Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].CC1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N:10]1O>C(O)C>[N+:15]([C:13]1[CH:12]=[CH:11][N:10]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:14]=1)([O-:17])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC1C=C([N+](=O)[O-])C=CN1O
Solvent: CCO
Product: CC(=O)OCc1cc([N+](=O)[O-])ccn1
Temperature: 110 °C
Reaction time: 0.03 h

Procedure:
To acetic anhydride (60 mL, 0.635 mol) at 110° C. under a nitrogen atmosphere was added 2-methyl-4-nitro-pyridin-1-ol (15)(17.1 g, 111 mmol) portionwise over 1 minute. After approximately 2 minutes the solution began to darken and heating maintained at 100-120° C. for 30 minutes and then allowed to cool to 80° C. Ethanol (60 mL) was added and the solution was concentrated under vacuum; residue slurried in water (140 mL) and the mixture neutralised with NaHCO3 (ca. 40 g). The aqueous liquor was extracted with ethyl acetate (4×100 mL, combined extracts washed with brine (2×100 mL, dried over Na2SO4, concentrated in vacuo to a crude oil. The material was subjected to flash chromatography eluent hexane:TBME (2:1). A brown oil was isolated, single peak in LC-MS analysis, (6.44 g 30%); m/z (LC-MS, ESP), RT=3.65 mins, (M+H) 197.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.C([Li])CCC.[OH-].[Na+]>O.C(OCC)C>[CH3:17][N:16]1[C:12]([C:3]2[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=2[B:18]([OH:23])[OH:19])=[CH:13][CH:14]=[N:15]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
An 250-mL round-bottom flask was charged with 5-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1H-pyrazole (2.956 g, 9.69 mmol), diethyl ether (74.5 ml), and triisopropyl borate (2.70 ml, 11.63 mmol). The flask was cooled to −78° C. for 10 minutes, after which butyllithium (2.5M in hexanes) (4.65 ml, 11.63 mmol) was added dropwise. The mixture was stirred for 30 min, then warmed to room temperature. A 2N aq. NaOH solution (100 mL), and the resulting biphasic mixture was stirred vigorously for 1 h. The mixture was diluted with water, and the layers separated. The ethereal layer was extracted with water (2×) and the water layers were combined, and washed with diethyl ether. The ether layers were back-extracted once more, and all aqueous layers combined and acidified to about pH 2 with 6N aq HCl to give a clear solution. The aqueous layer was extracted with ethyl acetate (2×), and the combined organics were dried over sodium sulfate, filtered and concentrated. The residue was concentrated from DCM to give (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (2.36 g, 8.74 mmol, 90% yield) as a yellow solid. m/z (ESI) 271.2 (M+H)+.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH:5]=[CH:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH3:12].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH:3]#[C:4][CH:5]=[CH:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC#CC=CC#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#CC=CC#CCCCC
Yield: 80 %

