Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([CH2:14][C:15]1[N:19]2[C:20]3[C:25]([NH:26][C:27](=[O:28])[C:18]2=[N:17][N:16]=1)=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][CH:21]=3)([O:11]CC)=[O:10])C>C(#N)C>[P:9]([CH2:14][C:15]1[N:19]2[C:20]3[C:25]([NH:26][C:27](=[O:28])[C:18]2=[N:17][N:16]=1)=[CH:24][C:23]([C:29]([F:31])([F:30])[F:32])=[CH:22][CH:21]=3)([OH:10])([OH:11])=[O:8]
Reactant: CCOP(=O)(Cc1nnc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n2c(CP(=O)(O)O)nnc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Bromotrimethylsilane (0.75 ml, 5.8 mmol) was added to a suspension of 1-[(diethoxyphosphoryl)methyl]-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (315 mg, 0.78 mmol) in 15 ml of dry acetonitrile in a flame-dried flask under nitrogen, and the resulting solution was stirred overnight at 40° C. After evaporation to dryness, the residue was stirred with 25 ml of water for 1 h. Then the water was removed under reduced pressure by azeotropic distillation with 1-propanol, and the residue was crystallized by trituration with a mixture of ether and ethanol followed by light petroleum. The solid was recrystallized from water, and dried in vacuo to give 189 mg (70%) of the title compound, m.p.>290° C. dec. (DSC); 1H-NMR (DMSO-d6): δ 3.96 (d, 2H), 7.64 (d, 1H), 7.69 (s, 1H), 8.47 (d, 1H), 12.28 (s, 1H); IR (KBr): 1712 cm-1 ; MS (FAB): m/e 349 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(F)cc1OCc1ccc(OC)cc1
Yield: 95 %

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (0.88 mol) was dissolved in CH3CN (1.5 l). Para methoxy benzylchloride (1.3 mol) and K2CO3 (2.2 mol) were added. The mixture was refluxed for 12 h. The mixture was filtered to remove the solid. The solvent was removed under vacuum. The resulting residue was purified by flash column chromatography (eluent: CH2Cl2). Yield 270 g (90% purity, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[C:24](=[O:25])[CH2:23][NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:24](=[O:25])[CH2:23][N:22]([CH3:29])[C:21]2=[O:26])=[CH:27][CH:28]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CNC(=O)N1Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CC(=O)N(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{4-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]benzyl}imidazolidine-2,4-dione (Example 84, 19 mg, 0.048 mmol) was dissolved in N,N-dimethylformamide and treated with potassium carbonate (8.6 mg, 0.062 mmol, 1.3 equiv) and iodomethane (5.4 μL, 0.086 mmol, 1.8 equiv). After stirring at ambient temperature for 1 hour, additional iodomethane (5.4 μL, 0.086 mmol, 1.8 equiv) and potassium carbonate (8.6 mg, 0.062 mmol, 1.3 equiv) were added and the mixture was placed into a preheated oil bath at 50° C. for 2.5 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate (30 mL) and washed with sodium bicarbonate (2×20 mL, aqueous saturated). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (85:15 to 36:64; water with 0.05% trifluoroacetic acid:acetonitrile with 0.05% trifluoroacetic acid) to afford the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 7.53 (1H, d, J=6.5 Hz); 7.51 (2H, d, J=6.7 Hz); 7.48 (2H, d, J=2.7 Hz); 7.45 (1H, d, J=2.9 Hz); 4.73 (2H, s); 4.55 (2H, d, J=7.2 Hz); 3.92 (2H, s); 3.02 (3H, s); 1.47-1.39 (1H, m); 0.72-0.67 (2H, m); 0.54-0.50 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 410.1380 [(M+H)+; calculated for C21H21ClN5O2: 410.1378].
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[CH2:2].Cl.[NH2:12][OH:13].C(=O)(O)[O-].[Na+]>CC(O)C.C(OCC)(=O)C>[OH:13][N:12]=[C:7]([NH2:8])[C:6]1[CH:9]=[CH:10][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1
Reactant: C=Cc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C(N)=NO)cc1
Temperature: 80 °C
Yield: 96.7 %

Procedure:
To a mixture of 4-vinylbenzonitrile (4.36 g, 33.8 mmol) and hydroxylamine hydrochloride (4.69 g, 67.5 mmol) in 2-propanol (50 mL) was added sodium bicarbonate (11.34 g, 135 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried MgSO4, filtered, and concentrated to yield 5.3 g of N′-hydroxy-4-vinylbenzimidamide. MS (m+1)=163. HPLC Peak RT=0.53 minutes (Analytical Method B).
