Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:15][CH2:14][N:13]2[C:4](=[N:5][C:6]3[C:11]([C:12]2=[O:16])=[CH:10][CH:9]=[C:8]([CH:17]=[CH2:18])[CH:7]=3)[CH2:3]1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1/[CH:18]=[CH:17]/[C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:16])[N:13]3[CH2:14][CH2:15][C:2]([CH3:19])([CH3:1])[CH2:3][C:4]3=[N:5]2)=[CH:10][CH:9]=1
Reactant: C=Cc1ccc2c(=O)n3c(nc2c1)CC(C)(C)CC3
Reactant: Fc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC1(C)CCn2c(nc3cc(/C=C/c4ccccc4F)ccc3c2=O)C1
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of 7,7-dimethyl-3-vinyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (116 mg, 0.4 mmol, 1 equiv), 1-bromo-2-fluorobenzene (140 mg, 0.8 mmol, 2 equiv), Cs2CO3 (260 mg, 0.8 mmol, 2 equiv), Pd(OAc)2 (576 mg, 0.08 mmol, 0.2 equiv), Ph3P (88 mg, 0.32 mmol, 0.8 equiv), Et3N (80 mg, 0.8 mmol, 2 equiv) and (n-Bu)4NI (256 mg, 0.8 mmol, 2 equiv) in NMP was stirred at 140° C. for 20 minutes in a microwave reactor. After that, the reaction mixture was cooled to rt. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by silica gel chromatography to produce 53 mg desired product. MS (ESI): 349 (MH+); 1H NMR (300 MHz, CD3OD) δ 8.20-8.17 (d, J=8.12 Hz, 1H), 7.80-7.68 (m, 2H), 7.56 (s, 1H), 7.43-7.19 (m, 3H), 7.15-6.99 (m, 2H), 4.12-3.92 (t, J=13.20 Hz, 2H), 2.82 (s, 2H), 1.85-1.72 (t, J=12.84 Hz, 2H), 1.15 (s, 6H). mGluR5 PAM EC50: +++.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:21]([N:24]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=2[O:39][CH3:40])[C:25]2[S:29][N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1I)#[N:2].[F-].[Cs+].C([Sn](CCCC)(CCCC)[C:48]1[CH:53]=[CH:52][N:51]=[N:50][CH:49]=1)CCC>CN(C)C=O.[Cu]I>[C:1]([C:3]1[CH:4]=[C:5]([S:21]([N:24]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=2[O:39][CH3:40])[C:25]2[S:29][N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[C:48]1[CH:53]=[CH:52][N:51]=[N:50][CH:49]=1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3I)c(C#N)c2)c(OC)c1
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 30 °C

Procedure:
A mixture of 3-Cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 429, 33.07 g, 47.08 mmol) in dimethylformamide (140 mL) was treated with copper (I) iodide (1830 mg, 9.60 mmol) and cesium fluoride (14.4 g, 94.2 mmol). The mixture was sparged with nitrogen for 15 minutes. Then 4-(tributylstannyl)pyridazine (19.1 g, 51.8 mmol) dissolved in dimethylformamide (10 mL) was added and the reaction heated to 30° C. The reaction was cooled, poured onto water (1 L) and extracted with diethylether (4×450 mL). The combined extracts were washed with water (6×500 mL), dried over magnesium sulfate and evaporated to furnish an orange foam. This residue was purified using column chromatography (using a gradient of 100% heptane with 2% triethylamine to 40:60 ethylacetate:heptane with 2% triethylamine) to furnish the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([N:20]2[CH2:44][CH2:43][C:23]3([CH2:27][N:26]([C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH:25]([C:38]([O:40]CC)=[O:39])[CH2:24]3)[CH2:22][CH2:21]2)[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([N:20]2[CH2:21][CH2:22][C:23]3([CH2:27][N:26]([C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH:25]([C:38]([OH:40])=[O:39])[CH2:24]3)[CH2:43][CH2:44]2)[N:3]=1
Reactant: CCOC(=O)C1CC2(CCN(c3nc(N)nc(NCc4ccc5ccccc5c4)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: Nc1nc(NCc2ccc3ccccc3c2)nc(N2CCC3(CC2)CC(C(=O)O)N(C(=O)OCc2ccccc2)C3)n1

