Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)CCl.C1C=[N:20]C2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:20])=[O:6]
Reactant: On1nnc2cccnc21
Reactant: Cc1c(Br)cccc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1c(Br)cccc1C(N)=O
Temperature: 25 °C
Yield: 92.8 %

Procedure:
3-bromo-2-methylbenzoic acid (5.00 g, 23.3 mmol) was dissolved in DMF (41.6 ml) and EDC (5.46 g, 28.5 mmol), HOAt (3.97 g, 29.2 mmol), ammonium chloride (4.90 g, 90.9 mmol), and diisopropylethylamine (12.5 ml, 71.8 mmol) were added. The reaction was stirred at room temperature over the weekend, and then poured into water (100 ml). The resultant precipitate was filtered, washed with water, collected, and dried under vacuum to give the title compound (4.63 g, 93%). MS (ESI pos. ion) m/z: 214 (M+H). Calc'd Exact Mass for C8H8BrNO: 213.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]1([CH2:26][NH2:27])[CH2:25][CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN1CCCC1=O.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.CS([O-])(=O)=O.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.[Pd+2]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:27][CH2:26][CH:23]3[CH2:25][CH2:24]3)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CC1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Agent: [Pd+2]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: CS(=O)(=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc2c(cc(NCC3CC3)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 100 °C

Procedure:
A suspension of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20.0 mg, 0.0644 mmol, from Step 7), cyclopropylmethylamine (51 μL, 0.60 mmol, Aldrich), tBuBrettPhos Pd G3 (6.5 mg, 0.0076 mmol, Aldrich) and Cs2CO3 (0.045 g, 0.14 mmol) in N-methylpyrrolidinone (0.3 mL) and water (0.030 g) was degassed and heated at 100° C. for 4.5 h, after which time the reaction mixture was filtered and the product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (10.5 mg, 47%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[C:7]1[CH:8]=[C:9]([O:13]C)[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(C)C>CN1CCCC1=O.O.[OH-].[NH4+].C(O)C>[N:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: CCO
Solvent: O
Product: Oc1cccc(-n2ccnc2)c1

Procedure:
Imidazole (34 g, 0.5 mole), m-bromoanisole (51 mL, 0.4 mole), potassium carbonate (52 g), and cuprous chloride (2.4 g) in 300 ml N-methyl-2-pyrrolidone was heated at reflux for 4 hours. The cooled mixture was diluted with water and 100 ml concentrated ammonium hydroxide. The product was extracted into toluene-ethylacetate (several times until TLC of aqueous layer showed only a trace amount of product). All the organic extracts were combined, filtered, extracted once with water and then three times with a total of 300 ml 48% hydrobromic acid. The hydrobromic acid extracts were combined and heated at reflux for 6 hours and then concentrated. The residue was redissolved in water and basified first with sodium hydroxide and at the end with sodium bicarbonate to get a final pH of 8. Some isopropyl ether was added to cause the product to crystallize out. The solid was filtered, rinsed with water, and dried at 80° C. in a vacuum oven to obtain 50.9 g (79.5% yield). A small portion of this solid was dissolved in absolute ethanol, filtered, concentrated, and recrystallized. The recrystallized material melted at 169°-170° C.
Reaction SMILES: [C:1]([Si:5]([O:18][CH:19]1[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21][CH2:20]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N-]>ClCCl>[CH2:32]([O:31][C:29]([CH:28]1[CH:22]2[CH:23]1[CH2:24][CH2:25][CH:19]([O:18][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:20][CH2:21]2)=[O:30])[CH3:33]
Reactant: CC(C)(C)[Si](OC1CCC=CCC1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)C1C2CCC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CCC21

Procedure:
To a solution of Example 8C (2.2 g, 6.28 mmoles) and Rh2(OAc)4 (2 mg, 4.3 μmol) in dichloromethane (2 mL), ethyl diazoacetate (0.717 g, 6.28 mmoles) in dichloromethane (4 mL) was added over two hours via a syringe pump. The solvent was evaporated in vacuo and product purified by flash column chromatography (hexanes:ethyl acetate 100:0 to 80:20) to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][CH:4]=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:36][CH2:37][F:38])(=O)=O)=CC=1.Cl>CN(C=O)C>[F:38][CH2:37][CH2:36][N:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2](=[O:1])[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4]1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CCOC(=O)c1c[nH]cc(-c2ccccc2)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)cc(-c2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
Ethyl 4-oxo-5-phenyl-1,4-dihydropyridine-3-carboxylate (190 mg) was suspended in DMF (2.5 ml). Cesium carbonate (509 mg) and 2-fluoroethyl 4-methylbenzenesulfonate (256 mg) were sequentially added and the mixture was stirred at 50° C. for three hours. A 1 N aqueous hydrochloric acid solution was added under ice cooling, and the organic layer was extracted with ethyl acetate, washed with water and brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->40:1 (v/v)] to give 181 mg of the title compound as an oily substance.
Reaction SMILES: [O-]S(OOS([O-])(=O)=O)(=O)=O.[K+].[K+].S(=O)(=O)(O)O.CN(C)C=O.[Br:23][C:24]1[CH2:28][CH:27]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:39](=[O:46])[NH:40][CH:41]([CH:43]2[CH2:45][CH2:44]2)[CH3:42])=[O:30])[N:26]([C:47]2[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][N:48]=2)[N:25]=1>O>[Br:23][C:24]1[CH:28]=[C:27]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:39](=[O:46])[NH:40][CH:41]([CH:43]2[CH2:45][CH2:44]2)[CH3:42])=[O:30])[N:26]([C:47]2[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][N:48]=2)[N:25]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Yield: 90.3 %

