Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Yield: 99.8 %

Procedure:
4-(4-Nitrophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (20 g, 65 mmol) was dissolved in anhydrous ethanol (250 mL) and 10% Pd/C (1.8 g) was added. The mixture was stirred for 1.5 h under 10 psi of hydrogen and filtered through a Celite pad. The pad was washed with ethyl acetate (3×100 mL) and the combined solution was evaporated in vacuo to yield 4-(4-aminophenyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (18 g, 98% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>C1C=CC=CC=1>[C:16]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Cl
Reactant: OCCCCCCBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCCCCBr
Yield: 65.2 %

Procedure:
Into a reactor, 30 g of 6-bromo-1-hexanol, 18.4 g of triethylamine, and 500 ml of benzene were charged, to which a solution of 16.5 g of acryloyl chloride in 200 ml of benzene was added dropwise, while stirring and cooling with ice, and stirred for 3 hours to give a reaction solution. The reaction solution was washed with a 3N-HCl and then with water, dried over sodium sulfate anhydride, and thereafter the solvent was evaporated and the residue was purified by the silica gel column chromatography (eluent; toluene) to give 25.4 g (Y., 65.1%) of 6-bromohexyl acrylate.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:24][NH2:25].[BH4-].[Na+].[OH-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:25][CH2:24][C:23]2[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:21]([C:20]([F:19])([F:33])[F:34])[CH:22]=2)[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)OC(=O)N1CCCC(=O)c2ccccc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 5-Oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (283 mg, 1.14 mmol), 3,5-Bis(trifluoromethyl)benzylamine (304 mg, 1.25 mmol) and titanium(IV) isopropoxide (0.43 ml, 1.43 mmol) was stirred at room temperature for 6 hours. The mixture was diluted with methanol (5 ml) and treated with sodium borohydride (65 mg, 1.71 mmol), then stirred at room temperature for 18 hours. The mixture was treated with 0.1N NaOH (25 ml) and stirred for 10 minutes, then filtered through Celite. The filtered residue washed successively with diethyl ether and dichloromethane. The filtrate was transferred to a separatory funnel and the organic layer was separated, dried (Na2SO4) and concentrated to provide crude 5-(3,5-Bis-trifluoromethyl-benzylamino)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester, which was elaborated without purification.
Reaction SMILES: C1(S[CH2:8][N:9]2[S:13](=[O:15])(=[O:14])[N:12]3[CH2:16][CH2:17][CH2:18][CH:11]3[C:10]2=[O:19])C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][CH2:8][N:9]1[S:13](=[O:15])(=[O:14])[N:12]2[CH2:16][CH2:17][CH2:18][CH:11]2[C:10]1=[O:19]
Reactant: O=C1C2CCCN2S(=O)(=O)N1CSc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C1C2CCCN2S(=O)(=O)N1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 2-phenylthiomethyl-tetrahydropyrrolo[1,2-b]1,2,5-thiadiazol-3(2H)-one 1,1-dioxide (5 g) in 130 ml of methylene chloride was added sulfuryl chloride (2.02 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo, the residue triturated in hexane (2x, 150 ml, 75 ml) with stirring, the solvent decanted, and the resulting solid filtered and dried to afford 2.96 g (92%) of 2-chloromethyltetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3(2H)-one 1,1-dioxide (Formula II: R1 =H; R2 and R3 together =-(CH2)3 -; X'=Cl) as a solid, m.p. 46.5°-47.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=O>>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1/[CH:18]=[C:9]1/[C:10](=[O:11])/[C:12](=[CH:18]/[C:17]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=2[O:15][CH3:14])/[O:13][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[O:8]/1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Product: COc1ccc(/C=C2\Oc3ccc(C)cc3O/C(=C\c3ccc(OC)cc3OC)C2=O)c(OC)c1

