Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](I)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:27]([CH:35]1[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:27]([OH:34])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:35]3[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]3)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nc2ccc(C(O)(c3ccccc3)C3CCN(C(C)=O)CC3)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (1.3 M, 0.73 mL, 0.94 mmol) was added dropwise to an ice-water cooled, stirring solution of 3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-4-chloro-6-iodo-2-methoxyquinoline (300 mg, 0.63 mmol, Intermediate 20: step c) in dry tetrahydrofuran (6 mL). After 10 minutes, a solution of 1-(4-benzoylpiperidin-1-yl)ethanone (218 mg, 0.94 mmol, Intermediate 18) in tetrahydrofuran (5 mL) was added dropwise. After 30 minutes, the flask was warmed to 23° C. After 1 hour, the flask was warmed to 55° C. After 30 minutes, the flask was allowed to cool to 23° C. Water (20 mL), saturated aqueous sodium chloride solution (20 mL), and ethyl acetate (100 mL) were added. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (5 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 5% methanol-dichloromethane provided the title compound which was further purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. 1H NMR (500 MHz, CDCl3) δ ppm 8.47 (s, 1H), 8.32-8.25 (m, 1H), 8.06 (s, 1H), 7.80-7.72 (m, 1H), 7.72-7.62 (m, 1H), 7.57-7.48 (m, 4H), 7.44-7.38 (m, 2H), 7.37-7.29 (m, 2H), 7.26-7.18 (m, 1H), 4.75-4.63 (m, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 3.90-3.75 (m, 1H), 3.17-2.99 (m, 1H), 2.76 (t, J=11.8 Hz, 1H), 2.66-2.49 (m, 1H), 2.28 (s, 1H, rotamer), 2.27 (s, 1H, rotamer), 2.05 (s, 3H, rotamer), 2.04 (s, 3H, rotamer), 1.75-1.62 (m, 1H), 1.55-1.28 (m, 3H); MS (ESI): mass calcd. for C33H32ClN5O3, 581.2. m/z found, 582.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:13].[OH-].[K+].[Cl:16][C:17]([Cl:21])([Cl:20])[S:18]Cl>O>[Cl:16][C:17]([Cl:21])([Cl:20])[S:18][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:12])[N:2]([CH3:1])[C:3]1=[O:13]
Reactant: Cn1c(=O)[nH]c2ccccc2c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)c2ccccc2n(SC(Cl)(Cl)Cl)c1=O
Yield: 35.3 %

Procedure:
To a suspension of 3.52 g (0.02 mole) 3-methyl-2,4-dioxo-1,3-dihydroquinazoline in 25 ml water was added a solution of 1.12 g (0.02 mole) potassium hydroxide in 15 ml water. To this clear, basic solution was added, dropwise, a mixture of 3.72 g (0.02 mole) trichloromethanesulfenyl chloride and 0.15 g of an emulsifier (as in example 1) in 2.5 ml water while maintaining the reaction mixture at 0°-5° C. The reactants were mixed so that the reaction mixture was kept at a pH greater than 7. The precipitate that formed was filtered off and the filter cake washed with water and air-dried. This was then extracted with hot benzene and the benzene removed under vacuum to yield a semi-solid oil which completely solidified on standing. The solid was recrystallized from benzene-cyclohexane to afford 2.3 g (35%) of 1-trichloromethylthio-3-methyl-2,4-dioxo-1,3-dihydroquinazoline having a melting point of 128°-129° C. Reaction of the benzene insoluble solids with additional trichloromethylsulfenyl chloride followed by the same work-up described above afforded additional product, giving an overall yield of 60%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]#[C:15][CH3:16])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.C(OCC)C.[Cu]Cl>[CH3:21][Si:22]([C:25]#[C:26][C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH2:19][CH3:20])[C:10]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]#[C:15][CH3:16])=[O:11])[CH:5]=[N:6][CH:7]=1)([CH3:24])[CH3:23]
Reactant: C#C[Si](C)(C)C
