Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:29]([N:13]1[C:12](=[O:24])[C:11]2([CH2:25][CH2:26][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:14]1=[O:23])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccc(F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccccc2)C(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione (12 mmol) and DMF (20 mL). Cool in an ice bath. Add NaH (18 mmol) in several portions. After the addition is complete, add benzyl bromide (18 mmol). Allow the reaction mixture to warm to ambient temperature. After 3 h, cool the reaction vessel using an ice bath and cautiously add 10% aqueous citric acid (20 mL). When gas evolution has ceased, pour into an additional 20 mL of 10% aqueous citric acid and extract using ethyl acetate (3×60 mL). Extract the combined organics with saturated aqueous NaCl, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]=[O:13]>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:12][OH:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1CCO
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromo-1-methyl-2-nitro-benzene (f-1) (0.01134 mol) and paraformaldehyde (0.009 mol) in DMSO (5 ml) and Triton-B (035 ml) was stirred at 50° C. for 2 hours, then cooled to room temperature and purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98.5/1.5; 35-70 μm). The pure fractions were collected and the solvent was evaporated. Yield: 1.18 g of 2-(4-Bromo-2-nitro-phenyl)-ethanol (f-2) (42%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[N:25]([C:26](=[O:55])[CH2:27][C@@H:28]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][C:39]=2[S:48]([C:51]([F:54])([F:53])[F:52])(=[O:50])=[O:49])[CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:24][CH2:23][O:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Si](OC[C@H]1COCCN1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C1(SC[C@H](NC2C=CC(S(=O)(=O)N)=CC=2S(C(F)(F)F)(=O)=O)CC(O)=O)C=CC=CC=1>>[Si:1]([O:18][CH2:19][C@@H:20]1[N:25]([C:26](=[O:55])[CH2:27][C@@H:28]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][C:39]=2[S:48]([C:51]([F:52])([F:54])[F:53])(=[O:49])=[O:50])[CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:24][CH2:23][O:22][CH2:21]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[Si](OC[C@H]1COCCN1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Product: CC(C)(C)[Si](OC[C@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Yield: 24 %

Procedure:
The title product (0.2 g, yield: 24%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 104. (R)-3-((tert-Butyldiphenylsilyloxy)methyl)morpholine, hydrochloride salt (INTERMEDIATE 107, 0.200 g, 0.24 mmol) and (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoic acid (INTERMEDIATE 8, 0.500 g, 1.00 mmol) were used as starting material. The title product was purified by column chromatography (ISCO, eluting with 0→100% DCM/10% MeOH in DCM).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([C:15]3[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:17]=[CH:18][CH:19]=3)[CH:14]=1)[O:11][C:10]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[CH:9][C:8]2=[O:33])=[O:4]>CO.[Rh].[Pd]>[CH3:34][N:2]([CH3:1])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=1)[O:11][C:10]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[CH:9][C:8]2=[O:33])=[O:4]
Reactant: CN(C)C(=O)c1cc(-c2cccn2C(=O)OC(C)(C)C)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: [Pd]
Agent: [Rh]
Solvent: CO
Product: CN(C)C(=O)c1cc(C2CCCN2C(=O)OC(C)(C)C)c2oc(N3CCOCC3)cc(=O)c2c1
Reaction time: 3.5 h
Yield: 49.7 %

Procedure:
A solution of tert-butyl 2-(6-(dimethylcarbamoyl)-2-morpholino-4-oxo-4H-chromen-8-yl)-1H-pyrrole-1-carboxylate (0.6 g, 1.28 mmol) in MeOH (10 mL) was hydrogenated over 5% Rh/Al2O3 (NanoThales CatCart cartridge, product ID THS 02118) with the H-Cube (Continuous flow hydrogenation apparatus HC-2.5S from THALES Nanotechnology Inc. Budapest H-1031; Zahony u.7.; Hungaria) at 10 bars, 50° C. and a flow rate of 1 mL/min. for 3.5 h with continuous recycling. The cartridge was replaced by a 10% Pd/c cartridge and hydrogenation was pursued for 6 h at 60 bars and 60° C. The mixture was evaporated to dryness to give a solid which was triturated in diethyl ether, filtered and dried under vacuum at 50° C. to afford pure tert-butyl 2-(6-(dimethylcarbamoyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate (0.30 g, 50%) as a white solid. The crude product was used as such for the next step. Mass Spectrum: m/z [M+H]+=472.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18]1/[C:19](=O)[O:20][CH2:21][CH2:22]/1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18]1/[C:19](=[S:33])[O:20][CH2:21][CH2:22]/1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\CCOC2=O)c1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\CCOC2=S)c1Cl
Yield: 75.9 %

