Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)=[C:14]([NH2:15])[C:9]2=[C:8]([CH3:22])[C:7]=1[Cl:23].[H-].C([Al+]CC(C)C)C(C)C.CCOC(C)=O.CCCCCC>C1COCC1>[CH:18]1([NH:17][C:16]([C:13]2[S:12][C:10]3=[N:11][C:6]([O:5][CH2:4][CH2:3][OH:2])=[C:7]([Cl:23])[C:8]([CH3:22])=[C:9]3[C:14]=2[NH2:15])=[O:21])[CH2:20][CH2:19]1
Reactant: COC(=O)COc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(Cl)c(OCCO)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of (3-amino-5-chloro-2-cyclopropylcarbamoyl-4-methyl-thieno[2,3-b]pyridin-6-yloxy)-acetic acid methylester (0.250 g, 0.676 mmol) in THF (3 ml) at −78° C. is added dropwise a solution of diisobutylaluminum hydride (1.5M in toluene)(1.35 ml, 2.03 mmol). The reaction solution is stirred at −78° C. for 30 minutes, then room temperature for 1 hour. If the reaction is not complete, according to TLC (2:1 EtOAc:hexane), an additional 1.0 eq of diisobutylaluminum hydride (1.5M in toluene)(0.45 ml, 0.676 mmol) may be added. After 15 minutes, the reaction is quenched by the addition of 3 ml of a 1:1 mixture of MeOH:water. The reaction mixture is partitioned between water and EtOAc (50 ml each), and the layers are shaken and separated. The aqueous layer is extracted with 2×50 ml of EtOAc, and the combined organic layers are dried (anhydrous magnesium sulfate), filtered, and concentrated to give a yellow solid. This solid is taken up in 2:1 EtOAc:hexane, and once dissolved, a yellow precipitate is formed. The yellow solid is collected by filtration and dried in the vacuum oven at 60° C. overnight to afford the title compound as a yellow solid (0.155 g, 67%). Mass (m/z): 342.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[CH3:12].[NH2:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:12])[CH:4]=3)=[N:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: Cc1cc(CC(=O)O)ccc1Br
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Br)c(C)c3)nc2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2-(4-bromo-3-methylphenyl)acetic acid 24-5 (100 mg, 0.44 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (96 mg, 0.44 mmol) and HATU (200 mg, 0.53 mmol) in DMF (2 mL) was added DIEA (230 uL, 1.32 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na2SO4 and the solvent was evaporated. The residue was subject to silica gel flash chromatography to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-bromo-3-methylphenyl)acetamide 159-1. MS m/z 431.1 (M+1).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][Si:8]([CH3:19])([CH3:18])[C:9]1[O:13][CH:12]=[C:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH:10]=1.[C:20](Cl)(=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1.CCOCC>[C:20]([O:17][CH2:16][CH2:15][CH2:14][C:11]1[CH:10]=[C:9]([Si:8]([CH3:7])([CH3:18])[CH3:19])[O:13][CH:12]=1)(=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: C[Si](C)(C)c1cc(CCCO)co1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCCCc1coc([Si](C)(C)C)c1
Reaction time: 14 h

Procedure:
Pyridine (0.06 ml, 0.72 mmol) was added to a mixture of 3-(5-trimethylsilyl-3- furyl)propan-1-ol (from above) and lauroyl chloride (0.17 ml. 0.72 mmol) in tetrahydrofuran (4 ml) at room temperature. After 14 hours, the mixture was diluted with ether (10 ml) and washed successively with water, copper (II) sulphate and brine. Evaporation of the dried (magnesium sulphate) organic layers gave an oil, which was purified by preparative TLC (20×20 cm, 500μ silica plate; developed with 10% ethyl ether/petroleum ether). The title ester was obtained as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([CH2:11][CH3:12])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[Na].C[O-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:11]([C:6]1[N:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[N:3]=[C:2]([O:1][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:36][N:37]=[N:38][N:39]=3)=[CH:25][CH:24]=2)[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:12]
Reactant: CCCc1c(O)nc(C(F)(F)F)nc1CC
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCc1c(CC)nc(C(F)(F)F)nc1OCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 50 °C
Yield: 9 %

