Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:8]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:9][C:10]([OH:12])=[O:11]>ClCCl>[C:1]1([S:7][O:12][C:10](=[O:11])[CH2:9][NH:8][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)OSc1ccccc1
Yield: 62 %

Procedure:
Using thiophenol and Z-Gly.OH, Example 78 was repeated; except that dichloromethane was used in place of ethyl acetate as the extraction solvent, to obtain N-benzyloxycarbonyl-glycine-phenythio ester (hereinafter represented by ##STR12## in a yield of 62%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](O)=O.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]2[CH:36]=[C:37]([NH2:49])[C:38]([NH2:48])=[CH:39][C:40]=2[O:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[CH:29]=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[NH:49][C:37]2[CH:36]=[C:35]([O:34][C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[C:40]([O:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[CH:39][C:38]=2[N:48]=1
Reactant: Nc1cc(Oc2cccnc2)c(Oc2cccnc2)cc1N
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: c1cncc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.7 mg of pyrazine-2-carboxylic acid and 20 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added to a pyridine (1 ml) solution of 15 mg of 4,5-bis(pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 1 (step 3), and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was suspended in 1 ml of phosphorus oxychloride, and the reaction liquid was stirred overnight at 100° C. Phosphorus oxychloride was evaporated away under reduced pressure, and this was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=15/1+0.1% aqueous ammonia) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:15]([CH3:16])=[CH:14][S:13][CH:12]=1)[OH:4].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[C:15]([CH3:16])=[CH:14][S:13][CH:12]=2)[C:2]([F:1])([F:17])[F:18])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: Cc1cscc1-c1ccccc1C(O)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cscc1-c1ccccc1C(Oc1cc(Cl)nc(N)n1)C(F)(F)F
Temperature: 110 °C
Yield: 75.8 %

Procedure:
A mixture of 2,2,2-trifluoro-1-[2-(4-methyl-thiophen-3-yl)-phenyl]-ethanol (100 mg, 0.37 mmol), 2-amino-4,6-dichloro-pyrimidine (54 mg, 0.33 mmol), cesium carbonate (481 mg, 1.48 mmol) and 1,4-dioxane (1 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 100 mg of 4-chloro-6-{2,2,2-trifluoro-1-[2-(4-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine, yield: 76%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].Br[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(=O)CC>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[O:13][CH2:15][C:16]#[N:17])([O-:3])=[O:2]
Reactant: N#CCBr
Reactant: O=[N+]([O-])c1cc(O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: N#CCOc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 61.8 %

