Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([Cl:13])[CH:3]=1.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([CH3:24])[CH:18]=[C:17]([CH3:25])[N:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:13][C:4]1[CH:3]=[C:2]([NH:1][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([CH3:24])[CH:18]=[C:17]([CH3:25])[N:16]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccc(N)cc1Cl
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Nc2nc(C)cc(C)c2[N+](=O)[O-])cc1Cl
Temperature: 50 °C
Reaction time: 9 h
Yield: 30.8 %

Procedure:
To a mixture of methyl 2-(4-amino-2-chlorophenyl)acetate (step 4, 2.6 g, 13.0 mmol) and 4,6-Dimethyl-3-nitro-2-pyridine (step 2 of Example 1, 2.4 g, 13.0 mmol) in DMSO was added diisopropylethylamine. The resulting mixture was stirred for 9 h at 50° C. To the mixture was poured into water and extracted with ethyl acetate (3×30 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give a brown oil. This was purified by SiO2 column chromatography with developing hexane/ethyl acetate (10/1) to give 1.4 g (29%) of title compound as yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([OH:8])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:3]=1.CCN(CC)CC.[O:23](S(C(F)(F)F)(=O)=O)[S:24]([C:27]([F:30])([F:29])[F:28])(=O)=[O:25]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[S:24]([O:8][C:5]1[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])(=[O:25])=[O:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(-n2nc(C)c(C)c2O)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(-n2nc(C)c(C)c2OS(=O)(=O)C(F)(F)F)n1
Temperature: -78 °C
Yield: 74.8 %

Procedure:
To the 500 mL round-bottomed flask with 3,4-dimethyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-ol (6.68 g, 33 mmol) were added Et3N (5.5 mL, 39 mmol) and 35 mL CH2Cl2. the solution was cooled in dry ice acetone bath. Tf2O (6.1 mL, 36 mmol) was added slowly. The mixture was stirred at −78° C. and allowed to warm to room temperature. The mixture was then concentrated in vacuo. The crude product was purified using a Biotage Horizon System (0 to 25% EtOAc/hexane) to afford a colorless oil (8.28 g).
Reaction SMILES: [Zn:1].[Br:2]CCBr.Cl[Si](C)(C)C.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1>O1CCCC1>[Br-:2].[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][Zn+:1])=[CH:14][CH:15]=1
Reactant: BrCCBr
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: [Zn]
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(C[Zn+])cc1
Product: [Br-]
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
In a dried flask was zinc powder (0.769 g, 11.76 mmol) suspended in anhydrous tetrahydrofuran (20 mL) under nitrogen. The resulting suspension was warmed to 60° C., then 1,2-dibromoethane (0.042 mL, 0.49 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.050 mL, 0.39 mmol) was added and stirred at room temperature for 1 h. Then, 1-(bromomethyl)-4-(trifluoromethoxy)benzene (2.5 g, 9.80 mmol) in tetrahydrofuran (5 mL) was added over 2 min, then stirring continued at room temperature for 22 h. The stirring was switched off to let the solids settle. The supernatant was used in next transformation
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.[C:24]([O:28][C:29]([N:31]1[CH2:34][CH:33]([C:35](O)=[O:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:35]([CH:33]3[CH2:34][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32]3)=[O:36])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4Cl)nc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a mixture of (R)-5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Example 8, Step A; 20 mg, 0.06 mmol), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (15 mg, 0.072 mmol), and HATU (28 mg, 0.072 mmol) was added 0.6 mL acetonitrile to make a solution. After cooling in an ice bath for 10 minutes, DIEA (0.032 mL, 0.18 mmol) was added to the reaction drop-wise. The reaction was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was directly purified by reverse-phase column chromatography, eluting with 5 to 70% acetonitrile/water to yield the final product as an off-white solid (19 mg, 61% yield). MS (apci) m/z=515.0 (M+H).
Reaction SMILES: Br[CH2:2][CH:3]([OH:8])[CH:4]([OH:7])[CH2:5]Br.[OH2:9].[OH2:10].O.O.O.O.O.O.O.O.O.O.[P:21]([O-:25])([O-:24])([O-:23])=[S:22].[Na+].[Na+].[Na+]>CN(C=O)C.O.[N+]([O-])([O-])=O.[Ag+]>[OH2:7].[OH2:23].[OH2:9].[OH2:7].[P:21](=[S:22])([OH:25])([OH:24])[OH:23].[P:21](=[S:22])([OH:25])([OH:24])[OH:23].[CH2:2]([OH:10])[C@H:3]([C@@H:4]([CH2:5][OH:9])[OH:7])[OH:8]
Reactant: OC(CBr)C(O)CBr
Reactant: [O-]P([O-])([O-])=S
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@@H](O)[C@H](O)CO
Product: OP(O)(O)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 285 %

