Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Br:25])[NH2:21].C(=O)(O)[O-].[Na+]>C(O)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[Br:25]
Reactant: Nc1ccc(Br)c(Br)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)c(Br)c1
Yield: 31.9 %

Procedure:
A mixture of 6.20 g (26.6 mmol) of 4-chloro-6-nitro-quinoline-3-carbonitrile and 8.00 g (31.9 mmol) of 3,4-dibromoaniline in 160 mL of ethanol was refluxed under N2 for 5 h. Saturated sodium bicarbonate was added and volatile material was removed. The residue was slurried with hexane, collected, washed with hexane and water and dried. The insoluble material was repeatedly extracted with boiling ethyl acetate and the solution was then filtered through silica gel. The solvent was removed to give 3.80 g of green solid: mass spectrum (electrospray, m/e): M+H 449.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C:18](=[CH:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH2:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C:18](=[CH:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: C[C@]12CC=C3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@]12CC=C3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Yield: 71 %

Procedure:
A suspension of 900 mg of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),9(1l)-tetraene in 19 ml of methanol and 1.9 ml of water is refluxed with 900 mg of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed three times with water, once with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. After crystallization from hexane, 0.5 g of 17-difluoromethylene-estra-1,3,5(10),9(11)-tetraen-3-ol is obtained as colorless crystals with a melting point of 134-135° C., [α]D22 =+89° (c=0.515% in pyridine).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:25])=[C:22]([OH:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:25])=[C:22]([CH:23]=1)[O:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Nc1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 140 °C
Reaction time: 12 h
Yield: 30.4 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.2 g, 6.7 mmol) in N,N-dimethylformamide (60 mL) were added 5-amino-2-bromophenol (1.9 g, 10 mmol) and potassium carbonate (1.8 g, 13 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, the mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→100/0). The solvent was evaporated under reduced pressure and the obtained solid was washed with diisopropyl ether to give the title compound (0.79 g, 31%) as a yellow powder.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:5][CH:4]=1)(=[O:40])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)nc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (6-cyano-pyridin-3-yl)-amide (0.12 g, 0.2 mmol) prepared in Example 182 in DMSO (2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.36 g, 3 mmol), then aqueous solution (1N) of NaOH (1 mL, 1 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (6-carbamoyl-pyridin-3-yl)-amide as a white solid (Yield 80 mg, 65%)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH:29](C(OCC1C=CC=CC=1)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:11][C:12](=[O:28])[C@H:13]([CH3:27])[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:47]([C:49]1[CH:50]=[CH:51][C:52]([C:55]([OH:57])=O)=[N:53][CH:54]=1)#[N:48]>>[CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[NH:11][C:12](=[O:28])[C@H:13]([CH2:27][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:46])[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18][C:55]([C:52]1[CH:51]=[CH:50][C:49]([C:47]#[N:48])=[CH:54][N:53]=1)=[O:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@H](NC(=O)CCNC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccccc1
Product: N#Cc1ccc(C(=O)NCCC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)nc1

Procedure:
N-[3-[(Benzyloxy)carbonyl]-N-[N-[N-(t-butoxycarbonyl)-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester was deprotected and coupled with 5-cyano-2-pyridinecarboxylic acid to give N-[3-[(benzyloxy)carbonyl]-N-[N-[(5-cyano-2-pyridyl)carbonyl]-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester, m.p. 157°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:13][C:14]=1[CH2:15][CH3:16].BrC1N=C(CC)C(N[CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([O:50][CH3:51])[CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:40]2[C:49]3[C:44](=[CH:45][CH:46]=[C:47]([O:50][CH3:51])[CH:48]=3)[CH2:43][CH2:42][CH2:41]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCCc3ccc(OC)cc32)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2ccc(OC)cc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.51, 7.34, 7.10, 6.99, 6.83, 5.47, 4.68, 3.78, 2.85, 2.65, 2.53, 2.15, 2.01, 1.27, 1.21; 13C NMR (100 MHz, CDCl3) δ 173.14, 157.25, 150.37, 149.81, 139.28, 138.42, 136.72, 136.05, 134.21, 133.33, 131.82, 129.41, 129.26, 128.65, 126.39, 112.41, 54.61, 48.17, 28.92, 28.00, 26.49, 25.27, 19.52, 12.19, 10.54; HRMS (FAB) calcd for C25H27Cl2N3O+H 456.1609, found 456.1601.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20](=O)[CH2:21][CH3:22]>CCOCC.O>[CH2:2]([O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH2:19][C:20]2[CH:22]=[CH:21][C:20]([CH:19]3[C:21]4[CH:22]=[CH:5][CH:7]=[CH:8][C:20]=4[CH2:19][CH2:22][C:21]4[CH:10]=[CH:11][CH:12]=[CH:19][C:20]3=4)=[CH:22][CH:21]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(Cc2ccc(C3c4ccccc4CCc4ccccc43)cc2)C1
Temperature: 50 °C
Yield: 77 %

