Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.[NH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=1>ClCCl.CN(C)C1C=CN=CC=1.O>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=3)[N:12]=[C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[O:20])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCC(=O)O)c(-c3ccccc3)nn12
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCC(=O)Nc3ccccn3)c(-c3ccccc3)nn12
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
To a stirred solution of 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic acid (60 mg) in dichloromethane (2 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.3 mg) and 2-aminopyridine (20 mg) and the reaction mixture was stirred for 10 minutes. 4-Dimethylaminopyridine (2 mg) was added and the reaction mixture was stirred at room temperature for 15 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of ethyl acetate and n-hexane (1:2) to give 5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide (55.7 mg) as an yellow amorphous.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7](=[O:9])[CH3:8])=[CH:5][N:6]=1.[C:10]1([S-:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+].CC(C)=O.[OH-].[Na+]>O>[C:10]1([S:16][C:2]2[S:3][C:4]([C:7](=[O:9])[CH3:8])=[CH:5][N:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1cnc(Cl)s1
Reactant: [S-]c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cnc(Sc2ccccc2)s1
Reaction time: 3 h

Procedure:
1-(2-Chloro-thiazol-5-yl)-ethanone (221 mg, 1.37 mmol) and sodium benzenethiolate (226 mg, 1.71 mmol) were added to acetone (20 mL) and stirred for 3 h. The suspension was poured into water (100 mL) containing 2 M aqueous NaOH (10 mL) and extracted with DCM (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated to give the product. Yield=314 mg, 97%.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].[NH:17]1[CH2:31][CH2:30][CH2:29][C@@H:18]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].Cl.C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([N:17]1[CH2:31][CH2:30][CH2:29][C@@H:18]1[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:9])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Boc-L-Ile-OH 1/2 H2O (1.13 g, 4.7 mmol), H-D-Pro-OBzl HCl (1.14 g, 4.7 mmol) and HOBt H2O (72 mg, 0.47 mmol) were dissolved in DMF (10 ml), and TEA (0.66 ml, 4.7 mmol) and DCC (1.16 g, 5.64 mmol) were added under ice cooling, followed by stirring overnight at room temperature. After filtering and concentrating, the reaction mixture was redissolved in ethyl acetate and washed sequentially with 10% citric acid, 4% NaHCO3 and aqueous saturated sodium chloride. After drying over anhydrous MgSO4 and concentrating, purification was effected by flash silica gel chromatography (1% MeOH/CHCl3) to yield 1.76 g (89%) of the titled compound as an oily material.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[CH:10]=[CH:9][C:8]=2[NH2:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:21]([C:23]1[N:24]=[C:25]([C:36]([O-])=[O:37])[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)#[N:22].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)[CH:10]=[CH:9][C:8]=2[NH:19][C:36]([C:25]2[N:26]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=[C:23]([C:21]#[N:22])[N:24]=2)=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccc(Cc2nnn[nH]2)cc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Cc2nnn[nH]2)cc1C1=CCCCC1

