Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:24]=[CH:23][N:22]([CH3:25])[C:18]4=[CH:19][CH:20]=3)[O:15][CH:14]([OH:26])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl.CN(C)C1C=CN=CC=1>[C:33]([O:26][CH:14]1[CH2:13][CH:12]([C:4]2[CH:5]=[C:6]([O:10][CH3:11])[C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)[C:21]2[C:16](=[C:17]3[CH:24]=[CH:23][N:22]([CH3:25])[C:18]3=[CH:19][CH:20]=2)[O:15]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C2CC(O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C2CC(OC(C)=O)Oc3c2ccc2c3ccn2C)cc(Br)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of 4-(3-bromo-4,5-dimethoxyphenyl)-2-hydroxy-7-methyl-pyrrolo[2,3-h]chroman (37 mg, 0.089 mmol) in dichloromethane (0.5 ml) at 0° C. was added pyridine (0.010 ml, 0.133 mmol), 4-dimethylaminopyridine (1.0 mg, 0.0082 mmol) and acetic anhydride (0.010 ml, 0.111 mmol) and the resulting solution was stirred at 0° C. for 0.5 h. The solution was then stirred at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane and the organic solution was extracted with water and a saturated aqueous solution of sodium bicarbonate. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (20% ethyl acetate/hexane) to give 39 mg (90%) of the title compound. 1H NMR (CD3CN): 7.10 (dd, 1H); 7.02 (m, 1H); 6.94-6.84 (m, 2H); 6.72-6.60 (m, 1H); 6.53 (m, 1H); 6.43 (m, 1H); 4.38-4.19 (m, 1H); 3.80-3.74 (m, 9H); 2.56-2.40 (m, 1H); 2.32 (m, 1H); 1.96 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10](=[O:11])[C:9]2([CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12]2)[N:8](C(OC(C)(C)C)=O)[CH2:7][C@H:6]1[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)(O)=[O:2].[NH2:33][C:34]1[CH:35]=[C:36]2[C:49](=[CH:50][CH:51]=1)[CH2:48][C@:38]1([C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]1=[O:47])[CH2:37]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[F:31][C:29]1[CH:30]=[C:25]([C@H:6]2[N:5]([CH2:4][C:1]([NH:33][C:34]3[CH:35]=[C:36]4[C:49](=[CH:50][CH:51]=3)[CH2:48][C@:38]3([C:46]5[C:41](=[N:42][CH:43]=[CH:44][CH:45]=5)[NH:40][C:39]3=[O:47])[CH2:37]4)=[O:2])[C:10](=[O:11])[C:9]3([CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12]3)[NH:8][CH2:7]2)[CH:26]=[C:27]([F:32])[CH:28]=1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C2(COCCOC2)NC[C@H]1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21

Procedure:
0.114 g (0.25 mmol) tert-butyl (R)-4-carboxymethyl-3-(3,5-difluoro-phenyl)-5-oxo-8,11-dioxa-1,4-diaza-spiro[5.6]dodecane-1-carboxylate were stirred together with 67.9 mg (0.27 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 63.3 mg (0.33 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-hydrochloride, 44.6 mg (0.33 mmol) HOBt, 35 μl (0.25 mmol) TEA and 1.5 ml DMF, overnight at RT. The solvent was spun off and the residue was stirred with 15 ml of a methanolic hydrochloric acid (1.25N) for 1 h at 50° C. The reaction mixture was concentrated by rotary evaporation and the residue was purified by PR-HPLC. The product-containing fractions were concentrated by rotary evaporation and the residue was triturated with diisopropylether. After suction filtering the solid was washed with diisopropylether and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(OC(=O)N(C)C)c2ccccc2n1
Solvent: ClC(Cl)Cl
Product: Cc1cc(OC(=O)N(C)C)c2ccccc2[n+]1[O-]
Temperature: 0 °C

