Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:32])[C@@H:7]([O:9][C:10]1[N:31]=[CH:30][C:13]2[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]=2[CH:11]=1)[CH:17]=[C:16]([C:22]1[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=1)[N:15]=3)[CH3:8])(C)(C)C>Cl.O1CCOCC1>[CH:27]([N:23]1[C:22]([C:16]2[N:15]=[C:14]3[N:18]([CH2:19][CH2:20][O:21][C:12]4[CH:11]=[C:10]([O:9][C@@H:7]([CH3:8])[C:6]([OH:32])=[O:5])[N:31]=[CH:30][C:13]=43)[CH:17]=2)=[N:26][CH:25]=[N:24]1)([CH3:29])[CH3:28]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(=O)O)cc1OCC2
Yield: 63.7 %

Procedure:
A solution of (S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9 triaza-benzo[e]azulen-8-yloxy]-propionic acid tert-butyl ester (206 mg, 0.47 mmol) in HCl in dioxane (4N, 5 mL) was heated at 50° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue triturated with MeCN. The product was collected by filtration and dried in vacuo at 50° C. to yield (S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionic acid as a beige solid (115 mg, 66%). LCMS: RT=2.72 min, [M+H]+=385
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:15][CH2:16]1)=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 10 g (36.8 mmol) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester in 100 mL of CH2Cl2 were added 3.15 mL (40.5 mmol, 1.3 eq) of methanesulfonyl chloride followed by 6.68 mL (47.9 mmol, 1.3 eq) of triethylamine. Then the reaction mixture was stirred at RT for 1 h. 1M HCl was added, the phases were separated and the inorganic phase was washed with ether. The combined organic phases were washed with water and dried over magnesium sulfate. Concentration of the solution yielded 12.64 g (98%) of trans-methanesulfonic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester as colorless oil, MS: 367 (M+NH4+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C@:13]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:17]([C:18](=[O:20])[CH3:19])[N:16]=[C:15]([C:21]3[CH:26]=[C:25](Br)[CH:24]=[CH:23][C:22]=3[F:28])[CH2:14]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Li]CCCC.Cl[Si:41]([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C@:13]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:17]([C:18](=[O:20])[CH3:19])[N:16]=[C:15]([C:21]3[CH:26]=[C:25]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:24]=[CH:23][C:22]=3[F:28])[CH2:14]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CCC[C@@]2(c3ccccc3)CC(c3cc(Br)ccc3F)=NN2C(C)=O)CC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(CCC[C@@]2(c3ccccc3)CC(c3cc([Si](C)(C)C)ccc3F)=NN2C(C)=O)CC1
Temperature: 25 °C

Procedure:
To a solution of 53 mg (0.100 mmol) 3-7 in 0.75 mL anhydrous THF at −78° C. under N2 was added 60 μL (0.150 mmol) 2.5 M n-BuLi in hexanes dropwise. Immediately following this addition, 51 μL (0.400 mmol) chlorotrimethylsilane was added, the cooling bath was removed, and the reaction warmed to room temperature. After 30 min the reaction was quenched with saturated aqueous NH4Cl solution and partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic phase was washed with water, brine, dried with Na2SO4 and concentrated. The residue was purified by reverse-phase preparatory HPLC with CH3CN/H2O (with 0.1% TFA). The fractions containing the desired product were poured into saturated aqueous NaHCO3 solution and extracted with EtOAc and concentrated to yield the freebase 3-8 as a clear, colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[OH-].[K+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([S:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Yield: 33 %

Procedure:
To a solution of indole 3-carboxaldehyde (8y) (100 mmol) in ethanol (500 mL) at RT was added potassium hydroxide (1.1 equiv). The mixture was stirred until total solubilization. The ethanol was completely removed in vacuum and the residual was dissolved in acetone (250 mL) followed by adding benzenesulfonyl chloride (1.1 equiv, 110 mmol). The reaction mixture was stirred for half hour. The precipitate was filtered off and the filtrate was concentrated and recrystallized from methanol to give a white solid. Yield: 33%. 1H NMR (500 MHz, CDCl3) δ 10.17 (s, 1H), 8.25-8.39 (m, 2H), 7.97-8.09 (m, 3H), 7.69 (t, J=7.33 Hz, 1H), 7.59 (t, J=7.5 Hz, 2H), 7.39-7.54 (m, 2H). MS (ESI) calcd for C15H11NO3S 285.1. found 286.0 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[CH2:11][C@H:10]([O:12][CH3:13])[CH2:9][CH2:8][C@@H:7]1[N:14]1[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OCC2C=CC=CC=2)[C:15]1=[O:30])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:19][C@H:16]1[CH2:17][CH2:18][N:14]([C@H:7]2[CH2:8][CH2:9][C@@H:10]([O:12][CH3:13])[CH2:11][C@H:6]2[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:15]1=[O:30]
Reactant: [H][H]
Reactant: CO[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CNC(C)=O)C1
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CNC(C)=O)C1
Yield: 98.4 %

