Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH2:5]1)(=[O:3])[CH3:2].[Cl-:21].[Na+]>C(#N)C.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([Cl:21])[CH:11]=2)[CH:6]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: [Cl-]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CN2C(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc2c(cc1Cl)N(C(C)=O)CC2CCNC(C)=O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a solution of N-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide (0.29 mmol) in acetonitrile (1.5 ml) is added bis(trifluoroacetoxyiodobenzene) (PIFA 1.2 eq) and the medium is left stirring for 1 min at room temperature. Saturated sodium chloride solution (0.5 ml) is next added and, after 15 min, the mixture is diluted with dichloromethane (10 ml) and dried over magnesium sulphate. The crude product obtained after evaporation is chromatographed on a column of flash silica (5/95 methanol/dichloromethane) and N-[2-(1-acetyl-6-chloro-5-methoxyindolin-3-yl)ethyl]acetamide (70 mg) is thus obtained.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>C1(C)C=CC=CC=1>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][CH:25]2[CH2:26][CH2:27][N:22]([C:20]([O:19][CH2:17][CH3:18])=[O:21])[CH2:23][CH2:24]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: NCCC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(NCCC(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
In a reactor equipped with a water trap, a solution of 3,3-diphenylpropylamine (4.9 g) and 1-ethoxycarbonyl-4-piperidone (4.0 g) in toluene (100 mL) was refluxed for 2 hours. This reaction mixture was concentrated under reduced pressure and the residue was dissolved in 80 mL of ethanol. After this solution was cooled with ice, 1.8 g of sodium cyanoborohydride and a small amount of bromocresol green were added. Then, 4N-hydrogen chloride solution in ethanol was added dropwise until the reaction mixture had turned yellow and, after completion of dropwise addition, the mixture was further stirred for 30 minutes. This reaction mixture was poured into an excess of aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure to give ethyl 4-[(3,3-diphenylpropyl)amino]-1-piperidinecarboxylate. This product was dissolved in 80 mL of N,N-dimethylformamide, followed by addition of 2.8 mL of benzyl bromide and 3.2 g of potassium carbonate, and the mixture was stirred at room temperature for 2 hours. This reaaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1 to 7:3 ) to provide 7.8 g of the title compound. Yield based on 3,3-diphenylpropylamine was 73%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[F:12][C:13]([F:22])([F:21])[C:14]1[C:19](O)=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:22])([F:21])[F:12])=[CH:15][CH:16]=1
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: Oc1ccccc1C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(O[C@H](CCCl)c2ccccc2)cc1

Procedure:
The title compound was prepared by the method of example 55 using [S]-3-chloro-1-phenylpropanol (2.57 g, 15 mmol), α,α,α-trifluoro-cresol (2.4 g, 15 mmol) in THF (40 ml) at room temperature. Workup provided the optically pure title compound as a thick liquid, bp 180°-200° C./0/5 mm. [α]D +2.3° (c 10, CHCl3 ; 13C NMR (CDCl3): 140.50, 129.39, 128 66, 127,56, 127.38, 127.19, 127.01, 126.34, 116.45, 77.82, 41.69, 41.38. Mass spectrum (El): 153/155 (45), 91 (100). (Cl): 314/316, (1, M+), 153/155 (100). Anal. Calcd. for C16H14ClNO: C, 61.05; H, 4.45; Cl, 11.29; F, 18.12. Found: C, 61.06; H, 4.51; Cl, 11.16; F, 8.22.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3C=CC=CC=3)=[C:31]([NH:43][CH:44]=[O:45])[CH:30]=2)[OH:28])=[CH:17][CH:16]=1)C1C=CC=CC=1.C[OH:48]>C(O)(=O)C.[OH-].[OH-].[Pd+2].ClCCl>[C:36]([OH:48])(=[O:35])[CH3:37].[C:36]([OH:48])(=[O:35])[CH3:37].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([NH:43][CH:44]=[O:45])[CH:30]=2)[OH:28])=[CH:19][CH:20]=1
Reactant: O=CNc1cc([C@@H](O)CNCCCCc2ccc(CCCCNC(=O)OCc3ccccc3)cc2)ccc1OCc1ccccc1
Reactant: CO
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: NCCCCc1ccc(CCCCNC[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of [4-(4-{4-[2-(4-benzyloxy-3-formylaminophenyl)-2-(R)-hydroxyethylamino]butyl}phenyl)butyl]carbamic acid benzyl ester (8) (84 mg, 0.14 mmol), palladium dihydroxide (28 mg, 10% Pd(OH)2 on carbon, 50% wet), three drops of acetic acid, methanol (5 mL), and dichloromethane (5 mL) was stirred at rt for 16 h under atmospheric hydrogen pressure. The catalyst was filtered through a Celite pad and the filtrate was concentrated by rotary evaporation and further dried under high vacuum to give the desired amine diacetic acid salt 11 as a yellow solid (69 mg, 99%): 1H NMR (500 MHz, CD3OD) δ 1.68 (m, 8H), 1.93 (s, 6H), 2.63 (m, 4H), 2.91 (m, 2H), 3.08 (m, 4H), 4.83 (m, 1H), 6.88 (d, 1H), 7.05 (d, 1H), 7.11 (s, 4H), 8.10 (s, 1H), 8.30 (s, 1H); m/z (ESI) 400 [C23H33N3O3+H]+.
Reaction SMILES: [CH3:1][O:2][NH2:3].[N:4]([C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[O:9][N:8]=1)=[C:5]=[O:6]>O1CCCC1>[CH3:1][O:2][NH:3][C:5]([NH:4][C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[O:9][N:8]=1)=[O:6]
Reactant: CC(C)(C)c1cc(N=C=O)no1
Reactant: CON
Solvent: C1CCOC1
Product: CONC(=O)Nc1cc(C(C)(C)C)on1

