Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:10]=[C:11]([CH:35]([CH3:37])[CH3:36])[C:12]2[O:16][C:15]([C:17]3[CH:33]=[CH:32][C:20]([C:21]([NH:23][CH2:24][C@H:25]4[O:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:22])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:34]=1)#[N:8].Br[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=1>CO>[C:7]([C:9]1[CH:10]=[C:11]([CH:35]([CH3:37])[CH3:36])[C:12]2[O:16][C:15]([C:17]3[CH:33]=[CH:32][C:20]([C:21]([NH:23][CH2:24][C@H:25]4[O:31][CH2:30][CH2:29][N:28]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=5)[CH2:27][CH2:26]4)=[O:22])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:34]=1)#[N:8]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCNCCO4)cc3)oc12
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CCN(Cc5cccc(C(F)(F)F)c5)CCO4)cc3)oc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a mixture of 36 mg of potassium carbonate in methanol (3 ml) was added 37 mg of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-[(7S)-1,4-oxazepan-7-ylmethyl]benzamide (INTERMEDIATE 20) followed by 1-(bromomethyl)-3-(trifluoromethyl)benzene (13 μl). The mixture was heated to 70° C. and stirred for 8 h, and then cooled and added directly to a 40M samplet for purification via column chromatography on a Biotage Horizon 40M column, eluting with 1 column volume of 100% hexanes, followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 4 column volumes of 100% ethyl acetate, to provide the title compound (28 mg, 56%). Mass spectrum (ESI) 577.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.4 Hz, 2H), 7.96 (d, J=6.0 Hz, 2H), 7.94 (s, 1H), 7.61 (s, 1H), 7.52 (m, 3H), 7.44 (t, J=7.5 Hz, 1H), 6.65 (bs, 1H), 3.96 (m, 2H), 3.81 (m, 2H), 3.70 (s, 2H), 3.68 (m, 2H), 3.48 (sept, J=7.0 Hz, 1H), 3.25 (m, 1H), 2.74 (m, 2H), 2.01 (m, 1H), 1.82 (m, 1H), 1.46 (d, J=7.0 Hz, 6H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([C:25](=[O:43])[C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:41])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:28][C:27]=3[CH3:42])[CH2:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.[I-].[Na+].[C:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:49])[CH3:48].Cl>CN(C)C=O.C(OCC)C>[ClH:24].[C:47]([N:50]1[CH2:55][CH2:54][N:53]([CH2:11][CH2:12][CH:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([C:25](=[O:43])[C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:41])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:28][C:27]=3[CH3:42])[CH2:16][CH2:15][CH2:14]2)[CH2:52][CH2:51]1)(=[O:49])[CH3:48]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)cc1
Reactant: CC(=O)N1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.5 %

Procedure:
To a solution of 5-[2-(p-toluenesulfonyloxy)ethyl]-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.25 g) in dry dimethylformamide (20 ml) are added sodium iodide (0.178 g) and 4-acetylpiperazine (0.152 g), and the mixture is stirred at room temperature for one hour. The mixture is heated at 50° C. for 2 hours, and further at 60° C. for 3 hours. To the reaction solution are added 1N-hydrochloric acid and diethyl ether, and the aqueous layer is collected and neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The dichloromethane layer is washed with water, dried, and the solvent is distilled off. To the resulting residue is added hydrochloric acid/ethanol to give 5-[2-(4-acetyl-1-piperazinyl)ethyl]-7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride (150 mg) as colorless amorphous.