Procedure:
Calone is reacted with 2,4-dimethoxybenzaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(2,4-dimethoxyphenyl)-meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:10](=O)([OH:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([O:11][C:10]([N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: c1cc2c(s1)CCNC2
Reactant: CC(C)(C)OC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine (1.3 g, 9.0 mmol) was dissolved in dichloromethane (25 ml), and the solution was mixed with t-butyl bicarbonate (3.1 ml, 13 mmol) and triethylamine (1.3 ml, 9. 0 mmol) and stirred at room temperature for 13 hours. The reaction solution was mixed with dichloromethane, washed with water and saturated brined and dried with anhydrous sodium sulfate. When the solvent was removed by evaporation from the organic layer under a reduced pressure and the thus obtained material was separated and purified by a silica gel column chromatography, it was able to isolate a part of the title compound, but the most part was obtained as its mixture with t-butyl bicarbonate (total yield, 2.3 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].Br[CH2:14][CH2:15][C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][C:17]=1[Cl:31].C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[Cl:31][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][C:16]=1[CH2:15][CH2:14][NH:1][C@@H:2]([CH3:12])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[O:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCBr)c(Cl)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
(1R,2S)-2-Amino-1-(4-hydroxyphenyl)propan-1-ol (70 mg) and ethyl 2-[4-(2-bromoethyl)-3-chlorophenoxy]-2-methyl-propionate (147 mg) were dissolved in N,N-dimethylformamide (2 ml), N,N-diisopropylethylamine (118 μl) was added to the solution, and the mixture was stirred for 2.5 hours at 80° C. After the reaction mixture was cooled, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate/ethanol=20/1) gave ethyl 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]-2-methylpropionate (98 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][N:15]([C:28]([C:30]2[N:31]=[CH:32][N:33]([CH3:35])[CH:34]=2)=[O:29])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>CN(C=O)C.[Cl-].C([N+](CC)(CC)CC)C>[F:25][C:24]([F:26])([F:27])[O:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:15]([CH2:14][CH:11]1[CH:12]2[CH:10]1[CH2:9][N:8]([CH2:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:13]2)[C:28]([C:30]1[N:31]=[CH:32][N:33]([CH3:35])[CH:34]=1)=[O:29]
Reactant: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CN(C(=O)OC(C)(C)C)CC32)c1
Reactant: O=C(CBr)OCc1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)CC2C3CN(CC(=O)OCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring solution of 6-{[(1-Methyl-1H-imidazole-4-carbonyl)-(3-trifluoromethoxy-benzyl)-amino]-methyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester prepared above (2.63 gm, 5.63 mmol) in 30 mL DMF was added potassium carbonate (3.89 gm, 28.2 mmol), tetraethylammonium chloride (150 mg), followed by benzyl 2-bromoacetate (0.88 mL, 5.63 mmol). The reaction was stirred at room temperature for 20 hours and quenched with water. The mixture was diluted with ethyl acetate, the layers separated and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to yield 2.8 gm of crude material. The crude material was purified by flash chromatography to yield 2.7 gm of benzyl 2-(6-((N-(3-(trifluoromethoxy)benzyl)-1-methyl-1H-imidazole-4-carboxamido)methyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)acetate; MS (M+1) 543.3.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([C:21]#[N:22])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:24][CH2:25][C:26]1[C:42]([F:43])=[CH:41][C:29]([O:30][Si](C(C)C)(C(C)C)C(C)C)=[CH:28][C:27]=1[F:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C.CC(O)=O>[F:43][C:42]1[CH:41]=[C:29]([OH:30])[CH:28]=[C:27]([F:44])[C:26]=1[CH2:25][CH2:24][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:21]#[N:22])=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1-c1ccccc1
Reactant: CC(C)[Si](Oc1cc(F)c(CCBr)c(F)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(CCc2c(F)cc(O)cc2F)n2cnnc2)cc1-c1ccccc1
Reaction time: 48 h
Yield: 49 %

Procedure:
NaH (60% dispersion in mineral oil, 0.039 g, 0.98 mmol) was added to a solution of 5-(4H-1,2,4-triazol-4-ylamino)biphenyl-2-carbonitrile (CAB06022) (0.23 g, 0.88 mmol) in DMF (5 mL). After stirring for 30 minutes a solution of PMW04158 (0.38 g, 0.97 mmol) in DMF (3 mL) was added and stirring was continued for 48 h. TBAF (1M in THF, 1.35 mL) was added and after 30 minutes the reaction mixture was poured onto H2O (15 mL) and acidified with 3M aq. AcOH. The product was extracted with EtOAc (0.3×25 ml) and the combined organics were washed with H2O (4×50 ml) and brine (50 mL) then dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified using the Combiflash system (CHCl3/Acetone) to give the title compound (0.18 g, 50%) as a white solid; 1H NMR (270 MHz, DMSO-d6) 2.81 (2H, t, J=7.5, CH2), 4.01 (2H, t, J=7.5, CH2), 6.41-6.51 m, ArH), 6.61 (1H, d, J=2.2, ArH), 7.45-7.56 (5H, m, ArH), 7.83 (1H, d, J=8.8, ArH), 8.93 (2H, s, NCHN), 10.40 (1H, s, OH); HRMS (ESS) calcd. for C13H18F2N5O1 (M++1) 418.1474. found 418.1466; LC/MS (ES+) tr=1.39 min, m/z 418.0 (M++1, 100%).
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=O.[NH2:15][CH2:16][CH:17]([OH:29])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1>CCO>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][N:19]1[CH2:18][CH:17]([OH:29])[CH2:16][NH:15][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[I:1]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1ccccc1I
Solvent: CCO
Product: O=C(COc1ccccc1I)NCC(O)CN1CCc2ccccc2C1
Temperature: 80 °C
Yield: 95 %

