Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].Cl[SiH:6](Cl)Cl.C=CC.[Si:12]([Cl:16])([Cl:15])([Cl:14])[Cl:13]>>[Cl:4][CH2:1][CH2:2][CH2:3][SiH3:6].[Si:12]([Cl:16])([Cl:15])([Cl:14])[Cl:13]
Reactant: C=CCCl
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: C=CC
Product: [SiH3]CCCCl

Procedure:
Thus, for example, in the reaction of allyl chloride with trichlorosilane, 25-30 mol. % of the allyl chloride entering into the reaction is converted by this side reaction into propylene, accompanied by the formation of equivalent quantities of silicon tetrachloride. The molar ratio of chloropropylsilane formed to silicon tetrachloride in the crude product is a measure of the selectivity of the reaction and typically attains values of between 2.33:1 (70% yield, based on allyl chloride) and 3:1 (75% yield). It is also known that the formation of propylene can be lessened by a special reaction procedure in pressurized apparatus. However, the result of this procedure is that the propylene obtained in the side reaction undergoes a further quantitative reaction with the hydrogen silane used, with the formation of propylsilanes. Even in the reactions carried out in the conventional manner under normal pressure, the propylene originating from the side reaction largely enters into a further side reaction with hydrogen silane to form the corresponding propylsilanes (cf. also DE 34 04 703 C) (see, for example, equation 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[C:17](=O)[NH:16][CH2:15][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].B.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:15][NH:16][CH2:17]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCC2CCCCC12c1ccc(Cl)c(Cl)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Clc1ccc(C23CCCCC2CNC3)cc1Cl
Yield: 25.1 %

Procedure:
7a-(3,4-Dichlorophenyl)octahydro-1H-isoindol-1-one (65 mg, 0.2287 mmol) was diluted in THF (2 mL) and borane (0.7 mL, 1 M in THF, 3 eq) and heated in the microwave for 15 minutes (max temp=100° C.). After cooling, the mixture was stirred with 6N HCl for thirty minutes and washed with MTBE. The aqueous layer was basicified with KOH and extracted with MTBE. The organic phase was evaporated and filtered (aminopropyl cartridge) to give 3a-(3,4-dichlorophenyl)octahydro-1H-isoindole (15.5 mg, 24%) as a clear oil. A further portion was later found in the organic wash and separated by silica gel filtration to give 19 mg (26%) additional product. LCMS Rt=7.60 min, m/z=270 (M+1). 1H NMR (CDCl3, δ): 7.43 (d, J=2.3 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.19 (dd, J=2.3, 8.5 Hz, 1H), 3.1 (m, 2H), 2.9 (m, 1H), 2.6 (m, 2H), 2.0-1.2 (m, 8H). 13C NMR (CDCl3, δ, mult): 146.7(0), 132.3(0), 130.1(1), 129.7(0), 128.9(1), 126.2(1H), 59.9(2), 49.6(2), 47.9(0), 41.0(1), 32.8(2), 24.2(2), 22.0(2), 21.4(2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[O:13]=[S:14]1(=[O:31])[CH2:19][CH2:18][N:17]2[CH2:20][CH2:21][CH2:22][C@@H:23]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:16]2=[N:15]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[O:30][C:27]1[CH:26]=[CH:25][C:24]([C@H:23]2[C:16]3=[N:15][S:14](=[O:31])(=[O:13])[CH2:19][CH2:18][N:17]3[CH2:20][CH2:21][CH2:22]2)=[CH:29][CH:28]=1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4cc(F)c(F)c(F)c4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
A mixture of (3,4,5-trifluorophenyl)boronic acid (1882 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (1000 mg), pyridine (7.21 mL), cesium carbonate (1162 mg), diacetoxycopper (1296 mg) and powdered 4A MS (10.0 g) in MeCN (36 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (196 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:12][NH:5][C:4]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(OC)c(N)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CNc1cc(OC)ccc1OC
Temperature: 40 °C
Reaction time: 72 h
Yield: 30.5 %

