Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36][OH:37])[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:37][N:36]=[C:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(=NO)c1cccc(F)c1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
71 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 46 mg (0.30 mmol, 1.5 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 68 mg (72% of theory)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5]1.Cl[C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:20])[C:16]=1[C:17]([OH:19])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>CN(C)C=O.C(N(CC)CC)C>[Cl:20][C:15]1[C:16]2[C:17](=[O:19])[N:4]([CH3:3])[CH2:5][CH:6]([CH2:7][CH2:8][Cl:41])[O:9][C:11]=2[CH:12]=[N:13][CH:14]=1
Reactant: CN1CCC(O)C1
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CC(CCCl)Oc2cncc(Cl)c2C1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of 2.1 g (60% in oil, 0.052 mole) of sodium hydride in 125 ml of dimethylformamide heated to 60° C. under a nitrogen gas blanket was added a solution of 2.65 g (0.026 mole) of N-methyl-3-pyrrolidinol and 5.0 g (0.026 mole) of 3,5-dichloropyridine-4-carboxylic acid in 40 ml of dimethylformamide dropwise at such a rate as to maintain 60° C. Subsequent to this addition, the mixture was heated to 75° C. for 3 hr. The solvent was then removed by rotary evaporation (60° C., 5 mm). The entire solid residue was suspended in 150 ml methylene chloride and hydrogen chloride added until a pH of 3 was reached. To the resulting mixture was added 15 g (0.057 mole) of triphenylphosphine and 15 g carbon tetrachloride and the entire mixture heated to reflux. After 1 hr, 7.5 g (0.029 mole) of triphenylphosphine and 7.5 g carbon tetrachloride was added, followed by the same increments 1 hr later. The reaction was driven to completion by adding 20 ml of triethylamine. The reaction mixture was washed with 6×50 ml of 3N hydrochloric acid, dried over sodium sulfate, filtered and concentrated by rotary evaporation. To the residue was added ethyl acetate, which caused much tarry material to fall out of solution, leaving the desired product and triphenylphosphie oxide in solution. The mixture was chromatographed by column chromatography using silica gel as the stationary phase and ethyl acetate as eluent. Similar fractions were combined and ethyl acetate removed by rotary evaporation, yielding 0.6 g (7%), of white crystals, m.p. 134°-38° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][N:12]=1.N#N.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[F:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: N#Cc1cccnc1Cl
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccnc1-c1ccc(F)nc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To an oven-dried, N2-purged, 250-mL, round-bottomed flask containing a magnetic stir bar were added the commercially available 2-chloro-3-cyanopyridine (1.25 g, 9.00 mmol), the commercially available 2-fluoropyridine-5-boronic acid (845 mg, 6.00 mmol), and dichlorobis(triphenylphosphine)pallalium(II) (211 mg, 0.300 mmol). The flask was sealed with a septum and purged with N2 atmosphere. Anhydrous dioxane (45 mL) and a N2-purged solution of cesium carbonate (5.86 g, 18.0 mmol) in water (45 mL) were added via syringe. The reaction mixture was heated to ˜90° C. in an oil bath and stirred for 2 hours. The reaction was monitored by LC-MS. After cooling to room temperature, the solvent/volatiles were removed by rotary evaporator to give a thick brown oil. Water (75 mL) was added and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (4×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown solid. The product was recrystallized from ethyl acetate/hexanes to give 1.01 g (84%) of the title compound as a tan powder. MS (ESI+) m/z 200.0 (M+H)+; 1H NMR (DMSO-d6) δ 7.43 (dd, J=8.6, 2.9 Hz, 1H), 7.70 (dd, J=8.1, 5.1 Hz, 1H), 8.49 (d, J=1.7 Hz, 1H), 8.51 (d, J=1.7 Hz, 1H), 8.74 (d, J=2.7 Hz, 1H), 8.98 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:28]([C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]>C1COCC1.C(OCC)(=O)C>[C:28]([C:30]1[CH:31]=[C:32]([S:37]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 70.8 %