Procedure:
4-Hydroxy-6-ethyl-5-propyl-2-(trifluoromethyl)pyrimidine (1.2 g, 5 mmole) was converted to the sodium salt with sodium methoxide (275 mg). The sodium salt was dissolved in DMF and mixed with 2.8 g (5 mmole) of 5-(4'-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole [U.S. Pat. No. 4,870,186], and the mixture heated at 50° C. for 18 hours. The solvent was evaporated to dryness and the residue was triturated with excess water to give a gum which was extracted into EtoAc. The organic layer was washed with H2O twice, dried over Na2SO4 and evaporated to a thick oil (4 g). One gram of this oil was treated with dry HCl saturated methanol for 3 hours then evaporated to dryness. The residue was triturated with hexane twice and decanted to afford a gum. The rest of the material was treated in the same way to provide a total of 2 g of crude product. Flash chromatography through silica gel and elution with CHCl3 contg. 4% MeOH gave 210 mg of the desired compound as a white solid. TLC, Silica gel (CHCl3 -MeOH-NH4OH,7:3:2%) Rf 0.55 MS (DCI) [M+H]+ 469
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[CH:10][S:11][CH:12]=1.O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][C:37]([F:40])([F:39])[F:38])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]3[O:19][N:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][C:37]([F:38])([F:39])[F:40])[N:27]=3)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[CH:10][S:11][CH:12]=1
Reactant: Cc1cscc1-c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cscc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1C(F)(F)F

Procedure:
Oxalyl chloride (106 μL; 1.26 mmol; 3 eq.), Intermediate 32 (120 mg; 0.42 mmol; 1 eq.), Intermediate 2 (92 mg; 0.42 mmol, 1 eq.) and DIEA (217 μL; 1.26 mmol; 3 eq.) were reacted according to general procedure 2. Purification by crystallisation from MeOH afforded the title compound as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.CCN(CC)CC.[Cl:32][C:33]1[CH:34]=[C:35]([CH:40]=O)[CH:36]=[N:37][C:38]=1[CH3:39].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl>[ClH:32].[Cl:32][C:33]1[CH:34]=[C:35]([CH2:40][NH:3][CH:4]2[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]3[N:21]4[C:22]5[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=5[CH:18]=[CH:19][C:20]4=[O:23])[CH2:12]3)[CH2:8][CH2:9]2)[CH:36]=[N:37][C:38]=1[CH3:39]
Reactant: Cc1ncc(C=O)cc1Cl
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ncc(CNC2CCN(C[C@@H]3Cn4c(=O)ccc5ccc(=O)n3c54)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
A solution of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (63.3 mg, 0.170 mmol) and Et3N (0.022 ml, 0.154 mmol) in CHCl3 (3 ml) was stirred at room temperature for 15 min then 5-chloro-6-methyl-3-pyridinecarbaldehyde (for a synthesis see WO20006/137485 A1 Example 256) (24 mg, 0.154 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 h then NaBH(OAc)3 (98 mg, 0.463 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was monitored by LCMS and when full conversion was observed, it was quenched with 10% NaHCO3 and extracted with DCM several times. The organic layer was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography using a 5 g silica gel cartridge, and mixtures of DCM and MeOH as eluent afforded 9 mg (13%) of the expected product as the free base. It was dissolved in MeOH (2 ml). HCl (1M solution in Et2O, 0.02 ml, 0.02 mmol) was added dropwise. After stirring at room temperature for 20 min, the solvent was evaporated. (1R)-1-[(4-{[(5-Chloro-6-methyl-3-pyridinyl)methyl]amino}-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione hydrochloride (92.5 mg, 0.194 mmol, 49%) was obtained as a yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2cccc(F)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 3-fluorobenzyl bromide
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[C:10](/[CH:12]=[CH:13]/[CH2:14][O:15][CH3:16])[CH:9]=[C:8](/[CH:17]=[CH:18]/[CH2:19][O:20][CH3:21])[CH:7]=2)[CH2:3][CH2:2]1.[H][H]>[Pd].CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[C:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: COC/C=C/c1cc(/C=C/COC)cc(C(=O)NC2CC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCCc1cc(CCCOC)cc(C(=O)NC2CC2)c1

Procedure:
An EtOAc (0.15 M) solution of N-cyclopropyl-3,5-bis[(1E)-3-methoxyprop-1-en-1-yl]benzamide (1 eq.) from the previous step was eluted through an H-Cube hydrogenation apparatus equipped with a 10% palladium over carbon cartridge at a rate of 1 mL/min with EtOAc as the eluent. The hydrogenation was carried out using full hydrogen setting at RT. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]2=[O:23])[CH2:10][CH2:9]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].CO>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]2=[O:23])[CH2:10][CH2:9]1
Reactant: O=C1Cc2ccccc2N1C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1Cc2ccccc2N1C1CCNCC1
Reaction time: 1 h