Procedure:
To a 100 ml three neck round bottom flask was added 2,5-dimethoxyaniline (1.53 g), anhydrous potassium carbonate (1.66 g), acetonitrile (25 ml) and iodomethane (1.42 g). The reaction mixture was stirred at 40° C. for 3 days under nitrogen in the dark. The reaction mixture was quenched with ethyl acetate (50 ml) and filtered. The residue was washed with ethyl acetate (3×20 ml) The filtrate and the washings were combined and washed with water (3×30 ml). The organic layer was filtered through MgSO4 and evaporated under reduced pressure. The residue was dissolved in a minimum amount of ethyl acetate/hexane 1:8. The solution was placed on a wet column of silica gel (80 g) and eluted with ethyl acetate/hexane: 300 ml (1:8), 500 ml (1:5) to afford 0.51 g of N-methyl-2,5-dimethoxyaniline. To a 50 ml three neck round bottom flask with compound 117 (0.32 g, 1.61 mmol), N-methyl-2,5-dimethoxyaniline (0.40 g) and anhydrous potassium carbonate (0.27 g) was added anhydrous DMSO (3 ml) and the reaction mixture stirred at 45° C. for 8 h under nitrogen in the dark. Distilled water (10 ml) was added to precipitate the product and the suspension stirred for 2 h and then cooled to 5° C. and filtered. The solid was washed with cold water (2×2 ml) suspended in MeOH (200 ml). Silica gel (1 g) was added and the suspension sonicated and then heated to 50° C. for 15 min. The suspension was then evaporated under reduced pressure and dried in vacuo at room temperature for 10 h. The residue was powdered and poured on top of a wet column of silica gel (40 g) and eluted with 5% of MeOH in CHCl3. Fractions corresponding the product spot (TLC) were pooled and evaporated. The residue was washed with ether and air dried to afford 0.15 g (28%) of compound 434 as a white solid.
Reaction SMILES: OC(C(F)(F)F)=O.[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][NH:9][C:10]([CH:12]1[CH2:17][CH:16]([O:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH2:15][N:14]([CH3:25])[CH:13]1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11]
Reactant: [H][H]
Reactant: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CC=C(c2ccccc2)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN1CC(Oc2ccncc2)CC(C(=O)NO)C1C(=O)N1CCC(c2ccccc2)CC1
Yield: 91.2 %

Procedure:
A mixture of (2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide TFA salt (4 mg, 0.00001 mol) in 1 mL of MeOH was hydrogenated in the presence of 5% Pd/BaSO4, under balloon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was concentrated to dry to yield The titled compound (4 mg, 100%). MS (ESI): (M+H)+=439.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].CN([CH:15]=[C:16]([C:22]([CH3:24])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:22]([CH3:24])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=[N:11]1
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1C

Procedure:
By the method of Example 3, Step C, 25.9 g (0.122 mole) of 2,4,6-trichlorophenylhydrazine and 22.7 g (0.123 mole) of ethyl 2-dimethylaminomethyleneacetoacetate were reacted in ethanol, yielding 1-(2,4,6-trichlorophenyl)-4-ethoxycarbonyl-5-methyl-1H-pyrazole as tan solid; mp 112.5°-113° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.C([C:22]1[C:23]([N:31]=[CH:32][N:33]([CH3:35])C)=[N:24][C:25]([CH2:28][CH2:29][CH3:30])=[CH:26][CH:27]=1)#N>C(O)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)=[C:2]([NH:1][C:35]2[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH3:30])=[N:24][C:23]=3[N:31]=[CH:32][N:33]=2)[CH:7]=1
Reactant: CCCc1ccc(C#N)c(N=CN(C)C)n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Solvent: CC(=O)O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ncnc2n1
Temperature: 130 °C
Yield: 78.1 %

Procedure:
The product from Example 7b (49 mg 0.231 mmol) and the product from Example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to 130° C. for 1.5 hours. After cooling to room temperature and removal of the acetic acid solvent under vacuum methanol (3 mL) was added to the oil which caused a solid to form which was triturated with methanol to provide the title compound 80 mg, 78%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.95 (t, J=7.4 Hz, 3H), 1.89 (m, 2H), 2.02 (s, 3H), 2.32 (s, 3H), 2.89 (t, J=7.5 Hz, 2H), 7.06 (s, 2H), 7.21 (t, J=8.5 Hz, 2H), 7.30 (s, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.52 (m, 1H), 8.52 (s, 1H), 8.74 (d, J=7.7 Hz, 1H), 10.00 (s, 1H); MS (ESI)+ m/z 444 (M+H)+.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.C(ON=O)(C)(C)C.[C:19](#[N:21])C>>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:19]#[N:21])=[N:3][CH:4]=1
Reactant: CC#N
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: CC(C)(C)ON=O
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Yield: 41 %