Procedure:
N-(2,4-Dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 18, 42.8 g, 170 mmol) was dissolved in anhydrous THF (600 mL) and stirred under a nitrogen atmosphere at −78° C. A 1M solution of LiHMDS in THF (238 mL, 238 mmol) was added dropwise over 30 minutes maintaining the temperature between −65° C. and −70° C. The reaction mixture was left at −78° C. for 5 minutes, then allowed to warm to −10° C. over 1.5 hours. Upon reaching −10° C., the brown reaction mixture was cooled to −78° C. again, and a solution of 3-cyano-4-fluorobenzene sulfonyl chloride (48.6 g, 221 mmol) in THF (200 mL) was added dropwise over 30 minutes maintaining the temperature between −65° C. and −70° C. The brown solution was allowed to warm gradually to ambient temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with a saturated ammonium chloride solution, and extracting with further ethyl acetate. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a brown residue. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution) to afford the title compound as a white solid (52.3 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[OH:8].[N:12]1([CH2:17][C:18]2[CH:23]=[C:22](C3C=CC(O)=CC=3)[C:21]([C:31]#[N:32])=[CH:20][CH:19]=2)[CH:16]=[N:15][CH:14]=[N:13]1>>[N:12]1([CH2:17][C:18]2[C:23]([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=3)=[CH:22][C:21]([C:31]#[N:32])=[CH:20][CH:19]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: N#Cc1ccc(Cn2cncn2)cc1-c1ccc(O)cc1
Product: N#Cc1ccc(Cn2cncn2)c(-c2ccc(O)c(Cl)c2)c1

Procedure:
The title compound was prepared from 15 and 3-chloro-4-hydroxyphenylboronic acid using similar conditions to those described for the synthesis of 19. Chromatography (EtOAc) eluted 52 as a white crystalline solid (0.089 g, 46%), mp 243-245° C.; 1H NMR δH (270 MHz, DMSO-d6) 5.46 (s, 2H), 7.05 (d, J=8.4 Hz, 1H), 7.15-7.23 (m, 2H), 7.44 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.80 (dd, J=1.7 Hz, 7.9 Hz, 1H), 7.98 (s, 1H), 8.43 (s, 1H) and 10.51 (br s, 1H); LCMS (APCI−) m/z (rel intensity) 311 (35, [37CIM+H]−), 309 (100, [35CIM+H]−); HRMS (ES+) m/z calcd. for C16H12ClN4O [M+H]+: 311.0694, found 311.0689.
Reaction SMILES: O1CCCC1.[CH3:6][S:7]([NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([Cl:17])=[O:16])=[CH:13][CH:12]=1)(=[O:9])=[O:8].[CH2:20]([N:22]([CH2:34][CH3:35])[CH2:23][CH2:24][NH:25][C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:33])[CH3:21].[OH-].[NH4+]>C(#N)C>[ClH:17].[CH2:34]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][N:25]([C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:33])[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([NH:10][S:7]([CH3:6])(=[O:9])=[O:8])=[CH:12][CH:13]=1)[CH3:35]
Reactant: CCN(CC)CCNc1c(C)cccc1C
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCN(CC)CCN(C(=O)c1ccc(NS(C)(=O)=O)cc1)c1c(C)cccc1C
Product: Cl
Temperature: 25 °C