Procedure:
3,5-Dinitrophenol (15.0 g) and 10.75 g of bromoacetonitrile were dissolved in 85 ml of 2-butanone and the solution was treated with 33.78 g of potassium carbonate. The heterogenous mixture was stirred and heated at 70° C. for 5 hours, cooled to room temperature, poured into ethyl acetate, washed with water, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography eluting with dichloromethane/hexane (3:1) to give 11.24 g of (3,5-dinitrophenoxy)-acetonitrile as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:52])[C:4]1[CH:51]=[CH:50][C:7]([C:8]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([S:20]([C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=4)(=[O:22])=[O:21])[CH:18]=3)[N:13]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:12]=2)=[O:9])=[CH:6][CH:5]=1.O1CCCC1.O.[OH-].[Li+]>O>[F:30][C:25]1[CH:24]=[C:23]([S:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:12]=[C:11]3[NH:10][C:8](=[O:9])[C:7]2[CH:50]=[CH:51][C:4]([C:3]([OH:52])=[O:2])=[CH:5][CH:6]=2)(=[O:22])=[O:21])[CH:28]=[C:27]([F:29])[CH:26]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-terephthalamic acid methyl ester (400 mg, 0.56 mmol), tetrahydrofuran (8 mL), water (4 mL) and lithium hydroxide hydrate (35 mg, 1.5 eq) was stirred at room temperature overnight. The solvents were evaporated to dryness. The residue was taken up with ethyl acetate, washed with 5% aqueous solution of potassium bisulfate, brine, dried over sodium sulfate and evaporated to dryness affording the crude title compound that was used as such for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:14][CH2:13][NH:12][CH:11]([CH3:10])[CH2:16]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccc(Cl)cc2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
3.49 g (17.0 mmol) 4-Chlorobenzylbromide was added dropwise to a mixture of 2.04 g (20.4 mmol) 2-Methyl piperazine and 2.40 ml (17 mmol) triethylamine in 60 ml DMF at room temperature. The reaction mixture was stirred for 16 hours at room temperature, the poured onto aq. sodium bicarbonate solution and extracted with ethylacetate. Purification of the crude product by flash chromatography gave 2.26 g (10.1 mmol, 59%) of 1-(4-chloro-benzyl)-3-methyl-piperazine as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[F:23][C:24]1[CH:25]=[N:26][NH:27][C:28]=1[Sn](CCCC)(CCCC)CCCC.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([F:22])=[C:2]([C:28]3[NH:27][N:26]=[CH:25][C:24]=3[F:23])[CH:3]=2)=[CH:9][CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(-c2[nH]ncc2F)c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (Stage 20.2, 200 mg, 0.497 mmol), 4-fluoro-5-(tributylstannyl)-1H-pyrazole (211 mg, 0.472 mmol) and Pd(PPh3)4 (28.7 mg, 0.025 mmol) in DMSO (1.5 mL) in a sealed vial was stirred at 100° C. for 20 h under an argon atmosphere. The RM was diluted with EtOAc (30 mL), treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc 95:5 to 6:4) to give the title product as a white solid. HPLC (Condition 5) tR=7.20 min, UPLC-MS (Condition 3) tR=1.12 min, m/z=400.1 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH2:14]([CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)[C:15]#[CH:16]>>[CH2:14]([CH:17]1[CH2:22][CH2:21][N:20]([C:2]([O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:3])[CH2:19][CH2:18]1)[C:15]#[CH:16]
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: C#CCC1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
4-(nitro)phenyl chloroformate (5.0 g, 24.8 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (4.25 g, 19.0 mmol) according to general procedure 1. Yield=5.72 g, 80%. m/z MH+=289.04. HPLC rt=10.4 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH:8]2[CH2:11][N:10]([C:12]3[N:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:13]=3[C:14]([O:16]C)=[O:15])[CH2:9]2)[CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH:8]2[CH2:11][N:10]([C:12]3[N:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:13]=3[C:14]([OH:16])=[O:15])[CH2:9]2)[CH:3]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cc(C)on2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(OC2CN(c3ncc(C(F)(F)F)cc3C(=O)O)C2)no1
Yield: 98.8 %

Procedure:
To a solution of methyl 2-(3-((5-methylisoxazol-3-yl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D88) (20 mg, 0.056 mmol) in 1,4-dioxane/water (3 ml/1 ml), lithium hydroxide monohydrate (3.52 mg, 0.084 mmol) and the resulting mixture was heated at 130° C. under microwave irradiation 10 min (2 cycles of 5 min each). Solvents were evaporated in vacuo and the residue was taken in a mixture water/1M HCl (5 ml/15 ml) and extracted with ethyl acetate (3×20 ml). Collected organics, after solvent evaporation, afforded the title compound (D129) (19 mg)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:28]=[CH:27][CH:26]=[CH:25][C:10]=2[C:11]([NH:13][O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)=[O:12])=[CH:3][CH:2]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:20]([C:19]2[CH:18]=[CH:17][C:16]([CH2:15][O:14][NH:13][C:11](=[O:12])[C:10]3[CH:25]=[CH:26][CH:27]=[CH:28][C:9]=3[NH:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:24][CH:23]=2)=[O:21])[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(CONC(=O)c2ccccc2NCc2ccncc2)cc1
Product: CN1CCN(C(=O)c2ccc(CONC(=O)c3ccccc3NCc3ccncc3)cc2)CC1

