Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][N:31]([CH3:39])[C:32]([C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:36]4[CH2:37][CH2:38][C@H:34]([C:32]([N:31]([CH3:39])[CH3:30])=[O:33])[CH2:35]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CN(C)C(=O)[C@H]1CCNC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@H](C(=O)N(C)C)C3)n(C)c2n1
Reaction time: 18 h
Yield: 37.2 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol) and (S)-pyrrolidine-3-carboxylic acid dimethylamide (44 mg, 0.31 mmol) in DCE (5 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 70:30) to afford 398 as a cream solid (50 mg, 38%). LCMS (Method G): RT=5.90 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.28 (m, 2 H); 4.35 (m, 4 H); 3.98-3.80 (m, 9 H); 3.40-3.25 (m, 3 H); 3.20-2.78 (m, 10 H); 2.15-2.07 (m, 2 H) and 1.50-1.41 (m, 3H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[C:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)[CH3:2]>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
A flask was charged with EtOH (700 ml), tert-butyl 3-(2-ethoxy-2-oxoethylidene)pyrrolidine-1-carboxylate (246 g, 965 mmol) and Pd/C (40 g). Then the flask was charged with H2 (3 L). The resulting solution was stirred overnight. The reaction mixture was filtered and concentrated to afford tert-butyl 3-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[C:17]([F:18])=[C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[C:17]([F:18])=[C:16]([N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[CH3:25])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)c(F)c(C(=O)OCC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)c(F)c(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Dissolve 6-fluoro-5-methanesulfonylamino-N-methyl-N-propyl-isophthalamic acid ethyl ester (0.160 g, 0.444 mmol) in DMF (1.0 mL). Add potassium carbonate (44.4 mg, 0.32 mmol), iodomethane (41.5 μL, 0.67 mmol) and tetrabutylammonium bromide (14.3 mg, 0.04 mmol) to the solution. Stir the resulting slurry at room temperature for 16 h. Quench with saturated aqueous sodium sulfate solution (10 mL) and extract with ethyl acetate (3×30 mL). Combine the organic layers and dry (magnesium sulfate). Azeotrope the residue with xylenes to remove residual DMF. Purify (silica gel chromatography, eluting with 40:60 ethyl acetate:dichloromethane) to give the title compound as a solid (111 mg, 67%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]OC)=[N:5][N:4]=[C:3]1[SH:10].[C:11](O)(=O)CC.CNC(=S)NN>>[CH3:1][N:2]1[C:6]([CH2:7][CH3:11])=[N:5][N:4]=[C:3]1[SH:10]
Reactant: CCC(=O)O
Reactant: COCc1nnc(S)n1C
Agent: CNC(=S)NN
Product: CCc1nnc(S)n1C

Procedure:
The reaction was performed similar to the method described for the preparation 4-Methyl-5-methoxymethyl-4H-[1,2,4]triazole-3-thiol by reacting 16.4 g of N,N′-carbonyldiimidazol (0.101 mol) with 5 g of propionic acid (0.067 mol) and 14.2 g of 4-methyl-3-thiosemicarbazid (0.135 mol). Yield: 3.8 g
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH2:19])[C:6]([NH:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:7][CH:8]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21].O>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])[C:20](=[O:21])[NH:19][C:5]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Cl)cc1Nc1ccc(Cl)cc1N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)cc1-n1c(=O)[nH]c2cc(Cl)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Chloro-N1-(5-chloro-2-methoxy-phenyl)-benzene-1,2-diamine hydrochloride (6.3 g, 20 mmol) in tetrahydrofurane (70 ml) was added carbonyldiimidazole (9 g 55 mmol). The reaction mixture was stirred at 60° C. overnight, poured into water (app. 200 ml) and extracted with ethylacetate, and the organic phase was washed with brine and evaporated to an oil. The title compound was crystallized from toluene.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH:13]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:19]=[C:16]1[CH2:15][CH2:14][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:18][N:17]1[CH:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(Br)CC