Procedure:
A sample of the benzyl (S)-1-((1S,2S,4R)-2-(acetamidomethyl)-4-methoxycyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (614 mg, 1.471 mmol) and Pd/C (62.6 mg, 0.294 mmol) were stirred in MeOH (30 mL) at room temperature under 50 psi hydrogen atmosphere for 2 h. The suspension was filtered through Celite with EtOAc, concentrated and dried in vacuo to yield N-(((1S,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-methoxycyclohexyl)methyl)acetamide (410 mg, 1.447 mmol, 98% yield) as a white solid. LC/MS found [M+H]+=284.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][CH2:7][NH:8][C:9](=O)[O:10]CC>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:9](=[O:10])[NH:8][CH2:7][CH2:6]2
Reactant: CCOC(=O)NCCc1cccc(OC)c1
Solvent: O
Product: COc1ccc2c(c1)CCNC2=O
Temperature: 25 °C
Yield: 137.6 %

Procedure:
A mixture of ethyl 3-methoxyphenethylcarbamate (7.32 g, 32.8 mmol) and polyphosphoric acid (30 g) was heated at 120° C. for 2 h after which H2O (100 mL) was added and the mixture was cooled to RT. The mixture was extracted with EtOAc (6×100 mL), dried (MgSO4) and concentrated to yield crude 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (8.0 g, 138%) as a sticky gum. 1H NMR (400 MHz, acetone-d6): δ 7.88 (d, J=8.4 Hz. 1H), 7.04 (brS, 1H), 6.87 (dd, J=8.4, and 2.4 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 3.84 (s, 3H), 3.49 (t, J=6.4 Hz, 2H), 2.94 (t, J=6.2 Hz, 2H); MS (ESI) m/z: 178.0 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[N+:16]([O-:18])=[O:17])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+]>CS(C)=O>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-:18])=[O:17])=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cc2ccccc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(Cc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.5 %

Procedure:
To a mixture of 2-benzyl-5-((E)-2-nitro-vinyl)-pyridine (1.2 g, 5.0 mmol) described in Manufacturing Example 210-1-5, acetic acid (300 mg, 5.0 mmol), and dimethyl sulfoxide (10 mL) was added sodium borohydride (94 mg, 2.5 mmol), which was stirred for 10 minutes at room temperature. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and passed through a glass filter provided with NH silica gel (eluted with ethyl acetate). The eluate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (260 mg, 22%).
Reaction SMILES: [P:1](O)([OH:4])([OH:3])=[O:2].[O:6]=[C:7]([CH2:9][N:10]([C:12](=[NH:14])[NH2:13])[CH3:11])[OH:8].[P:15]([O:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[C:39]3[N:38]=[CH:37][N:36]=[C:34]([NH2:35])[C:33]=3[N:32]=[CH:31]2)[C@H:27]([OH:40])[C@@H:26]1[OH:41])([O:18][P:19]([OH:22])([OH:21])=[O:20])(=[O:17])[OH:16].C(N[C@H](C(O)=O)CS)(=O)C>>[P:15]([O:23][CH2:24][C@H:25]1[O:29][C@@H:28]([N:30]2[C:39]3[N:38]=[CH:37][N:36]=[C:34]([NH2:35])[C:33]=3[N:32]=[CH:31]2)[C@H:27]([OH:40])[C@@H:26]1[OH:41])([O:18][P:19]([O:21][P:1]([OH:4])([OH:3])=[O:2])([OH:22])=[O:20])(=[O:16])[OH:17].[O:6]=[C:7]([CH2:9][N:10]([C:12](=[NH:13])[NH2:14])[CH3:11])[OH:8]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: O=P(O)(O)O
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: CN(CC(=O)O)C(=N)N
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Temperature: 37 °C

