Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@@H:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@@H:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:20][CH2:19]2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CCN(CC)[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CCN(CC)[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1

Procedure:
Following general procedure F, {6-bromo-4-[cis-4-(diethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (31 mg, 0.070 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.150 mmol) to afford the desired product (14.1 mg, 39%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.25 (s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 4.77 (s, J=12.7 Hz, 1H), 3.98 (s, 3H), 3.50-3.41 (m, 1H), 3.23 (q, J=7.2 Hz, 4H), 2.97-2.88 (m, 1H), 2.22 (d, J=12.9 Hz, 2H), 2.09-1.85 (m, 6H), 1.35 (t, J=7.3 Hz, 6H), 1.24-1.17 (m, 2H), 1.18-1.09 (m, 2H); ESI MS m/z 522 [C30H36ClN3O3+H]+; HPLC 98.3% (AUC), tR=11.07 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:12]=2)=[O:9])=[CH:4][N:3]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[N:3][CH:4]=2)=[O:9])=[CH:12][C:13]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1
Reactant: COc1ccc(NC(=O)c2ccc(Br)nc2)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccncc1
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: COCCOC
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(-c3ccncc3)nc2)cc1N1CCN(C)CC1

Procedure:
2-Bromo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]pyridine-5-carboxamide (0.125 g;0.31 mmol) was stirred with 4-pyridylboronic acid (0.038 g;0.31 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g) and anhydrous sodium carbonate (0.036 g;0.34 mmol) in water (5 ml) and DME (5 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (20 ml) and extracted into CHCl3. The organic extracts were combined, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 5%MeOH/CHCl3 to yield a orange/yellow gum(0.060 g;48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.Cl.[NH2:17][OH:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[N:17][OH:18])[CH2:8][CH2:7]1
Reactant: NO
Reactant: O=C1CCN(Cc2cccc(Cl)c2)CC1
Agent: Cl
Product: ON=C1CCN(Cc2cccc(Cl)c2)CC1

Procedure:
1-(3-Chlorobenzyl)-4-piperidone oxime is prepared from 1-(3-chlorobenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:32]=[CH:31][C:18]([O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])[N:21]=2)=[CH:17][CH:16]=1>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])[N:21]=3)=[CH:31][CH:32]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3ccnc(NCCCO)n3)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 154 mg (0.880 mmol) 4-t-butyl-phenyl isocyanate in 3 ml THF was given at 0° C. to a solution of 229 mg (0.880 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 5 ml THF within 10 min. After stirring overnight the reaction mixture was evaporated and the residue purified by chromatography on silica gel (dichloromethane/methanol 97:3). The obtained material was washed with dichloromethane and the precipitate was isolated by filtration and dried. Yield: 80 mg (21%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]1[O:16][N:15]=[C:14]([CH2:17][N:18]2[C:26]3[C:21](=[C:22]([C:29]([F:32])([F:31])[F:30])[C:23]([C:27]#[N:28])=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH2:33][CH2:34][CH3:35])[N:13]=1.O[Li].O.O.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]1[O:16][N:15]=[C:14]([CH2:17][N:18]2[C:26]3[C:21](=[C:22]([C:29]([F:31])([F:30])[F:32])[C:23]([C:27]#[N:28])=[CH:24][CH:25]=3)[CH:20]=[C:19]2[CH2:33][CH2:34][CH3:35])[N:13]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)OC)ccc2Cl)n1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)O)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 70.9 %