Procedure:
0.24 g of potassium peroxodisulfate and 0.02 g of sulfuric acid were added to a N,N-dimethylformamide 3 ml solution comprising 0.10 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxamide, followed by reflux with heating. 1.5 hours later, the reaction liquid was stood to cool and poured to 10 ml of water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/2) to obtain 0.09 g of the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1>>[F:9][C:10]([F:20])([F:21])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14][CH:13]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1cccs1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1cccs1

Procedure:
Prepared in a similar manner as described in example 4 from thiophene-2-carboxylic acid and (4-(trifluoromethoxy)phenyl)methanamine. MS (M+H, 303).
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[CH2:7][CH2:6][C:5]1=[O:22])[CH:2]=[CH2:3].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)(Cl)Cl>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][C:4]1([CH2:1][CH:2]=[CH2:3])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=2)[CH2:7][CH2:6][C:5]1=[O:22])[CH3:29]
Reactant: C=CCC1C(=O)CCc2ccc(OCc3ccccc3)cc21
Reactant: CCOC(=O)CBr
Solvent: ClC(Cl)Cl
Product: C=CCC1(CC(=O)OCC)C(=O)CCc2ccc(OCc3ccccc3)cc21

Procedure:
Crude 1-allyl-7-benzyloxy-3,4-dihydro-2(1H)-naphthalenone (VIIIc), 22.9 g (78.5 mmol) was reacted with ethyl bromoacetate by the method of Example 5 to yield 25.5 g (87%) crude crystalline IXc. Recrystallization from ethanol gave 19.5 g (66%) m.p. 83°-85°. IR (CHCl3) 1725, 1710 cm-1 (ketone and ester); NMR δ, 1.05 and 3.96 (triplet and quartet for OCH2CH3) 4.8-5.8 (m, 5, olefinic and PhCH2O), 5.15 (s, 2, PhCH2O), 6.80-7.55 (m, 8, ArH).
Reaction SMILES: [CH:1]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:2]=1[NH:3][C:4]1[C:5]2=[CH:6][CH:7]=[C:8]2[C:16]=1[N:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23])[C:14]1[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=1.[CH2:28]1[C:33](=[O:34])[N:32](Cl)[C:30](=[O:31])[CH2:29]1.CCN(CC)CC>C(Cl)Cl>[CH:1]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:2]=1[NH:3][C:4]1[C:5]2=[CH:6][CH:7]=[C:8]2[C:16]=1[N:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][N:32]1[C:33](=[O:34])[CH2:28][CH2:29][C:30]1=[O:31])[C:14]1[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Sc1ccccc1-n1c2ccccc2c2ccc3c4ccccc4[nH]c3c21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(=O)N1Sc1ccccc1-n1c2ccccc2c2ccc3c4ccccc4[nH]c3c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
27.3 g (75 mmol) of 2-(12H-11,12-diazaindeno[2,1-a]fluoren-11-yl)benzenethiol are added to a solution of 10 g (75 mmol) of NCS in 150 ml of CH2Cl2 at 0° C., 10.5 ml (75.3 mmol) of Et3N are subsequently added, and the mixture is stirred at room temperature for 18 h. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The residue is recrystallised from acetone and finally sublimed in a high vacuum. Yield: 30 g (66 mmol), 85% of theory, purity according to HPLC 88.3%.
Reaction SMILES: N[C:2]1[N:6]=[C:5]([CH:7]2[CH2:9][CH2:8]2)[NH:4][N:3]=1.[BrH:10].N([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.O.[Cu]Br>[Br:10][C:2]1[N:6]=[C:5]([CH:7]2[CH2:9][CH2:8]2)[NH:4][N:3]=1
Reactant: Nc1n[nH]c(C2CC2)n1
Reactant: Br
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: Brc1n[nH]c(C2CC2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5.0 g of 3-amino-5-cyclopropyl-1H-[1,2,4]triazole were dissolved in 30 ml of acetic acid and 20 ml of a 48% aqueous hydrogen bromide solution were added dropwise. Subsequently, a solution of 3.1 g of sodium nitrite in 10 ml of water was added dropwise at 0° C. in the course of 10 min and the mixture was subsequently stirred at 0° C. for 10 min. The suspension thus obtained was added in portions at 0° C. to a suspension of 11.6 g of copper(I) bromide in 20 ml of a 24% aqueous hydrogen bromide solution. Subsequently, it was stirred at room temperature for 1 h, then the mixture was added to 400 ml of a saturated aqueous sodium carbonate solution and precipitated copper compound was filtered off. The mixture was washed with 100 ml of EA, then the phases were allowed to separate and the aqueous phase was extracted a further two times with 100 ml each of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 2.5 g of the title compound were obtained as a light yellow oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O.Cl>[C:1]1([N:7]2[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCN(c2ccccc2)CC1
Temperature: 50 °C

