Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br-].[Li+].BrBr.BrBr.[Li+].[Br-].N1C2C(=CC=CC=2)C=C1C(O)=[O:31]>C(O)C.C(O)(=O)C.[Zn].C(O)(C)(C)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:31]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: BrBr
Agent: [Br-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1Cc2cc(C(=O)O)ccc2N1
Reaction time: 1 h

Procedure:
Indole-5-carboxylic acid 5.00 g (31.0 mmol) solution in ethanol 99% 120 mL and tert-butanol 180 mL in a 1 L RB flask was cooled on ice bath to +5° C. Meanwhile, a solution of lithium bromide 9.0 g (103.6 mmol) in neat acetic acid 60 mL was placed into an addition funnel. Neat bromine 5.0 mL (16.0 g; 100.1 mmol) was then charged to this LiBr solution and the resulting bromine+LiBr solution was dropwise added into the vigorously stirred indolecarboxylic acid solution at +5° C. over a 90 min period. (After a complete addition the addition funnel was then washed with EtOH (2×5 mL) and the washings were added to the reaction mix). At the end of the bromine addition the cooling bath was let to expire and the reaction mix was stirred at +5 to +15° C. bath for 1 hour and at 15° C. for additional 15 min. The reaction mixture was then diluted with additional acetic acid 100 mL. Zn dust 20 g [Aldrich; <10 μM] (306 mmol) was added in one portion (gas evolution) and the mixture was stirred in an open flask on ambient water bath overnight (16 hours). The next day, the precipitated solids were collected by filtration, washed with ethanol and dried by suction. The solid (containing a mix of the product, unreacted Zn metal and Zn salts) was transferred into a large beaker on a hotplate, suspended in boiling methanol (300 mL) and filtered. The extraction with boiling methanol was repeated twice more, to separate the unreacted Zn metal from the product. The combined methanolic filtrates were evaporated to dryness. Separately, the acetic acid+LiBr-containing filtrates from the reaction mix were concentrated to a small volume on rotovap and the produced salt-rich residue was diluted with water 0.6 L and acidified with 6M HCl to about pH=1.5. This mixture was then combined with the evaporation residue obtained from the methanolic filtrates. The solids in the flask were re-suspended by a brief sonication (5 min) and the slurry was cooled down on ice bath, then placed into a freezer (−20° C.) for 4 hours. The precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on highvac. Y=5.23 g (95%) of a light tan solid. 1H-NMR (d6-DMSO, 400 MHz): 12.58 (br s, 1H), 10.72 (s, 1H), 7.82 (dd, 8.3 Hz, 1.6 Hz, 1H), 7.75 (s, 1H), 6.88 (d, 8.3 Hz, 1H), 3.54 (s, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:29][CH2:30][NH2:31])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:41]([C:45]1[CH:50]=[CH:49][C:48]([N:51]=[C:52]=[O:53])=[CH:47][CH:46]=1)([CH3:44])([CH3:43])[CH3:42]>C(Cl)Cl>[C:41]([C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:52]([NH:31][CH2:30][CH2:29][CH2:28][N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[O:17]2)[CH:32]([CH3:34])[CH3:33])=[O:53])=[CH:47][CH:46]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCN)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCNC(=O)Nc3ccc(C(C)(C)C)cc3)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
A suspension of N1-(((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-N1-isopropylpropane-1,3-diamine (1.11 g, 2.00 mmol, crude from step 6) in methylene chloride (40 mL) was treated dropwise with a solution of 1-tert-butyl-4-isocyanatobenzene (0.36 mL, 2.0 mmol) in methylene chloride (3.5 mL) and allowed to stir at room temperature. After 1 h, reaction was complete by HPLC. The reaction mixture was concentrated to yield a glass. The crude material was purified by flash chromatography (100 g silica gel, 2-4% 7N NH3 in CH3OH/CH2Cl2 to yield the title compound (1.07 g, 73%) as a foam: MS (ESI+) for C40H55N7O6 m/z 730.4 (M+H)+; (ESI−) for C40H55N7O6 m/z 728.5 (M−H)−; HPLC purity, 89% (ret. time, 3.78 min).
Reaction SMILES: [N+:1]([C:4]1[CH:51]=[CH:50][C:7]([CH2:8][CH:9]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-])=O)=[CH:43][CH:42]=2)[C:10]([O:12][CH:13]2[CH2:37][CH2:36][C@@:35]3([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@@H:34]3[CH2:33][CH2:32][C@@:31]3([CH3:39])[C@H:19]4[CH2:20][CH2:21][C@@H:22]3[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:14]2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Zn].CO.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[C:10]([O:12][CH:13]2[CH2:37][CH2:36][C@@:35]3([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@@H:34]3[CH2:33][CH2:32][C@@:31]3([CH3:39])[C@H:19]4[CH2:20][CH2:21][C@@H:22]3[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:14]2)=[O:11])=[CH:50][CH:51]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(OC(=O)C(Cc5ccc([N+](=O)[O-])cc5)Cc5ccc([N+](=O)[O-])cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(OC(=O)C(Cc5ccc(N)cc5)Cc5ccc(N)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 69.3 %