Reactant: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(Br)c1
Agent: Cl[Cu]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1cncc(C#C[Si](C)(C)C)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
2-(5-Bromo-3-pyridyloxy)-N-(4-methylpent-2-yn-4-yl)butyramide (0.40 g), trimethylsilylacetylene (0.24 ml), copper (I) chloride (0.015 g) and palladium dichloride bis(triphenyl)phosphine (0.030 g) in dry triethylamine (4 ml) were sealed in a glass tube and heated to 90° C. for 3 hours. The mixture was cooled to ambient temperature and stored for 18 hours. Further trimethylsilylacetylene (0.24 ml) and palladium dichloride bis(triphenyl)-phosphine (0.030 g) were added and the mixture re-heated in the sealed tube for another 5.5 hours. The reaction mixture was cooled to ambient temperature, stored for 72 hours, diluted with diethyl ether and washed with water (three times). The organic phase was separated, dried over magnesium sulphate and evaporated under reduced pressure to give a dark yellow gum, ca. 0.4 g, containing the required product, which was used in the next Stage without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1.C(=O)(O)[O-].[Na+].C1COCC1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N+:30]([O-:32])=[O:31]>O>[N+:30]([C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=1[N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([OH:8])[CH2:3]1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: O[C@@H]1CCCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCC[C@@H](O)C1
Reaction time: 14 h

Procedure:
To a 100-mL round bottom flask (RBF) was added (R)-piperidin-3-ol hydrochloride (1.29 g, 9.37 mmol), sodium bicarbonate (2.76 g, 32.8 mmol), THF and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.31 ml, 9.37 mmol). The yellow mixture was heated to 75° C. with a water-cooled reflux condensor and allowed to stir 14 h. The reaction was filtered through a glass frit, rinsing with EtOAc, and concentrated in vacuo to give (R)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol as an orange oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[N:5]=[C:4]([NH2:19])[N:3]=1>C1COCC1.[Pd]>[NH:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][C:6]3[CH:7]=[CH:2][N:3]=[C:4]([NH2:19])[N:5]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1
Reactant: Nc1nc(Cl)cc(Oc2ccc3ncccc3c2)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc3c(c2)CCCN3)n1

Procedure:
A solution of 5.4 g (0.02 mol) 4-chloro-6-(quinolin-6-yloxy)-pyrimidin-2-ylamine in 600 mL of THF is hydrogenated during 21 h in the presence of 1.2 g Pd/C (10% Engelhard 4505). Then the catalyst is filtered off and the filtrate concentrated in vacuuo. The residue is partitioned between ethyl acetate and conc. sodium bicarbonate solution and the organic layer washed with brine, dried and evaporated. The crude product is purified by flash-chromatography on silica gel using dichloromethane/methanol 95:5 as eluent. Fractions with pure compound are pooled and evaporated. The crystalline material is triturated with ether, filtered and dried to give the title compound: m.p. 180-182° C.; MS: [M+1]+=243; TLC (dichloromethane/methanol 95:5): Rf=0.4.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:26])[C:21]([CH3:23])([CH3:22])[O:20][B:19]([CH:24]=[CH2:25])[O:18]1.CCN(CC)CC>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[CH3:22][C:21]1([CH3:23])[C:17]([CH3:26])([CH3:16])[O:18][B:19](/[CH:24]=[CH:25]/[C:2]2[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:20]1
Reactant: Brc1ccc(CCN2CCOCC2)cc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)OB(/C=C/c2ccc(CCN3CCOCC3)cc2)OC1(C)C
Temperature: 80 °C
Yield: 76.8 %

Procedure:
To a mixture of 4-(4-bromophenethyl)morpholine (731 mg, 2.71 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.5 mL, 2.95 mmol, 1.1 eq.) and toluene (10 mL) in a 20 mL microwave vial was added Et3N (0.76 mL, 5.4 mmol, 2 eq.), followed by Pd(PtBu3)2 (14 mg, 0.027 mmol, 1 mol %). The resulting mixture was purged with argon, then capped and heated at 80° C. (oil temp.) for 2 h. After cooling to rt, it was quenched with sat. NaHCO3 (10 mL), H2O (10 mL), extracted with EtOAc (30 mL×2) and dried (Na2SO4). After evaporation of the solvents, the residue was purified by Biotage column system (EtOAc/hex gradient: 0-100%) to give (E)-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenethyl)morpholine as a white solid (714 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=8.0 Hz, 2H), 7.38 (d, J=19.0 Hz, 1H), 7.19 (d, J=7.8 Hz, 2H), 6.13 (d, J=18.3 Hz, 1H), 3.75 (t, J=4.4 Hz, 4H), 2.84-2.77 (m, 2H), 2.63-2.56 (m, 2H), 2.53 (br, pseudo s, 4H), 1.32 (s, 12H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)NC=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].OC1C=C(OCC2C=CC=CC=2)C=CC=1C(OC)=O.OC1C=C(OCC2C=CC3C(=CC=CC=3)C=2)C=CC=1C(OC)=O.OC1C=C(OCC2C3C(=CC=CC=3)C=CC=2)C=CC=1C(OC)=O.OC1C=C(OCC2C=CC3OCOC=3C=2)C=CC=1C(OC)=O.OC1C=C(OCCC2C=CC=CC=2)C=CC=1C(OC)=O.OC1C=C(OCC2C=CC(C(C)C)=CC=2)C=CC=1C(OC)=O.OC1C=C(OCC2C=CC([N+]([O-])=O)=CC=2)C=CC=1C(OC)=O.OC1C=C(OCC2C=CC(F)=CC=2)C=CC=1C(OC)=O.OC1C=C(OCC2C=CC(Cl)=C(Cl)C=2)C=CC=1C(OC)=O.OC1C=C(OCC2C=CC(OC)=CC=2)C=CC=1C(OC)=O.OC1C=C(OCC2C=CC=C(OC)C=2)C=CC=1C(OC)=O>>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OCCc2c[nH]c3ccccc23)cc1O
Agent: COC(=O)c1ccc(OCCc2ccccc2)cc1O
Agent: COC(=O)c1ccc(OCc2ccc(C(C)C)cc2)cc1O
Agent: COC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1O
Product: COC(=O)c1ccc(OCCCc2ccccc2)cc1O

Procedure:
methyl 2-hydroxy-4-(2-(3-indolyl)ethoxy)benzoate; methyl 2-hydroxy-4-benzyloxybenzoate, m.p. 101-102° C.; methyl 2-hydroxy-4-(2-naphthylmethoxy)benzoate; methyl 2-hydroxy-4-(1-naphthylmethoxy)benzoate; methyl 2-hydroxy-4-(3,4-methylenedioxybenzyloxy)benzoate (solid); methyl 2-hydroxy-4-(2-phenylethoxy)benzoate; methyl 2-hydroxy-4-(4-isopropylbenzyloxy)benzoate, m.p. 68-70° C.; methyl 2-hydroxy-4-(4-nitrobenzyloxy)benzoate, m.p. 178-180° C.; methyl 2-hydroxy-4-(4-fluorobenzyloxy)benzoate, m.p. 82-84° C.; methyl 2-hydroxy-4-(3,4-dichlorobenzyloxy)benzoate, m.p. 134-136° C.; methyl 2-hydroxy-4-(4-methoxybenzyloxy)benzoate; and methyl 2-hydroxy-4-(3-methoxybenzyloxy)benzoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=3)[CH:14]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][C:32]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:33]=1[CH:34]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[N:17]([CH2:18][CH2:19][CH3:20])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][CH2:34][C:33]4[C:36]([CH3:41])=[CH:37][C:38]([CH3:40])=[CH:39][C:32]=4[CH3:31])[CH:23]=3)[CH:14]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: CCCN1Cc2cc(Oc3cccc(CN)c3)ccc2N=C1NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCN1Cc2cc(Oc3cccc(CNCc4c(C)cc(C)cc4C)c3)ccc2N=C1NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Under N2, a mixture of [6-(3-aminomethyl-phenoxy)-3-propyl-3,4-dihydro-quinazolin-2-yl]-carbamic acid tert-butyl ester (0.0007 mol) and 2,4,6-trimethyl-benzaldehyde (0.0007 mol) in DCE (10 mL) was stirred at room temperature, then NaBH(OAc)3 (0.2 g) was added, and the reaction mixture was stirred overnight at room temperature. A saturated NaHCO3 solution was added, and the layers were separated. The organic layer was dried, filtered off and the solvent was evaporated. The residue was purified by Biotage column chromatography (gradient eluent: CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C:17]2=[CH:16][CH2:15][C@@:14]2([CH3:22])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:30]([O:1][C@@H:2]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C:17]2=[CH:16][CH2:15][C@@:14]2([CH3:22])[C@H:8]3[CH2:9][CH2:10]/[C:11]/2=[CH:12]/[CH3:13])[CH2:3]1)(=[O:32])[CH3:31]