Procedure:
The title compound was prepared from 2-cyclohex-1-enyl-4-(1H-tetrazol-5-ylmethyl)-phenylamine (as prepared in the previous step, 40 mg, 0.15 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 67 mg, 0.21 mmol), PyBroP (116 mg, 0.249 mmol) and DIEA (68 μL, 0.39 mmol) according to the procedure in Example 11, step (f) (60 mg, 76%). Mass spectrum (ESI, m/z): Calcd. for C25H32N8O2Si, 505.2 (M+H), found 504.9.
Reaction SMILES: [C:1]1([N:7]=[C:8]([CH2:10][C:11](=O)[CH3:12])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:1]1([NH:7][C:8](=[CH:10][C:11](=[N:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:12])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(C)=Nc1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(=CC(C)=Nc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
Then, 605 g of 2-phenylimino-4-pentanone solid and 449 g of anilinehydrochloride were dissolved in 2000 ml of ethanol, and the solution was refluxed for 2 hours. After the solution was cooled at the room temperature, green solid was precipitated. The green solid was separated and dried under vacuum pumping. Then the solid was suspended in 1000 ml of diethylether, and 150 g of NaOH solution in 1200 ml of water was added. The slurry mixture was, then, stirred for 1 hour at the room temperature. Then an organic layer was separated and dried over MgSO4. The solid was filtrated, and solvents were removed by vacuum pumping to get green solid. The green solid was recrystallized to get 650 g of solid (yield=75%). NMR analysis confirmed the structure; 1H-NMR(CDCl3) δ1.95(s, 2CH3), 4.93(s,═CH), 7.02(m, Ph), 7.31(m, Ph), and 13.2(brs, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH2:34][O:35][C:36]([F:39])([F:38])[F:37])(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][O:35][C:36]([F:39])([F:38])[F:37])[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cn(C(CCOC(F)(F)F)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
500 mg (1.29 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 495 mg (1.89 mmol) of 2-(trifluoromethoxy)ethyl trifluoromethanesulphonate and 1.39 ml (1.39 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 10 ml of THF were reacted according to General Method 7B. Purification by column chromatography (24 g silica cartridge, flow rate: 35 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 386 mg (62% of theory)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.Cl>>[CH3:1][CH:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7]1
Reactant: Brc1nccs1
Reactant: CC1CNCCN1
Agent: Cl
Product: CC1CN(c2nccs2)CCN1
Yield: 90.2 %

Procedure:
30.06 g (300.0 mmol) of 2-methylpiperazine were combined with 4.51 ml (50.0 mmol) of 2-bromothiazole. This mixture was fused and refluxed 5 min. The reaction mixture was cooled and taken up in 10% strength hydrochloric acid and washed with EA. The aqueous phase was set to pH>12 with a 10% strength aq. NaOH solution and then extracted with EA. The organic phase was dried over MgSO4 and conc. in vacuo. There were obtained 8.26 g (45.1 mmol, 90%) of 3-methyl-1-thiazol-2-ylpiperazine.
Reaction SMILES: [I:1]I.[B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[F:24][C:25]([F:45])([F:44])[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]1[CH:36]=[CH:37][N:38]=[C:31]1[C:30]([NH:39][CH2:40][CH2:41][CH2:42][OH:43])=[N:29]2>C(#N)C>[I:1][C:36]1[N:32]2[C:33]3[C:28]([N:29]=[C:30]([NH:39][CH2:40][CH2:41][CH2:42][OH:43])[C:31]2=[N:38][CH:37]=1)=[CH:27][C:26]([C:25]([F:44])([F:24])[F:45])=[CH:35][CH:34]=3
Reactant: II
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2ccnc12
Agent: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(I)cnc12
Yield: 62 %

Procedure:
To a 10-min stirred mixture of iodine (245 mg, 0.966 mmol, 0.6 eq) with Selectfluor™ (399 mg, 1.13 mmol, 0.7 eq) in acetonitrile (10 mL) under argon is added the 3-{[7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4-yl]amino}propan-1-ol (500 mg, 1.61 mmol, 1 eq). The dark red mixture is stirred at rt for 24 h. The precipitate is filtered out, washed with acetonitrile and dissolved in 150 mL of EtOAc. This organic phase is washed with a saturated solution of ammonium chloride, a saturated solution of sodium hydrogenocarbonate, a saturated solution of sodium hydrogen sulfite, then dried over magnesium sulfate and concentrated. A first batch of desired product is obtained as a white solid (135 mg, 0.31 mmol). To the remaining red liquor is added 0.7 additional equivalent of Selectfluor™ and 0.6 additional equivalent of iodine and the mixture is stirred under argon at rt for 16 h. Similar work-up allows the collection of a second batch (298 mg, 0.68 mmol, overall yield 62%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 110 °C
Yield: 99 %

