Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][CH2:33][CH:34]([NH2:37])[CH2:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:33]([CH:34]([NH:37][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)=[CH:26][CH:25]=1)[CH2:35][CH3:36])[CH3:32]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: CCC(N)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCC(CC)NCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (40 mg, 0.09 mmol) in DMSO (900 μL) and acetic acid (2 drops) was added 3-pentanamine (108 μL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 34.5 mg of the title compound (74%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=3)[O:8][C:7](=[O:28])[C:6]=2[CH:5]=[C:4]2[NH:29][CH:30]=[N:31][C:3]=12.[CH3:32][NH2:33]>>[CH3:32][NH:33][C:7]([C:6]1[C:11]([NH:10][C:9]([C:12]2[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:16]=2)=[O:8])=[C:2]([Cl:1])[C:3]2[N:31]=[CH:30][NH:29][C:4]=2[CH:5]=1)=[O:28]
Reactant: CN
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nc[nH]c3cc12
Product: CNC(=O)c1cc2[nH]cnc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Yield: 26 %

Procedure:
See example H3 using 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1H-7-oxa-1,3,5-triaza-cyclopenta[b]naphthalen-8-one as starting material and 3 equivalents of methylamine (40% in H2O). A white solid is obtained within 26% yield. m.p.: 190-192° C.; LC/MS: 498/500 (M+1)+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>ClCCl>[CH2:16]([O:15][C:13](=[O:14])[NH:4][CH:1]1[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)OCc1ccccc1
Reaction time: 2 h
Yield: 587.7 %

