Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=O)[C@H:12]2[CH2:17][C@@H:9]1[CH2:10][C@H:11]2[F:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:34][C:35]1[CH:39]=[C:38]([Br:40])[S:37][C:36]=1[C:41]([NH2:43])=[O:42]>O1CCCC1.O>[Br:40][C:38]1[S:37][C:36]2[C:41](=[O:42])[NH:43][C:14]([C@@H:13]3[C@H:12]4[CH2:17][C@H:9]([CH2:10][C@H:11]4[F:18])[N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:34][C:35]=2[CH:39]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]([C@H](F)C2)[C@H]1C(=O)O
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]([C@H](F)C2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of (1R*,3S,4R*,5R)-2-(tert-butoxycarbonyl)-5-fluoro-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (2.65 g) and triethylamine (1.42 ml) in tetrahydrofuran (35 mL) was added 2-methylpropyl chlorocarbonate (1.34 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. To the reaction system was added a solution of 3-amino-5-bromothiophene-2-carboxamide (1.88 g) produced in Example 1, step D, in tetrahydrofuran (10 mL), and the mixture was stirred at 60° C. for 18 hr. Water was added to the reaction mixture, and the separated aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane). To the obtained pale-yellow solid were added 2M aqueous sodium hydroxide solution (34 mL) and ethanol (200 mL), and the mixture was stirred at 80° C. for 8 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. To the reaction system was added water (20 mL), and the precipitate was collected by filtration to give the title compound (2.82 g) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N+:12]([O-:15])([OH:14])=[O:13].[N:16]#[C:17][NH2:18]>C(O)C>[N+:12]([O-:15])([O-:14])=[O:13].[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:17]([NH2:18])=[NH2+:16]
Reactant: N#CN
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: O=[N+]([O-])O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1NC(N)=[NH2+]
Product: O=[N+]([O-])[O-]
Temperature: 0 °C
Yield: 34 %

Procedure:
2-Methyl-5-nitro aniline (10 g, 65 mmol) was dissolved in ethanol (25 mL), and concentrated HNO3 (4.6 mL) was added to the solution dropwise followed by 50% aqueous solution of cyanamide (99 mmol). The reaction mixture was refluxed overnight and then cooled to 0° C. The mixture was filtered and the residue was washed with ethyl acetate and diethyl ether and dried to provide N-(2-Methyl-5-nitro-phenyl)-guanidinium nitrate (4.25 g, yield: 34%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>ClCCl.CO.CCCCCC>[Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(CCBr)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2-bromoethyl)benzoic acid (4.58 g, TCI) in a mixture of dichloromethane (50 ml) and methanol (50 ml) was added dropwise with a 2.0 M solution of (trimethylsilyl)diazomethane in hexane (11.0 ml, ALD) over 10 minutes, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then the residue was purified by column chromatography (Flash, hexane:ethyl acetate=15:1) to obtain the title compound (Intermediate ia-01, 4.32 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:16]2[N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:13]([CH2:26][CH2:27][O:28][CH3:29])[C:12]=2[C:11]([O:30][CH3:31])=[CH:10][C:9]=1[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)[OH:33].C(N(CC)CC)C>ClCCl.CS(C)=O>[Br:7][C:8]1[C:16]2[N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=3)[N:13]([CH2:26][CH2:27][O:28][CH3:29])[C:12]=2[C:11]([O:30][CH3:31])=[CH:10][C:9]=1[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)=[O:33]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C(O)c3cccc(OC)c3)cc(OC)c21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(C(=O)c3cccc(OC)c3)cc(OC)c21
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a solution of 0.16 ml oxalylchloride in 4 ml dichloromethane, 0.27 ml DMSO (in 0.8 ml dichloromethane is slowly added at −60° C. This mixture is stirred under argon at −60° C. for 0.5 h. Then 250 mg (0.463 mmol) [4-Bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-(3-methoxy-phenyl)-methanol (in 2 ml dichloromethane) are added and stirring is continued at −60° C. for 1 h. 1 ml triethylamine is added and the reaction mixture is allowed to warm to room temperature, poured on water and extracted (3×) with dichloromethane. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 179 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[I:12]I.C([O-])(O)=O.[Na+].O>C1COCC1>[I:12][C:7]1[CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=[CH:9][C:8]=1[OH:11].[I:12][C:9]1[C:8]([OH:11])=[CH:7][CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=1
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(I)c(O)cn1
Product: CS(=O)(=O)c1ccc(O)c(I)n1

