Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1.[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:20][C:21]2[NH:25][N:24]=[C:23]([CH2:33][CH2:34][C:35]3[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=3)[CH:22]=2)=[O:16])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(N2CCN3CCCC3C2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN5CCCC5C4)cc3)[nH]n2)cc(OC)c1
Yield: 10.2 %

Procedure:
4-(3,4,6,7,8,8a-Hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared as for Example 94, but starting from methyl 4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate (193 mg, 0.7 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (292 mg, 0.84 mmol) and 1M NaHMDS (1.23 ml, 1.23 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 33-53% gradient of acetonitrile in water, containing 1% 0.880 ammonia. The clean fractions were combined and evaporated to afford the title compound (34 mg, 10%); 1H NMR (399.9 MHz, DMSO-d6) δ 1.37-1.41 (1H, m), 1.67-1.77 (2H, m), 1.84-1.88 (1H, m), 1.99-2.06 (1H, m), 2.09 (1H, t), 2.18-2.25 (1H, m), 2.80-2.84 (1H, m), 2.87 (4H, s), 3.01-3.06 (2H, m), 3.73 (6H, s), 3.80-3.83 (1H, m), 3.96-3.98 (1H, m), 6.33 (1H, t), 6.42-6.45 (3H, m), 6.97 (2H, d), 7.90 (2H, d), 10.28 (1H, s), 12.07 (1H, s)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](S(C1C=CC(C)=CC=1)(=O)=O)[CH:13]=[C:12]2[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]2)[CH:31]=[CH:30][N:29]=1.[OH-].[Na+]>O1CCOCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]2)[CH:31]=[CH:30][N:29]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(-c3c[nH]c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 100 °C
Yield: 91.5 %

Procedure:
A solution of (R)-tert-butyl 3-(2-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylate (500 mg, 0.757 mmol) in dioxane (10 mL) was treated with aqueous 1N NaOH (5 mL) and heated at 100° C. for 2 h. The resulting mixture was cooled to RT, and quenched with ice cold water. The resulting precipitate was collected by filtration, washed with ice cold water and dried to obtain the pure (R)-tert-butyl 3-(2-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylate (350 mg, 92%). (R)-tert-butyl 3-(2-(5-(2,6-difluorophenyl)-1H-indol-3-yl)pyrimidin-4-ylamino)piperidine-1-carboxylate (350 mg, 0.69 mmol) was treated with ethanolic HCl (10 mL). The reaction mixture was stirred at RT for 16 h and then extracted with DCM. The combined organic layers were dried; filtered and concentrated to give the crude product, which was purified by recrystallization using 10% MeOH in CHCl3 to yield (R)-2-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-4-amine MS (ESI, pos. ion) m/z: 406 (M+1).
Reaction SMILES: C([Sn]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(CCCC)CCCC)CCC.[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=1>CN(C=O)C.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>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:23]1[N:22]=[N:21][C:20]([Cl:19])=[CH:25][CH:24]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cccs2)nn1
Temperature: 80 °C
Yield: 47.1 %

Procedure:
A mixture of tri-n-butylstannylthiophene (6.26 g, 16.78 mmol), 3,6-dichloropyridazine (5.00 g, 33.56 mmol), tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) and few crystals of 1,2-ditert-butyl of 2,6-di-tert-butyl-4-methylphenolo in dry DMF (50 mL) was deareated twice with nitrogen. The reaction mixture was heated at 80° C. for 6 hours and, after cooling, poured onto water (100 mL). A white precipitate was collected, washed several times with water and dried under vacuum. This solid was taken up with ether (25 mL) and filtered to afford 3.01 g of almost pure product. Finally, this solid was crystallized from MeOH—H2O to give the pure target compound as white crystals (1.56 g, 7.90 mmol, 47.3% yield). Mp 155° C.; 1H NMR (CDCl3) δ 7.75 (1H, d, 2J=11.0), 7.68 (1H, d, 2J=3.6), 7.54 (1H, d, 2J=5.0), 7.51 (1H, d), 7.18 (1H, dd).
Reaction SMILES: C(NC(C)C)(C)C.[Li].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[Br:17][C:18]1[C:19]([F:29])=[C:20]([F:28])[C:21](F)=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]>C1COCC1>[Br:17][C:18]1[C:19]([F:29])=[C:20]([F:28])[C:21]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Reactant: Nc1ccccc1Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of lithium diisopropylamine (49.0 mL, 2 M in THF/heptane) in THF (40 mL) was added 2-chlorophenylamine (6.50 mL, 60.6 mmol) at −78° C. After vigorous stirring for 10 minutes, a solution of 5-bromo-2,3,4-trifluoro-benzoic acid (2) (7.70 g, 30.2 mmol) in THF (60 mL) was added. The dry-ice bath was removed and the reaction mixture stirred for 4 hours at room temperature. The mixture was concentrated, treated with 10% aqueous HCl (75 mL), and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification by trituration with boiling CH2Cl2 gave 7.24 g (66%) of the desired acid (3) as a yellow solid
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16].C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:15]([C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[N:7]3)[CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)#[N:16]
Reactant: N#Cc1cccc(N2CCNCC2)c1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cccc(N2CCN(CCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-cyano phenylpiperazine (5.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.6 g compound (I-41) with a yield of 70.5%. ESI-MS [M+H]+: m/z 360.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:18][C:19]([Cl:23])([Cl:22])[C:20]#[N:21]>CCOCC>[Cl:18][C:19]([Cl:23])([Cl:22])[C:20](=[NH:21])[O:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC(c1ccccc1)c1ccc(Br)cc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: N=C(OC(c1ccccc1)c1ccc(Br)cc1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(4-bromophenyl)(phenyl)methanol from example 67 step 2 (175 g, 0.665 mol) was dissolved in Et2O (700 mL) and sodium hydride (2.66 g of 60% dispension in oil, 0.067 mol, 0.1 eg) was added. Reaction mixture was cooled to 0° C. and trichloroacetonitrile (96 g, 0.665 mol, 1 eg) was added dropwise over 15 min. Reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. Mixture was evaporated to dryness and solid was stirred in hexane for 18 hours. The solid was filtered to give the product.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Cl:42]Cl>ClCCl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:42])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Reactant: ClCl
Solvent: O
Solvent: ClCCl
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 88 %

