Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]2[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Br:33])[CH:28]=1>O1CCCC1>[Br:33][C:29]1[CH:28]=[C:27]([NH:26][C:17]2[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([NH:13][C:8](=[O:11])[CH:9]=[CH2:10])[CH:15]=3)[N:20]=[CH:19][C:18]=2[C:24]#[N:25])[CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Triethylamine (0.359 g, 3.55 mmol) and acryloyl chloride (0.321 g, 3.55 mmol) were added to an ice cold solution of 1.00 g (2.96 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran under N2. After stirring overnight at 25° C., volatile material was removed and the residue was slurried with water and collected. Recrystallization from ethanol gave 0.580 g of brown solid: mass spectrum (electrospray, m/e): M+H 393, 395.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][CH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:16]=2[O:15][C:14]1=[O:30]>C(Cl)(Cl)Cl>[CH3:12][CH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([S:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[O:9])[C:16]=2[O:15][C:14]1=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1C(=O)Oc2c(Sc3ccccc3Cl)cccc21
Solvent: ClC(Cl)Cl
Product: CC1C(=O)Oc2c1cccc2S(=O)c1ccccc1Cl
Yield: 63.2 %

Procedure:
A solution of m-chloroperbenzoic acid (1.3 g) in chloroform (20 ml) was added dropwise to a solution of 3-methyl-7-(2-chlorophenylthio)-2,3-dihydrobenzofuran-2-one (1.8 g) in chloroform (20 ml) in 10 minutes at a temperature below 6° C. with stirring, and the mixture was stirred at the same temperature for 30 minutes and then filtered. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and water in turn, dried and evaporated under reduced pressure. The oily residue was crystallized with ethanol to give 3-methyl-7-(2-chlorobenzenesulfinyl)-2,3-dihydrobenzofuran-2-one (1.2 g), mp. 120°-122° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.[OH-].[NH4+:13]>CO.[Cu]Br>[CH:9]([O:8][C:4]1[CH:3]=[C:2]([NH2:13])[CH:7]=[N:6][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: [NH4+]
Agent: [Cu]Br
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1cncc(N)c1
Temperature: 170 °C
Yield: 72 %

Procedure:
Crude 5-bromo-3-isopropoxypyridine (3.71 g, 17.18 mmol) was dissolved in methanol (46 mL) and added to concentrated ammonium hydroxide (29.7%, 14.8 M, 50 mL) and copper(I) bromide (2.46 g, 17.18 mmol) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 170° C. (oil bath temperature) for 24 h. After cooling, the solution was concentrated by rotary evaporation. Sodium carbonate solution (17.6%, 200 mL) was added, and the mixture was extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation to give 1.88 g (72.0%) of a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1)[Si:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Br:24])=[C:14]([Si:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=1)[Si:8]([CH3:11])([CH3:9])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N(C(=O)OC(C)(C)C)[Si](C)(C)C)cc1[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(c1ccc(CBr)c([Si](C)(C)C)c1)[Si](C)(C)C

Procedure:
A suspension of tert-butyl[4-methyl-3-(trimethylsilyl)phenyl](trimethylsilyl)carbamate (3.00 g, 8.55 mmol), N-bromosuccinimide (NBS, 1.59 g, 8.97 mmol), 2,2′-azobis(2-methylpropionitrile) (AIBN, 42 mg, 0.26 mmol) in CCl4 (40 mL) was refluxed under N2 for 16 h. The reaction mixture was cooled down; hexanes (100 mL) were added and the solid was filtered off and washed with EtOAc. The combined filtrate was washed with aq. NaHCO3, dried over Na2SO4, filtered, concentrated on rotavap and further dried under vacuum. This material was not purified but used directly in the next step (˜80%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[OH:32][CH:33]([CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])[C:34](=[O:54])[CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][C:51](O)=[O:52])=[O:44].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:51](=[O:52])[CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][C:43](=[O:44])[NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][C:34](=[O:54])[CH:33]([OH:32])[CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)COCCOCC(=O)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCC(=O)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO

Procedure:
30 is prepared similarly to 18 starting from 68 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one, 76 mg of [2-({2-[2-(3,4,5,6,7-pentahydroxy-2-oxoheptyloxy)ethoxy]ethylcarbamoyl}methoxy)-ethoxy]acetic acid (27), 62 μl of diisopropylcarbodiimide and 44 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 30: C43H55F2N3O14 (875.93) MS (ESI) 876 (M+H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:26][CH:25]=2)=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:16]([N:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[NH:1][C:40](=[O:42])[N:23]2[C:24]1[CH:25]=[CH:26][C:27]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2N)cc1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ccc(-n2c(=O)[nH]c3c(N(Cc4ccccc4)Cc4ccccc4)ncnc32)cc1
Reaction time: 1 h
Yield: 217.4 %

Procedure:
To a stirred solution of tert-butyl 4-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate (38) (5.4 g, 10.6 mmol) and TEA (2.14 g, 21.2 mmol) in dry DCM (60 mL) at 0° C. and under N2 atmosphere, was added a solution of triphosgene (1.07 g, 3.6 mmol) in dry DCM (30 mL) dropwise during 1 h. Stirring was continued for 1 h before the reaction was quenched with water (20 mL). The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0 to 20% ethyl acetate in petroleum ether) to give tert-butyl 4-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (39) (4.2 g, 74%) as a light brown solid. LC-MS (ESI): m/z (M+1) 537.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]=1[F:19].C([Li])CCC.C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C>C1COCC1>[F:1][C:2]1[C:3]([F:19])=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[CH:6][C:7]=1[B:29]([OH:30])[OH:28]
Reactant: CCCCCOCCCCOc1cccc(F)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCOCCCCOc1ccc(B(O)O)c(F)c1F
Reaction time: 2 h

Procedure:
To a solution of 1,2-difluoro-3-(4-pentyloxybutoxy)-benzene (24), (1 equi.) in THF (5 mL/mmole), butyllithium (1.3 equi.) was added at −78° C. The reaction mixture was stirred at that temperature for 2 hr,. Then triisopropylborate (1 equi.) was added at that temperature. The reaction mixture was stirred at that temperature for 1 h and at room temperature for 10 h, quenched with water, extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by recrystallization from hexane gave 2,3-difluoro-4-(4-pentyloxybutoxy)phenylboronic acid (25), as a white solid (75%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[N:2]=1.[N+:15]([O-])([O-:17])=[O:16].[Na+]>OS(O)(=O)=O>[N+:15]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[N:2]=[CH:1]2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1cc2ccccc2cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Methyl isoquinoline-3-carboxylate (9.58 g, 51.2 mmol) in concentrated H2SO4 (100 mL) at 0° C. was treated with sodium nitrate (4.79 g, 56.4 mmol) in small portions such that the temperature was maintained below 5° C. Ten minutes after addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was poured over ice and adjusted to pH between 7 and 8 and filtered to afford the title compound as a bright yellow solid (11.44 g, 96%). MS (ESI+) m/z 233 (M+H)+; 1H NMR (DMSO, 300 MHz) δ 3.97 (s, 3H), 8.06 (t, J 8.2, 1H), 8.72 (dt, J 1.0, 8.2, 1H), 8.78 (dd, J 1.0, 7.8, 1H), 9.11 (s, 1H), 9.65 (s, 1H).
Reaction SMILES: Br[C:2]1[S:11][C:5]2[S:6][C:7](Br)=[C:8]([Br:9])[C:4]=2[C:3]=1[Br:12].C(O)(=O)C>[Zn].O>[Br:9][C:8]1[C:4]2[C:3]([Br:12])=[CH:2][S:11][C:5]=2[S:6][CH:7]=1
Reactant: Brc1sc2sc(Br)c(Br)c2c1Br
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Brc1csc2scc(Br)c12
Yield: 72.5 %

