Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Cl.Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Clc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCN(c2ccncc2)CC1
Yield: 14.6 %

Procedure:
Using a similar procedure to that described in Example 52, 5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethyl)aminobenzamide (400 mg, 1.05 mmol), 4-chloropyridine hydrochloride (791 mg, 5.27 mmol), triethylamine (533 mg, 5.27 mmol), and ethanol (3 mL) yielded 70 mg (15%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:32]3[N:8]([N:9]([CH3:33])[CH2:10][O:11][C:12]=3[C:13]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:27]C(OC)=O)[N:21]=3)[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:34]([OH:36])=[O:35])[C:5]2=[O:37].CN1[CH2:44][CH2:43][O:42][CH2:41]C1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:32]3[N:8]([N:9]([CH3:33])[CH2:10][O:11][C:12]=3[C:13]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:27][C:2]4[CH:13]=[CH:12][CH:44]=[C:43]([O:42][CH3:41])[CH:3]=4)[N:21]=3)[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:34]([OH:36])=[O:35])[C:5]2=[O:37]
Reactant: CN1CCOCC1
Reactant: COC(=O)Cn1nc(N2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn5c4c3OCN5C)CC2)ccc1=O
Solvent: c1ccncc1
Product: COc1cccc(Cn2nc(N3CCN(c4c(F)cc5c(=O)c(C(=O)O)cn6c5c4OCN6C)CC3)ccc2=O)c1
Yield: 28 %

Procedure:
As described for compound 20a, 25 was obtained starting from 24 (300 mg, 0.99 mmol, 2.0 eq.), pyridine (4 mL,) N-methylmorpholine (0.2 mL, 4.0 mmol, 4.0 eq.) and TNOC (140 mg, 0.50 mmol, 1.0 eq.). The crude product was purified by T.L.C. preparative to afford the title compound (80 mg, 28%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:25]=2)[S:3]1.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>N1C=CC=CC=1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:26](=[O:28])[CH3:27])=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:25]=2)[S:3]1
Reactant: Nc1ccc(Cc2nc3cc(CC4SC(=O)NC4=O)ccc3o2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Cc2nc3cc(CC4SC(=O)NC4=O)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.99 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(4-aminobenzyl)benzoxazole, 2 ml of acetic anhydride and 10 ml of pyridine is stirred at room temperature overnight. 10% Hydrochloric acid is added thereto, and the solution is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate, whereby 0.56 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(4-acetamidobenzyl)benzoxazole is obtained.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].[CH3:12][NH:13][CH3:14].C(O)C>>[CH3:12][N:13]([CH3:14])[C:3](=[O:2])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CNC
Reactant: CCCCC(=O)CC(=O)OC
Solvent: CCO
Product: CCCCC(=O)CC(=O)N(C)C
Temperature: 100 °C
Reaction time: 24 h

Procedure:
0.632 mol (100 ml) methyl-3-oxoheptanoate (3-oxo-heptanoic acid methylester) and 227 ml 33% dimethylamine solution in ethanol (approx. 1.26 mol dimethylamine) was stirred for 4 hours at 110° C. in a pressure reactor. After cooling off, the solvents were distilled off on a rotavap, the raw product was taken up in 40 ml water, 30 ml 32% HCl and 40 ml ethanol and stirred for 24 hours at 100° C. The mixture was again concentrated to dryness by evaporation, taken up again in 300 ml acetic ester and filtrated, the solvents were then distilled off on the rotavap. 26 g of raw product was purified over 500 g silica gel 60 (mobile solvent: acetic ester:hexane 1:1, flow 50 ml/min, fraction size: 100 ml, product: fractions 20-35), the product was obtained as a mobile oil. 17.8 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[CH3:34][C:35]1([C:41]([O:43][CH2:44][CH2:45][N:46]([CH3:48])[CH3:47])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:38]3[CH2:39][CH2:40][C:35]([CH3:34])([C:41]([O:43][CH2:44][CH2:45][N:46]([CH3:47])[CH3:48])=[O:42])[CH2:36][CH2:37]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CN(C)CCOC(=O)C1(C)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)C1(C)CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (3 mL) was added 2-(dimethylamino)ethyl 4-methylpiperidine-4-carboxylate hydrochloride (87 mg, 0.35 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (38.0% MeCN up to 42.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 38.0% in 2 min); Detector, UV 254/220 nm. This resulted in 49.7 mg (41%) of the formic acid salt of 2-(dimethylamino)ethyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate. LCMS (Method 28) [M+H]+=659.2, RT=1.23 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.2, 7.2 Hz), 8.68-8.64 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 4.16 (t, 2H, J=5.6 Hz), 3.97-3.93 (m, 1H), 3.75-3.71 (m, 1H), 3.25-3.20 (m, 1H), 3.00-2.94 (m, 1H), 2.48-2.47 (m, 2H), 2.33 (s, 6H), 2.16-1.95 (m, 2H), 1.49-1.44 (m, 2H), 1.18 (s, 3H).
Reaction SMILES: FC(F)(F)C([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH:8]([CH:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]#[N:28])=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=O.FC(F)(F)C(N1C2CCC1CC(C1C3C=CC(C4NN=NN=4)=CC=3OC3C1=CC=CC=3)C2)=O>>[CH:10]12[NH:5][CH:6]([CH2:12][CH2:11]1)[CH2:7][CH:8]([CH:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]#[N:28])=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2
Reactant: N#Cc1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2C(=O)C(F)(F)F
Agent: O=C(N1C2CCC1CC(C1c3ccccc3Oc3cc(-c4nnn[nH]4)ccc31)C2)C(F)(F)F
Product: N#Cc1ccc2c(c1)Oc1ccccc1C2C1CC2CCC(C1)N2

