Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]CC4C=CC=CC=4)[CH:15]=3)[CH:10]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][NH:38]3)=[CH:30][CH:29]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[CH:10]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][NH:38]3)=[CH:30][CH:29]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(OCCC3CCCCN3)cc2)cc1Cl
Solvent: CCOC(C)=O
Product: Oc1ccc2c(c1)CCN(c1ccc(Cl)c(Cl)c1)C2Cc1ccc(OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 3.1 %

Procedure:
A solution of 2-(3,4-dichlorophenyl)-6-(phenylmethoxy)-1-{4-[(2-piperidyl)ethoxy]benzyl}-1,2,3,4-tetrahydroisoquinoline (0.380 g, 0.63 mmol) was placed under a nitrogen atmosphere and dissolved in ethyl acetate (5 ml). The flask was evacuated and flushed with nitrogen. To the flask was added palladium (10% wt. on activated carbon, 0.190 g). The flask was flushed and evacuated with nitrogen followed by hydrogen. The reaction was allowed to stir under the hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered through celite and concentrated. The product was purified by preparative HLPC (C-18 column, 10-100% acetonitrile/water with 0.1% trifluoroacetic acid) to provide the title compound (0.010 g, 3% yield). 1H NMR (CDCl3) 6.7-7.2 (m, 10H), 4.7 (t, 1H), 4.2-4.4 (m, 2H), 3.6-4.0 (m, 4H), 3.3-3.6 (m, 3H), 3.0-3.1 (m, 1H), 2.7-2.9 (m, 3H), 2.6-2.7 (m, 1H), 1.8-2.1 (m, 4H), 1.4 (m, 2H); ES−MS (m/z) 511 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N+:22]([O-])([OH:24])=[O:23].O>C(O)(=O)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][C:16]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: CCOC(=O)c1ccc(OCCOC)c(OCCOC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of ethyl 3,4-bis(2-methoxyethoxy)benzoate (23.23 g, 77.87 mmol) in acetic acid (80 mL) was added dropwise to concentrated nitric acid (21 mL) cooled with an ice bath at such a rate as to keep the internal temperature below 5° C. After 30 min, the solution was allowed to warm to room temperature and stirred for 48 h. The solution was poured onto iced water (400 mL) and extracted with ethyl acetate (3×100 mL). The organic phases were combined and washed cautiously with saturated aqueous sodium bicarbonate (3×200 mL) and brine (2×100 mL). The organic phase was dried (Na2SO4) and concentrated to give the title compound as a solid (24.82 g, 93%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]([CH3:31])[CH3:30])[CH:23]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:38]>>[Cl:38][C:21]1[N:16]2[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][CH:29]([CH3:31])[CH3:30])[CH:23]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:12]=3)=[C:17]2[CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)Nc1cc(-c2nn3ccccc3c2-c2ccnc(NC3CCCC3)n2)ccn1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Product: CC(C)Nc1cc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)ccn1
Yield: 77.9 %