Procedure:
Heat a solution of 2-amino-5-bromo-3-nitropyridine (2.18 g, 10 mmol), cuprous cyanide (1.33 g, 15 mmol) and tert-butylnitrite (2.0 mL, 15 mmol) in acetonitrile (50 mL) to 60° C. for 2 hours. Cool the solution and partition between ethyl acetate (100 mL) and saturated aqueous NaHCO3 (100 mL). Extract the aqueous solution with ethyl acetate (2×50 mL), wash with water (100 mL), brine (100 mL), dry (MgSO4) and evaporate. Purify the solid by flash chromatography on silica gel (25% ether/75% hexane) to obtain the title compound as a pale yellow solid (934 mg, 41%).
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:14])C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:37][CH:36]([CH2:38][OH:39])[CH2:35][N:34]3[CH:40]=[C:41]([C:43]([NH2:45])=[O:44])[N:42]=[C:33]3[C:32]=2[CH:46]=1>ClCCl.O>[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:37][CH:36]([C:38]([OH:14])=[O:39])[CH2:35][N:34]3[CH:40]=[C:41]([C:43](=[O:44])[NH2:45])[N:42]=[C:33]3[C:32]=2[CH:46]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(CO)C2
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
TEMPO (17 mg, 0.11 mmol, 0.33 equiv) and PhI(OAc)2 (255 mg, 0.79 mmol, 2.37 equiv) were added to a stirred suspension of 10-bromo-6-(hydroxymethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (113 mg, 0.33 mmol, 1.00 equiv) in dichloromethane (4 mL) and water (0.8 mL) at 0° C. After 30 min the resulting mixture was warmed to room temperature and stirred overnight. The reaction was then quenched by the addition sodium bicarbonate and washed with dichloromethane. The pH value of the aqueous solution was adjusted to 2 by 2N hydrogen chloride. The aqueous layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in to 85 mg (crude) of 10-bromo-2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-6-carboxylic acid as a white solid.
Reaction SMILES: [Br-].[Li+].C[Mg]Br.[F:6][C@H:7]1[CH2:24][C@@:22]2([CH3:23])[C@@H:18]([CH2:19][CH2:20][C:21]2=[O:25])[C@H:17]2[C@H:8]1[C@@H:9]1[C:14]([CH:15]=[CH:16]2)=[CH:13][C:12](=[O:26])[CH2:11][CH2:10]1.[CH3:27][Si](Cl)(C)C>O1CCCC1.C(OCC)C.ClCCl.[Cu](I)I.CN1C(=O)N(C)CCC1>[F:6][C@H:7]1[CH2:24][C@@:22]2([CH3:23])[C@@H:18]([CH2:19][CH2:20][C:21]2=[O:25])[C@H:17]2[C@H:8]1[C@@H:9]1[C:14]([CH2:15][C@H:16]2[CH3:27])=[CH:13][C:12](=[O:26])[CH2:11][CH2:10]1
Reactant: C[Si](C)(C)Cl
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: I[Cu]I
Agent: C[Mg]Br
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOCC
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 15.2 g (79.8 mmol) of copper iodide in 70 ml of dry tetrahydrofuran is cooled to 0° C., mixed with 28.7 g (330 mmol) of lithium bromide and 27.8 ml of DMPU, stirred first for 30 minutes at this temperature and then cooled to −30° C. While being stirred, 52 ml of methylmagnesium bromide in diethyl ether (3 molar solution) is then added in drops, stirred for another 30 minutes, and the gray-colored suspension is mixed with a solution that consists of 10.0 g (34.7 mmol) of 11β-fluoroestra-4,6-diene-3,17-dione, 24.3 ml of DMPU and 23 ml of trimethylsilyl chloride in 60 ml of dichloromethane. After the addition is completed, it is allowed to stir for another 1.5 hours between −30→−10° C., the cold bath is removed, and 35 ml of ethyl acetate is carefully added at room temperature while being stirred vigorously. For working-up, the reaction solution is diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution that is free of copper, and the organic phase is dried on sodium sulfate. The crude product is chromatographed on silica gel (hexane-ethyl acetate, gradient of up to 1:1), yield 3.1 g (30%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:24](=[O:30])[C:25]([O:27]CC)=O)[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11](=[O:23])[CH2:10]2)([CH3:8])[CH3:7])[CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:24](=[O:30])[C:25]([OH:27])=[C:10]3[CH:9]([CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[C:11]3=[O:23])[C:6]2([CH3:8])[CH3:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=O)N(CC1CC1)C(C)(C)C1CCN(Cc2ccc(F)cc2)C(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC1(C)C2CCN(Cc3ccc(F)cc3)C(=O)C2=C(O)C(=O)N1CC1CC1
Reaction time: 3 h