Procedure:
A solution of 10 ml of methanol containing 296 mg of 1-(1-benzyl-4-piperidyl)indol-2-one was treated with 300 mg of palladium hydroxide catalyst. The resulting suspension was hydrogenated at atmospheric pressure for 60 minutes at 23° C. More catalyst was added (100 mg) and the hydrogenation was continued for 30 minutes more. The reaction mixture was filtered through Celite, concentrated and azeotropically dried with toluene to yield 217 mg of 1-(4-piperidyl)indol-2-one.
Reaction SMILES: [CH:1]1([N:7]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:32]=[CH:31][C:20]([CH2:21][NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[CH:1]1([N:7]([CH2:33][CH:34]2[CH2:35][CH2:36]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:31][CH:32]=3)=[O:15])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
A solution of tert-butyl N-{4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]benzyl}glycinate (Example 73; 60 mg; 0.12 mmol) in DCM (5 ml) was treated with trifluoroacetic acid (200 μl; 2.61 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The solvents were removed to give the title compound as a yellow oil in 77% yield.
Reaction SMILES: [SH:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](I)[CH3:25]>CN(C=O)C>[CH2:24]([S:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1)[CH3:25]
Reactant: CCOC(=O)c1c(S)nc2ccncc2c1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(SCC)nc2ccncc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of ethyl 2-mercapto-4-methyl-1,6-naphthyridine-3-carboxylate (0.22 g, 0.89 mmol, 1 eq.) in dry DMF (5 ml) was added K2CO3 (0.37 g, 2.66 mmol, 3 eq.) at 0° C. followed by the addition of ethyl iodide (0.41 g, 2.66 mmol, 3 eq.). The reaction mixture was stirred at RT for 1 h. Afterwards the mixture was poured into ice water (10 ml) and extracted with EtOAc (3×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over anhydrous Na2SO4 to provide the crude product, which was purified by CC (EtOAc/hexane 2:3) to yield ethyl 2-(ethylthio)-4-methyl-1,6-naphthyridine-3-carboxylate (0.18 g, 0.65 mmol, 73%).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([S:7]([C:10]2([C:11]#[N:12])[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)CC#N)cc1
Reactant: BrCCCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: Cc1ccc(S(=O)(=O)C2(C#N)CCCC2)cc1
Yield: 84 %

Procedure:
Similarly to Example 1 paragraph (a), by reaction of 2 g (10.2 mmol) of (toluene-4-sulfonyl)-acetonitrile with 1.35 ml (11.3 mmol) of 1,4-dibromobutane, 50 ml of aqueous soda solution, 233 mg (1 mmol) of benzyltriethylammonium chloride. 2.14 g of 1-(toluene-4-sulfonyl)cyclopentanecarbonitrile is obtained in the form of a brown powder. (Yield=84%)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13]C(C)(C)CO)=[O:12])=[CH:9][N:8](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=1.[I-].[Na+].CN[C@@H]1CCCC[C@H]1NC.ClC1C=C2C(C=NN2)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[N:3]1[CH:2]=[CH:7][N:6]=[C:5]2[NH:8][CH:9]=[C:10]([C:11]([NH2:13])=[O:12])[C:4]=12
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Clc1ccc2cn[nH]c2c1
Solvent: Cc1ccccc1
Product: NC(=O)c1c[nH]c2nccnc12
Temperature: 110 °C
Yield: 242 %

Procedure:
To a stirred solution of 2-bromo-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 316 μmol) in toluene (2 mL) was added copper (I) iodide (3.17 mg, 35.4 μmol), sodium iodide (94.7 mg, 631 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (11.5 mg, 80.5 μmol). The reaction mixture was sealed under nitrogen and the mixture heated at 110° C. for 15 h. 6-Chloro-1H-indazole (48.2 mg, 316 μmol) and potassium phosphate tribasic (141 mg, 663 μmol) were added and the mixture degassed and filled with nitrogen, then heated in a sealed tube at 110° C. for 15 h. The mixture was filtered, the cake washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave 2-(6-chloro-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (124 mg, 76%). 1H NMR (CDCl3) δ: 9.14 (s, 1H), 8.51-8.55 (m, 1H), 8.38 (s, 1H), 8.26 (d, J=1.0 Hz, 1H), 7.91 (s, 1H), 7.78 (dd, J=8.5, 0.5 Hz, 1H), 7.33 (dd, J=8.5, 1.8 Hz, 1H), 5.73 (s, 2H), 3.80 (s, 2H), 3.57-3.64 (m, 2H), 1.56 (s, 6H), 0.96 (dd, J=8.8, 7.8 Hz, 2H), −0.02 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][CH2:17][O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:20]1([CH2:19][O:18][CH2:17][CH:16]=[C:11]2[CH2:12][CH:13]3[NH:8][CH:9]([CH2:15][CH2:14]3)[CH2:10]2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=CCOCC1CC1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(COCC1CC1)=C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.3 %