Reactant: O=C1CCC(c2ccccc2)CN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC)N1CC(c2ccccc2)CCC1=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
In a 1 l three necked flask fitted with reflux condenser, magnetic stirrer and dropping funnel under inert atmosphere, 9.8 g (87 mmoles) of potassium t-butoxide were suspended in 600 ml of dry toluene. 11.8 g (67 mmoles) of 5-phenyl-2-piperidinone 25 were added, and the mixture stirred for 30 min. 17 g (87 mmoles) of ethyl 2-bromobutanoate were added and the temperature raised to 70° C. for 5 hours. 600 ml of ethyl acetate were added, the solution was washed twice with brine, the organic phase dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by PrepLC (1 kg SiO2, CH2Cl2/EtOH, 97.5/2.5) to give 3.7 g of pure ester 26 as a mixture of diastereomers, 70.4% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH2:11]1[CH2:16][C:14](=[O:15])[CH:13](Cl)[CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:13]2[CH2:12][CH2:11][CH2:16][C:14]2=[O:15])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: O=C1CCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1OC1CCCC1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-2-methoxyphenol (6.31 g), α-chlorocyclopentanone (6.9 ml), potassium carbonate (9.57 g), and DMF (63 ml) was stirred at 90° C. for 2 hours. α-Chlorocyclopentanone (14 ml) was further added to the mixture, followed by stirring at 90° C. for one hour. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic, layer was washed with a 1N aqueous solution of sodium hydroxide and then with a saturated saline, and dried over sodium sulfate. The solvent, was distilled off, and the residue was purified by column chromatography (silica gel, hexane:ethyl acetate=2:1) to give Compound IIl-a (11.8 g, 99%) as an oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:25][Sn]Cl>Cl.CCO>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:7]1[CH:8]=[CH:9][C:10]([Cl:25])=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[CH:2]2)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2c(Cl)ccnc12
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 68.5 %

Procedure:
In a similar fashion using route 1 general procedure 4, N-(5-chloro-quinolin-8-yl)-2-nitro-benzenesulfonamide (Intermediate 246) (600 mg, 1.64 mmol), SnCl2 (940 mg, 4.94 mmol), 6N HCl (5-6 drops) and EtOH (12 ml) at 80° C. for 3 h, gave the title compound (375 mg, 55%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].O>CO>[C:14]1([O:13][C:11]([N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH2:3]2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Clc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(Oc1ccccc1)N1C=CC=C(Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of 3-chloro-pyridine (6.0 g, 53 mmol) in methanol (50 mL) was added NaBH4 (2.6 g, 69 mmol) at −78° C., following addition of phenyl chloroformate (8.3 g, 53 mmol) at same temperature. The mixture was stirred at r.t. for 0.5 h. Then water (200 mL) was added slowly into the solution. The precipitate was collected by filtration to give crude product (Yield: 8.2 g, 67%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([C:14]([C:16]2([N:19]3[CH:23]=[N:22][C:21]([Cl:24])=[N:20]3)[CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]2([C:16]3([N:19]4[CH:23]=[N:22][C:21]([Cl:24])=[N:20]4)[CH2:17][CH2:18]3)[CH2:4][O:15]2)=[CH:25][CH:26]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ccc(C2(C3(n4cnc(Cl)n4)CC3)CO2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
60 ml of absolute dimethyl sulphoxide are added dropwise at 10° C. under a nitrogen atmosphere to a stirred mixture of 2.5 g (83 mmol) of sodium hydride (80 per cent of substance) and 17.6 g (80 mmol) of trimethyl sulphoxonium iodide. Stirring is continued for one hour at 20° C., and a solution of 20 g (71 mmol) of 1-(4-chlorobenzoyl)-1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropane in 30 ml of dimethyl sulphoxide is subsequently added at 10° C. After the reaction mixture has been stirred for 48 hours at 20° C., it is warmed for another hour at 40° C. and then poured into water. The mixture is extracted several times using ethyl acetate, and the combined organic phases are washed with water, dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. This procedure gives 21 g (100% of theory) of 2-(4-chlorophenyl)-2-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-oxirane in the form of an oil. 1H-NMR (200 MHz, CDCl3): δ=0.8-1.4 (m, 4H); 2.92 (d, 1H); 3.15 (d, 1H); 7.10 (d, 2 H); 7.38 (d, 2H); 7.75 (s, 1H). ##STR18##
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2Br)[CH2:3]1.[CH3:29][C:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[N:32](C2CCCCO2)[N:31]=1>>[NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2[C:33]2[NH:32][N:31]=[C:30]([CH3:29])[CH:34]=2)[CH2:3]1
Reactant: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2Br)C[C@@H]1O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)ccc2N2C[C@H](N)[C@@H](O)C2)[nH]n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 76 using 4-((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (Stage 76.1) and 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford the title compound as white solid. HPLC (Condition 7) tR=5.763 min, UPLC-MS (Condition 8) tR=0.82 min, m/z=478.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.52 (br. s, 2H) 2.26 (br. s, 3H) 2.71-2.86 (m, 2H) 3.10 (br. s, 1H) 3.23-3.38 (m, 2H) 3.67-3.79 (m, 1H) 4.95 (br. s, 1H) 6.09 (s, 1H) 6.77 (d, J=8.21 Hz, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.77-7.94 (m, 4H) 10.08 (s, 1H) 12.45 (br. s, 1H).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[NH:9][C:10](=O)[O:11]CC)(=[O:3])[NH2:2].[OH-].[Na+]>CCO>[NH:9]1[C:8]2[C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[O:5][C:4]=2[C:1](=[O:3])[NH:2][C:10]1=[O:11]
Reactant: CCOC(=O)Nc1c(C(N)=O)oc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1[nH]c(=O)c2oc3ccccc3c2[nH]1
Temperature: 25 °C

Procedure:
Ethyl 2-carbamoylbenzofuran-3-ylcarbamate (114 mg, 0.460 mmol, 1.0 eq) in a 5% NaOH solution (3.7 mL, 4.60 mmol, 10.0 eq) and EtOH (2.2 mL) was heated to reflux for 1 h. After the mixture was cooled to room temperature, the product was precipitated by adding HCl (conc., 37%) and a solid was collected by filtration and washed with water and Et2O. This compound (40 mg, 43%) was used for the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH2:20][CH3:21])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[CH:38][N:37]=[C:36]2[S:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([S:45][C:36]3[C:35]4[C:40](=[CH:41][C:42]([O:43][CH3:44])=[C:33]([O:32][CH3:31])[CH:34]=4)[N:39]=[CH:38][N:37]=3)[CH:47]=2)=[O:19])[N:7]([CH2:20][CH3:21])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Sc2ncnc3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Yield: 19.1 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-ethyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.523 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (100 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane: methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-ethyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (30 mg, 19%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) 89.12 (s, 1H), 8.70 (s, 1H), 8.53 (s, 1H), 7.85 (s, 1H), 7.52 (m, 1H), 7.43 (m, 1H), 7.35-7.36 (m, 2H), 7.25 (m, 1H), 6.04 (s, 1H), 4.00 (s, 6H), 3.93 (m, 2H), 1.21-1.29 (m, 12H); LC-MS (ESI) m/z 507 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=2)[O:3]1.[C:18]([O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([CH3:21])([CH3:20])[CH3:19].C(OCC)(=O)C>S(Cl)(Cl)=O.CCCCCC>[C:18]([O:22][C:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:15][C:14]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[O:16])=[CH:29][CH:30]=1)=[O:32])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Reactant: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)Cc1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of 2,2,4,4-tetramethyl chroman-6-carboxylic acid (0.1 g, 0.43 mmol) in thionyl chloride (10 mL) was refluxed for 2 h. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in 5 mL of dichloromethane and treated with triethyl amine (5 mL) followed by tert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.088 g, 0.427 mmol). After 0.5 h, the reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to afford the title compound (0.1 g, 55%).