Procedure:
To a solution of methyl 4-chloro-3-(3-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)benzoate (Example 293) (0.190 g, 0.378 mmol) in 1,4-dioxane (70 mL) was added LiOH—H2O (0.063 g, 1.50 mmol) and water (30 mL). The mixture was stirred at rt for 17 h followed by cooling to 0-5° C. The solution was made acidic using concentrated HCl, extracted into Et2O, dried (MgSO4) and concentrated to afford a pure solid (0.131 g, 71% yield): MS (ES) m/z 488 (M+).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([NH2:15])[CH:14]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[NH2:16][C:11]1[CH:12]=[C:13]([NH:15][C:5](=[O:7])[CH3:6])[CH:14]=[C:9]([Cl:8])[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(N)cc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(N)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DMAP (50 mg) and acetic anhydride (3.9 g, 37.9 mmol) were added sequentially and dropwise to a cold solution of 5-chloro-benzene-1,3-diamine (4.5 g, 31.6 mmol) in pyridine (22 mL) keeping the internal temperature below 0° C. The reaction mixture was allowed to warm to rt, stirred for 2 h, cooled to 0° C., quenched by addition of ice cooled water, and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH, 99:1) to afford the title compound. tR: 0.18 min (LC-MS 2); ESI-MS: 184.9 [M+H]+ (LC-MS 2); Rf=0.32 (hexane/EtOAc, 1:4).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]([O:49][C:50]([NH:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[NH:58][C:57]([C:62](O)=[O:63])=[CH:56]2)=[O:51])([CH3:48])[CH3:47].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:62]([C:57]2[NH:58][C:59]3[C:55]([CH:56]=2)=[CH:54][C:53]([NH:52][C:50](=[O:51])[O:49][C:46]([CH3:47])([CH3:45])[CH3:48])=[CH:61][CH:60]=3)=[O:63])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
HATU (2.75 g, 7.23 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.50 g, 4.82 mmol), 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (1.33 g, 4.82 mmol) and diisopropylethylamine (1.26 mL, 7.23 mmol) in DMF (10 mL). The mixture was stirred at RT overnight. The reaction mixture was extracted with EtOAc and water and the organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel flash chromatography (5-50% EtOAc:hexane) to give an off-white solid which was triturated with EtOAc:hexane, filtered and dried to afford the title compound (1.36 g, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 9.07 (br. s., 1H), 8.95 (t, 1H), 7.78 (s, 1H), 7.71 (br. s., 1H), 7.41-7.55 (m, 3H), 7.36 (t, 1H), 7.21-7.30 (m, 1H), 7.15 (d, 1H), 7.03 (s, 1H), 4.37-4.68 (m, 2H), 1.44 (s, 9H). ES-LCMS: m/z 569 (M+H).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[F:8][C:9]([F:13])([F:12])[CH2:10][OH:11].FC(F)(F)C(O)=O.C(ON=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>>[F:8][C:9]([F:13])([F:12])[CH2:10][O:11][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC(F)(F)F
Reactant: Nc1cccnc1
Agent: CC(C)(C)ON=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)COc1cccnc1
Temperature: 15 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A reactor vessel is charged with 3-aminopyridine (2.0 g, 21 mmol), 2,2,2-trifluoroethanol (15 g, 150 mmol), and trifluoroacetic acid (3.63 g, 31.8 mmol). The solution is cooled to 15° C. and then t-Butylnitrite (2.51 g of a 96% solution, 23.4 mmol) is added drop-wise to the vessel so that the temperature rises to the range 25° C.-30° C. Potassium carbonate (4.4 g) is added to the vessel and the reaction mass is stirred overnight followed by dilution with water and extraction with ethyl acetate. The solvent is evaporated to obtain 3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (3.94 g, crude yield 59.5%) with an actual yield of 56.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13]Cl)[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1.ClC1C=CC2OCC[NH:30][CH:29](C3C=CC=CC=3)C=2C=1.CN>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12](=[O:15])[CH2:13][NH:30][CH3:29])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[CH:22]=1
Reactant: O=C(CCl)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)NCCO2
Agent: CN
Solvent: ClCCl
Product: CNCC(=O)N1CCOc2ccc(Cl)cc2C1c1ccccc1
Reaction time: 18 h

Procedure:
Crude 7-chloro-4-(2-chloroacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine, prepared as described in Example 4a starting with 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (1.82 g, 7.0 millimoles), was dissolved in 125 ml CH2Cl2 and the solution was saturated with gaseous monomethylamine. The reaction solution was stoppered and allowed to stand at room temperature for 18 hours, followed by unstoppering and warming on a steam bath for 30 minutes. The resulting CH2Cl2 solution was washed with two portions of saturated NaHCO3, dried over Na2SO4, filtered and rendered free of solvent to afford crude 7-chloro-4-(2-methylaminoacetyl)-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine as a light viscous oil which was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.C([Li])CCC>CCOCC>[N:15]1[CH:16]=[CH:17][C:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[B:18]([OH:23])[OH:19])=[CH:13][CH:14]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccc(Br)c(-c2ccncc2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1ccc(C(F)(F)F)cc1-c1ccncc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A 250-mL round bottom flask was charged with 4-(2-bromo-5-(trifluoromethyl)phenyl)pyridine (0.242 g, 0.801 mmol), Ether (6.16 ml), and triisopropyl borate (0.223 ml, 0.961 mmol). The flask was cooled to −78° C. for 10 minutes, after which butyllithium (2.5M in hexanes) (0.385 ml, 0.961 mmol) was added dropwise. After 30 minutes the dry-ice bath was removed, and 2N aq NaOH (10 mL), and the resulting biphasic mixture was stirred vigorously. After 1 h, the mixture was diluted with water, and the layers separated. The ether was then extracted with water (×2) and the water layers were combined, and washed with ether. The ether layers were back-extracted once more, and all aqueous layers combined and neutralized to ˜pH=7 with 1N aq HCl to give a clear solution. The aqueous was extracted with DCM (×3) and the combined organics were dried over sodium sulfate, filtered and concentrated. The dried residue was taken up in DCM, and concentrated to give (2-(pyridin-4-yl)-4-(trifluoromethyl)phenyl)boronic acid (0.136 g, 0.509 mmol, 63.6% yield) as an off-white solid. [M+H]+=268.1
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][C:7]([N+:16]([O-:18])=[O:17])=[CH:8][C:9]=2[CH3:15])[N:4]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:15][C:9]1[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4]2
Reactant: COc1nc2cc([N+](=O)[O-])cc(C)c2nc1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC

Procedure:
A suspension of 0.249 g (1.0 mmol) of 2,3-dimethoxy-5-methyl-7-nitro-quinoxaline, 0.178 g (1 mmol) of N-bromosuccinimide and 0.016 g (0.1 mmol) of azo-isobutyronitrile in 3 ml of CCl4 is heated at reflux for 20 hours. The reaction mixture is washed with water and brine and concentrated using a rotary evaporator. Crystallization from ethyl acetate yields the title compound. TLC: hexane/ethyl acetate 6/1: Rf=0.63, 1H-NMR (CDCl3): δ 8.64 (d, J=3, 1H), 8.41 (d, J=3, 1H), 5.02(s, 2H), 4.27(s, 3H), 4.20 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.IC.[C:25]([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:25])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc2c(=O)n(-c3cccc(Br)c3C)c(=O)[nH]c12
Agent: [Cs+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cccc2c(=O)n(-c3cccc(Br)c3C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 3-(3-bromo-2-methylphenyl)-8-methoxyquinazoline-2,4(1H,3H)-dione (535 mg, 1.48 mmol), iodomethane (0.185 mL, 2.96 mmol) and Cs2CO3 (965 mg, 2.96 mmol) in THF (20 mL) was stirred at room temperature overnight. The mixture was filtered and concentrated. The residue was dissolved in DCM, washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated. The residue was purified by column chromatography on silica gel (40 g silica), eluting with EtOAc-hexanes (gradient from 0-100%), to give 3-(3-bromo-2-methylphenyl)-8-methoxy-1-methylquinazoline-2,4(1H,3H)-dione (442 mg). Mass spectrum m/z 375, 377 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.90 (dd, J=7.2, 2.3 Hz, 1H), 7.66 (dd, J=8.0, 1.2 Hz, 1H), 7.31-7.22 (m, 2H), 7.22-7.19 (m, 1H), 7.17-7.13 (m, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH2:24]([NH:27][C:28]([CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:29])[CH2:25][CH3:26]>>[O:29]=[C:28]([NH:27][CH2:24][CH2:25][CH3:26])[CH2:30][CH2:31][CH2:32][C:33]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:34]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CCCNC(=O)CCCC(=O)O
Product: CCCNC(=O)CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 4-propylcarbamoyl-butyric acid to yield (3aR,4S,7aR)-methyl 4-(5-oxo-5-(propylamino)pentanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+H]=938; RT=1.19 min; UPLC Method I
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13]C)[C:5]=1[CH:15]=[O:16].B(Cl)(Cl)Cl>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([OH:13])[C:5]=1[CH:15]=[O:16]
Reactant: COC(=O)c1c(C)c(OC)cc(OC)c1C=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(C)c(OC)cc(O)c1C=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a suspension of 95.3 g of 2-formyl-3,5-dimethoxy-6-methylbenzoic acid methyl ester in 250 ml of dichloromethane were added 800 ml of a 1M solution of boron trichloride in dichloromethane over 40 min at a temperature of 5°-10° C. The mixture was allowed to warm to 20° C. within 30 min and stirring was continued at room temperature for 4 h. The clear solution was cooled to 5° C. and then poured into a mixture of 1.5 I of ice-water and 0.5 l of dichloromethane. The layers were separated and the aqueous phase was back-extracted with 0.4 l of dichloromethane. The organic layers were washed with water, dried over sodium sulfate and evaporated in vacuo. Crystallization of the residual material from ethyl acetate/hexane provided 77.3 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid methyl ester as colorless crystals of m.p. 118°-119° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10])=[C:2]=[O:3].[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[NH2:18].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[NH:18][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[C:2]=[O:3]
Reactant: COCCOC(N)=O
Reactant: O=C=NCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCCOC(=O)NC(=O)CCCCCN=C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
8.8 g (50 mmol) of 6-isocyanato-caproyl chloride were introduced into 25 ml of toluene. A mixture of 5.95 g (50 mmol) of carbamic acid-β-methoxyethyl ester, 3.96 g (50 mmol) of pyridine and 15 ml of toluene was added dropwise at 0° C. The mixture was stirred for 6 hours at 25° C. and then heated to 60° C. for 10 hours. It was diluted with 100 ml of toluene and extracted once with 50 ml of 0.1N HCl. The organic phase (MgSO4) was dried and filtered and the solvent was evaporated off. 5.1 g of a product similar in its properties to the product from Example 2 were obtained. Yield: 5.1 g=40%.
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[CH2:35]([SH:44])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:35]([S:44][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCS
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Product: CCCCCCCCCSc1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1