Procedure:
2.62 g (3.75 mmol) Cholest-5-en-3-yl 2-(4-nitrobenzyl)-3-(4-nitrophenyl)-propanoate and 0.79 g (14.77 mmol) ammonium chloride were suspended in 90 ml of a mixture consisting of methanol:water 9:1. 4.90 g (74.96 mmol) zinc powder was then added in 10 minutes. The reaction mixture was then allowed to react at 45° C. for 6 hours and partitioned between dichloromethane and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. First chromatography of the residue on 50 g silica gel using toluene:ethyl acetate 1:1 as eluant and second chromatography on 50 g silica gel using tert.butyl methylether as eluant yielded 1.66 g Cholest-5-en-3-yl 2-(4-aminobenzyl)-3-(4-aminophenyl)-propanoate as white powder.
Reaction SMILES: OC([CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)=O.[C:9]([O-:12])(=[O:11])[CH3:10].[Na+].C(OO)(=O)C>C(Cl)Cl.C(O)(=O)C.[C].[Ru]>[C:9]([O:12][CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)(=[O:11])[CH3:10]
Reactant: O=C1CC(C(=O)O)N1
Reactant: CC(=O)[O-]
Agent: [Ru]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)OC1CC(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
0.3 of 4-hydroxycarbonylazetidine-2-one, 0.43 g of anhydrous sodium acetate and 100 mg of 5% ruthenium-carbon were suspended in a mixture of 12 ml of methylene chloride and 4 ml of acetic acid and cooled to -3° C., to which 1.1 ml of acetic acid solution containing 40% peracetic acid was carefully dropped, subjected to stirring at 0° C. for 1 hour. The catalyst was separated by suction filtration, then solvent was distilled off under reduced pressure. 20 ml of n-hexane was added thereto. Undissolved matter was filtered off, the filtrate was concentrated under reduced pressure to obtain 0.37 g of the title compound (yield: 82%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Br:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]2[C:9]=1[C:10]([S:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[C:11]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][N:12]12.[NH4+].[Cl-]>C1COCC1.[Zn].[Cu]>[Br:7][C:8]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]2[C:9]=1[C:10]([S:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[C:11]1[C:21]([CH2:2][C:3]([O:5][CH3:6])=[O:4])([OH:22])[CH2:20][CH2:19][CH2:18][N:12]12
Reactant: COC(=O)CBr
Reactant: O=C1CCCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)CC1(O)CCCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Yield: 42.5 %