Reaction SMILES: [I:1][CH3:2].[CH:3]([O:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][C:14]=2[O:23][CH3:24])=[C:11]([C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)[CH:10]=[CH:9][CH:8]=1)([CH3:5])[CH3:4]>CS(C)=O.CCOCC>[I-:1].[CH:3]([O:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][C:14]=2[O:23][CH3:24])=[C:11]([C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N+:29]=2[CH3:2])[CH:10]=[CH:9][CH:8]=1)([CH3:5])[CH3:4]
Reactant: CI
Reactant: COc1cc(OC(C)C)ccc1-c1c(OC(C)C)cccc1C1=NC(C)(C)CO1
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1cc(OC(C)C)ccc1-c1c(OC(C)C)cccc1C1=[N+](C)C(C)(C)CO1
Product: [I-]
Reaction time: 72 h

Procedure:
Add iodomethane (12.43 g, 0.0875 mole) to a stirred solution of 2-(6,4'-diisopropyloxy-2'-methoxy-biphenyl-2-yl)-4,4-dimethyloxazoline (5.80 g, 0.0146 mole) in dry DMSO (30 mL). Stir the resulting mixture for about 72 hours, then dilute with ether (600 mL). Collect the precipitated solid by filtration, then triturate with CHCl3 (400 mL) and filter. Discard the insoluble solid and concentrate the filtrate to obtain the title compound as an off-white solid. m.p. 213°-214° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:12])[CH2:8][CH2:9][CH2:10][OH:11].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.O>CN(C)C=O.CN(C1C=CC=CN=1)C>[CH3:14][C:13]([Si:17]([CH3:19])([CH3:18])[O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[OH:12])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCC(O)c1ccccn1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCC(O)c1ccccn1
Yield: 51.8 %

Procedure:
A solution of the product from step (a) (0.67 g), tert-butylchlorodimethylsilane (0.6 g), triethylamine (0.56 ml) and dimethylaminopyridine (0.01 g) in dimethylformamide (5 ml) was stirred for 2hat 0° C. and at 20° C. for 16 h. Water was added and the mixture was extracted with ethyl acetate (three times). The combined organic extracts were washed with water, dried (sodium sulphate), evaporated and purified by chromatography on silica eluting with petrol-acetone to give the sub-title compound as a colourless oil (0.58 g).
Reaction SMILES: [NH:1]([C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[C@H:2]([C:28]([N:30]([CH3:60])[C@H:31]([C:47]([NH:49][CH2:50][CH2:51]OCC1C=CC=CC=1)=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)=[O:29])[CH2:3][C:4]1[N:8]=[CH:7][N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=1.C(O)(C(F)(F)F)=O.C(OCC)C.[CH3:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88]>C(Cl)Cl>[CH2:64]([O:63][C:61](=[O:62])[NH:1][CH:2]([C:28](=[O:29])[N:30]([CH:31]([C:47](=[O:48])[NH:49][CH2:50][CH2:51][C:85]1[CH:84]=[CH:83][CH:88]=[CH:87][CH:86]=1)[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:35][CH:34]=1)[CH3:60])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: CCCCCC
Reactant: CN(C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCOCc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)C(Cc1c[nH]cn1)NC(=O)OCc1ccccc1)C(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cbz-His(Trt)-NMe-Tyr(OBn)-NH—CH2—CH2-OBn (from Step 3, 0.5 g, 0.55 mmol) was treated with 50 mL of 50% TFA in methylene chloride. The solution was stirred at room temperature for 2 hours. The solvent was reduced in volume and diethyl ether/hexane (200 mL) was added to the residue. The solution was cooled to −40° C. overnight. The ether/hexane was decanted and the residue dried in vacuo. Purification was carried out by reverse-phase preparative HPLC (C-18) reverse-phase column, 20% to 60% of 0.1% TFA in acetonitrile against 0.1% TFA in water, 100 minutes, 13 mL/min) to give 37.5 mg of a white foam; MS-ES 661 (m+1).
