Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][N:5]([CH:17]1[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:28][C:29]1([CH3:38])[CH2:34]C(O)[CH2:32][C:31]([CH3:37])([CH3:36])[NH:30]1.[NH2-].[Li+].CO>CCCCCCC>[CH3:28][C:29]1([CH3:38])[CH2:34][CH:1]([O:2][C:3](=[O:27])[CH2:4][N:5]([CH:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:32][C:31]([CH3:37])([CH3:36])[NH:30]1
Reactant: CCCCCCCCCCCN(CC(=O)OC)C1CC(C)(C)NC(C)(C)C1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCCC
Solvent: CO
Product: CCCCCCCCCCCN(CC(=O)OC1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Yield: 63.2 %

Procedure:
To the same flask as used in Example 1 were added 39.4 g (0.1 mole) of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-undecanylglycine methyl ester, 17.3 g (0.11 mole) of 2,2,6,6-tetramethyl-4-piperidinol, 0.23 g of lithium amide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the heptane layer. The heptane layer was separated, and heptane in the layer was removed by distillation to obtain 32.1 g of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-undecanylglycine(2,2,6,6-tetramethyl-4-piperidinyl)ester as a pale brown liquid. Yield, 61% based on N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-undecanylglycine methyl ester.
Reaction SMILES: C1([N:7]=C=NC2CCCCC2)CCCCC1.[C:16]([NH:23][C@H:24]([C:32]([OH:34])=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:16]([NH:23][C@H:24]([C:32]([NH2:7])=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
Dicyclohexylcarbodiimide (348 mg, 1.69 mmol) was added to a chilled solution of Boc-L-phenylalanine (387 mg, 1.46 mmol) and the ammonium salt of 1-hydroxybenzotriazole (248 mg, 1.63 mmol) in DMF (5 ml). The solution was stirred at 0° C. for 90 min, then at room temperature for 2 h. The reaction mixture was filtered, and the filtrate poured into water (77 ml). The emulsion was extracted with diethylether (1×200 ml), the layers separated, and the organic phase washed with 5% NaHCO3, water and brine, then dried (sodium sulphate) , filtered, and the filtrate concentrated in vacuo to give Boc-L-phenylalanine amide (370 mg, 96%). Analytical HPLC in the condition of example 1a), using a linear gradient of 20% A to 80% A over 25 min, then 80% A for 10 min, showed a single peak at 14.92 min.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][CH:13]2[CH2:16][C:15]([F:18])([F:17])[CH2:14]2)(=O)=O)=CC=1.[Na+].[I-].[H-].[Na+].[CH2:23]([O:25][C:26](=[O:37])[CH:27]([NH:33][C:34](=[O:36])[CH3:35])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24].S(C1C=CC(Br)=CC=1)([O-])(=O)=O.[I-]>CN(C=O)C>[C:34]([NH:33][C:27]([CH2:12][CH:13]1[CH2:14][C:15]([F:17])([F:18])[CH2:16]1)([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:26]([O:25][CH2:23][CH3:24])=[O:37])(=[O:36])[CH3:35]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: O=S(=O)(OCC1CC(F)(F)C1)c1ccc(Br)cc1
Agent: O=S(=O)([O-])c1ccc(Br)cc1
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC(F)(F)C1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C

Procedure:
(3,3-Difluorocyclobutyl)methyl 4-bromobenzenesulfonate (500 mg, 1.47 mmol) and NaI (220 mg, 1.47 mmol, 1.0 equiv) were stirred in dry DMF (4 mL). In a separate 3-neck, 100 mL flask NaH (60 wt % in oil, 352 mg, 8.82 mmol, 6 equiv) was slurried in dry DMF (20 mL). The flask was cooled to 0° C. and diethyl-2-acetamidomalonate was added via syringe. After gas evolution ceased, the solution of the (3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate and NaI In DMF was added. The resulting solution was heated to 45° C. for 17 h. After this time no remaining brosylate or iodide was observed by TLC and LC-MS. The mixture was quenched by dropwise addition of water (10 mL) and the DMF was removed in vacuo. The residue was partitioned between ether and water and the layers separated. The aqueous layer was extracted with additional ether and the combined organic layers were washed with brine. The residue was evaporated and the desired product was purified by flash chromatography on silica, eluting with 0 to 50% EtOAc in hexanes. The fractions were stained with ceric ammonium molybdate; the desired product is contained in the second spot. This afforded diethyl 2-acetamido-2-((3,3-difluorocyclobutyl)methyl)malonate (474 mg, 99%).
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1[NH:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)Cl>[CH2:2]([C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](Cc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Product: c1ccc(C[C@H]2CNCCN2)cc1
Reaction time: 16 h
Yield: 141.8 %

