissolved in THF (40 mL) at room temperature. 4-(2-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.4 g, 8.6 mmol) and triphenylphosphine (2.7 g, 10.32 mmol) were added. Diisopropyl azodicarboxylate (2.05 mL, 10.32 mmol) was added dropwise to the solution. The reaction was stirred overnight, concentrated under reduced pressure, and purified using silica gel chromatography (100% ethyl acetate) to afford the title compound (2.5 g, 55%).
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)=[O:16].FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[CH3:1][CH2:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)=[O:16]
Reactant: CCOCCn1c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Temperature: 25 °C

Procedure:
Mix 1-[[(2-ethoxy)ethyl]-1H-benzimidazol-2-yl][1-(t-butyloxycarbonyl)-4-piperidinyl]methanone (10.07 g, 26.67 mmol) and trifluoroacetic acid (75 mL). Stir at room temperature until the reaction is complete. Pour onto water and carefully neutralize with solid sodium hydrogen carbonate. Extract into ethyl acetate (2×), wash with brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].C[NH:12][CH2:13][C:14]([OH:16])=[O:15].[H-].[Na+]>>[C:14]([CH2:13][NH:12][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])([OH:16])=[O:15]
Reactant: CNCC(=O)O
Reactant: COC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Product: O=C(O)CCCCCNCC(=O)O

Procedure:
In this reaction scheme, methyl 6-bromohexanoate is alkylated with methyl glycine in the presence of sodium hydride to afford the 6-[(carboxymethyl)amino]hexanoic acid. Treatment of 6-[(carboxymethyl)amino]hexanoic acid with sodium hydroxide affords the corresponding 6-[(carboxymethyl)amino]hexanoic acid disodium salt.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[O:6][C:7](=[O:21])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:4].[NH2:22][C:23]1[C:31]([C:32](O)=[O:33])=[C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:25]2[N:24]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:22][C:23]1[C:31]([C:32]([NH:2][CH:3]([C:5]2[O:6][C:7](=[O:21])[C:8]3[C:13]([C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:4])=[O:33])=[C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:25]2[N:24]=1
Reactant: Nc1nn2cccnc2c1C(=O)O
Reactant: CC(N)c1oc(=O)c2ccccc2c1-c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1c(N)nn2cccnc12)c1oc(=O)c2ccccc2c1-c1ccccc1
Yield: 28.3 %

Procedure:
3-(1-aminoethyl)-4-phenyl-1H-isochromen-1-one hydrochloride (intermediate E2, 50 mg, 0.166 mmol), 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (32.5 mg, 0.182 mmol), HOBt (30.4 mg, 0.199 mmol), HBTU (17.25 mg, 0.033 mmol) and DIPEA (61.0 μl, 0.349 mmol) were reacted in DCM (1 ml) at RT for 18 hrs. The crude was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give the title compound (20 mg, 28%).