Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=CN(C)C)=[CH:7][N:6]=1)=[O:4].I([O-])(=O)(=O)=[O:17].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=[O:17])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(C=CN(C)C)cn1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cnc(C=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A solution of the 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylic acid methyl ester (415 mg, 2.0 mmol) in tetrahydrofuran and water (10 mL, 1:1) was treated with powdered sodium periodate (1.3 g, 6.07 mmol). The mixture was stirred at 25° C. for 30 min, at which time, thin layer chromatography suggested complete conversion to a product less polar than starting material. The reaction mixture was concentrated in vacuo nearly to dryness, and the residue was partitioned with ethyl acetate (50 mL) and a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (2×50 mL). Each of the organic extracts was washed with a saturated aqueous sodium chloride solution (25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude aldehyde, 5-formyl-pyrazine-2-carboxylic acid methyl ester (180 mg), as an orange oil which was used without further characterization or purification.
Reaction SMILES: [CH:1]1([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3Cl)[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1.[CH3:18][NH2:19]>O>[CH3:18][NH:19][C:13]1[C:14]2[N:15]=[CH:16][N:8]([C:9]=2[N:10]=[CH:11][N:12]=1)[C@@H:1]1[S:5][C@H:4]([CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: CN
Reactant: OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1
Solvent: O
Product: CNc1ncnc2c1ncn2[C@H]1CC[C@@H](CO)S1
Yield: 77 %

Procedure:
The anomeric mixture of 20 (0.132 g, 0.49 mmol) in a steel bomb was stirred with 20 mL 40% methylamine in water at 80° C. overnight. After solvent removal in vacuo, the residue was purified by preparative TLC with 9:1 chloroform/methanol to give 100 mg (77%) of the anomeric mixture. The anomers were partially separated by a Dowex 1×4 (-OH) column with 10% aqueous methanol to give 37 mg of impure β anomer which was recrystallized from hexane-ethyl acetate to afford 22.5 mg of pure β anomer by HPLC; mp. 131°-134° C.; FAB MS 266 (M+H)+ ; 1H NMR (DMSO-d6) δ 8.4 (s, 1, H-2), 8.2 (s, 1, H-8), 7.7 (brs, 1, NH), 6.2 (m, 1, 1'-H), 5.15 (m, 1, 5'-OH), 3.75 (m, 1, 5 '-H), 3.6 (m, 2, 4'-H, 5'-H), 2.95 (s, 3, CH3), 2.4 (m, 2, 4'-H's), 2.15 (m, 1, 3'-H), 2.0 (m, 1, 3'-H).
Reaction SMILES: [CH3:1][C:2]12[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[NH:16][CH:17]=[C:9]([C:10]=34)[CH2:8][CH:3]1[NH:4][CH2:5][CH2:6][O:7]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]12[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[NH:16][CH:17]=[C:9]([C:10]=34)[CH2:8][CH:3]1[N:4]([CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:5][CH2:6][O:7]2
Reactant: CC12OCCNC1Cc1c[nH]c3cccc2c13
Reactant: ICCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC12OCCN(CCOc3ccccc3)C1Cc1c[nH]c3cccc2c13
Temperature: 60 °C
Yield: 45.8 %