Procedure:
In a similar manner as described in Example 17 from N-cyclopentyl-4-{2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-2-pyrimidinamine (166 mg, 0.401 mmol), n-butyllithium (753 μL, 1.6 M in hexanes, 1.20 mmol) and carbon tetrachloride (155 μL, 1.60 mmol) was formed 4-{7-chloro-2-[2-(isopropylamino)-4-pyridinyl]pyrazolo[1,5-a]pyridin-3-yl}-N-cyclopentyl-2-pyrimidinamine (140 mg, 78%). Rf 0.21 (1:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.36 (d, 1H), 8.19 (d, 1H), 8.07 (d, 1H), 7.36 (m, 1H), 7.13 (d, 1H), 6.90 (d, 1H), 6.81 (s, 1H), 6.52 (d, 1H), 5.25–5.21 (br, 2H), 4.35 (m, 1H), 3.89 (m, 1H), 2.18–2.04 (m, 2H), 1.80–1.50 (m, 6H), 1.22 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:20][NH2:21].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH3:9])[C:6]([NH:21][CH2:20][C:19]1[CH:18]=[C:17]([F:16])[CH:24]=[C:23]([F:25])[CH:22]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)O
Reactant: NCc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(=O)NCc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of 2.92 g (20 mmol) methyl-malonic acid monoethyl ester in 100 ml of tetrahydrofuran 2.86 g (20 mmol) of 3,5-difluorobenzylamine, 3.83 g (20 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 2.70 g (20 mmol) of 1-hydroxybenzotrizole hydrate and 2.58 g (20 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. After concentration in vacuo 0.5 N HCl (50 ml) was added and the mixture was extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate=3:1) to yield 4.29 g (79%) of the tide compound as white crystalline solid.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[N+:16]([O-])([OH:18])=[O:17]>O>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a 5-liter, 3-necked, round-bottom flask, equipped with a stirrer and thermometer, is added 2.0 liters of concentrated H2SO4 and 800 g of powdered (about 1-2 microns) p-chlorobenzoic acid. The mixture is stirred and cooled to 0° C. in an oil bath. To the cooled mixture is added 432 ml of 71 weight percent nitric acid in water solution dropwise. The nitric acid solution is added at a rate slow enough to maintain the temperature lower than about 30° C. Upon completion of adding nitric acid, the temperature is raised to 37° C. over 3 hours. The reaction mixture is then cooled to 15° C. To the cooled mixture is added 0.75 liter of room temperature water at a rate so as to keep the reaction temperature below about 40° C. The product is isolated by filtration using fritted glass funnel and washed with 1.5 liters of room temperature water. The washed product is air-dried until a constant weight is observed to yield 1.0174 kg of 4-chloro-3-nitrobenzoic acid, which has a melting point of 178° C.-179.5° C. This is a yield of 99 mole percent. This material can be used without further purification.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([O:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1=[O:18].C(N(CC)CC)C.CO>>[CH3:15][Si:14]([CH3:17])([CH3:16])[O:13][C@H:5]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3][C:4]1=[O:18]
Reactant: C[Si](C)(C)OC1C(=O)N([Si](C)(C)C)C1c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: C[Si](C)(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of N-trimethylsilyl-3-trimethylsiloxy-4-phenyl-azetidin-2-one (140 g, 0.46 mol) in hexanes (600 mL) at ambient temperature was added triethylamine (101 g, 1 mol), methanol (22 g, 0.7 mol) and the mixture was stirred for 15 minutes resulting in crystal formation of the N-desilylated product. The mixture was cooled to 0° C. for 15 min and the white crystals were collected by vacuum filtration, washed with cold hexanes, and dried to a constant weight of 94 g (87% yield). Mp: 118 to 120° C., 1H NMR (400 MHz, CDCl3) δ (ppm): −0.08 (s, 9H), 4.79 (d, J=4.4 Hz, 1H), 5.09 (dd, J=4.4, 2.7 Hz, 1H), 6.16 (bm, 1H), 7.3 to 7.4 (m, 5H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:9])[CH3:8])(=O)C.[OH-].[Na+].C(O)C>O>[C:11]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]([OH:9])([CH3:8])[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCC(C)(O)c1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(O)(CCO)c1ccccc1-c1ccccc1

