Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][CH:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:27])[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CCOCC>[CH2:7]([N:14]1[CH2:15][C@H:16]([CH3:27])[C@H:17]([NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1C(=O)N(Cc2ccccc2)CC1NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 35.3 %

Procedure:
To a suspension of lithium aluminum hydride (3.61 g) in absolute ether (150 ml) was added dropwise a solution of 1-benzyl-4-t-butoxycarbonylamino-3-methyl-2-oxopyrrolidine (14.46 g) in absolute ether (100 ml) with stirring for an hour at -5°~3° C. After stirring for an hour at 0° C., the reaction mixture as poured into ice-water and added 50% aqueous sodium hydroxide solution, the organic layer was separated, washed with water and saturated aqueous sodium chloride successively, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from acetonitrile to give the title compound (4.87 g) as colorless prisms, mp 134°-140° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[Br:19]Br>ClCCCl>[Br:19][C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:18])[C:6]3([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:17][CH2:16][CH2:15][C:13]=1[C:14]=23
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Reactant: BrBr
Solvent: ClCCCl
Product: O=C1Nc2ccc(Br)c3c2C1(CCCCBr)CCC3
Temperature: -20 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A 20 ml portion of 1,2-dichloroethane solution containing 0.50 g (1.62 mmol) of 2a-(4-bromobutyl)-2a,3,4,5-tetrahydrobenz[cd]-indole-2(1H)-one was cooled to −20° C. and mixed with 0.10 ml (1.94 mmol) of bromine. The reaction solution was stirred at −20° C. for 1 hour, extracted with chloroform and then washed with saturated sodium thiosulfate aqueous solution and saturated sodium bicarbonate aqueous solution in that order. After drying (Na2SO4), the solvent was evaporated under a reduced pressure, and the thus obtained residue was re-precipitated from ethyl acetate-hexane to obtain 0.54 g of the title compound (86% in yield).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9](O)=[O:10])=[CH:5][N:4]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+].[Na].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>C(OCC)C>[F:13][C:2]([F:1])([F:12])[C:3]1[N:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][N:8]=1
Reactant: O=C(O)c1cnc(C(F)(F)F)nc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [BH4-]
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: OCc1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To 0.2 g of 2-trifluoromethyl-pyrimidine-5-carboxylic acid 2 mL of diethyl ether were added, and the solution was cooled in ice-water bath to 0° C. Then 0.126 mL of N-methylmorpholine were added, followed by 0.135 mL of isobutyl-chloroformate. The reaction was left stirring for one hour at room temperature. The yellow solid formed was filtered and washed with diethyl ether. To the filtrate, 0.115 g (3.12 mmol) of sodium borohydride was then added at 0° C. and left stirring at that temperature for one hour. 5 mL of a saturated aqueous solution of sodium and potassium tartrate were then added and the mixture was extracted twice with ethyl acetate, dried with magnesium sulphate, filtered and concentrated to afford 0.09 g of (2-Trifluoromethyl-pyrimidin-5-yl)-methanol as an oil, which was used without further purification.
Reaction SMILES: CS(C)=O.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][CH2:15][C:6]=12.CCN(CC)CC.O>C(Cl)Cl>[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[CH2:11][C:12](=[O:16])[CH2:13][CH2:14][CH2:15][C:6]=12
Reactant: OC1CCCc2ncccc2C1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCCc2ncccc2C1
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
In an oven-dried 500 mL round-bottomed flask was OXALYL CHLORIDE (3.42 mL, 39.1 mmol) in CH2Cl2 (100 mL) to give a colorless solution at −55° C. under nitrogen. DMSO (5.54 mL, 78 mmol) was added dropwise over 10 min. After the solution was stirred for an additional 30 min, 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-6-ol (5.79 g, 35.5 mmol) (azeotroped with dry benzene) dissolved in 20 ml CH2Cl2 (plus 20 ml rinse) was added via canuula over 5 min. The reaction mixture was stirred at −50-−55° C. for an additional 40 min (the solution became milky). Et3N (24.74 mL, 178 mmol) was added via syringe at −50° C. and the reaction mixture was stirred for 30 min (Gel like and difficult to stir. Needs occasional shaking at ambient temperature). 100 ml water was added, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×100 ml). The combined organic layers were dried with Na2SO4, and concentrated to a tan oil with some solids. Purification by FCC up to 10% MeOH/CH2Cl2 afforded the desired product as an orange oil (4.947 g, 86% for 4 steps). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.28-8.38 (m, 1 H) 7.37 (d, J=7.63 Hz, 1 H) 7.00-7.13 (m, 1 H) 3.65 (s, 2 H) 3.10-3.18 (m, 2 H) 2.50-2.60 (m, 2 H) 2.01 (dd, J=6.71, 4.88 Hz, 2 H); 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 207.23 (s, 1 C) 160.24 (s, 1 C) 147.98 (s, 1 C) 137.20 (s, 1 C) 128.85 (s, 1 C) 122.25 (s, 1 C) 48.89 (s, 1 C) 43.96 (s, 1 C) 36.15 (s, 1 C) 24.70 (s, 1 C).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CN1CCOCC1>CN1CCCC1>[N:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]2)=[CH:15][CH:16]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)C1CCNCC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCN(c2ccncc2)CC1
Temperature: 100 °C