Procedure:
23 g (0.1 mole) of 2-methyl-4-dimethylaminocarbonyloxyquinoline were dissolved in 150 ml of dry chloroform free of alcohol and, while stirring and externally cooling with ice-water, 25 g 3-chloroperbenzoic acid (70% strength) dissolved in 400 ml chloroform were added dropwise.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:28])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (15.0 mg, 66.6 μmol) using the same procedure employed for Example 1 (2), but with 3-trifluoromethylphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a sticky oil (1.2 mg, 4%) having the following characteristics.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:50][C:45]2[CH:46]=[CH:47][CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCC[C@@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:50][C@@H:45]5[CH2:46][CH2:47][CH2:48][NH:49][CH2:44]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)N[C@@H]4CCCNC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-Boc-3-aminopiperidine. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC and basified using sodium bicarbonate solution to give free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.33 (m, 2 H) 1.30-1.80 (m, 7 H) 1.81-2.02 (m, 4 H) 2.31-2.45 (m, 2 H) 2.81 (d, J=12.63 Hz, 1 H) 2.97 (d, J=8.08 Hz, 1 H) 3.29 (s, 3 H) 3.71-3.90 (m, 3 H) 3.94 (s, 3 H) 4.89 (d, J=8.59 Hz, 1 H) 5.32-5.45 (m, 2 H) 6.01 (ddd, J=17.56, 12.76, 10.86 Hz, 1 H) 7.41-7.53 (m, 2 H) 7.82 (s, 1 H) 8.00 (d, J=7.83 Hz, 1 H) 8.12 (s, 1 H) 8.31 (d, J=8.08 Hz, 1 H). [M+H] calc'd for C28H36FN7O3, 538; found 538.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:28])([F:27])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[CH2:17][C@@H:18](OS(C)(=O)=O)[CH2:19][CH3:20])=[CH:11][CH:10]=1.O>O1CCCC1>[CH2:19]([C@H:18]1[N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([F:28])([F:27])[F:7])=[CH:10][CH:11]=2)[C:16](=[O:26])[CH2:17]1)[CH3:20]
Reactant: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.2 %

Procedure:
99.2 mg (0.884 mmol) of potassium tert-butoxide was suspended in tetrahydrofuran (1.5 mL) and a tetrahydrofuran solution (1.5 mL) containing 300 mg (0.884 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-methanesulfonyloxypentanoic acid amide produced in Example 3 was added dropwise thereto at room temperature for 5 minutes. After stirring at room temperature for further 5.5 hours, water (5 mL) was added and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone as a brown solid (194.0 mg). The reaction yield of the product was determined by the method described in Example 7 to be 81%.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:21][C@H:22]([CH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[C@H:23]([CH3:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(C(C)(C)C)(C)C.Br[C:44]1[C:45]([O:52][CH3:53])=[N:46][C:47]([O:50][CH3:51])=[N:48][CH:49]=1>C(O)C.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>[CH3:51][O:50][C:47]1[N:46]=[C:45]([O:52][CH3:53])[C:44]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C@H:23]([C@H:22]([OH:21])[CH2:35][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[CH3:34])=[CH:30][CH:29]=2)=[CH:49][N:48]=1
Reactant: COc1ncc(Br)c(OC)n1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(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: Cc1ccccc1
Solvent: CCO
Product: COc1ncc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)c(OC)n1
Temperature: 120 °C

Procedure:
Toluene (4 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.200 g, example 15f)), and tetrakis(triphenylphosphine)palladium(0) (0.020 g) were added to a solution of 5-bromo-2,4-dimethoxypyrimidine (0.209 g) in ethanol (1 ml). The mixture was heated at 120° C. for 4 hours.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[C:15]([NH2:30])(=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1>[C:15](=[S:2])([NH2:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCCCCCCCCCCCC(N)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(N)=S
Yield: 105.6 %

Procedure:
Phosphorus pentasulfide (9.8 g, 0.044 mol) was added to a mixture of tetradecanamide (8.6 g, 0.04 mol) in dry THF (250 mL) and the mixture refluxed overnight, concentrated in vacuo, and heated with methanol (200 mL), filtered, and the filtrate concentrated in vacuo to yield a pale yellow solid (10.28 g, 99%) used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11]([O:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:17]([O:16][C:15]([N:14]([O:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[C:1](=[O:4])[CH:2]=[CH2:3])=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A solution of acryloyl chloride (700 μL; 779.8 mg; 8.6 mmole) dissolved in dry dichloromethane (20 mL) was cooled at 0° C. with an ice bath. A mixture of tert-butyl N-(tert-butoxycarbonyloxy)carbamate (31) (2.0038 g; 8.6 mmole) and triethylamine (1.32 mL; 958.3 mg; 9.5 mmole) in dry dichloromethane (20 mL) was slowly added over a period of 1 hour to the cooled solution. The ice bath was removed after 4 hours and the reaction mixture was left stirring overnight while its temperature warmed up gradually to room temperature. Water (100 mL) was added to the reaction and the layers were separated. The organic solution was washed with a 10% ammonium chloride solution (3×80 mL), water (2×100 mL), and finally brine (1×100 mL). The organic layer was then dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate (90:10) to elute the product. The purification gave 690 mg (28%) of N-(tert-butoxycarbonyl),N-(tert-butoxycarbonyloxy)acrylamide (32) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>>[C:4]([C:3]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH:1][S:14]([NH2:15])(=[O:17])=[O:16])#[N:5]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: NS(=O)(=O)Cl
Product: COc1cc(C#N)c(NS(N)(=O)=O)cc1OC

