Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:5][OH:6])[CH2:3][NH2:4].C(N(C(=O)C)[C:11]1[C:12]([I:29])=[C:13]([C:17]([I:28])=[C:18]([N:21]([C:25](=[O:27])[CH3:26])C(=O)C)[C:19]=1[I:20])[C:14](Cl)=[O:15])(=O)C.[OH-].[NH4+].[CH3:35][C:36]([N:38](C)C)=[O:37]>>[OH:1][CH:2]([CH2:5][OH:6])[CH2:3][NH:4][C:14](=[O:15])[CH:13]1[C:17]([I:28])=[C:18]([NH:21][C:25](=[O:27])[CH3:26])[C:19]([I:20])=[CH:11][C:12]1([NH:38][C:36](=[O:37])[CH3:35])[I:29]
Reactant: NCC(O)CO
Reactant: CC(=O)N(C)C
Reactant: CC(=O)N(C(C)=O)c1c(I)c(C(=O)Cl)c(I)c(N(C(C)=O)C(C)=O)c1I
Agent: [NH4+]
Agent: [OH-]
Product: CC(=O)NC1=C(I)C(C(=O)NCC(O)CO)C(I)(NC(C)=O)C=C1I
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2,3-Dihydroxypropylamine (12.10 g, 0.0133 mole) in DMA (10 ml) was added to an ice-cold solution of 3,5-bis-diacetylamino-2,4,6-triiodobenzoyl chloride (29) (35.83 g, 0.05 mole) in DMA (50 ml), with stirring, for 10 min. The reaction mixture was stirred at room temperature, and let stir for 5 hours. Concentrated ammonium hydroxide (30 ml) was added. After 30 min, all solvents were removed in vacuo at 60° C. To the residue, 1N hydrochloric acid (50 ml) was added and the solvent removed in vacuo. The residue was mixed with ice cold water (150 ml) and the precipitate was filtered, washed with water and dried to obtain the product, N-(2',3'-dihydroxypropyl) 2,5-bis-acetylamino-2,4,6-triiodobenzamide (30), as a white solid in high yield. TLC: (silica gel): 0.36 in CHCl3 /MeOH 8:2. NMR: (DMSO-d6): COCH3 (2.02, singlet, 6H); (--CH2 -- and --CH protons (3.05 to 3.85, broad multiplet, 5H); --OH (4.2, singlet); ArCOHN-(8.4 to 8.7, broad triplet, 1H); Ar--NHCO-- (9.85 to 10.15, broad doublet, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]O.S(Cl)(Cl)=O.[SH:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1>ClCCl.C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][S:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1
Reactant: COCCCNc1ccccc1CO
Reactant: Sc1ncc[nH]1
Solvent: CCO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCCCNc1ccccc1CSc1ncc[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a solution of 2.9 g (14.8 mmol) of 2-(3-methoxypropyl) aminobenzyl alcohol in 29 ml of dichloromethane was dropwise added a solution of 1.3 ml (17.8 mmol) of thionyl chloride in 3 ml of dichloromethane under chilling with ice for a period of 5 min. The resulting mixture was stirred for 15 min. at room temperature. The solvent was distilled off under reduced pressure at room temperature. To the residue was added 10 ml of dichloromethane. The obtained dichloromethane solution was little by little added to a solution of 2.22 g (22.2 mmol) of 2.mercaptoimidazole in 22 ml of ethanol, and then the mixture was stirred for 15 min. at room temperature. Ethanol was distilled off under reduced pressure. To the residue were added ice and saturated aqueous sodium hydrogencarbonate. The resulting mixture was treated with ether for extraction. The organic portion was collected and sequentially washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 2.7 g of the desired compound as a pale yellow oil. (Yield: 65.8 %)
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([Si:17]([CH3:28])([CH3:27])[C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20]([F:25])[C:19]=1[F:26])([CH3:16])([CH3:15])[CH3:14].[F:29][C:30]1[C:35]([C:36](N(OC)C)=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1>C1COCC1>[Si:17]([C:18]1[C:19]([F:26])=[C:20]([F:25])[N:21]=[C:22]([C:36]([C:35]2[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:37])[C:23]=1[F:24])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1F