Procedure:
To a cooled solution (0° C.) of ethyl ((cyclopropylmethyl){1-[1-(4-fluorobenzyl)-2-oxopiperidin-4-yl]-1-methylethyl}amino)(oxo)acetate (1.56 g, 3.73 mmol) in DMF (15 mL) was added LiHMDS (1M in THF, 5.59 mL, 5.59 mmol) dropwise over 1 min. After stirring for 3 hours, the product mixture was concentrated under vacuum and purified using reverse phase HPLC on C18 stationary phase eluting with a gradient of 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 4.61 (s, 2H), 3.41 (d, J=6.8 Hz, 2H), 3.32 (d, J=2.8 Hz, 1H), 3.31 (s, 1H), 2.87 (dd, J=13.2; 4.2 Hz, 2H), 1.93 (m, 1H), 1.65 (m, 1H), 1.44 (s, 3H), 1.21 (s, 3H), 1.02 (m, 1H), 0.47 (m, 3H), 0.36 (m, 1H) ppm. ES MS M+1=373.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCCBr
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Li]C(C)(C)C
Product: BrCCCCc1cccc(C2OCCO2)c1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a clean and dry 2000 ml round bottom flask equipped with a 500 ml addition funnel, low temperature thermometer and magnetic stir bar was transferred anhydrous tetrahydrofuran (800.0 ml) under nitrogen. 2-(3-bromophenyl)-1,3-dioxolane (33.0 ml, 0.2183 mol) was added to this flask by syringe. The reaction vessel was placed into a dry ice/acetone bath until a temperature of <−65° was achieved. The reaction mixture was then allowed to stir for 45 minutes at a stirring speed of 550 rpm in order to verify the integrity of the stirring apparatus at this temperature. Tert-butyllithium solution (257.0 ml, 0.4690 mol) was transferred to the addition funnel by cannula, then added dropwise to the reaction never allowing the temperature to rise above −65° C. Following addition, the reaction was allowed to stir for a period of 30 minutes. The vessel was then removed from the dry ice/acetone bath and allowed to warm to a temperature of −20° C. The vessel was then again placed into the dry ice/acetone bath until a temperature of <−65° was achieved. 1,4-dibromobutane (103.5 ml, 0.8740 mol) was added to the reaction dropwise via syringe, maintaining the current temperature. The reaction was allowed to stir for 30 minutes at this temperature following addition. The reaction was slowly warmed to room temperature over the following 12 hours. After warming, the reaction was quenched by the addition of isopropanol (20.0 ml) via syringe.
Reaction SMILES: O[CH:2]([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH:3]1[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[S:18]1[CH:19]=[CH:20][C:16]([CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]2)=[CH:17]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(O)c2ccsc2)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1cc(CC2CCCNC2)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.3 %

Procedure:
1.0 g (3.36 mmol) of tert-butyl 3-(hydroxythiophen-3-ylmethyl)piperidine-1-carboxylate as diastereomer mixture were stirred with 15 ml of trifluoroacetic acid at 0° C. After 15 min, 0.80 ml (5.04 mmol) of triethylsilane were added dropwise, the cold bath was removed, and the mixture was stirred at room temperature for 18 h. Conventional work-up gave 0.41 g of 3-thiophen-3-ylmethylpiperidine; HPLC/MS (M+H)+=182 as oil.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:9]([CH3:19])=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH2:12][N:11]3[C:17]=2[CH3:18])[CH:5]=[CH:4][N:3]=1.[NH:20]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[N:23][N:22]=[N:21]1>>[CH3:18][C:17]1[N:11]2[CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:10]2=[C:9]([CH3:19])[C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:26][CH:27]=2)[N:7]=1
Reactant: Cc1c(-c2ccnc(F)n2)c(C)n2c1C(=O)NCC2
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Product: Cc1c(-c2ccnc(Nc3ccc(-c4nnn[nH]4)cc3)n2)c(C)n2c1C(=O)NCC2