Procedure:
8.5 g of methoxyamine was added very slowly to a stirred solution of 15 g of 4A in 600 ml of tetrahydrofuran. The resulting mixture was filtered and the solid was triturated with ether to give 1-methoxy-3-(5-(tertiary-butyl)-1,2-oxazol-3-yl)urea (4B), m.p.: 145°-148° C.
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.[C:20](NC1C=CN([C@@H]2O[C@H](CO)[C@@H](O)C2)C(=O)N=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:20]([NH:15][C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:19]=2[N:18]=[CH:17][N:16]=1)[C@@H:2]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)c1ccccc1
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Solvent: O
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1

Procedure:
This compound was prepared from 2'-deoxyadenosine monohydrate by the same procedure used for the preparation of N4 -benzoyl-2'-deoxycytidine.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](NC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:36]1([C@H:42]([NH2:44])[CH3:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:44][C@@H:42]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH3:43])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(N[C@H](C)c3ccccc3)nc2n(C)c1=O
Yield: 52.8 %

Procedure:
Using a procedure analogous to Example A1, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.081 g, 0.16 mmol) and (R)-1-phenylethanamine (0.058 g, 0.48 mmol) were combined in THF (1 mL) to provide (R)-1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-7-oxo-2-(1-phenylethylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as a white solid (0.048 g, 53% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=7.2 Hz, 1H), 8.39 (brs, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.43-7.35 (m, 3H), 7.31-7.27 (m, 2H), 7.18 (t, J=7.2 Hz, 1H), 7.08 (d, J=12.8 Hz, 1H), 5.12 (t, J=7.2 Hz, 1H), 3.54-3.46 (m, 3H), 2.01 (s, 3H), 1.44 (s, 9H); (ESI) m/z: 569.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:3].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][CH3:32]>>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:29][CH2:30][CH2:31][CH3:32])[CH:8]=[C:7]2[CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:3]
Reactant: CCCCBr
Reactant: NC(=O)c1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Agent: [H-]
Agent: [Na+]
Product: CCCCn1cc(CCNC(=O)OCc2ccccc2)c2cc(C(N)=O)ccc21