Reaction SMILES: [Cl:1][C:2]1([F:24])[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]1=[C:4]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:19]([CH2:18][CH2:17][C:4]1[CH:5]([C:12]([OH:14])=[O:13])[NH:6][C:7]2[C:3]=1[C:2]([Cl:1])([F:24])[CH:10]=[C:9]([Cl:11])[CH:8]=2)([OH:21])=[O:20]
Reactant: CCOC(=O)CCC1=C2C(=CC(Cl)=CC2(F)Cl)NC1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCC1=C2C(=CC(Cl)=CC2(F)Cl)NC1C(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 4,6-dichloro-4-fluoro-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (1.13 g, 3 mmol) was dissolved in 15 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 0.38 g of lithium hydroxide trihydrate (3 equiv.) in 15 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×15 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 292-294° C. 1H-NMR (DMSO-d6) δ 2.48 (m, 2H, 2′-H); 3.48 (m, 2H, 1′-H); 7.49 (dd, 1H, 2J=6 Hz, 7-H); 11.98 (s, 1H, NH); 12.72 (b, 2H, 2CO2H). 13C-NMR (DMSO-d6) δ 20.1 (C-2′); 36.1 (C-1′); 112.5 (C-7); 113.0, 113.2, 117.6, 117.7, 121.3, 121.4 (C-5); 122.3 (C-4); 127.7 (C-6); 132.5 (C-3); 147.2 (C-3a); 149.0 (C-2); 162.5 (2′-CO2H), 173.6 (2-CO2H). LC-MS (m/z): 337 [M-NH4+]+, 320 [M]+, 318 [M]−. Purity (LC-MS): 98.6%.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]=1Br)=[O:12])[CH2:3]2.C(=[NH:36])(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1.C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:22]([NH2:36])=[CH:21][CH:20]=[CH:19][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1sc2ccccc2c1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
87 mg (0.22 mmol) of N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzothiophene-2-carboxamide hydrochloride, 47.1 mg (0.26 mmol) of benzophenone imine, 12.1 mg (0.02 mmol) of rac-BINAP, 45.8 mg (0.48 mmol) of sodium tert-butoxide and 6.0 mg (0.01 mmol) of Pd2(dba)3 are put under argon in a heat-dried flask. 1.5 ml of toluene are added, and the reaction mixture is heated to 80° C. After 30 min, 0.5 ml of THF, and after 6 h a further 6.0 mg (0.01 mmol) of Pd2(dba)3, are added. After a further 6 h, a filtration (0.45 μm filter) is followed by purification by preparative HPLC. The resulting benzophenone imine adduct is dissolved in a 1:1 mixture of THF and methanol with the addition of 20% by volume 1 N hydrochloric acid. After 1 h at room temperature, the reaction mixture is concentrated. The resulting solid is stirred with acetonitrile and filtered. Drying under high vacuum results in 17 mg (21% of theory) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(OC([N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=3)[NH:22][C:21]2=[O:37])[CH2:16][CH2:15]1)=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:36][N:33]1[CH2:32][CH2:31][N:30]([C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:37])[N:20]([CH:17]2[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]2)[CH2:29]3)[CH2:35][CH2:34]1
Reactant: CN1CCN(c2ccc3c(c2)CN(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc3c(c2)CN(C2CCNCC2)C(=O)N3)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
2 mL of trifluoroacetic acid were added to the ice-cooled solution of 1.1 g (2.561 mmol) of 3,4-dihydro-3-[1-(1,1-dimethylethoxycarbonyl)-4-piperidinyl]-6-(4-methyl-1-piperazinyl)-2(1H)-quinazolinone in 20 mL of methylene chloride. The reaction mixture was stirred for 15 hours at ambient temperature and for 5 hours at 40° C. and then evaporated down in vacuo. The residue remaining was taken up in 5 mL of water, the solution formed was saturated with potassium carbonate and extracted exhaustively with dichloromethane. The combined extracts were evaporated down in vacuo. The residue obtained was purified by column chromatography on silica gel using dichloromethane/methanol 9/1 (v/v) to start with, then dichloromethane/methanol/concentrated ammonia 70/30/3 (v/v/v) as eluant. The appropriate fractions were evaporated down in vacuo, the residue remaining (0.5 g; 59% of theoretical) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[C:10]3[N:14]([C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1.[O-]S([O-])=O.[Na+].[Na+].[C:36]([O-])([O-])=O.[Na+].[Na+].CI>O.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:36])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[C:10]3[N:14]([C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(-c2ccc(F)cc2)c(-c2ccc(S(=O)(=O)Cl)cc2)c2n1CCC2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCO
Product: COC(=O)c1c(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c2n1CCC2

Procedure:
4-[2-(4-Fluorophenyl)-3-methoxycarbonyl-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonyl chloride (1.7 g, 3.8 mmol), suspended in water (10 ml), is treated with Na2SO3 (0.56 g, 4.4 mmol) and then with Na2CO3 (0.72 g, 6.8 mmol) and stirred at 70° C. for 2 h. The solution is treated with a solution of CH3I (0.88 g, 6.2 mmol) in ethanol (20 ml) and heated under reflux for 2 h. After cooling, the ethanol is removed in vacuo, the residue is treated with water (25 ml) and the product from the reaction is taken up in ethyl acetate (2×30 ml). The ethyl acetate phase is washed with conc. NaCl solution and water, dried using Na2SO4 sicc. and the filtrate is concentrated. After removing the solvent in vacuo, 0.4 g (25%) of methyl 2-(4-fluorophenyl)-1-(4-methylsulphonylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate remains as a residue having a concentration of 77%.