Procedure:
A mixture of the title compound from Step 1 (3.0 g, 17.34 mmol), I2 (6.6 g, 26.01 mmol), NaHCO3 (2.2 g, 26.20 mmol) and KI (0.72 g, 4.34 mmol) in THF (30 mL) and H2O (30 mL) was stirred at 60° C. for 18 hrs. Water (100 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-iodo-6-methylsulfonylpyridin-3-ol (700.0 mg) and 2-iodo-6-methylsulfonylpyridin-3-ol (700.0 mg). 2-iodo-6-methylsulfonylpyridin-3-ol: 1H NMR (CDCl3, 400 MHz) δ 12.08 (brs, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 3.19 (s, 3H). 4-iodo-6-methylsulfonylpyridin-3-ol: 1H NMR (CDCl3, 400 MHz) δ 12.0 (brs, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 3.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH2:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>C1(C)C=CC=CC=1.O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:26]2[CH2:27][CH2:28][CH:23]([C@H:20]3[CH2:21][CH2:22][C@H:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]3)[CH2:24][CH:25]=2)[C:3]=1[F:8]
Reactant: Fc1ccccc1F
Reactant: CCC[C@H]1CC[C@H](C2CCCCC2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](C2CC=C(c3cccc(F)c3F)CC2)CC1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
First, 46 g of 1,2-difluorobenzene and 240 ml of dehydrated tetrahydrofuran were put in an argon-replaced 2 flask, and cooled to −60° C. Then 315 ml of a hexane solution containing n-butyllithium at a concentration of 1.6 mol/l was dropped into the resultant mixture while being stirred for one hour, and further stirred keeping the same temperature for two hours. Subsequently, 470 ml of dehydrated tetrahydrofuran containing 80 g of 4-(trans-4-propylcyclohexyl)cyclohexane dissolved therein was dropped and stirred keeping the same temperature for two hours. The resultant mixtures was left to gradually resume room temperature, stirred for eight hours and cooled again to 0° C. The reaction solution was poured into dilute hydrochloric acid to acidify the reaction solution. Toluene was added to the resultant solution for extraction. The resultant toluene layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue, 2 g of p-toluenesulfonic acid, and 1 of toluene were put in a 2 flask provided with a water content quantitative tube, and subjected to azeotropic dehydration under reflux for five hours. After the reaction, the reaction solution was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was distilled (b.p. 151° C./16 Pa) and recrystallized from acetone to obtain 55.7 g (Y: 48.6%) of 1,2-difluoro-3-[4-(trans-4-propylcyclohexyl)cyclohexenyl]benzene. The purity of the resultant compound was 98.0% as measured by GC.
Reaction SMILES: [Si:1]([CH:8]([OH:24])[C@H:9]1[O:13][C@@H:12]([N:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[NH:16][C:15]2=[O:22])[CH2:11][C@@H:10]1[OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:31](Cl)(=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[Si:1]([CH:8]([OH:24])[C@H:9]1[O:13][C@@H:12]([N:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[NH:16][C:15]2=[O:22])[CH2:11][C@@H:10]1[O:23][C:31](=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CN1CN([C@H]2C[C@H](O)[C@@H](C(O)[Si](C)(C)C(C)(C)C)O2)C(=O)NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCC(=O)O[C@H]1C[C@H](N2CN(C)C(=O)NC2=O)O[C@@H]1C(O)[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Yield: 88.7 %

Procedure:
To a solution consisting of 3.59 gm. (0.010 mole) of 1-(5-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione and 30 ml. A. R. pyridine that had been cooled to 5° C. was added, with stirring, 2.55 gm. (0.0116 mole) of freshly distilled lauroyl chloride. This reaction mixture was stirred for 18 hours at 25° C. Then it was cooled to 10° C. and 3 ml. water was added. This mixture was stirred at 25° C. while the solvents were removed by evaporation under reduced pressure. The residue thus obtained was dispersed in a solvent mixture consisting of 100 ml. chloroform and 50 ml. saturated aqueous sodium bicarbonate. The aqueous and organic phases were allowed to stabilize and the organic phase was saved. It was washed two times with 50 ml. portions of saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The dried chloroform solution was filtered and the filter was washed with chloroform. The filtrate and washings were combined and the chloroform was removed by evaporation under reduced pressure. There was thus obtained 4.8 gm. (88.7% yield) of 1-(5-tert-butyldimethylsilyl-3-O-lauroyl-2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O.[Cl:16][C:17]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:18]=1[C:19]([NH:21][C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=1)=[O:20]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:39]2[CH:40]=[CH:41][C:17]([Cl:16])=[C:18]([CH:38]=2)[C:19]([NH:21][C:22]2[N:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:25]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=2)=[O:20])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)n(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3cccc(N)n3)ccc2Cl)n(-c2ccccc2)n1
Temperature: 100 °C
Yield: 51 %