Procedure:
A 2.0 g quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 10 ml of dichloromethane and to the solution was added 5 to ml of water. The mixture was cooled in an ice bath with stirring while thereto was added dropwise over 30 minutes about 10 ml of methylene chloride having dissolved therein 6.9 mmol of chlorine gas. After the addition, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layer thus separated and the dichloromethane layer were washed successively with aqueous solutions each of NaHCO3, Na2S2O3 and NaCl and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 1.87 g of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 88% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([CH:16]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C([Li])CCC.CN([CH:26]=[O:27])C>C1COCC1>[Si:9]([O:8][CH2:7][C:6]1[CH:16]=[C:2]([CH:3]=[CH:4][C:5]=1[Cl:17])[CH:26]=[O:27])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(C=O)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution of [(5-bromo-2-chlorobenzyl)oxy](tert-butyl)dimethylsilane from the previous step (1 eq.) in THF (0.08 M) was added, at −78° C., n-butyl lithium (2.5 M hexane solution, 1.1 eq) dropwise over 15 min. The reaction mixture was stirred at −78° C. for a further 30 min before DMF (2 eq.) was slowly added. The resulting solution was allowed to warm to RT over 3 h and then quenched with H2O. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded an orange oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][C@H:24]1[O:30][C:31](=[O:33])[CH3:32].[N:34]#CBr.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([C:29]#[N:34])[CH2:25][C@H:24]1[O:30][C:31](=[O:33])[CH3:32]
Reactant: N#CBr
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)C[C@H]1OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C#N)C[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To compound of example 126 (2.9 g, 6.15 mmol) in dry CHCl3 (40 mL) at 0° C. was added cyanogen bromide (2.1 g, 19.8 mmol). The reaction mixture was stirred at room temperature for 8 h. It was poured into water (100 mL) and extracted with CHCl3 (3×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated. The solid residue obtained was purified using a silica gel column and 2% IPA+1% liquor NH3 in CHCl3 as eluant to obtain the title compound.
Reaction SMILES: [N:1]1([C:30](OC(C)(C)C)=[O:31])[CH2:29][CH2:28][CH2:27][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].Cl.CCOC(C)=O.[NH:44]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:45](C(ON1C(=O)CCC1=O)=O)[CH3:46]>CCN(CC)CC>[NH:44]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:45]([C:30]([N:1]1[CH2:29][CH2:28][CH2:27][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4])=[O:31])[CH3:46]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared from 28.9 g of Boc-Pro-Arg(NO2)-OBzl, 150 ml of 4N HCl-AcOEt, 8 ml of Et3N and 16.3 g of Boc-Ala-OSu in the same manner as in Example 8-(1).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Cl:14]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(Cl)cc(C(C)C)c1N
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred solution of 2,6-diisopropylaniline (47 grams) in N,N-dimethylformamide (886 mL) was added N-chlorosuccinimide (37.3 grams) and the mixture was stirred overnight. The resulting dark red solution was poured into water (12 L) and extracted with diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting dark red oil was purified by filtration through silica gel, eluting with 6:1 hexane/methylene chloride to afford 32 grams of the title compound. 1H NMR δ 7.02 (s, 2), 3.71 (br s, 2), 2.91 (qq, 2, J=6.9 Hz), 1.27 (d, 6, J=6.9 Hz), 1.27 (d, 6, J=6.9 Hz).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Brc1ncccn1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ncccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 2-bromopyrimidine
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=2[O:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:3][CH2:2]1.O[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([O:12][CH2:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[O:11])=[CH:8][C:7]=2[O:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:3][CH2:2]1
Reactant: O=C(CO)OCc1ccccc1
Reactant: CS(=O)(=O)Oc1cc(C(=O)O)ccc1OCC1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Yield: 52.3 %