Procedure:
Prepared as in Example 77a from 2-amino-4,5-dimethoxybenzonitrile and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ 3.77-3.80 (d, J=14.8, 6H), 7.05 (s, 1H), 7.06 (s, 1H), 7.29 (s, 1H), 9.15 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36]OCC3)[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18].Cl[C:40]1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=C(N2C=C(CCOS(C3C=CC(C)=CC=3)(=O)=O)N=N2)C=CC=1C)=O.C(N)CC>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][NH:32][CH2:37][CH2:36][CH3:40])[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)OCCc2cn(-c3ccc(C)c(C(=O)c4ccc(Nc5ccc(F)cc5F)cc4Cl)c3)nn2)cc1
Reactant: Cc1ccc(-n2cc(CCN3CCOCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: CCCN
Product: CCCNCCc1cn(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 138, using compound 435 (0.24 mmol) and propylamine (0.5 mL). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 15:85 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>[OH-].[Na+]>[CH2:15]([O:14][C:12]([NH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of l-aminocyclohexane-1-carboxylic acid (10.0 g, 70.0 mmol) in a 1M NaOH solution (100 mL) was added benzyl chloroformate (12.0 ml, 84.0 mmol). The reaction mixture was stirred for 2 h while maintaining pH 9 by addition of a 1M NaOH solution as necessary. The resulting solution was washed with Et2O (2×100 mL), then the aqueous layer was adjusted to pH 0 with a conc. HCl solution and the solution was extracted with EtOAc (3×150 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield 1-(benzyloxycarbonylamino)cyclohexane-1-carboxylic acid (17.3 g, 89%): TLC (25% EtOAc/hex) Rf0.07.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]([C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].CCN(CC)CC>C1COCC1>[C:11]([C:13]1[CH:14]=[C:15]([NH:19][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[CH:16]=[CH:17][CH:18]=1)#[CH:12]
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A dry 25 mL flask was charged with 2-methylbenzoyl chloride (0.155 g, 1.00 mmol) was cooled to room temperature, and THF (10 mL) was added. 3-Ethynyl-phenylamine (0.117 g, 1.00 mmol) was added to the THF solution of the acid chloride followed by NEt3 (0.272 mL, 2.00 mmol), and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature and partitioned between EtOAc (10 mL) and H2O (15 mL). The organic layer was washed with then washed once with 1M HCl (˜20 mL) followed by of saturated aqueous NaHCO3 (˜20 mL) and of brine (˜20 mL). The organic extracts were concentrated and the crude residue was purified by chromatography (silica gel, gradient elution EtOAc/hexanes 10 to 70%). The product containing fractions were concentrated to give the title compound as a tan solid (434 mg, 0.88 mmol, 88%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].CCOCC.S(=O)(=O)(O)O.[CH2:18](O)[CH2:19][CH2:20]C>>[C:1]([O:6][CH2:7][CH2:18][CH2:19][CH3:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCO
Reactant: C=C(C)C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: C=C(C)C(=O)OCCCC
Reaction time: 6 h
Yield: 91.2 %

Procedure:
74.1 g (1.0 mole) of n-butanol, 250.2 g (2.5 moles) of methyl methacrylate, 0.25 g of hydroquinonemonomethyl ether and 2.45 (0.025 mole) of concentrated sulfuric acid were added to a flask to conduct a reaction in the same manner as in Example 1. The reaction was carried out for 6 hours. The reaction results were 96.5% conversion of n-butanol and 91.2% yield of n-butyl methacrylate. However, it was found by gas chromatography that a high boiling point by-product was present and 0.004 mole of methacrylic acid (2660 ppm. based on n-butyl methacrylate) was produced as a by product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH2:9].[F:10][C:11]([F:36])([F:35])[C:12]1[CH:34]=[CH:33][CH:32]=[CH:31][C:13]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[N:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:28]([C:25]1[N:26]=[N:27][C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14](=[O:15])[C:13]3[CH:31]=[CH:32][CH:33]=[CH:34][C:12]=3[C:11]([F:36])([F:35])[F:10])[CH2:21][CH2:20]2)=[CH:23][CH:24]=1)=[O:29]
Reactant: NCCc1ccccn1
Reactant: O=C(Cl)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(NCCc1ccccn1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 28, making variations only as required to use 2-pyridin-2-ylethylamine in place of 2-aminopyridine to react with 6-[4-(2-trifluoromethyl-benzoyl)piperazin-1-yl]pyridazine-3-carbonyl chloride, the title compound was obtained as a white powder (30%). m.p. 151-154° C. 1H NMR (300 MHz, DMSO-d6) δ 9.07, 8.78, 8.43, 7.99-7.61, 7.52, 7.34, 3.79-3.60, 3.35-3.14. MS (ES+) m/z 485.3 (M+1).
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:21][CH2:20][CH2:19]C[CH2:17][C:7]3=[C:8]2[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.C(OC1C=CC(C2C=C3N=C4C(=CN3N=2)CCCC4)=CC=1)C1C=CC=CC=1.[H][H]>[Pd]>[N:1]1[N:9]2[C:4]([N:5]=[C:6]3[C:7](=[C:8]2[C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:17][CH2:19][CH2:20][CH2:21]3)=[CH:3][CH:2]=1
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: c1ccc(COc2ccc(-c3cc4nc5c(cn4n3)CCCC5)cc2)cc1
Product: Oc1ccc(-c2c3c(nc4ccnn24)CCCC3)cc1

