Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][S:10](Cl)(=[O:12])=[O:11].[Cl-].[CH:15]1([O:21][C:22]([C:24]2[N:25]=[C:26]([CH:29]3[CH2:34][CH2:33][NH2+:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][S:10]([N:32]1[CH2:31][CH2:30][CH:29]([C:26]2[S:27][CH:28]=[C:24]([C:22]([O:21][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:23])[N:25]=2)[CH2:34][CH2:33]1)(=[O:12])=[O:11]
Reactant: O=C(OC1CCCCC1)c1csc(C2CC[NH2+]CC2)n1
Reactant: O=S(=O)(Cl)Cc1cc(F)ccc1F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OC1CCCCC1)c1csc(C2CCN(S(=O)(=O)Cc3cc(F)ccc3F)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, (2,5-difluorophenyl)methanesulphonyl chloride (226 mg) is added to a solution of 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidinium chloride (VII-1, 330 mg) and triethylamine (303 mg) in dichloromethane (5 ml). The mixture is stirred at room temperature overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulphate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives cyclohexyl 2-{1-[(2,5-difluorobenzyl)sulphonyl]piperidin-4-yl}-1,3-thiazole-4-carboxylate (156 mg, 32%).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[C:33]([NH2:35])[C:32](I)=[CH:31][N:30]=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:28][C:29]1[CH:34]=[C:33]([NH2:35])[C:32]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[O:38][CH3:37])=[CH:31][N:30]=1
Reactant: COc1ccccc1B(O)O
Reactant: Nc1cc(Cl)ncc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: COc1ccccc1-c1cnc(Cl)cc1N
Temperature: 75 °C
Yield: 80.5 %

Procedure:
Potassiumphosphate (18.28 g, 79 mmol), triphenyl phosphine (1.04 g, 3.97 mmol), 2-chloro-5-iodo-4-aminopyridine (10.1 g, 39. mmol), 2-methoxybenzeneboronic acid (8.44 g, 55.57 mmol) and palladium acetate (0.45 g, 1.98 mmol) were sequentially added to degassed acetonitrile (300 mL) and water (100 mL) under nitrogen. The reaction mixture was heated at 75° C. for overnight, then cooled to room temperature. The organic layer was separated and aqueous layer and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and performed column chromatography using hexanes and ethyl acetate as eluent. 7.5 g of title compound was isolated.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5](#[N:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Cl-].[Zn+2].[Cl-]>[C:6]1([C:5]2[NH:12][N:3]=[N:2][N:1]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Product: c1ccc(-c2nnn[nH]2)cc1

Procedure:
As outlined in Scheme 8, benzonitrile is treated with sodium azide and zinc chloride to give 5-phenyltetrazole 14 which is converted to the N-trityl derivative 15 by treatment with triphenylmethyl chloride and triethylamine. The zinc reagent 16 was prepared by treatment with n-butyllithium followed by zinc chloride. Coupling with 4-iodotoluene using the catalyst bis(triphenylphosphine)nickel(II) dichloride gives the biphenyl product 17 in high yield. Treatment with N-bromosuccinimide in refluxing carbon tetrachloride, in the presence of a radical initiator such as benzoyl peroxide or 2,2'-azobisisobutyronitrile (AIBN), gives bromide 18.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Li]CCCC.[Si:24]([O:31][CH2:32]/[C:33](=[N:35]/[S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])/[CH3:34])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C[Al](C)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Si:24]([O:31][CH2:32][C:33]([NH:35][S:36]([C:38]([CH3:39])([CH3:41])[CH3:40])=[O:37])([C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1)[CH3:34])([C:27]([CH3:30])([CH3:28])[CH3:29])([CH3:26])[CH3:25]
Reactant: CCCCCCCCc1ccc2nc(Br)sc2c1
Reactant: C/C(CO[Si](C)(C)C(C)(C)C)=N\S(=O)C(C)(C)C