Procedure:
To a solution of cyclopropylamine (5.0 g, 87.5 mmol) and triethylamine (30 mL) in dichloromethane (100 mL) at 0° C. was added dropwise benzyl chloroformate (15.0 mL, 10.5 mmol) and the resulting mixture was stirred for 2 h. Additional benzyl chloroformate (1 mL) was added and the resulting reaction mixture was stirred overnight. The reaction was then quenched by addition of a saturated NaHCO3 and the separated aqueous phase was extracted several times with dichloromethane. The combined dichloromethane extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (15% EtOAc to 5% MeOH/EtOAc) to give cyclopropyl-carbamic acid benzyl ester (11.8 g, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](N)=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].N(OCCC(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccccc2)c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
3-Amino-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (64.8 g) synthesized in Reference Example 15 was dissolved in tetrahydrofuran (500 mL), isoamyl nitrite (98.5 g) was added, and the mixture was stirred at 65° C. for 3 hr. After cooling, the reaction mixture was concentrated under reduced pressure. Hexane (500 mL) was added to the residue, and the residue was washed by suspending and filtered. The obtained solid was vacuum dried to give the title compound (43.0 g) as a white solid.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:7]=[C:8]([F:19])[C:9]=1[N:10]1[CH2:16][C:15](=[N:17][OH:18])[C:12]2([CH2:14][CH2:13]2)[CH2:11]1.[CH2:31](Br)[CH3:32]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:7]=[C:8]([F:19])[C:9]=1[N:10]1[CH2:16][C:15](=[N:17][O:18][CH2:31][CH3:32])[C:12]2([CH2:13][CH2:14]2)[CH2:11]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CC(=NO)C4(CC4)C3)c(F)c2)C(=O)O1
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCON=C1CN(c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC12CC2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
While being maintained at 0° C., KOH (0.13 g, 2.4 mmol) was added to a solution of the (S)—N-{{3-[3,5-difluoro-4-(7-hydroxydimono?-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}methyl}acetamide (0.8 g, 1.4 mmol) obtained in Example 3 in 10 mL of DMF, and then slowly droplets of ethyl bromide (0.4 mL, 5.6 mmol) were added with stirring for 3 hours. After the reaction terminated, the reaction mixture was poured into cold water and extracted with ethyl acetate. The organic phase was washed with water and brine and dehydrated over anhydrous magnesium sulfate. Purification through flash column chromatography (n-hexane/ethyl acetate=1:4) afforded the target compound in a white pure form (0.52 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16](OC)=O>>[CH3:12][O:13][C:14](=[O:20])[CH2:15][C:16]1[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[N:11]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1ccncc1S(N)(=O)=O
Product: COC(=O)CC1=NS(=O)(=O)c2cnccc2N1
Temperature: 180 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
4-amino-pyridine-3-sulfonic acid amide (0.25 g, 1.44 mmol) was suspended in malonic acid dimethyl ester (5 mL, 43.75 mmol). The flask was purged with nitrogen and the mixture was stirred at 180° C. for 60 min. Upon cooling, the mixture was diluted with ethyl acetate (5 mL) causing immediate precipitation of an undesired side product. The solid was removed by vacuum filtration and rinsed with ethyl acetate (2 mL). The filtrate was passed through a plug of silica gel, eluting with ethyl acetate followed by 5% methanol in ethyl acetate. The fractions containing the 5% methanol in ethyl acetate were combined and concentrated in vacuo to afford the desired product, (1,1-dioxo-1,4-dihydro-1λ6-pyrido[4,3-e][1,2,4]thiadiazin-3-yl)-acetic acid methyl ester (0.135 g, 0.529 mmol, 37%) as a yellow oil. LC-MS (ESI) calculated for C9H9N3O4S 255.03, found 256.0 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][N:43]1[C:48]2[CH:49]=[CH:50][C:51]([S:53](Cl)(=[O:55])=[O:54])=[CH:52][C:47]=2[O:46][CH2:45][CH2:44]1>C(#N)C>[CH3:42][N:43]1[C:48]2[CH:49]=[CH:50][C:51]([S:53]([O:1][C:2]3[CH:10]=[CH:9][C:8]([C:11]4[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]5[C:18]([CH:19]=4)=[CH:17][C:16]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:15][CH:14]=5)=[C:7]4[C:3]=3[CH2:4][NH:5][C:6]4=[O:34])(=[O:55])=[O:54])=[CH:52][C:47]=2[O:46][CH2:45][CH2:44]1
Reactant: CN1CCOc2cc(S(=O)(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCOc2cc(S(=O)(=O)Oc3ccc(-c4cc5cc(CN6CCCCC6)ccc5n4C(=O)OC(C)(C)C)c4c3CNC4=O)ccc21
Yield: 58 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0324 g, 0.0702 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0590 mL, 0.421 mmol) and 3,4-dihydro-4-methyl-1,4-benzoxazine-7-sulfonyl chloride (0.0520 g, 0.211 mmol) to obtain 4-(3,4-dihydro-4-methyl-1,4-benzoxazin-7-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0274 g, yield 58%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH:8]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[NH:6][C:5]=2[N:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1.[CH:37]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:27]([O:26][C:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[CH:14]=[CH:13][C:12]([C:7]3[N:6]=[C:5]4[N:4]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:3]=[C:2]([CH3:1])[C:10]4=[C:9]([O:11][CH3:37])[CH:8]=3)=[CH:17][CH:16]=2)[CH2:23][CH2:22]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: Cc1nn(-c2ccccc2)c2[nH]c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc(=O)c12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc2c1c(C)nn2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 50 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-(4-(3-methyl-4-oxo-1-phenyl-4,7-dihydro-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)piperazine-1-carboxylate (330 mg, 0.87 mmol, 1.00 equiv) in tetrahydrofuran (15 mL), PPh3 (488 mg, 1.86 mmol, 2.20 equiv), MeOH (36 mg, 1.12 mmol, 1.10 equiv). To the resulting mixture was then added DEAD (237 mg, 1.36 mmol, 2.00 equiv) dropwise with stirring at 0-5° C. The resulting solution was stirred for 30 min at room temperature. The reaction was then quenched by the addition of water (5 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers combined. The resulting mixture was washed with water (1×3 mL). The resulting mixture was dried over anhydrous magnesium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (PE-1:100) to yield 4-[4-(4-methoxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester as a white solid. MS (m/z): 500 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:30])=[CH:25][CH:24]=1
Reactant: OC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc(Cl)cc3)CC2)cc1