Procedure:
A mixture of the above iodide (1.80 g, 0.0044 mol), (R)-3-piperidinecarboxylic acid ethyl ester (0.69 g, 0.0044 mol) and anhydrous potassium carbonate (1.82 g, 0.0132 mol) in 2-butanone (30 ml) was heated to 50° C. for 6 h. After cooling, the mixture was diluted with ether (50 ml) and water (50 ml) and the phases were separated. The organic phase was washed with water (30 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the oily residue (2.1 g) was purified by gradient column chromatography on silica gel (40 g) using benzene and ethyl acetate as eluents. The benzene/ethyl acetate (9:1) fraction afforded 1.50 g (77%) of (R)-1-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-benzyl)-3-piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH3:7].[C:9]([CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])#[N:10].C(O)(=O)C.N1CCCCC1>>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:9]#[N:10])=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CCC(=O)OCc1ccccc1
Reactant: CCCC(=O)CCC
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCCC(CCC)=C(C#N)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 26.5 %

Procedure:
To a mixture of 4-heptanone (2.0 mL, 14.3 mmol) and benzyl cyanoacetate (2.51 g, 14.3 mmol) at 0° C. was added acetic acid (0.08 mL, 1.43 mmol), then piperidine (0.14 mL, 1.43 mmol) dropwise. The ice bath was removed, and stirring continued for 10 min. Additional acetic acid (0.08 mL) and piperidine (0.14 mL) were added, followed by the additional of oven-dried 4A molecular sieves such that stirring was not impeded. The mixture was stirred for 1 h, then partitioned between EtOAc and sat. sodium bicarbonate (NaHCO3) (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide 1.03 g (27%) of 2-cyano-3-propyl-hex-2-enoic acid benzyl ester as a colorless oil. 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.24 (s, 2H), 2.71 (m, 2H), 2.52 (m, 2H), 1.60 (m, 2H), 1.49 (m, 2H), 1.00 (t, J=7.3 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H). 13C NMR δ 182.46, 161.72, 135.37, 128.83, 128.58, 128.21, 115.87, 104.77, 67.26, 40.77, 35.80, 22.36, 21.86, 14.54, 14.32. LRMS: m/z 272.1 (M+1). IR (neat) 2223, 1729 cm−1. Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.44; H, 7.80; N, 5.22.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][C:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:18][N:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:32]([O:31][C:29](=[O:30])[CH2:28][C:19]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:18][N:17]=[C:16]([C:11]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([OH:8])[CH:10]=2)[CH2:20]1)([CH3:34])([CH3:35])[CH3:33]
Reactant: Cc1cc(OCc2ccccc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Yield: 91.3 %

Procedure:
A mixture of tert-butyl 3-(3-(benzyloxy)-5-methylphenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (674 mg), 10% Pd/C (containing about 55% water, 67 mg), and THF (7 mL) was stirred overnight at room temperature in a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (500 mg).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)Cl>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:1][NH:2][C:3]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:12])=[O:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(NO)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)ONC(=O)OCc1ccccc1