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:10][C:11](=[O:13])[CH3:12])(=O)[CH3:8].[CH3:14][C@H:15]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:16]/[CH:17]=[CH:18]/C(O)C>>[C:11]([O:10][CH:7](/[CH:18]=[CH:17]/[CH2:16][C@H:15]([CH3:14])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:8])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCC[C@@H](C)C/C=C/C(C)O
Solvent: c1ccncc1
Product: CC(=O)OC(C)/C=C/C[C@H](C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A flame-dried, 250 mL, three-necked flask containing a magnetic stirring bar was charged under argon with 7.9 g (8.1 mL, 0.10 mol) of dry pyridine. After cooling in an ice-bath, 10.2 g (9.4 mL, 0.10 mol) of acetic anhydride and then 10.0 g (0.051 mol) of (2RS,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol were added dropwise, and the reaction was stirred for 2 hours at 0° C. and then overnight at 20° C. The reaction mixture was poured onto 2N HCl/ice and extracted with 2×200 mL of ether. The combined extracts were washed with 2N HCl, sat. NaHCO3 solution, and brine, dried over Na2SO4, filtered and evaporated. Kugelrohr distillation at ca. 105°-130° C./0.1 mmHg afforded 12.05 g (99%) of (2RS,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol acetate as colorless liquid. Calcd. for C15H26O 2 (238.4): C, 75.58; H, 10.99; Found: C, 75.47; H, 11.04%. [α]D25 =-2.16° (2.04% in CHCl3).
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[N:27]=[C:20]3[C:21]([CH3:26])=[N:22][CH:23]=[C:24]([CH3:25])[N:19]3[N:18]=2)=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:25][C:24]1[N:19]2[N:18]=[C:17]([C:3]3[C:2]([C:28]#[N:29])=[CH:7][N:6]4[CH:8]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:10]=[C:5]4[CH:4]=3)[N:27]=[C:20]2[C:21]([CH3:26])=[N:22][CH:23]=1
Reactant: CN(C)C=O
Reactant: Cc1ncc(C)n2nc(-c3cc4nc(-c5ccccc5)cn4cc3Br)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ncc(C)n2nc(-c3cc4nc(-c5ccccc5)cn4cc3C#N)nc12
Reaction time: 1.25 h

Procedure:
A 2-dram pressure rated scintillation vial was charged with 2-(6-bromo-2-phenylimidazo[1,2-a]pyridin-7-yl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (20 mg, 0.048 mmol) and suspended in DMF (477 mL). To that stirring solution was added zinc cyanide (5.60 mg, 0.048 mmol). The vial was sealed and degassed using dry argon and sonication for 1 minute. Tetrakis(triphenylphosphine)palladium(0) (16.5 mg, 0.014 mmol) was then added in one portion. The vial was resealed, flushed with argon, and placed in a reaction block preheated to 90° C. After 1.25 hours, LCMS showed complete conversion of starting material to a major peak with the desired product (m/z=366 [M+H]+). Upon cooling, a solid began to form. The crude material was purified by HPLC method 10. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (1H, s), 8.65 (1H, s), 8.46 (1H, s), 8.14 (1H, s), 8.09 (2H, d, J=7.28 Hz), 7.50-7.56 (2H, m), 7.40-7.46 (1H, m), 2.88 (3H, s), 2.78 (3H, s). Mass found 366 [M+H]+.