Procedure:
Following the method of Example 16(i), [2-[5-(aminocarbonyl)-1H-indol-3-yl]ethyl]carbamic acid, phenylmethyl ester (1.5 g), sodium hydride (0.16 g) and 1-bromobutane (1 ml) gave a pale brown oily solid (1.5 g). Chromatography on a silica column (Kieselgel 60, 60 g) eluted with chloroform containing 1% methanol gave the title compound (1.0 g) as a colourless crystalline solid m.p. 138°-9° (ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:4][C:3]1=2.[CH3:22]C1C(C#C)=CC2C(C)(C)CCC(C)(C)C=2C=1.COC(Cl)=O.C([Li])CCC>>[CH3:22][C:5]1[C:6]([C:14]#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:21])([CH3:1])[C:3]=2[CH:4]=1
Reactant: C#Cc1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC(=O)Cl
Agent: [Li]CCCC
Product: CCOC(=O)C#Cc1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
Employing the same general procedure as used for the preparation of ethyl 3-[5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl]propiolate (Compound A), but instead using 1.9 g of (3-methyl-5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethyne, 940 mgs (10 mmols) of methylchloroformate and 8.8 mmols of n-butyllithium the title compound was obtained as an oil.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].[CH2:35]([NH2:37])[CH3:36].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH:37][CH2:35][CH3:36])(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CCN
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. THF (3 ml) was stirred with molecular sieve (4 Å, 30 mg) for 30 min. (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 50 mg, 62 μmol), ethylamine (2 M solution in THF; 94 μl, 0.19 mmol, 3 eq.) and triethylamine (9 μl, 62 μmol, 1 eq.) were added, and the mixture was stirred at RT for 12 h. The reaction solution was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (29.9 mg, 93% of theory).
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:43]NC1CCCC1>CS(C)=O.C1COCC1>[CH:1]1([N:6]([CH3:43])[C:7]([NH:9][C@:10]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=2)([C:18]2[CH:23]=[C:22]([O:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])[CH:21]=[C:20]([F:31])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1CCCC1)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: CNC1CCCC1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CN(C(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1)C1CCCC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea (20 mg, 0.033 mmol), prepared as described in Procedure 3, 4, 5, 6 and 2, in DMSO/THF (0.1 mL/0.1 mL) was added N-methylcyclopentanamine (32 mg, 0.33 mmol). The resulting solution was stirred at 120° C. under microwave irradiation for 1800 sec. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was then washed with H2O, sat. NaCl and dried over Na2SO4. The organic solvent was evaporated under reduced pressure and the resulting residue was purified by prep HPLC (Phenomenex AXIA Luna 75×30 mm, 5μ column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-1-methylurea (Example 246) as white lyophillate (13 mg, 65% yield). LCMS: [M+H] 619.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [Br-].[Li+].Cl[C:4]1([O:17][C:12]1([CH:14]([CH3:16])[CH3:15])[CH3:13])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(=O)([O-])[O-].[Li+].[Li+]>O>[CH:14]([C:12](=[CH2:13])[C:4](=[O:17])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])([CH3:16])[CH3:15]
Reactant: CC(C)C1(C)OC1(Cl)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: O
Product: C=C(C(=O)C(=O)OC(C)(C)C)C(C)C
Temperature: 5 °C
Reaction time: 48 h
Yield: 85.2 %

Procedure:
118 g of anhydrous lithium bromide were added under an inert atmosphere to a mixture of 117.5 g of tert.butyl 2-chloro-2,3-epoxy-3-isopropyl-butanoate and 18.5 g of lithium carbonate in 1.15 liters of hexamethylphosphonotriamide cooled to 5°C and after the temperature was returned to room temperature, the mixture was stirred under a nitrogen atmosphere for 48 hours. 500 ml of distilled water were added thereto and the mixture was poured into an ampoule containing a mixture of water-petroleum ether (9-1). The mixture was decanted and the aqueous phase was extracted with petroleum ether. The combined ether phases were washed with water, dried over magnesium sulfate and the petroleum ether was evaporated under reduced pressure to obtain 84.6 g of tert.-butyl 3-isopropyl-2-oxo-3-butenoate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:24]/[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: COC(=O)CON
Product: COC(=O)CO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 31 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and methyl 2-(aminooxy)acetate (intermediate K) in 31% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, CD3OD), δ ppm 9.32 (s, 1H), 8.86 (m, 1H), 8.38 (d, 1H), 8.06 (m, 2H), 7.90 (dd, 1H), 7.56 (dd, 1H), 6.24 (s, 2H), 4.87 (s, 2H), 3.79 (s, 3H), 2.45 (s, 3H). LCMS (method B): [MH]+=392, tR=2.16 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][CH:8]2[CH:10]=[CH:11][S:12][CH:7]2[CH:6]=1)=[O:4].[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CC#N>C(N(CC)CC)C>[S:9]1[C:5]([C:3](=[O:4])[CH2:2][O:24][C:22]([CH:21]2[CH2:25][CH2:26][CH2:27][N:20]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:23])=[CH:6][CH:7]2[S:12][CH:11]=[CH:10][CH:8]12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(CBr)C1=CC2SC=CC2S1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)C1=CC2SC=CC2S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Crude 2-Bromo-1-(3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-ethanone (2.48 mmol assuming complete conversion from starting material) was treated with Boc-proline and MeCN (25 mL). Triethylamine was added and the solution was stirred at RT for 1 h then concentrated. The crude residue was purified by silica column chromatography (14% to 35% EtOAc/Hex) to afford the title compound (595 mg, 61%).
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:26][O:25][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:27]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(I)cc2)cc1)OC
Reactant: OB(O)c1ccncc1
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccncc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-iodo-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 270, Step A) and 4-pyridyl boronic acid by following the procedure described for Example 270 (Steps B and C). 1H-NMR (CDCl3, 200.15 MHz): δ 8.67–8.65 (m, 2H), 8.16 (d, 2H, J=6.6), 7.90 (d, 2H, J=8.8), 7.16–7.09 (m, 4H), 6.82 (d, 2H, J=8.8), 4.26 (t, 2H, J=6.2), 4.13 (t, 2H, J=6.2), 3.90 (dd, 1H, J=7.7, 4.8), 2.97 (dd, 1H, J=14.3, 5.1), 2.83 (dd, 1H, J=14.3, 7.7), 2.24 (qn, 2H, J=5.9).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16]C)=[O:14].[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[C:3]([OH:11])=[C:4]([C:8]([C:9]2[CH2:16][O:15][C:13](=[O:14])[C:12]=2[OH:18])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(F)c1O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OCC(C(=O)c2cccc(F)c2O)=C1O
Yield: 40.3 %

