Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1([OH:29])[CH2:28][CH2:27][CH2:26]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:41]I>C1COCC1>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]1([O:29][CH3:41])[CH2:26][CH2:27][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CI
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C2(O)CCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 1-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclobutanol (17.3 mg, 0.031 mmol) in THF (0.2 mL) at 0° C. was added sodium hydride (5 mg, 0.1 mmol). The mixture was stirred at room temperature for 30 minutes and methyl iodide (20 μL, 0.3 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. Solvent was removed in vacuo. The residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20% ethyl acetate in hexane) to afford the title compound (11.1 mg, 63%). 1H NMR (400 MHz, CDCl3) δ ppm 1.64-1.76 (m, 1H) 1.98-2.10 (m, 1H) 2.33-2.43 (m, 2H) 2.43-2.53 (m, 2H) 2.85 (s, 3H) 4.17-4.21 (m, 3H) 4.75 (s 2H) 4.86 (s, 2H) 7.41-7.46 (m, 2H) 7.50 (d, J=8.30 Hz, 1H) 7.73 (s, 2H) 7.76 (s, 1H). MS (ES+) Calc 567.2, Found: 568.4 (M+1) According to the procedure described in example 31 and using the corresponding ketone reagent, example 32 was prepared.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:6][CH:7]=1.C([O:34][C:35](=[O:38])[CH2:36]Br)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:27])[F:28])[CH:20]=2)[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:36][C:35]([OH:38])=[O:34])=[CH:15][CH:16]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(N(CCc2ccc(O)cc2)Cc2cccc(OC(F)(F)F)c2)nc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N(CCc2ccc(OCC(=O)O)cc2)Cc2cccc(OC(F)(F)F)c2)nc1

Procedure:
Similarly prepared by alkylation of 4-(2-{(5-methylpyridin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenol with tert-butyl-bromo-acetate, followed by standard TFA hydrolysis (general procedure I).
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][C@@H:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5][N:4]1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[Cl:33][C@H:3]1[CH2:7][C@@H:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5][N:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:2]1
Reactant: COCO[C@@H]1C[C@H](CO)N(CCc2ccc(OC)cc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCO[C@@H]1C[C@H](Cl)CN(CCc2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76 %