Procedure:
HCl (4.0 M solution with 1,4-dioxane, 45 mL, 180 mmol) was added to a stirring solution of tert-butyl (3S)-3-benzyl-1-piperazinecarboxylate (5.0 g, 18 mmol, Waterstone Technology, Carmel, Ind.) and CH2Cl2 (36 mL) at room temperature. After 16 h, the reaction mixture was concentrated to give 4.5 g (2S)-2-benzylpiperazine (4.5 g) as its dihydrochloride salt. The material was used in the next step without purification.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:34]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:34][C:22]1[CH:23]=[C:24]([C:26]2[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=2)[NH:25][C:21]=1[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:5])=[O:6])=[CH:8][CH:9]=1)[CH2:14][CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1cnc(-c2cc(Cl)c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (300 mg) in tetrahydrofuran (5 mL) was added N-chlorosuccinimide (82.3 mg) at 0° C., and the mixture was stirred at 50° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (210 mg). The mixture of the obtained positional isomers was dissolved in hexane-2-propanol (700:300, volume ratio, 18.8 mL), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRY LTD.). Using hexane-2-propanol (700:300, volume ratio) as a mobile phase, the solution was eluted at flow rate 60 mL/min and at 30° C., and the fraction was separated at retention time 22.0 min, and concentrated. The obtained solid was dissolved in ethyl acetate and the insoluble material was filtered off. The filtration was concentrated to give the title compound (85.9 mg, yield 27%) as a colorless amorphous solid. MS: 521 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[C:8]([CH2:21][NH2:22])=[CH:7]2.Br[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C(O)CCC>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[C:8]([CH2:21][NH:22][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[CH:7]2
Reactant: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CN
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCCCO
Product: COc1ccc(F)cc1-c1nc2c(Cl)cccc2cc1CNc1ncnc2[nH]cnc12
Temperature: 100 °C

Procedure:
To a stirred mixture of (8-chloro-2-(5-fluoro-2-methoxyphenyl)quinolin-3 yl)-methanamine (190.4 mg, 0.601 mmol) and 6-bromopurine (126 mg, 0.631 mmol) in 1-butanol (3.300 mL, 36.1 mmol) was added N,N-ethyldiisopropylamine (0.209 mL, 1.20 mmol). The mixture was heated to 100° C. overnight. The solvents were removed and the residue subjected to chromatography: gradient/isocratic 1H NMR (500 MHz, DMSO-d6) δ ppm 12.93 (1 H, br. s.), 8.28 (1 H, br. s.), 8.09 (2 H, s), 7.96 (1 H, d, J=8.1 Hz), 7.91 (1 H, d, J=7.3 Hz), 7.55 (1 H, t, J=7.8 Hz), 7.26-7.33 (1 H, m), 7.21 (1 H, dd, J=8.6, 3.2 Hz), 7.15 (1 H, br. s.), 3.77 (3 H, s), 3.32 (2 H, s) Mass Spectrum (ESI) m/e=335.1 (M+1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25](CC(N)=O)[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>>[C:36]([O:35][C:33](=[O:34])[CH2:32][N:25]1[CH2:26][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:24]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(=O)OC(C)(C)C)C3)ccc1-2

Procedure:
Following a similar procedure to 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide using tert-butyl bromoacetate, {3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetic acid tert-butyl ester was isolated as a colourless oil (97 mg, 33%). LCMS: RT=3.63 min, [M+H]+=482
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=2[Cl:21])=[CH:8][CH:7]=1)=[O:5])[CH3:2].Cl>C(O)C>[ClH:21].[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:21])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2Cl)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Yield: 192.1 %

Procedure:
2′-Chloro-5′-nitro-biphenyl-4-carboxylic acid ethyl ester (1.04 g) in ethanol 30 ml) and 2M HCl (5.0 ml) was hydrogenated at RTP for 3 h. The mixture was then filtered through celite and the solvent evaporated to give the title compound as a dark red solid (1.02 g) which was used in the next stage without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[Li]CCCC.CN([CH:29]=[O:30])C>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:6]2[O:5][C:4]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:3][C:2]=2[CH:29]=[O:30])=[CH:9][CH:10]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(Sc2oc(C3CCOCC3)nc2Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc(C2CCOCC2)oc1Sc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 118.6 %

