Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.O=C1CCCCC1C(OCC)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu](I)I>[N+:1]([C:4]1[CH:5]=[C:6]([S:10][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Brc1cccnc1
Reactant: O=[N+]([O-])c1cccc(S)c1
Agent: I[Cu]I
Agent: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Sc2cccnc2)c1
Yield: 43.1 %

Procedure:
3-nitrophenylmercaptan (5 g, 32 mmol), 3-bromopyridine (6.1 g, 38.6 mmol), ethyl 2-oxocyclohexylformate (1.1 g, 6.5 mmol), copper iodide (608 mg, 4.2 mmol), cesium carbonate (2.3 g, 70.6 mmol) were dissolved in 500 ml of DMSO, reacted under microwaves at 100° C. for 8 h. After being extracted with water and DCM, the organic phase was dried and separated with column chromatography to obtain an object product 3.2 g.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1)(=O)=O.[Cl-].[Li+].[CH2:17]([O:19][C:20](=[O:40])[C:21]1[CH:26]=[CH:25][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][CH:22]=1)[CH3:18].[F-].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[CH2:17]([O:19][C:20](=[O:40])[C:21]1[CH:22]=[CH:23][C:24]([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)=[CH:25][CH:26]=1)[CH3:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)cc1
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C2=CCCCC2)cc1
Temperature: 25 °C
Reaction time: 38 h
Yield: 60.8 %

Procedure:
Cyclohexen-1-yl trifluoromethanesulfonate (1.00 g, 4.34 mmol), lithium chloride (0.551 g, 13.0 mmol) and tris-dibenzylideneacetone di-palladium (0) (79.5 mg, 0.0868 mmol) were combined in anhydrous N-methylpyrrolidinone (20 mL) and the resulting solution deoxygenated by sparging with nitrogen for 30 minutes. To the catalyst solution was added a solution of 4-(tri-n-butyl-stannyl)-benzoic acid ethyl ester of Step A (2.10 g, 4.77 mmol) in anhydrous N-methylpyrrolidinone (9 mL). The reaction was stirred at room temperature for 38 hours, followed by addition of 1 M potassium fluoride (5 mL). After stirring for 3 hours, the reaction mixture was diluted with ethyl acetate (200 mL) and filtered through celite. The filtrate was washed with 1 M potassium fluoride, water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 10% ethyl acetate in hexane. A solid was isolated which was recrystallized from pentane (−20° C.) to afford the title compound (0.608 g) as a white solid, m.p. 66° C.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.Cl>CN(C)C=O.O>[CH3:10][C:2]([O:1][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)([CH3:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Reactant: BrCCCOC1CCCCO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)OCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (22 mL) of tert-butyl 2-hydroxy-2-methylpropanoate (1.0 g) in N,N-dimethylformamide was added sodium hydride (250 mg) under an ice bath, and the mixture was stirred at room temperature for 1 hour. Thereafter, under an ice bath, 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.88 mL) was added dropwise, and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and 1N hydrochloric acid under an ice bath, followed by extraction with t-butyl methyl ether. The organic layer was sequentially washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain the title compound having the following physical property values, as a mixture (400 mg) with tert-butyl 2-hydroxy-2-methylpropanoate.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:35])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:34])[CH2:12][CH2:13][C@@:14]3([CH2:31][CH2:32][NH2:33])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:37])[CH3:36])(=[O:3])[CH3:2].[O:38](C(OC(C)(C)C)=O)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:35])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:34])[CH2:12][CH2:13][C@@:14]3([CH2:31][CH2:32][NH:33][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:38])[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:36])[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(CCN)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(CCNC(=O)OC(C)(C)C)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-aminoethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (34) (5.3 g, 10.36 mmol), TEA (2.165 mL, 15.53 mmol) and TEA (2.165 mL, 15.53 mmol) in dichloromethane (DCM) (100 mL) stirred at room temp was added BOC2O (2.404 mL, 10.36 mmol). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was poured into ice water (300 ml) and the solids were collected and dried to give (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(2-((tert-butoxycarbonyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (35) (5.8 g, 8.34 mmol, 81% yield) as a white foam. This was ssed crude in next reaction without further purification. 1H NMR (400 MHz, CHLOROFORM-d) b=4.58-4.37 (m, 2H), 3.26-2.96 (m, 4H), 2.93-2.72 (m, 2H), 2.28 (d, J=18.8 Hz, 1H), 2.11-0.71 (m, 53H); LC/MS: m/z calculated 611.5. found 634.3 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:1](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-methylphenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-methylstyryl benzylsulfide. The title compound was obtained in 70% yield following oxidation. 1HNMR (CDC13) δ2.48 (3H, s), 4.60 (2H, s), 6.68 (1H, d, JH,H=11.94), 7.20-7.65 (9H aromatic+1H ethylenic).
Reaction SMILES: C([O:4][C:5]1[CH:42]=[CH:41][C:8]([CH2:9][C:10]2[CH:15]=[C:14]([C@:16]3([O:34][C@H:33]([CH2:35][O:36]C(=O)C)[C@@H:28]([O:29]C(=O)C)[C@H:23]([O:24]C(=O)C)[C@H:18]3[O:19]C(=O)C)[OH:17])[CH:13]=[CH:12][C:11]=2[CH3:40])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].Cl>CO.O1CCCC1>[OH:17][C@:16]1([C:14]2[CH:13]=[CH:12][C:11]([CH3:40])=[C:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:42][CH:41]=3)[CH:15]=2)[O:34][C@H:33]([CH2:35][OH:36])[C@@H:28]([OH:29])[C@H:23]([OH:24])[C@H:18]1[OH:19]
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(C)c(Cc3ccc(OC(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-acetoxybenzyl)-1-methyl-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene (1.8 g) in a mixture of methanol (30 mL) and tetrahydrofuran (15 mL) is treated with aqueous potassium hydroxide solution (4 mol/L, 3.8 mL). The reaction solution is stirred at ambient temperature for 30 min and then neutralized with hydrochloric acid (1 mol/L). The resulting mixture is concentrated under reduced pressure, diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried (sodium sulphate) and concentrated.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=1[O:11][CH:12]([CH3:14])[CH3:13])[CH3:2].[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([B:20]([OH:25])[OH:21])[CH:7]=[CH:6][C:5]=1[O:11][CH:12]([CH3:14])[CH3:13])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1cc(I)ccc1OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 68.7 %

