Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:34][CH2:33][C:9]2[N:10]([CH2:18][C:19]([C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])(O)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1.[OH-].[K+].O>CN1C(=O)CCC1>[CH3:5][N:6]1[CH2:34][CH2:33][C:9]2[N:10]([CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([N:27]([CH3:28])[CH3:29])=[O:26])[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccc(C(=O)N(C)C)c2)CCN(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.3 %

Procedure:
Thionyl chloride (0.8 mL, 11.02 mmol) was added to a solution of 3-[2-(2,8-dimethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-hydroxy-1-methyl-ethyl]-N,N-dimethylbenzamide (500 mg, 1.23 mmol) and the reaction mixture was stirred at RT for 1 h. The solvent was removed under vacuum to obtain the crude product as a foamy solid which was dissolved in NMP (5 mL). The mixture was stirred for 5 min and powdered KOH (553 mg, 9.87 mmol) was added, and the mixture heated at 85° C. for 45 min. After completion of reaction, the mixture was poured into water and extracted with EtOAc (3×30 mL). The organic layer washed with water, dried over sodium sulfate and concentrated under vacuum to obtain the crude product (600 mg) which was purified by reverse phase HPLC to yield 3-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-vinyl]-N,N-dimethyl-benzamide (30 mg) as free base. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.76 (d, 1H), 7.70 (s, 1H), 7.52 (t, 1H), 7.44 (d, 1H), 7.30 (s, 1H), 7.18-7.06 (m, 3H), 4.58 (m, 2H), 3.70 (m, 2H), 3.18 (m, 2H), 3.12 (s, 6H), 3.05 (s, 3H), 2.42 (s, 3H), 1.98 (s, 3H).
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=1)[N:9]=2.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl.CO>[CH:30]1([CH2:29][N:7]2[C:6]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH:27][CH3:28])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:32][CH2:31]1
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: CNc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCOCC4)n(CC4CC4)c3n2)cn1
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-N-methylpyrimidin-2-amine (103.3 mg, 0.21 mmol) and morpholine (74.3 mg, 0.85 mmol) was heated at 140° C. and stirred for 3 hours. Morpholine (74.3 mg, 0.85 mmol) was added, the resulting mixture was further stirred for 3 hours, left standing to cool followed by the addition of dichloromethane-methanol (10:1), and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=10:1) to give the title compound (87.1 mg, 91%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([C@H:8]([NH:10][C:11]([C@@H:13]2[CH2:18][C@@H:17]3[C@@H:15]([CH2:16]3)[N:14]2[C:19](=[O:33])[CH2:20][N:21]2[C:25]3=[CH:26][N:27]=[CH:28][CH:29]=[C:24]3[C:23]([C:30]([NH2:32])=[O:31])=[N:22]2)=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:40]>C(O)(=O)C>[C:30]([C:23]1[C:24]2[C:25](=[CH:26][N+:27]([O-:40])=[CH:28][CH:29]=2)[N:21]([CH2:20][C:19]([N:14]2[C@H:13]([C:11](=[O:12])[NH:10][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:34])[CH3:9])[CH2:18][C@@H:17]3[C@H:15]2[CH2:16]3)=[O:33])[N:22]=1)(=[O:31])[NH2:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(N)=O)c2ccncc21)c1cccc(Cl)c1F
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(N)=O)c2cc[n+]([O-])cc21)c1cccc(Cl)c1F
Temperature: 55 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-((1R,3S,5R)-3-((R)-1-(3-chloro-2-fluorophenyl)ethylcarbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Example 702, 150 mg, 0.31 mmol) in acetic acid (4 mL) was added 3-chlorobenzoperoxoic acid (85 mg, 0.50 mmol) at 55° C. The reaction mixture was stirred at 55° C. for 18 h and then cooled to RT. Volatiles were evaporated and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford the title compound as a white solid. MS: 501 [M+H]+; tR (HPLC conditions c): 3.64 min.
