Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[CH:9]=1.C1C(=O)N([Br:56])C(=O)C1>C(#N)C>[CH3:48][Si:2]([CH3:1])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[C:9]=1[Br:56]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)cc1
Solvent: CC#N
Product: COC(=O)Cc1ccc(Oc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound, methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate (150 mg, 0.22 mmol) was dissolved in ACN (10 mL). NBS (40 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 1 h. After concentration, the product, methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate was used in the next step without further purification. HPLC-MS tR=2.70 min (UV254 nm); mass calculated for formula C36H46BrN5O5Si2 763.2, observed LCMS m/z 764.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].[CH:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:20]([CH3:22])[CH3:21])[CH:28]=1)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: CC(C)c1cccc(B(O)O)c1
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cl
Product: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1cccc(C(C)C)c1

Procedure:
The title compound was prepared in analogy to example 20 step C from 4,6-dichloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (200 mg, 0.67 mmol) and 3-isopropylphenylboronic acid (99 mg, 0.6 mmol). Off-white sticky liquid (90 mg, 35%). LC-MS: 382 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19](O)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:31]([O:33][NH2:34])[CH3:32].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>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH:18]([OH:22])[C:19]([NH:34][O:33][CH2:31][CH3:32])=[O:20])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCON
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
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
Product: CCONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The reaction was carried out in analogy to reaction step 20.3 of Example 20 by reacting 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-ethylhydroxylamine hydrochloride using HATU (1.2 equivalents) as coupling reagent and DIPEA (6.8 equivalents) as base. ESI-MS [M+H]+=440.2
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: C1CCNC1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and pyrrolidine. LCMS (Method C): 524 (M+H)+, Retention time 11.6 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[C@@:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])([CH3:11])[O:9]2)[CH:7]=1.CO.[Cl-].[NH4+].[N-:24]=[N+:25]=[N-:26].[Na+]>O>[N:24]([C@H:8]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=1)[C@@:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])([OH:9])[CH3:11])=[N+:25]=[N-:26]
Reactant: C[C@@]1(c2cc(F)ccc2F)O[C@@H]1c1cncc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@](O)(c1cc(F)ccc1F)[C@H](N=[N+]=[N-])c1cncc(Br)c1
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
Placed 3-bromo-5-((2R,3S)-3-(2,5-difluorophenyl)-3-methyloxiran-2-yl)pyridine (100 mg, 0.307 mmol), methanol (12 mL), water (1.500 mL), ammonium chloride (32.8 mg, 0.613 mmol), and sodium azide (120 mg, 1.840 mmol) in a microware tube and stirred for five minutes then sealed the tube and lowed it to a 110° C. oil bath for 18 hour. The reaction mixture was concentrate to provide a white solid to which was added 25 mL water then extracted it by ether (25 mL×3). Combined all ether layer, dried over magnesium sulfate, concentrated to afford clear wax which was purified via column chromatography (5% to 35% EtOAc/Hex) to provide (1R,2R)-1-azido-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol (96.2 mg, 0.248 mmol, 81% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J=2.1 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.06 (t, J=1.8 Hz, 1H), 7.40 (ddd, J=9.8, 6.2, 3.2 Hz, 1H), 7.33-7.15 (m, 2H), 6.14 (s, 1H), 5.13 (s, 1H), 1.33 (d, J=0.9 Hz, 3H), Mass spec.: 371.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([OH:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(CC(=O)C(=O)O)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H](O)C(=O)O)cc1Cl
Temperature: -35 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere a mixture of 2.6 g (12.23 mmol) 3-(3-chloro-4-methyl-phenyl)-2-oxo-propionic acid and 2.1 mL (15.1 mmol) triethylamine in 40 mL THF was cooled to −35° C. Then a solution of 5.87 g (18.30 mmol) (1R)-B-chlorodiisopinocampheylborane in 20 mL THF was added dropwise so that the reaction temperature remained between −35° C. and −25° C. The cooling bath was removed and the reaction mixture was stirred overnight at RT. While cooling with ice 30 mL 1 M NaOH and 60 mL diethyl ether were added dropwise and the mixture was stirred for 15 min. The aqueous phase was separated off, the organic phase was extracted twice with 20 mL 1 M NaOH and once with 20 mL water. The combined aqueous phases were acidified with semiconc. HCl while cooling with ice, extracted twice with 60 mL EtOAc and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][Cl:37].O>CN(C)C=O>[Cl:37][CH2:36][CH2:35][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: ClCCBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (compound 390) (86 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (330 mg) and 1-bromo-2-chloroethane (1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give 1-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-quinolin-2-yl}-ethanone (75 mg, yield 74%).
Reaction SMILES: [C:1]([C:3]1[S:7][N:6]=[C:5]([CH3:8])[C:4]=1[C:9](OC)=[O:10])#[N:2].CO.[BH4-].[Li+]>C(OCC)C>[C:1]([C:3]1[S:7][N:6]=[C:5]([CH3:8])[C:4]=1[CH2:9][OH:10])#[N:2]
Reactant: COC(=O)c1c(C)nsc1C#N
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: Cc1nsc(C#N)c1CO
Temperature: 40 °C
Reaction time: 2 h
Yield: 123.5 %