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH2:20][NH2:21])[C:10]3[N:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][CH:29](OCC)OCC)[CH3:27]>>[CH2:26]([O:28][CH:29]=[N:21][CH2:20][CH2:19][CH2:18][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[CH:25]=[CH:24][CH:23]=[N:22][C:10]1=2)[CH3:27]
Reactant: CCOC(OCC)OCC
Reactant: NCCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Product: CCOC=NCCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Reaction time: 8 h

Procedure:
A solution of 8.8 g (0.021 mole) of 6-phenyl-11H-pyrido [2,3-b][1,4]bezodiazepine-11-propanamine in 150 ml of triethylorthoformate was heated at refux for 41/2 hr and allowed to stand overnight. The mixture was concentrated in vacuo, the residue was washed with pet-ether (30°-60° C.). Chemical ionization mass spec indicated the product was a mixture containing the title compound.
Reaction SMILES: ClC(Cl)(Cl)C([N:5]=[C:6]=[O:7])=O.[CH3:10][O:11][C:12](=[O:58])/[CH:13]=[CH:14]\[C@H:15]([CH3:57])[C@H:16]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C@@H:17]([CH3:48])/[CH:18]=[C:19](/[CH3:47])\[CH2:20][C@H:21]([CH3:46])[C@@H:22]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C@H:23]([CH3:37])[C@@H:24]([OH:36])[C@@H:25]([CH3:35])[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:58])/[CH:13]=[CH:14]\[C@H:15]([CH3:57])[C@H:16]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:51])[CH3:52])[C@@H:17]([CH3:48])/[CH:18]=[C:19](/[CH3:47])\[CH2:20][C@H:21]([CH3:46])[C@@H:22]([O:38][Si:39]([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:41])[CH3:40])[C@H:23]([CH3:37])[C@@H:24]([O:36][C:6]([NH2:5])=[O:7])[C@@H:25]([CH3:35])[CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COC(=O)/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C(/C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](O)[C@@H](C)COCc1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C(/C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](OC(N)=O)[C@@H](C)COCc1ccccc1
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Trichloroacetyl isocyanate (106 mg, 0.56 mmol, 1.5 eq) is added to a solution of (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S)-5,11-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-13-hydroxy-4,6,8,10,12,14-hexamethyl-15-(phenylmethoxy)-2,7-pentadecadienoic acid methyl ester (266 mg, 0.37 mmol) in CH2Cl2 (5 mL) at 23° C. The mixture is stirred for 30 min. The solvent is removed. The residue is chromatographed (10% EtOAc in hexane) to give 208 mg (74%) of the desired compound as a white foam.