Procedure:
To a boiling suspension of 300 mg of Zn-copper couple in 4 mL of THF was added dropwise methyl bromoacetate (720 mg, 4.7 mmol). The suspension was stirred at reflux for 30 minutes and a solution of the ketone of Step 4 (200 mg, 0.5 mmol) in THF (1 mL) was added. The reaction mixture was stirred at reflux for 5 h and saturated aqueous NH4Cl solution was added and extracted with EtOAc. The combined organic layers were washed with brine and water, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc in Hexanes to provide 106 mg of the title compound as a pale brown solid.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][CH2:10]1.[OH-].[K+]>CC(O)C>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCN(CCCOc2ccc(OC)cc2Cl)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1ccc(OCCCN2CCNCC2)c(Cl)c1
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of 3.56 parts of ethyl 4-[3-(2-chloro-4-methoxyphenoxy)propyl]-1-piperazinecarboxylate monohydrochloride, 3.6 parts of potassium hydroxide and 80 parts of 2-propanol was stirred overnight at reflux temperature. After evaporation, the residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and crystallized from 2-propanol. The product was filtered off and dried, yielding 1.33 parts (37.1%) of 1-[3-(2-chloro-4-methoxyphenoxy)propyl]piperazine dihydrochloride; mp. 190° C. (int. 13).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](OC(C(F)(F)F)C(F)(F)F)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=1
Reactant: Cc1cc(O)cc(Br)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)OC(C(F)(F)F)C(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2cc(C)c(NC(=O)c3cccc(NC(=O)c4ccccc4)c3)c(Br)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 12.2 %

Procedure:
0.30 g of N-(2-bromo-6-methyl-4-hydroxyphenyl) 3-(benzoylamino)benzamide, 0.23 g of 1,1,1,3,3,3-hexafluoroisopropyl p-toluenesulfonate, 0.19 g of potassium carbonate and 0.03 g of 18-crown-6 ether were added to 5 ml of N,N-dimethylformamide, and the resulting mixture was stirred at 70° C. for 6 hours. 100 ml of ethyl acetate was added thereto and washed with water (50 ml×2). The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed under a reduced pressure to obtain a residue. The resulting residue was purified by silica gel column chromatography (n-hexane EtOAc=3:1) to obtain 0.05 g of the desired product (Yield: 13%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:11])[C:7](=[N:12][OH:13])[C:8](=[O:10])[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)C(=NO)C(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
t-Butyl-3-oxobutyrate (158 g, 1 mol) was dissolved in 200 mL of acetic acid in a 500 mL 3-neck round bottom flask equipped with a thermometer, addition funnel and mechanical stirring. The mixture was cooled in an ice bath to about 10° C. Sodium nitrite (69 g, 1 mol) was added over 75 minutes keeping the temperature under 15° C.. The cold bath was removed and the mixture stirred for 30 minutes and then allowed to stand for 3.5 hours to give t-butyl-2-hydroximino-3-oxobutyrate.
Reaction SMILES: ClC1C(Cl)=C(C)NC=1C(N[C@@H]1CCN(C2SC(C([O-])=O)=CN=2)C[C@@H]1F)=O.OCC(CO)([NH3+])CO.[Br:35][C:36]1[CH:37]=[C:38]([C:42]([O:44]CC)=[O:43])[NH:39][C:40]=1[CH3:41]>>[Br:35][C:36]1[CH:37]=[C:38]([C:42]([OH:44])=[O:43])[NH:39][C:40]=1[CH3:41]
Reactant: CCOC(=O)c1cc(Br)c(C)[nH]1
Agent: Cc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C(=O)[O-])s3)C[C@@H]2F)c(Cl)c1Cl
Agent: [NH3+]C(CO)(CO)CO
Product: Cc1[nH]c(C(=O)O)cc1Br