Reactant: CON(C)C(=O)c1cccnc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(=O)c2cccnc2F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (66.78 g, 92.49 mL, 659.9 mmol) in THF (1.360 L) was cooled to −20° C. under nitrogen. nBuLi (2.5M in hexane) (253.0 mL of 2.5 M, 632.4 mmol) was added dropwise via cannula at such a rate as to maintain the internal temperature below −15° C. The solution was warmed to 0° C. then immediately re-cooled to −90° C. Tert-butyl-dimethyl-(2,3,5-trifluoro-4-pyridyl)silane (136 g, 549.9 mmol) was added dropwise via cannula at such a rate as to maintain the internal temperature below −85° C. After complete addition the solution became an orange suspension. The reaction mixture was stirred at −85° C. for 1 h then 2-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (116.5 g, 632.4 mmol) was added dropwise over 1 h keeping the internal temperature below −85° C. The mixture turned dark green then dark red during addition. The mixture was stirred at −85° C. for 45 min after which time Lc/Ms indicated the reaction was complete. The cooling bath was removed and the mixture warmed to −50° C. Saturated ammonium chloride solution NH4Cl (300 mL) was added and the mixture allowed to warm up to RT. The mixture was diluted with EtOAc (2.5 L). The aqueous phase was separated and extracted with more EtOAc (500 ml). The combined organics were washed with brine and partially concentrated in vacuo. The solution was dried over magnesium sulfate, filtered and concentrated in vacuo to a brown oil. The crude was purified on silica gel, eluting with 0-20% ethyl acetate in petroleum ether. This gave the title compound as a yellow oil which solidified on standing (159.6 g, 78%); 1H NMR (CDCl3) 0.35 (6H, s), 0.88 (9H, s), 7.29 (1H, m), 8.13 (1H, m), 8.37 (1H, m); 19F NMR (decoupled) −112.47, −106.7, −89.3, −61.95; MS ES (+) 371.14 (M+1).
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[CH3:8][C:9]([CH3:13])([CH3:12])[CH:10]=[CH2:11].[SiH:14]([Cl:17])([Cl:16])[Cl:15]>>[Si:14]([CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH3:8])([Cl:17])([Cl:16])[Cl:15].[Si:1]([CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH3:8])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: CC[SiH](CC)CC
Reactant: C=CC(C)(C)C
Reactant: Cl[SiH](Cl)Cl
Product: CC(C)(C)CC[Si](Cl)(Cl)Cl
Product: CC[Si](CC)(CC)CCC(C)(C)C
Yield: 59.8 %
Yield: 8.3 %

Procedure:
In a 100 ml apparatus, there were combined 11.6 g (0.1 mol) of Et3SiH, 8.4 g (0.1 mol) of 3,3-dimethyl-1-butene, and 13.6 g (0.1 mol) of Cl3SiH. Pt Catalyst solution was added (0.05 ml) at 24° C., causing a rapid exothermic reaction to 57° C. in 4 min. Vacuum distillation yielded 1.82 g (8.3%) of Cl3SiCH2CH2CMe3 and 11.95 g (59.8%) of Et3SiCH2CH2CMe3. This example shows that Cl3SiH is an effective promoter at the equimolar level for the reaction between Et3SiH and 3,3-dimethyl-1-butene.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([Br:11])=[CH:4][N:3]=1.C(O[Na])=O>CN(C=O)C.O.CCOC(C)=O.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:11][C:5]1[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:2]=[N:3][CH:4]=1
Reactant: Brc1ncc(Br)c2occc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=CO[Na]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cncc2ccoc12
Temperature: 100 °C
Yield: 77 %

Procedure:
A suspension of 4,7-dibromofuro[3,2-c]pyridine (3.50 g, 12.6 mmol), HCO2Na (2.59 g, 38.1 mmol) and Pd(PPh3)4 (360 mg, 0.32 mmol) in dry DMF (35 mL) was heated at 100° C. (bath temperature) under Ar for 9 h. LC-MS showed the reaction was almost complete. The mixture was diluted with water (50 mL) and EtOAc (200 mL). Layers were separated and the organic phase was washed with water (3×40 mL), brine (40 mL), and dried over Na2SO4. The solvent was removed and residue was purified by silica gel chromatography eluting with Hexanes-EtOAc (80:20→70:30) to provide the title compound as an off-white solid (1.92 g, 77%). 1H NMR (CDCl3, 400 MHz): δ=6.98 (d, J=2.3 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H), 8.62 (s, 1H), 8.89 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13].CO>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:15][CH:12]([CH3:14])[CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)N
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred, cold (0° C.) solution of 4-bromo-1-fluoro-2-nitrobenzene (7 g, 32 mmol) in dichloromethane (100 mL) was added isopropylamine (5 mL, 64 mmol). The mixture was allowed to stir at 0° C. for 3 h and room temperature overnight. It was diluted with water and extracted with CH2Cl2. The organic layer was washed with water and brine, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo to give a crude red solid. Trituration with MeOH afforded the title compound as an orange-red solid. MS (ESI, pos. ion) m/z: 260.7 (M+1).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][C:13]([N:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([CH3:21])[CH2:16]3)=[O:14])[CH2:3]1)[CH2:9]2.[C:22](Cl)(=[O:24])[CH3:23].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][C@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([C:13]([NH:12][CH:5]2[CH:4]3[CH2:3][C:2]4([O:1][C:22](=[O:24])[CH3:23])[CH2:9][CH:8]([CH2:7][CH:6]2[CH2:11]4)[CH2:10]3)=[O:14])[CH2:16]1
Reactant: CC(=O)Cl
Reactant: C[C@H]1CCCN(C(=O)NC2C3CC4CC2CC(O)(C4)C3)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC12CC3CC(C1)C(NC(=O)N1CCC[C@H](C)C1)C(C3)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-3-Methyl-piperidine-1-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide 0.15 g (0.51 mmol), 0.109 ml of acetyl chloride, 0.3 ml of pyridine in 1.5 ml of methylene chloride was stirred at room temperature overnight. A saturated NaHCO3 solution was added, the organic phase extracted with methylene chloride, washed with HCl 1 N solution and dried over sodium sulphate. Flash chromatography on silica gel (eluant CH2Cl2/MeOH: 95/05) yielded 75 mg of the title compound
Reaction SMILES: [C:1](=[O:3])=[O:2].[S:4]([O-:8])([O-:7])(=[O:6])=[O:5].[Ca+2:9].[NH3:10]>>[C:1](=[O:5])([O-:3])[O-:2].[Ca+2:9].[S:4]([O-:8])([O-:7])(=[O:6])=[O:5].[NH4+:10].[NH4+:10]
Reactant: N
Reactant: O=C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Product: O=C([O-])[O-]
Product: [NH4+]

Procedure:
The existing technology for preparation of nano calcium carbonate is bubbling carbon dioxide into a calcium hydroxide slurry to obtain nano calcium carbonate, while the present invention is injecting carbon dioxide into a calcium sulfate slurry containing ammonia to obtain nano calcium carbonate with byproduct ammonium sulfate. The principle of the present invention is as follows: due to the calcium hydroxide is more alkaline than ammonia, the reaction formula (1) cannot be carried out; instead, according to the reaction formula (2) and (3), the carbon dioxide is firstly reacted with ammonia to generate ammonium carbonate, and then ammonium carbonate and calcium sulfate react to get calcium carbonate and ammonium sulphate. The nano calcium carbonate can be obtained by controlling the speed of the formation of calcium carbonate. CaSO4+2NH3+2H2O→(NH4)2SO4+Ca(OH)2  (1) 2NH3+CO2+H2O→(NH4)2CO3  (2) (NH4)2CO3+CaSO4→(NH4)2SO4+CaCO3  (3)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:13][C@@H:14]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[CH2:15][N:16]([CH3:29])S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)=[C:7]2[C:12]=1[N:11]=[CH:10][N:9]=[CH:8]2)#[N:2].[OH-:37].[Na+].OO>CS(C)=O>[F:36][C:32]1[CH:31]=[C:30]([C@H:14]([NH:13][C:6]2[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[C:12]3[C:7]=2[CH:8]=[N:9][CH:10]=[N:11]3)[CH2:15][NH:16][CH3:29])[CH:35]=[CH:34][CH:33]=1