Procedure:
A solution of 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoic acid (0.300 g, 1.048 mmol), benzyl 2-hydroxyacetate (0.174 g, 1.048 mmol), EDC (0.603 g, 3.14 mmol), and DMAP (0.128 g, 1.048 mmol) in DCM (25 ml) was stirred at RT for 2 hours. The mixture was diluted with DCM and washed with HCl 1N and NaHCO35%. The organic phase was dried over Na2SO4, the solvent was removed under vacuum, and the crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=80:20 to 75:25). A further purification by trituration with EtOH was required to obtain 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoate (0.238 g, 0.548 mmol, 52.3% yield, MS/ESI+ 434.9 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8](Cl)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)c1sc2ncc(Cl)nc2c1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ncc(-c3ccsc3)nc2c1N
Temperature: 95 °C
Yield: 88 %

Procedure:
A solution of the methyl 7-amino-2-chloro-thieno[2,3-b]pyrazine-6-carboxylate prepared as described in Example 10C (0.190 g), thiophene-3-boronic acid (0.100 g), Pd(dppf)C12 (0.032 g) and triethylamine (0.22 mL) in degassed DMF was heated to 95° C. for 4 h, cooled, quenched in water and extracted with 1:1 Et2O/EtOAc (3×). The organics were washed 3× with water, brine, dried (Na2SO4), filtered and solvent evaporated to give 0.200 g (88%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.95 (3H, s), 6.23 (2H, br s), 7.50 (1H, dd), 7.79 (1H, dd), 8.05 (1H, dd), 9.00 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Br)cc(N)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (150 g, 544 mmol) in ethanol (750 mL), ammonium chloride (150 g, 2777 mmol) dissolved in water (750 mL) and iron powder (93.3 g, 1636 mmol) were added under stirring. Resulting reaction mass was heated at 80° C. for 7 h. On completion, reaction mass was filtered through celite giving washing of water and ethyl acetate, filtrate was extracted with ethyl acetate. Combined organic layers were dried, concentrated under reduced pressure giving the desired compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1([S:14](O)(=[O:16])=[O:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.O=S(Cl)[Cl:34]>>[CH2:1]([O:8][C@@H:9]([CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1([S:14]([Cl:34])(=[O:16])=[O:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 52 %

Procedure:
A mixture of (R)-1-(2,3-bis(benzyloxy)propyl)cyclopropane-1-sulfonic acid (630 g) and DMF (30 mL) in SOCl2 (1.5 L) was refluxed for 2 hours until HPLC analysis showed the reaction had gone to completion. The reaction mixture was concentrated to dryness and the residue purified on silica gel chromoatography with eluent: heptane for 5 minutes, then IPAC: heptanes=1:30; heptanes 1:10 resulting in the product as a red oil (298.5 g; 52% yield; 95% purity). 1H NMR (CDCl3, 400 MHz): δ 7.34 (m, 10H), 4.68 (d, 1H), 4.56 (bs, 1H), 4.53 (d, 1H), 4.16 (m, 1H), 3.54-3.62 (m, 2H), 2.63 (dd, 1H), 2.01 (q, 1H), 1.52-1.81 (m, 3H), 1.16 (m, 1H), 2.22 (bs, 1H), 1.75 (t, 2H), 1.38-1.40 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([NH:12]C(=O)OC(C)(C)C)[CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11])[CH2:3][CH2:2]1>Cl.C(OCC)(=O)C.O>[CH:1]1([CH2:4][C@H:5]([NH2:12])[CH2:6][O:7][CH2:8][CH2:9][O:10][CH3:11])[CH2:3][CH2:2]1
Reactant: COCCOC[C@H](CC1CC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOC[C@@H](N)CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
(S)-tert-Butyl 1-cyclopropyl-3-(2-methoxyethoxy)propan-2-ylcarbamate (1.01 g, 4 mmol) was dissolved in HCl/ethyl acetate (10 mL) and stirred at room temperature for 30 min. Then the reaction mixture was concentrated to give a residue, which was dissolved in H2O (10 mL) and then washed with ethyl acetate (2×10 mL). The pH of the aqueous layer was adjusted to 9˜10 with 5 N NaOH solution. After extraction with ethyl acetate (3×20 mL) the combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated to give the title product (0.072 g, 11%) as yellow oil; MS (EI): m/e=174.2 [M+Na]+.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[S:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:30][C:31]1[C:32]([O:46][CH3:47])=[C:33]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1>CN(C=O)C>[C:37]([C:35]1[CH:34]=[C:33]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[C:32]([O:46][CH3:47])=[C:31]([NH:30][C:13]([C:11]2[S:10][C:9]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[CH:12]=2)=[O:15])[CH:36]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2s1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3cccc([N+](=O)[O-])c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of the above carboxylic acid (900 mg) in DMF was added EDC (1.2 eq) and HOBT (1.2 eq). After stirring for 10 min, N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (1.0 eq) was added. The suspension was stirred at room temperature for 48 h. The DMF was removed in vacuo and the resulting oil was dissolved in EtOAc, washed with water three times, followed by saturated NaHCO3 solution and brine. The organics were dried over MgSO4, filtered and concentrated to give a crude yellow solid which was triturated with 30% EtOAc/hex (small amount) and filtered to provide 7-nitro-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide as a bright yellow solid (1.4 g, 72%).