Reaction SMILES: C(OC(N[C@H](C(O)=O)CC1C=CC(O)=CC=1)=O)(C)(C)C.[CH:21]1([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[Br:34]CC(OCC)=O>CN(C)C=O>[BrH:34].[CH:28]1([NH:27][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)CBr
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CN(C)C=O
Product: Br
Reaction time: 15 h

Procedure:
A mixture of 7 g (0.025 mol) of t-butyloxycarbonyl-L-tyrosine, 4.53 g (0.025 mol) of dicyclohexylamine and 4.18 g (0.025 mol) of ethyl bromoacetate in 40 ml of dimethylformamide is stirred for 15 hours. The precipitate of dicyclohexylamine hydrobromide which has formed is filtered off and washed with ethyl acetate. The combined filtrates are evaporated to dryness under reduced pressure. An oily residue is obtained which is taken up in ethyl acetate and washed twice with a 2N solution of sulphuric acid, once with water, twice with a solution of potassium bicarbonate and, finally, once with water. After desiccation over magnesium sulphate, the solution is evaporated to dryness. An oily residue is obtained which is dissolved in 50 ml of acetic acid containing 1.8 g (0.05 mol) of gaseous hydrochloric acid. The solution is allowed to stand for 30 minutes and then evaporated to dryness under reduced pressure, and the residue is recrystallised several times from a mixture of isopropanol and ether. 5.7 g of the hydrochloride (yield 75%), which melts at 176°, are collected. [α]Dt = + 12.2°.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][C:18](Br)=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(O)(O)[C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1.[F-].[K+].O1CCCC1>C(=O)([O-])[O-].[Na+].[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(PC2CCCCC2)CCCCC1.C1(C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]1[CH2:15][CH2:14][C@H:13]([O:16][CH2:17][C:18]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CC[C@H](OCC(Br)=Cc2ccccc2)C1)OCc1ccccc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: C1CCC(PC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1ccc(C(=Cc2ccccc2)CO[C@H]2CC[C@H](NC(=O)OCc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
A stirred mixture of 10 g of racemic trans [3-(2-bromo-3-phenyl-allyloxy)-cyclopentyl]-carbamic acid benzyl ester, 4.7 g of p-tolylboronic acid, 160 mg of o-biphenyl dicyclohexylphosphine, 52 mg of palladium acetate, 4 g of potassium fluoride and 25 mL of anhydrous tetrahydrofuran was stirred at room temperature for 1 h then heated to 50° C. for 3h under nitrogen atmosphere. The mixture was cooled diluted with 50 mL of sodium carbonate and extracted with 3×100 mL portions of ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography using a gradient of 0% to 25% ethyl acetate in hexane gave 10.8 g of product as a crystalline solid: MS (m+1)=442.3; 1H NMR (400 MHz, CDCl3) 7.35 (m, 4H), 7.1 (m, 8H), 7.0 (d, 2H), 6.6 (s, 1H), 5.1 (s, 2H), 4.7 (br s, 1H), 4.2 (s, 2H), 4.1 (m, 1H), 2.37 (s, 3H), 2.2 (m, 2H), 1.986 (m, 1H), 1.78 (m, 1H), 1.62 (m, 1H), 1.4 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12](=[O:14])[CH3:13])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CO.C1COCC1.CC(=O)OCC>[Br:15][CH2:13][C:12]([C:6]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1)=[O:14]
Reactant: [Br-]
Reactant: COc1cc(C(C)=O)cc(C(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)CBr)cc(C(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 149.6 %

Procedure:
1-(3-Isopropyl-5-methoxyphenyl)ethanone (O2.030; 425 mg) was dissolved in methanol/THF 15 ml/15 ml) and admixed while stirring with phenyltrimethylammonium tribromide (831 mg). After stirring at RT for 3 h, the reaction mixture was added to 50 ml of 20% citric acid and stirred for 1 h. After adding water and EA, the EA phase was removed, dried and concentrated. The residue was dissolved in acetonitrile (50 ml), and 2 N sulfuric acid (15 ml) was added to the solution. After standing at RT for 2 h, the mixture was admixed with water and extracted with EA. The EA phase was washed with saturated sodium hydrogencarbonate solution, dried and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-50% within 30 min). 520 mg of the title compound were obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][C:13]2[CH:20]=[C:19]([C@@:21]34[O:28][C@@:25]([CH2:29][OH:30])([CH2:26][O:27]3)[C@@H:24]([OH:31])[C@H:23]([OH:32])[C@H:22]4[OH:33])[CH:18]=[CH:17][C:14]=2[C:15]#[N:16])=[CH:10][CH:9]=1.I[CH2:37][CH3:38]>CC(C)=O.C(OCC)(=O)C>[CH2:37]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]2[CH:20]=[C:19]([C@@:21]34[O:28][C@@:25]([CH2:29][OH:30])([CH2:26][O:27]3)[C@@H:24]([OH:31])[C@H:23]([OH:32])[C@H:22]4[OH:33])[CH:18]=[CH:17][C:14]=2[C:15]#[N:16])=[CH:34][CH:35]=1)[CH3:38]