Procedure:
With reference to the FIGURE there is described, schematically, a mechanical system for continuous analyses of a large number of serum samples. Such devises are well-known, e.g., the Technicon AAII by Technicon Corp., Tarrytown, N.Y. In the FIGURE, the serum sample is placed in sample tray 1 which delivers the sample through line 3 to unified pumping head 5 at a rate of 0.32 cc/min. Simultaneously a mixture of creatine phosphate, adenosine diphosphate, Mg++ and N-acetylcystein is monitored (0.60 cc/min.) through line 7 into pumping head 5 and air is monitored through line 9 at a rate of 0.32 cc/min. N-acetylcysteine (N-Ac) is required as a CPK activator. The air and CP/ADP/N-Ac/Mg++ streams are mixed in coil 11 and subsequently combined with sample stream 3. The unified stream is passed through heater bath 13 wherein the stream is heated to about 37° C. Thereafter the heated stream is passed into the upper chamber 15 of dialyzer 16. Any CPK present in the sample catalyzes reaction between the CP and ADP to produce ATP and creatine. The ADP, ATP and creatine diffuse through membrane 17 into the second chamber 19 of dialyzer 16. The second chamber of the dialyzer also contains NAD/glucose/Mg++ mixture injected into the system through line 21 (1.00 cc/min.) via pumping head 5. The NAD/glucose/Mg++ mixture is mixed with air injected via line 23 (0.32 cc/min.) through pumping head 5. The NAD/glucose/Mg++ air stream procedes via line 25 into dialyzer chamber 19 and is combined with ATP from the upper chamber 15. Thereafter the unified stream is passed through line 31 through coiled tube 33 and flow cell 41. Thereafter the sample is passed through line 51 and pumping head 5 to a waste receptable.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].CC([N-]C(C)C)C.[CH2:17]1[O:19][CH2:18]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:17][CH2:18][OH:19]
Reactant: Clc1cncc(Cl)c1
Reactant: C1CO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dichloropyridine (4.0 g, 27.0 mmol) in THF (70 mL) was added LDA (1.8 M in THF/heptane/ethylbenzene, 22.0 mL, 39.6 mmol) at −78° C. and the mixture was stirred at the same temperature for 2 h, and then ethylene oxide (1.2 M in THF, 25 ml, 30.0 mmol) was added. The reaction mixture was allowed to warm to room temperature gradually and stirred for 1 h at room temperature. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine (2 times) and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give compound B1-1 (3.1 g, 60%) as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[S:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[C:10]=2[CH:9]=1)(=[O:3])[CH3:2].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]1([CH2:29][N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)[CH2:28][O:27]1.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([OH:27])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[CH2:28][N:14]1[C:15](=[O:16])[C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[S:17][C:11]=2[N:12]=[CH:13]1
Reactant: CC(=O)OCCCc1cc2c(=O)[nH]cnc2s1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCCCc1cc2c(=O)n(CC(O)(Cn3cncn3)c3ccc(F)cc3F)cnc2s1
Yield: 31 %

Procedure:
6-(3-Acetoxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A26) (0.5 g, 2 mmole) and 1[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole of the Formula (5) (0.47 g, 2 mmole) were taken in two neck round bottom flask under inert atmosphere, dry ethyl acetate (5 ml) was added followed by flame dried potassium carbonate (0.55 g, 4 mmole) and tetrabutylammonium bromide (0.76 g, 2.4 mmole) the mixture was stirred under reflux for 12 hours, Cooled, diluted with water (15 ml), extracted with ethyl acetate (3×10 ml), dried, concentrated and purified by column chromatography afforded the pure 3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-yl-propyl]-6-(3-acetoxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one (1-A26) (0.3 gm, 31%). 1HNMR (CDCl3, 200 MHz): 1.96-2.10 (m, 2H), 2.06 (s, 3H), 2.92 (t, J=8 Hz, 2H), 4.11 (t, J=6 Hz, 2H), 4.27 (d, J=14 Hz, 1H), 4.60 (d, J=14 Hz, 1H), 4.73 (d, J=14 Hz, 1H), 4.85 (d, J=14 Hz, 1H), 6.74-6.92 (m, 2H), 7.10 (s, 1H), 7.45-7.59 (m, 1H), 7.91 (bs, 1H), 7.95 (s, 1H), 8.36 (bs, 1H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[C:17]([NH:24][C@H:25]([C:27](O)=[O:28])[CH3:26])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].Cl.C(N=C=N)C.ON1C2C=CC=CC=2N=N1.[Li+].[OH-].Cl>CN(C)C=O.C(OCC)(=O)C.O1CCCC1.O.CO>[C:20]([O:19][C:17]([NH:24][CH:25]([CH3:26])[C:27]([NH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:28])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CCCN
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)NCCCC(=O)O
Yield: 72 %