Procedure:
A mixture of 2,3,4,5-tetrabromothieno[2,3-b]thiophene (0.83 g, 1.8 mmol), zinc dust (0.29 g, 4.4 mmol), and acetic acid (30 ml) is refluxed for 2 h. The reaction mixture is poured into water, extracted with DCM, washed with aqueous saturated sodium carbonate solution, dried (Na2SO4), and concentrated under reduced pressure. The product is purified by recrystallisation from hot methanol to obtain white fibrous crystals (389 mg, 72%). M/Z (298, t, M+). Found C, 24.5; H, 0.8. Calc. for C6H2Br2S2C, 24.2; H, 0.7. 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 2H). 13C NMR (300 MHz, CDCl3) δ 139.35, 137.42, 126.44, 102.96.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.I[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (141.3 mL of a 0.32M stock solution, 45.0 mmol) cooled to −78° C. was treated with (3-chloro-phenyl)-acetic acid (3.41 g, 20.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.7 mL, 3:1). The resulting reaction solution was stirred at −78° C. for 1 h. Iodomethylcyclopentane (4.64 g, 22.08 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.64 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. The solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (1×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g, 72.9%) as a yellow solid: mp 70-72° C.; EI-HRMS m/e calcd for C14H17ClO2 (M+) 252.0917, found 252.0915.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([C:25]([NH:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)C1CCCC1
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(B(O)O)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
Dissolve 4-aminomethylphenyl boronic acid hydrochloride (1.0 g, 5.34 mmol) in DCM (50 mL), add triethylamine (1.64 mL, 11.74 mmol) and cool the mixture to 0° C. Add cyclopentanecarbonyl chloride (778 mg, 5.78 mmol) and warm to room temperature. Stir the reaction mixture for 18 h, filter and wash the solid with DCM (10 mL) to give the title compound as a fine white powder (1.1 g, 83%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1)=[O:22]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)c1
Reaction time: 5 h

Procedure:
A microwave vial was charged N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 650 mg, 2.02 mmol), 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 403 mg, 2.22 mmol) and DIPEA (1058 μl, 6.06 mmol) in dry DMSO (6.7 ml). The reaction was subjected to microwave irradiation at 120° C. for 2 hours and then at 140° C. for 5 hours. Upon cooling the mixture was partitioned between ethyl acetate and water, washing with water and brine, dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then further purified by column chromatography (basic silica 0-100% DCM/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH:13]=O.Cl.[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH3:27])[N:23]=[C:24]([NH2:26])[CH:25]=1)=[O:20])[CH3:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:27][N:22]1[C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])=[CH:25][C:24]([NH:26][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:23]1
Reactant: CCOC(=O)c1cc(N)nn1C
Reactant: Cc1onc(-c2ccccn2)c1C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1cc(NCc2c(-c3ccccn3)noc2C)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a mixture of 5-methyl-3-(pyridin-2-yl)isoxazole-4-carbaldehyde (811 mg, 4.31 mmol) and 5-amino-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester hydrochloride (886 mg, 4.31 mmol) in MeOH (36 mL) was added molecular sieves (1.3 g). The reaction mixture was stirred at RT for 1 h. Then acetic acid (3.45 mL, 60.3 mmol) was added. After stirring for additional 5 min, sodium cyanoborohydride (542 mg, 8.62 mmol) was added in portions over 2 min and the reaction mixture was stirred at RT for 30 min, then evaporated. The residue was extracted with dichloromethane and then washed with a saturated solution of sodium hydrogen carbonate. The organic layers were washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, dichloromethane) afforded the title compound as a white solid (814 mg, 55%). MS: m/e=342.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1