Procedure:
A solution of 1,4-dibromo-2,3-butanediol (1.0 g, 4.0 mmol) in 5 ml DMF is added to sodium thiophosphate dodecahydrate (3.8 gm, 10.1 mmol) in 20 ml H2O. The mixture is stirred overnight at room temperature. A 5% silver nitrate solution is added to precipitate excess sodium thiophosphate. The precipitate is filtered out and the filtrate dried under high vacuum. The solid residue is triturated with methanol and filtered to yield 1.8 g (3.8 mmol) of threitol bis-phosphorothioate tetrahydrate.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:19]=1[C:20](O)=O.[CH3:29][NH:30][NH2:31].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[CH3:29][N:30]([C:20](=[S:41])[C:19]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:18]=1[O:17][CH3:16])[NH2:31]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: CNN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=S)N(C)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.8 %

Procedure:
DCC (4.5 g, 21.8 mmol) was added in one portion to a solution of 2,5-dimethoxybenzoic acid (3.6 g, 20 mol), methylhydrazine (1.2 ml, 23 mmol) and DMAP (30 mg, cat.) in CH2Cl2 (60 ml) cooled in an ice bath. The reaction mixture was stirred overnight at room temperature. The slurry was cooled at −20° C. for 1 h and filtered. The CH2Cl2 solution was evaporated and the residue was dried in vacuum. The resulting crude product was dissolved in toluene (50 ml). To this solution was added Lawesson's reagent (5.8 g, 14 mmol). The mixture was refluxed for 40 min, cooled to room temperature, and directly subjected to silica gel column chromatography (eluent: 25% to 35% ethyl acetate in hexanes) to give the 2,5-dimethoxythiobenzoic acid N-methylhydrazide (3.7 g, yield: 82%) as off-white solid. 1H NMR (300 MHz, CDCl3): δ 6.88-6.80 (m, 3H), 5.46 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.28 (s, 3H).
Reaction SMILES: FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O.C([C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[N:55]=[CH:54][CH:53]=[CH:52][C:40]=3[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:45]=3[F:51])=[O:42])=[CH:34][C:33]=2[F:56])[CH:28]=[CH:27][N:26]=1)(=O)N.O.[N:58]1C=CC=CC=1.[ClH:64]>CN(C=O)C>[ClH:64].[NH2:58][C:25]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]3[N:55]=[CH:54][CH:53]=[CH:52][C:40]=3[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:45]=3[F:51])=[O:42])=[CH:34][C:33]=2[F:56])[CH:28]=[CH:27][N:26]=1
Reactant: c1ccncc1
Reactant: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Agent: Cl
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Temperature: 0 °C
Yield: 35 %