Procedure:
To a solution of 4.50 g (20.2 mmol) of (2R,4R)-(+)-2-(hydroxymethyl)-4-(methoxymethoxy)-1-(4-methoxyphenethyl)pyrrolidine and 2.40 ml of triethylamine (23.8 mmol) in dichloromethane (35 ml) was added 2.62 ml (22.9 mmol) of methanesulfonylchloride and the mixture was stirred at room temperature for 4.5 hours. The mixture was diluted with dichloromethane and the solution was washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate:n-hexane=1:2) to give 4.82 g (87.2%) of (3S,5R)-(+)-3-chloro-5-(methoxymethoxy)-1-(4-methoxyphenethyl)piperidine as colorless oil.
Reaction SMILES: [C:1]1([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:16]([C:18](Cl)=[O:19])=[CH:17][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([NH2:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>O1CCCC1>[CH2:21]([NH:33][C:18]([C:16]1[CH:15]=[CH:14][C:10]2[C:11](=[O:13])[O:12][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]=2[CH:17]=1)=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCN
Reactant: O=C(Cl)c1ccc2c(=O)oc(-c3ccccc3)nc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNC(=O)c1ccc2c(=O)oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The synthesis started out from 2-phenyl-7-chlorocarbonyl-4H-3,1-benzoxazin-4-one, whose synthesis is descried in L. Jakisch et al., Journal of Polymer Science: Part A: Polymer Chemistry 2003; 41(5): 655-667 (there compound 10a). 2.855 g (10 mmol) of this substance was suspended in 100 ml of dry tetrahydrofuran at 0° C. in a 250 ml three-necked flask provided with magnetic stirrer, reflux condenser and drying tube. A mixture of 1.854 g (10 mmol) of n-dodecylamine, 1.012 g (10 mmol) of triethylamine and 20 ml of dry tetrahydrofuran was then slowly added dropwise at from 0 to 5° C. The reaction mixture was subsequently stirred at room temperature for 2 hours, and the resultant precipitate of triethylammonium chloride was then filtered off with suction and the filtrate was evaporated on a rotary evaporator. The solid residue was washed with water and dried at 60° C. under reduced pressure. Recrystallization from ethanol gave 2.85 g of product.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: NCCCCc1cccnc1
Reactant: COc1cccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C/C(=O)NCCCCc2cccnc2)c2cccc(OC)c2)c1
Yield: 89.2 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (32.36 g) and 3-pyridinebutanamine (11.4 g) in tetrahydrofuran (120 mL) was stirred for 18 hours at room temperature and was worked up in the usual manner. The crude material was purified by HPLC (ethyl acetate) and then triturated with ether-hexane to furnish 29.6 g of (E)-5,5-bis (3-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 84°-86° C. Crystallization of the product from ethyl acetate-ether provided 29.0 g of amide, mp 86°-88° C.
Reaction SMILES: [C:1]([C:3]1([N:21]2[CH2:24][C:23]([F:26])([F:25])[CH2:22]2)[CH2:20][CH2:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4]1)#N.[C:27]1([Mg]Br)[CH:32]=[CH:31]C=[CH:29][CH:28]=1>C1COCC1>[F:25][C:23]1([F:26])[CH2:24][N:21]([C:3]2([C:1]3[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=3)[CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]3)[CH2:19][CH2:20]2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(C#N)(N1CC(F)(F)C1)CC2
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(c1ccccc1)(N1CC(F)(F)C1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
The crude tert-butyl 9-cyano-9-(3,3-difluoroazetidin-1-yl)-3-azaspiro[5.5]-undecane-3-carboxylate was taken up in THF (20 ml) and PhMgBr (12 ml) was added at 0° C. The reaction mixture was stirred at room temperature overnight. The mixture was quenched with NH4Cl solution at 0° C. and was then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (silica gel (100-200)) to obtain the desired compound. Yield: 31%
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:37][C:38]([NH:40][C:41]1[N:49]=[CH:48][N:47]=[C:46]2[C:42]=1[N:43]=[CH:44][N:45]2[CH2:50][C:51](O)=[O:52])=[O:39])[C:28]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][O:31][C:30]=2[CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:51](=[O:52])[CH2:50][N:45]2[CH:44]=[N:43][C:42]3[C:46]2=[N:47][CH:48]=[N:49][C:41]=3[NH:40][C:38]([O:37][CH2:27][C:28]2[CH:36]=[CH:35][C:34]3[O:33][CH2:32][O:31][C:30]=3[CH:29]=2)=[O:39])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccc4c(c3)OCO4)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2nc3ccccc3s2)C(=O)C1)OCc1ccc2c(c1)OCO2

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(piperonyloxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.64 (s, 1H), 8.58 (s, 0.6H), 8.57 (s, 0.4H), 8.34 (m, 1H), 8.31 (s, 0.4H), 8.28 (s, 0.6H), 8.27 (m, 1H), 7.72 (m, 2H), 7.04 (s, 1H), 6.94 (d, 1H), 6.90 (d, 1H), 6.01 (s, 2H), 5.39 (s, 1.2H), 5.28 (s, 0.8H), 5.09 (s, 2H), 4.57 (s, 0.8H), 4.29 (m, 2.4H), 4.09 (t, 2H), 3.88 (t, 0.8H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CCN(CC)CC.[C:18](Cl)([CH3:20])=[O:19]>C(Cl)Cl>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:18](=[O:19])[CH3:20])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a white suspension of 1-(2-aminophenyl)ethanone (25 g, 185 mmol) and Et3N (33.4 mL, 240 mmol) in DCM at 0° C. was added dropwise AcCl (15.70 mL, 222 mmol) in 25 mL DCM. The reaction mixture was then stirred at r.t. for 2 h. After the reaction went to completion as monitored by LC-MS, the reaction mixture was cooled to 0° C., and was then quenched with H2O (100 mL). The organic phase was isolated; the aqueous layer was extracted with DCM. The organic phases were combined, and washed with H2O and brine. The resulting organic phase was dried over anhydrous MgSO4, filtered and concentrated to dryness to give crude N-(2-acetylphenyl)acetamide, which was used in the next step without further purification (30 g, yield 92%). MS (m/z): 136 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)=[CH:3][CH:4]=1
Reactant: COCOc1ccc(Br)cc1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOc1ccc(-c2ccncc2)cc1
Temperature: 80 °C
Yield: 74.2 %