Procedure:
A solution of (E)-3-[[2-[(2,6-dichloro-3-methyl-phenyl) amino]phenyl]methylene]-4,5-dihydro-2(3H)-furanone (386 mg, 1.11 mmol) and Lawesson's Reagent (273 mg, 0.68 mmol) in 15 mL of toluene is heated at reflux for 1.5 hours. The solution is concentrated in vacuo and purified by flash chromatography eluting with hexane:ethyl acetate (3:1) to provide 188 mg (47%) of (E)-3-[[2-[(2,6-dichloro-3-methylphenyl)amino]-phenyl]methylene]-4,5-dihydro-2(3H)-furanthione; mp=163°-165° C. dec.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[C:11](N)[C:12]=1[Cl:13])[C:9]([CH3:16])([CH3:15])[CH2:8][C:7]2([CH3:18])[CH3:17])=[O:3].S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[CH3:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([OH:20])[C:12]=1[Cl:13])[C:9]([CH3:16])([CH3:15])[CH2:8][C:7]2([CH3:18])[CH3:17])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)c1cc2c(c(N)c1Cl)C(C)(C)CC2(C)C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc2c(c(O)c1Cl)C(C)(C)CC2(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
21.1 g of (6-chloro-7-amino-1,1,3,3-tetramethyl-5-indanyl) methyl ketone are introduced into 48 ml of concentrated sulphuric acid and, after the warming to 50° C., the mixture is treated slowly with 140 ml of distilled water. After cooling down to 0°-5° C., there is introduced dropwise into the mixture over a period of 45 minutes a solution of 5.5 g of sodium nitrite in 20 ml of water. The resulting cold mixture is introduced dropwise while stirring over a period of 2 hours into a solution, held at 70° C., of 60 ml of water and 60 ml of concentrated sulphuric acid. The mixture is cooled, then introduced into ice-water and extracted three times with ether. The organic phase is washed with a sodium chloride solution, dried over sodium sulphate and freed from solvent under reduced pressure. The residue is purified by adsorption on silica gel using hexane/ether (19:1) for the elution. The (6-chloro-7-hydroxy-1,1,3,3-tetramethyl-5-indanyl) methyl ketone obtained from the eluate melts at 78°-80° C. after recrystallisation from hexane/ether.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH:15]=[O:16])=[CH:4][C:3]=1[CH2:19][OH:20].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].O.C(Cl)(Cl)Cl>ClCCl.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH:15]=[O:16])=[CH:4][C:3]=1[CH2:19][O:20][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1
Reactant: C1=COCCC1
Reactant: N#Cc1ccc(Oc2ccc(Br)c(CO)c2)c(C=O)c1
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Br)c(COC3CCCCO3)c2)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of 4-[4-bromo-3-(hydroxymethyl)phenoxy]-3-formylbenzonitrile (25.5 g, 76.8 mmol), 3,4-dihydro-2H-pyran (10.4 mL, 115 mmol), and dl-10-camphorsulfonic acid (356 mg, 2 mol %) in dichloromethane (300 mL) was stirred at room temperature for 2 h. Sodium carbonate (3 g) was added, and the mixture was poured into water/chloroform. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (85:15 hexane/ethyl acetate) to give 4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-formylbenzonitrile (28.0 g, 88%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.Br[CH2:14][CH2:15][CH2:16]Br>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:16][CH2:15][CH2:14]2)[CH:2]=1
Reactant: BrCCCBr
Reactant: CCOC(=O)Cc1cccnc1
Product: CCOC(=O)C1(c2cccnc2)CCC1

Procedure:
Prepared in a similar manner to that described above by reacting ethyl 2-pyridin-3-ylacetate with 1,3-dibromopropane to give ethyl 1-pyridin-3-ylcyclobutane-1-carboxylate which was then hydrogenated to give the desired compound as a brown oil (quantitative reaction).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([SH:9])[N:6]2[N:10]=[C:11]([C:13]([O:15]C)=O)[N:12]=[C:5]2[N:4]=1.[NH2:17][OH:18].Cl>CO>[SH:9][C:7]1[N:6]2[N:10]=[C:11]([C:13]([NH:17][OH:18])=[O:15])[N:12]=[C:5]2[N:4]=[C:3]([CH2:2][OH:1])[CH:8]=1
Reactant: NO
Reactant: COC(=O)c1nc2nc(CO)cc(S)n2n1
Agent: Cl
Solvent: CO
Product: O=C(NO)c1nc2nc(CO)cc(S)n2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59.8 %