Procedure:
A solution of 2.84 g. of 1-acetoxy-3-p-biphenylyl-3-butanol and 2 g. of NaOH in 30 ml. of 80% ethanol is boiled for 3 hours. Water is added and the mixture is extracted with chloroform and the extract is evaporated to give 3-p-biphenylyl-1,3-butanediol, m.p. 115°-117°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C(OC(=O)[NH:32][CH2:33][CH2:34][CH2:35][NH2:36])(C)(C)C.C(Cl)CCl>CN(C=O)C>[NH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[N:16]=2)[CH:18]=1
Reactant: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NCCCNC(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 9 (1 mmol) was coupled with (3-Amino-propyl)-carbamic acid tert-butyl ester (3 mmol) using EDC (2 mmol) in DMF (10 mL). The DMF was removed by rotary evaporation and the residue purified by flash chromatography on silica gel (ethyl acetate as eluent.) The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 392. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.68 (s, 1H) 8.35-8.5 (m, 3H) 8.1 (d, 1H) 7.7 (m, 1H) 7.48 (d, 1H) 7.2 (d, 2H) 6.68 (d, 2H) 3.8 (m, 2H) 3.55 (m, 2H) 3.05 (m, 2H) 2.9 (m, 4H) 2.0 (t, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH:18]3[CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH:18]3[CH2:20][CH2:19]3)(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[Br:21]
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ncc(-c2ccc(S(=O)(=O)NC3CC3)cc2)cc1Br
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of 4-(6-amino-pyridin-3-yl)-N-cyclopropylbenzenesulfonamide (1.04 g, 3.59 mmol) in DCM (12 mL) was added portionwise N-bromosuccinimide (0.64 g, 3.59 mmol). The reaction was stirred for 1 h, then was filtered. The filtrate was washed with sat. aq. Na2S2O4 (20 mL), sat. aq. NaHCO3 (10 mL), then dried over Na2SO4 and concentrated to give 4-(6-amino-5-bromo-pyridin-3-yl)-N-cyclopropyl-benzenesulfonamide (1.07 g, 81% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.30 (d, J=2.01 Hz, 1H), 8.12 (d, J=2.01 Hz, 1H), 7.92 (d, J=8.53 Hz, 2H), 7.76 (d, J=8.53 Hz, 2H), 2.19 (tt, J=6.71, 3.58 Hz, 1H), 0.17-0.83 (m, 4H). MS (EI) m/z: 368, 370 [M+H]+. HPLC (Sunfire C18 4.6 mm×50 mm, 10-90% MeCN:10 mM aq. NH4OAc, 2 min gradient) tR=1.68 min, 90% integrated area.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.[OH-].[Na+]>CCOC(C)=O.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:13]([C:12]3[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:19][C:11]=3[F:10])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3o2)c(F)c1
Temperature: 195 °C
Yield: 80.5 %

Procedure:
2-Amino-4-bromophenol (1.77 g, 9.4 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.4 mmol) were dissolved in polyposphoric acid (60 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H2O) followed by evaporation of EtOAc afforded the crude. Crude was purified on combiflash with a gradient mixture of EtOAc and Petether (33:67) to obtain the titled compound (2.8 g) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH:21]2[CH2:23][CH2:22]2)[CH:16]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([CH:21]3[CH2:23][CH2:22]3)[CH:16]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)ccc1Br
Reactant: Cn1nc(C2CC2)cc1N
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cc(C2CC2)nn1C

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 5-Amino-3-cyclopropyl-1-methylpyrazole was performed in accordance with the general method of Example 78, step 3 to yield the title compound as an orange solid, MS (ISP): m/e 301.4 (M+H+).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:17]=[C:18]([C:29](OCC)=[O:30])[N:19]([CH3:28])[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1>>[N:2]1([NH:1][C:29]([C:18]2[N:19]([CH3:28])[C:20]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[C:16]([C:10]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=3[Cl:8])[N:17]=2)=[O:30])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Product: Cn1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 36, Step B (Method B), but using neat 1-aminopiperidine (3 mL), ethyl 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole-2-carboxylate (30 mg, 0.073 mmol) was converted to the title compound after purification by Prep TLC (40% ethyl acetate in hexanes).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[Br:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Br:25][CH2:26][C:27]([N:5]([CH2:4][C:3]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:2]=1[F:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:28]
Reactant: CCCCCCCNCc1ccc(F)cc1F
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CBr
Reaction time: 2 h
Yield: 80.2 %