Procedure:
Using an adaptation of the method described in Procedure 23, substituting 9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-9H-xanthene-3-carbonitrile, 3j for 2,2,2-trifluoro-1-{3-[3-(1H-tetrazol-5-yl)-9H-xanthen-9-yl]-8-aza-bicyclo-[3.2.1]oct-8-yl}-ethanone, 4j, the title compound 9-(8-aza-bicyclo[3.2.1]oct-3-yl)-9H-xanthene-3-carbonitrile, 1m was obtained.
Reaction SMILES: [NH3:1].F[C:3]1[C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:7][CH:6]=[C:5]([F:16])[N:4]=1.O>C(N)=O>[NH2:1][C:3]1[C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:7][CH:6]=[C:5]([F:16])[N:4]=1
Reactant: N
Reactant: CCCCOC(=O)c1ccc(F)nc1F
Solvent: NC=O
Solvent: O
Product: CCCCOC(=O)c1ccc(F)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
To a mechanically stirred solution of ammonia (14 grams (g)) in formamide (300 milliliter (ml)) was added all at once butyl 2,6-difluoropyridine-3-carboxylate (29 g, 0.135 mole). The resulting mixture was stirred overnight at room temperature. The mixture was then poured into water (1500 ml) and the product was filtered. After washing with several portions of water, the solid was dissolved in chloroform, dried (MgSO4) and the solvent evaporated. The resulting solid (26 g, m.p.=84°-120° C.) was separated via preparative high pressure liquid chromatography (8:2 hexane-acetone) to give first the desired butyl 2-amino-6-fluoropyridine-3-carboxylate (10 g) which after recrystallization from hexane had a m.p.=88.5°-90.5° C. Eluting second was the isomeric butyl 6-amino-2-fluoropyridine-3-carboxylate (9 g) which after recrystallization from toluene had a m.p.=132.5°-134° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:80][C:81]1[CH:87]=[CH:86][CH:85]=[CH:84][C:82]=1[NH2:83].C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:80][C:81]1[CH:87]=[CH:86][CH:85]=[CH:84][C:82]=1[NH:83][C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:24]
Reactant: Nc1ccccc1F
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1F)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Yield: 6 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2-fluoroaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][C:25]=2Br)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([F:17])[F:16])[CH:12]=[C:11]([C:18]#[N:19])[CH:10]=1.N[C:36]1C=CC(S(N)(=O)=O)=CC=1Br>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][C:25]=2[CH3:36])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([F:16])[F:17])[CH:12]=[C:11]([C:18]#[N:19])[CH:10]=1
Reactant: N#Cc1cc(Oc2ccc(CC(=O)Nc3ccc(S(N)(=O)=O)cc3Br)cc2Br)cc(C(F)F)c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1Br
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)Cc1ccc(Oc2cc(C#N)cc(C(F)F)c2)c(Br)c1