Procedure:
Methyl 5-(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-2-carboxylate (100 mg) (0.416 mmol) are dissolved in about 5 ml of methanol. 275 mg (8.3 mmol) of hydroxylamine are added thereto at room temperature while stirring within 48 hours. The reaction mixture is made acid (pH 5.5) with 3N aqueous hydrochloric acid. The product is filtered off under suction and crystallized from methanol. There are obtained 60 mg of 7-mercapto-N-hydroxy-5-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidine-2-carboxamide as beige crystals of melting point 238°-239° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH:22]4[CH2:26][NH:27]C(OC(C)(C)C)=O)=[O:20])=[C:15]([Cl:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH:22]4[CH2:26][NH2:27])=[O:20])=[C:15]([Cl:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(NC(=O)c1ccc(C(=O)N2CCCC2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.25 g (0.446 mmol) of N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-chloro-4-[2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide (Example 9) is dissolved in 10 mL of dichloromethane and after the addition of 0.68 mL (8.9 mmol) of trifluoroacetic acid stirred for 1 hour at ambient temperature. After elimination of the volatile constituents in vacuo, the residue is taken up in ethyl acetate, the solution washed twice with 2 molar sodium hydroxide solution and three times with demineralized water, and dried over sodium sulfate. Finally, the solvent is eliminated in vacuo. Yield: 120 mg (58%; mixture of all four stereoisomers); Rf value: 0.10 (silica gel; dichloromethane/ethanol=9:1); C22H23Cl2N5O2 (460.36); mass spectrum: (M+H)+=460/462/464 (chlorine isotope).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH:16]([F:18])[F:17])[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:33][O:34][C:35]1[C:40]2[O:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:43]=3[C:39]=2[C:38]([CH:51](OC(=O)C2C=CC=CC=2)[CH2:52][C:53]2[C:58]([Cl:59])=[CH:57][N:56]=[CH:55][C:54]=2[Cl:60])=[CH:37][CH:36]=1>O1CCCC1.CN(C1C=CN=CC=1)C>[Cl:59][C:58]1[CH:57]=[N:56][CH:55]=[C:54]([Cl:60])[C:53]=1[CH2:52][CH:51]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([O:15][CH:16]([F:17])[F:18])=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:7]=1)[C:38]1[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[C:40]([O:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)[CH:39]=1
Reactant: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)c2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Reactant: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(C(Cc2c(Cl)cncc2Cl)OC(=O)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (268 mg, 1.04 mmoles) is dissolved in dry tetrahydrofuran (30 mL) and EDC (237 mg, 1.24 mmoles), HOBT (190 mg, 1.24 mmoles), TEA (0.172 mL, 1.24 mmoles), DMAP (30 mg) are added to the solution. The mixture is stirred at room temperature for 40 minutes, then Benzoic acid 1-(4-methoxy-8-nitro-dibenzofuran-1-yl)-2-(3,5-dichloro-pyridin-4-yl)-ethyl ester is added and the reaction mixture is stirred at 70° C. for 32 hours. The solvents are then evaporated and the crude mixture is purified by chromatography on SiO2 (hexane:AcOEt from 10:1 to 7:3) to afford 300 mg of the pure title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[OH:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH2:21][CH2:22]2)[CH:34]=[CH:35][C:36]=1[OH:37]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCOCC2)CC1)C1CC1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: O=C(c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1N1CCC(CN2CCOCC2)CC1)C1CC1
Yield: 61.7 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(morpholinomethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.065 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (34 mg, 0.200 mmol) to afford the desired product (20.3 mg, 62%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.73 (s, 1H), 8.29 (s, 1H), 8.04-7.98 (m, 2H), 7.71 (d, J=2.3 Hz, 1H), 7.54 (dd, J=8.4, 2.3 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 3.74-3.71 (m, 3H), 3.53 (d, J=12.7 Hz, 2H), 3.34 (s, 3H), 3.26-3.15 (m, 2H), 2.59-2.46 (m, 4H), 2.38 (d, J=6.7 Hz, 2H), 1.98 (d, J=12.9 Hz, 3H), 1.66-1.52 (m, 2H), 1.36-1.27 (m, 2H), 1.27-1.20 (m, 2H); ESI MS m/z 506 [C29H32ClN3O3+H]+; HPLC 98.0% (AUC), tR=10.44 min.
Reaction SMILES: [P:1]([OH:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].P(=O)(O)(O)[OH:10]>>[CH2:3]([O:2][P:1](=[O:10])([OH:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: O=P(O)(O)O
Reactant: CCOP(O)OCC
Product: CCOP(=O)(O)OCC

Procedure:
100 parts by weight of diethyl hydrogen phosphite and 50 parts by weight of phosphoric acid are mixed and reacted. The reaction is exothermic and the temperature of the reactants are keep below their boiling point for 30 minutes to 1 hour thereby producing a diethyl hydrogen-phosphoric acid compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CSC.B>C1COCC1>[C:4]1([C@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@@H](O)c1ccccc1
Temperature: 0 °C