Reaction SMILES: [C:1]1(B(O)O)[C:9]([CH3:10])=[C:7]([CH3:8])[CH:6]=[C:4]([CH3:5])[C:2]=1[CH3:3].[CH2:14](O)[CH2:15][CH2:16]O.Br[C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][C:26](Br)=[CH:27][CH:28]=3)[C:23]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:22]=2[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>O.C1(C)C=CC=CC=1>[CH3:3][C:2]1[C:4]([CH3:5])=[CH:6][C:7]([CH3:8])=[C:9]([CH3:10])[C:1]=1[C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][C:26]([C:14]4[C:4]([CH3:5])=[C:2]([CH3:3])[CH:1]=[C:9]([CH3:7])[C:15]=4[CH3:16])=[CH:27][CH:28]=3)[C:23]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:22]=2[CH:21]=1
Reactant: Cc1cc(C)c(C)c(B(O)O)c1C
Reactant: OCCCO
Reactant: CCCCCCCC1(CCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCC1(CCCCCCC)c2cc(-c3c(C)c(C)cc(C)c3C)ccc2-c2ccc(-c3c(C)c(C)cc(C)c3C)cc21
Temperature: 110 °C

Procedure:
0.04 mol of durylboronic acid is initially charged in a 1-liter 3-neck flask with 600 ml of toluene, admixed with 0.04 mol of propane-1,3-diol and heated on a water separator until no further water is separated out. Afterward, the water separator is removed and replaced by a reflux condenser, and 0.01 mol of 2,7-dibromo-9,9-diheptylfluorene and 11.6 g of potash dissolved in 42 ml of water are added to the reaction mixture. The flask is then repeatedly evacuated under reduced pressure and flooded with argon in order to add the catalyst, tetrakis(triphenylphosphine)palladium. Finally, the mixture is heated to 110° C. for 48 h and purged with argon during this time. For workup, the organic phase is washed repeatedly with water, extracted and concentrated to dryness. The residue is washed in methanol and filtered off with suction. The crude product is purified by chromatography on silica gel by means of cyclohexane.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([NH:16][C@H:17]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>>[NH2:1][C@H:2]([C:14]([NH:16][C@H:17]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[F:42][C:43]([F:48])([F:47])[C:44]([O-:46])=[O:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Product: O=C([O-])C(F)(F)F

Procedure:
Boc-L-Asp(OBzl)-L-Phe-OBzl (9.91 g) was dissolved in a mixture of trifluoroacetic acid (50 ml) and dichloromethanie (50 ml). The resultant solution was stored at room temperature for 2 hr. The reaction mixture was evaporated to dryness to yield a residue which was triturated with ether, collected, washed thoroughly with ether and dried under high vacuum to yield L-Asp(OBzl)-L-Phe-OBzl, trifluoroacetate salt (8.36 g) as a white solid: NMR (CDCl3) δ 2.88(2H,m), 3.07(2H,m), 4.33(1H,m), 4.78(1H,m), 5.02(2H,s), 5.06(2H,q), 6.20(3H,vbr), 7.04(2H,m), 7.26(13H,m), 7.65(1H,d); m/Z 461 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:11]=[CH:12]N(C)C)=[CH:7][N:6]=1)=[O:4].Cl.[OH2:17].[Cl-].[Na+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:12]=[O:17])=[CH:7][N:6]=1)=[O:4]
Reactant: O
Reactant: COC(=O)c1cnc(C=CN(C)C)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1cnc(CC=O)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A solution of 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylic acid methyl ester (prepared as in Example 41, 600 mg, 2.9 mmol) in benzene (5 mL) was treated with a solution of a 1M aqueous hydrochloric acid solution (5 mL) and water (5 mL) and then stirred vigorously at 50° C. for 60 min. The mixture was cooled and then treated with sodium chloride (2 g). The mixture was extracted with benzene (3×25 mL). Each extract was washed with a saturated aqueous sodium chloride solution (2×20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(2-oxo-ethyl)-pyrazine-2-carboxylic acid methyl ester (295 mg, 56%) as yellow crystals.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[N:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[CH3:45]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:39]4[CH:40]=[CH:41][N:36]=[C:37]([CH3:45])[CH:38]=4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:28]([N:30]2[CH2:33][C:32]([F:35])([F:34])[CH2:31]2)=[O:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: Cc1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CC(F)(F)C4)C3)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared in analogy to Example 120 using (1R,2R,4R)-4-(4-Bromo-2-trifluoromethyl-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 117) and 2-picoline-4-boronic acid. Yellow solid. MS (EI): 597.1 (M+H)+.