Procedure:
Bis(trifluoroacetoxy)iodobenzene (0.10 g, 0.23 mmol) was added to a solution of 2-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (0.080 g, 0.17 mmol), water (0.006 g, 0.33 mmol) and pyridine (0.27 mL, 3.33 mmol) in anhydrous DMF (5 mL) at room temperature. The reaction mixture was stirred for 69 hours before 6N aq HCl (2 mL) was added and the reaction stirred for an additional fifteen minutes. The mixture was extracted twice with Et2O and the combined organic layers discarded. The aqueous layer was neutralized with 1M NaHCO3(aq) then extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The resultant residue was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and lyophilized to an off-white solid that was dissolved in anhydrous THF (2 mL), cooled to 0° C. and treated with HCl (4N in dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.029 g, 35%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.72 (s, 1H), 10.49 (s, 1H), 8.32-8.40 (m, 2H), 8.13 (dd, 1H, J=13.7, 2.4 Hz), 7.82-7.92 (m, 3H), 7.29-7.53 (m, 4H), 7.05-7.15 (m, 1H), 6.97-7.01 (m, 1H), 6.64-6.66 (m, 1H), 6.12 (d, 1H, J=2.4 Hz); HRMS(ESI+), 452.1334 (M+H)+ calc, 452.1341 (M+H)+ found.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]#[C:26][C:27]3[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=3)[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]#[C:26][C:27]3[N:32]=[CH:31][C:30]([NH:33][CH3:1])=[CH:29][CH:28]=3)[CH2:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=CO
Product: CNc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To 0.50 mL (6.8 mmol) of acetic anhydride is added 0.32 mL (8.4 mmol) of 88% formic acid dropwise under nitrogen. Anhydrous tetrahydrofuran (10 mL) is added, and the solution is heated at 50° C. for 2 hours. To the cooled solution is added a suspension of 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) (0.8 g, 2.6 mmol) in 10 mL of tetrahydrofuran, and the solution is stirred at room temperature for 18 hours. The mixture is concentrated in vacuo, and the residue is partitioned between dichloromethane and 5% ammonium hydroxide. The organic layer is dried and concentrated in vacuo. The residue, in 10 mL of tetrahydrofuran, is added dropwise under nitrogen to a suspension of 0.14 g (3.9 mmol) of lithium aluminum hydride in 20 mL of dry tetrahydrofuran at 0° C. The reaction mixture is stirred at 0° C. for 5 hours. The reaction is quenched by sequential addition of 0.52 mL of 10% hydrochloric acid solution, 0.52 mL of 30% sodium hydroxide solution, and 0.52 mL of water. The resulting mixture is filtered through diatomaceous earth (Celite), evaporated in vacuo, and chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound, containing 0.5 mol of water; mp 164.5°-165.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([S:21]([CH3:24])(=[O:23])=[O:22])=[N:17][CH:18]=3)[N:13]([CH3:25])[C:12]2=[O:26])C=[C:7]([O:9][CH3:10])[CH:8]=1.S(Cl)([Cl:30])(=O)=O.Cl[CH2:33][Cl:34]>>[Cl:30][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:33]([Cl:34])[C:5]=1[N:11]1[CH2:20][C:19]2[C:14](=[N:15][C:16]([S:21]([CH3:24])(=[O:23])=[O:22])=[N:17][CH:18]=2)[N:13]([CH3:25])[C:12]1=[O:26]
Reactant: ClCCl
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)(=O)=O)nc3N(C)C2=O)c1
Product: COc1cc(OC)c(Cl)c(N2Cc3cnc(S(C)(=O)=O)nc3N(C)C2=O)c1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 3-(3,5-dimethoxyphenyl)-1-methyl-7-(methylsulfonyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (400 mg, 1.06 mmol) in 15 mL of dichloromethane was added sulfuryl chloride (285 mg, 2.12 mmol) at 0° C., and then stirred at 0° C. for 3 h. LCMS showed the reaction was completed. The reaction mixture was diluted with 20 mL of dichloromethane, washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (450 mg, 96%) as a yellow solid, which was directly used in the next step without further purification. MS (ES+) C16H16Cl2N4O5S requires: 446, 448. Found: 447, 449 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]([CH2:8][C@@:9]12[CH2:21][CH2:20][CH2:19][N:10]1[C@@H](C(Cl)(Cl)Cl)[O:12][C:13]2=O)[CH3:7].[NH3:25].CO>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]([CH2:8][C@@:9]1([C:13]([NH2:25])=[O:12])[CH2:21][CH2:20][CH2:19][NH:10]1)[CH3:7]
Reactant: CN(Cc1cccc(F)c1)C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Reactant: N
Solvent: CO
Product: CN(Cc1cccc(F)c1)C[C@@]1(C(N)=O)CCCN1
Temperature: 50 °C
Reaction time: 120 h

Procedure:
(3R,7aR)-7a-{[(3-Fluoro-benzyl)-methyl-amino]-methyl}-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (Stage K.1, 385 mg, 0.973 mmol) was added to 7 M ammonia in MeOH (6.950 mL, 48.7 mmol) under argon and heated in a sealed vessel at 50° C. for 6 days and then at 75° C. for 5 days. The RM was then evaporated and the residue purified by flash chromatography using a 12 g RediSep® silica gel column (eluent 5% MeOH in DCM) to give the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=[O:12].[H-].[Na+].[CH3:15]I>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:15])[CH:8]=[C:7]2[CH:11]=[O:12]
Reactant: O=Cc1c[nH]c2c(F)cccc12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C=O)c2cccc(F)c21
Reaction time: 1 h