Procedure:
To 15 mL of tetrahydrofuran under nitrogen atmosphere add 0.74 g (4.7 mmol) of 4-[(methylsulfonyl)amino]benzoyl chloride then add 0.89 g (0.40 mmol) of N,N-diethyl-N'-(2,6-dimethylphenyl)-1,2-ethanediamine. When the addition is complete allow the reaction to stir at reflux. Monitor the progress of the reaction by thin-layer chromatography (concentrated aqueous ammonium hydroxide: acetonitrile, 1:9). Upon completion of the reaction, cool the mixture to room temperature. Filter the resulting solid and wash the solid with tetrahydrofuran. Recrystallize from acetonitrile to provide the title compound.
Reaction SMILES: CCN(CC)CC.[C:8]([O:16][CH2:17][C:18]#[CH:19])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:20](=[N:22]/[OH:23])\[CH3:21]>C(Cl)(Cl)Cl>[C:8]([O:16][CH2:17][C:18]1[O:23][N:22]=[C:20]([CH3:21])[CH:19]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C/C=N/O
Reactant: C#CCOC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(COC(=O)c2ccccc2)on1
Reaction time: 8 h

Procedure:
To a solution of chloroform, Et3N (0.435 ml, 3.12 mmol), prop-2-ynyl benzoate (1 g, 6.24 mmol), and (E)-acetaldehyde oxime (0.571 ml, 9.37 mmol) at 0° C. was added bleach (23.12 ml, 18.73 mmol). The reaction was stirred overnight before the layers were separated and the aqueous extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (3-methylisoxazol-5-yl)methyl benzoate. m/z (ESI) 218 [M+H]+.
Reaction SMILES: [Na].[C:2]1([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[C:2]1([N:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:15]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(C=Nc2ccccc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=Nc2ccccc2)cc1
Yield: 69.4 %

Procedure:
(a) To 170 ml of absolute ethanol is added 1.48 g of sodium, and 8.4 g of 4-(N-phenylformimidoyl)phenol is added to the mixture at room temperature with stirring to prepare a solution. 12.5 g of ethyl 2-bromo-2-methylpropionate is added to the solution, and the mixture is refluxed under heating for 5 hours. After the reaction, the ethanol is distilled off. The residue is dissolved in ether and thereafter washed with 5% aqueous solution of sodium hydroxide and then with water. After drying the resulting mixture, the ether is distilled off to give 9.2 g of ethyl 2-[4-(N-phenylformimidoyl)phenoxy]-2-methylpropionate. Infrared absorption spectrum (liquid film) 1735, 1280, 1245, 1170, 1140, 1020 cm-1.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23].Cl.[OH-].[Na+]>CCO.O>[CH2:7]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[C:12]([N+:22]([O-:24])=[O:23])[CH:13]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Nc1ccc(Cc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Aminodiphenylmethane (5.00 g, 27 mmol) was added in portions to acetic anhydride (26 mL, 273 mmol) with rapid stirring. A solid mass formed which was liberated by the addition of 15 mL additional acetic anhydride. The reaction was allowed to cool to ambient temp, and nitric acid (2.0 mL, 41 mmol) was added slowly dropwise via addition funnel over 30 min. The homogeneous red mixture was allowed to stir overnight and poured into a rapidly stirring solution of 30 mL water, 7 mL conc. HCl, and 24 mL EtOH (exothermic!). The reaction was allowed to cool and was then heated to reflux for ˜4 h, cooled and poured onto ice and neutralized with 10N NaOH to pH 8-9. The aqueous layer was extracted 3×DCM and dried over sodium sulfate, filtered, and concentrated. The resulting dark red oil was purified by silica gel chromatography, ISCO 120 g, 0-20% EtOAc/hexanes, to give 4-benzyl-2-nitrobenzenamine as a red oil. MS (ESI) m/z: Calculated: 228.1; Observed: 229.0 (M++1).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of methyl 4-formylbenzoate (25 g) in methylene chloride (250 mL) is added successively N,N-dimethylethylenediamine (67 g), acetic acid (87 mL), and sodium triacetoxyborohydride (50.6 g). The mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and to the residue is added a saturated potassium carbonate solution. The mixture is extracted with ethyl acetate, and the organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give methyl 4-[[[2-(dimethylamino)ethyl]amino]methyl]-benzoate (31.9 g, yield; 89%) as a colorless oil. MS (APCI) m/z: 237 [M+H]+
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9](B4OC(C)(C)C(C)(C)O4)[CH:10]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.Br[C:24]1[CH:37]=[CH:36][C:27]([CH2:28][N:29]2[CH2:33][C@@H:32]([CH3:34])[O:31][C:30]2=[O:35])=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl>[CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:24]4[CH:37]=[CH:36][C:27]([CH2:28][N:29]5[CH2:33][C@@H:32]([CH3:34])[O:31][C:30]5=[O:35])=[CH:26][CH:25]=4)[CH:10]=3)[C:5]2=[O:22])[CH2:2][CH2:3]1
Reactant: C[C@@H]1CN(Cc2ccc(Br)cc2)C(=O)O1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cc2)C(=O)O1
Yield: 35.9 %