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc2nc(C(C)(CO[Si](C)(C)C(C)(C)C)NS(=O)C(C)(C)C)sc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A toluene (2 mL) solution of 2-bromo-6-octylbenzo[d]thiazole (167 mg, 0.515 mmol) was cooled down to −78° C., then 2.5 N n-BuLi (0.2 mL, 0.515 mmol) was added to the mixture drop wise, and the mixture was stirred at −78° C. for 30 min. The toluene (2 mL) solution of (E)-N-(1-(tert-butyldimethylsilyloxy)propan-2-ylidene)-2-methylpropane-2-sulfinamide (100 mg, 0.344 mmol) was cooled down to −78° C., then 2.0 N AlMe3 (0.26 mL, 0.515 mmol) was added to the mixture drop wise, and the mixture was stirred at −78° C. for 30 min. The mixture of (E)-N-(1-(tert-butyldimethylsilyloxy)propan-2-ylidene)-2-methylpropane-2-sulfinamide was added to the mixture of the lithiated 2-bromo-6-octylbenzo[d]thiazole and stirred at −78° C. for 1 h. Then saturated NH4Cl solution was added to the mixture to quench the reaction. The mixture was extracted with EtOAc and purified by silica gel chromatography using PE/EA (5/1) to give is the title compound. (90 mg, 48%). EDI-MS (M+1): 539. 1H NMR (300 MHz, CDCl3) δ 7.858 (d, 1H), 7.626 (s, 1H), 7.252 (s, 1H), 4.031 (d, 2H), 3.850 (d, 1H), 3.470 (s, 1H), 2.699 (t, 2H), 1.797 (s, 3H), 1.623 (t, 2H), 1.295-1.261 (m, 21H), 0.850 (s, 9H), 0.012 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:13][C:12]=12.O.[NH:33]1[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1.C(N(CC)CC)C>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([N:33]3[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]3)=[N:13][C:12]=12
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3c(-c4ccccc4F)nnn3c3ccccc23)cc1
Reactant: O=C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Yield: 76 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-[1,2,3]triazolo[1,5-α]quinazoline (Example 1, step b) (3.0 g, 6.91 mmol), 4-piperidone monohydrate, hydrochloride salt (1.28 g, 8.3 mmol) and triethylamine (3.0 ml, 21 mmol) in dry N,N-dimethylformamide (25 ml) was stirred at 60° C. under nitrogen for 4 h. The mixture was diluted with water (100 ml) and extracted with 10% methanol:dichloromethane (150 ml). The extract was dried (Na2SO4), filtered and concentrated. The residual solid was washed with diethyl ether-ethyl acetate and dried in vacuo to give 3-(2-fluorophenyl)-5-(4-oxopiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (1.90 g, 76%). δH (360 MHz; DMSO) 2.67 (4H, t, J=6), 3.99 (4H, t, J=6), 7.33-7.48 (3H, m), 7.78 (1H, dd, J=7 and 7), 8.05-8.11 (2H, m), 8.25 (1H, d, J=8), 8.58 (1H, d, J=8); m/z (ES+) 362 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:21][CH3:22])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].C(N(CC)CC)C.O>C(OCC)(=O)C.C(OC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]([O:21][CH3:22])=[O:20])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: COC(C)=O
Product: COC(=O)c1ccccc1NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 17.6 g of 3-phenylpropanoyl chloride in 40 ml of ethyl acetate is added dropwise to a solution of 15.7 g of methyl anthranilate and 21 g of triethylamine in 60 ml of methyl acetate. The mixture is stirred at room temperature for 24 hours, water is added, and the organic phase is separated off and, after the solvent has been evaporated off, methyl 2-(3-phenylpropanoylamino)benzoate is obtained as an orange-colored oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([NH:25][C:26]1[S:30][N:29]=[C:28](/[C:31](=[N:35]/[O:36][CH2:37][C:38]([F:41])([F:40])[F:39])/[C:32](O)=[O:33])[N:27]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[NH2:43][C@@H:44]1[C:67](=[O:68])[N:46]2[C:47]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=3)=[O:56])=[C:48](/[CH:51]=[CH:52]\[CH2:53][Cl:54])[CH2:49][S:50][C@H:45]12.C[Si](C)(C)NC(=O)C>C(OCC)(=O)C.O1CCCC1.CN(C)C=O>[C:6]([NH:25][C:26]1[S:30][N:29]=[C:28](/[C:31](=[N:35]/[O:36][CH2:37][C:38]([F:39])([F:41])[F:40])/[C:32]([NH:43][C@@H:44]2[C:67](=[O:68])[N:46]3[C:47]([C:55]([O:57][CH2:58][C:59]4[CH:60]=[CH:61][C:62]([O:65][CH3:66])=[CH:63][CH:64]=4)=[O:56])=[C:48](/[CH:51]=[CH:52]\[CH2:53][Cl:54])[CH2:49][S:50][C@H:45]23)=[O:33])[N:27]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)/C(=N\OCC(F)(F)F)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OCC(F)(F)F)c4nsc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 60.6 %

Procedure:
A mixture solution comprising dimethylformamide (0.247 ml) and tetrahydrofuran (3 ml) was cooled to -10° C., and phosphorus oxychloride (0.297 ml) was added thereto and stirred for 40 minutes with ice-cooling. To the resulting solution was added the tetrahydrofuran solution (4 ml) of 2-(5-tritylamino-1,2,4-thiadiazol-3-yl)-(Z)-2-(2,2,2-trifluoroethyl)oxyiminoacetic acid (1.36 g), followed by stirring for further one hour at the said temperature. The resulting reaction solution was added to a mixture solution comprising p-methoxybenzyl 7β-amino-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate hydrochloride (1.145 g), N-(trimethylsilyl)acetamide (2.09 g) and ethyl acetate (10 ml), with cooling at -20° C., followed by elevating the temperature up to 0° C. with stirring for one hour. After ethyl acetate was added to the reaction solution, this was washed with wather and dried with anhydrous sodium sulfate. The solvent was evaporated out and the residue was purified by silicagel column chromatography to obtain the desired product (1.43 g).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].P(=O)(O)(O)O.[OH-].[Na+]>CC(C)=O.[Cl-].[Zn+2].[Cl-]>[CH3:2][C:3]1([CH3:5])[O:4][C@@H:3]([C@H:5]2[O:6][C@@H:11]3[O:12][C:9]([CH3:11])([CH3:7])[O:10][C@@H:9]3[C@H:7]2[OH:8])[CH2:2][O:1]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Temperature: 25 °C
Reaction time: 30 h
Yield: 91 %

Procedure:
To a suspension of 100 grams of anhydrous D-glucose in one liter of anhydrous acetone is added 80 grams of anhydrous zinc chloride and 5 grams of 85% phosphoric acid. The mixture is stirred for 30 hours at room temperature and then neutralized with a 50% NaOH solution. The insoluble materials are removed by filtration and washed with acetone. The combined filtrates are evaporated under reduced pressure to heavy syrup and the residual syrup is diluted with 500 ml. of chloroform. The chloroform solution is extracted three times with water and concentrated in vacuo to give crude 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose. The crude product is purified by crystallization from a chloroform and hexane mixture to give 77 grams (91% yield based on the D-glucose consumed) of a pure product having a melting point of 105°-109° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([N:27]2[CH2:30][CH:29]([OH:31])[CH2:28]2)[C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:14][CH:13]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([N:27]2[CH2:28][C:29](=[O:31])[CH2:30]2)[C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])=[CH:14][CH:13]=1