Procedure:
To a solution of ethyl 2-(2-iodophenoxy)acetate (900 mg, 2.94 mmol) in EtOH (3 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (677 mg, 3.24 mmol). The reaction mixture was heated under microwave conditions at 80° C. for 3 h, cooled and concentrated. The crude product was used in the next step without further purification. (1.3 g, yield 95%) MS (ESI+) e/z: 467.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.80 (dd, J=1.0, 7.8 Hz, 1H), 7.41-7.30 (m, 1H), 7.15-7.05 (m, 3H), 7.05-6.99 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.87-6.76 (m, 1H), 4.66-4.53 (m, 2H), 4.06 (quin, J=5.9 Hz, 1H), 3.77-3.63 (m, 2H), 3.58 (dd, J=4.5, 13.6 Hz, 1H), 3.38 (dd, J=6.4, 13.7 Hz, 1H), 2.98-2.86 (m, 2H), 2.86-2.76 (m, 2H), 2.66-2.57 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].N1C=CC=CC=1>C(Cl)Cl>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=1)(=[O:26])=[O:27])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
2-Aminobenzophenone (20 mg) was dissolved in 1 mL of methylene chloride and 4-nitrobenzenesulfonyl chloride (34 mg, 1.5 equiv) was added thereto followed by pyridine (16 mL, 2 equiv). After 10 minutes the reaction mixture was oncentrated in vacuo, subjected to flash chromatography (eluting with 0% to 25% EtOAc/hexane) to provide N-(2-benzoylphenyl)-4-nitrobenzenesulfonamide. ESMS, M+H+ found: 383.1.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](=N)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)C>[C:11](=[N:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C#N)c(N)c1
Solvent: CC(Cl)Cl
Product: Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Yield: 78.1 %