Procedure:
7-Fluoroindole-3-carboxaldehyde (2.5 g) in dry THF (20 ml) was added to a cold (0°) suspension of sodium hydride (73.2% dispersion in oil; 652 mg) in dry THF (20 ml) under nitrogen and the mixture was stirred for 1h. Methyl iodide (2.5 ml) was added, and the resulting mixture was stirred for 2h at 0°. The mixture was then poured into saturated brine solution (300 ml) and extracted with ether (2×300 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (2.66 g), m.p. 92°-94°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([Si:8]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[N:9]1[C:13]2=[N:14][CH:15]=[C:16]([NH2:18])[CH:17]=[C:12]2[CH:11]=[CH:10]1)([CH3:7])[CH3:6].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:22]([Si:8]([CH:5]([CH3:7])[CH3:6])([CH:19]([CH3:21])[CH3:20])[N:9]1[C:13]2=[N:14][CH:15]=[C:16]([NH:18][C:1](=[O:3])[CH3:2])[CH:17]=[C:12]2[CH:11]=[CH:10]1)([CH3:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N)cnc21
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.8 %

Procedure:
Acetyl chloride (75 μL, 1.0 mmol) was added to a solution of 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (230 mg, 0.8 mmol) and 4-dimethylaminopyridine (5 mg) in pyridine (1.6 mL). The mixture was stirred at RT for 24 h and a saturated solution of ammonium chloride (30 mL) and ethyl acetate (30 mL) were added. The separated aqueous layer was extracted with ethyl acetate (3×25 mL) and the combined organic layers were dried, filtered and concentrated to provide an oil which was purified by preparative HPLC to afford N-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide (140 mg, 53%) as an oil: LCMS; m/z 332 (M+H+). B. At RT under argon, a solution of borane-dimethylsulfide complex (665 μL, 6.6 mmol, 10 M) was added to N-methyl-N-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide (110 mg, 0.33 mmol) in THF (3.0 mL). The mixture was heated to 65° C. for 2 h., cooled down and a 6N hydrochloric acid solution was slowly added. The mixture was heated to 100° C. and vigorously stirred for 12 h., cooled down and a 6 N sodium hydroxide solution was added until pH 7 was reached. The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried, filtered and evaporated to provide an oil which was purified through silica gel-SCX column (arylsulfonic acid with washes with methanol and 2N NH3 in methanol) to afford ethyl-(1H-pyrrolo[2,3-b]pyridin-5-yl)-amine. LCMS; m/z 203 (M+AcCN), 162 (M+H)+.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([S:17]([NH:20][C@H:21]([C:29]([OH:31])=O)[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18])[CH:9]=[CH:8]2.C(OCC)C.S(Cl)([Cl:39])=O>>[N:1]#[N:2].[ClH:39].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[C:10]([S:17]([NH:20][C@H:21]([C:29]([Cl:39])=[O:31])[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])(=[O:19])=[O:18])[CH:9]=[CH:8]2
Reactant: O=S(Cl)Cl
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc2cc1OC
Agent: N#N
Solvent: CCOCC
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.00 g of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginine in 20 ml of thionyl chloride was stirred for 2 hours at room temperature. Addition of cold dry diethyl ether resulted in a precipitate which was collected by filtration and washed several times with dry diethyl ether to give N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl chloride hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[C:6]([CH3:10])(C)[CH:5]=[C:4]([C:11]([CH3:21])=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH3:20])[CH:14]=2)[CH:3]=1.[CH2:22](C1OC1)Cl.C(O)(C)C.[OH-].[Na+]>O>[CH3:10][C:6]1[CH:5]=[C:4]([C:11]([CH3:21])=[CH:12][C:13]2[CH:14]=[C:15]([CH3:20])[C:16]([OH:19])=[C:17]([CH3:22])[CH:18]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:8]
Reactant: CC(=Cc1ccc(O)c(C)c1)C1=CC(C)(C)C(O)C(C)=C1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(=Cc1cc(C)c(O)c(C)c1)c1cc(C)c(O)c(C)c1
Temperature: 55 °C

