Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.P(CCCC)(CCCC)CCCC.O[C:37]1[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:39]([CH3:50])[CH:38]=1>C1COCC1>[CH3:50][C:39]1[CH:38]=[C:37]([O:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:22])[F:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:49]=[CH:48][C:40]=1[O:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
To a solution of 1-[4′-(trifluoromethyl)-4-biphenylyl]-1-pentanol (250 mg, 0.81 mmol) in dry THF (20 mL) under nitrogen at 0° C. (ice/water bath) was added nBu3P (0.41 mL, 1.64 mmol), followed by ethyl (4-hydroxy-2-methylphenoxy)acetate (170 mg, 0.81 mmol) and ADDM (420 mg, 1.64 mmol) portion-wise. After stirring the mixture for 18 hours at rt under nitrogen the solvent was removed under vacuum. The residue was partitioned between water and EtOAc and the aqueous re-extracted with EtOAc (3×30 mL). The organic combined extract was dried (MgSO4) and then reduced under vacuum. Purification by flash chromatography (silica), eluting with cyclohexane:EtOAc (9:1) afforded the title compound as a colourless gum (310 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][CH2:10][C@@H:11]([C:13]([NH:15][C@H:16]([C:21]([N:23]1[CH2:41][CH2:40][CH2:39][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:22])[CH2:17][C:18](=[O:20])[OH:19])=[O:14])[NH2:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+](C1C=CC(O[C:52](=[O:76])[C@H:53]([CH:65](CC2C=CC=CC=2)[C:66]([OH:68])=[O:67])[NH:54][C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])=CC=1)([O-])=O>>[C:55]([NH:54][C@H:53]([C:52]([NH:12][C@H:11]([C:13]([NH:15][C@H:16]([C:21]([N:23]1[CH2:41][CH2:40][CH2:39][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26])=[O:22])[CH2:17][C:18](=[O:19])[OH:20])=[O:14])[CH2:10][O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:76])[CH2:65][C:66](=[O:67])[O:68][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([O:57][CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)=[O:56]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)COCc1ccccc1)C(=O)O
Reactant: O=C(N[C@H](C(=O)Oc1ccc([N+](=O)[O-])cc1)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A method which comprises reacting O-benzyl-L-seryl-L-aspartyl-L-prolyl-L-arginine hydrochloride with N-carbobenzoxy-β-benzyl-L-aspartic acid p-nitrophenyl ester to give N-carbobenzoxy-O-benzyl-L-aspartyl-O-benzyl-L-seryl-L-aspartyl-L-prolyl-L-arginine.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](I)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:32]([C:34]1[O:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:37]5[O:38][C:34]([CH:32]=[O:33])=[CH:35][CH:36]=5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(I)cc34)c2)no1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(-c5ccc(C=O)o5)cc34)c2)no1
Temperature: 55 °C
Yield: 87 %

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-iodoquinazolin-4-yloxy)phenyl]urea from the previous step (0.21 g, 0.4 mmol), 5-formylfuran-2-ylboronic acid (0.07 g, 0.51 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.035 g, 0.05 mmol), and 1.0 M Na2CO3 solution (3 mL) in EtOH (2 mL) and 1,2-dimethoxyethane (3 mL) was heated at 55° C. for 1 hour. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 30-60% EtOAc/hexane as eluants to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-(5-formylfuran-2-yl)quinazolin-4-yloxy]phenyl}urea as solid (0.172 g, 87%). 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 9.53 (br, 1H), 8.80 (d, 1H), 8.78 (s, 1H), 7.32 (dd, 1H), 8.07 (d, 1H), 7.67 (m, 2H), 7.34-7.54 (m, 3H), 7.07 (d, 1H), 7.01 (d, 1H), 5.94 (s, 1H), 1.32 (s, 9H); LC-MS (ESI) m/z 498 (M+H)+.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[NH2:23]>C(O)COCCO.[Cl-].[Na+].O>[CH3:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Reactant: COc1ccc(N)c(C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c(C)c1