Reactant: N#Cc1cccc([C@H](c2ccc(Cl)cc2)N2CC(O)C2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc([C@H](c2ccc(Cl)cc2)N2CC(=O)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 21.1 mL (0.24 mol) of oxalyl chloride in 500 mL CH2Cl2, a solution of 34.2 mL (0.48 mol) of DMSO in 50 mL CH2Cl2 was added slowly at −78° C. After the reaction mixture was stirred for 30 min., a solution of 36.02 g (0.12 mol) of 3-[(S)-(4-chlorophenyl)(3-hydroxyazetidin-1-yl)methyl]benzonitrile in 50 mL of CH2Cl2 was added and stirred for another 45 min. Then 82.8 mL (0.60 mol) of triethylamine was added and the mixture was stirred for 30 min. at −78° C. The mixture was warmed to rt and stirring continued for 30 min. Then the mixture was poured into 1000 mL of ether and 200 mL of aq NaHCO3. The water layer was extracted with two 200 mL portions of ether. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 4.03-4.07(m, 4H), 4.65(s, 1H), 7.33-7.43 (m, 4H), 7.45 (t, 1H, J=7.8 Hz), 7.56 (d, 1H, J=7.5 Hz), 7.72 (d, 1H, J=7.5 Hz), 7.81 (s, 1H); Mass Spectrum: m/e=297, (M+1, 35Cl), 299 (M+1, 37Cl).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[F:14][C:15]([F:20])([F:19])C([O-])=O.[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.[Cu]I>[F:14][C:15]([F:20])([F:19])[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])C(F)(F)F
Reactant: COC(=O)c1ccc(OC)c(I)c1
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(C(F)(F)F)c1
Yield: 77.1 %

Procedure:
9.7 g of methyl 3-iodo-4-methoxybenzoate, 9.4 g of potassium trifluoroacetate and 12.9 g of copper(I) iodide were heated at 160° C. for 5 h in 250 ml of DMF. The mixture was poured onto 500 ml of NaHCO3 solution, the precipitate which was deposited was filtered off and both the precipitate and the aqueous phase were extracted with ethyl acetate. The combined organic phases were concentrated, and the residue was purified by flash chromatography using hexane/ethyl acetate 3:1. 6 g of methyl 3-trifluoromethyl-4-methoxybenzoate were obtained;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N.[CH3:12]O>>[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: O=C(O)c1cncc(O)c1
Reactant: CO
Agent: N
Product: COC(=O)c1cncc(O)c1
Reaction time: 24 h

Procedure:
A mixture of 1 g of 5-hydroxynicotinic acid, 2 g Amberlyst 15 ion-exchange resin and 150 mL of methanol was heated to reflux with stirring for 24 hrs, cooled, basified with 10% ammonia in methanol, filtered and concentrated under reduced pressure. The residue was taken up in 50 mL of chloroform and dried over MgSO4. Concentration under reduced pressure gave a tan crystalline solid: MS (m+1)=154.1; 1H NMR (400 MHz, CDCl3) 8.68 (s, 1H), 8.32 (s, 1H), 7.72 (s, 1H), 3.94 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH3:60])=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH3:60])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (20 mg) and triethylamine (12 μL) are dissolved in dichloromethane (2 mL), treated with methyl chloroformate (4.5 μL) and stirred for 12 hours at room temperature. Triethylamine (12 μL) and methyl chloroformate (4.5 μL) are added and the mixture is stirred for 5 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is directly used in the next step. LC (method 5): tR=1.20 min; Mass spectrum (ESI+): m/z=773 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]=1[NH2:23])(=[O:3])[CH3:2].[C:24](OCC)(OCC)(OCC)[CH3:25]>Cl.N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:8]2[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]=2[N:23]=[C:24]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNc1c(C)c(C)nc(Oc2ccccc2)c1N
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OCCn1c(C)nc2c(Oc3ccccc3)nc(C)c(C)c21
Temperature: 95 °C
Yield: 98.2 %

Procedure:
1-[(3-Amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]eth-2-yl acetate (10.5 g, 33.29 mmol), toluene (100 mL), pyridine hydrochloride (0.077 g, 0.6659 mmol), and triethyl orthoacetate (9.1 mL, 49.94 mmol) were combined with stirring and the resulting mixture was heated to a gentle reflux (about 95° C.) for 1.5 hours. The reaction was complete. The resulting reaction mixture was concentrated under reduced pressure to white solids, which were dissolved in ethyl acetate. The ethyl acetate solution was washed with water (3×) and brine (2×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was triturated with diethyl ether, filtered off, and dried at 60° C. overnight to provide 11.1 g of pure product, which was carried on to the next step.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2([C:27]([O:29]CCCC)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])CCC.O[Li].O>>[C:27]([C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][C:17](=[O:34])[CH2:16][CH2:15][CH2:14][CH2:13][C:8]2([C:6]([OH:7])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:23][CH2:24][CH2:25][CH2:26]1)([OH:29])=[O:28]
Reactant: CCCCOC(=O)C1(CCCCC(=O)CCCCC2(C(=O)OCCCC)CCCC2)CCCC1
Agent: [Li]O
Solvent: O
Product: O=C(CCCCC1(C(=O)O)CCCC1)CCCCC1(C(=O)O)CCCC1
Yield: 99.3 %

Procedure:
Compound 107g was prepared likewise Method D starting from 106g (7.25 g, 15.0 mmol) and LiOH.H2O (3.21 g, 76.4 mmol) to give 107g (5.46 g, 95% pure by 1H NMR, 94%, mp=99-103° C.) as a white solid. An analytical sample was obtained after recrystallization from iPr2O/heptane. mp=104-106° C. 1H NMR: δ 2.39 (t, J=6.9 Hz, 4H), 2.18-2.10 (m, 4H), 1.69-141 (m, 20H), 1.27-1.14 (m, 4H). 3C NMR: δ 211.1, 184.6 (2×), 53.9 (2×), 42.5 (2×), 39.0 (2×), 35.9 (4×), 25.7 (2×), 24.9 (4×), 24.0 (2×). Anal. calcd for C21H34O5: C, 68.82; H, 9.35, found: C, 68.78; H, 9.47.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].C([Li])(CC)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH:22]=[O:23].O>O1CCCC1.C1CCCCC1.C(OCC)(=O)C>[CH3:1][NH:2][C:3](=[O:11])[C:4]1[C:9]([CH:22]([OH:23])[C:21]2[CH:20]=[C:19]([O:18][CH3:17])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10]
Reactant: CNC(=O)c1ccccc1Cl
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CNC(=O)c1c(Cl)cccc1C(O)c1cc(OC)c(OC)c(OC)c1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A solution of N-methyl-2-chlorobenzamide (13.0 g) in tetrahydrofuran (300 ml) is cooled to −70° C., and thereto is added dropwise a 1.3M solution of sec-butyl lithium in cyclohexane (130 ral) over a period of 20 minutes. The mixture is stirred at −60° C. for 30 minutes, and thereto is added dropwise a solution of 3,4,5-trimethoxybenzaldehyde (15.0 g) in tetrahydrofuran (100 ml) over a period of 10 minutes. The mixture is stirred at the same temperature for one hour, and thereto are added water and ethyl acetate (300 ml). The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give N-methyl-2-chloro-6-[hydroxy-(3,4,5-trimethoxyphenyl)methyl]benzamide (19.2 g) as listed in Table 54.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7]
Reactant: COc1cc(Br)cc(C)c1C#N
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(N2CCOCC2)cc(C)c1C#N
Temperature: 40 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
A solution of 4-bromo-2-methoxy-6-methyl-benzonitrile (synthesized according to the methods described in sections a) and b) of example 10) (2.0 g, 8.85 mmol), morpholine (1.2 ml, 12.8 mmol) and caesium carbonate (3.9 g, 12.0 mmol) in toluene (75 ml) is degassed and flushed with argon for 30 min and the mixture is heated to 40° C. followed by the addition of tris(dibenzylideneacetone)-dipalladium(0) (0.37 g, 0.39 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.55 g, 0.88 mmol). The resulting mixture is stirred at 110° C. for 16 h. After completion of the reaction (monitored by TLC), the mixture is poured into water (60 ml) and extracted with ethyl acetate (3×50 ml).The combined organic layers are washed with water (2×50 ml), brine (2×30 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (silica gel, 25% ethyl acetate/hexane) affording 2-methoxy-6-methyl-4-morpholin-4-yl-benzonitrile (0.6 g, 2.58 mmol, 29%).