Procedure:
3,3',5,5-Tetramethyl-4,4'-dihydroxy-alphamethylstilbene (211.78 grams, 1.50 hydroxyl equivalent) from A. above, epichlorohydrin (693.98 grams, 7.50 moles), deionized water (60.35 grams, 8.0 percent by weight of the epichlorohydrin used) and isopropanol (373.68 grams, 35 percent by weight of the epichlorohydrin used) are added to a two liter glass resin kettle reactor equipped with a chilled water condenser, mechanical stirrer, nitrogen purge (1 liter per minute), thermometer and thermostatically controlled infrared heating lamps and heated to 55° C. with stirring under a nitrogen atmosphere. Once the 55° C. reaction temperature is achieved, sodium hydroxide (54.0 grams, 1.35 mole) dissolved in deionized water (216 grams) is added dropwise to the reactor over a 45 minute period, so as to maintain reaction temperature between 55 and 58° C. Ten minutes after completion of the aqueous sodium hydroxide addition, the stirring is stopped and the aqueous layer which separates from the reaction mixture is pipetted off and discarded. Stirring is resumed and after a total of twenty minutes following completion of the initial aqueous sodium hydroxide addition, a second solution of sodium hydroxide (24.0 grams, 0.60 mole) dissolved in deionized water (96 grams) is added to the reactor over a twenty minute period and so as to maintain the 55° C. reaction temperature. Fifteen minutes after completion of the aqueous sodium hydroxide addition, the recovered reaction mixture is added to a separatory funnel and washed with 500 milliliters of deionized water. The separated organic layer is washed a second time (500 milliliters deionized water), recovered and then rotary evaporated under vacuum for 45 minutes at 110° C. then 30 minutes at 140° C. and 5 mm Hg. The product is recovered (293.84 grams) as a light amber colored, transparent liquid (at 24° C.) with an epoxide equivalent weight of 227.80.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[N-:11]=[N+:12]=[N-:13].[Na+].CO.[C:17](OC(=O)C)(=O)[CH3:18]>>[CH3:17][C:18]1[N:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]([OH:10])=[O:9])[N:13]=[N:12][N:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnccc1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: Cc1nnnn1-c1cnccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminopyridine-4-carboxylic acid (50.0 g, 0.36 mol) was suspended in acetic anhydride (250 mL) then heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum. The solid residue was slurried with heptane then concentrated under vacuum. The resulting solid was covered with acetic acid (300 mL), then sodium azide (23.5 g, 0.36 mol) was added. The reaction exothermed to 50° C. The reaction mixture was allowed to stir at ambient temperature overnight. The precipitate was isolated by filtration then slurried with methanol and filtered. The solid was dissolved in 10% sodium hydroxide. The solution was heated on a steam bath for 30 minutes, allowed to cool to ambient temperature then neutralized with 6N hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and dried to provide 64.5 g of 3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylic acid as an off white solid, m.p. 214-215° C. (decomposition).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[OH-].[Mg].[Ca:7]>>[C:1](=[O:2])([O-:4])[O-:3].[C:1](=[O:2])([OH:4])[O-:3].[Ca+2:7].[C:1](=[O:2])([OH:4])[O-:3]
Reactant: [Ca]
Agent: O=C([O-])[O-]
Agent: [Mg]
Agent: [OH-]
Product: O=C([O-])O
Product: [Ca+2]

Procedure:
Magnesium bicarbonate and/or calcium bicarbonate exist as solution with low solubility. They are not stable, and by heating they will decompose and form magnesium or/and calcium carbonate or precipitate(s) of basic carbonate. Therefore, they are not common products. The present invention uses mineral(s), oxide(s), hydroxide(s) of magnesium or/and calcium with low purity as raw materials, and these raw materials are processed through at least one step of calcination, hydration, and carbonation to produce solution(s) of magnesium bicarconate or/and calcium bicarbonate. By controlling the temperature of carbonation and the concentration, and keeping carbon dioxide in solution being saturated, the magnesium bicarbonate and/or calcium bicarbonate could keep stable at a certain concentration in solution. The precipitating mother liquor containing magnesium is used to produce magnesium hydroxide through alkali conversion. And then the magnesium hydroxide is used for carbonation to prepare magnesium bicarbonate. At the same time, carbon dioxide, which is produced from calcination of the magnesium and calcium minerals or their metal carbonate, is collected for the carbonation to prepare magnesium bicarbonate and/or calcium bicarbonate. The resources are efficiently recycled in the whole process, and CO2 emission and wastewater pollution can be efficiently avoided. More importantly, the production cost of metals declines a lot.