Reaction SMILES: [O:1]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH3:13][NH2:14]>C(O)(C)C>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][CH2:6][C:7]([NH:14][CH3:13])=[O:8]
Reactant: O=C1CCCc2ccccc2O1
Reactant: CN
Solvent: CC(C)O
Product: CNC(=O)CCCc1ccccc1O
Temperature: 25 °C

Procedure:
A solution of 1.0 g of 4,5-dihydro-3H-benzo[b]oxepin-2-one and 40 ml of 10% methylamine in isopropanol is heated in an autoclave at 100° C. over 16 hours. The reaction mixture is cooled to room temperature and concentrated by evaporation. The title compound is obtained as white crystals from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (4:1 EtOAc-heptane); Rt=2.66.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23]([CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[CH:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:22]4)[N:15]=2)[CH:7]=[N:8][C:9]=1[O:10][CH:11]([CH3:12])[CH3:13]
Reactant: COC(=O)CCc1cc2cc(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(c3)cc(CCC(=O)O)n4C)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
Sodium hydroxide (63 mg) was added to a solution of methyl 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoate (D116) (72 mg) in THF (5 mL), isopropanol (5 mL) and water (2.5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[5-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoic acid (E91) (12 mg). δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.71 (2H, t), 3.03 (2H, t), 3.75 (3H, s), 5.46 (1H, m), 6.40 (1H, s), 7.60 (1H, d), 7.82 (1H, dd), 8.24 (1H, d), 8.56 (1H, d), 8.93 (1H, d), 12.33 (1H, s); MS (ES): C22H21ClN4O4 requires 440; found 441.1 (M+H+).
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C[N:9]1[CH2:14][CH2:13][CH:12]=[C:11]([C:15]2[O:16][CH:17]=[C:18]([CH3:20])[N:19]=2)[CH2:10]1>ClC(Cl)C>[ClH:1].[CH3:20][C:18]1[N:19]=[C:15]([C:11]2[CH2:10][NH:9][CH2:14][CH2:13][CH:12]=2)[O:16][CH:17]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: Cc1coc(C2=CCCN(C)C2)n1
Solvent: CC(Cl)Cl
Product: Cc1coc(C2=CCCNC2)n1
Product: Cl

Procedure:
3.25 g of alpha-chloroethyl chloroformate is added at -5° C. under inert atmosphere to a solution of 3.65 g of [1-methyl-3-(4-methyl-oxazol-2-yl)-1,2,5,6-tetrahydropyridine] in 70 cm3 of dichloroethane, and the mixture is heated under reflux for 2 hours. The solvent is evaporated, the residue is taken up in ether, filtered, the solvent is evaporated, the residue is taken up in 30 cm3 of methanol, heated under reflux for 45 minutes and the solvent is eliminated. After crystallization from ethanol, 1.9 g of expected product is obtained.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([NH:11][C:12](=[O:27])[CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][N:7]1[CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[CH:28]([N:7]1[CH2:8][C@@H:9]([NH:11][C:12](=[O:27])[CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:6]1[C:4]([OH:5])=[O:3])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)[C@@H]1C[C@H](NC(=O)CC(c2ccccc2)c2ccccc2)CN1C(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(CC(c1ccccc1)c1ccccc1)N[C@H]1C[C@@H](C(=O)O)N(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To the solution of (2S,4S)-1-benzhydryl-4-(3,3-diphenyl-propionylamino)-pyrrolidine-2-carboxylic acid ethyl ester (37) (0.25 g, 0.5 mmol) in THF (15 ml), MeOH (5 ml) and water (5 ml) was added LiOH (0.1 g, 2.45 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was neutralized with 2N HCl to pH˜2 and dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2: MeOH (10:1) to give 0.12 g of desired product.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH2:9]1.CN(C=O)C>O>[Br:1][C:2]1[N:6]=[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15](=[O:21])[O:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:12][CH2:13]2)[S:4][N:3]=1
Reactant: CC(C)COC(=O)NC1CCNCC1
Reactant: Clc1nc(Br)ns1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COC(=O)NC1CCN(c2nc(Br)ns2)CC1
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (0.21 g, 1.1 mmol), isobutyl piperidin-4-ylcarbamate (0.23 g, 1.2 mmol), and DMF (2 mL) was sealed in a microwave vessel and heated by microwave irradiation at 100° C. for two minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield isobutyl 1-(3-bromo-1,2,4-thiadiazol-5-yl)piperidin-4-ylcarbamate. LC/MS: m/z 365.0 (M+H)+ at 3.20 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).