Procedure:
Ethyl isonipecotate (6.0 g, 38.66 mmol), 4-chloropyridine hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 g mL, 85.00 mmol), were dissolved in N-methylpyrrolidine (50 mL) and the resulting solution was heated at 100° C. for 48 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc and washed with water and brine (2×100 mL), then dried (Na2SO4) and evaporated. The resulting residue was purified by flash chromatography (5% MeOH/CHC13) to afford 8-1 as a crystalline solid.
Reaction SMILES: C1(NC2N3N=CC(C=O)=C3N=C([C:16]3[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=3)C=2)CC1.CCN=C=NCCCN(C)C.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.[CH3:52][O:53][CH2:54][CH2:55][CH2:56][NH2:57]>CN(C=O)C.C(OCC)(=O)C>[CH3:52][O:53][CH2:54][CH2:55][CH2:56][NH:57][C:21]([C:19]1[S:20][CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(C(=O)O)s3)nc12
Reactant: COCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCCNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (30 mg, 0.091 mmol), EDCI (19 mg, 0.10 mmol), Et3N (14 μL, 0.10 mmol), and HOBt (14 mg, 0.10 mmol) in 2 mL of DMF pre-stirred for 5 minutes was added 3-methoxypropylamine (10 μL, 0.10 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate, washed with H2O, brine, dried over MgSO4, filtered, and evaporated to dryness to provide 30 mg of 547-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-N-(3-methoxypropyl)thiophene-2-carboxamide (83%). LCMS (M+1=400)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].CCN(CC)CC>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: NO
Reactant: Cc1cc(C=O)ccc1Br
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C=NO)ccc1Br
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a mixture of 4-bromo-3-methyl-benzaldehyde (372 mg, 1.87 mmol) and hydroxylamine hydrochloride (306.5 mg, 4.41 mmol) in ethanol (5 mL) at rt was added Et3N (0.15 mL). The reaction mixture was heated under reflux for 2 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in EA (10 mL), washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 4-bromo-3-methylbenzaldehyde oxime (384 mg; yield 96%) as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][C@H:13]([CH3:28])[C@:14]2([OH:27])[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[F:36]C(F)(F)C([O-])=O.[Na+].[F-].[Na+].FF.S([O-])([O-])(=O)=S.[Na+].[Na+]>N1C=CC=CC=1.FC(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@:21]2([F:36])[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][C@H:13]([CH3:28])[C@:14]2([OH:27])[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[C@H](C)[C@]2(O)C(C)=O)C1
Agent: FF
Agent: O=S([O-])([O-])=S
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: FC(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4C[C@H](C)[C@](O)(C(C)=O)[C@@]4(C)CC[C@@]32F)C1
Yield: 50 %

Procedure:
3β-Acetoxy-17α-hydroxy-16β-methyl-5α-pregnan-20-one (1 g, prepared by treatment of the corresponding 3β-ol with acetic anhydride in pyridine) was dissolved in fluorotrichloromethane (250 ml) and chloroform (200 ml) containing sodium trifluoroacetate (ca. 2 g) and sodium fluoride (ca. 2 g). The resulting solution was cooled to -78° and vigourously stirred, whereupon fluorine from four 750 cc bottles (8-10% v/v fluorine in nitrogen) was added over 9-10 hours. The reaction solution was then poured into aqueous sodium thiosulphate and the organic layer was separated, washed with water, dried over potassium carbonate and evaporated to dryness. The residue was purified by liquid chromatography, eluting with cyclohexane containing 30% v/v ethyl acetate and 0.1% v/v pyridine, to yield 3β-acetoxy-9α-fluoro-17α-hydroxy-16β-methyl-5α-pregnan-20-one (50%); m.p. 150° (after recrystallisation from acetone); PMR spectrum includes signals at δ2.20 (21-Me), 2.00 (3-O.CO.CH3), 0.92 (19-Me) and 0.87 (18-Me); FMR φ*+179.5 ppm. (Found: C, 70.51; H, 9.20; F, 4.48; C24H37FO4 requires C, 70.55; H, 9.18, F, 4.65%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:15]3[C@H:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)[CH2:9][C:8]2=[O:16])[CH2:3][CH2:2]1.C[O-].[Na+].O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[O:16]=[C:8]1[CH2:9][C@@H:10]2[C@H:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]1[CH:4]1[CH2:3][CH2:2][N:1]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:6][CH2:5]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: O=C1C[C@H]2CCCCC2N1C1CCNCC1
Agent: C[O-]
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: CCOC(=O)N1CCC(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CC1
Temperature: 25 °C