Procedure:
Prepared by the procedure described for Intermediate 1 using Intermediate 187 as the starting material.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[F:15][C:16]([F:23])([CH3:22])[C:17](OCC)=[O:18]>CCOCC>[Cl:9][C:4]1[CH:3]=[C:2]([C:17](=[O:18])[C:16]([F:23])([F:15])[CH3:22])[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CCOC(=O)C(C)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(F)(F)C(=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a magnetically stirred solution of 4-bromo-1,2-dichlorobenzene (5.64 g, 24.98 mmol) in dry Et2O (109 mL) was added n-BuLi (10.86 mL, 24.98 mmol) via an addition funnel under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 30 min, A solution of ethyl 2,2-difluoropropanoate (3.0 g, 21.7 mmol) in Et2O (10 mL) was added dropwise over 15 min and allowed to stir for 1 h. The reaction was then carefully quenched with 1 N HCl (4 mL) and allowed to warm to 23° C. The solution was dilute with Et2O and washed with water. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the resulting material was purified via flash column chromatography using 100% hexanes to 5% acetone/95% hexanes as eluent. The relevant fractions were concentrated under reduced pressure to afford the title compound as a colorless oil (3.89 g, 71%): 1H NMR (400 MHz, CDCl3) δ 8.21-8.18 (m, 1H), 7.99-7.93 (m, 1H), 7.59 (dd, J=8.4, 4.2 Hz, 1H), 1.89 (t, J=19.6 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −92.08-−93.21 (m); EISMS m/z 240 ([M−H]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([NH:15][C:16](=[O:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[C:19]([CH3:30])[CH:18]=1)[C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[N:6]=1.C(N(CC)CC)C.[Cl:39][CH2:40][CH2:41][N:42]=[C:43]=[O:44]>O1CCCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:5]([C@@H:4]([NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[C:19]([CH3:30])[CH:18]=3)[CH2:3][CH2:2][NH:1][C:43]([NH:42][CH2:41][CH2:40][Cl:39])=[O:44])=[N:6][C:7]=2[CH:13]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N[C@@H](CCNC(=O)NCCCl)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
0.3 g (0.528 mmol) of (1S)—N-[3-amino-1-(5-chloro-1H-benzimidazol-2-yl)propyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is suspended in 10 mL of tetrahydrofuran and 0.1 mL (1.056 mmol) of triethylamine and, after the addition of 56 mg (0.528 mmol) of 2-chloroethyl isocyanate, stirred for 16 hours at ambient temperature. Then the solution is concentrated, the residue is taken up in dichloromethane, washed several times with water, and the combined organic extracts are dried and concentrated by evaporation. Yield: 49%; Rf value: 0.30 (silica gel; dichloromethane/ethanol=9:1); C26H30Cl2N6O3 (545.47); mass spectrum: (M+H)+=545/547 (chlorine isotope).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:2].Cl[CH2:15][CH2:16][C:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2>>[N:21]12[CH2:22][CH2:23][CH2:24][C:17]1([CH2:16][CH2:15][N:3]([C:4]1[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=1)[CH:1]=[O:2])[CH2:18][CH2:19][CH2:20]2
Reactant: ClCCC12CCCN1CCC2
Reactant: O=CNc1cccc2ccccc12
Product: O=CN(CCC12CCCN1CCC2)c1cccc2ccccc12

Procedure:
The procedures described in Example 2 were repeated except that N-formyl-1-naphthylamine (1.90 g, 11.1 mmol ) and 5-(2-chloroethyl)-1-azabicyclo[3.3.0]octane (hydrochloride, 2.57 g, 12.2 mmol ) were employed In this case, the desired compound was obtained as a colorless liquid (1.80 g, 52.6%)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9](I)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([CH:17]=[CH2:18])[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:2]=1[NH2:1]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Add tetrakis palladium(triphenylphosphine)(0) (5.00 g, 4.33 mmol) to a mixture of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (Example 3, Step 3) (17.25 g, 49.99 mmol) and tributyl(vinyl)tin (16.10 mL, 55.14 mmol) in toluene (500 mL) and heat at reflux for 14 h. Allow the reaction to cool to room temperature dilute the mixture with ethyl acetate (1 L). Wash the mixture with saturated aqueous potassium fluoride solution (3×300 mL), then water (300 mL), followed by brine (500 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvents under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the title compound as a pale yellow solid (8.73 g, 71%): TLC Rf 0.52 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 3.89 (s, 3H), 5.21-5.30 (m, 1H), 5.60-5.71 (m, 1H), 5.98 (bs, 2H), 6.83-7.02 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]CC)=[O:28])=[CH:22][CH:21]=3)=[O:17])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:34].[OH-].[Na+]>O>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=3)=[O:17])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:34]
Reactant: CCOC(=O)Cc1ccc(CNC(=O)c2cc(C(=O)NCc3ccc(F)c(C)c3)ncn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(CNC(=O)c2cc(C(=O)NCc3ccc(CC(=O)O)cc3)ncn2)ccc1F
Temperature: 25 °C
Reaction time: 120 h