Procedure:
Prepared by a similar procedure as described for preparation of example 405. Starting materials: 4-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid (see example 404) and 1-methylpiperazine. The title compound was crystallised from toluene. 13C-NMR (DMSO-d6) δ 168.6, 167.2, 149.5, 148.9, 148.2, 137.3, 135.7, 132.4, 128.7, 128.0, 126.8, 121.9, 114.8, 113.3, 111.4, 76.4, 54.4, 46.8, 45.5, 44.8.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:15])([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:14])([CH3:15])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=1)(=[O:27])=[O:26]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CCOC(=O)CC(C)(C)c1csc(N)n1
Product: CCOC(=O)CC(C)(C)c1csc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 3-(2-amino-1,3-thiazol-4-yl)-3-methylbutanoate (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic method to give a white solid (55.0 mg) with purity >90%. MS (pos) m/z 451.2, 453.2.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C:6](O[Si](C)(C)C)=[C:5](O[Si](C)(C)C)[CH2:4]1)[CH3:2].Cl.Cl.[NH2:20][CH2:21][C:22]([NH2:24])=[NH:23]>>[CH2:1]([N:3]1[CH2:7][C:6]2[C:5](=[N:23][C:22]([NH2:24])=[CH:21][N:20]=2)[CH2:4]1)[CH3:2]
Reactant: N=C(N)CN
Reactant: CCN1CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Agent: Cl
Product: CCN1Cc2ncc(N)nc2C1

Procedure:
This compound was prepared analogous to Example 22 from 1-ethyl-2,5-dihydro-3,4-bis(trimethylsilyloxy)-pyrrole and α-amino-acetamidine dihydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH:23]=[CH2:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:25][O-:26].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][O:26][CH3:25])(=[O:22])=[O:21])[CH2:16][CH2:15]1
Reactant: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
The mixture of 5-bromo-3-[1-(ethenylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (150 mg, 0.36 mmol), sodium methoxide in methanol (25%, 1.0 mL) and methanol (2.0 mL) was stirred at 80° C. for 1 hr. After which time the reaction mixture was concentrated under reduced pressure. The residue was purified by combiflash to give the title compound (100.0 mg, 63%).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)=O.[CH3:11][NH:12][CH3:13]>COCCOC.C1COCC1>[CH3:11][N:12]([CH2:1][C:3]1[O:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)[CH3:13]
Reactant: CNC
Reactant: O=Cc1ccc(B(O)O)o1
Solvent: COCCOC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(B(O)O)o1
Reaction time: 0.08 h

Procedure:
To a solution of (5-formyl-2-furyl)boronic acid (50 mg, 0.36 mmol) in DME (1.0 mL) was added a 2.0M solution of dimethylamine in THF (0.53 mL, 1.0 mmol). The reaction mixture stirred for 5 minutes before resin bound MP-BH(OAc)3 (2.2 mmol/g, 0.33 g, 0.714 mmol) was added. The reaction mixture was stirred at room temperature for five hours and an additional 1 equivalent of dimethylamine in THF was added and stirring continued overnight. The reaction mixture was filtered through a plug of glass wool and the resin was washed with DME. The THF/DME filtrate solution containing the desired compound was used immediately in subsequent reactions.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:5][CH:4]([CH:6]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47].C(N(CC)CC)C>ClCCl>[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH:47][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH:6]([CH:4]2[CH2:3][C:2]([CH3:1])([CH3:28])[CH2:5]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:8][CH:9]=1
Reactant: Cc1cc2ccccc2nc1NC(c1ccc(C(=O)O)cc1)C1CC(C)(C)C1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccccc3cc2C)C2CC(C)(C)C2)cc1