Temperature: 250 °C
Yield: 160.3 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.0 g, 19 mmol) was dissolved in diethylene glycol(30 ml) and 2-methyl-4-methoxyaniline(6.1 ml, 46 mmol) was added. The reaction mixture was refluxed at 250° C. for 15 hours, diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 6.6 g of desired compound as solid in 91% of yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH2:12])=[O:11])=[N:4][NH:5][C:6]=1[CH:7]([CH3:9])[CH3:8].N[C:14](N)=[O:15].C(O)(=O)C>[OH-].[Na+]>[OH:15][C:14]1[N:12]=[C:10]([OH:11])[C:3]2[NH:4][N:5]=[C:6]([CH:7]([CH3:9])[CH3:8])[C:2]=2[N:1]=1
Reactant: NC(N)=O
Reactant: CC(C)c1[nH]nc(C(N)=O)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)c1n[nH]c2c(O)nc(O)nc12
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Mixture of 4-amino-5-isopropylpyrazole-3-carboxamide (770 mg, 4.58 mmol) and urea (1.4 g, 4.58 mmol) was fused at 180° C. for 30 min. After cooling, the solid was dissolved in 2.3 mL of 2 M sodium hydroxide. The boiling solution was acidified with glacial acetic acid and the warm solution was filtered. This solution was cooled to 5° C. and the product started to precipitate after a few minutes. The crude product (1.3 g) was recrystallized twice from a hot water. Yield 78.5%; mp=295-298° C. 1H NMR (300 MHz, DMSO): 1.21 d (6H, J=6.6 Hz), 3.17 sept (1H, J=6.6 Hz). MS (EI): 194(94; C8H10N4O2); 179(100; C7H7N4O2); 162(51; C7H4N3O2); 136(15); 123(7); 95(8); 81(13); 54(26); 43(23).
Reaction SMILES: O.O.O.[Na+:4].[Na+].[Na+].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:18](=[O:21])([O-:20])[O-:19])[P:14](=[O:17])([OH:16])[O-:15]>O>[OH2:8].[Na+:4].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:14](=[O:15])([OH:16])[O-:17])[P:18](=[O:19])([OH:20])[OH:21].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:14](=[O:15])([OH:16])[O-:17])[P:18](=[O:19])([OH:20])[OH:21].[Na+:4]
Reactant: COCCCNC(P(=O)([O-])[O-])P(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: COCCCNC(P(=O)([O-])O)P(=O)(O)O
Yield: 130.9 %

Procedure:
In water (5 ml) was dissolved 3-methoxypropylaminomethylenebisphosphonic acid trisodium salt trihydrate (1.0 g), and the solution was passed through a column packed with Amberlite CG-50 (H+ type, 75 ml). Elution was conducted with water. From the acidic fraction thus eluted, 3-methoxypropylaminomethylenebisphosphonic acid monosodium salt hemihydrate (0.67 g, 87%) was obtained as colorless prisms, m.p. 277°-279° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C@:32]([OH:36])([C:34]#[CH:35])[CH3:33])[CH:28]=1>>[OH:36][C@:32]([C:29]1[CH:28]=[C:27]([CH3:26])[O:31][N:30]=1)([CH3:33])[C:34]#[C:35][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:7](=[N:14][C:13]([C:15]([NH2:17])=[O:16])=[C:12]3[CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:6]=2[CH:25]=1
Reactant: NC(=O)c1nc2n(c1CN1CCOCC1)CCOc1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(CN4CCOCC4)n2CCO3)no1

Procedure:
Following Procedure F, 10-bromo-3-(morpholinomethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound as a colorless solid after purification by SFC. LC MS: 478.2 [M+H]+; 1H NMR (400 MHz, DMSO) δ 8.52 (d, J=1.9 Hz, 1H), 7.57 (s, 1H), 7.33 (dd, J=8.5, 2.0 Hz, 1H), 7.09 (s, 1H), 7.03 (d, J=8.5 Hz, 1H), 6.50 (s, 1H), 6.46 (s, 1H), 6.35 (s, 1H), 4.50 (br m, 4H), 3.97 (br s, 2H), 3.52 (br m, 4H), 2.40 (s, 3H), 2.39 (m, 2H), 1.80 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[Br:21][CH2:22][CH2:23][CH2:24]Br.[NH4+].[Cl-]>C1COCC1>[Br:21][CH2:22][CH2:23][CH2:24][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCBr
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a 0° C. solution of diisopropylamine (14.35 mL, 0.102 mol) in 70 mL of THF was added n-BuLi (68 mL, 0.102 mol). The mixture was stirred at 0˜5° C. for 30 min. After the mixture was cooled to −78° C., ethyl isobutyrate (13.7 mL, 0.102 mol, 1 eq.) was added drop wise and stirring was maintained at −78° C. for 1 h. 1,3-Dibromopropane (1.01 equiv, 10.5 mL) was added drop wise at −78° C. and stirring was maintained at −78° C. for 1 h. Reaction was then warmed up to 23° C. over 2 hrs. Reaction mixture was added to an aqueous NH4Cl solution and extracted with EtOAc. The organic layer was washed with 1N HCl and brine, dried over MgSO4, filtered and concentrated down to give 23 g of crude product. The residue was purified by silica gel chromatography (5% to 30% EtOAc in hexanes) to provide 17.4 g (73% yield) of ethyl 5-bromo-2,2-dimethylpentanoate 90.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1[C:31]([CH:36]=O)=[N:32][CH:33]=[CH:34][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:36][C:31]2[C:30]([CH3:29])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccnc1C=O
Reactant: CC(C)(C)OC(=O)NC1CCC(NCc2ncccc2-c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1-c1ccccc1)C1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B: Reaction of the above amine and 3-methyl-2-pyridinecarboxaldehyde in CH2Cl2 with NaBH(OAc)3 gave {4-[(3-methyl-pyridine-2-ylmethyl)-(3-phenyl-pyridin-2-ylmethyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 0.86 (q, 2H, J=10.8 Hz), 1.14 (q, 2H, J=11.1 Hz), 1.41 (s, 9H), 1.58 (d, 2H, J=11.7 Hz), 1.85 (s, 2H), 1.91 (s, 3H), 2.11 (s, 1H), 2.21 (s, 1H), 3.19 (br s, 1H), 3.80 (s, 2H), 3.84 (s, 2H), 4.23 (br s, 1H), 7.00 (dd, 1H, J=7.4, 5.1 Hz), 7.21-7.30 (m, 7H), 7.49 (dd, 1H, 7.8, 1.5 Hz), 8.25 (d, 1H, J=3.9 Hz), 8.53 (dd, 1H, J=4.8, 1.8 Hz). Conversion to the HBr salt using General Procedure D gave COMPOUND 259 as a pale yellow solid. 1H NMR (D2O) δ 1.29-1.48 (m, 4H), 1.90 (d, 2H, J=10.2 Hz), 2.02 (d, 2H, J=9.6 Hz), 2.37 (s, 3H), 2.66 (br t, 1H, J=8.1 Hz), 3.09 (br s, 1H), 4.12 (s, 2H), 4.35 (s, 2H), 7.42 (d, 2H, J=4.5 Hz), 7.59 (s, 3H), 7.81 (t, 1H, J=6.6 Hz), 8.01 (t, 1H, J=6.3 Hz), 8.28 (d, 1H, J=7.8 Hz), 8.45 (d, 1H, J=7.8 Hz), 8.51 (d, 1H, J=5.7 Hz), 8.77 (d, 1H, J=5.7 Hz). 13C NMR (D2O) δ 14.56, 17.18, 25.80, 29.46, 49.67, 50.80, 51.86, 60.40, 126.08, 126.54, 129.68, 130.35, 133.97, 137.79, 138.70, 140.93, 141.18, 148.35, 148.41, 150.54, 151.18. ES-MS m/z 387 [M+H]+. Anal. Calcd. for C25H30N4.3.3HBr.2.2CH3OH: C, 45.12; H, 5.86; N, 7.74; Br, 36.42. Found: C, 45.22; H, 5.69; N, 7.97; Br, 36.19.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[CH:22][C:23]([OH:25])=O.[C:26]([CH:28]1[CH2:30][NH:29]1)#[N:27]>C(OCC)C>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[CH:22][C:23]([N:29]1[CH2:30][CH:28]1[C:26]#[N:27])=[O:25]
Reactant: N#CC1CN1
Reactant: O=C(O)C=Cc1ccco1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: N#CC1CN1C(=O)C=Cc1ccco1
Reaction time: 8 h

Procedure:
The same compound is obtained by introducing 2.1 g. dicyclohexylcarbodiimide, dissolved in 10 ml. diethyl ether, at 0° C. into a solution of 1.38 g. β-(2-furyl)acrylic acid and 0.68 g. 2-cyanoaziridine in 30 ml. diethyl ether, stirring for 2 hours at 0° C. and leaving to stand overnight at ambient temperature; after analogous purification on a silica gel column, there is obtained 0.9 g. of an oil which solidifies after standing for several days. After trituration with petroleum ether, the compound melts at 59°-61° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1)=[O:7].[CH3:17][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:7][C:6]([C@@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:17]