Procedure:
2.4 g (5.2 mmol) of ethyl [4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]acetate were taken up in 150 ml of water, after which 10 ml of water and 0.227 g (5.7 mmol) of NaOH were added. After 5 days of stirring at room temperature, the solvent was removed under reduced pressure and the residue was stirred up with ethanol and filtered off. This resulted in 1.51 g (67%) of [4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenyl]acetic acid. MS (ES+): m/e=436.15.
Reaction SMILES: [Cl:1]Cl.[C:3]([NH:7][N:8]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C>CCCCC>[C:3]([N:7]=[N:8][C:9]([Cl:1])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(=NNC(C)(C)C)c1ccccc1
Reactant: ClCl
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)N=NC(C)(Cl)c1ccccc1

Procedure:
1-t-Butylazo-1-chloro-1-phenylethane was prepared in 99% crude yield by adding 34.8 grams (0.49 moles) of chlorine to a pentane solution of 92.8 grams (0.49 moles) of acetophenone t-butylhydrazone and 50.5 grams (0.50 moles) of triethylamine at 0° C., filtering off the insoluble triethylamine hydrochloride that forms and evaporating the pentane under reduced pressure. The yield was 109 grams of a yellow liquid.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Product: O=C(NC1CCOCC1)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 88 %

Procedure:
As described for example 323 g, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (150 mg, 0.46 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (160 mg, 88%) which was obtained as a white solid. MS: m/e=398.3 [M+H]+.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.C([Li])CCC.[C:19]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Br[C:38]1[CH:39]=[CH:40][C:41]2[O:50][CH2:49][CH2:48][C:47]3[C:43](=[N:44][N:45]([C:51]4[N:52]([C:56]5[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=5[F:63])[N:53]=[CH:54][N:55]=4)[CH:46]=3)[C:42]=2[CH:64]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1CCCCC1.C(OCC)(=O)C>[CH2:35]([O:34][C:32]([C:29]1([C:38]2[CH:39]=[CH:40][C:41]3[O:50][CH2:49][CH2:48][C:47]4[C:43](=[N:44][N:45]([C:51]5[N:52]([C:56]6[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=6[F:63])[N:53]=[CH:54][N:55]=5)[CH:46]=4)[C:42]=3[CH:64]=2)[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:27][CH2:28]1)=[O:33])[CH3:36]
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(Br)ccc2OCC3)c(F)c1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.5 %

Procedure:
To a solution of dicyclohexylamine (291 L, 1.463 mmol) in anhydrous toluene (3 mL) was added 2.5M n-butyllithium in hexanes (563 L, 1.575 mmol) dropwise at RT under nitrogen. After complete addition the mixture was stirred at RT for 10 min then ethyl N-Boc-piperidine-4-carboxylate (305 L, 1.24 mmol) was added drop wise at RT and the mixture was stirred for 30 min. The mixture was added to 9-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (500 mg, 1.13 mmol), di(dibenzylideneacetone)-palladium (35 mg, 0.06 mmol), tri-tert-butylphosphonium tetrafluoroborate (17.4 mg, 0.06 mmol) at RT under nitrogen then heated to 100° C. After heating for 17 hr the mixture was allowed to cool to RT and subjected to flash chromatography (SiO2, gradient 0 to 50% ethyl acetate in cyclohexane) to afford the title compound (200 mg, 29%). LCMS RT=4.93 min, M+H+=621.