Procedure:
A solution of triethylamine (3.1 mL, 1.1 equivalent) and methyl 4-aminobutyrate hydrochloride (3.2 g, 1.05 equivalent) in 25 ml of anhydrous N,N-dimethylformamide was stirred at −10° C. under N2 atmosphere for 10 minutes. Sequential addition of Boc-L-alanine (3.8 g, 1.0 equivalent), N-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.2 g, 1.1 equivalents), 1-hydroxybezotriazole (1.8 g, 0.6 equivalent), and 15 mL of anhydrous N,N-dimethylformamide was carried out at the same temperature. The final solution was stirred under N2 atmosphere at room temperature overnight and diluted with ethyl acetate. The resulting solution was washed sequentially with 1 M HCl(aq), saturated NaHCO3(aq), and saturated NaCl(aq), followed by a rapid filtration through a pad of silica gel and Na2SO4. The filtrate was concentrated and dried under reduced pressure to give a crude paste (4.8 g). The paste was stirred in a mixture of 50 mL of tetrahydrofuran, 25 mL of methanol, and 20 mL of water with the presence of LiOH (0.45 g, 1.1 equivalents) for 1 hour at room temperature. The solution was acidified with concentrated HCl and extracted with ethyl acetate. The organic extracts were combined and washed with saturated NaCl(aq) and rapidly filtered through a pad of silica gel and Na2SO4. The filtrate was concentrated and dried under reduced pressure to give 4-(2-t-butoxycarbonylamino-propionylamino)butyric acid as a paste (4.0 g, 72% yield); H1-NMR (DMSO-d6), δ=1.1 ppm (d, 3H), 1.3 ppm (s, 9H), 1.6 ppm (p, 2H), 2.2 ppm (t, 2H), 3.0 ppm (m, 2H), 3.8 ppm (m, 1H), 6.8 ppm (d, 1H), 7.8 ppm (t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([F:22])[F:21])=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:23]=1.C[O-].[Na+].C([NH2:29])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH:20]([F:21])[F:22])=[C:14]([C:16]([NH2:29])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:23]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1C(F)F)C1CC(C1)c1ccc(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: NC(=O)c1nc2n(c1C(F)F)C1CC(C1)c1ccc(Br)cc1-2
Yield: 100 %

Procedure:
10-bromo-3-(difluoromethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L Methyl 10-bromo-3-(difluoromethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 70.2 mg (100% yield) of the crude title compound which was carried forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](O)=[O:14])=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:21][NH:22][CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([N:22]([CH3:23])[CH3:21])=[O:14])=[C:11]([CH3:16])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1onc(-c2ccc(Cl)cc2)c1C(=O)N(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To 3-(4-chlorophenyl)-5-methylisoxazol-4-carboxylic acid (25 mg, 0.10 mmol) was added thionyl chloride (1 mL) and the neat solution allowed to stir 60° C. After 30 min, excess thionyl chloride was evaporated and dimethyl amine (40 μL, 0.08 mmol, 2 M in THF) was added and allowed to stir overnight at ambient temperature. The residue was purified using reversed phase HPLC to afford the title compound (5 mg). HRMS (ESI, pos. ion) m/z calcd for C13H13ClN2O2: 264.0666, found 264.0671.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][C:14]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:11])[CH3:10]>C(Cl)(Cl)Cl>[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:2]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH3:1])=[CH:15][C:14]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(CBr)cc1C(C)(C)C
Reactant: CNC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(CN(C)C2CCCCC2)cc1C(C)(C)C