Reactant: CCI
Reactant: N#Cc1ccc([C@]23OC[C@](CO)(O2)[C@@H](O)[C@H](O)[C@H]3O)cc1Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2C#N)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
Potassium carbonate (8 mg, 0.058 mmol) was added to a solution of intermediate 2-(4-hydroxy-benzyl)-4-((1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]oct-5-yl)-benzonitrile (see example 6; 8.9 mg, 0.022 mmol) in acetone (0.4 mL), followed by iodoethane (4 microL, 0.044 mmol) at room temperature. The mixture was stirred at 45° C. overnight. The mixture was diluted with ethyl acetate (60 mL) and washed with water. The organic layer was dried over sodium sulfate and evaporated to dryness. Purification by preparative Thin Layer Chromatography over silica gel (eluting with methanol in dichloromethane: 1 to 9 in volume) allowed isolation of desired product 7A (2.4 mg; 26% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]([OH:5])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.Cl.[NH2:30][C@@H:31]1[C:39]2[C:34](=[C:35]([C:40]3[S:44][C:43]([C:45]4[CH:46]=[CH:47][C:48]([O:53][CH:54]([CH3:56])[CH3:55])=[C:49]([CH:52]=4)[C:50]#[N:51])=[N:42][N:41]=3)[CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1>CN(C=O)C>[C:50]([C:49]1[CH:52]=[C:45]([C:43]2[S:44][C:40]([C:35]3[CH:36]=[CH:37][CH:38]=[C:39]4[C:34]=3[CH2:33][CH2:32][C@@H:31]4[NH:30][C:3](=[O:5])[CH2:2][OH:1])=[N:41][N:42]=2)[CH:46]=[CH:47][C:48]=1[O:53][CH:54]([CH3:56])[CH3:55])#[N:51]
Reactant: O=C(O)CO
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NC(=O)CO)s2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Prepared using General Procedure 6. A solution of 2-hydroxyacetic acid (4 mg, 0.05 mmol), HOBt (8.8 mg, 0.06 mmol), EDC (12.5 mg, 0.06 mmol) and DIEA (15 mg, 0.11 mmol) in DMF (1 mL) was stirred for 30 min before the addition of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 in DMF (0.5 mL). The reaction mixture was stirred at room temperature overnight. The crude reaction mixture was preparative HPLC to produce 10 mg (50%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyacetamide 7 as white solid. LCMS-ESI (m/z) calculated for: C23H22N4O3S: 434.1; found 435.1 [M+H]+, tR=3.11 min. 1H NMR (400 MHz, CDCl3) δ 8.19 (dd, J=8.9, 2.3 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 5.71-5.46 (m, 1H), 4.76 (dt, J=12.2, 6.1 Hz, 1H), 4.21 (s, 2H), 3.46 (ddd, J=17.0, 8.7, 3.6 Hz, 1H), 3.30-3.09 (m, 1H), 2.69 (ddd, J=16.6, 8.3, 4.0 Hz, 1H), 2.08-1.80 (m, 2H), 1.46 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 167.44, 166.23, 162.20, 145.53, 142.82, 133.89, 133.79, 129.53, 128.28, 127.20, 126.93, 123.12, 116.03, 114.38, 104.22, 73.06, 62.72, 54.46, 33.91, 31.98, 22.24.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:3]1(C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].N12CCCC1=NCCC2>CC1C=CC=CC=1C>[CH3:1][C:2]1([CH3:19])[CH:4]([CH:5]=[C:6]([Cl:7])[Cl:8])[CH:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Agent: C1CN=C2CCCN2C1
Solvent: Cc1ccccc1C
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Yield: 61.7 %

Procedure:
77 g (0.25 mol) of diethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1,1-dicarboxylate were dissolved in 300 g of o-xylene and 150 g of 1,5-diaza-bicyclo[4.3.0]non-5-ene were added. The mixture was then heated to the boil for 12 hours. After cooling, the mixture was rendered weakly acid with ice-cold dilute hydrochloric acid. The organic phase was separated off and the aqueous phase was extracted twice more by shaking with methylene chloride. The combined organic phases were washed with sodium chloride solution and then with water and dried with Na2SO4. Fractional distillation gave 36.6 g of ethyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1-carboxylate in the form of a cis/trans mixture in which the trans form greatly predominated.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1.C1N2CCN(CC2)C1>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:29][CH2:28][NH:27][CH:26]([C:22]5[S:21][CH:25]=[CH:24][CH:23]=5)[CH2:31]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1csc(C2CNCCN2)c1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNC(c4cccs4)C3)c(F)cc2c1=O