Procedure:
To a solution of 2-amino-4-methyl benzonitrile (20 g, 151 mmol) in 1000 mL of dichloroethane is added benzophenone imine (30 g, 166 mmol). The solution is refluxed for 48 hours After this time, the solution is cooled to ambient temperatures. The solution is washed with sat. NaHCO3, water and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated under vacuum. The product is further purified by recrystallization from t-butyl ether. The title compound (25.5 g, 118 mmol) is obtained as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ7.88 (m, 2H), 7.42 (m, 3H), 7.32 (m, 7H), 6.79 (d, 1H), 6.58 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7](Cl)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:25]([O:31][C@@H:32]1[C@H:36]([O:37][S:38]([CH3:41])(=[O:40])=[O:39])[C@@H:35]([CH2:42][O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])[O:34][C@H:33]1[N:50]1[CH:57]=[CH:56][C:54]([NH2:55])=[N:53][C:51]1=[O:52])(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(Cl)(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:55][C:54]2[CH:56]=[CH:57][N:50]([C@@H:33]3[O:34][C@H:35]([CH2:42][O:43][C:44](=[O:49])[C:45]([CH3:46])([CH3:47])[CH3:48])[C@@H:36]([O:37][S:38]([CH3:41])(=[O:40])=[O:39])[C@H:32]3[O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:51](=[O:52])[N:53]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@H](OC(=O)C(C)(C)C)[C@@H]1OS(C)(=O)=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(Nc2ccn([C@@H]3O[C@H](COC(=O)C(C)(C)C)[C@@H](OS(C)(=O)=O)[C@H]3OC(=O)C(C)(C)C)c(=O)n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
4,4'-Dimethoxytrityl chloride (685 mg, 2.02 mmol) was added to a solution of Compound C5 (825 mg, 1.69 mmol) in anhydrous pyridine (4 ml) and the mixture was stirred at room temperature for 3 hours. After cooling, aqueous 50% pyridine was added to decompose an excess of the reagent, and the mixture was extracted with ether containing a small amount of chloroform. The organic layer was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The organic solvents were evaporated, the remaining pyridine was removed as the toluene azeotrope and the residue was subjected to silica gel chromatography [eluant; chloroform-ethyl acetate-triethylamine (80:20:1)]to give 1.280 g of the desired compound, C6 (yield 96%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:31])[C:13]2[CH:18]=[N:17][C:16](S(C)(=O)=O)=[N:15][C:14]=2[N:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:24]=1)=[O:10])[CH3:7]>>[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:31])[C:13]2[CH:18]=[N:17][C:16]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:14]=2[N:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:24]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: COCCN
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCOC)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 2-methoxy-ethylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (27 mg, 0.07 mmol). 8-Cyclohexyl-5-oxo-2-(2-methoxy-ethylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (20 mg, 80%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C19H26N4O4: 375.2 (M+H). Found: 375.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:11]Br.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[C:8]([Br:11])=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2occc12
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nccc2occ(Br)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
To the solution of 4-chloro-furo[3,2-c]pyridine (4.2 g, 0.03 mol) In CCl4 (77 ml) was added Br2 (2.4 ml, 0.046 mol) at 0° C. and the resultant reaction mixture was stirred for 4 hours at room temperature. The resultant suspension was poured into the mixture of ethyl acetate and 10% Na2SO3. The corresponding organic phase was separated and dried over Na2SO4 and concentrated in vacuo. The crude residue was dissolved in THF (100 ml) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (5.6 ml) was added at 0° C. The resultant reaction mixture was stirred for 2 hours at room temperature and poured into NaHCO3 and ethyl acetate. The organic layers were separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on a silica gel column to afford the titled compound (5.4 g) 1H NMR (400 MHz, CDCl3) ppm 8.32 (d, J=5.8 Hz, 1H), 7.72 (s, 1H), 7.44 (d, J=5.8 Hz, 1H), 7.26 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]2)[CH:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:3]1.[H-].[Na+].I[CH3:27]>CN(C=O)C>[CH3:27][N:3]1[CH:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NC2c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCCN(C(=O)OC(C)(C)C)C2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A stirred solution of rac-tert-butyl 1-oxo-3-phenyl-2,6-diazaspiro[3.5]nonane-6-carboxylate (1.18 g, 3.73 mmol) in DMF (20 ml) was cooled to 0° C. and treated with NaH (194 mg, 4.85 mmol) followed by iodomethane (303 ul, 4.85 mmol). The mixture was left to warm to room temperature. After 5 hours, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was separated and washed with brine, dried (MgSO4) and concentrated in vacuo to yield a the title compound as a yellow oil;
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:6]1=[O:15]
Reactant: COC(=O)CBr
Reactant: NC1Cc2ccccc2NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(N)Cc2ccccc21
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Sodium hydride (60% in oil, 2.52 g, 63.0 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1 h)-one hydrochloride (J. Med. Chem. 28, 1985, 1511–16; 5.0 g, 25.2 mmol), in anhydrous DMF (100 mL) at 0° C. over a period of 5 min keeping the internal temperature at <10° C. The reaction was stirred for a further 30 min before addition of methyl bromoacetate (2.85 mL, 30.2 mmol), then stirred for a further 60 min. The reaction was quenched by addition of 1M aqueous HCl (5 mL) and the volatiles were removed by evaporation. The residue was dissolved in DCM (250 mL) and washed with sat. aqueous NaHCO3 (100 mL) and the organic layer was dried (MgSO4), filtered and evaporated to yield the title compound (5.89 g, 100%) as yellow paste which was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]4[N:14]=3)[C@@:11]([CH2:26][OH:27])([CH3:25])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([C:22]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:23])=[C:15]4[N:14]=3)[C@@:11]([CH2:26][OH:27])([CH3:25])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@@]1(CO)CC[C@H](c2cncc(F)c2)N1c1ccn2ncc(C(=O)O)c2n1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1cnn2ccc(N3[C@@H](c4cncc(F)c4)CC[C@@]3(C)CO)nc12

Procedure:
Prepared according to the method of Example 212, Step F, using 5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and isopropyl amine. The title compound was obtained as a white solid (7.2 mg, 46% yield). MS (apci) m/z=413.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].O.[CH:13]([NH2:15])=O>>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:13][N:15]=[C:4]2[OH:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: NC=O
Solvent: O
Product: Oc1ncnc2ccc(Br)cc12
Temperature: 165 °C
Yield: 95 %

Procedure:
A suspension of 2-amino-5-bromobenzoic acid (5.4 g, 25 mmol) in formamide (40 ml) was heated at 165° C. for 6 hours. After cooling to room temperature, water (100 ml) was added to the reaction mixture. The precipitate was collected by filtration, washed with water and dried over P2O5, yielding the title compound as a white solid (5.3 g, yield: 95%) which was characterized by its mass spectrum as follows: MS (m/z): 225 ([M+H]+, 100).