Procedure:
To acetophenone (19.47 mL, 166.6 mmol) in THF (100 mL) was added (S)-(−)-2-methyl-CBS-oxazaborolidine (4.62 g, 16.6 mmol), and the reaction was cooled to 0° C. Borane methyl sulfide complex (2M in THF; 50 mL, 100 mmol) was added over 15 minutes, and the reaction was stirred at room temperature. Aqueous work-up gave the title compound.
Reaction SMILES: [NH:1]([CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[NH2:2].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])N(CCO)N=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:1]([CH:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)[N:2]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: NNC1CCOCC1
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCOCC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 4-hydrazinotetrahydropyran as described for compound 35. Crystallized from methanol. M.p. 175°-177° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].Cl.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.N1C=CC=CC=1.Cl>CN(C=O)C>[CH2:5]([O:4][C:2](=[O:3])[NH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([Br:10])=[CH:12][CH:13]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)COC(=O)Cl
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)COC(=O)NCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
Isobutyl chloroformate (0.152 ml, 1.17 mmol) was added to a solution of 4-bromo-benzylamine hydrochloride (200 mg, 0.899 mmol) and pyridine (0.182 ml, 2.25 mmol) in DMF (2.0 ml), and the mixture was stirred at room temperature for 1.5 hours. A 1 N aqueous HCl solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give (4-bromo-benzyl)-carbamic acid isobutyl ester (180 mg, 70%).
Reaction SMILES: [CH:1]12BC(C[CH2:7][CH2:8]1)CCC2.C(Br)C#C.[OH-].[Na+].[C:16]([O:20][C:21]([N:23]1[CH2:35][C@@H:34]([CH3:36])[N:33]2[C@H:25]([CH2:26][C:27]3[C:32]2=[N:31][C:30](Br)=[CH:29][CH:28]=3)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1.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.C(OCC)(=O)C.O>[C:16]([O:20][C:21]([N:23]1[CH2:35][C@@H:34]([CH3:36])[N:33]2[C@H:25]([CH2:26][C:27]3[C:32]2=[N:31][C:30]([CH:7]2[CH2:8][CH2:1]2)=[CH:29][CH:28]=3)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: B1C2CCCC1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C4CC4)nc3N21
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A suspension of 150.0 mg (1.23 mmol) 9-borabicyclo[3.3.1]nonane and 47 μl (0.62 mmol) propargyl bromide in 1 ml tetrahydrofuran was heated to reflux for 2 h. The mixture was cooled to room temperature then 0.61 ml (1.83 mmol) of a degassed 3M sodium hydroxide solution was added and after 1 h a mixture of 0.20 g (0.54 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) and 19.0 mg tetrakis(triphenylphosphine)palladium in 1 ml tetrahydrofuran was added. The mixture was heated to reflux for 16 h then cooled to room temperature and poured into water and ethyl acetate; the phases were separated. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with 1M aqueous sodium hydroxide solution and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with n-hexane as eluant to afford the desired product as a colorless oil (35.2%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C([O-])(O)=O.[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O>[CH2:13]([O:20][C:21]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
To the solution of azetidine-3-carboxylic acid (1 g, 10 mmol) of tetrahydrofuran/water (50 ml:50 ml) was added NaHCO3 (2.05 g, 25 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and adjusted to pH=2, extracted with ethyl acetate. The residue was dried in vacuum. 2.4 g of crude 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH2:20])[CH:16]=[CH:17][C:18]=1[F:19]>CN(C=O)C.C(OCC)(=O)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:2]2[C:3]3[CH:10]=[CH:9][N:8]([CH3:11])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cn1ccc2c(Cl)ncnc21
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 82.7 %

Procedure:
A mixture of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (398.8 mg, 2.4 mmol) and 3-chloro-4-fluoro-phenylamine (378 mg, 2.6 mmol) in DMF (6 mL) was stirred at room temperature for 2 minutes. To it was added silver triflate (672 mg, 2.6 mmol), the mixture was then stirred at 90° C. for 2 hours. The reaction was then diluted with ethyl acetate and filtered off the precipitate, washing the precipitate with 10% ammonia solution. The filtrate was extracted with ethyl acetate, dried and concentrated. The residue was triturated with ethyl acetate and filtered to give 549.1 mg (83%) of (3-chloro-4-fluoro-phenyl)-(7-methyl-7H-pyrrolo(2,3-d]pyrimidin-4-yl)-amine as an off-white solid. 1H NMR (300 MHz, DMSO-d6) 9.48 (s, 1H, NH), 8.35 (s, 1H), 8.29 (dd, J=2.7 & 6.8Hz, 1H), 7.75-7.80 (m, 1H), 7.37 (t, J=9.3 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 6.77 (d, J=3.1 Hz, 1H), 3.75. (s, 3H, CH3). MS 277 [M++1].