Procedure:
5-Cyano-4-methoxycarbonyl-3-methyl-isothiazole (1.14 g, 6.3 mmol) was dissolved in diethyl ether (20 ml) and methanol (0.38 ml, 9.4 mmol). Lithium borohydride (204 mg, 9.4 mmol) was added and the mixture was stirred at 40° C. for 2 hours. The reaction was quenched by addition of aqueous hydrochloric acid (1M) (20 ml). The two phases were separated and the aqueous phase was extracted with diethyl ether (2×20 ml). The combined organic phases were dried over magnesium sulfate and concentrated to give a crude product (1.2 g), which consisted of a 1:1 mixture of methyl ester and product. The mixture was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:15])(=O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([Cl:15])[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCC(=O)CC(=O)OC
Solvent: ClCCl
Product: CCCCC(=O)C(Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-oxo-heptanoic acid methyl ester (5.0 g, 31.6 mmol) in dry dichloromethane (80 mL) add sulfurylchloride (2.82 mL). Stir the reaction mixture at room temperature for 30 minutes then add water (20 mL) and the reaction mixture extracted five times with portions of 30 mL of dichloromethane. Wash the combined organic extracts with water, saturated aqueous solution of NaHCO3 and brine and then dry over MgSO4. Remove the solvent under reduced pressure to give 2-chloro-3-oxo-heptanoic acid methyl ester (6.0 g), which was used in the next step without further purification. To a solution of 2-chloro-3-oxo-heptanoic acid methyl ester (6.0 g, 31.1 mmol) in ethanol (50 mL) add 4-(trifluoromethyl) thiobenzamide (6.4 g, 31.2 mmol). Heat the reaction mixture to reflux overnight. Remove the solvent under reduced pressure and purify the residue by chromatography on silica gel (eluting with a gradient of n-heptane:ethyl acetate (100:1 to 60:1)) to give 4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-carboxylic acid methyl ester (7.4 g) as a yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br>CN1C(=O)CCC1.CCOCC>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:8][CH:9]=1
Reactant: BrCCOCCBr
Reactant: CCOC(=O)Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCOC(=O)C1(c2ccc(F)cc2)CCOCC1
Temperature: 0 °C
Yield: 97 %