Procedure:
To a degassed solution of 1-bromo-4-(methoxymethoxy)benzene (360 mg, 1.66 mmol), pyridin-4-ylboronic acid (307 mg, 2.50 mmol), and Cs2CO3 (1.09 g, 3.35 mmol) in THF (5 mL) was added Pd(PPh3)4 (190 mg, 0.16 mmol). The reaction mixture was heated at 80° C. overnight and diluted with EtOAc (50 mL). It was washed with H2O (2×25 mL), dried over Na2SO4, and concentrated. Purification on a silica gel column gave the desired product as a white solid (265 mg). NMR (CDCl3): 8.63 (d, 2H), 7.67 (d, 2H), 7.47 (d, 2H), 7.16 (d, 2H), 5.24 (s, 2H), 3.52 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:25])[C:13]([N:15]([CH3:24])[N:16]=CC1C=CC=CC=1)=[O:14])[CH3:2]>Cl.CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:25])[C:13]([N:15]([CH3:24])[NH2:16])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: CO
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a test tube (outside diameter 21 mm φ×overall length 160 mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(phenylmethylidene)hydrazine ((40-b)-(15)-5), 0.5 ml of methanol, 10 mg of 10 wt % Pd-c and one drop of concentrated hydrochloric acid were added and the mixture was stirred at 0° C. for 7 hours under hydrogen atmosphere. An unsolved substance was removed by filtration and washed with methanol. The filtrates were combined and concentrated under reduced pressure to give 70 m g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][NH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)[CH3:2].[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:51]([O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][C@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]2[C:33]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:40]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:18][CH2:19][CH3:20])[CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[O:41])=[CH:49][CH:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(CNCc1ccnc2ccccc12)OCC
Product: CCOC(CN(Cc1ccnc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 76.3 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, 2,2-diethoxy-N-(quinolin-4-ylmethyl)ethanamine (Compound IX-4) (274 mg, 1.0 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (689 g, 1.5 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=5:1 to 2:1) to obtain the title compound (546 mg, 76%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.[CH3:26][O:27][C:28](=[O:40])[C@H:29](O)[CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CO>C(OCC)(=O)C>[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH2:30][O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:34])[CH3:33]
Reactant: COC(=O)[C@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CO[Si](C)(C)C(C)(C)C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2