Procedure:
0.25 g (0.0011 mol) of 1-(4-chloro-benzyl)-piperidin-4-ol and 0.39 ml (0.0028 mol) of triethylamine were dissolved in 11 ml of toluene, treated with 0.184ml (0.0014mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.135 9 (39%) of 1-(4-chloro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=C)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC[O:24]C(C)=O>CC(O)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]=[O:24])[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
4-Allyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.97 g, 10 mmol) was dissolved in iPrOH (50 mL) and H2O (10 mL). To this was added a aqueous solution of NaIO4 (4.68 g, 21.8 mmol) in water (40 mL), followed by addition of OsO4 (8.4 mg, crystals, in one portion) at rt. The solution was stirred at rt. After 30 min, milky cloudy formed. Stirring was continued overnight. TLC and LC/MS did not detect the SM, but it was still very milky. The reaction mixture was poured into ice water (20 mL) and EtOAc (30 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (3×15 mL). The combined extracts were washed with brine, and concentrated to dryness to obtain a liquid. The liquid was subject to a distillation under reduced pressure to remove isopropanol. The remaining liquid was purified on a 50 g silica gel column, eluted with MeOH in DCM (0-5%). Note: the product is not UV active. Anisaldehyde visualization was used. The product fractions were collected and concentrated to yield 1.03 g (34% yield) of the title compound as a liquid.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[Li]CCCC.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[CH2:1]([S:4][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:2][CH3:3]
Reactant: CCOC(=O)CCCCCBr
Reactant: CCCS
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCSCCCCCC(=O)OCC
Reaction time: 0.17 h

Procedure:
A solution of propanethiol (0.609 ml, 6.72 mmol) in anhydrous THF (10 ml) was cooled to −10° C. in a nitrogen atmosphere. 2 M nBuLi (4.03 ml, 8.07 mmol) was added dropwise and the mixture was then stirred for 10 minutes. A solution of ethyl 6-bromohexanoate in anhydrous THF (5 ml) was then added and the mixture was stirred for 40 minutes. The reaction mixture was quenched by adding water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was then purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give ethyl 6-(propylthio)hexanoate as a colorless oily substance (1.46 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].Cl[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 94.9 %

Procedure:
To a solution of 5.0 g (0.0307 moles) of 2,4-dichlorophenol dissolved in 150 ml of DMSO was added 1.23 g (0.0307 moles) of NaOH. The slurry was heated at 60° C. for 15 minutes and 5.04 g (0.0276 moles) of 2-chloro-5-nitrobenzonitrile was added. The mixture was heated at 75° C. for 3.25 hrs. The reaction mixture was cooled and poured into water. The product was collected by filtration, washed well with water and dried, yielding 8.1 g of product (95.3% yield). Recrystallization from ethanol afforded purified 2-(2,4-dichlorophenoxy)-5-nitrobenzonitrile, mp 153.5°-154.5° C.
Reaction SMILES: [NH2:1][CH:2]([C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:14][C:15]1[CH:16]=[C:17]2[C:23]([C:24]3[N:29]=[C:28](S(C)=O)[C:27]([F:33])=[CH:26][N:25]=3)=[CH:22][N:21]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:18]2=[N:19][CH:20]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:33][C:27]1[C:28]([NH:1][CH:2]([C:9]([CH3:12])([CH3:13])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:29][C:24]([C:23]2[C:17]3[C:18](=[N:19][CH:20]=[C:15]([F:14])[CH:16]=3)[N:21]([S:34]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:22]=2)=[N:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(F)cnc32)cc1
Reactant: CCOC(=O)CC(N)C(C)(C)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)CC
Temperature: 80 °C