Procedure:
A solution of 1-(3-fluoro-2-hydroxyphenyl)ethanone (30 g) and diethyl oxalate (31 g) in ethanol (600 mls) was added dropwise to sodium ethoxide (from 9.85 g of sodium) in ethanol (600 mls) and the mixture was stirred and heated at reflux for 2 days. After the mixture had cooled, it was diluted with 60-80 petrol and the solid was collected and dried. A suspension of the product in water (1.2 l) was stirred with formaldehyde (24 mls of 37%) for 1.5 hours. The solid was filtered out, the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum. The aqueous solution was acidified to pH 3, the precipitate was collected, washed with water and recrystallised from acetone/water to give the title compound as yellow needles (18.7 g). M.p. 194°-208°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[C:30](B(O)O)=[C:29]([CH3:34])[O:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+].C1COCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:26]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:9]3[CH2:10][C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:15])([CH3:16])[CH2:14]3)=[CH:6][CH:7]=2)=[C:29]([CH3:34])[O:28][N:27]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(Br)cc2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
An round-bottomed flask was charged with 16 (192 mg, 0.5 mmol), Pd(Ph3P)4 (58 mg, 0.05 mmol), (3,5-dimethyl-4-isoxazolyl)boronic acid (141 mg, 1.0 mmol), 2 N aqueous Na2CO3 (0.5 mL, 1 mmol), and THF (5 mL). The reaction mixture was refluxed for 18 h. The mixture was cooled to RT, diluted with EtOAc (100 mL), and then the mixture was washed with H2O (1×25 mL), brine (1×25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography to give 136 mg (68%) of the title product 22 as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.94 (s, 6H), 0.97 (s, 6H), 1.31 (s, 2H), 1.97 (s, 2H), 2.01 (s, 2H), 2.28 (s, 3H), 2.41 (s, 3H), 7.32-7.14 (m, 9H). LCMS (APCI): m/z 400 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[CH:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.N1C=CC=CC=1>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]3[NH:31][N:30]=[N:29][N:24]=3)=[CH:25][CH:26]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C(=Cc1ccc(-c2nnn[nH]2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 100 °C

Procedure:
A mixture of 1.15 g (3.17 mmol) of 4-(4-(2-quinolinylmethyloxy)styryl)benzonitrile 1.03 g (15.86 mmol) of sodium azide, and 1.83 (15.86 mml) of pyridine hydrochloride in 15 ml of DMF is heated at 100° C. for 48 hours and then poured into ice water. The precipitate that forms is filtered off and suspended in hot methanol and filtered to give 5-(4-(4-(2-quinolinylmethyloxy)styryl)phenyl)tetrazole. (M.P. 241° C.-243° C.)