Procedure:
8-Phenyl-1,4-dioxa-8-azaspiro[4.5]decane (18.1 g, 82.5 mmol) was dissolved in a mixture of acetic acid (150 mL), water (150 mL), and conc. hydrochloric acid (38 mL) and the resulting solution was heated to 50° C. for 18 hrs. The reaction mixture was cooled in an ice-water bath, and sodium hydroxide pellets were added in portions until the mixture was neutralized. This mixture was extracted with dichloromethane (3×300 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give a dark oil. Chromatography on silica gel, eluting with hexane—10% ethyl acetate gave the product as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N-]>ClC(Cl)C.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:11][C@@H:9]([CH3:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:12])[CH3:20]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C[C@H](O)CNC(=O)OC(C)(C)C
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)CO[C@@H](C)CNC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 69.4 %

Procedure:
1.16 g (6.61 mmol) of (S)-(2-hydroxy-propyl)-carbamic acid t-butyl ester was dissolved in 20 mL of dichloroethane, then 0.66 mL (9.84 mmol) of ethyl diazoacetate was added thereto. 57 mg (0.12 mmol) of rhodium acetate was dropwise added thereto, and then heated to at 80° C. for 2 hour. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 1.2 g (4.59 mmol) of the title compound in a yield of 69%.
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([Mg]Cl)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1COCC1.O>[C:2]1([C:1]([OH:9])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCC[Mg]Cl
Reactant: COC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCC(O)(CCCCCCCC)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl benzoate (14.34 g, 105.3 mmol) was dissolved in anhydrous THF (43 mL) and this mixture was cooled to 0° C. A solution of n-octylmagnesiumchloride in THF (200.0 mL, 2.0M, 400 mmol) was then added dropwise, keeping the temperature at less than 10° C. Upon completion of addition, the mixture was left to stir at 0° C. for 2 hours. A solution of hydrochloric acid in water (400 mL, 1.0 M) was then added dropwise keeping the temperature at less than 25° C. The mixture was diluted with iProAc (420 mL) and the resulting organic layer was washed with 1.0 M HCl (1×70 mL), washed with brine (1×70 mL), dried over sodium sulfate and evaporated to yield a colorless liquid. The crude material was purified by silica gel column chromatography to afford a clear colorless liquid (21.0 g). 1H NMR (300 MHz, CDCl3, δ): 7.41-7.30 (m, 4H), 7.28-7.20 (m, 1H), 1.90-1.70 (m, 4H), 1.35-1.20 (m, 23H), 1.11-0.96 (m, 2H) and 0.92-0.83 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=O.[CH3:15][NH:16][CH2:17][CH2:18][NH2:19]>>[CH3:15][N:16]1[CH2:17][CH2:18][N:19]=[C:5]1[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: CNCCN
Product: Cc1cccc(C2=NCCN2C)c1[N+](=O)[O-]
Temperature: 190 °C
Yield: 75 %

Procedure:
A solution of methyl 3-methyl-2-nitrobenzoate (3.0 g, 15.4 mmol) in N-methylethylene diamine (5 g, 68 mmol) was heated at reflux for 1.5 hour, at which point the solvent was removed at 130° C. under reduced pressure. The residue was then heated at 190° C. for 1.25 hour before being cooled on ice to give the title compound of Step A (75% pure) as a brown oil.
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1>>[OH:8][C:4]1[CH:3]=[C:2]([C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:9])[CH:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=C(Br)CCC1
Reactant: OB(O)c1cccc(O)c1
Product: O=C1C=C(c2cccc(O)c2)CCC1
Yield: 64 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 3-hydroxyphenylboronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography yielded the product (83 mg, 64%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD): δ 7.22 (t, J=7.8 Hz 1H), 7.05 (ddd, J=7.8, 1.5, 0.9 Hz, 1H), 6.98 (t, J=1.5 Hz, 1H), 6.83 (ddd, J=8.1, 2.4, 1.2 Hz, 1H), 6.31 (t, J=1.2 Hz, 1H), 2.79 (td, J=6.0, 1.5 Hz, 2H), 2.46 (t, J=6.0 Hz, 2H), 2.12 (quintet, J=6.6 Hz, 2H). 13C (75 MHz, CD3OD): 202.5, 163.4, 158.8, 141.3, 130.7, 125.2, 118.4, 118.2, 113.8, 38.1, 29.2, 23.9. LCMS (ESI): mass calcd for (C12H12O2) m/z 188.08; measured [M+H]+: m/z 189.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[N+:13]([O-:24])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(OCc2ccccc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 119 %

