Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-][CH2:2]C.[Na+].C([C:7]1[S:11][C:10]([CH3:12])=[C:9]([CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1)=O.[N:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N+]=[N-].[Cl-].[NH4+]>C(O)C>[CH2:17]([O:16][C:15]([N:14]([CH3:2])[C:13]1[C:9]2[NH:25][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:12][C:10]=2[S:11][C:7]=1[CH3:8])=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1sc(C=O)cc1CNC(=O)OCc1ccccc1
Reactant: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2sc(C)c(N(C)C(=O)OCc3ccccc3)c2[nH]1
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a solution (20 mL) of sodium ethoxide (0.68 g) in ethanol was added dropwise a mixture of benzyl (5-formyl-2-methyl-3-thienyl)methylcarbamate (0.72 g) and ethyl azidoacetate (1.3 g) under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated. The obtained residue was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in toluene (20 mL), and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography to give ethyl 3-{[(benzyloxy)carbonyl](methyl)amino}-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate (91 mg, yield 10%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:35])=[C:6]([N:8]2[CH2:33][CH2:32][C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[O:24])=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[C:9]2=[O:34])[CH:7]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OC(=O)C)C>[CH3:35][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[C:38]([C:37]([F:36])([F:47])[F:48])[CH:39]=2)=[CH:7][C:6]=1[N:8]1[CH2:33][CH2:32][C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)=[O:24])=[CH:21][CH:22]=3)[N:14]=[CH:15][C:10]=2[C:9]1=[O:34]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N1CCc2nc(Nc3ccc(C(=O)N4CCN(C)CC4)cc3)ncc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
To a solution of 6-(5-Amino-2-methyl-phenyl)-2-[4-(4-methyl-piperazine-1-carbonyl)phenylamino]-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one (70.7 mg, 0.15 mmol), 3-Trifluoromethyl benzoic acid (28.5 mg, 0.15 mmol), and DIPEA (78 μl, 0.45 mmol) in DMF was added HATU (59 mg, 0.15 mmol), and the reaction mixture was stirred for 3 hour at room temperature. The reaction mixture was diluted with ethylacetate and washed with 5% aqueous sodium bisulphate solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography (SiO2, 2-10% methanol in chloroform) to give 69.8 mg (72.3%) of N-(4-Methyl-3-{2-[4-(4-methyl-piperazine-1-carbonyl)phenylamino]-5-oxo-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl}-phenyl)-3-trifluoromethyl-benzamide [24] as a pale yellow solid.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[C:20]=1[Br:25]>>[Br:25][C:20]1[C:21]([CH3:24])=[N:22][O:23][C:19]=1[NH:18][S:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccccc1-c1ccc(S(=O)(=O)Cl)s1
Product: COc1ccccc1-c1ccc(S(=O)(=O)Nc2onc(C)c2Br)s1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 1. Reaction of 2-chlorosulfonyl-5-(2-methoxyphenyl)thiophene with 5-amino-4-bromo-3-methylisoxazole gave N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyoxyphenyl)thiophene-2-sulfonamide in 32% yield, m.p. 114-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=2)[CH2:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[NH:7][C:6]1=[O:25])=[O:4].[H-].[Na+].CI.[C:30](OCC)(=O)C.CCCCCC>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=2)[CH2:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[N:7]([CH3:30])[C:6]1=[O:25])=[O:4]
Reactant: COC(=O)[C@@H]1C(=O)Nc2ccccc2C[C@H]1c1ccc2c(c1)OCO2
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CI
Product: COC(=O)[C@@H]1C(=O)N(C)c2ccccc2C[C@H]1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (+/-)-Trans-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(3,4-methylenedioxyphenyl)-2H-1-benzazepine-2-one (0.35 g, 1.03 mmol) in DMF (3 ml) was added to a mixture of sodium hydride (0.036 g, 1.2 mmol, 80% mineral oil dispersion) and the mixture stirred 1 h at ambient temperature. Methyl iodide (0.4 ml, 0.91 g, 6.43 mmol) in DMF (0.5 ml) was added and the mixture stirred 48 h at ambient temperature. The reaction was quenched in water (50 ml) and extracted with ethyl acetate (3×10 ml). The combined extracts were dried (MgSO4), filtered and the solvent removed at reduced pressure to give 0.40 g of crude product. Chromatography on silica gel with 30:70 ethyl acetate-hexane gave 0.335 g of the title compound as a viscous oil. The oil was treated with hexane and the resulting white solid collected and dried to give 0.226 g (62%) of the title compound; mp 125°-127°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([O:50][CH2:51][C:52]2([CH2:64]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:57][O:56][CH:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[O:54][CH2:53]2)(=[O:49])=[O:48])=[CH:43][CH:42]=1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:64][C:52]2([CH2:51][O:50][S:47]([C:44]3[CH:43]=[CH:42][C:41]([CH3:40])=[CH:46][CH:45]=3)(=[O:48])=[O:49])[CH2:57][O:56][CH:55]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)[O:54][CH2:53]2)=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)COC(c3ccccc3)OC2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCC2(COc3ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc3)COC(c3ccccc3)OC2)cc1
Temperature: 100 °C

Procedure:
To 466 mg (1.0 mmol) of di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-L-glutamate in 12 mL N,N-dimethylformamide were added 138 mg (1.0 mmol) of potassium carbonate and 533 mg (1.0 mmol) of (2-phenyl-1,3-dioxane-5,5-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (Heterocycles 34. (1992), 739), and the resulting suspension was heated for 2 h at 100° C. in a microwave oven. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using a dichloromethane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: COC1C=CC(NC2N=NC(C(NC(C3CCOCC3)=O)C)=CN=2)=CC=1.[NH2:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29].[CH3:45][O:46][C:47]1[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=1[C:49](O)=[O:50]>>[CH3:45][O:46][C:47]1[CH:55]=[CH:54][CH:53]=[CH:52][C:48]=1[C:49]([NH:27][CH:28]([C:30]1[N:35]=[N:34][C:33]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[N:32][CH:31]=1)[CH3:29])=[O:50]
Reactant: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Reactant: COc1ccccc1C(=O)O
Agent: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCOCC3)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3OC)nn2)cc1
Yield: 93.2 %

Procedure:
In a similar manner as described for Intermediate 50, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 2-methoxybenzoic acid (68 mg, 0.45 mmol) to give 2-(methyloxy)-N-[1-(3-{[4-(methyloxy)phenyl]amino-}-1,2,4-triazin-6-yl)ethyl]benzamide (145 mg) as a yellow solid. MS m/z 380 (M+1).
Reaction SMILES: [N+:1]([CH:3]([CH3:8])[C:4](OC)=[O:5])#[C-:2].[NH2:9][CH2:10][CH:11]1[CH2:16][CH:15]2[CH2:17][CH:13]([C:14]2([CH3:19])[CH3:18])[CH:12]1[CH3:20]>>[CH:13]12[CH2:17][CH:15]([C:14]1([CH3:18])[CH3:19])[CH2:16][CH:11]([CH2:10][NH:9][C:4](=[O:5])[CH:3]([N+:1]#[C-:2])[CH3:8])[CH:12]2[CH3:20]
Reactant: [C-]#[N+]C(C)C(=O)OC
Reactant: CC1C(CN)CC2CC1C2(C)C
Product: [C-]#[N+]C(C)C(=O)NCC1CC2CC(C1C)C2(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 5.7 g (50 mmoles) of methyl α-isocyanopropionate and 8.3 g (50 mmoles) of (+)-3-aminomethylpinane is stirred for 15 hours at room temperature, initially with slight cooling. After distilling off the resulting methanol in a high vacuum at 80° C., 11.6 g of crystalline α-isocyanopropionic acid (+)-3-pinylmethylamide of melting point 58°-59° C. remain. IR spectrum (KBr): 3,230 (N--H), 2,130 (N≡C), 1,670 cm-1 (C=O).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]1[CH2:21][CH2:20][N:19](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:17]1)[C:11](=[O:32])[N:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=1)[C:9]2=[O:44])(=[O:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:43][O:42][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[O:40][CH3:41])[CH2:33][N:10]1[C:9](=[O:44])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:7]=2)[N:12]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:11]1=[O:32]
Reactant: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCN(C(=O)OCc4ccccc4)CC3)c2=O)cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCNCC3)c2=O)cc1OC
Yield: 99.1 %

Procedure:
A mixture of 0.1 g of benzyl 4-{6-[(acetylamino)methyl]-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carboxylate obtained in stage 5.6, 0.016 g of ammonium formate and 0.018 g of Pd/C (10%) in 2 ml of EtOH purged beforehand with nitrogen is irradiated under a microwave field at 800° C. for 30 min. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 0.077 g of the expected product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][NH:5][CH:6]=1.OP([O-])([O-])=O.[K+].[K+].[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CN(C=O)C>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[N:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1c[nH]nn1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)nn1