Procedure:
Hydrolysis of 2-benzyl 3-ethyl 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate using the LiOH general method provided 8-(4-amino-6-((naphthalen-2-ylmethyl)amino)-1,3,5-triazin-2-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid.
Reaction SMILES: C([NH:3][CH:4]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:5][C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)=O.S(=O)(=O)(O)O>C(O)C.O1CCCC1.O>[NH2:3][CH:4]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:5][C:6]1[CH:18]=[CH:17][C:9]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C=Cc1ccc(CC(NC=O)c2cccnc2)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C=Cc1ccc(CC(N)c2cccnc2)cc1
Temperature: 65 °C
Reaction time: 17 h
Yield: 95.8 %

Procedure:
Ethyl 4-[2-formamido-2-(3-pyridyl)ethyl]cinnamate (0.40 g) was dissolved in a mixed solvent of 10 ml of ethanol, 10 ml of tetrahydrofuran and 8 ml of water, followed by addition of 0.40 ml of concentrated sulfuric acid and heating to 65 ° C., and stirred for 17 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, followed by addition of CH2Cl2 and water and subsequent gradual addition of saturated aqueous solution of sodium hydrogencarbonate to adjust the mixture to weak alkalinity. The organic phase was separated and extracted from aqueous phase with methanol-methylene chloride (5:95 v/v), followed by washing in saturated aqueous sodium chloride solution, drying over magnesium sulfate and evaporation of the solvent, to produce 0.35 g of ethyl 4-[2-amino-2-(3-pyridyl)ethyl]cinnamate.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:22][C:21]=1[OH:32])=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C>[CH2:38]([O:37][C:35]([CH2:34][O:32][C:21]1[CH:22]=[C:23]([O:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][C:20]=1[C:18](=[O:19])[CH:17]=[CH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:36])[CH3:39]
Reactant: CCCCCCCc1ccccc1C=CC(=O)c1ccc(OCC=C(C)C)cc1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCc1ccccc1C=CC(=O)c1ccc(OCC=C(C)C)cc1OCC(=O)OCC
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a suspension of 310 mg of 60% oily sodium hydride in 10 ml of dry DMF was added dropwise a solution of 2.8 g of 2-n-heptyl-2'-hydroxy-4'-(3-methyl-2-butenyloxy)chalcone in 10 ml of DMF with ice cooling. Then, 1.2 g of ethyl bromoacetate was added, and the mixture was stirred at room temperature for an hour. After neutralization with dilute hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel column with n-hexane containing 1% ethyl acetate to give 1.83 g of 2'-ethoxycarbonylmethoxy-2-n-heptyl-4'-(3-methyl-2-butenyloxy)-chalcone. To a solution of this compound in 30 ml of ethanol was added 15 ml of 10% aqueous potassium carbonate solution, and the mixture was stirred at 60° C. for 4.5 hours. After neutralization with dilute hydrochloric acid with ice cooling, the precipitated solid was collected by filtration and recrystallized from ethanol to give 1.23 g of 2'-carboxymethoxy-2-n-heptyl-4'-(3-methyl-2-butenyloxy)chalcone as pale yellow plates.
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8]C=CC=2)[C:6](=O)[C:5]1=O)CC.[NH:15]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[C:16]1=[O:17].BrCCC(C)C>>[CH2:5]([N:15]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[C:16]1=[O:17])[CH2:6][CH:7]([CH3:12])[CH3:8]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CC(C)CCBr
Product: CC(C)CCN1C(=O)C(=O)c2ccccc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using commercially available isatin (purchased from Fisher Scientific) and 1-bromo-3-methyl butane (purchased from Fisher Scientific). 1H NMR δ 7.58 (m, 2H), 7.10 (t, 1H), 6.89 (d, 1H), 3.73 (t, 2H), 1.58 (m, 3H), 1.00 (d, 6H).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@@H:3]1[OH:16].[CH3:17][S:18][C:19](SC)=[N:20][C:21]#[N:22]>N1C=CC=CC=1>[C:21]([N:20]=[C:19]([S:18][CH3:17])[NH:1][C@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]1[OH:16])#[N:22]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H](N)[C@H]1O
Reactant: CSC(=NC#N)SC
Solvent: c1ccncc1
Product: CSC(=NC#N)N[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O