Procedure:
The crude of (3aR)-1-piperidin-4-yloctahydro-2H-indol-2-one (110 mg) was dissolved in MeOH (3 mL) and sodium methoxide (25 μL) was added followed by ethyl 4-oxopiperidine-1-carboxylate (77 μL, 0.5 mmol. A solution of sodium cyanoborohydride (35 mg, 0.5 mmol) and zinc chloride (29 mg, 0.25 mmol) in MeOH (1 mL) was added drop wise at room temperature and the mixture was stirred at room temperature over night. The solvent was then removed under reduced pressure and the residue dissolved in dichloromethane (60 mL). Washed with 1N NaOH (5 mL) and brine, dried and concentrated in vacuo. The residue was purified by high pH Prep LCMS to provide the title compound. 1H NMR (400 MHz, METHANOL-D4): δ ppm 1.24 (t, J=6.45 Hz, 3H), 1.27-1.49 (m, 6H), 1.62 (d, J=12.50 Hz, 2H), 1.55-1.73 (m, 1H), 1.78 (d, J=9.77 Hz, 1H), 1.82-2.17 (m, 7H), 2.18-2.33 (m, 3H), 2.33-2.43 (m, 1H), 2.49 (t, J=12.11 Hz, 1H), 2.69-2.86 (m, 2H), 3.02 (t, J=10.94 Hz, 2H), 3.12 (t, J=10.16 Hz, 1H), 3.72-3.85 (m, 1H), 4.09 (q, J=7.03 Hz, 2H), 4.16 (d, J=12.89 Hz, 2H). MS (M+1): 378.3
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[H-].[K+]>C1COCC1.[Cl-].[Na+].O.C(O)(=O)C>[C:3]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1=[O:15])([O:6][CH3:7])=[O:8]
Reactant: COC(=O)OC
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCCCC1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 137.7 %

Procedure:
To sodium hydride (60% oil dispersion, 10 g) was added a solution of dimethyl carbonate (18.02 g, 200 mmol) in dry THF (50 mL). The mixture was stirred at reflux temperature (100° C.), and then, a solution of cyclohexanone (7.8 g, 80 mmol) in dry THF (20 mL) was added dropwise to the mixture using a syringe pump. After two minutes of addition, potassium hydride (30% oil dispersion, 0.9 g) was added to initiate the reaction. The addition of cyclohexanone was continued over a period of 1 h. The mixture was refluxed and stirred for an additional 30 min after complete addition of cyclohexanone, when the reaction mixture lumped. It was cooled down in an ice bath for 20 min. The mixture was hydrolyzed by the slow addition of 3M aqueous acetic acid (75 mL), then poured into brine (100 mL) and extracted with CH2Cl2 (150 mL×4). The combined organic layers were dried over MgSO4 and filtered. The filtrate was evaporated in vacuo to give a thick yellow liquid (17.2 g). The liquid was distilled under reduced pressure to give 2 (11.3 g, 91%) as a colorless liquid [bp 38-43° C. (0.05-0.075 mm Hg, bath temp: 75-78° C.)]. See Ruest et al., 1976.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[CH:16]=[CH:17][N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:21])=O>C(=O)(O)[O-].[Na+]>[Cl:21][C:13]1[N:12]2[CH:16]=[CH:17][N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: Oc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc(-c2cc3nccn3c(Cl)n2)c(Cl)c1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
12.0 g (42.84 mmol) of 7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-ol are introduced into 131.6 g (858.27 mmol) of phosphoryl chloride and heated at 120° C. for 5 h. A clear solution is produced after 10 min. The mixture is allowed to cool, and then 2000 ml of saturated aqueous sodium bicarbonate solution are cautiously added. Towards the end, about 100 g of solid sodium bicarbonate are also added, and the mixture is stirred at pH 7 for 10 min. The precipitate is filtered off with suction, thoroughly washed with water, suspended in a little isopropanol and sucked dry. It is then washed once more with petroleum ether and dried under high vacuum at 50° C. 11 g (81% of theory) of the product are obtained as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[O:46]1[CH2:47][CH2:48][N:43]([C:2]2[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=2)[CH2:44][CH2:45]1
Reactant: Nc1cncc(Br)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Nc1cncc(N2CCOCC2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-bromopyridin-3-amine (1.5 g, 8.67 mmol), X-Phos (0.33 g, 0.69 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.32 g, 0.35 mmol) and morpholine (3.78 g, 43.3 mmol) in THF (17.3 mL) was added a 1.0M solution of lithium bis(trimethylsilyl)amide in THF (47.7 mL, 47.7 mmol). The resulting mixture was heated to 65° C. and stirring continued for 3 h. After which, the reaction was cooled to rt and then poured into water (100 mL) and extracted with EtOAc (2×150 mL) and DCM (2×150 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0 to 100% DCM in EtOAc) to give 5-morpholinopyridin-3-amine. Mass Spectrum (ESI) m/e=180.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[S-:8][C:9]#[N:10].CN([S+](N(C)C)N(C)C)C>C(#N)C>[CH2:2]([S:8][C:9]#[N:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: N#C[S-]
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CC#N
Product: CCCCCCSC#N
Reaction time: 3 h
Yield: 85 %