Procedure:
Treatment of compound (a5) from Example 5 with TBAF according Method C of the above-described General Synthesis Procedures I produced the title compound in 80% yield.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH2:12][C:11]([NH2:14])=[N:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[N:21]1[CH:26]=[CH:25][C:24]([C:27](=O)[CH2:28][C:29](OCC)=[O:30])=[N:23][CH:22]=1>C(O)C>[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH2:12][C:11]2=[N:14][C:27]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][N:23]=3)=[CH:28][C:29](=[O:30])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCN=C(N)CC1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)N1CCc2nc(-c3ccncn3)cc(=O)n2CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
To a suspension of 13.4 g (60.45 mmol) of 5-amino-2,3,6,7-tetrahydro-[1,4]diazepine-1-carboxylic acid ethyl ester monohydrochloride (synthesis as described in WO9716430) in 50 mL of ethanol was added 10.29 g (74.50 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 10 min, 14.47 g (74.50 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate was added and the resulting mixture was stirred under reflux for 2.5 hours. The cooled solution was evaporated to remove solvent. The mixture was dissolved with water and diethyl ether. After stirring, the resulting solid was filtered, washed with water and diethyl ether to afford 8.80 g (46%) of the desired compound as a powder.
Reaction SMILES: [CH2:1]([NH:6][C:7]([NH2:9])=[S:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11].[O-]CC.[Na+].C(O)(=O)C>C(O)C.O>[NH2:11][C:10]1[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7](=[S:8])[NH:9][C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC#N
Reactant: CCCCCNC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCCn1c(N)cc(=O)[nH]c1=S
Temperature: 75 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
N-Pentylthiourea (10.0 g, 0.068 mol) was mixed with ethyl cyanoacetate (9.3 g, 0.082 mol) and sodium ethoxide (6.4 g, 0.094 mol) in ethanol (60 mL). The mixture was stirred at 75° C. overnight. After cooling, a solution of 10% acetic acid in water (150 mL) was added. The solid formed was collected by filtration and washed with water to afford the desired product (9.5 g, 65% yield). LCMS calculated for C9H16N3OS: (M+H) 214.1. found 214.1.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[CH3:19][O:20][C:21]1[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=1[CH:23]=[N+:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:23]([C:22]2[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=2[O:20][CH3:19])[N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Reactant: COc1ccccc1C=[N+]1CCCC1
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccccc2OC)N2CCCC2)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and 1-(2-methoxy-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 24.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:16])C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([CH3:44])[CH3:43])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH3:55])=[CH:24][CH:23]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([CH3:44])[CH3:43])=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:55]=[O:16])=[CH:26][CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1)c1ccccc1
Temperature: 76 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
AIBN (1.0 mg, 6.1 μmol) was added to a stirring solution of NBS (4.6 mg, 0.026 mmol) and 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (11 mg, 0.024 mmol) in CCl4 (1 mL). The mixture was heated to 76° C. and allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (3.4 mg, 0.028 mmol) and subjected to microwave irradiation (150° C.) for 5 min. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give to give the expected product 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (7.5 mg, 0.016 mmol, 66% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 10.31 (1H, s), 8.84 (1H, s), 8.79 (1H, s), 8.65 (1H, s), 8.19-8.26 (3H, m), 7.89-7.97 (2H, m), 7.59-7.67 (1H, m), 7.54 (2H, t, J=8.55 Hz), 7.42 (2H, d, J=7.93 Hz), 7.30 (2H, t, J=7.63 Hz), 7.13-7.23 (1H, m), 1.71 (6H, s). LC-MS retention time: 1.75 min; m/z (MH+): 479. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32]CC)=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][S:2][C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:13][CH:14]=2)[C:6]2[C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: CCOC(=O)c1cccc2nc(SC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 90.4 %

Procedure:
A solution of ethyl 2-methylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.2 g) in a methanol (5 ml) solution containing 1N NaOH (1.3 ml) was heated under reflux for 2 hours. The reaction mixture was adjusted to about pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration, and recrystallized from ethyl acetate-hexane to give colorless crystals (0.17 g, 81%), m.p. 223-225° C. (decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:17]([F:20])([F:19])[F:18])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)#[N:2]>[Ni].C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:17]([F:18])([F:19])[F:20])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)ccc1C(F)(F)F
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(CN)ccc1C(F)(F)F

Procedure:
The sub-title compound was prepared in accordance with the procedure in Example 59, step (g) using tert-butyl N-[5-cyano-2-(trifluoromethyl)phenyl]-carbamate (8.5 g; 29.7 mmol), Ra—Ni (174 mg; 2.97 mmol), H2 (5 atm) and THF (60 mL). Yield: 8 g (93%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH:8]=1.C(C(C(C(OCC)=O)O)O)(OCC)=[O:27].C(N(CC)C(C)C)(C)C.OOOO.C1(C(C)C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].O>[F:25][C:2]([F:24])([F:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[NH:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:27])[CH:8]=1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: FC(F)(F)CCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(Cc1cc(OCCCC(F)(F)F)ccn1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-[4-(4,4,4-Trifluorobutoxy)pyridin-2-yl-methylthio]-1H-benzimidazole (6.0 g) was dissolved in ethyl acetate (150 mL). Molecular Sieve 4A (6.0 g) and water (290 μL) were added, and the mixture was stirred for 15 minutes at room temperature. Subsequently, diethyl (+)-tartrate (6.7 g) and tetraisopropyl titanate (4.6 g) were added, and the mixture was stirred for one hour at 50° C. The temperature of the mixture was returned to room temperature. N,N-Diisopropylethylamine (2.8 mL) and 88% cumene hydroxyperoxide (2.7 mL) were added, and the mixture was stirred for four hours at room temperature. A saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was stirred for 30 minutes, followed by filtration through the Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, and brought to dryness over sodium sulfate anhydrate. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel: NH-DM1020 (product of Fuji Silicia), chloroform:methanol=10:1), whereby (−)-2-[4-(4,4,4-trifluorobutoxy) pyridin-2-yl-methanesulfinyl]-1H-benzimidazole was obtained (4.5 g).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH-].[CH2:7]([N+:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[CH2:20]([N+:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22][CH3:23]
Reactant: C=CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Product: C=CC(=O)[O-]
Temperature: 65 °C
Reaction time: 6 h