Procedure:
A solution of (3R,4S)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.40 g) and dimethyl N-cyanoimidodithiocarbonate [(CH2C=C--N--] (1.61 g) in pyridine (12 ml) was stirred at 80° C. for 10 hours, and then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 5% aqueous hydrochloric acid, and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (48 g) and eluted with a mixture of chloroform and methanol (20:1). The fractions containing the object compound were combined and concentrated in vacuo to give (3R,4S)-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.17 g).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:20]2[N:21]=[C:22]([CH2:37][CH2:38][CH2:39][CH3:40])[N:23]=[C:24]([NH:25]CC3C=CC(OC)=CC=3OC)[C:19]=2[NH:18][N:17]=1.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.FC(F)(F)C(O)=O>C(#N)C>[CH2:37]([C:22]1[N:23]=[C:24]([NH2:25])[C:19]2[NH:18][N:17]=[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:20]=2[N:21]=1)[CH2:38][CH2:39][CH3:40]
Reactant: C1CCNCC1
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(CCCCCCCBr)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCc1nc(N)c2[nH]nc(CCCCCCCN3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 284.3 %

Procedure:
Triethylamine (0.085 mL, 0.608 mmol) was added to a solution of 3-(7-bromoheptyl)-5-butyl-N-(2,4-dimethoxybenzyl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (150 mg, 0.203 mmol) and piperidine (0.060 mL, 0.608 mmol) in anhydrous acetonitrile (7 mL). The solution was stirred at ambient temperature for 1.5 hours. Additional piperidine (0.060 mL, 0.608 mmol) and triethylamine (0.085 mL, 0.608 mmol) were added to the reaction mixture and stirring at ambient temperature was continued for 17 hours. The reaction mixture was evaporated in vacuo to yield a clear oil. The oil was partitioned between ethyl acetate (20 mL) and water/brine (1:1, 5 mL). The organic layer was separated, passed through a hydrophobic frit and evaporated in vacuo to yield a clear oil. The oil was dissolved in trifluoroacetic acid (3 mL, 38.9 mmol) and heated at 60° C. for 3 hours. The reaction mixture was evaporated in-vacuo and the residue was dissolved in 3:1 chloroform:IPA (20 mL) and washed with aqueous sodium hydroxide (0.1M, 5 mL). The organic phase was separated using a hydrophobic frit and the aqueous back extracted with 3:1 chloroform:IPA (20 mL). The combined organic extracts were evaporated in-vacuo to yield a yellow oil (215 mg). The oil was dissolved in MeOH:DMSO (1:1) (3×1 mL) and purified by MDAP (Method B). Appropriate fractions were combined and evaporated in-vacuo to yield a brown oil (88.2 mg). The oil was dissolved in MeOH:DMSO (1:1) (1 mL) and purified by MDAP (Method A). Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a white solid (40.5 mg).
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][CH:15]=O)[CH:10]=[CH:11][CH:12]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH:15]=[CH2:2])[CH:8]=1
Reactant: O=CCCc1cccc(Br)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CCCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
A solution of 1.34 gm (3.77 mmol) of methyltriphenylphosphonium bromide in THF at 0° C. was treated dropwise with 2.3 mL of 1.6 M n-BuLi in hexanes (3.77 mmol), stirred at 0° C. for 0.25 h, cooled to −78° C., treated dropwise with a solution of 3-(3-bromophenyl)propionaldehyde (0.7 gm, 3.28 mmol) in THF, stirred at −78° C. for 1 h, allowed to warm to room temperature, quenched with aqueous NH4Cl and concentrated under reduced pressure. The resultant residue was taken up in EtOAc, washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of this concentrate on silica gel with a gradient of 0.5% EtOAc-hexanes to 2.0% EtOAc-hexanes gave 1-bromo-3-but-3-enylbenzene as an oil, 0.35 gm (50% yield); 1H NMR (400 MHz, CDCl3) δ: 2.33 (m, 2H), 2.66 (t, 2H, J=7.4 Hz), 4.98 (m, 2H), 5.79 (m, 1H), 7.12 (m, 2H), 7.30 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][CH:12]([OH:14])[CH3:13].[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:14][CH:12]([CH3:13])[CH2:11][NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: CC(O)CBr
Reactant: Cc1cccc(C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1NCC(C)O