Procedure:
N-(2,4-difluorobenzyl)-N-heptylamine (2.004 g, 8.304 mmol) was dissolved in DCM (30 ml). It was then cooled in an ice-bath. Triethylamine (1.092 g, 10.796 mmol) was added and then bromacetyl chloride (1.438 g, 9.135 mmol) was dropped in. The mixture was stirred for 2 hours (ice-bath). It was then washed with water (with additional of 1% hydrochloric acid, pH-3), water and brine, and dried (magnesium sulphate) and evaporated. The crude oil product was dissolved in DCM, then loaded onto a column (ISOLUTE®SI 5 g/25 ml) and eluted with more DCM. Oil product 2.412 g was obtained, yield 80%
Reaction SMILES: [Br:1]Br.[C:3]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(Cl)Cl>[CH2:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([Br:1])[C:3](=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: BrBr
Reactant: O=C1CCCCCCCCCCC1
Solvent: ClCCl
Product: O=C1CCCCCCCCCCC1Br
Reaction time: 0.25 h
Yield: 90 %

Procedure:
An amount of 183.8 gm (1.15 mol) of bromine was added dropwise with refluxing under a nitrogen atmosphere to a well agitated solution comprising 182.3 gm (1 mol) of cyclododecanone in 275 ml of methylene chloride over a period of six hours. Agitation was continued for 15 minutes and approximately one-half of the solvent was distilled off. The solution obtained by this method contained approximately 235 gm of α-bromocyclododecanone (90% yield) and was further reacted directly.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[Br:31][CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[CH3:33]>ClCCl>[Br:31][CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]3[CH:17]=[C:16]4[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]5[CH2:22][CH2:23]5)=[O:20])[N:14]=[CH:15]4)=[CH:10][CH:9]=3)[CH:7]=2)=[O:39])=[CH:36][CH:35]=1)[CH3:33]
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Reactant: CC(Br)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(C(C)Br)cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (51.8 mg, 0.163 mmol) and pyridine (0.05 mL, 0.6 mmol) in 2 mL dichloromethane was added a solution of the residue from Step 1 in 2 mL dichloromethane. The resulting mixture was stirred at room temperature for 1.5 hours, and then carried forward without purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]([C:28]([OH:30])=O)=[CH:7][C:8]1[CH:9]=[C:10]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])[CH:11]=[CH:12][C:13]=1[Cl:14].CN(C)C=O>C1(C)C=CC=CC=1>[Br:5][C:6]([C:28]([Cl:3])=[O:30])=[CH:7][C:8]1[CH:9]=[C:10]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[N:17]([CH3:26])[C:16]2=[O:27])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)O)c2)c1=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=C(Br)C(=O)Cl)c2)c1=O

Procedure:
1.6 g of thionyl chloride were added to a solution of 4.5 g of 3-[3-(2-bromo-2-carboxyethenyl)-4-chlorophenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine and 0.1 ml of dimethylformamide in 100 ml of toluene. The reaction mixture was heated slowly to the reflux temperature, stirred under reflux for 5 hours and evaporated down, and the residue was dried under greatly reduced pressure.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[CH2:4][OH:5].[C:13]([N:17]=[C:18]=[S:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(O)C>[C:13]([NH:17][C:18]([NH:2][C@H:3]([CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[CH2:4][OH:5])=[S:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)CCc1ccsc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=S)N[C@@H](CO)CCc1ccsc1
Temperature: 20 °C