Procedure:
Following the procedures of Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol and (R)-3-(tert-butyl-dimethyl-silanyloxy)-2-hydroxy-propionic acid methyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid methyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=4.48 min, [M+H]+=568
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[N:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)Cn1nc(C(N)=O)c2ccncc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1nn(CC(=O)O)c2cnccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetate (663 mg, 2.40 mmol) in CH2Cl2 (20 mL) was added TFA (10 mL, 130 mmol), and the resulting mixture was stirred at RT for 6 h. The reaction mixture was concentrated in vacuo, the residual solid was suspended in methanol and volatiles were removed again in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH2:17][N:18]([CH3:29])[S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:30]([C:32]1[CH:37]=[C:36]([C:2]2[CH:16]=[C:15]([CH2:17][N:18]([CH3:29])[S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=2[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:35]=[CH:34][CH:33]=1)#[N:31]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1)S(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(-c2cccc(C#N)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
To a DMF (50 mL) solution of t-butyl 2-(2-bromo-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (3) (1.25 g, 2.6 mmol, 1 eq) was added 3-cyanobenzeneboronic acid (0.57 g, 3.8 mmol, 1.5 eq, Frontier Scientific, Inc., Logan, Utah, USA), potassium carbonate (1 g, 7.7 mmol, 3 eq), and tetrakis(triphenylphoshine)palladium (0.15 g, 0.13 mmol, 0.05 eq). The mixture was stirred at 90° C. for 18 h. After concentration in vacuo, the residue was extracted between EtOAc (100 ml) and brine (100 mL). The separated EtOAc layer was dried (Na2SO4), concentrated and purified via silica gel chromatography (linear gradient of 0% EtOAc/hexanes to 100% EtOAc/hexanes) to yield 0.78 g (59.8%) of t-butyl 2-(2-(3-cyanophenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (4). 1HNMR (CDCl3, 300 MHz): δ 7.80 (m, 4H), 7.58 (m, 1H), 7.48 (t, 1H), 7.21 (m, 4H), 6.79 (d, 1H), 4.52 (s, 2H), 4.11 (s, 2H), 2.61 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([NH:20][CH:21]([CH:29]([CH3:31])[CH3:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:20]([CH:21]([CH:29]([CH3:31])[CH3:30])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:40]1=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(CC(CNCc2ccccc2)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(CC2CN(Cc3ccccc3)C(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 32 %

Procedure:
t-Butyl 2-(2-benzylamino-1-(4-methoxybenzyl)ethylamino)-3-methylbutyrate (0.64 g; 1.5 mmol) was dissolved in toluene (40 ml). Triethylamine (457 μL; 3.3 mmol) and triphosgene (0.49 g; 1.65 mmol) were added. The reaction mixture was stirred at RT for 4.5 h. It was then washed with water (1×), saturated NaHCO3 solution (1×) and again with water (1×). The organic phase was dried over Na2SO4 and concentrated in a rotary evaporator. The crude product was chromatographed on an SiO2 cartridge (EtOAc/n-heptane 1:3). t-Butyl 2-(3-benzyl-5-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (0.22 g, 0.48 mmol) was obtained as a yellow oil. MS: 453.20 (M+H); Rt: 1.94 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH:25]([Sn](CCCC)(CCCC)CCCC)=[CH2:26]>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH:25]=[CH2:26])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Product: C=Cc1cc(C)c(NS(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Yield: 81.9 %

Procedure:
In the same manner as described in Example 139, 700 mg (1.69 mmol) of the product of Example 10 and 0.73 ml (2.5 mmol) of vinyltributyltin provided 500 mg (82%) of the desired product as a white solid. Electrospray Mass Spec 362 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1ccccc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2ccccc2-c2ccccc2)n1
Yield: 65 %

Procedure:
Using Method DD (reaction time: 20 hours) with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 2-phenyl-phenol (268 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:2), the title compound was obtained (238 mg). Yield: 65%. 1H NMR (250 MHz, DMSO-d6) δ 7.31-7.61 (m, 9H, Harom), 8.43 (s, 1H, HPz 5), 8.46 (s, 1H, HPz 3). m/z: 283.1 [(M+H)+, calcd for C16H11ClN2O 282.1].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[F:23])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2ccccc2F)cc1

Procedure:
To a solution of mono-N-(t-butoxycarbonyl)-1,4-phenylenediamine (1.58 g) and triethylamine (1.50 mL) in 25 mL of dichloromethane is added o-fluorobenzoyl chloride (1.20 g). A solid formed immediately forms and is filtered and washed with fresh solvent to yield a white solid, 1.90 g.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1.[CH3:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25]>>[CH3:22][N:23]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)=[CH:5][CH:4]=1)[S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Reactant: CNS(C)(=O)=O
Product: CN(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)S(C)(=O)=O

Procedure:
The title compound was prepared from 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole and N-methyl methanesulfonamide using a similar procedure to that described for Description 15.