Temperature: 85 °C
Reaction time: 60 h
Yield: 23.9 %

Procedure:
A mixture of 4-methyl-[1,2,3]-triazole (60 g, 0.72 mol), K2HPO4 (250 g, 1.44 mol) and 3,4-difluoronitrobenzene (80 ml, 0.723 mol) in DMF (3.4 litres) was stirred at 85° C. under N2 for 2.5 days. After removal of DMF in vacuo, the residue was chromatographed on silica gel with 0-5% ethyl acetate in dichloromethane to give the title compound as a light yellow solid (38.3 g, 24%). The other two isomers were also isolated.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]3[NH:9][CH:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=[CH:4][C:3]=1[O:22][CH3:23].O1CCOCC1>O>[OH:15][C:12]1[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]=[C:8]2[C:7]3[C:2]([Br:1])=[C:3]([O:22][CH3:23])[CH:4]=[CH:5][C:6]=3[O:14][C:13]=12
Reactant: COc1ccc2oc3c(c2c1Br)NC(c1ccccc1)CC3=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2oc3c(O)cc(-c4ccccc4)nc3c2c1Br
Temperature: 110 °C
Yield: 91.7 %

Procedure:
A mixture of 13B (2.0 g, 0.0053 mol), FeCl3.6H2O (6 g) and 1,4-dioxane (20 mL) was heated to 110° C. and reacted overnight. After reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 13C (1.8 g, 90.4% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.C([O:17][C:18]1[C:22]([CH:23]=O)=[C:21]([CH3:25])[N:20]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:19]=1)C1C=CC=CC=1.C(OC1C(C=O)=C(C)N(C2C=CC=CC=2)N=1)C1C=CC=CC=1>>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:23][C:22]2[C:18](=[O:17])[NH:19][N:20]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:21]=2[CH3:25])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CCc1ccc(Br)cc1
Reactant: Cc1c(C=O)c(OCc2ccccc2)nn1-c1ccc(F)cc1
Agent: Cc1c(C=O)c(OCc2ccccc2)nn1-c1ccccc1
Product: CCc1ccc(Cc2c(C)n(-c3ccc(F)cc3)[nH]c2=O)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 1-bromo-4-ethylbenzene and 3-benzyloxy-1-(4-fluorophenyl)-4-formyl-5-methyl-1H-pyrazole instead of 4-bromoanisole and 3-benzyloxy-4-formyl-5-methyl-1-phenyl-1H-pyrazole, respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[O:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:19]=[CH:18]1>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:21]2[O:17][CH:18]=[N:19][CH:20]=2)=[CH:23][CH:24]=1)(=[O:29])=[O:30])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc(Br)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-amino-5-bromo-phenyl)-phenyl-methanone and 121 mg of 4-oxazol-5-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 7.25–7.35 (m, 5H), 7.45–7.49 (m, 4H), 7.63–7.71 (m, 4H), 7.95 (s, 1H), 9.67 (s, 1H). MS: m/z 484.3 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[C:3]=1[OH:11].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=S)=[CH:15][CH:14]=1.C(N(CC)CC)C.C(OCC)(=O)C>O1CCCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[O:11][C:3]3[C:4]([CH:8]([CH3:9])[CH3:10])=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:15][CH:14]=1
Reactant: CC(C)c1cccc(N)c1O
Reactant: S=C=Nc1ccc(Br)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc2nc(Nc3ccc(Br)cc3)oc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
A solution of 2-amino-6-isopropylphenol (0.354 g, 2.34 mmol) and 4-bromophenylisothiocyanate (0.500 g, 2.34 mmol) in tetrahydrofuran (35 mL) was stirred at room temperature for 3 h. Anhydrous copper (II) sulfate (3.361 g, 21.06 mmol), silica gel (3.361 g), and triethylamine (0.236 g, 0.33 mL, 2.34 mmol) were added, and the mixture stirred at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite and the washed with diethyl ether (3×50 mL). The filtrate was concentrated to afford a brown solid. The solid material was applied to silica gel and passed through a pad a silica gel along with ethyl acetate (3×50 mL). The filtrate was concentrated to afford N2-(4-bromophenyl)-7-isopropyl-1,3-benzoxazol-2-amine (0.702 g, 91%). RP-HPLC Rt 18.066 min, 86% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 333 (MH+).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=1[OH:20])[CH2:2][CH2:3][CH3:4].[C:26](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.O>[CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:24])([CH3:23])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=1[O:20][CH3:26])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C=O)ccc1O
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