Procedure:
A solution of 1.2 g of (2R)-2-amino-4-(3-thienyl)-1-butanol, hydrochloride in 40 mL of ethanol, is combined with 1.1 mL of tert-butylisothiocyanate and 1 mL of triethylamine and magnetically stirred under inert atmosphere at a temperature of about 20° C., then heated for 20 hours at a temperature of about 50° C. The reaction medium is concentrated under reduced pressure (2 kPa) at a temperature of about 50° C. The solution is evaporated to obtain a residue, which is purified by chromatography under argon pressure (70 kPa), on a column of silica gel (particle size 60-200 μm; diameter 3.6 cm; height 20 cm), eluting with a mixture of cyclohexane-ethylacetate (60/40 by volume) and obtaining fractions of 30 mL. The fractions containing the expected product are collected and evaporated under reduced pressure (2 kPa) at a temperature of about 40° C. About 0.73 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(2-thien-3-ylethyl)ethyl]thiourea are obtained in the form of a colorless oil. [1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 1.42 (s, 9H); from 1.60 to 1.95 (mt, 2H); 2.60 (t large, J=8 Hz, 2H); 3.38 (mt, 1H); 3.50 (mt, 1H); 4.26 (mf, 1H); 4.80 (mf, 1H); 7.01 (dd, J=5 and 1.5 Hz, 1H); from 7.15 to 7.25 (mt, 2H); 7.20 (s, 1H); 7.46 (dd, J=5 and 3 Hz, 1H)].
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[C:24]([NH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:26])[CH3:25]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:24]([NH:27][C:28]1[CH:33]=[C:32]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH:31]=[CH:30][CH:29]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CC(=O)Nc1cccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)c1
Temperature: 110 °C
Yield: 35 %

Procedure:
A mixture of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 1.0 equivalent), 3-acetamidophenylboronic acid (2.0 equivalents), and PdCl2(dppf) (0.08 equivalent) in 1:2 saturated NaHCO3/dioxane (0.15 M with respect to 2D) was heated at 110° C. for 15 minutes in the microwave. After cooling to room temperature, the crude mixture was filtered and the filtrate was purified by preparatory LC-MS to give the titled compound (35%) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 2.09 (s, 3H) 5.20 (s, 1H) 6.60 (d, J=2.27 Hz, 1H) 7.52-7.57 (m, 1H) 7.60-7.64 (m, 2H) 7.73-7.77 (m, 1H) 7.84-7.89 (m, 1H) 7.99-8.07 (m, 2H) 8.20 (d, J=2.27 Hz, 1H) 8.28 (t, J=1.77 Hz, 1H) 10.24 (s, 1H) 11.28 (s, 1H). ESI-MS: m/z 430.3 (M+H)+.
Reaction SMILES: Cl.CC(O)=O.[NH:6](C(OC(C)(C)C)=O)[C@H:7]([C:15]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:25])[NH2:24])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>>[NH2:6][C@H:7]([C:15]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:24])[NH2:25])=[O:16])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Yield: 100.1 %

Procedure:
Into 538 ml of 2N HCl/AcOH was dissolved 79.8 g (0.13 mole) of BOC-Phe-Arg-CHA.HCl. After reacting it at room temperature for one hour, the deposited matter was collected by filtration, washed with AcOH and ether and dried to obtain 41.8 g (58.7%) of H-Phe-Arg-CHA.2HCl.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6](Cl)[N:5]=1.[CH3:21][CH2:22][CH:23]([OH:25])[CH3:24]>>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6]([O:25][C@@H:23]([CH2:22][CH3:21])[CH3:24])[N:5]=1
Reactant: CCC(C)O
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [H-]
Agent: [Na+]
Product: CC[C@@H](C)Oc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A flask was charged with sodium hydride (60% oil dispersion, 300 mg, 7.5 mmol) which was washed with hexanes before the addition of (±)-cis-4-(2-amino-6-chloro-9H--purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (800 mg, 3 mmol) in ~10 mL of R-(-)-2-butanol. The solution was stirred at room temperature for 3 hours then at 60° C. (oil bath) for 1 hour. The solution was allowed to cool to room temperature before neutralization with 1 H HC1. The solution was concentrated and the residue chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform (0.81 g, 89%). Crystallization of such a sample from ethanol-acetonitrile yielded an off-white powder, m.p. 159-161° C.