Procedure:
To 3.7 mL of 2-fluoro-nitrobenzene are added 8.73 g of 4-methoxyaniline (2 equivalents). The whole is heated to 110° C. overnight. The medium is taken up in ethyl acetate, successively washed with water, a saturated solution of sodium bicarbonate and then with a saturated solution of sodium chloride. The organic phase is dried on magnesium sulfate, filtered and then concentrated under reduced pressure. With silica gel chromatography of the residue (petroleum ether/ethyl acetate: 90/10) 8.63 g of the desired product are isolated.
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH2:20])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8].[CH3:36][NH:37][C:38](Cl)=[O:39]>ClCCl>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH:20][C:38]([NH:37][CH3:36])=[O:39])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8]
Reactant: CNC(=O)Cl
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (5.09 μL, 0.063 mmol) was added to a solution of isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.010 g, 0.025 mmol) in dichloromethane (200 μL). Methylcarbamic chloride (0.003 g, 0.030 mmol) was added, and the reaction stirred at rt for 18 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with 1 N aqueous HCl, and the organic phase was separated and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-6-(3-methylureido)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 455 [M+H]+.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([O:9][C:10]1[CH:18]=[C:17]([CH2:19][C:20]2[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[N:24][CH:25]=2)[CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)[CH3:8].[CH3:28][N:29]([CH3:34])[S:30](Cl)(=[O:32])=[O:31]>CN(C)C=O>[CH3:28][N:29]([CH3:34])[S:30]([N:14]1[C:15]2[C:11](=[C:10]([O:9][CH2:7][CH3:8])[CH:18]=[C:17]([CH2:19][C:20]3[C:21]([NH2:27])=[N:22][C:23]([NH2:26])=[N:24][CH:25]=3)[CH:16]=2)[CH:12]=[CH:13]1)(=[O:32])=[O:31]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc2[nH]ccc12
Reactant: CN(C)S(=O)(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc2c1ccn2S(=O)(=O)N(C)C
Yield: 53 %

Procedure:
Potassium tert-butylate (42 mg, 0.37 mmol) was added to a solution of 5-(4-ethoxy-1H-indol-6-ylmethyl)-pyrimidine-2,4-diamine (Example 1; 100 mg, 0.353 mmol) in N,N-dimethylformamide (5 mL). After 15 min dimethylsulfamoyl chloride (53 mg, 0.37 mmol) was added, then after 30 min the solvent was distilled off and the residue partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Suspension of the residue in ether and collection of the precipitate afforded the title compound (73 mg, 53%). Off-white solid.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[N:11]=[CH:12][N:13]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)C=CC=CC=1.C([Li])CCC.CCCCCC.O=[CH:58][CH2:59][C@H:60]([NH:68][C:69]([O:71][CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)=[O:70])[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62].[Cl-].[Na+]>O1CCCC1>[C:73]1([CH2:72][O:71][C:69]([NH:68][C@@H:60]([CH2:59]/[CH:58]=[CH:9]/[C:10]2[N:11]=[CH:12][N:13]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:14]=2)[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:70])[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CC=O)NC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)[C@H](C/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
50.93 g (820 mmol) of triphenyl[[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]phosphonium chloride in solution in 333 ml of tetrahydrofuran are introduced, under argon, into a three-necked round-bottomed flask. 51.2 ml of a 1.6M solution of n-butyllithium in hexane (820 mmol) are added dropwise, at -70° C. After stirring for 30 minutes at -70° C., the reaction mixture is quickly poured into 270 ml of a 0.253M solution, cooled to -70° C., of 1,1-dimethylethyl (S)-4-oxo-2-[[(phenylmethoxy)carbonyl]amino]butanoate in tetrahydrofuran (683 mmol). The mixture is allowed to return to room temperature overnight. The mixture is hydrolysed with 280 ml of a saturated aqueous sodium chloride solution. The aqueous phase is separated from the organic phase and extracted with 2 times 140 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated to dryness. Purification is carried out by chromatography on a column of silica gel, the eluent being a hexane/ethyl acetate gradient.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:2].[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[C:1]([CH2:3][CH2:4][C:5]1[C:6]([C:25]2[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=2[F:23])=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:2]
Reactant: COC(=O)c1cnc(OS(=O)(=O)C(F)(F)F)c(CCC#N)c1
Reactant: COc1ccc(F)c(B(O)O)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: Cc1ccccc1
Product: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(CCC#N)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
Under a nitrogen atmosphere, to a mixture of methyl 5-(2-cyanoethyl)-6-(((trifluoromethyl)sulfonyl)oxy)nicotinate (700 mg), 2-fluoro-5-methoxyphenylboronic acid (700 mg), tetrakis(triphenylphosphine)palladium (237 mg) and toluene (10 mL) was added 2 M aqueous sodium carbonate solution (3.1 mL), and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was filtered, and the filtrate was diluted with ethyl acetate and THF. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (635 mg) as a colorless oil.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH:26]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30](=[O:31])[CH2:29][CH:26]5[CH2:28][CH2:27]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)CC1CC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC1CC1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (22.4 mg, 67.9%), MS (ISP) m/z=413.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 2-cyclopropylacetic acid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:20]#[N:21])[C:10]([CH3:19])=[C:11]([C:14]([O:16]CC)=[CH2:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.O.[Br:23]N1C(=O)CCC1=O>O1CCCC1>[Br:23][CH2:16][C:14]([C:11]1[C:12]([F:13])=[C:6]2[O:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:8][C:7]2=[C:9]([C:20]#[N:21])[C:10]=1[CH3:19])=[O:15]
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)CBr)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.9 %