Procedure:
To a solution of 2-ethoxy-4-iodo-1-isopropoxybenzene (2.39 g, 7.8 mmol) in THF (25 mL) at −78° C., n-BuLi (1.6 M in hexanes, 6.83 mL, 1.4 eq) was slowly added. The reaction mixture was stirred at −78° C. for 20 min, followed by addition of triisopropyl borate (4.95 mL, 21.5 mmol). The mixture was stirred at −78° C. for 3.0 h and then warmed up to rt over 1.0 h. It was quenched by addition of 5% citric acid (20 mL), followed by a solution of Na2S2O3. After extraction with EtOAc and drying over Na2SO4, the crude product was purified by chromatography to give 1A (1.2 g, 67% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.41 (d, J=6.15 Hz, 6H) 1.49 (t, J=7.03 Hz, 3H) 4.21 (q, J=7.03 Hz, 2H) 4.64 (m, 1H) 7.02 (d, J=8.35 Hz, 1H) 7.70 (s, 1H) 7.79 (m, 1H).
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:31])[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:31])[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Yield: 92.6 %

Procedure:
Acetic acid (3 ml) and zinc powder (2.4 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate (1.8 g) in anhydrous dimethylformamide (10 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was extracted by pouring into a mixture of 5% hydrochloric acid (50 ml) and ethyl acetate (40 ml). The ethyl acetate layer was washed with water and dried. After the solvent was distilled off, the residue was dissolved in ether and allowed to stand, after which the precipitating crystals were collected by filtration and dried to give 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid (1.2 g), mp 175° C. (dec.).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[Cl:9].C(=O)([O-])[O-].[Na+].[Na+].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.B(O)O.OO>C(O)C.C1C=CC=CC=1>[Cl:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: OO
Solvent: CCO
Solvent: c1ccccc1
Product: Clc1ccc(Cl)c(-c2cccnc2)c1
Temperature: 25 °C