Reaction SMILES: [C:1]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>[I-].[Na+]>[C:1]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOP(OCC)OCC
Reactant: CCOC(=O)c1ccc(OCCCCCCBr)cc1
Agent: [I-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(OCCCCCCP(=O)(OCC)OCC)cc1

Procedure:
[I; Ar is 4-C2H5OOCC6H4, Y is O(CH2)6, R is C2H5 ] was prepared from 15 g of 6-(4-carbethoxyphenoxy)hexyl bromide, 8.3 g of triethyl phosphite and a crystal of sodium iodide as a catalyst, according to the procedure of Example 1, and had the b.p. 190°-196° C. (0.2 mm); yield 9.5 g; MIC vs. herpes simplex type 2=6 mcg/ml. The IR and NMR spectra were consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2C=CC=CC=2)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C]=[O:19].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)(Cl)Cl.O.C(O)=O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]=[O:19])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: Clc1ccccc1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: [C]=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=CO
Product: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 4-chlorobiphenyl (18.8 g.) and aluminium chloride (29.5 g.) was stirred in chlorobenzene (150 ml.) at 55°-60° C., in a pressure vessel. The vessel was pressurised to 2 bars with an equimolar mixture of carbon monoxide and hydrogen chloride (prepared by the action of 98-100% formic acid on chlorosulphonic acid). These reaction conditions were maintained for a period of 4 days. After this time the reaction mixture was added, with stirring, to a mixture of ice (500 g.) and water (500 ml.). The organic phase was separated and the aqueous phase was extracted with chlorobenzene (50 ml.). The combined organic phases were then washed successively with 2 M hydrochloric acid (100 ml.) and water (2×100 ml.), and evaporated onto chromotographic silica gel (40 g.). The residue obtained was added to the top of a column of chromatographic silica gel (160 g.) made up in carbon tetrachloride. The column was then washed through with carbon tetrachloride (2000 ml.) and then eluted with chloroform (2000 ml.) The fractions containing material of Rf value (system: SiO2 ; methylene chloride/carbon tetrachloride 1:1 v/v) were combined and evaporated to give 4-(4-chlorophenyl)benzaldehyde (7.3 g.) m.p. 108°-112° C. (after recrystallisation from aqueous acetonitrile).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[C:9]=2[CH2:8][CH2:7]1)C.CO.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:6]([CH2:5][C:4]([OH:19])=[O:3])[CH2:7][CH2:8][C:9]=3[C:17]=2[CH:16]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(F)cc21
Reaction time: 2.5 h

Procedure:
To a solution of 1.24 g of the ester from Step 1 in 14 mL of tetrahydrofuran (THF) at room temperature, 7 mL of MeOH followed by 7 mL of 2N NaOH were added. After 2.5 h, the reaction mixture was poured into a separatory funnel containing ethyl acetate (EtOAc)/1N HCl. The phases were separated and the acidic phase was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness to yield 1.08 g of a crude and unstable waxy brown oil that was used as such in the next step (>90% purity).