Procedure:
48 gm of N-methyl-cyclohexylamine were added to 56 gm of 4-acetylamino-3-tert.butyl-benzyl bromide in 500 ml of chloroform, and the mixture was refluxed for 1.5 hours. Subsequently, the reaction mixture was extracted three times with water, and the organic phase was evaporated. The residue was purified column-chromatography on silicagel with chloroform/methanol (5:1), and 4-acetylamino-3-tert.butyl-N-cyclohexyl-N-methyl-benzylamine hydrochloride, m.p. 240°-243° C (decomp.), was crystallized from a solution of the purified base in absolute ethanol/ether by addition of absolute ethanolic hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:18])[NH:15][CH2:16][CH2:17][C:12]=3[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:26][CH2:27][C:28]#[N:29]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[C:14](=[O:18])[N:15]([CH2:26][CH2:27][C:28]#[N:29])[CH2:16][CH2:17][C:12]=3[C:11]([C:19]([F:22])([F:20])[F:21])=[N:10]2)=[CH:7][CH:8]=1
Reactant: N#CCCBr
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)NCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCC#N)CC3)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
1-(4-Methoxy-phenyl)-3-trifluoromethyl-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (1.00 g, 3.213 mmol) was dissolved in N,N-dimethylformamide (75 mL) and cooled to 0° C. Sodium hydride (60%, 0.321 g, 8.032 mmol) was added followed by 3-bromopropionitrile (0.533 mL, 6.425 mmol). The reaction was stirred at rt overnight, quenched with 1N hydrochloric acid (250 mL), extracted with ethyl acetate (3×200 mL), washed with water (2×200 mL), washed with brine (1×200 mL), dried over MgSO4, concentrated, and purified by flash chromatography using 0–100% ethyl acetate/hexanes gradient as the eluent to afford the title compound (1.03 g, 88%): Mass Spec 382.4(M+H+H2O)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23].Cl>O1CCCC1>[Cl:20][CH2:21][C:22]([NH:4][C:3]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:2]=1[CH3:1])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C)c(N)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C)c(NC(=O)CCl)c1
Reaction time: 27 h

Procedure:
To a solution of 2-methyl-5-methoxyaniline (4.7 g) in tetrahydrofuran (50 ml), under nitrogen, was added diisopropylethylamine (12.6 ml) followed by dropwise addition of chloroacetyl chloride (2.7 ml) and the mixture stirred under nitrogen for 27 hours. The solution was poured into 2M aqueous hydrochloric acid (150 ml), extracted into diethyl ether (3×150 ml), washed with brine, dried (MgSO4), and concentrated to give the sub-title compound as a brown oil (5.15 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][C:3]=1[O:13]C.N[C:16]1C=CC(O)=C(C)C=1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([CH3:16])=[C:3]([OH:13])[CH:4]=2)[N:9]=1
Reactant: Cc1cc(N)ccc1O
Reactant: COc1cc2ccc(C)nc2cc1Cl
Product: Cc1ccc2cc(O)c(C)cc2n1

Procedure:
Compound 2B was prepared following the procedure used to prepare compound 1B of Example 1, except that 4-amino-2-methylphenol (2A) was used instead of compound 1A. LCMS-ESI+ (m/z): 174.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:47]1[CH:52]=[C:51]([O:53][C@@H:54]([C@H:56]2[CH2:60][O:59][C:58]([CH3:62])([CH3:61])[O:57]2)[CH3:55])[N:50]=[C:49]([S:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[C:66]=2[F:72])[N:48]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:72][C:66]1[C:67]([F:71])=[CH:68][CH:69]=[CH:70][C:65]=1[CH2:64][S:63][C:49]1[N:48]=[C:47]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:52]=[C:51]([O:53][C@@H:54]([C@H:56]2[CH2:60][O:59][C:58]([CH3:61])([CH3:62])[O:57]2)[CH3:55])[N:50]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1

Procedure:
A mixture of methanesulfonamide (0.11 g), tris(dibenzylideneacetone)dipalladium (0) (26 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (14 mg), cesium carbonate (0.14 g) and 4 chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-pyrimidine (the subtitle product of example 45 step v) (0.12 g) in dioxane (6 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 15 min. Saturated aqueous ammonium chloride was added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (1:19 to 3:7 gradient) as eluent to give the subtitle compound as a yellow oil. Yield: 0.12 g.