Reactant: [OH-]
Reactant: CN(C[C@@H](Nc1ccc(C#N)c2ncncc12)c1cccc(F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC[C@@H](Nc1ccc(C(N)=O)c2ncncc12)c1cccc(F)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N—[(S)-2-(8-Cyano-quinazolin-5-ylamino)-2-(3-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide (120.00 mg; 0.24 mmol; 1.00 eq.) in DMSO (8 ml) was added aqueous 2.0M NaOH (0.59 ml; 1.18 mmol; 5.00 eq.) and aqueous 35% hydrogen peroxide (0.14 ml; 1.42 mmol; 6.00 eq.) and continued stirring at 40° C. overnight. The crude product was purified by prep-HPLC to yield the desired product, which was then added of acetonitrile (2 ml), thiophenol (0.1 ml), CsCO3 (200 mg), and stirred at 40° C. overnight. The crude was purified by prepHPLC to afford the title product. LC-MS (M+H=434, obsd.=434).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[CH2:8][C:7]1=[O:26])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:28]([O:30][NH2:31])[CH3:29].[OH-].[Na+]>C(O)C.O>[CH2:28]([O:30][NH:31][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][N:17]=2)[CH2:8][C:7]1=[O:26])[CH2:2][CH2:3][CH3:4])[CH3:29]
Reactant: CCCC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cn2)CC1=O
Reactant: CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCC(NOCC)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cn2)CC1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
0.6 Gram of 2-butyryl-5-[2-(5-trifluoromethyl-2-pyridylthio)ethyl]cyclohexane-1,3-dione was dissolved in a mixed solvent of 10 ml of ethanol and 1 ml of water, and 0.2 g of ethoxyamine hydrochloride and 0.07 g of sodium hydroxide were added to the resulting solution which was then stirred at room temperature for 2.5 hours. The reaction solution was poured into water, weakly acidified and extracted with ethyl acetate. After removing ethyl acetate, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.45 g of 2-(1-ethoxyaminobutylidene)-5-[2-(5-trifluoromethyl-2-pyridylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[CH2:26][CH2:25][NH:24][CH2:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]4[NH:17][C:18](=[O:20])[NH:19][C:15]=4[CH:14]=3)[N:12]=2)[CH2:3][CH2:2]1.Cl[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[CH2:26][CH2:25][N:24]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:23][C:9]=3[N:10]=[C:11]([C:13]3[CH:22]=[CH:21][C:16]4[NH:17][C:18](=[O:20])[NH:19][C:15]=4[CH:14]=3)[N:12]=2)[CH2:5][CH2:6]1
Reactant: O=c1[nH]c2ccc(-c3nc4c(c(N5CCOCC5)n3)CCNC4)cc2[nH]1
Reactant: Clc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(-c3nc4c(c(N5CCOCC5)n3)CCN(c3ncccn3)C4)cc2[nH]1

Procedure:
Step 3—Synthesis of compound ug: 5-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)-1H-benzo[d]imidazol-2(3H)-one (0.297 g, 0.843 mmol), 2-Chloropyrimidine (0.145 g, 1.27 mmol), N,N-Dimethylformamide (10.0 mL, 129 mmol) and N,N-Diisopropylethylamine (0.588 mL, 3.38 mmol) were combined. The reaction solution was microwaved on 300 watts, 120° C. for 30 minutes on a CEM microwave. The reaction solution was filtered and washed with dichloromethane. LC/MS-m/z+431.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:4]([O:20][CH3:21])[CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27]>>[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[C:26]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:20][CH3:21])[CH2:15][C:16]([F:18])([F:17])[F:19])=[O:27]
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC(F)(F)F
Product: COc1cc(F)ccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 133, intermediate a) and 3-fluoro-5-(trifluoromethyl)benzoic acid chloride (CAS RN 171243-30-4). The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50), followed by preparative HPLC using a gradient of methanol:water (10:50 to 95:5). Colorless solid (22%). MS (ESI): m/z=491.099 [M+H]+.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[C:9]([Cl:30])[C:10]([C:13]2[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=[N:11][CH:12]=1.[CH3:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=[C:34]([O:47][CH2:48][C:49]2([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50]2)[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:30][C:9]1[CH:8]=[C:7]([C:37]2[CH:36]=[N:35][C:34]([O:47][CH2:48][C:49]3([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:52][CH2:51][CH2:50]3)=[CH:33][C:32]=2[CH3:31])[CH:12]=[N:11][C:10]=1[C:13]1[N:14]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1
Reactant: CCOC(=O)C1(COc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cn2)CCC1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ncc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2cc(C)c(-c3cnc(-c4nc(C(F)(F)F)cn4COCC[Si](C)(C)C)c(Cl)c3)cn2)CCC1
Temperature: 65 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
N,N-dimethylformamide (3 mL) was added to 5-bromo-3-chloro-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (365 mg), ethyl 1-({[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]-oxy}methyl)cyclobutanecarboxylate (300 mg) and palladium chloride (dppf) methylene chloride complex (33 mg), and after adding 2N aqueous sodium carbonate solution (1.2 mL) to the mixture, the atmosphere was replaced with nitrogen and the mixture was stirred at 65° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain ethyl 1-[({5′-chloro-4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)methyl]cyclobutanecarboxylate (318 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=O.[C:14](#[N:18])[CH2:15][C:16]#[N:17].CN(C)C(C)C.[NH2:25][C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][C:27]=1[OH:33]>C(O)C>[NH2:17][C:16]1[O:33][C:27]2[C:28]([CH:5]([C:4]3[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:2]([Br:1])[CH:3]=3)[C:15]=1[C:14]#[N:18])=[CH:29][CH:30]=[C:31]([NH2:32])[C:26]=2[NH2:25]
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Nc1cccc(O)c1N
Reactant: N#CCC#N
Agent: CC(C)N(C)C
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc(N)c3N)cc(Br)c1OC
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A suspension of 3-bromo-4,5-dimethoxybenzaldehyde (1500 g, 6.12 moles, 1.1 eq) and malononitrile (404 g, 6.12 moles, 1.1 eq) in ethanol 99% (12 L, 7 volumes) was stirred at room temperature under N2(g). Dimethylisopropylamine (339 mL, 2.78 moles, 0.5 eq) was added slowly (which caused an exotherm from about 14° C. to about 26° C.) and the reaction mixture was stirred at room temperature for about 2 h under N2(g). The yellow thick suspension was analyzed by HPLC to monitor the appearance of the Knoevenagel intermediate and the disappearance of the aldehyde. 2,3-Diaminophenol (690.66 g, 5.56 moles, 1 eq) was added and the reaction mixture was stirred at room temperature overnight. The resulting beige-brown suspension was filtered and the cake was washed with cold CH2Cl2 (3000 mL). The solids were dried under vacuum to give 2,7,8-triamino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromene (1.9 kg, 82% yield). 1H NMR (300 MHz) (DMSO-d6, ppm): 3.71 (s, 3H), 3.82 (s, 3H), 4.43 (s, 2H), 4.56 (s, 1H), 4.70 (s, 2H), 6.09 (d, J=8 Hz, 1H), 6.26 (d, J=8 Hz, 1H), 6.76 (s, 2H), 6.78 (d, J=2 Hz, 1H), 6.90 (d, J=2 Hz, 1H).
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O[C:18](=[O:20])[CH3:19])(=O)C>S(=O)(=O)(O)O>[C:5]([O:13][C:1]12[CH2:10][C:5]3([O:11][C:3](=[O:12])[CH3:2])[CH2:6][CH:7]([CH2:9][C:3]([O:12][C:18](=[O:20])[CH3:19])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:11])[CH3:4]
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OC12CC3CC(OC(C)=O)(C1)CC(OC(C)=O)(C3)C2
Temperature: 100 °C

Procedure:
92.12 g (0.5 mol) of 1,3,5-adamantanetriol are suspended in 153.14 g (1.5 mol) of acetic anhydride. Subsequently, 10 drops of concentrated sulfuric acid are added and the mixture is stirred on a rotary evaporator (without vacuum) until a homogeneous solution has formed. Subsequently, the mixture is heated to 100° C. under reflux for 2 h. After cooling, the reaction mixture is added to 300 ml of ice-water and extracted with dichloromethane. The combined organic phases are deacidified with sodium carbonate solution and washed with water. The mixture is dried over magnesium sulfate and filtered, and the solvent is removed under reduced pressure. 150.50 g (0.48 mol; 97.0%) of a colorless oil are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([NH:15][NH:16][C:17]([C@@H:19]1[CH2:25][CH2:24][C@@H:23]2[CH2:26][N:20]1[C:21](=[O:32])[N:22]2[O:27][S:28]([OH:31])(=[O:30])=[O:29])=[O:18])=[O:14])(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl.CCOCC>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([NH:15][NH:16][C:17]([C@@H:19]1[CH2:25][CH2:24][C@@H:23]2[CH2:26][N:20]1[C:21](=[O:32])[N:22]2[O:27][S:28]([OH:31])(=[O:30])=[O:29])=[O:18])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of compound 288 (0.1 g, 0.2 mmol) in DCM (10 mL) at 0° C. was added TFA (0.5 mL) dropwise. After addition, the mixture was stirred at 0° C. for 3 h then diluted with 50 mL of ether. The solid was collected by filtration and washed with additional ether and dried to afford the title compound Compound 40 (Table 2) as a white solid (0.07 g, 72%)
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH:12]=O)=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:14][NH2:15].[BH4-].[Na+].O>CO>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][NH:15][CH3:14])=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1cccc2c1OCCCO2
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cccc2c1OCCCO2
Reaction time: 3 h
Yield: 86 %

Procedure:
3,4-Dihydro-2H-benzo[b][1,4]dioxepine-6-carbaldehyde (269 mg, 1.51 mmol) was dissolved in anhydrous methanol (7 ml). Methylamine (0.60 ml of 33% solution in ethanol, 4.82 mmol) was added and the reaction was stirred for 3 hours. The solution was concentrated to a yellow oil and then dissolved in anhydrous methanol (7 ml). Sodium borohydride (58.3 mg, 1.54 mmol) was added and the mixture was stirred overnight at room temperature. Water (10 ml) was added and the solution was concentrated. Sodium hydroxide (20 ml, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×40 ml). Combined organic layers were dried over MgSO4, filtered and concentrated to afford (3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylmethyl)-methyl-amine (251 mg, 86%) as a brown oil: 1H NMR (400 MHz, DMSO-d6) δ 6.96 (dd, J=8.0, 4.0 Hz, 1H), 6.88-6.82 (m, 2H), 4.10-4.05 (m, 4H), 3.60 (s, 2H), 2.25 (s, 3H), 2.10-2.06 (m, 2H).