Yield: 55.6 %

Procedure:
2.8 g (0.01 mole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Example A) are heated to 140° C. together with 1.8 g (0.011 mole) of 2-(2-thienyl)piperazine and 2.2 g (0.02 mole) of 1,4-diazobicyclo[2.2.2]octane in 6 ml of DMSO for 2 hours. The mixture is concentrated under high vacuum, the residue is stirred with 20 ml of water, and the precipitate is filtered off with suction and boiled in 20 ml of methanol. 2.4 g (56% of theory) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[3-(2-thienyl)-1-piperazinyl]-3-quinolinecarboxylic acid of melting point 252°-254° C. (with decomposition) are obtained. The melting point remains unchanged after recrystallization from glycol monomethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[Si]([C:13]([F:16])([F:15])[F:14])(C)(C)C.[F-].[K+]>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:13]([F:16])([F:15])[F:14])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Brc1cnc(I)nc1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A mixture of 5-bromo-2-iodo-pyrimidine (30 g, 0.11 mol), TMSCF3 (30 g, 0.21 mol), KF (9.2 g, 0.16 mol) and CuI (30 g, 0.16 mol) in DMF (300 mL) was stirred at room temperature overnight. The reaction mixture was quenched by NH3.H2O (600 mL) and extracted with EtOAc (500 mL×3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether) to give 5-bromo-2-trifluoromethyl-pyrimidine (4 g, yield: 16.7%). 1H NMR (CDCl3 400 Hz): δ8.90 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH:33]([CH3:35])[CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:1][C:2]([CH3:20])([CH3:21])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([N:36]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:13])=[O:4]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: CC(C)CNCC(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)N(CC(C)C)CC(C)C)c2c1
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 15.4 μL di-i-butylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.42 min. (m/Z=318.2, 402.2, 424.2).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3[CH:11]=[C:12]([OH:17])[C:13]([Cl:16])=[N:14][CH:15]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:18]([O:17][C:12]1[C:13]([Cl:16])=[N:14][CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)[CH:11]=1)(=[O:20])[CH3:19]
Reactant: Oc1cc(-c2ccc3ncsc3c2)cnc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(-c2ccc3ncsc3c2)cnc1Cl
Temperature: 60 °C
Yield: 37.1 %

Procedure:
A dry 5 mL, one neck round bottom flask was charged with 5-(benzo[d]thiazol-6-yl)-2-chloropyridin-3-ol (0.0120 g, 0.046 mmol), a stirbar, 0.5 mg DMAP and 1 mL anhydrous pyridine. The flask was fitted with an inert atmosphere inlet. The solution was treated with acetic anhydride (0.017 ml, 0.18 mmol), and the inert atmosphere needle was removed. The closed system was heated in a 60° C. oil bath for 60 minutes, and cooled. The solution was concentrated in vacuo, and purified using a 19×150 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186002381; Gradient: 0→5 min@20 mL/min, 25% B; 5.0→35 min@20 mL/min, linear gradient to 55% B; 35→45@20 mL/min, isocratic at 55% B, 45→55 min@20 mL/min, step to 100% B; 55→60 min@20 mL/min, step to 25% B; 60 min end; A=water; B=2% TFE in ACN). A band that eluted from 21.3 to 23.3 minutes was isolated. The solvent was removed in vacuo to afford 5-(benzo[d]thiazol-6-yl)-2-chloropyridin-3-yl acetate (0.0052 g, 37% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 2.43 (s) 7.71 (dd) 7.78 (d) 8.16 (d) 8.24 (d) 8.58 (d) 9.08 (s). 13C NMR (101 MHz, chloroform-d) δ ppm 20.79 (s) 120.61 (s) 124.38 (s) 125.67 (s) 130.70 (s) 133.35 (s) 134.97 (s) 136.67 (s) 143.53 (s) 143.81 (s) 144.86 (s) 153.46 (s) 155.23 (s) 168.08 (s). HPLC-MS: 2.09 min (92.8%@215 nm; 95.0% @254 nm; m/z=305.0, calculated for C14H9ClNO2S+H+=305.0).