Procedure:
A mixture of NaH (1.7 g, 71 mmol) in 100 mL NMP stirred at 0° C., was treated dropwise with a mixture of ethyl 2-(4-fluorophenyl)acetate (5.2 g, 29 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (6.6 g, 29 mmol) in 20 mL ether. The mixture was allowed to warm to room temperature and stirred for 5 hours, M+1=253. The mixture was then carefully quenched with 100 mL H2O, and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The combined organic layers were then dried over anhydrous Na2SO4 and concentrated in vacuo to give 7.1 g of the crude product as a pale yellow oil. MS (m/z)=253 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][N:10]3[CH2:19][CH2:20][CH2:21][C:9]=23)[CH:5]=[CH:4][N:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>>[C:13]1([C:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:25][CH:22]([CH3:24])[CH3:23])[CH:7]=3)=[C:9]3[CH2:21][CH2:20][CH2:19][N:10]3[N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cc(-c2c(-c3ccccc3)nn3c2CCC3)ccn1
Reactant: CC(C)N
Product: CC(C)Nc1cc(-c2c(-c3ccccc3)nn3c2CCC3)ccn1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
In an autoclave, a mixture of 1.10 g (0.39 mmol) of 3-(2-fluoropyridin-4-yl)-2-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole and 1.5 ml of isopropylamine is heated at 140° C. After 16 h, the reaction mixture is concentrated under reduced pressure. After purification by column chromatography on silica gel (cyclohexane/ethyl acetate), 50 mg (35%) of the desired product are obtained; log P(HCOOH): 1.21; 1H-NMR (DMSO-d6): 7.81 (d, 1H), 7.36 (m, 5H), 6.28 (s, 1H), 6.21 (m, 2H), 4.15 (dd, 2H), 3.84 (m, 1H), 2.98 (dd, 2H), 2.59 (m, 2H), 1.08 (d, 6H).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:11]3[CH2:16][C:15](=[O:17])[C:14]([C:18](=O)[CH2:19][CH3:20])=[C:13]([OH:22])[CH2:12]3)=[CH:4][C:3]=2[O:2]1.Cl.[CH2:24]([O:26][NH2:27])[CH3:25]>>[CH2:24]([O:26][N:27]=[C:18]([C:14]1[C:15](=[O:17])[CH2:16][CH:11]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:12][C:13]=1[OH:22])[CH2:19][CH3:20])[CH3:25]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)OCCO3)CC1=O
Agent: Cl
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)OCCO3)CC1=O

Procedure:
2-[1-(Ethoxyimino)propyl]-5-(3,4-ethylenedioxyphenyl)-3-hydroxycyclohex-2-en-1-one was prepared from 5-(3,4-ethylenedioxyphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one and ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1 part (iv). The product was obtained as an oil and was characterized by proton nuclear magnetic resonance spectroscopy. Pmr spectrum (CDCl3 ; δ in ppm): 1.08-1.40 (6H, 2xt); 2.27-3.25 (7H, m); 4.00-4.24 (6H, m); 6.65-7.27 (3H, m); 15.00 (1H, brs).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=2[N:20]=1)[C@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:12]([O:11][C@H:9]([CH3:10])[C@H:8]([NH2:7])[C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=2[N:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
To a solution of [(1R,2R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propyl]carbamic acid tert-butyl ester (0.971 g, 2.0 mmol) in DCM (15 mL) was added TFA (8 mL) and the mixture stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 min, then the organic fraction was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound (100 mg, 13%). LCMS (Method C): RT 2.59 min [M+H]+ 376.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9](=[CH:14][N:15]([CH3:17])[CH3:16])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1.O1CCCC1.CCOCC.N(C[C:39]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40])C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9](=[CH:14][N:15]([CH3:16])[CH2:17][C:39]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:40])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1
Reactant: CN(C)C=C1N=C(c2ccccc2Cl)c2cc(Br)ccc2N(C)C1=O
Reactant: CNCC(=O)N1CCOCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C=C1N=C(c2ccccc2Cl)c2cc(Br)ccc2N(C)C1=O)CC(=O)N1CCOCC1
Temperature: 160 °C

Procedure:
A suspension of 8.4 gm of 7-bromo-5-(2'-chlorophenyl)-1,3-dihydro-3-(dimethylamino-methylene)-1-methyl-2H-1,4-benzodiazepin-2-one in 45 gm of sarcosine morpholide was heated to 160°C, while stirring, whereby a clear solution was formed after some time, which was stirred for 90 minutes more at 160°C. Thereafter, the reaction mixture was allowed to cool and was then taken up in a mixture consisting of 150 ml each of tetrahydrofuran and ether. The resulting solution was washed three times with 100 ml of water each, and the organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was purified on a silicagel column, using a 19:1-mixture of chloroform and methanol as the flow agent. Those fractions containing the desired compound were combined, the solvent mixture was distilled off in vacuo, and the residue was recrystallized from tetrahydrofuran, yielding the compound of the formula ##SPC8##
Reaction SMILES: [CH:1]1([C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])[CH2:3][CH2:2]1.Cl.[NH2:11]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]1([C:4]2[O:9][N:11]=[C:6]([CH3:7])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C2CC2)on1
Yield: 81.3 %