Reaction SMILES: [OH2:1].[C@@H:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.N1C=CC=CC=1.[H-].[Na+].[N+:28]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33]Br)([O-:30])=[O:29]>CN(C=O)C>[N+:28]([C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][C@@:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:3]1[OH:1])([O-:30])=[O:29]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Nc1ncnc2c1ncn2[C@]1(Cc2ccccc2[N+](=O)[O-])O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 39.8 %

Procedure:
2'-Deoxyadenosine monohydrate (538 mg, 2.0 mmol, Aldrich Chemical, Milwaukee, Wisc.) was dried by evaporation with anhydrous pyridine (2 times, 10 ml) under vacuum. The residue was dissolved in anhydrous DMF (10 ml, Aldrich, Milwaukee, Wisc.) under an argon atmosphere, and sodium hydride (88 mg, 2.2 mmol, 1.1 equiv, 60% dispersion in oil) was added and stirred for 40 mins at room temperature. 2-Nitrobenzyl bromide (710 mg, 3.3 mmol, 1.5 equiv) was added and the solution was stirred for 4 hours at room temperature. The DMF was removed by evaporation under vacuum, and the residue was partitioned between ethyl acetate and water (20 ml each). The aqueous phase was extracted with ethyl acetate (20 ml) and the combined extracts were washed with water (20 ml) and dried over magnesium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel (50 g, using 3% MeOH in CH2Cl2) to yield 2'-deoxy-N6 -bis-ortho-nitrobenzyladenosine (320 mg, 30%).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][CH:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[CH2:42][CH2:41]4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:41][CH2:42][CH:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[CH2:44][CH2:45]4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1C1CCC(c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C)C(C2CCC(c3ccccc3)CC2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/2 v/v, 60 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(4-phenylcyclohexyl)-1H-pyrrol-2(5H)-one (1.0 g, 2.58 mmol, 1 eq) and MeOH (20 ml); yield: 0.100 g (10%); MS m/z: 402.2 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.53 (s, 1H), 8.32 (s, 1H), 7.64 (m, 2H), 7.25-7.08 (m, 7H), 4.81 (s, 1H), 3.87 (s, 3H), 2.20-2.20 (m, 2H), 2.01 (s, 3H), 1.78-1.4 (m, 5H), 1.37-1.14 (m, 7H); HPLC (METHOD [A]): rt 14.80 min (96.02%)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][CH2:23]CO2)=[C:16](COCOC)[CH:15]=1.Cl>C1COCC1.O>[F:13][C:14]1[CH:15]=[CH:16][C:17]2[B:20]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[O:24][CH2:23][C:18]=2[CH:19]=1
Reactant: COCOCc1cc(F)ccc1B1OCCO1
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc2c(c1)COB2c1cccnc1
Reaction time: 1 h
Yield: 7.7 %

Procedure:
To a solution of 3-bromopyridine (731 mg, 4.63 mmol) in THF (5 mL) was added isopropylmagnesium chloride (1 M in THF; 2.3 mL) at room temperature under nitrogen atmosphere, and the mixture was stirred for 1 h. To the mixture was added compound 6 (1.11 g, 4.63 mmol) in THF (4 mL), and the mixture was stirred at room temperature overnight. Water was added and the pH was adjusted to 7 with 1 N HCl. Then the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure, and the residue was dissolved in THF (30 mL). To the mixture was added 1 N HCl (10 mL), and the mixture was refluxed overnight. The pH was adjusted to 7 with aqueous NaHCO3 and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was recrystallized from i-Pr2O to afford compound 15 (76 mg, 7.7%): mp 210-212° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.94 (s, 2H), 6.9-7.1 (m, 2H), 7.36 (br s, 1H), 7.66 (dd, J=6.7, 5.3 Hz, 1H), 8.19 (d, J=6.7 Hz, 1H), 8.24 (br s, 1H), 8.64 (d, J=5.3 Hz, 1H): ESI-MS m/z 214 (M+H)+; Anal (C12H9BFNO.0.6H2O)C, H, N.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=3)[N:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][CH2:35]Br>CN(C=O)C>[F:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[CH2:34][CH2:35][N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([F:19])([F:20])[F:21])=[N:16][N:17]=3)[N:14]=2)[CH2:8][CH2:7]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Fc1ccccc1CCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1CCN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