Procedure:
2-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (0.204 mmol, 60.9 mg) was mixed with (R)-3-(4-bromobenzyl)-5-methyloxazolidin-2-one (5F3) (0.185 mmol, 50 mg), tricyclohexylphosphine (0.022 mmol, 8.5 mg), tris(dibenzylidineacetone) dipalladium (0.009 mmol, 8.5 mg) and potassium phosphate (0.315 mmol, 66.7 mg) in dioxane (1mI) and water (0.5 ml). The mixture was heated to 130° C. for 10 minutes in the microwave before addition of DCM (3 ml) and water (2 ml). The phases were mixed and the organic phase collected using a hydrophobic fritted tube and concentrated under reduced pressure. Purification was achieved using basic HPLC to afford (R)-3-(4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)-5-methyloxazolid in-2-one (Example 5a) 24.1 mg (36%); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, 1H) 7.66 (d, 1H) 7.59 (m, 3H) 7.38 (d, 2H) 4.64 (m, 1H) 4.51-4.41 (m, 2H) 4.37 (s, 2H) 3.54 (m, 1H) 3.03 (m, 1H) 2.97 (m, 1H) 1.43 (d, 3H) 0.95-0.89 (m, 4H) m/z (M+H) 363.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][O:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][NH:8][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][O:11][CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCC(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COCCCC(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Carbazic acid tert-butyl ester (9.21 g) was dissolved in pyridine (120 ml), followed by addition of 4-methoxybutyric acid (9.06 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (20.0 g), and stirred at ambient temperature for 64 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was then washed with aqueous 1 mol/liter hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, N′-(4-methoxybutyryl)hydrazine carboxylic acid tert-butyl ester was obtained in yellow oil (9.30 g, 57%). The physico-chemical values are as follows.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:16][C:17]([NH2:19])=[O:18].C(N(CC)C(C)C)(C)C.[I-].[Na+]>C(#N)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:17]([NH2:19])=[O:18])[C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: NC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(N)=O
Yield: 88 %

Procedure:
A mixture of (R)-1-Boc-3-methylpiperazine (100 mg, 0.50 mmol), 2-bromoacetamide (103 mg, 0.75 mmol), N,N-diisopropylethylamine (129 mg, 1.00 mmol) and sodium iodide (7.5 mg, 0.050 mmol) in acetonitrile (2.0 ml) was subjected to microwave irradiation at 100° C. for 5 minutes. The mixture was filtered through a 5 g Strata™ SCX giga tube, eluting with dichloromethane, methanol and then 2 M ammonia in methanol, and purified by flash chromatography eluting with ethyl acetate to 17% (v/v) methanol in ethyl acetate to afford (R)-2-(4-Boc-2-methylpiperazin-1-yl)acetamide (114 mg, 0.44 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[C:11]1[C:12]([CH3:25])=[N:13][N:14]2[C:19](NCCN)=[CH:18][C:17]([CH3:24])=[N:16][C:15]=12.O1CCC(=O)CC1.C([BH3-])#N.[Na+].[ClH:37]>CO.CCOCC.C(O)(=O)C>[Cl:37][C:19]1[N:14]2[N:13]=[C:12]([CH3:25])[C:11]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=3[Cl:10])=[C:15]2[N:16]=[C:17]([CH3:24])[CH:18]=1
Reactant: Cl
Reactant: COc1cc(Cl)c(-c2c(C)nn3c(NCCN)cc(C)nc23)c(Cl)c1
Agent: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc(Cl)c(-c2c(C)nn3c(Cl)cc(C)nc23)c(Cl)c1
Reaction time: 1 h
Yield: 94 %