Procedure:
A mixture of 1-cyclopropylbutan-1,3-dione (65.3 g), hydroxylamine hydrochloride (36.6 g) and anhydrous potassium carbonate (71.8 g) in ethanol (375 ml) was stirred and heated at reflux for 2 hours. The mixture was cooled and filtered and the filtrate was evaporated to dryness. The residue was distilled under reduced pressure to give 5-cyclopropyl-3-methyl isoxazole containing approximately 20% 3-cyclopropyl-5-methylisoxazole (51.85 g) as a clear oil, b.p. 74° C./12 mm.Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:19](Cl)(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C1C=CC=CC=1>[C:19]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)OCc1ccccc1[N+](=O)[O-]

Procedure:
In 100 ml benzene were mixed 2-nitrobenzyl alcohol (7.65 g, 0.05 mol) and triethylamine (5.06 g, 0.05 mol). To the solution octadecanoyl chloride (15.14 g, 0.05 mol) was added dropwise with stirring. The mixture was stirred an additional one hour and the precipitated triethyl amine hydrochloride was removed by filtration. The filtrate was evaporated to dryness and the residue crystallized from ethanol (yield 13.0 g, m.p. 60°-61° C.). The tetradecanoate (m.p. 46° C.) (Compound 5), hexadecanoate (m.p. 54° C.) (Compound 6), heptadecanoate (m.p. 48° C.) (Compound 7), and 9-octadecenoate (Compound 8) esters of 2-nitrobenzyl alcohol were similarly prepared using corresponding acyl chlorides in place of octadecanoyl chloride.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([OH:14])[C@@H:12]([CH2:15]Br)[O:11][C@H:10]1[N:17]1[CH:24]=[CH:23][C:21](=[O:22])[NH:20][C:18]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([CH2:15][C@H:12]1[O:11][C@@H:10]([N:17]2[CH:24]=[CH:23][C:21](=[O:22])[NH:20][C:18]2=[O:19])[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:13]1[OH:14])=[N+:26]=[N-:27]
Reactant: O=c1ccn([C@@H]2O[C@H](CBr)[C@@H](O)[C@H]2OCc2ccccc2)c(=O)[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OCc2ccccc2)[C@@H]1O
Temperature: 60 °C
Yield: 38.6 %

Procedure:
2'-O-Benzyl-5'-bromo-5'-deoxyuridine (4.3 g) was dissolved in DMF (86 ml) and sodium azide (7 g) added. The mixture was stirred and heated at 60° C. for 45 mins. After cooling and decanting from unreacted sodium azide the DMF was evaporated to dryness. The residue was dissolved in ethyl acetate and washed twice with water, dried and evaporated to dryness. The residue was chromatographed on Merck silica gel (Art. 9385). Elution with 10% methanol in toluene gave 1.5 g of pure 5'-azido-2'-O-benzyl-5'-deoxyuridine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[NH:41]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH:43]=[N:42]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2cn[nH]c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Yield: 42.9 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (24 mg, 0.048 mmols), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (28 mg, 0.144 mmols), potassium carbonate (40 mg), and Pd(PPh3)4 (3 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (10 mg, 43%)
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([O:16][CH3:17])[CH:15]=1)[O:12][C:11]([CH3:19])([CH3:18])[CH:10]=[C:9]2[CH2:20][OH:21].Cl>C1COCC1>[OH:21][CH2:20][C:9]1[C:8]2[C:13](=[C:14]([O:16][CH3:17])[CH:15]=[C:6]([CH:2]=[O:1])[CH:7]=2)[O:12][C:11]([CH3:19])([CH3:18])[CH:10]=1
Reactant: COc1cc(C2OCCO2)cc2c1OC(C)(C)C=C2CO
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(C=O)cc2c1OC(C)(C)C=C2CO

Procedure:
The above prepared (6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromen-4-yl)-methanol was dissolved in 3 ml of THF and treated at 0° with 1.5 ml of 3N HCl. 60 min. later, the reaction mixture was poured onto crushed ice/AcOEt, the organic layer washed with water and brine, dried over magnesium sulfate and evaporated to dryness. Flash chromatography (SiO2 with n-hexane/AcOEt=1/1) afforded 123 mg of the title compound as colourless, viscous oil.