A stirred solution of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine dihydrochloride (0.173 g, 0.5 mmol), DIPEA (0.300 mL, 1.75 mmol) and 2-fluorophenethyl bromide (0.084 mL, 0.60 mmol) in DMF (2 mL) was heated at 100° C. for 2.5 hours. The reaction was incomplete and further DIPEA (0.300 mL, 1.75 mmol) and 2-fluorophenethyl bromide (0.084 mL, 0.60 mmol) were added. The solution was stirred at 100° C. for a further 90 minutes. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[2-(2-fluorophenyl)ethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (0.131 g, 66.4%) as a crisp foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[C:8]2[C:19](O)([CH3:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:9]=2[O:10][CH:11]=1)[CH3:2].[SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[CH3:40][C:41]([Si:44](Cl)([CH3:46])[CH3:45])([CH3:43])[CH3:42].N1C=CN=C1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[C:8]2[C:19]([CH3:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:22][Si:44]([C:41]([CH3:43])([CH3:42])[CH3:40])([CH3:46])[CH3:45])[C:9]=2[O:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CCc1coc2c1C(C)(O)c1ccccc1C2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCc1coc2c(O[Si](C)(C)C(C)(C)C)c3ccccc3c(C)c12
Temperature: 0 °C
Yield: 369.9 %

Procedure:
A solution of 24.0 mg (0.076 mmol, 1.0 eq) of alcohol 16 in 5.0 mL of dry CH2Cl2 was stirred in a 5 mL round bottom flask at room temperature under argon. To this solution was added 36.6 μL of Et3SiH (0.229 mmol, 3.0 eq). The solution was then cooled to 0° C. in an ice water bath. After cooling, 28.0 μL (0.220 mmol, 2.9 eq) of BF3-Et2O was slowly added and the resulting solution was stirred until all the starting material was consumed by TLC (1:1 hexane:EtOAc, Rf=0.56). After alcohol 16 was completely consumed (˜15 minutes), 69.0 mg (0.456 mmol, 6.0 eq) of TBSCl and 31.0 mg (0.456 mmol, 6.0 eq) of imidazole were added at once and the ice water bath was removed. The solution was then stirred at room temperature until the reaction was complete by TLC (1:1 hexane:EtOAc, Rf=0.80). Upon completion (˜18 hours) the solution was diluted with CH2Cl2 and washed with a saturated aqueous NH4Cl solution. The aqueous layer was then extracted twice with CH2Cl2 and the combined organic fractions were dried over MgSO4 and concentrated. Silica gel chromatography (hexane/EtOAc) yielded 116 mg (69%) of 17 as a colorless solid, Rf 0.80 (1:1 hexane:EtOAc). Mp: 92.4-93.5° C. 1H-NMR (500 MHz, CDCl3): 8.31 (1H, m), 8.10 (1H, m), 7.47 (3H, m), 4.20 (2H, q, J=7.1 Hz), 3.29 (2H, t, J=7.6 Hz), 2.93 (3H, s), 2.78 (2H, t, J=7.7 Hz), 1.28 (3H, t, J=7.2 Hz), 1.15 (9H, s), 0.27 (6H, s). 13C-NMR (500 MHz, CDCl3): 172.93, 143.40, 143.25, 132.82, 130.16, 127.98, 125.74, 124.02, 123.87, 123.69, 122.69, 119.97, 118.53, 60.84, 34.56, 26.24, 21.79, 18.93, 14.45, 14.42, −3.86. IR (cm−1): 2960 (m), 2854 (w), 1740 (vs), 1630 (w), 1461 (m), 1389 (s), 1247 (m), 1117 (m), 985 (s), 828 (s), 752 (s). Anal. Calcd. for C24H32O4Si: C, 69.86; H, 7.82. Found: C, 70.18; H, 8.02.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[N:20][N:21](C(OC(C)(C)C)=O)[CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:8][C:5]1[C:4]([F:9])=[CH:3][C:2]([C:18]2[CH:19]=[N:20][NH:21][CH:22]=2)=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Fc1cc(Br)cnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1cc(-c2cn[nH]c2)cnc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