Procedure:
To a methylene chloride (100 mL) solution of 5-benzyloxy-2-methyl-pyridine (5.99 g, 30.1 mmol) described in Manufacturing Example 127-1-1 was added m-chloroperbenzoic acid (8.79 g, 33.1 mmol, purity: 65%) at 0° C., which was stirred for 2 hours at room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture at 0° C., which was extracted with methylene chloride. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain 5-benzyloxy-2-methyl-pyridine-1-oxide (7.71 g). Acetic anhydride (77 mL) was added to 5-benzyloxy-2-methyl-pyridine-1-oxide (7.71 g) thus obtained, which was stirred for 80 minutes at 120° C. This mixture was cooled to room temperature and then concentrated under a reduced pressure. To an ethanol (50 mL) solution of this residue was added a 5 N sodium hydroxide aqueous solution (7 mL), which was stirred for 50 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. The residue was partitioned into saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (4.17 g, 54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([N:32](S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[C@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.SCC(O)=O.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:32][C@H:33]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: CC[C@@H](c1ccccc1)N([C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)CS
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Reaction time: 3 h
Yield: 64.8 %

Procedure:
(S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-[(4-nitro-benzenesulfonyl)-((S)-1-phenyl-propyl)-amino]-propionic acid methyl ester (1.8 g) was dissolved in 30 mL dry DMF, then 505 μL (670 mg) mercaptoacetic acid and 2.6 mL (2.6 g) DBU were added at rt. The reaction stirred for 3 h, then was partitioned between saturated aqueous NaHCO3 and diethyl ether. The organic layer was washed successively with aqueous NaHCO3, water, and brine, then was dried with Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 893 mg desired product after drying. 1H NMR (400 MHz, acetone-d6): 7.71 (d, 1H), 7.61 (d, 1H), 7.50-7.42 (m, 3H), 7.27-7.15 (m, 5H), 7.09 (m, 2H), 6.80 (d, 1H), 6.67 (d, 1H), 6.61 (m, 1H), 5.19 (s, 2H), 5.10 (m, 1H), 4.34 (m, 1H), 4.02 (m, 1H), 3.63 (s, 3H), 3.47 (t, 1H), 3.15 (t, 1H), 2.75 (m, 2H), 2.10 (s, 1H), 1.69-1.48 (m, 2H), 0.78 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH3:17])=[C:6]([N+:18]([O-])=O)[CH:5]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH3:17])=[C:6]([NH2:18])[CH:5]=1
Reactant: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c(N)c1
Reaction time: 3 h
Yield: 98.6 %

Procedure:
9.27 g 4-((1R,2R)-2-Methyl-cyclohexylamino)-3-nitro-benzoic acid methyl ester were dissolved in 100 ml ethanol, 0.20 g of palladium on carbon (10%) were added and the mixture was hydrogenated at 5 bar for 3 h. The catalyst was removed by filtration over celite, the filtrate was concentrated to obtain 8.20 g (99%) of 3-Amino-4-((1R,2R)-2-methyl-cyclohexylamino)-benzoic acid methyl ester. C15H22N2O2 (262.35), LCMS (method 8—1—1): Rt=0.77 min, m/z=263.15 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.Cl.[NH2:10][C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1Nc1cnnc(Cl)c1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
3,5-dichloropyridazine (1.6 g, 10.74 mmol), ethyl (cis)-2-aminocyclohexanecarboxylate hydrochloride (CA, 2.454 g, 11.81 mmol), and triethylamine (5.63 mL, 32.2 mmol) were added to DMSO (10.0 ml) and heated for 5 hrs at 120° C. and then allowed to stir at room temperature for 24 hr. Solvents were removed in vacuo. The residue was dissolved in EtOAc and then poured into sat. sodium bicarb. The aqeuous layer was removed and back extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate and concentrated to an oil. Purification on biotage again (DCM:MeOH, 0-9% B) and concentration afforded the product, I-22a, as a solid (2.207 g, 71.7%).