Procedure:
2-[3-Bromo-4-(3-cyano-5-difluoromethyl-phenoxy)-phenyl]-N-(2-bromo-4-sulfamoyl-phenyl)-acetamide I-64) was prepared analogously except in step 4, 4-amino-3-bromo-benzenesulfonamide was used in place of 4-amino-3-methyl-benzenesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH3:35][N:36]([CH3:40])[CH2:37]CO>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33][CH2:34][CH2:35][N:36]([CH3:40])[CH3:37])=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:19])=[O:20])=[C:13]([F:29])[CH:12]=3)[C:3]=12
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Reactant: CN(C)CCO
Product: CN(C)CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21

Procedure:
The representative procedure for amide formation was used in the reaction of methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.035 g, 0.067 mmol) with N,N-dimethylethanolamine (1 mL). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 7.50-8.07 min) afforded 2-(dimethylamino)ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate as an off-white solid (0.008 g, 0.014 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.24 (s, 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.48 (t, 1H), 7.32 (m, 3H), 5.23 (s, 2H), 4.29 (t, 2H), 2.86 (m, 2H), 2.39 (s, 6H); MS: (M−H)− 580.
Reaction SMILES: [CH3:1][Li].[CH2:3]([CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O>CCOCC>[CH2:3]([CH:10]1[C:15]([OH:16])([CH3:1])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [Li]C
Reactant: CCCCCCCCN1CCCC(=O)C1CCCCCCC
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCN1CCCC(C)(O)C1CCCCCCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
Methyl lithium (7 ml, 2 M solution in ether) was injected, under nitrogen, into a stirred solution of 2-n-heptyl-1-n-octylpiperidin-3-one (3.4 g) in dry ether (100 ml) at -78°. The mixture was allowed to warm gradually to room temperature. After 3 hours, thin layer chromatography indicated that some starting material remained. The solution was cooled to -78° and methyl lithium (3 ml, 2 M solution in ether) was injected. The mixture was allowed to warm gradually to room temperature and was allowed to stand for 2 days. Water (10 ml) was added dropwise and the ether phase was separated, dried over magnesium sulphate and evaporated in vacuo. The product was purified by column chromatography to give 2-n-heptyl-3-hydroxy-3-methyl-1-n-octylpiperidine as a yellow gum (1.47 g, 41% yield).
Reaction SMILES: [Br-:1].[Mg+2].[Br-].CS([CH2:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)(=O)=O>C(OCC)C>[Br:1][CH2:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1
Reactant: [Br-]
Reactant: CC1(C)OCC(CCS(C)(=O)=O)O1
Agent: [Mg+2]
Solvent: CCOCC
Product: CC1(C)OCC(CCBr)O1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Magnesium bromide etherate (40 g, 130 mmol) and a stir bar were added to a 2000 mL round bottom flask and flushed with nitrogen. A solution of 4-(2-methanesulfonylethyl)-2,2-dimethyl-1,3-dioxolane (34) (17.5 g, 78 mmol) in anhydrous diethyl ether (900 mL) was added via canulla, and the suspension stirred overnight. The ether was first decanted into a beaker. Water (200 mL) and ether (300 mL) were added to the precipitate and stirred for 5 minutes. The precipitate was dissolved, and the ether phase was then collected and added to the ether solution from the reaction. The organic phase was then washed, concentrated to about 500 mL, washed with water, dried over anhydrous Mg2SO4, filtered, and concentrated to yield a yellow oil (16.0 g). This was purified by flash chromatography to yield 10.6 g of product (50.7 mmol, 65%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([NH:5][CH2:6][CH2:7][C@:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([NH2:12])[CH2:9][CH:10]=[CH2:11])[CH3:4].C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:9]([C@:8]1([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6][N:5]([C@H:3]([C:2]([CH3:20])([CH3:1])[CH3:21])[CH3:4])[C:30](=[O:32])[NH:12]1)[CH:10]=[CH2:11]
Reactant: C=CC[C@@](N)(CCN[C@@H](C)C(C)(C)C)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)N1
Reaction time: 2 h
Yield: 131.6 %