Procedure:
2-Cyclopropyl-6-[1-(ethoxy)ethenyl]-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-78) (9.34 g, 30.1 mmol) was dissolved in tetrahydrofuran (450 ml), then water (27 ml) and N-bromosuccinimide (5.73 g, 31.58 mmol) were added all at a time, followed by stirring at room temperature for 45 minutes. After the reaction, the solvent was evaporated away under reduced pressure, followed by dilution with ethyl acetate and by washing with aqueous sodium thiosulfate solution and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography and eluted with a mixed solvent of n-hexane/ethyl acetate (4:1, v/v) to obtain the intended product (9.63 g, 95%) as a white solid.
Reaction SMILES: Br[C:2]1[S:19][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C@H:9]([CH3:11])[O:10][C:4]=2[C:3]=1[CH:20]([CH3:22])[CH3:21].[CH3:23]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>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.O>[CH3:11][C@H:9]1[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]2[S:19][C:2]([CH3:23])=[C:3]([CH:20]([CH3:22])[CH3:21])[C:4]=2[O:10]1
Reactant: CC(C)c1c(Br)sc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1sc2c(c1C(C)C)O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Yield: 92.9 %

Procedure:
A solution of tert-butyl (2S)-7-bromo-2-methyl-8-(1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (400 mg), methylboronic acid (245 mg), potassium phosphate (870 mg), tetrakis(triphenylphosphine)palladium (118 mg) and DME (6 mL) was stirred at 80° C. for 16 hr, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 3→7% ethyl acetate/hexane) to give the title compound (310 mg, 93%) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[OH:20][C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[OH:20][C:21]1[CH:22]=[C:23]([C:27]#[C:28][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=2)[C:7]([N:9]=[S@:10]([CH3:18])(=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:24]=[CH:25][CH:26]=1
Reactant: C#Cc1cccc(O)c1
Reactant: C[S@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[S@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.7 %

Procedure:
To a degassed solution of 2.0 mL DMF at room temperature containing (R)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (105 mg, 0.31 mmol), 3-hydroxyphenylacetylene (73 mg, 0.62 mmol) and triethylamine (0.13 mL, 0.93 mmol) was added dichlorobis(triphenylphosphine)palladium(II) (22 mg, 0.031 mmol) and copper(I)iodide (3 mg, 0.016 mmol). The reaction was stirred at room temperature for 1.5 hours. Additional 3-hydroxyphenylacetylene was added (30 mg, 0.25 mmol) and the reaction was stirred at room temperature for an additional 3.5 hours. After proceeding for 5 hours the reaction was partitioned between EtOAc and H2O and the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and concentrated. The residual dark oil was purified by chromatography (silica gel, CHCl3/EtOAc) and the product containing fractions were concentrated. The resulting solid was triturated with EtOAc/hexane to give the title compound as an off-white solid (37 mg, 32%).