Procedure:
A solution of N-benzyl piperidone (20.0 g, 53 mmol) and pyrrolidine (14.0 mL, 80 mmol) in 300 mL of toluene was warmed at reflux overnight with azeotropic removal of water. The reaction mixture was then cooled and concentrated under reduced pressure. The resultant dark oil was dissolved in 200 mL of ether, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[CH:7][CH:6]=1>N1C=CC=CC=1>[F:1][CH2:2][CH2:3][O:4][S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: OCCF
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCF)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
1 g (15.6 mmol) of 2-fluoroethanol was dissolved in pyridine (15 mL), and 6.5 g (34.1 mmol) of p-toluenesulfonic acid was added thereto over a period of 30 minutes while stirring on ice. The mixture was stirred at 0° C. under nitrogen atmosphere for 3 hours, and after adding 35 mL of ice water to the reaction mixture, extraction was performed with 30 mL of ethyl acetate. The obtained organic layer was washed three times with 30 mL of 1N hydrochloric acid, and then further washed with sodium carbonate solution and saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure to yield the title compound (3.19 g, 94%) as a colorless oil.
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].CI.[C:26](OCC)(=O)C>CN(C=O)C.[Ag-]=O>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][CH3:26])([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]
Reactant: CCOC(C)=O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Agent: O=[Ag-]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
(3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (100 mg, 0.32 mmol) was dissolved in DMF (3 mL). Then, molecular sieves (4 A), silver(I)oxide (355 mg, 1.53 mmol) and methyl iodide (0.40 ml, 6.38 mmol) was added and the black suspension stirred at room temperature for 48 hour. The reaction mixture was filtrated through celite and the filtrate evaporated. The crude yellow residue was subjected to silica gel flash chromatography (ISCO Companion CombiFlash; 40 g Gold silica gel cartridge, heptane/ethyl acetate gradient; ethyl acetate: 2% (2 min), 2-20% (3 min), 20% (8 min), 20-30% (2 min), 30% (8 min), 30-50% (3 min) and 50% (8 min) to yield (3aR,4S,7aR)-4-methoxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (15 mg, 0.04 mmol, 14% yield) as colorless oil. MS [2M+Na]677; RT=8.147 min HPLC Method III
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:5]=1)([O-:3])=[O:2].CC([O-])(C)C.[K+]>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:9][CH:10]=1)[NH:8][C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:11]2)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1C#Cc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]c(-c3ccccn3)cc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To the solution of 4-nitro-2-(pyridin-2-ylethynyl)aniline (1.5 g, 6.3 mmol) in DMF (50 mL) was added t-BuOK (1.5 g, 13 mmol). The reaction mixture was stirred at 90° C. for 2 h. The mixture was diluted with water and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford 5-nitro-2-(pyridin-2-yl)-1H-indole (1.0 g, 67% yield). 1H NMR (300 MHz, d-DMSO) δ 12.40 (s, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.58 (d, J=1.8 Hz, 1H), 8.07-7.91 (m, 3H), 7.59 (d, J=6.6 Hz, 1H), 7.42-7.37 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][N:7]=[C:6]2[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]=[C:28]=[S:29])[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][N:7]=[C:6]2[N:14]1[CH2:15][CH2:16][N:17]([C:28](=[S:29])[NH:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19]1
Reactant: S=C=NCc1cccnc1
Reactant: COc1cc2c(N3CCNCC3)ncnc2cc1C
Product: COc1cc2c(N3CCN(C(=S)NCc4cccnc4)CC3)ncnc2cc1C
Yield: 36 %

Procedure:
Substantially the same procedure as in Example 1 was repeated, except that 6-methoxy-7-methyl-4-(1-piperazinyl)quinazoline was used in place of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline, and the corresponding 3-picolyl isothiocyanate was used in place of phenyl isocyanate, to give the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]1([CH2:16][C:17]([N:19]2[CH2:26][CH2:25][CH2:24][C@H:20]2[C:21](O)=[O:22])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:22])[C@@H:20]2[CH2:24][CH2:25][CH2:26][N:19]2[C:17](=[O:18])[CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=C(O)[C@@H]1CCCN1C(=O)Cc1ccccc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Product: O=C(Nc1ccc(Br)cc1F)[C@@H]1CCCN1C(=O)Cc1ccccc1
Yield: 97.8 %

Procedure:
4-Bromo-2-fluoroaniline (1.0 g, 5.3 mmol) was treated with N-phenylacetylproline (1.3 g, 5.52 mmol) and EEDQ as described in Example 1 to provide 2.1 g of N-(4-bromo-2-fluorophenyl)-1-(phenylacetyl)-L-prolinamide. A portion of this intermediate (0.51 g, 1.26 mmol) was suspended in 5 mL toluene and treated with 0.38 mL of trans-1,2-bis(tri-n-butylstannyl)ethylene (0.69 mmol, 0.55 equiv) followed by 0.029 g of Pd(PPh3)4. The reaction was sealed under nitrogen and heated to 100° C. for 2 hours. The mixture was then cooled to room temperature and stirred vigorously with an equal volume of aqueous saturated KF for 2 hours. Filtration through diatomaceous earth (Celite®) followed by extractive workup and HPLC purification provided the desired product. 1H NMR (DMSO-d6, 500 MHz, mixture of rotamers) δ 10.10 and 9.86 (s, 1H), 7.94 and 7.81 (m, 1H), 7.52 (m, 1H), 7.20-7.35 (m, 16H), 4.82 and 4.64 (m, 2H), 3.65 (m, 4H), 1.94-2.11 (m, 8H); LCMS (Rt=1.76 min, m/z 677.34).