Reactant: C[Mg]Br
Reactant: COC(=O)[C@H]1CC[C@@H](C(=O)c2nccs2)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@@H](C(C)(O)c2nccs2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,3R)-methyl 3-(thiazole-2-carbonyl)cyclopentanecarboxylate (148 mg, 1.75 mmol) in THF (6 mL) and at −78° C. was added methylmagnesium bromide (582 mL, 1.75 mmol), the solution was stirred at −78° C. for 30 minutes. Saturated aqueous ammonium chloride was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc, organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was absorbed on silica and purified by flash chromatography to afford (1S,3R)-methyl 3-(1-hydroxy-1-(thiazol-2-yl)ethyl)cyclopentanecarboxylate. MS ESI calc'd. for C12H18NO3S [M+H]+ 256. found 256. 1H NMR (500 MHz, DMSO-d6) δ 7.67 (t, J=3.0 Hz, 1H), 7.50 (d, J=3.0 Hz, 1H), 3.58-3.57 (m, 3H), 3.52 (s, 1H), 2.75-2.62 (m, 1H), 2.43-2.35 (m, 1H), 1.97-1.91 (m, 1H), 1.78-1.51 (m, 4H), 1.46-1.44 (m, 3H), 1.25-1.19 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:24])[CH2:23][O:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[CH3:32][C:33]1[CH:37]=[C:36]([C:38](O)=[O:39])[O:35][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:24][C:38]([C:36]4[O:35][N:34]=[C:33]([CH3:32])[CH:37]=4)=[O:39])[CH2:21][O:22][CH2:23]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1cc(C(=O)O)on1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)COC2)no1
Product: Cc1cc(C(=O)NC2(C(=O)N[C@H]3CCc4cc(-c5cc(Cl)cc(F)c5-c5noc(C)n5)ccc43)COC2)on1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 3-amino-oxetane-3-carboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 49) was coupled with 3-methyl-isoxazole-5-carboxylic acid to yield the title compound as light yellow oil. MS: 552.1 (MH+, 1Cl).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CN1CCCN(C)C1=O.[NH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>C1(C)C=CC=CC=1>[CH2:31]([C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:22][C:14]=2[NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([N:42]4[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[N:17]=1)[CH3:32]
Reactant: C1CNCCN1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Solvent: CN1CCCN(C)C1=O
Solvent: Cc1ccccc1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(N5CCNCC5)ccn34)c12
Temperature: 105 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
N-(3-Ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (12 mg, 0.03 mmol; Example 74, Step A) was dissolved in toluene (0.2 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (0.1 mL) and piperazine (24 mg, 0.28 mmol) was added in one portion. The mixture was heated to 105° C. and stirred for 16 hours. The crude mixture was loaded onto a Biotage 12+ C-18 samplet and purified using a gradient of 10-65% acetonitrile/water to give N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(piperazin-1-yl)imidazo[1,2-a]pyridine-3-carboxamide as a white solid (12 mg). MS m/z 495.3 (M+1, APCI+)
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1>>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15]/[CH:16]=[CH:17]/[CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OC/C=C/COc3ccccc3)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OC/C=C/COc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (E)-(3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-but-2-enyloxy)-phenyl]-piperidine-1-carboxylate [Example 123 (k)] with 2-bromomethyl-naphthalene there was obtained tert-butyl (E)-(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(4-phenoxy-but-2-enyloxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 580 (M+H)+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:32]1([CH2:38][CH2:39][S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[OH:46][C:45]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][CH:10]=2)[O:16][C:42](=[O:43])[C:41]=1[S:40][CH2:39][CH2:38][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(Sc2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(Sc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(phenylthio)acetophenone (1.15 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (56 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 120-121° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 2.98 (t, 2 H), 6.72 (s, 1 H), 7.24 (m, 7 H), 7.45 (m, 5 H), 7.74 (d, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C(=O)N([Br:22])C(=O)C1.O>CN(C=O)C>[Br:22][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:11][CH2:12][C:13]#[N:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(CCC#N)cc1OC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)c(CCC#N)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1 g (5.3 mmoles) of 3-(3,4-dimethoxyphenyl)propanenitrile in 42 mL of DMF is cooled to 0° C. To the resulting solution there is added, little by little, 0.93 g of NBS (5.2 mmoles, 1 eq.). After stirring for 30 minutes at 0° C., the reaction mixture is brought back to ambient temperature and stirred for two hours. It is then hydrolysed using 170 mL of water and extracted twice with 130 mL of ethyl acetate. The organic phases are collected and then washed, first with saturated aqueous Na2S2O5 solution and then with water. After evaporating off the solvent under reduced pressure, 1.29 g of a colourless oil which crystallises into a white solid are obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[C:14](F)(F)[C:15](O)=[O:16]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:12][O:11][C:10]1[C:2]([F:1])=[C:3]2[C:7]([C:15](=[O:16])[CH2:14][O:6][CH2:4]2)=[CH:8][CH:9]=1
Reactant: COc1cccc(C(=O)O)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc2c(c1F)COCC2=O
Yield: 32 %

Procedure:
A solution of 2-fluoro-3-methoxyphenyl)-3-oxo-propanoic acid from Step 1 (1.96 g, 8.6 mmol) in 4 mL of trifluoroacetic acid and 2 mL of trifluoroacetic anhydride was stirred at room temperature for 1 hour. The solution was concentrated in vacuo, the residue dissolved in ether, and the ethereal solution was washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a solid that was purified by flash chromatography to provide 0.37 g (32%) of the desired ketone. The aqueous phase from the NaHCO3 was acidified, extracted with ether, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide 1.13 g, of recovered 2-fluoro-3-methoxyphenyl)-3-oxo-propanoic acid: mp 112°-118° C.; 1H NMR (CDCl3 /300 MHz) 7.86 (dd, J=8.66, 1.41 Hz, 1H), 7.00 (apparent t, J=8.26 Hz, 1H), 4.96 (s, 2H), 4.31 (S, 2H), 3.97 (S, 3H); 19F NMR (CDCl3 /282 MHz) -142.2 (d). Mass spectrum M+ =196.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=2)[CH:9]=1)(C)(C)C.F>C1COCC1>[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=2)[CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(Nc2ncc(C#N)s2)c1
Agent: F
Solvent: C1CCOC1
Product: N#Cc1cnc(Nc2cc(CO)ccn2)s1
Reaction time: 0.33 h

Procedure:
2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile (1.30 g, 3.75 mmol) was dissolved in 10 mL anh THF. Hydrogen-fluoride (Aldrich, 5.0 mL) was added and the reaction was stirred for 20 min. The bulk of the solvent was removed in vacuo and the resulting residue was diluted with half-saturated NaHCO3 (aq). A precipitate formed which was filtered and washed with water to afford the titled compound. 1H NMR (DMSO-d6) δ12.23 (bs, 1H), 8.30 (d, 1H, J=5.3 Hz), 8.26 (s, 1H), 7.15 (s, 1H), 6.99 (d, 1H, J=5.3 Hz), 5.49 (t, 1H, J=5.7 Hz) 4.54 (d, 2H, J=5.7 Hz).