Procedure:
6-amino-2-bromopyridine (835.5 mg, 4.83 mmol), sodium carbonate (1.39 g, 13.2 mmol) and water (0.5 mL) were added to the solution of ethyl 5-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate in dioxane obtained in Preparation 5. The reaction was degassed with nitrogen for 30 minutes before the addition of Pd(dppf)Cl2 with further degassing for 10 minutes. The reaction was heated to 100° C. for 16 hours. The reaction was cooled and eluted through a pad of silica, eluting with EtOAc (50 mL). The organic solution was washed with water (50 mL) dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 30-50% EtOAc in heptanes to afford the title compound as a pale yellow solid (1.02 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[C:6]([C:12]2[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([O:17][CH3:18])[C:11]=2[O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc(B(O)O)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2ccnc(Cl)n2)c(OC)c1OC
Yield: 74.1 %

Procedure:
In a 250 mL round-bottomed flask, 1.49 grams (10 mmol) of 2,4-dichloropyrimidine was combined with 2,3,4-trimethoxyphenylboronic acid (2.12 g, 10 mmol), sodium carbonate (2.12 g, 2 equivalents), and 1.15 g (0.1 equivalents) of tetrakis-triphenylphosphinepalladium. Toluene (50 mL) and water (5 mL) were added. The reaction was allowed to reflux under nitrogen overnight. The reaction was diluted with toluene and water and the organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated to afford the crude pyrimidine 5. The compound was purified on silica gel using an eluent of 30% acetone/hexane to afford 2.08 g (74%) of the product 5 as a white solid.
Reaction SMILES: [CH2:1]([NH:8]C)C1C=CC=CC=1.[CH2:10]([O:12][C:13](=[O:16])[C:14]#[CH:15])[CH3:11].[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:10]([O:12][C:13](=[O:16])[CH:14]=[CH:15][NH:8][CH2:1][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:11]
Reactant: Cc1ccccc1
Reactant: C#CC(=O)OCC
Reactant: CNCc1ccccc1
Product: CCOC(=O)C=CNCCc1ccccc1

Procedure:
With stirring and cooling a solution of 48.5 g (0.4 mol) of N-benzyl-N-methyl-amine was added dropwise to a solution of 39.2 g (0.4 mol) of propiolic acid ethyl ester in 200 ml of toluene in the course of 20 min. so as not to exceed a temperature of 30° C. The yellow, slightly opaque solution was evaporated at 50° C./30 torr until constant weight. 91.8 g of 3-(benzylmethyl-amino)acrylic acid ethyl ester were obtained as a yellow oil which was further used without purification.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([CH3:41])[CH2:10][C:11]1[C:16]2[C:17](I)=[N:18][N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:15]=2[CH:14]=[C:13]([Cl:40])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:43]([O-:46])(C)C.[Na+].C1COCC1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CCOC(C)=O>[Cl:40][C:13]1[CH:14]=[C:15]2[NH:19][N:18]=[C:17]3[C:16]2=[C:11]([CH2:10][CH:9]([CH3:41])[N:8]3[CH2:1][C:2]2[CH:7]=[CH:6][C:5]([O:46][CH3:43])=[CH:4][CH:3]=2)[N:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)NCc1ccccc1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2c3n[nH]c4cc(Cl)nc(c34)CC2C)cc1
Temperature: 55 °C

Procedure:
N-benzyl-1-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)propan-2-amine (670 mg, 0.958 mmol) and RuPhos pre-catalyst (70 mg, 0.096 mmol) were charged in a 2 dram vial, evacuated and backfilled with nitrogen and taken in toluene (4.8 mL). A solution of 2M NaOtBu in THF (1.2 ml, 2.4 mmol) was added and the reaction mixture was heated to 55° C. for 12 hours. The reaction mixture was cooled and diluted with EtOAc and washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-50% EtOAc-hexanes) gave 7-chloro-3-(4-methoxybenzyl)-4-methyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine. MS ESI calc'd. for C35H30ClIN4 [M+H]+ 572. found 572.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7](O)=[O:8])[CH:5]=1.[ClH:17]>S(Cl)(Cl)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([Cl:17])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1