5-bromo-2,3-difluoropyridine (2.0 g, 10.31 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (3.03 g, 10.31 mmol), Na2CO3 (2.186 g, 20.62 mmol) and Pd(Ph3P)4 (1.191 g, 1.031 mmol) were dissolved in dioxane (20 ml). The mixture was bubbled with Ar for 10 min. The reaction was stirred at 100° C. for overnight, cooled and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=30/1) to afford the title compound as white solid (1.0 g, 53.5% yield). LCMS (method B): [M+H]+=182, tR=1.98 min.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][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:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.CC1(O)CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][C:24]([CH3:28])([OH:25])[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)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC1(O)CCNC1
Agent: Cl
Product: CC1(O)CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

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 3-methylpyrrolidin-3-ol hydrochloride and isolated as white solid (14.1 mg, 75%). MS(m/e): 401.4 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH2:20])[C:12]#[CH:13]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:11][C:12]#[CH:13])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: C#CCOCCOCCN
Product: C#CCOCCOCCNc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 15.6 %

Procedure:
To 1-chloro-4-nitrobenzene (152 mg, 0.97 mmol, 1.0 equiv.) was added neat 2-(2-(prop-2-ynyloxy)ethoxy)ethanamine (s-5) (900 mg, 6.31 mmol, 6.5 equiv.), and the resulting slurry was heated to 100° C. for 19 hours. At the end of this period, the heating bath was removed, and the reaction content was mixed with water (50 mL) and then extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried with Na2SO4, concentrated under reduced pressure, and chromatographed (silica gel, 1×25 cm, 0% EtOAc in CH2Cl2, then 30% EtOAc in CH2Cl2 to yield 4-nitro-N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)aniline (s-7) as a dark yellow oil (40 mg, 16%). IR (thin film) 3351 (m), 3239 (m), 2858 (w), 2112 (w), 1599 (s), 1535 (w), 1500 (w), 1467 (s), 1284 (s), 1086 (s), 1034 (w); 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J=9.2 Hz, 2H), 6.53 (d, J=9.2 Hz, 2H), 5.05 (bs, 1H), 4.19 (d, J=2.4 Hz, 2H), 3.76-3.70 (m, 2H), 3.70-3.64 (m, 4H), 3.38 (q, J=5.3 Hz, 2H), 2.45 (t, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) □ 153.4, 138.0, 126.4, 111.2, 79.5, 74.9, 70.3, 69.1, 69.0, 58.5, 42.9. HRMS (ES+) calc'd for C13H16N2O4 (M+H) m/z 265.1144 Found 265.1177.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][C@H:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][C@@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: N[C@H]1CCc2ccccc21
Reactant: COc1ccc(C[C@@H]2NCCc3cc(OC)c(OC)cc32)cc1OC
Product: COc1ccc(C[C@H]2c3cc(OC)c(OC)cc3CCN2CC(=O)N[C@H]2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of (1S)-1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1S)-1-amino-indane
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:12][C:13]1[CH:14]=[N:15][N:16]([CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH:17]=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl.CCOC(C)=O>[CH3:22][C:19]([CH3:23])([CH2:20][O:21][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[CH2:18][N:16]1[CH:17]=[C:13]([I:12])[CH:14]=[N:15]1
Reactant: CC(C)(CO)Cn1cc(I)cn1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(COC1CCCCO1)Cn1cc(I)cn1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
p-Toluenesulfonic acid (44 mg, 0.26 mmol) was added to a stirring solution of 3-(4-iodopyrazol-1-yl)-2,2-dimethyl-propan-1-ol (Compound 47E, 500 mg, 1.79 mmol) in DCM (2.58 mL). The mixture was stirred under argon, chilled in an ice-bath, then dihydropyran (0.261 mL, 2.86 mmol) was added, stirred and gradually warmed to rt over 16 hrs. The reaction mixture was diluted with EtOAc and washed with brine (2×), dried over sodium sulfate, filtered and concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→10% EtOAc/Heptanes] to afford 597 mg of the title compound (92%). 1H NMR (400 MHz, CD3OD) δ 7.71 (s, 1H), 7.48 (s, 1H), 4.57 (t, J=3.5 Hz, 1H), 4.04-4.12 (m, 2H), 3.86 (d, J=3.0 Hz, 1H), 3.48-3.56 (m, 1H), 3.45 (d, J=9.3 Hz, 1H), 3.03 (d, J=9.6 Hz, 1H), 1.81-1.91 (m, 1H), 1.67-1.78 (m, 1H), 1.51-1.66 (m, 4H), 0.93 (d, J=4.8 Hz, 6H).