Procedure:
To a dry flask was added 4-bromo-5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole (810 mg, 2.162 mmol) and THF (21.6 mL), and the reaction mixture was cooled to 78° C. nBuLi (1.486 mL, 2.378 mmol) was added slowly and the reaction mixture was stirred at −78° C. for 5 min. DMF (0.837 mL, 10.81 mmol) was added and the reaction mixture was stirred at −78° C. for 10 min, quenched with water, allowed to warm to RT. The reaction mixture was extracted with EtOAc, washed with 3M LiCl, dried over sodium sulfate and concentrated in vacuo to give 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carbaldehyde (830 mg crude) to be used as is in the next step. MS: M+H=324.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].C1(CC#N)C=CC=CC=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(=O)(O)[O-:25].[Na+].Cl>O.C1C=CC=CC=1>[C:16]([OH:25])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S([O-])O
Reactant: OCc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: N#CCc1ccccc1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium permanganate (3.16 g, 0.02 mol) in water (35 ml) was stirred for 10 minutes and then cooled in a water bath while phenylacetonitrile or benzyl alcohol (0.011 mol), benzene (20 ml) and the catalyst (Table 5) (1mmol) were added. The mixture was stirred for 3 hours at room temperature and worked up by addition of 4% sodium bisulphite (60 ml), acidification with 2N hydrochloric acid, separation of organic layer and extraction of the aqueous layer with benzene (2×20 ml). The combined organic extracts were dried over magnesium sulphate and the solvent evaporated on a rotary evaporator. Recrystallization of the solid residue obtained gives pure benzoic acid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:19][CH2:18][CH2:17][N:8]3[C:9]4[CH:10]=[CH:11][C:12]([OH:16])=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]2=[O:20])[CH2:3][CH2:2]1.[CH:21]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>>[CH:1]1([CH2:4][N:5]2[CH2:19][CH2:18][CH2:17][N:8]3[C:9]4[CH:10]=[CH:11][C:12]([O:16][CH:27]5[CH2:28][CH2:29][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:25][CH2:26]5)=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]2=[O:20])[CH2:2][CH2:3]1
Reactant: CC(C)N1CCC(O)CC1
Reactant: O=C1c2cc3cc(O)ccc3n2CCCN1CC1CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCN(CC3CC3)C2=O)CC1
Yield: 45 %

Procedure:
The title compound was synthesized in analogy to example 1, from 2-cyclopropylmethyl-9-hydroxy-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butylazodicarboxylate, to give the desired product as a light yellow solid (45%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].CO[C:9]1[CH:18]=CC=C2[C:10]=1CC(NCCCCC1C3(CCCCC3)C(=O)NC1=O)CO2.[CH3:36][O:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH2:40][CH:41]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][N:53]1[C:57](=[O:58])[C:56]3([CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]3)[CH2:55][C:54]1=[O:64])[CH2:42][O:43]2>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:10]([N:48]([CH2:49][CH2:50][CH2:51][CH2:52][N:53]1[C:57](=[O:58])[C:56]2([CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]2)[CH2:55][C:54]1=[O:64])[CH:41]1[CH2:40][C:39]2[C:44](=[CH:45][CH:46]=[CH:47][C:38]=2[O:37][CH3:36])[O:43][CH2:42]1)[CH2:9][CH3:18]
Reactant: COc1cccc2c1CC(NCCCCC1C(=O)NC(=O)C13CCCCC3)CO2
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)CC3(CCCCC3)C1=O)CO2
Agent: O=C(O)C(=O)O
Product: CCCN(CCCCN1C(=O)CC2(CCCCC2)C1=O)C1COc2cccc(OC)c2C1

Procedure:
Using the procedure described in Example 29, but replacing the compound of Example 28 by the compound of Example 30, the product of the title is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[C:14](O)[C:11]([C:12]#[N:13])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:32])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[C:14]([Cl:32])[C:11]([C:12]#[N:13])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(O)cc(-c2cccc(Br)c2)nc1-c1ccc(Oc2ccccc2)cc1
Product: N#Cc1c(Cl)cc(-c2cccc(Br)c2)nc1-c1ccc(Oc2ccccc2)cc1
Temperature: 90 °C