Procedure:
A solution consisting of 121 g (1.0 mole), of 2,6-xylidine, 70 g (0.5 mole) 1-bromo-2-propanol and 100 ml of absolute toluene is heated under reflux for 24 hours. After cooling 300 ml 2 N sodium hydroxide are added. The organic layer is separated, washed with water until neutral, dried over sodium sulfate and evaporated in vacuo. The crude product is fractionally distilled to yield 59.6 g of N-(2'-hydroxypropyl)-2,6-xylidine, b.p. 81°-83°/0.1 Torr.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[N:14][CH:13]=[C:12]([C:23](=[O:25])[CH3:24])[N:11]=2)=[O:9])[C:4]([C:26](=[O:29])[NH:27][CH3:28])=[N:3]1.[BH4-].[Na+]>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[N:19][CH:18]=3)=[N:14][CH:13]=[C:12]([CH:23]([OH:25])[CH3:24])[N:11]=2)=[O:9])[C:4]([C:26](=[O:29])[NH:27][CH3:28])=[N:3]1
Reactant: CNC(=O)c1nn(C)cc1NC(=O)c1nc(C(C)=O)cnc1Nc1cncnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1nn(C)cc1NC(=O)c1nc(C(C)O)cnc1Nc1cncnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, cooled (0° C.) suspension of 6-acetyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carboxylic acid (1-methyl-3-methylcarbamoyl-1H-pyrazol-4-yl)-amide (12 mg, 30.4 μmol) in ethanol (2 ml) under an argon atmosphere was added sodium borohydride (1.15 mg, 30.4 μmol) in one portion. Stirring was continued for 1 hr at rt. More sodium borohydride (3 eq.) was added in one portion. The mixture was heated to reflux and stirring as continued for 30 min. The reaction was cooled to rt and concentrated. The crude product was purified by silica gel chromatography using a CH2Cl2/MeOH gradient as eluent. The title compound (4 mg, 33%) as yellow solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([N:15]([CH3:32])[C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.FC(F)(F)C(O)=O>CSC.C(S)(S)C>[NH2:1][C@@H:2]([C:13]([N:15]([CH3:32])[C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Agent: CC(S)S
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Yield: 74 %

Procedure:
Condensation of BocMeLeuOH (5.0 g.) and HMetNH2 (3.7 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocMeLeu-MetNH2 in 67% yield. De-t-butoxycarbonylation of BocMeLeu-MetNH2 (5.2 g.) using hydrogen chloride in ethyl acetate gave HMeLeu-MetNH2 in 90% yield. Condensation of BocDTrpOPFP (5.60 g.) and HMeLeu-MetHN2 (3.70 g.) by the activated ester method gave BocDTrp-MeLeu-MetNH2 in 55% yield. De-t-butoxycarbonylation of BocDTrp-MeLeu-MetNH2 (3.38 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HDTrp-MeLeu-MetNH2 in 74% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1.N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24].C(OCC)(=O)C>ClCCl>[F:15][C:4]1[CH:3]=[C:2]([NH:1][C:23](=[O:24])[O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:7]=[CH:6][C:5]=1[N:8]1[CH:9]=[CH:10][C:11](=[O:14])[CH2:12][CH2:13]1
Reactant: CC(C)COC(=O)Cl
Reactant: Nc1ccc(N2C=CC(=O)CC2)c(F)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1ccc(N2C=CC(=O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
To a cold (0° C.) stirring solution of the aniline from step 4 (62.0 g, 300.7 mmol) and pyridine (29.1 ml, 360.8 mmol) in dichloromethane (1095 ml) is added isobutyl chloroformate (42.9 ml, 330.7 mmol), and the mixture is stirred at ambient temperature for 90 min. Upon completion of the reaction the solvent is removed in vacuo, and the residual material is redissolved in dichloromethane (800 ml) and ethyl acetate (1100 ml). The mixture is washed with 10% aqueous HCl (1100 ml), and aqueous layer is extracted with 1:9/dichloromethane:ethyl acetate (1100 ml). The organic layers are combined and washed with brine (1100 ml). The organic layer is dried over MgSO4 and filtered. The filtrate is concentrated in vacuo. The residual material is recrystallized in 1:9/dichloromethane:ethyl acetate to afford 66.9 g (72% yield) of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (d, 6 H), 1.93 (m, 1 H), 2.47 (m, 2 H), 3.84 (m, 2 H), 3.89 (m, 2 H), 4.96 (d, 1 H) 7.29 (m, 2 H), 7.48 (m, 2 H), 9.92 (brs, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[S:24]1[C:28]([C:29](O)=[O:30])=[CH:27][C:26]2[CH:32]=[CH:33][CH:34]=[CH:35][C:25]1=2>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:29]([C:28]3[S:24][C:25]4[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=4[CH:27]=3)=[O:30])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1cc2ccccc2s1
Product: C[C@@]1(c2cc(NC(=O)c3cc4ccccc4s3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and benzo[b]thiophene-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:24]1([S:34](Cl)(=[O:36])=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>ClCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[S:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)(=[O:36])=[O:35])[CH2:4][CH2:3]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC1CCN(CC[C@H]2CCCN2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CCN(CC[C@H]2CCCN2S(=O)(=O)c2cccc3ccccc23)CC1
Reaction time: 12 h