Procedure:
(+/−)-4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoic acid (Intermediate 26, 1.0 eq.), 1-hydrobenzotriazole hydrate (1.2 eq.), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 eq.), beta-alanine methyl ester hydrochloride (1.1 eq.), and triethylamine (1.3 eq.) were combined in anhydrous dichloromethane in a similar manner as described in the experimental for intermediate 27 to provide (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid methyl ester which was resolved via chiral chromatography to provide the title compound. Preparative chiral SFC: (Chiralpak AD-H column, 21 mm×25 cm, 40% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier, 65.0 mL/min flow rate, 2.71 retention time); 1H NMR (400 MHz, CDCl3) δ 7.63-7.69 (m, 2H), 7.58 (t, J=3.9 Hz, 2H), 7.45-7.51 (m, 3H), 7.41 (ddd, J=8.4, 7.0, 1.6 Hz, 1H), 7.14 (ddd, J=8.0, 6.9, 1.2 Hz, 1H), 6.72 (t, J=6.0 Hz, 1H), 5.31 (dd, J=9.7, 6.7 Hz, 1H), 4.75 (d, J=6.8 Hz, 1H), 3.69 (q, J=6.2 Hz, 5H), 2.55-2.71 (m, 3H), 2.28 (d, J=0.8 Hz, 3H), 1.95 (ddd, J=11.2, 8.0, 3.0 Hz, 1H), 1.78 (dd, J=11.1, 9.0 Hz, 1H), 1.64-1.72 (m, 2H), 1.15 (s, 3H), 1.08 (s, 3H); MS (M+1): 460.4.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([N:6]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(C)(=O)=O)C1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
Methane sulfonyl chloride (204 mg, 1.78 mmol) was added to a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (300 mg, 1.62 mmol) and Et3N (197 mg, 1.94 mmol) in DCM (6 mL) at 0-5° C.; stirring was continued at 20-35° C. for 2 h. The reaction mixture was diluted with DCM, washed with water, aqueous NaHCO3 solution followed by brine to afford 250 mg of the title compound.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][S:9][CH2:8]1.CN(P(N(C)C)(N(C)C)=O)C.[CH3:23][N:24]1[N:28]=[N:27][C:26]([C:29]2[CH:39]=[C:38]([CH3:40])[C:32]([O:33][CH2:34][CH2:35][CH2:36]Br)=[C:31]([CH3:41])[CH:30]=2)=[N:25]1.[Cl-].[NH4+]>C1COCC1>[CH3:6][N:7]1[CH:11]=[C:10]([CH2:36][CH2:35][CH2:34][O:33][C:32]2[C:31]([CH3:41])=[CH:30][C:29]([C:26]3[N:27]=[N:28][N:24]([CH3:23])[N:25]=3)=[CH:39][C:38]=2[CH3:40])[S:9][CH2:8]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCBr
Reactant: CN1C=CSC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC1=CN(C)CS1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 27.7 %

Procedure:
n-BuLi (2.5M, 1.33 ml, 3.33 mmol) was added slowly at -78° C. to a solution of 3-methyl-thiazole (300 mg, 3.03 mmol) in 8 ml of THF under nitrogen. After stirring at -78° C. for 15 min, HMPA (1.08 g, 6.06 mmol) was added and the resulting mixture was stirred for 10 min. To the above mixture was added at -78° C. 3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propylbromide (985 mg, 3.03 mmol) in 5 ml of THF. The mixture was allowed to warm to 20° C. and stirred for 3 h. Saturated ammonium chloride solution was added and the aqueous layer was extracted with ether (3×), and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (15 cm column, ethyl acetate/hexane, 1/8-3/1) to afford 290 mg (28%) of 3-methyl-5-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]thiazole.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: NCCCSc1ccncc1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCCCSc1ccncc1
Yield: 91.1 %

Procedure:
To a solution of 700 mg (2.90 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 1.62 ml (11.6 mmol) of triethylamine in 30 ml of methylene chloride was added 0.36 ml (3.48 mmol) of butyryl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:1) to obtain 630 mg of the desired compound (91.1%, pale yellow oil).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J36) (360 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (302 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (430 mg, 73%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1>[N:8]1([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C#CC(=O)OCC
Reactant: C1CCNC1
Solvent: c1ccccc1
Product: CCOC(=O)C=CN1CCCC1
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of 29.43 g of ethyl propiolate (0.30 mol) in 200 ml of benzene was held at 25° in a water bath with magnetic stirring. A solution of 21.34 g of pyrrolidine in 50 ml of benzene was added dropwise over a period of 45 minutes, during which time the temperature rose to 35°. The clear brown solution was stirred overnight and the solvent removed under reduced pressure at 55°. The residue was distilled under reduced pressure to give 35.05 g of yellow oil, boiling point 110° (0.4 torr), which crystallized upon standing. The yellow solid was recrystallized from petroleum ether to give 31.36 (62%) of yellowish platelets, m.p. 37.5°-39.5°.