A mixture of Example 56A (350 mg, 0.97 mmol) and cesium carbonate (375 mg, 1.94 mmol) in DMF (20 mL) was treated with iodomethane (165 mg, 1.17 mmol). The mixture was stirred at rt for 2 hrs, diluted with H2O and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 246 mg (68%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.99 (t, J=7.36 Hz, 3 H) 1.36-1.51 (m, 2 H) 1.67 (s, 9 H) 1.68-1.78 (m, 2 H) 2.85 (dd, J=7.67 Hz, 2 H) 4.02 (s, 3 H) 7.11 (d, J=8.59 Hz, 1 H) 7.97 (dd, J=8.59, 2.15 Hz, 1 H) 7.96 (s, 1 H) 8.64 (d, J=2.15 Hz, 1 H) 9.96 (s, 1 H); MS (DCI/NH4+) m/z 375 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][CH:24]1[NH:25][CH2:26][CH2:27][N:22]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[CH2:23]1.[CH3:2][C:3]([CH3:8])([CH3:7])[CH:4]=[O:5]
Reactant: CC(C)(CBr)C(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C=O
Product: Fc1ccc(N2CCNC(Br)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
3-Bromo-2,2-dimethylpropionic acid (5.03 g, 27.8 mmol) was dissolved in DCM (60 mL). Oxalyl chloride (3.64 mL, 41.67 mmol) was added slowly over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in DCM (40 mL) and added to a solution of 4-fluorophenyl-piperazine (5.00 g, 27.8 mmol) and DIPEA (7.24 mL, 41.67 mmol) in DCM (30 mL) at 0° C. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred at room temperature for 16 hours. The reaction mixture was washed with 10% citric acid solution (2×100 mL), dried (MgSO4) and concentrated in vacuo to give 3-bromo-1-(4-fluorophenyl)piperazine-2,2-dimethylpropan-1-one (8.04 g, 84%) as a yellow solid which was used without further purification.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[CH2:24]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[CH:32]=[CH:31][C:29]([N:30]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:19]([CH2:18][CH:17]([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:28][CH:27]=1)[CH3:25]
Reactant: CCc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)CS(=O)(=O)Cl
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)CC(C)C)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 379.20 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride and 4-ethylaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:4]=1.[CH:16](O)=[O:17]>>[CH3:1][O:2][C:3]1[C:8]([NH:9][CH:16]=[O:17])=[CH:7][CH:6]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: O=CO
Reactant: COc1nc(N2CCOCC2)ccc1N
Product: COc1nc(N2CCOCC2)ccc1NC=O
Yield: 88 %

Procedure:
A solution of 2-methoxy-6-morpholinopyridin-3-amine (Preparation 70, 40 mg, 0.191 mmol) in formic acid (3 mL) was heated to reflux for 3 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between aqueous saturated NaHCO3 (40 mL) and EtOAc (40 mL). The aqueous layer was re-extracted with EtOAc (40 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried (MgSO4) and concentrated in vacuo, to give the title compound (40 mg, 88%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(O)C>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:29][C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: O=Cc1ccncc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccncc1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (1.0 g, 25 mmol) was added to a suspension of estrone (1.35 g, 5.0 mmol) and pyridine-4-carbaldehyde (595 mg, 5.0 mmol) in ethanol (40 mL) at room temperature. The resulting dark orange solution was stirred at room temperature for 4 hours. Then glacial acetic (ca. 10 mL) acid was added with stirring. The colour changed to light yellow and a light yellow solid precipitated. The solid was filtered off and washed with water (50 mL), ethanol (20 mL), diethyl ether (50 mL) and hexane (50 mL) and dried under high vacuum. Yield: 1.588 g (88%) light yellow solid. 1H-NMR (DMSO-d6, 400 MHz), δ: 0.92 (s, 3H, —CH3), 1.30-1.68 (m, 5H), 1.82-1.92 (m, 1H), 1.96-2.04 (m, 1H), 2.14-2.24 (m, 1H), 2.31-2.38 (m, 1H), 2.61-2.69 (m, 1H), 2.71-2.84 (m, 2H), 2.87-2.96 (m, 1H), 6.47 (d, J=2.3 Hz, 1H), 6.53 (dd, J=8.6, 2.3 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.28 (s, 1H), 7.60 (d, J=6.2 Hz, 2H), 8.65 (d, J=6.2 Hz, 2H), 9.05 (s, 1H, —OH). LRMS (FAB+): 360.2 (100, [M+H]+). LRMS (FAB−): 358.2 (100, [M−H]−). HRMS (FAB+): 360.196986 C24H26NO2 requires 360.196354.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[C:26]([NH:30][S:31](Cl)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>N1C=CC=CC=1>[C:26]([NH:30][S:31]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: CC(C)(C)NS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)NS(=O)(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 10 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (200 mg, 0.57 mmol) and N-tert-butylsulfamoyl chloride (J. Org. Chem.; 1976, 41, 4028) (108 mg, 0.63 mmol) as starting materials and pyridine as base.