Procedure:
To a solution of (R)-2-[2-(4-Methyl-piperidin-1-yl)ethyl]pyrrolidine (D6) 1 mmol and -diisopropylethylamine (1 mmol) in dichloromethane (10 mL) at 0° C. was added 1-naphthalene sulfonyl chloride. Stirring was continued at room temp. for 12 hours. The solution was washed with 10% aqueous NaOH and brine, dried and concentrated. The residue was purified by chromatography on silica gel to afford the title compound (MH30 387).
Reaction SMILES: [C:1]([N:11]1[CH2:18][C:17]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)(O)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3]CC1C=CC=CC=1)=O.C(CC(Cl)=S)(=O)C.[C:33]([S:36][C:37]1(C(O)=O)C(C(=O)C)=CCN1CC1OC=CC=1)(=[O:35])[CH3:34]>>[C:33]([S:36][CH2:37][C:1]([N:11]1[CH2:18][C:17]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:3])(=[O:35])[CH3:34]
Reactant: CC(=O)SC1(C(=O)O)C(C(C)=O)=CCN1Cc1ccco1
Reactant: O=C(O)[C@@H]1CC(O)(Cc2ccco2)CN1C(=O)OCc1ccccc1
Agent: CC(=O)CC(=S)Cl
Product: CC(=O)SCC(=O)N1CC(Cc2ccco2)=C[C@H]1C(=O)O

Procedure:
4-[(2-Furyl)methyl]-3,4-dehydro-L-proline from part (a) is reacted with 2-acetylthioacetyl chloride according to the procedure of Example 3 (b) to yield (2S)-1-[2-(acetylthio)-1-oxoethyl]-4-[(2-furyl)methyl]-2,5-dihydro-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=3[CH3:31])=[C:18]([CH3:32])[N:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH3:43])[C:37]=1B(O)O)[CH3:35].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH3:43])[C:37]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[C:19]([CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[CH:25]=[CH:24][C:23]=2[CH3:31])=[C:18]([CH3:32])[N:17]=1)[CH3:35]
Reactant: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCc1cccc(CC)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1-c1nc(C)c(COc2cc(C(C)C)ccc2C)c(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 90 °C
Reaction time: 40 h

Procedure:
A mixture of 4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (700 mg, 1.47 mmol), 2,6-diethylphenylboronic acid (394 mg, 2.21 mmol), 2 M aqueous sodium carbonate (2.21 mL, 4.42 mmol) and toluene (5 mL) is degassed with argon bubbling for 15 min. Pd(PPh3)4 (87 mg, 5 mol %) is added and the resulting yellow-colored mixture is heated at 90° C. under nitrogen with magnetic stirring for 40 h. The reaction mixture is partitioned between EtOAc (50 mL) and water (15 mL), the organic layer is separated, washed with water (15 mL), bring (15 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain a yellow liquid. Chromatography on a 30 g silica gel cartridge (10-30% EtOAc/Hexanes) affords the title compound as a colorless oil (along with recovered 4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester). LC/MS (Method 3), M+H=573.2, Rt=3.18 min.; 1H NMR (CDCl3) δ=7.26 (d, 1H), 7.12 (d, 3H), 6.83 (m, 2H), 4.99 (s, 2H), 3.51 (m, 4H), 2.90 (m, 6H), 2.55, (s, 3H), 2.42 (q, 4H) 2.24 (s, 3H), 1.28 (d, 6H), 1.10 (t, 6H).