Procedure:
A 50 ml two-necked round-bottom flask is charged with 2-iodo-1,4-dichlorobenzene (5.44 g), tetrakis(triphenyl-phosphine)palladium (3 mol %, Aldrich), benzene (40 ml), and aqueous sodium carbonate solution (20 ml of 2M solution). To this vigorously stirred mixture is added 3-pyridylboronic acid (2.71 g) dissolved in a minimum amount of 95% ethanol. The reaction mixture is heated to 90°-95° C. and refluxed for 9 hours under vigorous stirring. The reaction mixture is then cooled to room temperature and the excess boronic acid is oxidized by 30% hydrogen peroxide (0.25 ml) for 1 hour. The mixture is extracted with ether, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent is removed, and the crude product is purified by chromatography on Florisil eluting with pentane/dichloromethane (90/10) to give monomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12]>C(Cl)Cl.C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(CO)ccc2Cl)cc1OC
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Nc2cc(C=O)ccc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of N-(2-chloro-5-hydroxymethyl-phenyl)-3,4-dimethoxy-benzenesulfonamide (2.53 g, 7 mmol) in DCM/THF (1:1, 16 mL) was treated with MnO2 (12.3 g, 20 eq). The mixture was stirred at RT for 6 h, filtered over Celite and concentrated. The residue purified by chromatography on SiO2 (hex/EA 1:1, EA). The product was recovered as a pinkish oil (1.95 g, 77%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][CH:21]1[CH2:23][O:22]1.Cl>CC(OC)(C)C>[CH3:16][C:17]1([CH3:24])[CH:18]2[CH:19]1[CH2:20][CH2:21][CH:23]2[OH:22]
Reactant: CC(C)=CCCC1CO1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: CC1(C)C2CCC(O)C21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2,2,6,6-Tetramethylpiperidine (9.70 g, 69 mmol) was taken up in MTBE (100 mL) and chilled to −78° C. n-Butyllithium (43 mL, 1.6 M in n-hexane, 69 mmol) was added cautiously and the resulting solution allowed to stir at −78° C. for 30 minutes. The pale yellow solution was added via cannular transfer to a chilled (0° C.) solution of 2-(4-methyl-pent-3-enyl)-oxirane (4.33 g, 34.3 mmol) in MTBE (30 mL) over 30 minutes, allowed to warm slowly to room temperature and stirred under argon for 18 hours. The solution was then added to 1M aqueous hydrochloric acid (50 mL) and extracted into further MTBE (200 mL). Solvent was removed under reduced pressure and the resulting oil purified by column chromatography (0-40% EtOAc/n-hexane, silica). (±)-6,6-Dimethyl-bicyclo[3.1.0]hexan-2-ol was obtained as a yellow oil. 1H NMR (CDCl3): δ 4.15-4.10 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.70 (m, 1H), 1.62 (br s, OH), 1.56 (ddd, 1H, J1=12.9, J2=9.5, J3=2.9), 1.48 (br s, 1H), 1.14 (dd, 1H, J1=6.3, J2=1.2), 0.99 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]3[C:16](=[O:17])[C:15]([C:18]([O:20]CC)=[O:19])=[CH:14][N:13]=[C:10]32)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]=[C:10]32)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2n(c1=O)CCc1ccc(OC)cc1-2
Agent: Br
Product: O=C(O)c1cnc2n(c1=O)CCc1ccc(O)cc1-2
Yield: 81 %

Procedure:
A solution of ethyl 6,7-dihydro-10-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (5.0 g., 0.0175 mole) in 48% hydrobromic acid (125 ml.) was refluxed for 4 hours. The solution was cooled and the yellow product collected, washed with water, and dissolved in warm 0.5 N NaOH (80 ml.). The basic solution was treated with decolorizing carbon, filtered and the filtrate acidified with hydrochloric acid. The precipitated material was washed on the filter successively with water, ethanol and acetone to give 3.5 g. (81% yield) of the title acid, m.p. 326°-327°.
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].[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[F:24])([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: O=C(O)c1ccccc1F
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccccc1F

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 2-fluoro-benzoic acid to yield (3aR,4S,7aR)-4-(2-fluoro-benzoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=8.923 min; HPLC Method I
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=3[Cl:20])=[CH:11][CH:12]=2)=[C:4]([Cl:21])[CH:3]=1.[C:22]1([NH2:33])[C:27](F)=[C:26](F)[C:25](F)=[C:24]([NH2:31])C=1F.Cl.Cl>CCO>[Cl:20][C:14]1[CH:15]=[C:16]([N:19]=[N:31][C:24]2[CH:25]=[CH:26][CH:27]=[CH:22][N:33]=2)[CH:17]=[CH:18][C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]=[N:31][C:24]3[CH:25]=[CH:26][CH:27]=[CH:22][N:33]=3)=[CH:3][C:4]=2[Cl:21])=[CH:12][CH:11]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Nc1ccc(-c2ccc(-c3ccc(N)cc3Cl)o2)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: Clc1cc(N=Nc2ccccn2)ccc1-c1ccc(-c2ccc(N=Nc3ccccn3)cc2Cl)o1
Yield: 25 %