Procedure:
Using the method described for the preparation of 4-(6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-yl)-phenol, (4-benzyloxy-phenyl)-5,6,7,8-tetrahydro-pyrazolo[5,1-b]quinazoline and hydrogen in the presence of 10% Pd/C provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])[CH:5]=1.CO[CH:27](OC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCCCCCC>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:11]([S:12]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[O:22][CH3:23])(=[O:13])=[O:14])[C:6]=2[CH:5]=1)=[O:24]
Reactant: COC(OC)c1ccccc1
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Solvent: O
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)C(c1ccccc1)O2
Temperature: 100 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A mixture of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 30, step 1; 200 mg, 0.537 mmol), benzaldehyde dimethyl acetal (0.5 mL) and toluene-4 sulfonic acid monohydrate (10 mg, 54 mmol) was stirred at 100° C. for 48 h. After cooling, heptane was added, and the precipitate was collected by filtration to afford 3-(5-chloro-2-methoxy-benzenesulfonyl)-2-phenyl-2,3-dihydro-benzooxazole-5-carboxylic acid methyl ester (208 mg, 84%). Light yellow solid, MS (ISP)=460.2 (M+H)+.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[CH3:20][NH2:21].CO>C(Cl)(Cl)Cl>[CH3:20][NH:21][C:4]([C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[C:1]([NH:5][CH2:6][S:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)=[O:19])=[O:14]
Reactant: CN
Reactant: O=C1c2ccccc2C(=O)N1CSc1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1ccccc1C(=O)NCSc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
To a solution of 6.76 g (25.0 mmol) of 4-phthalimidomethylthiopyridine in 100 ml of chloroform, 5 ml of 40% methylamine-methanol solution was added, and the mixture was stirred at room temperature for 3 hours. Additional 5 ml of 40% methylamine-methanol solution was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10), and the resulting crude product was crystallized from methylene chloride-diethylether to give 2.645 g of the desired compound (35.1% yield, yellow crystals), mp. 118°-121° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]=1.[Br:17]N1C(=O)CCC1=O>ClCCl>[Br:17][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[CH:8][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1nc(-c2ccc(C)c([N+](=O)[O-])c2)no1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1nc(-c2ccc(CBr)c([N+](=O)[O-])c2)no1
Yield: 81.1 %

Procedure:
A solution of compound 1b (21 g, 96 mmol) and N-bromosuccinimide (20.5 g, 115 mmol) in dichloromethane (500 mL) was irradiated with a sun lamp for 2 h at rt. The reaction mixture was filtered through a short column of silica gel in dichloromethane and concentrated on a rotary evaporator. The residue was recrystallized (ethyl acetate/hexane/petroleum ether) to afford compound 1c as a white solid (23.2 g, 82%). ESI-MS m/e 300.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.[N+:14]([C:17]1[CH:18]=[CH:19][C:20](Br)=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23])([O-:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9][CH3:10])=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23])([O-:16])=[O:15]
Reactant: COc1cccc(OC)c1B(O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1c(OC)cccc1OC
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture of Example 1A, methyl 5-nitro-2-bromobenzoate (25.8 g, 99.2 mmol), (21.7 g, 119 mmol), cesium carbonate (97.1 g, 298 mmol), and dichlorobis(triphenylphosphine)palladium(II) (3.5 g, 5.0 mmol) in DMF (300 mL) was stirred for 24 hours at 80° C., cooled to 23° C., treated with water (600 mL), and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated, during which a light yellow solid precipitated. The mixture was placed in a freezer (−20° C.) for 2 hours and filtered to provide the desired compound. MS (DCI/NH3) m/z 318 (M+H)+ and 335 (M+NH4)+.