Procedure:
To a solution of benzyl hydroxycarbamate (1 g, 5.98 mmol) in DCM (20 ml) is added triethylamine (0.6 g, 5.98 mmol) and 2,2-dimethylpropanoyl chloride (0.74 ml, 5.98 mmol). After 2 hours the reaction mixture is quenched by the addition of water (10 ml) and the organics are extracted into DCM (2×20 ml), dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow oil which is used without any further purification. (1.6 g, 100%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.02 (1H, br. s.), 7.29-7.43 (5H, m), 5.22 (2H, s), 1.30 (9H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([O:19]C)=[CH:14][C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:24][C:23]([F:22])([F:33])[F:34])[CH:26]=2)[CH2:10][CH2:11][C:12]2[C:13]([CH3:21])=[CH:14][C:15]([OH:19])=[C:16]([CH3:18])[CH:17]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NCCc2cc(C)c(OC)cc2C)nc1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Product: CCc1cnc(N(CCc2cc(C)c(O)cc2C)Cc2cccc(OC(F)(F)F)c2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-2,5-dimethylphenyl)ethyl]pyrimidin-2-amine and 3-trifluoromethoxy benzyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:19]([C:20]2[NH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)=[CH:23][N:24]=2)[CH2:18][C:13]2(OCC[O:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH2:12][C:13](=[O:14])[CH2:18][CH:19]1[C:20]1[NH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=2)=[CH:23][N:24]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CC2(CC1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)NC(C(=O)N1CC(=O)CC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 60 °C
Reaction time: 72 h
Yield: 44.6 %

Procedure:
(1-{8-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-1,4-dioxa-7-aza-spiro[4.4]nonane-7-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (230.0 mg, 0.453 mmol) was dissolved in acetone (10 mL) and water (0.2 mL) and p-TsO.H2O (53 mg, 0.278 mmol) were added. The reaction was heated at 60° C. for 20 hours, after which additional p-TsOH.H2O (53 mg, 0.278 mmol) was added heating at 60° C. was continued. After three days, all volatiles were removed in vacuo. The crude material was taken into EtOAc and was washed with aqueous sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo gives the crude product. The crude material was purified via silica gel chromatography (eluent: EtOAc containing 10% MeOH/hexanes) to yield the product (93.9 mg, 0.202 mmol).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:4]=2[C:3]1=O.[C:15]([NH2:22])(=[S:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[S:21][C:2]2[CH2:8][CH2:7][O:6][C:5]3[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:4]=3[C:3]=2[N:22]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C1c2cc(Br)ccc2OCCC1Br
Solvent: CCO
Product: CCOC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Temperature: 80 °C
Yield: 66.5 %

Procedure:
To 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (3.4 g, 11 mmol) and ethyl thioamidooxalate (4.2 g, 32 mmol) was added ethanol (81 mL) and heated at reflux (at 80° C.) for 4 days. The reaction mixture was cooled to room temperature and cooled in an ice bath. The precipitate was collected by filtration to give 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (2.59 g, 69%). LC/MS (ESI+): m/z 355 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][C:9]([C:12](Cl)=[O:13])=[CH:8][CH:7]=1.[OH-].[Na+].CCOCC>C1COCC1>[C:15]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:13])=[CH:10][CH:11]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Glycine (5 mmol) was reacted with 4-biphenylcarbonyl chloride (about 5 mmol) in the presence of 1N NaOH solution (10 ml), ether (21 ml) and THF (2 ml) using the procedure described in Example 5. Most of the product precipitated as a solid on acidification of the aqueous layer during the work up. This was found to be quite insoluble in CHCl3 and EtOAc. It was largely dissolved in CH3CN (~35 ml) and filtered to remove insoluble material. Crystalline acid (0.81 g, 63%) was deposited on cooling, m.p. 207°-218° C. decomp.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1)(=O)=O.[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([C:20]4[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=4)[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7]1
Reactant: CS(=O)(=O)O[C@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Reactant: C[C@@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CCCN1[C@@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Temperature: 25 °C