Procedure:
A mixture of 6-(3-bromophenyl)-4-hydroxy-2-(4-phenoxyphenyl)nicotinonitrile (38.8 mg, 0.070 mmol) and phosphoryl trichloride (0.5 mL, 5.38 mmol) was heated to 90° C. for 17 h, then concentrated to give crude 6-(3-bromophenyl)-4-chloro-2-(4-phenoxyphenyl)nicotinonitrile, which was used in the next reaction without purification. MS (ES+) m/z: 461, 463 (M+H); LC retention time: 4.821 min (analytical HPLC Method A).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOCC.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:30]([C:27]4[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][N:28]=4)=[O:31])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cccc(F)c4)nc23)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a mixture of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 6, Step A; 50 mg, 0.17 mmol, prepared as described in a previous example), 5-methylpyrazine-2-carboxylic acid (46 mg, 0.34 mmol), and HATU (128 mg, 0.34 mmol) was added 0.7 mL DMF to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.088 mL, 0.5 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred for 2 hours. The reaction mixture was directly filtered, rinsing with acetonitrile and then with ether, to provide the final product as a beige solid (44 mg, 63% yield). MS (apci) m/z=418.2 (M+H).
Reaction SMILES: CO.[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)=[CH:30][CH:29]=2)([CH3:27])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=1.[OH-].[Na+:47]>O1CCOCC1>[Na+:47].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=3)=[CH:30][CH:29]=2)([CH3:27])[CH2:22][CH2:23][C:24]([O-:26])=[O:25])=[CH:17][CH:16]=1
Reactant: CC(CCC(=O)O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(CCC(=O)[O-])(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
To a solution in dioxane (10 mL) and methanol (10 mL) of 4,4-bis (4-(2-quinolylmethoxy)phenyl)pentanoic acid (320 mg, 0.56 mmol), prepared as in step 1, was added aqueous 1N sodium hydroxide (0.55 ml, 0.55 mmol). The mixture was then concentrated in vacuo. The product was crystallized by dissolving in CH2Cl2 and precipitation by dropwise addition of a mixture of ethyl acetate-ethyl ether (1:2): 1H NMR (300 MHz, DMSO--d6) d 1.47 (s, 3H), 1.63 (m, 2H), 2.18 (m, 2H), 5.31 (s, 4H), 6.95 (d, 4H, J=9 Hz), 7.08 (d, 4H, J=9 Hz), 7.64 (m, 4H), 7.78 (m, 2H), 8.00 (m, 4H), 8.40 (d, 2H, J=8 Hz); MS (FAB+) m/e 591 (M+H)+ ; (FAB-) 589 (M-H)-. Anal. Calc'd. for C37H31N2 O4Na.0.25 H2O:C, 74.67; H, 5.34; N, 4.71; Found: C, 74.57; H, 5.32; N, 4.52.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:32])[CH2:8][CH:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:19]=1)[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[CH3:35]I>C1COCC1.C(OCC)(=O)C>[CH3:35][N:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C:7](=[O:32])[CH2:8][CH:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:19]=1)[C:10]#[C:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CI
Reactant: COc1ccc(C(C#Cc2ccccc2)CC(=O)Nc2nccs2)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(C#Cc2ccccc2)CC(=O)N(C)c2nccs2)cc1OC1CCCC1
Temperature: 80 °C

Procedure:
To a solution of the compound from Example 22 (0.07 g, 0.16 mmol) in THF (2 mL) under an argon atmosphere was added 60% NaH/mineral oil suspension (0.008 g, 0.19 mmol), followed by methyl iodide (0.012 mL, 0.19 mmol). After heating at 80° C. for 0.25 h, the mixture was cooled to room temperature, was diluted with ethyl acetate, was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, eluting with 1:1 hexanes/ethyl acetate provided the title compound as a yellow resin (0.025 g, 34%). Anal. (C27H28N2SO3 ·0.375 H2O) calcd: C, 69.39; H, 6.20; N, 5.99. found: C, 69.52; H, 6.22; N, 5.78.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:43])=[C:4]([S:9]([N:12]([CH2:27][C:28]2[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=2)[CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:32][CH2:31][C:30]1[CH:29]=[C:28]([CH:42]=[CH:41][CH:40]=1)[CH2:27][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:43])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(CN(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 3-[(3,5-dichloro-N-((4′-fluorobiphenyl-4-yl)methyl]-2-hydroxyphenylsulfonamido) methyl)benzylcarbamate (1.0 g, 1.5 mmol, 1 eq) was dissolved in dry DCM, stirred for 10 minutes and cooled to 0° C. Trifluoroacetic acid (3.5 g, 309 mmol 20 eq) was added slowly at 0° C. The reaction mixture was stirred for 10 min and slowly brought to rt. After 4 h, the solvent was evaporated under reduced pressure, and ethyl acetate and 10% aq. NaHCO3 solution were added. The mixture was stirred for 10 minutes and the aqueous mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The crude salt (0.7 g, 82%) was used immediately in the next step. 1H NMR (400 MHz, DMSO-d6) δ 3.52 (s, 2H), 4.44 (s, 2H), 4.46 (s, 2H), 6.9-6.99 (t, 2H), 7.08-7.10 (d, 2H), 7.17-7.20 (m, 4H), 7.22-7.27 (m, 2H), 7.44-7.46 (d, 2H), 7.6-7.65 (t, 2H). MS (ESI): 546.0 (M+H)+.