Procedure:
To a stirred solution of N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-ethane-1,2-diamine (3.32 g, 8.7 mmol) and tetrahydro-4H-pyran-4-one (1.8 g, 18 mmol) in methanol (60 mL)/acetic acid (1.6 g) was added sodium cyanoborohydride (1.1 g, 17 mmol), portionwise. After stirring 1 hour the reaction was concentrated under reduced pressure and then extracted from saturated aqueous sodium bicarbonate with ethyl acetate. The combined extracts were dried (Na2SO4), concentrated under reduced pressure to give the crude product as a colorless foam (4.1 g, quant). A solution of the product in ether (150 mL) was treated with 1 M ethereal HCl which generated a precipitate that was collected by vacuum filtration to give the title compound (4.1 g, 94%) as a pink solid: +APcI MS (M+1)+464; 1H NMR (methanol-d4) δ: 7.14 (s, 2H), 6.38 (s, 1H), 4.03 (dd, 2H), 3.94 (br t, 2H), 3.86 (s, 3H), 3.50-3.38 (m, 5H), 2.51 (s, 3H), 2.26 (s, 3H), 2.05 (m, 2H), 1.68 (qd, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:7]=1.[Mn]([O-])(=O)(=O)=[O:30].[K+]>ClCCl.O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]([CH3:26])([CH3:25])[CH2:9][C:10]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]([OH:30])=[O:17])=[CH:14][CH:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccc(C=O)cc1)C(F)(F)F
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccc(C(=O)O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
To a solution of 106 mg (0.266 mmol) 4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]benzaldehyde in 5 mL dichloromethane was added 42 mg (0.266 mmol) of potassium permanganate and the reaction stirred at room temperature. The reaction was monitored by TLC. After several hours, a few drops of water were added and the potassium permanganate dissolved. After 1 hour, a few drops of glacial acetic acid was added followed by 42 mg (0.226 mmol) of potassium permanganate. After 4 days, the reaction was filtered through diatomaceous earth. The pH of the filtrate was adjusted (pH 6) with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organics layers were washed with 1 N aqueous HCl, dried over magnesium sulfate, and concentrated to leave a light brown oil. The crude residue was concentrated from hexanes-diethyl ether to afford and off-white solid. Recrystallization from hexanes-diethyl ether gave 26 mg (24%) of the title compound, m.p. 174° C.-177° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][C:6]([F:24])=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.Cl.[F:26][C:27]1([F:33])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>C(N(CC)CC)C>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:24])[N:3]=[C:2]([N:29]1[CH2:30][CH2:31][CH2:32][C:27]([F:33])([F:26])[CH2:28]1)[C:11]([C:12]1[N:16]=[N:15][NH:14][N:13]=1)=[C:10]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Fc1cc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2cc1Cl
Reactant: FC1(F)CCCNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Fc1cc2nc(N3CCCC(F)(F)C3)c(-c3nn[nH]n3)c(-c3ccccc3)c2cc1Cl

Procedure:
The title compound was prepared in analogy to example 102 step C from 2,6-dichloro-7-fluoro-4-phenyl-3-(1H-tetrazol-5-yl)-quinoline (prepared as described in example 107 step B), 3,3-difluoro-piperidine hydrochloride and triethylamine. Off-white solid. MS (ESI): 445.4 (M+H)+.