Procedure:
To a suspension of ethyl 3-amino-4,4-dimethylhexanoate, 27a, (0.19 g. 1.00 mmol) and 5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p- olylsulfonyl)pyrrolo[2,3-b]pyridine, 25a, (0.54 g, 1.20 mmol) in THF (14.4 mL) was added N,N-diisopropylethylamine (0.26 mL, 1.50 mmol). The mixture was refluxed at 80° C. overnight. After removing the solvents under reduced pressure, the crude product was purified by silica gel chromatography (0-50% EtOAc/Hexane gradient) to afford 155 mg of the desired product as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.61 (dd, J=9.0, 2.9 Hz, 1H), 8.56 (s, 1H), 8.33 (dd, J=2.7, 1.0 Hz, 1H), 8.11 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.19 (dd, J=10.1, 2.2 Hz, 1H), 4.94 (td, J=10.0, 3.7 Hz, 1H), 3.99 (dt, J=13.7, 6.8 Hz, 2H), 2.40 (s, 3H), 1.42 (dt, J=14.1, 6.9 Hz, 2H), 1.05 (t, J=7.1 Hz, 3H), 1.01-0.94 (m, 8H); 19F NMR (282 MHz, CDCl3) δ −130.39-133.75 (dd, J=9.0, 1.1 Hz, 1F), −158.56 (s, 1F); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=4.18 minutes (M+H) 572.07.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].O.C1COCC1.C(=O)(O)[O-].[Na+].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O>[CH2:29]([O:28][C:26]([N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:27])[CH3:30]
Reactant: COC(=O)CCNCc1cccs1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N(CCC(=O)OC)Cc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Compound 1040 (35.2 g, 176.6 mmol) in 1:1 water/THF (1. L) was added solid sodium bicarbonate (32.6 g, 388.6 mmol) and ethyl chloroformate (20.3 mL, 212.0 mmol). The reaction was stirred at room temperature overnight, at which point LCMS indicated complete disappearance of starting material. The reaction mixture was diluted with water, extracted with ethyl acetate, and the volatiles removed under reduced pressure to give methyl 3-(ethoxycarbonyl(thiophen-2-ylmethyl)amino)propanoate as a pale yellow oil (Compound 1041, 19.9 g, 41%); 1H NMR (300 MHz, CDCl3): δ 7.20-7.12 (m, 1H), 6.94-6.83 (m, 2H), 4.56 (s, 2H), 4.10 (td, J=14.5, 7.3 Hz, 2H), 3.52 (s, 3H), 3.46 (t, J=6.6 Hz, 2H), 2.47-2.39 (m, 2H), 1.97 (s, H) and 1.24-1.15 (m, 3H) ppm. The aqueous layer contained some 3-(ethoxycarbonyl(thiophen-2-ylmethyl)amino)propanoic acid (Compound 1042) resulting from hydrolysis of the methyl ester. Compound 1042 could be isolated by adjusting the pH of the aqueous layer to 2 with 6M HCl followed by extraction with 10% n-BuOH in chloroform, which after concentration gave the carboxylic acid as a pale yellow oil (17.33 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C@@H:55]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:56]([NH:58][CH3:59])=[O:57]>CN(C=O)C>[CH3:61][C:60]([CH3:63])([CH3:62])[C@H:55]([NH:54][C:12]([C:10]1[CH:9]=[N:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:56](=[O:57])[NH:58][CH3:59]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 8.7 %

Procedure:
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 0.1 g, 35 mmol) was suspended in DMF (3 mL). HBTU (266.14 mg, 0.7 mmol), DIEA (0.31 mL, 1.75 mmol) and (S)-2-amino-3,3,N-trimethyl-butyramide (CAN 89226-12-0, 52.82 mg, 0.42 mmol) were added and the reaction mixture was stirred at ambient temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Gemini-NX-C18, 5 μ, 30×100 mm/acetonitrile/0.1% ammonia in water) to give the desired product (15 mg, 10.39%) as white solid; LC-MS (UV peak area, ESI) 96.48%, 412.6 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[Cl:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2][NH:1][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(CNS(C)(=O)=O)c1ccccc1Cl

Procedure:
A solution of 330 mg (1.15 mmol) of the compound from Example 113A in 7 ml of pyridine was admixed at RT with 177 μl (2.29 mmol) of methanesulphonyl chloride. After 1 h the volatile constituents were removed on a rotary evaporator. The residue is purified by preparative HPLC [Method 23]. The product fraction was freed from the solvents on a rotary evaporator. Drying of the residue in an HV gave 312 mg (78% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:69])[NH:67][CH3:68])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)NC
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1cccc2ccccc12)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
(2-tert-Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.14 g; 0.54 mmol)(prepared as in example 33) was dissolved in methylene chloride (1 0 mL). 1-Hydroxy-7-azabenzotriazole (0.07 g; 0.54 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)-3-(1-naphthyl) propionamide (0.21 ; 0.54 mmol) was dissolved in methylene chloride (10 mL) and added. The reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (10 mL) was added. The reaction mixture was washed with water (30 mL), an aqueous solution of sodium hydrogen sulfate (10%; 20 mL) and an aqueous solution of sodium hydrogen carbonate (saturated; 20 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2×20 cm) using methylene chloride/ethyl acetate (1:1) as eluent to afford 0.27 g of (1,1-dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(1-naphthyl)ethyl)carbamoyl)methoxy)ethyl)carbamic acid tert butylester.