Procedure:
A suspension of 5-nitro-isophthalic acid mono methyl ester (22.52 g, 100.0 mmol) in thionyl chloride (50 ml) was heated to reflux for 6 hours (until the production of SO2 and HCl-gas ceased). The excess of thionyl chloride was removed under reduced pressure, the residue was dissolved in DCM and the product was precipitated by addition of hexane to give a white solid. Yield: 24.10 g (99%).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(C)([O-])C.[K+].F[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>C1COCC1>[CH2:1]([O:9][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[C:26]([F:27])([F:29])[F:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 110.5 %

Procedure:
A 12 L round bottom flask was inerted and charged with 1-octanol (103 g, 0.793 mol, 1 equiv), THF (2 L), 1 M potassium tert-butoxide (2 L, 2.5 equiv) and heated to 65° C. and held for 45 minutes. The reaction was charged over 1 hour with 4-fluoro-3-trifluoromethyl benzoic acid (165 g, 0.793 mol) while maintaining the temperature at 64 to 67° C. After 2 hours, the reaction mixture was sampled. The sample was concentrated, quenched into 1 N HCl, extracted with ethyl acetate, removed the ethyl acetate, diluted with acetonitrile and injected in to the HPLC. The reaction was complete. The reaction mixture was stirred overnight at 18 to 23° C. The mixture was cooled to 5 to 10° C. and cautiously quenched with water (1.6 L). The quench was exothermic and the temperature was maintained at T<10° C. The resulting mixture was concentrated under vacuum until no noticeable THF was coming off. The resulting aqueous mixture was acidified to pH 1 to 2 using 6 N HCl (400 mL). The mixture was extracted with MTBE (2×2.5 L). The MTBE phases were combined, washed with brine (2 L), dried with magnesium sulfate, filtered over Celite, concentrated to afford the title product (279 g, 111% yield, 95.6% AUC by HPLC) as a tan solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[CH:28]=[CH:27][S:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[C:21]3[CH:28]=[CH:27][S:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2sccc12
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2sccc12)c1nc2ccccc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Into a 10-mL sealed tube was placed (1S)-1-(1-phenyl-1H-1,3-benzodiazol-2-yl)ethan-1-amine from Example 4 (300 mg, 1.26 mmol, 1.00 equiv), 4-chlorothieno[2,3-d]pyrimidine (250 mg, 1.47 mmol, 1.16 equiv), N-ethyl-N-isopropylpropan-2-amine (322 mg) and BuOH (5 mL). The resulting solution was stirred for 1 overnight at 120° C. and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (0:100-80:20) to afford 260 mg (55%) of 143 as a light yellow solid. LC-MS (ES, m/z): 372 [M+H]+. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.19 (s, 1H), 7.70 (d, 1H), 7.68-7.08 (m, 10H), 5.74-5.67 (m, 1H), 1.73 (d, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][N:32]3[CH2:33][CH2:34][CH:29]([C:25]4[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=4)[CH2:30][CH2:31]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COc1ccc(Oc2ccc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)cc2)cc1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-methoxyphenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 459.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51]2[O:54][N:55]=[C:56]([C:57](O)=[O:58])[C:50]=2[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>CN(C)C=O>[N:1]1([C:57]([C:56]2[C:50]3[CH2:49][N:48]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])[CH2:53][CH2:52][C:51]=3[O:54][N:55]=2)=[O:58])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2onc(C(=O)O)c2C1
Reactant: C1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCc2onc(C(=O)N3CCCCC3)c2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Piperidine (1.1 ml, 11.18 mmol), N-methylmorpholine (3.68 ml, 33.54 mmol) and BOP reagent (6.42 g, 14.53 mmol) were added to a solution of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylic acid (3 g, 11.18 mmol) in dry dimethylformamide (100 ml) and the reaction mixture was stirred at room temperature for 16 hours. The solution was then concentrated in vacuo, the residue was taken up in ethyl acetate and the mixture was washed with NaHCO3 solution and NaCl solution. The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. Purification was carried out by chromatography on silica gel (100-200 mesh silica gel, 30% ethyl acetate in hexane). The yield was (71%).