Procedure:
A reaction flask was charged with 3-(2-cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester (138LH49) (0.115 g, 0.37 mmol) in DCM (2 mL). TFA (0.5 mL) was added and the reaction was stirred at rt for 3 h. The reaction mixture was quenched with 1 M NaOH and the product extracted into diethyl ether. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give the crude title compound (0.090 g).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Na+].[Br-].B(F)(F)F.CCOCC.[OH-].[Na+]>C(OCC)(=O)C.O>[OH:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Agent: FB(F)F
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1cc(O)c(C(=O)O)cc1OC
Temperature: 40 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
In 10 g of ethyl acetate were suspended 2.0 g of 2,4,5-trimethoxybenzoic acid (1a) and 1.45 g of NaBr in a stream of argon, to which 4.0 g of BF3.Et2O was then added dropwise at 25° C., followed by heat stirring at 40° C. for 3 hours. The reaction mixture was cooled with ice, to which 10 mL of water was then added dropwise at 10° C., followed by dropwise adding 7.5 g of a 25% (w/w) sodium hydroxide aqueous solution. Thereto was further added 10 mL of water before stirring, followed by filtering off insoluble inorganic matter. To the separated aqueous layer was dropwise added 3.94 g of 35% hydrochloric acid, followed by stirring for 10 minutes. The precipitated crystal was collected by filtration and washed with water. The resultant crystal was then dried under reduced pressure at 60° C. to provide 1.7 g of 2-hydroxy-4,5-dimethoxybenzoic acid (2a) at a yield of 91%.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([O:15][C@H:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:20])([F:19])[F:18])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C@H:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]([F:18])([F:19])[F:20])=[O:14])=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCCCCC[C@@H](OC(=O)c1ccc(O)cc1)C(F)(F)F

Procedure:
To a solution of the compound obtained in (1) above (3.8 g) in methanol (100 ml), was added 10% Pd on carbon (0.4 g). The mixture was subjected to hydrogenation in an atmosphere of hydrogen to obtain the titled compound (2.8 g).
Reaction SMILES: C([O:3][C:4]([C:6]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)=[CH:7][CH3:8])=[O:5])C>CO.[OH-].[Na+]>[NH2:14][C:11]1[S:12][CH:13]=[C:9]([C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH3:8])[N:10]=1
Reactant: CC=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC=C(C(=O)O)c1csc(N)n1

Procedure:
The product of example 82 was dissolved in a mixture of 20 ml methanol and 5 ml 2 n NaOH.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4]/[C:5](/[CH3:37])=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([N:17]([C:22]1[C:31]([C:32]([O:34]C)=[O:33])=[C:30]2[C:25]([CH:26]3[CH2:36][CH:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1)C(OC)=O)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4]/[C:5](/[CH3:37])=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:22]1[C:31]([C:32]([OH:34])=[O:33])=[C:30]2[C:25]([CH:26]3[CH2:36][CH:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1)(=[O:15])=[O:16])[CH3:39]
Reactant: CCN(CC)C/C(C)=C\c1cc(F)ccc1S(=O)(=O)N(C(=O)OC)c1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: O=CO
Product: CCN(CC)C/C(C)=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Yield: 87.8 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[N-[2-((Z)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzenesulfonyl]-N-methoxycarbonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 200, 0.264 g) and lithium hydroxide monohydrate (0.505 g) in dioxane (9 mL) and water (3 mL) was irradiated in the microwave at 130° C. for 40 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated in vacuo then azeotroped with a mixture of ethanol and toluene. The residue was triturated with 15% methanol in DCM, filtered and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-40%. The resultant solid was triturated with ether and filtered to give (1aRS,7bSR)-5-[2-((Z)-3-diethylamino-2-methylprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.202 g) as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](Br)[CH:9]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:30]2[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccnc(Br)c1
Reactant: OB(O)c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccnc(-c2ccncc2)c1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 4-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=53%).