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)C3=CC[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
Compound 1.5 (19.0 g, 63 mmol) was dissolved in CH2Cl2 (380 mL). Triethylamine (17.6 mL, 126.6 mmol), DMAP (0.772 g, 6 mmol) and acetic anhydride (8.98 mL, 94 mmol) were added sequentially at 25° C. under a nitrogen atmosphere. The resulting solution was stirred for 2 h at 25° C., at which point the reaction was determined by TLC to be complete. The reaction was quenched by the addition of ice-water (100 mL) and the phases were separated. The aqueous layer was extracted three times with DCM (3×150 mL). The organic fractions were combined and washed with saturated brine solution (100 mL), dried over anhydrous Na2SO4 (50 g), and filtered. The filtrate was concentrated under vacuum to afford compound 1.6a (22.0 g, 95% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:37])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][CH:26]([NH2:29])[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:37])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)N2CCC(N)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 94 %

Procedure:
tert-Butyl N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-yl)carbamate (194 mg) was stirred in dichloromethane (7 mL) and trifluoroacetic acid (3 mL) for 4 h. The reaction was concentrated in vacuo and dissolved in ethyl acetate. The solution was washed with 3.8 N NaOH and brine. The organic layer was dried with magnesium sulfate. The reaction was concentrated in vacuo to yield 0.15 g (94%) of desired product. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31-1.52 (m, 2H) 1.83-2.02 (m, 2H) 2.14-2.26 (m, 3H) 2.84-3.07 (m, 2H) 3.11-3.33 (m, 1H) 4.31 (d, J=13.47 Hz, 1H) 4.66 (d, J=13.19 Hz, 1H) 7.07 (d, J=8.38 Hz, 2H) 7.14-7.20 (m, 1H) 7.21-7.34 (m, 3H) 7.44 (d, J=1.98 Hz, 1H); [M+H]+ 463.4.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:27][CH3:28])=[CH:8][C:9]([O:25][CH3:26])=[C:10](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2>C(OCC)(=O)C>[S:1]1[C:5]([C:6]2[C:7]([O:27][CH3:28])=[CH:8][C:9]([O:25][CH3:26])=[C:10](/[CH:12]=[CH:13]\[C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C\C(=O)c1ccc(C(=O)O)cc1
Yield: 21.7 %

Procedure:
A solution of 4-[3E-(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid (Ex-3, 101.4 mg, 0.23 mmol) in ethyl acetate (889 ml) was stirred in a well lighted-area at room temperature for 36 hours. The solution was concentrated to a yellow solid. The crude material was purified on reversed-phase preparative plates (20×20 cm, RP-18 F254, 1 mm) eluted with MEOH/ACN/H2O (45:45:10) to give 22.2 mg of the title compound, which was 86% the cis isomer by NMR analysis. 1H-NMR (DMSO-D6, major isomer) δ 7.98 (s, 4H), 7.86 (m, 2H), 7.76 (d, J=9 Hz 1H), 7.56 (s, 1H), 7.28 (m, 2H), 7.17 (d, J=12 Hz, 1H), 6.78 (d, J=12 Hz, 2H), 6.71 (s, 1H), 3.94 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[N:14]1([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a stirred solution of 3-(chlorosulfonyl)benzoic acid (1.10 g, 5.00 mmol) in DCM (10 mL) was added piperidine (1.49 g, 17.5 mmol) at 0° C., and the resulting solution stirred for 30 minutes. The volatiles were then removed in vacuo and the residue treated with aqueous 1N KHSO4. The aqueous phase was then extracted with ethyl acetate (×3), and the combined organic phases dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford 3-(piperidin-1-ylsulfonyl)benzoic acid (1.22 g, 4.52 mmol, 