Procedure:
Using the procedure of Example 4 with 30 g of 5-chloro2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole and 17.6 g of nonyl mercaptan, the title compound is prepared.
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[Li]C(C)(C)C.[CH2:16]([N:18]([CH2:33][CH3:34])[CH2:19][CH2:20][N:21]1[C:31]2[C:26](=[C:27]([Br:32])[CH:28]=[CH:29][CH:30]=2)[C:24](=[O:25])[C:22]1=[O:23])[CH3:17].[NH4+].[Cl-]>C1COCC1>[CH2:33]([N:18]([CH2:16][CH3:17])[CH2:19][CH2:20][N:21]1[C:31]2[C:26](=[C:27]([Br:32])[CH:28]=[CH:29][CH:30]=2)[C:24]([OH:25])([C:2]2[C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[S:5][CH:6]=2)[C:22]1=[O:23])[CH3:34]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Brc1csc2ccccc12
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1C(=O)C(O)(c2csc3ccccc23)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To 3-bromobenzo[b]thiophene (146.5 mg, 2.2 eq) in anhydrous THF (2 mL) at −40° C. (bath temperature) was added t-BuLi (0.40 mL, 1.70 M in pentane, 2.1 eq). The resulting light yellow coloured solution was stirred for 30 minutes, after which 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added. Stirring was continued at −40° C. for 9 hours. Saturated aqueous NH4Cl (1.5 mL) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration, the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1%-2% MeOH in CHCl3) to give the title compound as a yellow/brown powder (119.3 mg, 84%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH2:14])=[CH:11]2)=[N:6]1.[O:16]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:30](=[O:31])[CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)=[CH:11]2)=[N:6]1
Reactant: CN(C)CCn1cc2cc(N)ccc2n1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)CCn1cc2cc(NC(=O)Cc3ccc(Oc4ccccc4)cc3)ccc2n1
Reaction time: 6 h

Procedure:
A mixture of 2-(2-Dimethylamino-ethyl)-2H-indazol-5-ylamine (49.0 mg, 0.243 mmol), (4-phenoxy-phenyl)-acetic acid (60.0 mg, 0.248 mmol), EDCI (57.0 mg, 0.298 mmol), N-hydroxybenzotriazole (40.0 mg, 0.296 mmol), N-methyl morpholine (64.0 mg, 0.633 mmol) and 2 mL of N,N-dimethylformamide was shaken for 6 hours. The solvents were removed under vacuo and the residue dissolved in 1.5 mL of a 1:1 mixture of dimethylsulfoxide/methanol was purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) ppm 2.49(s, 6H) 3.34 (t, 2H, J=6.44), 3.37 (s, 2H), 4.50 (t, 2H, J=6.44), 6.69–6.74 (m, 4H), 6.85 (m, 1H), 7.03 (m, 1H), 7.08–7.13 (m, 4H), 7.32 (m, 1H), 7.90 (s, 1H), 8.10 (s, 1H), 9.26 (s, 1H); MS (DCI/NH3) m/z 415 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13](Cl)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([CH:27]([NH2:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([NH:34][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(c1ccccc1)c1ccccn1
Reactant: O=C(Cl)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: O=C(NC(c1ccccc1)c1ccccn1)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1

Procedure:
211 mg of the title compound were obtained from 2-phenylsulfonylamino-5-chlorobenzoyl chloride and C-phenyl-C-pyridin-2-ylmethylamine in accordance with general method 5. MS (ES+): m/z=478 (M+1).