Procedure:
To a solution of (R)—N1—((S)-3,3-dimethylbutan-2-yl)-3-(4-fluorophenyl)hex-5-ene-1,3-diamine (600 mg, 2.05 mmol) and triethylamine (1.04 g, 10.25 mmol) in CH2Cl2 (10 mL) was added triphosgene (203 mg, 0.68 mmol) at 0° C., and the mixture was stirred for 2 h. The reaction was quenched with water, and the mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to afford (R)-4-allyl-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (285 mg, 44%). 1H NMR (CDCl3): 0.72 (s, 9H), 1.01 (d, 3H), 1.79 (m, 1H), 2.06 (m, 1H), 2.34 (m, 1H), 2.56 (m, 1H), 2.73 (m, 1H), 3.03 (m, 1H), 4.49 (m, 1H), 4.92 (5, 1H), 5.04-5.13 (m, 2H), 5.26 (m, 1H), 6.95-6.99 (m, 2H), 7.22-7.25 (m, 2H).
Reaction SMILES: [Na].[NH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].ClC1C([O:15][C:16](=O)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=C(Cl)C(Cl)=C(Cl)C=1Cl>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([N:2]2[CH2:6][CH2:5][CH2:4][C:3]2=[O:7])=[O:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)cc1
Reactant: O=C1CCCN1
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCCC2=O)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
7.0 g. of the sodium salt of 2-pyrrolidinone (prepared using sodium hydride) suspended in 120 ml. of dimethylformamide are added at -10° C. to a solution of 20.0 g. of p-methoxybenzoic acid pentachlorophenyl ester in 100 ml. of dimethylformamide. Subsequently, the mixture is stirred at room temperature for 1 hour and at 55° C. for 8 hours. The solvent is evaporated, the residue is treated with cold aqueous acetic acid solution and the mixture is extracted with ethyl acetate. The organic phase is washed with cold sodium bicarbonate solution and water, dried over sodium sulfate, filtered and evaporated. The residue is taken up in ethanol and stirred in an ice bath. The separated crystals are filtered off and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119°-120° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10]C(=O)CCC(=O)C1C=CC=CC=1)[C:3]([NH2:5])=[O:4].[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[C:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]([NH2:1])[C:3](=[O:4])[NH2:5])=[O:32])=[CH:33][CH:34]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: NC(=O)[C@@H](N)CCCCNC(=O)CCC(=O)c1ccccc1
Product: CC(=O)c1ccc(C(=O)NCCCC[C@H](N)C(N)=O)cc1

Procedure:
1.65 g of the title compound was prepared as described for (2S)-2-amino-6-(4-oxo-4-phenylbutyrylamino)hexanoic acid amide, using 4-acetylbenzoic acid instead of benzoylpropionic acid.
Reaction SMILES: C(O)=O.C(N(CC)CC)C.[CH:11]([CH:13]1[CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O.[CH3:26][C:27]1(C)[O:34]C(=O)CC(=O)[O:28]1>[OH-].[Na+]>[C:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH:13]1[CH2:11][CH2:26][C:27]([OH:34])=[O:28])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOCC1CCC(=O)O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
A mixture of formic acid (2.26 mL, 58.9 mmol) and triethylamine (3.36 mL, 24.11 mmol) was stirred for 5 minutes in an ice bath. To the mixture were added tert-butyl 3-formylmorpholine-4-carboxylate (0.47 g, 2.2 mmol) and Meldrum's acid (0.32 g, 2.2 mmol) in turn at 0° C. The reaction mixture was heated at 100° C. for 5 hours, and cooled down in an ice bath. To the resulting mixture was added aqueous NaOH solution (2 mol/L, 40 mL). The aqueous layer was extracted with EtOAc (50 mL×3) and the organic layer was discarded. To the aqueous layer was added EtOAc (80 mL), and the mixture was adjusted to pH 4-5 with HCl (1 mol/L) under stirring. The aqueous layer was extracted with EtOAc (80 mL). The organic layer was dried over anhydrous Na2SO4, then filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (0.23 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][CH2:15][NH2:16]>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][CH2:15][NH:16][CH:5]1[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]1
Reactant: NCCc1cccs1
Reactant: CN1CCC(=O)CC1
Product: c1csc(CCNC2CCNCC2)c1

Procedure:
Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.), thiophene-2-ethylamine (0.563 g, 1.0 eq.).
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[CH:9]=1.C1C(=O)N([Br:53])C(=O)C1>CC#N.C(Cl)Cl>[CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[C:9]=1[Br:53]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (128 mg, 0.199 mmol) in CH3CN/DCM (3/1 mL) was added NBS (42.5 mg, 0.239 mmol) and stirred at rt for 30 min. TLC showed complete conversion. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-15% EtOAc/Hexanes, Rf=0.6 in 20% EtOAc) to afford 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone as a pale yellow oil (125 mg).