Procedure:
A 7.4-g (0.45 mole) sample of 1-bromohexane was added at ambient temperature to a stirred solution of 11.1 g (0.05 mole) of tris(dimethylamino)sulfonium thiocyanate in 25 ml acetonitrile, and the rate of the reaction was followed by gas-liquid partition chromatography (glc). The reaction was one-half completed after 3 hr, and was essentially completed after 20 hr. The reaction mixture was poured into water and extracted with ether. The ether extract was dried (MgSO4) and distilled to give 5.47 g (85%) of n-hexyl thiocyanate as a colorless liquid, bp 93°-94° (10 mm).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.[OH-].[Na+].O>[N+:10]([C:7]1[CH:6]=[C:3]([C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: Sc1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 480 g of 2-chloro-5-nitro-benzaldehyde in 3.2 litres of ethanol is treated dropwise under a nitrogen atmosphere at 30°-40° C with stirring within 4 hours with a solution of 320 g of thiophenol in 120 g of sodium hydroxide, 2 litres of ethanol and 440 ml of water. The mixture is stirred for a further 30 minutes at 60° C, then cooled to 0° C and filtered. There is obtained crude crystalline 3-nitro-6-(phenylthio)-benzaldehyde of melting point 96°-100° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[C:31]([F:44])[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:33]=[CH:34][C:29]([O:28][C:27]4[CH:45]=[CH:46][CH:47]=[C:48]([F:49])[C:26]=4[F:25])=[CH:30][C:31]=3[F:44])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3F)cc2F)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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3F)c3c(N)ncnc32)C1
Yield: 51.1 %

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.8 g, 6.16 mmol, 1.0 eq), 2-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 6.16 mmol, 1.0 eq), Pd(PPh3)4 (0.28 g, 0.08 mmol, 0.07 eq) and Na2CO3 (1.7 g, 15.4 mmol, 2.5 eq) in dioxane/H2O (40/10 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated and purified by Pre-TLC to afford (R)-tert-butyl 3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (1.7 g, 51.1% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH2:9])[CH:8]=1.Br[C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH:11]=2)=[C:7]([NH:9][C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:36][CH:37]=2)[CH:8]=1
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(N)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(Nc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 97.8 %

Procedure:
A suspension of 5-methoxy-2-(6-methoxynaphthalen-2-yl)phenylamine (250 mg), 1-[2-(4-bromophenoxy)ethyl]piperidine (250 mg), tris(dibenzylideneacetone)dipalladium(0) (46 mg), tri-tert-butylphosphine (14 mg) and sodium tert-butoxide (130 mg) in toluene (2 ml) was stirred for 2.5 hours under nitrogen atmosphere at 100° C. A saturated aqueous solution of ammonium chloride was added thereto, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (415 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](O)=[O:22])[CH:16]=2)=[C:11]([CH3:24])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:22])[NH:35][C:34]3[CH:36]=[CH:37][C:31]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:32][CH:33]=3)[CH:16]=2)=[C:11]([CH3:24])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ccc1-c1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(NC(=O)OC(C)(C)C)ccc1-c1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2)c1
Reaction time: 18 h

Procedure:
A mixture of 4′-tert-butoxycarbonylamino-2′-methyl-biphenyl-3-carboxylic acid (436 mg), 4-morpholin-4-yl aniline (238 mg), triethylamine (0.55 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (757 mg) in dry DMF (1 ml) was stirred at 20 C for 18 h. Water (50 ml) was then added and the resulting colourless precipitate was collected by filtration and dried (680 mg)