Procedure:
Prepared by reaction of 7-(2-fluoropyrimidin-4-yl)-6,8-dimethyl-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one with 4-(1H-tetrazol-5-yl)-phenylamine.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([NH2:13])(=[O:12])=[O:11])[C:4]=2[CH2:3][O:2]1.C(N=[C:19]=[O:20])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([N:13]=[C:19]=[O:20])(=[O:11])=[O:12])[C:4]=2[CH2:3][O:2]1
Reactant: NS(=O)(=O)c1cccc2c1COC2
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1cccc2c1COC2

Procedure:
A mixture of 7.0 g of 1,3-dihydrobenzo[c]furan-4-sulfonamide, 4.0 ml of butyl isocyanate, 0.1 g of DABCO® and 150 ml xylene was heated to reflux. Phosgene (3.1 ml) was added in small portions to the reaction mixture while maintaining the reaction temperature >130°. When addition of phosgene was complete, the reaction mixture was heated to reflux (128°) for 1 hour, then cooled under nitrogen. The reaction mixture was filtered under nitrogen, and the filtrate was concentrated in vacuo to give 1,3-dihydrobenzo[c]furan-4-sulfonyl isocyanate as an amber oil. The crude sulfonyl isocyanate was dissolved in methylene chloride (total volume=28 ml) for reaction with amino heterocycles.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)=[O:13])=[CH:8][C:7]=1[Br:25]>O1CCCC1.CO.C(OCC)(=O)C>[Br:25][C:7]1[CH:8]=[C:9]([C:12]([NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)=[O:13])[CH:10]=[CH:11][C:6]=1[C:5]([OH:26])=[O:4]
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)O)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (21.5 mg, 0.54 mmol) was added to a solution of 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid methyl ester (Example 83; 208 mg, 0.54 mmol) in tetrahydrofuran/methanol (2:1; 1.8 mL). The solution was allowed to stir at room temperature for 4 h and then more sodium hydroxide (21.5 mg, 0.54 mmol) was added. The solution was allowed to stir at room temperature overnight, then it was diluted with ethyl acetate and the solution was washed with 1N hydrochloric acid solution (10 mL), washed with brine, dried (MgSO4), filtered and concentrated to give crude 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid. This was mixed with a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (213.5 mg, 0.64 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (203.5 mg, 0.54 mmol), 1-hydroxybenzotriazole (72.6 mg, 0.54 mmol) and diisopropylethylamine (281 μL, 1.61 mmol) in N,N-dimethylformamide (1.5 mL). The solution was allowed to stir for 3 h, then ethyl acetate (20 mL) was added. The solution was washed with 1N hydrochloric acid solution (10 mL), saturated sodium bicarbonate solution (15 mL) and each aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered, evaporated and chromatographed over silica gel (3-5% methanol/dichloromethane) to give rac.-N-[2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (206.8 mg, 69% yield) as a pale yellow solid.
Reaction SMILES: [Br:1][CH:2]1[C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)([C:7]([F:10])([F:9])[F:8])[O:5][N:4]=[C:3]1[C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH:26]2[CH2:29][S:28][CH2:27]2)=[O:24])=[C:21]([CH3:32])[CH:20]=1.C(=O)([O-])[OH:34].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl.O>[Br:1][CH:2]1[C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=[C:3]1[C:19]1[CH:31]=[CH:30][C:22]([C:23]([NH:25][CH:26]2[CH2:29][S:28](=[O:34])[CH2:27]2)=[O:24])=[C:21]([CH3:32])[CH:20]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)ccc1C(=O)NC1CSC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)ccc1C(=O)NC1CS(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[4-bromo-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-thietan-3-yl-benzamide (145 mg) (Example A22) in dichloromethane (8 ml) was added a solution of sodium hydrogen carbonate (128 mg) in water (4 ml). A solution of 3-chloroperoxybenzoic acid (“MCPBA”) (48 mg) in dichloromethane (1 ml) was added dropwise. The reaction mixture was stirred at ambient temperature for 4 hours. Dichloromethane was evaporated and the residue partitioned between aqueous sodium carbonate (1M) and ethyl acetate. The phases were separated and the aqueous phase extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to give Compound No. A25 of Table A (101 mg) and Compound No. A26 of Table A (17 mg) as colorless solids.