Procedure:
To a solution of 4,6,6a,8,9,10a-hexahydro-10a-methyl-7H-indolo[3,4-gh][1.4]benzoxazine (85 mg, 0.37 mmol) in DMF (5 ml) were added potassium carbonate (255 mg, 1.9 mmol) and 1-iodo-2-phenoxyethane (99 mg, 0.4 mmol). The mixture was heated at 60° C for 24 hours. After completion of the reaction, the reaction mixture was added to a mixture of ice water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (2:1), to afford 59 mg (46%) of the title compound as an amorphous crystalline product.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[O:11][CH2:10]1)[CH:2]=[CH2:3].[NH2:16][CH2:17][CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]3[CH:29]([CH3:35])[CH2:30][C:31](=[O:34])[NH:32][N:33]=3)[CH:25]=[CH:24][C:22]=2[N:23]=1>>[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:11])[CH2:10][NH:16][CH2:17][CH2:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([C:28]3[CH:29]([CH3:35])[CH2:30][C:31](=[O:34])[NH:32][N:33]=3)[CH:25]=[CH:24][C:22]=2[N:23]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1OCC1CO1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(CCN)[nH]c2c1
Product: C=CCOc1ccccc1OCC(O)CNCCc1nc2ccc(C3=NNC(=O)CC3C)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 1-(2-allyloxy-phenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)O)n2)cc1Cl
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(=O)N3CCOCC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a solution containing {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid (prepared in example 3, 100 mg, 0.22 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (121 μL, 0.24 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (28 μL, 0.24 mmol) was added to the solution. After 1 h, morpholine (21 μL, 0.24 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with saturated aqueous ammonium chloride solution, the organic phase was concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-morpholin-4-yl-2-oxo-ethyl)-1H-pyrazol-3-yl]-propionamide (71 mg, 62%) as a white solid: ESI-LRMS m/e calcd for C24H31ClN4O5S [M+] 522.17, found 523.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.18 (m, 2H, CH2), 1.41-1.95 (m, 8H, 4×CH2), 2.15-2.24 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.46 (m, 2H, NCH2), 3.55 (t, J=7.5 Hz, 1H, CH),), 3.58-3.70 (m, 6H, 2×OCH2 and NCH2), 4.81 (s, 2H, NCH2), 6.71 (m, 1H, Ar), 7.34 (m, 1H, Ar), 7.42 (m, 1H, Ar), 7.56 (m, 1H, Ar), 8.04 (d, Jo=8.1 Hz, 1H, Ar), 8.10 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([O-:14])=O)[N:4]=1.[CH2:17]([NH2:19])[CH3:18]>>[CH2:17]([NH:19][C:12]([C:5]1[N:4]=[C:3]([C:2]([F:1])([F:16])[F:15])[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]=12)=[O:14])[CH3:18]
Reactant: CCN
Reactant: O=C([O-])c1nc(C(F)(F)F)n2c1CNCC2
Product: CCNC(=O)c1nc(C(F)(F)F)n2c1CNCC2
Temperature: 50 °C
Reaction time: 12 h

Procedure:
3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (1 g, 4 mmol) was dissolved in 40 mL of ethylamine solution (60%). After stirring at 50° C. for 12 hours, the reaction mixture was concentrated under reduced pressure to obtain the crude N-ethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 7a (1.15 g) as a white solid. The product was used directly in the next reaction without purification.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH:23]=2)=O)[CH2:19][CH2:18]1.O>C1COCC1>[CH:17]1([C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][O:29][CH2:30][O:31][CH3:32])[CH:23]=2)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:18][CH2:19]1
Reactant: COCOCc1cc(C(=O)C2CC2)ccn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccnc(COCOC)c1)C1CC1

Procedure:
To a suspension of 60% sodium hydride (1.09 g) in THF (30 mL) was added ethyl diethylphosphonoacetate (6.46 mL) at 0° C., and then cyclopropyl(2-((methoxymethoxy)methyl)pyridin-4-yl)methanone (1.20 g) was added. The reaction mixture was heated under reflux for 2 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.36 g) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[Li]C(C)(C)C.[C:13](=[O:15])=[O:14]>CCOCC.CCCCC>[Br:7][C:6]1[C:2]([C:13]([OH:15])=[O:14])=[CH:3][S:4][CH:5]=1
Reactant: O=C=O
Reactant: Brc1cscc1Br
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: O=C(O)c1cscc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a solution of 3,4-dibromothiophene (15 g, 62 mmol) in 80 mL ether under a positive nitrogen atmosphere was added dropwise 75 mL 1.7M t-BuLi in pentane at below -73° C. and the resulting reaction solution was stirred at -78° C. for 0.5 h. After that, the ether solution was poured into dry ice and extracted with water. The aq solution was washed with ether and then acidified with concentrated HCl. The solid was filtered and air-dried to give 9 g of 4-bromo-3-thiophenecarboxylic acid, yield 70.3%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+].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>[C:40]1([C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
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
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(-c5ccccc5)c4)c3)ncnc21
Temperature: 80 °C
Yield: 95.8 %

Procedure:
To a solution of 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (from Example 429) (60 mg, 0.0001 mol) in 1,4-dioxane (2 mL, 0.02 mol), phenylboronic acid (15 mg, 0.00012 mol) and sodium bicarbonate (30 mg, 0.0003 mol) in water (0.5 mL, 0.03 mol) were added. The resulting mixture was degassed using nitrogen. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled through the reaction again. The reaction was heated at 80° C. in oil bath for 1 hour. Water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give 3-(5-phenylpyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (50 mg, 80%) as a crude product. MS (ES): 522 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCNc1cccc(Cl)c1
Yield: 51.2 %