Procedure:
A 5 liter glass reaction vessel, fitted with a magnetic stirrer, a hose connector, and a septum were purged with nitrogen. Operating in an atmosphere of nitrogen, 297 grams of poly(isobutylene-co-parabromomethylstyrene) (Mv=1.2M, 1.7% para-bromomethylstyrene) was placed into the vessel along with 3.5 liters of xylenes. The polymer was dissolved with stirring under a partial vacuum of 100 mm Hg with a nitrogen sparge attached at the bottom of the solution. A xylene solution of tetrabutylammonium acrylate was prepared in a second flask under nitrogen by placing 100 ml xylenes, 60 ml tetrabutylammonium hydroxide (1M in methanol) and 6.0 g acrylic acid together with stirring. The contents of the flask was concentrated to half its volume and then diluted to 0.5 liters with more xylenes. This solution was then added to the flask containing the poly(isobutylene-co-para-bromomethylstyrene) and the temperature of the solution was raised to 65° C. The reaction was complete in six hours and the polymer was isolated by precipitation in isopropanol. The polymer was dried in a vacuum oven at 1 mm Hg, 40° C. The analysis for the acrylate content (FTIR and NMR) indicate that the modified polymer has 0.24 meq/gram which is consistent with the complete conversion of acrylic acid to acrylic ester and total conversion of the benzylbromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][OH:6]
Reactant: COCCOc1cccc(C(=O)OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOc1cccc(CO)c1OC
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of methyl 2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}benzoate (0.54 g, 2.3 mmol) at 0° C. was added a solution of lithium aluminum hydride in tetrahydrofuran (1M, 2.8 mL, 2.8 mmol) and the resulting mixture was stirred for one hour. It was then quenched with ethyl acetate (1 mL) and 5% sodium hydroxide solution (1 mL), diluted with ether (100 mL), and filtered. The filtrate was washed water and brine (100 mL each), dried over sodium sulfate, filtered and concentrated to give (2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)methanol (0.37 g, 1.7 mmol, 78% yield). 1H NMR (400 MHz, CDCl3): 7.02-6.93 (d, d, 1H), 6.92-6.87 (m, 2H), 4.68 (s, 2H), 4.16-4.14 (m, 2H), 3.92 (s, 3H), 3.79-3.77 (m, 2H), 3.45 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH2:24]([Mg]Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 13 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (300 mg, 0.974 mmol) obtained in Example 1 was dissolved in THF and 1.2 equivalents of benzylmagnesium chloride were added thereto, followed by stirring for 3 hrs at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 50 mg of the titled compound (yield: 13%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[CH:32]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([O:39][CH3:40])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1cc(NC(=O)c2c(N)ncnc2Cl)cc(OC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(OC)c1
Temperature: 120 °C
Yield: 58 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.75 mmol), 4-amino-6-chloro-N-(3,5-dimethoxyphenyl)pyrimidine-5-carboxamide (575 mg, 1.23 mmol), DIEA (650 μl, 3.73 mmol) and cesium fluoride (227 mg, 1.49 mmol) were suspended in tert-butanol (7 ml) and the mixture was heated overnight at 120° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate and washed with water and brine. After evaporation of the solvent, the residue (720 mg, 33% purity, 58% yield) was used in the next synthetic step without further purification.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:28])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([C:17]#[N:18])[CH2:15][C@@H:14]([CH2:19][O:20][Si](C(C)(C)C)(C)C)[O:13]3)[C:6]=2[N:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:1][C:2]1[NH:3][C:4](=[O:28])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[C@H:16]([C:17]#[N:18])[CH2:15][C@@H:14]([CH2:19][OH:20])[O:13]3)[C:6]=2[N:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](C#N)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#C[C@@H]1C[C@@H](CO)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.3 %