Procedure:
A stirred solution of (S)-1-(6-(4-cyanophenyl)benzo[d]thiazol-2-yl)pyrrolidin-3-yl methanesulfonate (Reference Example 13c, 32 mg, 0.080 mmol), (R)-2-methylpyrrolidine (27.3 mg, 0.320 mmol), and N,N-diisopropylethylamine (0.17 mL, 0.961 mmol) in acetonitrile (2 mL) was heated to 150° C. under microwave irradiation for 20 minutes. The reaction mixture was cooled to room temperature then purified by silica gel chromatography (98:2:0 to 98:2:1 dichloromethane/methanol/aqueous NH4OH). Fractions containing product were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give to give 4-(2-((2R,3′R)-2-methyl-1,3′-bipyrrolidin-1′-yl)benzo[d]thiazol-6-yl)benzonitrile. 1H NMR (300 MHz, CD3OD) δ ppm 1.17 (d, J=6 Hz, 3H), 1.45-1.57 (m, 1H), 1.73-1.90 (m, 2H), 1.98-2.20 (m, 2H), 2.24-2.35 (m, 1H), 2.62 (q, J=8 Hz, 1H), 2.83-2.96 (m, 1H), 2.99-3.08 (m, 1H), 3.36-3.62 (m, 3H), 3.69-3.78 (m, 1H), 3.86-3.93 (m, 1H), 7.57 (d, J=8 Hz, 1H), 7.65 (dd, J=2, 9 Hz, 1H), 7.80 (q, J=9 Hz, 4H), 8.03 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 389 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:15])[CH3:2].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>O1CCCC1>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[C:17](=[O:18])[NH:15]2
Reactant: CCOC(=O)CNCc1c(C)cccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CN1Cc2c(C)cccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
To a cooled solution of 15.00 g (67 mmole) of N-(2-amino-6-methyl benzyl) glycine ethyl ester in 300 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere was added a solution of 11.72 g (72 mmole) of 1,1'-carbonyldiimidazole in 200 ml of anhydrous tetrahydrofuran at such a rate that the temperature did not exceed 5°. Upon complete addition, the solution was allowed to stir at room temperature for 2 hours, heated to reflux for 18 hours, cooled to room temperature and the tetrahydrofuran removed in vacuo. The residue was dissolved in methylene chloride (250 ml), washed with 5% aqueous hydrochloric acid (2×100 ml), then water (100 ml). The methylene chloride extract was dired (Na2SO4) and the solvent removed in vacuo affording 14.0 g (83% yield) of a colorless solid. purification was effected by crystallization from nitromethane; m.p.; 184°-5°.
Reaction SMILES: [C:1]([C:4]1[C:13]([CH3:14])=[N+:12]([O-:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:16])(=[O:3])[CH3:2].[Br:17]Br>CO>[C:1]([C:4]1[C:13]([CH2:14][Br:17])=[N+:12]([O-:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: BrBr
Solvent: CO
Product: CC(=O)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 71 %

Procedure:
To a stirred suspension of 343 g. (1.57 mol.) of 2-acetyl-3-methylquinoxaline 1,4-dioxide in 3,000 ml. of methanol was added (1.74 mole) of bromine over a period of 2 hours. The reaction mixture was then stirred for 5 days at room temperature. The resulting yellow solid was collected by suction filtration, washed with methanol and ether, and dried to give 331 g. (71% yield) of 2-acetyl-3-bromomethylquinoxaline 1,4-dioxide, m.p. 164°-166° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH2:9]Br)[C:3]=1[O:11][CH3:12].[C-:13]#[N:14].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH2:9][C:13]#[N:14])[C:3]=1[O:11][CH3:12]
Reactant: COc1c(Br)cc(Br)cc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1c(Br)cc(Br)cc1CC#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of the product of stage (c) (183 g) in ethanol (150 ml) was heated to reflux. A solution of sodium cyanide (25 g) in hot water (50 ml) was added which maintained gentle refluxing. The mixture was then stirred for 5 minutes, poured into ice water, and the product was filtered off, taken up in dichloromethane, washed with water, dried over magnesium sulphate and filtered. The solvent was removed to give a brown oil which slowly crystallised. Recrystallisation from petroleum ether gave the title product as colourless needles, mp 87°-88° C.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH2:19][CH:20]([OH:22])[CH3:21])[N:17]=[CH:16][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:22][CH:20]([CH3:21])[CH2:19][N:18]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][N:28]([CH2:27][C:26]([CH3:42])([OH:43])[CH3:25])[CH:32]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:15][CH:16]=[N:17]1
Reactant: CC(O)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(O)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following the procedure for 114, 1-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propan-2-ol was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 459. MS(ESI+) 467.1. 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=8.3, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.95 (s, 1H), 7.43 (dd, J=8.3, 1.8, 1H), 7.30 (d, J=1.7, 1H), 4.95 (d, J=5.3, 1H), 4.82 (dd, J=13.3, 7.5, 1H), 4.76-4.66 (m, 2H), 4.46-4.32 (m, 2H), 4.28-4.14 (m, 1H), 4.03 (s, 2H), 3.44 (t, J=5.0, 2H), 1.16 (d, J=6.3, 3H), 1.10 (s, 6H)