90%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:32]1[N:33]=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CCC[C@@H]1C#N>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][C@@H:23]2[C:32]#[N:33])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: N#C[C@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@@H]2C#N)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-pyrrolidine-2-carbonitrile hydrochloride and isolated as light-yellow solid (9.7 mg, 52%). MS (m/e): 396.4 (MH+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([Si](C(C)C)(C(C)C)C(C)C)[CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C1COCC1.O>[N:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCOCC2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(N3CCOCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
Add 1N solution of tetrabutylammonium fluoride (0.70 mL, 0.70 mmol) to a solution of 3-Morpholin-4-yl-1-triisopropylsilanyl-1H-indole (0.20 g, 0.56 mmol) in THF (2.0 mL). Stir at room temperature for 2 h, dilute with water, and extract with EtOAc. Wash EtOAc with saturated NaHCO3, water, dry (Na2SO4), and concentrate under vacuum. Purify the residue by flash chromatography using 20 to 80% of EtOAc in hexanes to give the title compound (0.10 g 89%). MS (ES) 203.1 (M+1)+.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH:11]1[C:19]([Br:20])=[CH:18][N:17]2[C:13](=[N:14][CH:15]=[CH:16]2)[CH:12]=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>>[CH:11]1[C:19]([Br:20])=[CH:18][N:17]2[C:13](=[N:14][CH:15]=[C:16]2[CH:4]=[O:5])[CH:12]=1
Reactant: Brc1ccc2nccn2c1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnc2ccc(Br)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 250 mL RB flask was charged with DMF (21.3 ml, 274 mmol) and cooled to 0° C.; phosphorus oxychloride (2.46 ml, 26.4 mmol) was added dropwise. This was stirred for 1 hour, then 6-bromoH-imidazo[1,2-a]pyridine (2.00 g, 10.2 mmol) was added in one portion. This was stirred at 100° C. for 5 hours and at room temperature for 16 hours. The flask was cooled to 0° C. and slowly neutralized with 6N aq. NaOH and sat. aq. NaHCO3, resulting in the formation of a precipitate which was collected by filtration to give 6-bromoH-imidazo[1,2-a]pyridine-3-carbaldehyde as a yellow-orange solid.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[C:10](=[O:26])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:9][N:6]1[C:7](=[O:8])[C:2]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[C:3]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:10](=[O:26])[C:4]2=[CH:5]1
Reactant: CN1CCNCC1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Product: CN1CCN(c2c3c(cn(C)c2=O)C(=O)N(CCc2ccc4ccccc4n2)C3=O)CC1

Procedure:
The title compound was prepared in analogy to the process described in Example 1 starting from 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (see Example c1)) and 1-methyl-piperazine.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](I)[CH3:15].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:14]([N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[NH:9][C:8]1=[O:11])[CH3:15]
Reactant: CCI
Reactant: Cc1cccc2[nH]c(=O)[nH]c12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)[nH]c2c(C)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17.10 g of 4-methyl-1,3-dihydrobenzimidazol-2-one in 250 ml of anhydrous N,N-dimethylformamide is admixed at 0° C. with 4.070 g of sodium hydride dispersion (60%). The reaction mixture is stirred at 0° C. over a further 30 minutes and 7.5 ml of ethyl iodide are added dropwise. The reaction mixture is stirred at 30° C. over 14 hours, poured onto 500 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (2×500 ml). The combined organic phases are washed with 500 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (200:5:1 dichloromethane-methanol-25% conc. ammonia); Rt=3.17.