Procedure:
2,5-Bis[2-chloro-4-(2-pyridylimino)aminophenyl]furan (4j, DB712) was prepared according to the procedure for 4f using diamine 3d and S-(2-naphthylmethyl)2-pyridylthioimidate hydrobromide as starting materials. Free base: orange crystalline solid, mp 189-190° C. (EtOH). Yield: 25%. 1H NMR (DMSO-d6): 6.85 (br s, 4NH), 7.02 (dd, 2H), 7.08 (d, 2H), 7.17 (s, 2H), 7.56 (m, 2H), 7.93-7.98 (m, 4H), 8.29 (d, 2H), 8.64 (m, 2H). Dihydrochloride: yellow/orange solid, mp>180° C. dec. 1H NMR (DMSO-d6): 7.45 (s, 2H), 7.60 (d, 2H), 7.80 (s, 2H), 7.86 (dd, 2H), 8.23 (m, 4H), 8.50 (d, 2H), 8.90 (d, 2H), 9.54 (br s, 2H), 10.23 (br s, 2H), 11.98 (br s, 2H). MS (EI): m/z 530, 528, 526 (M+, 13.2, 69.8, 100), 426, 424, 422 (7.9, 48, 72.4), 322, 320, 318 (2.6, 17.4, 26.6). Anal. Calcd. for C28H20Cl2N6O.2.0HCl.1.5H2O (627.35): C, H, N, Cl.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.Br[Zn][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1.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>[Br:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1
Reactant: CCOC(=O)CC[Zn]Br
Reactant: Brc1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cc(Br)ccn1
Temperature: 85 °C

Procedure:
Nitrogen was bubbled through a solution of 2,4-dibromopyridine (0.25 g, 1.06 mmol) in THF (2 ml) for ˜10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.122 g, 0.106 mmol) was added and the flask sealed with a septa. Bromo (3-ethoxy-3-oxopropyl)zinc (3.17 ml, 1.58 mmol) was added slowly via syringe and the reaction mixture was heated at 85° C. for 16 hours. Upon cooling, the reaction mixture was partitioned between DCM and brine. The organic layer was dried (Na2SO4), concentrated under reduced pressure and the residue was purified by silica gel chromatography (gradient elution with EtOAc/Hexanes 7 to 60%) to give ethyl 3-(4-bromopyridin-2-yl)propanoate as a pale yellow oil. MS ESI calc'd. for C10H13BrNO2 [M+H]+ 258 and 260. found 258 and 260. 1H NMR (500 MHz, CDCl3) δ 8.33 (d, J=5.1 Hz, 1H), 7.39 (bs, 1H), 7.30 (dd, J=5.2, 1.7 Hz, 1H), 4.12 (q, J=6.7 Hz, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.79 (t, J=6.4 Hz, 2H), 1.23 (t, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:4]([CH3:30])[C:5]([C:28]#[N:29])=[C:6]2[C:10]=1[O:9][C:8]([N:11]([CH3:27])[CH2:12][C:13]1[N:14](CC3C=CC(OC)=CC=3)[N:15]=[CH:16][N:17]=1)=[N:7]2>FC(F)(F)C(O)=O>[F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:4]([CH3:30])[C:5]([C:28]#[N:29])=[C:6]2[C:10]=1[O:9][C:8]([N:11]([CH3:27])[CH2:12][C:13]1[NH:14][N:15]=[CH:16][N:17]=1)=[N:7]2
Reactant: COc1ccc(Cn2ncnc2CN(C)c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)Cc3ncn[nH]3)nc2c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
7-Fluoro-2-[N-[[2-(4-methoxybenzyl)-2-H-[1,2,4]triazol-3-yl]methyl]methylamino]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-164) (0.33 g, 0.68 mmol) was dissolved in trifluoroacetic acid (5 ml), and stirred at room temperature for 16 hours, then at an external temperature of about 60° C. for 6 hours. The solvent was evaporated away under reduced pressure, then ethyl acetate and aqueous sodium hydrogencarbonate solution were added, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a colorless solid (0.24 g, 97%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:34]([O:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][CH:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:37])([CH3:36])[CH3:35].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>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].O1CCOCC1>[C:34]([O:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][CH:43]([NH:50][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[N:14][CH:15]=3)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:9]=2)[CH:3]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(Br)c2)c2cnc(NCCN3CCOCC3)nc21
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2nn(COCC[Si](C)(C)C)c3nc(NCCN4CCOCC4)ncc23)c1)c1ccccc1
Temperature: 140 °C
Reaction time: 15 h

Procedure:
A sealed tube was charged with [3-(3-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 40 supra) (430 mg, 0.81 mmol), (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 2 supra) (300 mg, 1.13 mmol), DavePhos (63 mg, 0.16 mmol), K2CO3 (120 mg, 1.13 mmol), Pd2(dba)3 (37 mg, 0.04 mmol) and 1,4-dioxane (16 mL). This mixture was stirred at 140° C. for 15 hours under an atmosphere of N2. The mixture was cooled and filtered; the filtrate was evaporated under reduced pressure to give the crude product. It was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH, 150:1 to 50:1) to give crude (3-{3-[6-(2-morpholin-4-yl-ethylamino)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-phenylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester. (Yield 329 mg).