Procedure:
3-Chloroaniline (3.8 g, 0.03 moles) was dissolved in ethanol (5 ml) and ethyl acrylate (3.3 g, 0.033 moles) was added in ethanol (5 ml). Concentrated hydrochloric acid (1 ml) was added and the reaction mixture was heated at reflux for 48 hours. Evaporated to a low bulk and dissolved the residue in dichloromethane and water. Basified to pH 9 with aqueous ammonia and separated. Evaporated off the dichloromethane under reduced pressure to give the crude product as a yellow oil (5.4 g) Purified using a silica column eluted with isohexane:ethyl acetate 9:1 to give the required product (3.5 g, 51%) as a colourless oil.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)\[CH3:5].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Br:1][CH2:2][CH:3]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]1([CH3:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C/C(=C\CBr)c1cccc([N+](=O)[O-])c1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1C(CBr)C1(C)c1cccc([N+](=O)[O-])c1
Yield: 9.4 %

Procedure:
To a solution of 1-[(E)-3-bromo-1-methyl-1-propenyl]-3-nitrobenzene (Preparation 4, 4 g, 15.6 mmol) in dichloromethane (5 ml) was added rhodium (II) acetate dirner (100 mg, 0.22 nmnol). To the mixture was added dropwise at room temperature over 4.5 h a solution of ethyl diazoacetate (3.1 ml, 2.84 g, 25 mmol) in dichloromethane (15 ml). The mixture was filtered, concentrated in vacuo, and the residue purified by silica column (100 g) chromatography, eluting with 2:1 hexane/dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo, then purified further by preparative HPLC (Condition 1). Combination and evaporation of appropriate fractions gave the title compound as a colourless oil (0.5 g, 11%).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.[ClH:31].O1CCOCC1>CO>[ClH:31].[NH2:8][C@@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[CH2:11][OH:10]
Reactant: COc1ccc(Oc2ccc(C[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(Oc2ccc(C[C@H](N)CO)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude product obtained from step 1 (100 mg, 0.25 mmol, 1 eq.) in methanol (2 ml) was added 4N HCl in dioxane (2 ml, 8 mmol, 32 eq.). The resulting mixture was stirred at room temperature for 2 hr. And then the volatile material was removed under reduced pressure. The residue thus obtained was washed with ether (3×15 ml) to remove non-acidic impurities. After dried, 75 mg of desired product (HCl salt) was obtained as white solid (99% isolated yield). 1H NMR (400 MHz, DMSO-d6) 62.87 (m, 2H), 3.27-3.30 (m, 1H), 3.36-3.41 (m, 1H), 3.50-3.55 (m, 1H), 3.93 (s, 2H), 6.91-6.95 (m, 4H), 7.19-7.30 (m, 9H), 7.93 (s, brs, 2H); LCMS (UV, ESI), 274 (M+1), 95% purity.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[CH3:11][C:12]1([CH3:19])[C:16]([CH3:18])([CH3:17])[O:15][BH:14][O:13]1.C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1>O1CCCC1>[CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])(/[CH:6]=[CH:7]/[B:14]1[O:15][C:16]([CH3:18])([CH3:17])[C:12]([CH3:19])([CH3:11])[O:13]1)[CH3:5]
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: CC1(C)OBOC1(C)C
Solvent: C1CCOC1
Product: CC(C)(/C=C/B1OC(C)(C)C(C)(C)O1)O[Si](C)(C)C
Temperature: 60 °C
Yield: 22 %

Procedure:
To a solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (1.5 g, 9.6 mmol) in tetrahydrofuran (15 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.79 mL, 19.2 mmol), followed by 9-BBN dimer (0.117 g, 0.480 mmol). The mixture was heated at 60° C. for 24 hours, then cooled to ambient temperature and quenched by the careful addition of saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (2×15 mL). The organics were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, eluted with a gradient of 0-60% ethyl acetate in hexanes) to afford the title compound (600 mg, 22% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.06-0.08 (m, 9H) 1.19 (s, 12H) 1.25 (s, 6H) 5.41 (d, J=17.85 Hz, 1H) 6.53 (d, J=17.85 Hz, 1H); MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([OH:17])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:25]([Si:28](OS(C(F)(F)F)(=O)=O)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([O:17][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:25]([CH3:27])[CH3:26])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of Intermediate 63a (204 mg, 0.864 mmol) and Et3N (180 μL, 1.3 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate (279 μL, 1.04 mmol) and the mixture stirred at RT for 1 h. The mixture was washed with sat. aq. NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, then 10% MeOH in EtOAc, to give the title compound as a pale brown gum (290 mg, 86%). LCMS (Method 3): Rt 4.99 min, m/z 393 [MH+].
Reaction SMILES: [ClH:1].[F:2][C:3]([F:13])([F:12])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10]O)=[N:8][CH:9]=1.O=S(Cl)[Cl:16]>>[Cl:16][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:13])([F:12])[F:2])=[CH:9][N:8]=1.[ClH:1].[Cl:16][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:13])([F:12])[F:2])=[CH:9][N:8]=1
Reactant: OCc1ccc(C(F)(F)F)cn1
Reactant: O=S(Cl)Cl
Agent: Cl
Product: FC(F)(F)c1ccc(CCl)nc1
Reaction time: 0.17 h