Procedure:
To a stirred solution of (2R,3S,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-carbonitrile (compound 38h, crude, 100 mg) in THF (5 mL) was added TBAF solution (1M in THF, 6 mL, 6 mmol) at 0° C. After being stirred at room temperature for 4 hours, the reaction solution was washed with saturated NH4Cl solution, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to afford 9 mg of (2R,3S,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-3-carbonitrile (Example 38) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:12]12[CH2:17][CH:16]1[C:15](=[O:18])[O:14][C:13]2=[O:19].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]([C@H:16]2[CH2:17][C@H:12]2[C:13]([OH:19])=[O:14])=[O:18])=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: O=C1OC(=O)C2CC12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)[C@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.6 %

Procedure:
To a cold (0° C.) stirred solution of bromobenzene (9.09 g, 57.89 mmol) and AlCl3 (18.36 g, 137.84 mmol) in dry DCM (150 mL) was added 3-oxabicyclo[3.1.0]hexane-2,4-dione (5.40 g, 48.24 mmol). The reaction mixture was stirred at rt for 3 days. The dark-red solution was then poured into ice-cold water (120 mL), and conc. HCl (10 mL) was added. The solution was stirred for few minutes, and the layers were separated. The aqueous layer was extracted with DCM and the combined organic phases were washed with water, brine, dried over Na2SO4 and concentrated to give cis-2-(4-bromobenzoyl)cyclopropanecarboxylic acid (9.69 g, 65%). LC-MS ret. time 2.50; m/z 270 (MH+); 1H NMR (400 MHz, CD2Cl2) δ 1.54 (m, 1H), 1.85 (m, 1H), 2.37 (m, 1H), 2.88 (m, 1H), 7.65 (m, 2H), 7.90 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
69.1 g (0.5 mol) of para-hydroxybenzoic acid were first dissolved in 200 ml of water and 300 ml of isopropanol and this solution was adjusted to a pH of 10.5 at 20 to 25° C. using 87.4 g of NaOH solution (32% strength by weight aqueous solution, 0.7 mol). Metered into this solution then at a pH of 10.5, over the course of three hours, were 70.2 g (0.5 mol) of benzoyl chloride. The pH was held at 10.5 using 40.5 g of NaOH solution (32% strength by weight aqueous solution, 0.324 mol), and the temperature was held at 20 to 25° C. The batch was stirred for one hour thereafter. Subsequently the reaction mixture was adjusted to a pH of 7 at 20 to 25° C. using 5.3 g of HCl solution (32% strength by weight aqueous solution) and adjusted to a pH of 1.5 to 3 at 65 to 70° C. using 60 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to room temperature (25° C.) and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 119.1 g (98.3% of theory). According to HPLC and NMR measurement, the product was free from benzoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2([CH:22]([CH3:27])[CH2:23][N:24]([CH3:26])[CH3:25])[OH:21])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].Cl>C(O)(C)C.O1CCCC1.CCOCC>[ClH:4].[C:1]([O:21][C:16]1([CH:22]([CH3:27])[CH2:23][N:24]([CH3:26])[CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C2CCCCC2(O)C(C)CN(C)C)cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1ccc(C2CCCCC2(OC(C)=O)C(C)CN(C)C)cc1OC

Procedure:
The procedure of Example I(c) is followed using 6.5 ml acetyl chloride and 11.5 g 2-(3,4-Dimethoxyphenyl)-1-(2-dimethylamino-1-methylethyl)cyclohexanol and a reaction time of 6 hours to give 9.5 g. crude HCl salt which is dissolved in 50 ml isopropanol and diluted with 440 ml tetrahydrofuran and 60 ml ether to give 7.1 g product, m. 200°.