Procedure:
The mixture of (5-(trifluoromethyl)pyridin-2-yl)methanol HCl salt (293 mg, 1.4 mmol) and SOCl2 (1.5 ml) was stirred for 10 min. After this time, the solution was concentrated under reduced pressure to give the title compound, 2-(chloromethyl)-5-(trifluoromethyl)pyridine HCl salt.
Reaction SMILES: [C:1]([N:5]([C:15](=[O:24])[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]#[CH:29]>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:15](=[O:24])[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:28]#[CH:27]
Reactant: C#CCBr
Reactant: Cc1cc(C)cc(C(=O)N(NC(=O)c2ccccc2)C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCN(C(=O)c1ccccc1)N(C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirred suspension of N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine (1.5 g) in dimethylformamide (DMF) (20 ml) was added sodium hydride (200 mg of 60% oil dispersion) portionwise. After 15 min., propargyl bromide (0.6 g) was added to the reaction mixture dropwise and the reaction stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (5×20 ml). The organic layer was then dried over magnesium sulfate and the solvent removed under vacuum to afford N-(2-propynyl)-N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine as a yellow amorphous solid. The product, N-(2-propynyl)-N'-t-butyl-N-benzoyl-N'-(3,5-dimethylbenzoyl)hydrazine, was purified by column chromatography on silica gel (solvent system:methylene chloride) to afford a 70% yield as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[Cl:35])=[N:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:22][C:23]3[O:27][C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[Cl:35])=[N:25][CH:24]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1cccc(-c2ncc(CBr)o2)c1Cl
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2cnc(-c3cccc(Cl)c3Cl)o2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
49 mg (0.16 mmol) of the compound from Example 5A were reacted with 49 mg (0.16 mmol) of the compound from Example 55A analogously to the preparation of the compound in Example 77. This gave 35 mg (40% of theory) of the title compound.
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=O)C>O.COCCO>[N+:19]([C:17]1[CH:16]=[CH:15][C:14]2[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]=2[CH:18]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: O=[N+]([O-])c1ccc2c(c1)OCCCN2
Temperature: 100 °C
Yield: 93.4 %

Procedure:
1.00 M of Potassium hydroxide in Water (38 mL) was added to 3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (1.967 g, 7.388 mmol) in 2-Methoxyethanol (80 mL) at 80° C. and further heated at 100° C. for 3 h. The solution was cooled and diluted with 200 mL water and was extracted with EtOAc (3×100 mL). The organic extract was washed with water (2×50 mL) and brine (100 mL), dried over sodium sulfate and concentrated to give 3-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene as a yellow solid (1.34 g, 93%). 1H-NMR (CDCl3): 7.79 (s, 1H), 7.76 (d, 1H, J=8.8 Hz), 6.69 (d, 1H, J=8.8 Hz), 4.34 (s, 1H), 4.25 (t, 2H, J=5.9 Hz), 3.49 (m, 2H), 2.09 (m, 2H).
Reaction SMILES: O[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:18])=O.[OH-].[Na+]>C(OCC)(=O)C>[Cl:18][C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1
Reactant: CCOCCn1c(O)nc2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOCCn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine 2-hydroxy-1-(2-ethoxyethyl)-1H-benzimidazole (36.4 g, 177 mmol) and phosphorous oxychloride (72 mL) and reflux. After 30 minutes, cool to ambient temperature and pour the reaction mixture onto crushed ice. Adjust the pH to about 9 using aqueous 50% sodium hydroxide solution. Extract three times with ethyl acetate. Combine the organic layers and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give the 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole.