Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]([C:9]1[NH:10][C:11](=[O:21])[C:12]([OH:20])=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=1)([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[CH2:28]([O:20][C:12]1[C:11](=[O:21])[N:10]2[C:9]([C:6]([CH3:7])([CH3:8])[O:5][CH2:4][CH2:3][CH2:2]2)=[N:14][C:13]=1[C:15]([OH:17])=[O:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1nc(C(C)(C)OCCCCl)[nH]c(=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 60 °C
Reaction time: 5 h
Yield: 135.7 %

Procedure:
A suspension of intermediate 33, ethyl 2-(2-(3-chloropropoxy)propan-2-yl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (0.205 g, 0.64 mmol) and anhydrous potassium carbonate (0.361 g, 2.6 mmol) in anhydrous dimethylformamide (4 mL) was stirred at 60° C. for 5 hours. The reaction mixture was treated with benzyl bromide (0.122 g, 0.71 mmol) and stirred for 16 hours. Following this, 2 mL of H2O was added and the mixture stirred for an additional 24 hours. Solvent was removed by rotary evaporator and the resulting residue suspended in 0.5 N hydrochloric acid (16 mL). The crude product was extracted with ethyl acetate (2×15 mL), then dried (sodium sulfate), filtered, and concentrated to dryness by rotary evaporator to give 0.299 g (Yield>100%) of the title compound as a solid. LC/MS [M+H]+=345.21.
Reaction SMILES: [N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:25]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:26]([C:31]([NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[C:36]([Cl:43])[CH:35]=2)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.O>ClCCl>[N:1]1[C:6]2[O:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:38]([C:37]3[CH:41]=[CH:42][C:34]([NH:33][C:31]([C:26]4[C:25]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:32])=[CH:35][C:36]=3[Cl:43])=[O:39])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CNc1ccccc1O2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3cccnc3Oc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 0.198 g of 5,6-dihydropyrido[2,3-b][1,5]benzoxazepine, 0.155 g of N,N-diisopropylethylamine and 0.444 g of 4-[([1,1-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride in 12 ml of dichloromethane is stirred at room temperature for 2.5 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N Na2CO3, H2O, brine and dried (Na2 SO4). The solution is passed through a thin pad of hydrous magnesium silicate. The filter pad is washed with 50 ml of hexane-ethyl acetate (1:2) and the filtrate concentrated to dryness.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[N:13]([CH:19]3[CH2:24][CH2:23][N:22]([S:25]([C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([OH:33])=[O:32])(=[O:27])=[O:26])[CH2:21][CH2:20]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(=O)(=O)(O)O.[CH3:42]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[N:13]([CH:19]3[CH2:24][CH2:23][N:22]([S:25]([C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([O:33][CH3:42])=[O:32])(=[O:26])=[O:27])[CH2:21][CH2:20]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CO
Reactant: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C(=O)O)c4)CC3)C(=O)C2(C)C)cc1OC
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1

Procedure:
0.5 g 3-({4-[3-(3,4-Dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}sulfonyl)benzoic acid (compound described in example 25) are suspended in 20 ml of methanol, 0.2 ml concentrated sulfuric acid are added, and the reaction mixture is heated to reflux for 24 h. The solvent is removed under reduced pressure, the residue is taken up in DCM, the organic phase is washed with aqueous sodium carbonate solution (5%) and dried over MgSO4. The solvents are evaporated under reduced pressure and the crude product is crystallized from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:21]#[N:22])[C:18]=1[O:19]C)[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH2:8]1)=[O:6].[Cl-].[Li+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:21]#[N:22])[C:18]=1[OH:19])[C:5]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH2:8]1)=[O:6]
Reactant: COc1c(Cl)cc(C(=O)N2CSc3ccccc32)cc1C#N
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)N2CSc3ccccc32)cc(Cl)c1O
Reaction time: 2 h
Yield: 33.3 %

Procedure:
3-(3-chloro-5-cyano-4-methoxybenzoyl)-2,3-dihydro-1,3-benzothiazole (213 mg) was dissolved in N,N-dimethylformamide (2 mL), and lithium chloride (111 mg) was added to the solution, and then the mixture was stiffed at 100° C. for 2 hours. To the reaction solution, 1N hydrochloric acid was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1), and then crystallized from n-hexane-chloroform to obtain the title compound (68 mg) as a pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:10]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([C:20]([O:22]C)=[O:21])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[C:20]([C:9]1[S:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[C:10]=1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1sc2cccc(OC)c2c1CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2sc(C(=O)O)c(CCc3ccccc3)c12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a solution of 4-methoxy-2-methoxycarbonyl-3-(2-phenylethyl)benzo[b]thiophene (1.09 g) in tetrahydrofuran (6 mL)-methanol (21 mL) was added 1 mol/L aqueous sodium hydroxide solution (21 mL), and the mixture was heated for reflux for 3.5 hours. The reaction mixture was cooled to room temperature. To the mixture was added 2 mol/L hydrochloric acid (11 mL), and the precipitated crystals were collected by filtration. The crystals were dried under reduced pressure to give the title compound (1 g).
Reaction SMILES: C1C[O:4]CC1.[CH3:6][C:7]([CH3:40])([CH2:10][C@@:11]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:16][C:15](=[O:17])[N:14]([C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29](=[O:32])[N:28]([CH3:33])[CH:27]=3)=[CH:22][CH:21]=2)[CH3:19])[CH2:13][CH2:12]1)[C:8]#[N:9].C(N)(=O)C>Cl[Pd]Cl.O>[CH3:40][C:7]([CH3:6])([CH2:10][C@@:11]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:16][C:15](=[O:17])[N:14]([C@H:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29](=[O:32])[N:28]([CH3:33])[CH:27]=3)=[CH:22][CH:21]=2)[CH3:19])[CH2:13][CH2:12]1)[C:8]([NH2:9])=[O:4]
Reactant: C1CCOC1
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Agent: Cl[Pd]Cl
Agent: CC(N)=O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)C(N)=O)(c2ccccc2)OC1=O

Procedure:
A THF:H2O (2 mL, 3:1) solution of 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (55 mg, 0.12 mmol), acetamide (177 mg, 3 mmol) and PdCl2 (21 mg, 0.12 mmol) was stirred overnight. The solvent was removed and the crude material redissolved in CH3CN. The crude product was purified via prep HPLC to afford 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (28 mg). LC-MS Method 1 tR=1.25 min, m/z=488 (M+1); 1H NMR (CDCl3) 7.55 (dd, 1H, J=9 Hz, 3 Hz), 7.42 (d, 1H, J=3 Hz), 7.32 (d, 1H, J=4 Hz), 7.29 (m, 4H), 7.14 (d, 2H, 8 Hz), 7.00 (d, 2H, J=8 Hz), 6.79 (d, 1H, J=9 Hz), 5.66 (q, 1H, J=8 Hz), 3.62 (s, 3H), 2.95-2.89 (m, 1H), 2.5 (d, 1H, J=15 Hz), 2.26-2.1 (m, 3H), 2.2 (d, 1H, J=15 Hz), 2.5 (d, 1H, J=15 Hz), 2.26-2.10 (m, 3H), 2.2 (d, 1H, J=15 Hz), 1.53 (d, 3H, J=7 Hz), 1.22 (s, 3H), 1.20 (s, 3H)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[OH:25][CH:22]([CH2:23][OH:24])[CH2:21][NH:20][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: NCC(O)CO
Product: O=C(Nc1nc2cccc(NCC(O)CO)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and 3-amino-1,2-propanediol (1.0 mL) as a white powder (6 mg, 7%). HPLC, Rt: 1.65 min. (purity 99.5%). LC/MS, M+(ESI): 328.1, M−(ESI): 326.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7].[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1.Cl>ClCCl>[CH3:11][S:12]([O:1][CH2:2][CH2:3][CH:4]([CH2:8][CH2:9][O:10][S:12]([CH3:11])(=[O:14])=[O:13])[CH2:5][CH2:6][O:7][S:12]([CH3:11])(=[O:14])=[O:13])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(CCO)CCO
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an stirred ice-cooled solution of tris(2hydroxyethyl)methane (10 g, 0.0676 mol) in dichloromethane (50 ml) was slowly dripped a solution of methanesulphonyl chloride (40 g, 0.349 mol) in dichloromethane (50 ml) under nitrogen at such a rate that the temperature did not rise above 15° C. Pyridine (21.4 g, 0.27 mol, 4 eq) dissolved in dichloromethane (50 ml) was then added drop-wise at such a rate that the temperature did not rise above 15° C., exothermic reaction. The reaction was left to stir at room temperature for 24 h and then treated with 5 N hydrochloric acid solution (80 ml) and the layers separated. The aqueous layer was extracted with further dichloromethane (50 ml) and the organic extracts combined, dried over sodium sulphate, filtered and concentrated in vacuo to give tris[2-(methylsulphonyloxy)ethyl]methane contaminated with excess methanesulphonyl chloride. The theoretical yield was 25.8 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=[O:23].CN>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20][O:21][C:22](=[O:23])[NH:24][CH3:25])[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1

Procedure:
0.5 g of the compound [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol in Example 1 was dissolved in 10 ml of THF, to which solution was added 0.49 g (1.7 equivalents) of 1,1′-carbonyldiimidazole. The consumption of all the reactants was confirmed by TLC, and 2 equivalents of methyl amine were added to the reaction solution. 2 hours later, the solvent was distilled off under reduced pressure, 50 ml of a 1N—HCl aqueous solution was placed in the reactants, and the mixture was extracted three times with 30 ml of ethyl acetate. An obtained organic layer was distilled under reduced pressure, followed by column chromatography to obtain methyl-carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester as a desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N+:3]=1[O-].C1(C)C=CC(S([Cl:22])(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:22][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCl)nc1

Procedure:
Methyl 6-methylnicotinate 1-oxide (from Step 1) (6.0 g, 35.9 mmol) was added into the p-toluenesulfonyl chloride (10 g, 52.4 mmol) in 100 mL of 1,4-dioxane. The mixture was heated to reflux for 20 hours. Saturated sodium bicarbonate solution (200 ml) was added into the reaction and the mixture was transferred to separatory funnel. The compound was extracted using ethyl acetate (300 ml×2) and the combined ethyl acetate solution was dried over magnesium sulfate and evaporated to black solid (5.2 g, 78%). LC/MS, tr=1.52 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 186 (M+H). ES-HRMS m/z 186.0314 (M+H calcd for C8H9ClNO2 requires 186.0316).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([NH2:23])=O)=[CH:15][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]#[N:23])=[CH:15][CH:14]=3)[C:9]2=[O:24])=[CH:6][CH:7]=1
Reactant: NC(=O)CCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#CCCc1ccc(N2CCN(c3ccc(Br)cc3)C2=O)cc1
Temperature: 0 °C

Procedure:
To 750 mg of 1-(4-bromophenyl)-3-[4-[2-(aminocarbonyl)-ethyl]-phenyl]-imidazolidin-2-one and 320 mg of pyridine in 10 ml of tetrahydrofuran are added dropwise at -10° C., with stirring, 460 mg of trifluoroacetic acid anhydride in 1 ml of tetrahydrofuran. After stirring overnight at ambient temperature the reaction mixture is diluted with ice water and the precipitate obtained is suction filtered, washed and dried.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=O)[C:4]2=[N:3][CH:2]=1.[OH-].[Na+].BrCCCCBr>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[CH2:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][CH:9]=[C:4]2[N:3]=[CH:2]1
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: BrCCCCBr
Solvent: CS(C)=O
Product: C1=NC2=CNC3=C(Cc4ccccc43)N2C1

Procedure:
The procedure is performed as in Example 9, but starting with 1.1 g of 5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one, 40 ml of dimethyl sulphoxide, 2 g of sodium hydroxide pellets, 32 mg of tetrabutylammonium bromide and 0.6 ml of 1,4-dibromobutane. After drying at 80° C., 0.17 g of spiro[5H,10H-imidazo[1,2-a]indeno[l,2-e]pyrazine-10:1'-cyclopentane]-4-one is obtained, in the form of a white solid melting above 260° C. (Analysis % calculated C: 73.63, H: 5.45, N: 15.15, O: 5.77, % found C: 73.8, H: 5.8, N: 15.1, O: 6.0).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[O:30][CH:31]=[CH:32][CH:33]=1)CCC.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(Br)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(-c3ccco3)cc2)c1
Yield: 26.5 %

Procedure:
To a stirred solution of 1-(4-bromophenyl)-4-methyl-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole (0.1 g, 0.26 mmol) in dioxane (5 mL) was added 2-(tributylstannyl)furan (0.118 g, 0.33 mmol), LiCl (0.027 g, 0.64 mmol), tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.026 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 0.5 hours. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (4/1). The resulting solid was recrystallized from CH2Cl2/hexane to give the title compound (0.026 g, 26.5% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C@@H:5]([NH:13][C:14]1[S:15][C:16](=[CH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:36][CH2:35][C:30]4(OCCO4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[C:17](=[O:19])[N:18]=1)[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[NH2:38][CH2:39][C@@H:40]([C:42]1[CH:43]=[CH:44][C:45]([OH:53])=[C:46]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:47]=1)[OH:41].CNC1SC(=CC2C=CC(N3CCC(=O)CC3)=CC=2)C(=O)N=1.NC[C@@H](C1C=CC=C(Cl)C=1)O>>[CH2:1]([O:3][C:4](=[O:37])[C@@H:5]([NH:13][C:14]1[S:15][C:16](=[CH:20][C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:28][CH2:29][CH:30]([NH:38][CH2:39][C@H:40]([OH:41])[C:42]4[CH:43]=[CH:44][C:45]([OH:53])=[C:46]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:47]=4)[CH2:35][CH2:36]3)=[CH:25][CH:26]=2)[C:17](=[O:19])[N:18]=1)[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC4(CC3)OCCO4)cc2)S1)C(=O)OCC
Agent: CNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Agent: NC[C@H](O)c1cccc(Cl)c1
Product: CCOC(=O)CC[C@H](NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)S1)C(=O)OCC

Procedure:
The title compound was prepared from (2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioic acid diethyl ester(which was obtained in Intermediate 34) and N-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 10) according to the procedures of Intermediate 18 and Example 1 as a yellowish solid; mp>130° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.19(t, J=7.0 Hz, 3 H), 1.22(t, J=7.0 Hz, 3 H), 1.70-3.00 (m,14 H), 2.92(s, 3 H), 3.50-3.90 (m, 2 H), 4.05(q, J=7.0 Hz, 2 H), 4.14(q, J=7.0 Hz, 2 H), 4.48(dd, J=8.0, 4.3 Hz, 1 H), 4.68(dd, J=8.7, 5.4 Hz, 1 H), 6.82(d, J=8.2 Hz, 1 H), 7.02(dd, J=8.2, 2.0 Hz, 1 H), 7.05(d, J=8.9 Hz, 2 H), 7.18(d, J=2.0 Hz, 1 H), 7.40(d, J=8.9 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 359.5 ((M+2H)2+, 100%); 718.2 (MH+, 20%); HRMS Calcd. for C33H44N6O9S2 (MH+): 718.2575. Found: 718.2581.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH2:24][CH3:25])[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[F:26][C:27]1[CH:48]=CC(COC2N=C(C(O)=O)C=NC=2N2CCCC2)=[CH:29][CH:28]=1.N[C@@H](CC(C)C)CO>>[OH:1][CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:26])=[CH:48][CH:25]=2)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: O=C(O)c1cnc(N2CCCC2)c(OCc2ccc(F)cc2)n1
Reactant: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Agent: CC(C)C[C@H](N)CO
Product: CC(C)C[C@@H](CO)NC(=O)c1cnc(N2CCCC2)c(OCc2ccc(F)cc2)n1

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-(4-fluoro-benzyloxy)-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid and (S)-2-amino-4-methyl-pentan-1-ol (commercially available). m/z (ES+): 417.5 (M+H).
Reaction SMILES: BrC[CH2:3][C:4]1[C:5]2[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=2[C:7]2[C:8](=[O:21])[NH:9][C:10]([NH:14]C(=O)C(C)(C)C)=[N:11][C:12]=2[CH:13]=1.[C:26](O)(=[O:28])C>C[O-].[Na+]>[NH2:14][C:10]1[NH:9][C:8](=[O:21])[C:7]2[C:6]3[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=3[C:4]([CH2:3][O:28][CH3:26])=[CH:13][C:12]=2[N:11]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)Nc1nc2cc(CCBr)c3ccccc3c2c(=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Product: COCc1cc2nc(N)[nH]c(=O)c2c2ccccc12
Temperature: 65 °C

Procedure:
A solution of N-(6-(bromoethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.28 g, 0.72 mmole) in 0.3M sodium methoxide (25 ml) was stirred and heated at 65° C. under a nitrogen atmosphere for 4 hours. After cooling, the mixture was acidified to pH 6 with glacial acetic acid, and then all solvent was removed under reduced pressure. The residue was triturated with water (20 ml), then filtered, washed with water and acetone, and dried to give 3-amino-6-(methoxymethyl)benzo[f]quinazolin-1(2H)-one as an off-white solid. (0.12 g, 58%) 1H NMR(DMSO-d6, 200 MHz) d 3.39(s, 3H, OCH3); 4.85(s, 2H, CH2); 6.54(br s, 2H, NH2); 7.33(s, 1H, Ar): 7.44(dt, J=6.9, 1.4 Hz, 1H, Ar); 7.59(dt, J=6.9, 1.4 Hz, 1H, Ar); 7.96(dd, J=8.2, 1.0 Hz, 1H, Ar); 9.69(d, J=8 Hz, 1H, Ar); 11.11(br s, 1H, NH); 11.91(br s, <1H, pyr-NH+). Anal. Calculated for C14H13N3O2.1/2HOAc.1/10H2O: C, 62.75; H, 5.34; N, 14.64. Found C, 62.74; H, 5.31; N, 14.64.
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[CH3:8][S:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O.Cl.[OH-].[Na+]>C(O)C>[CH3:8][S:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]
Reactant: CSCCOc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSCCOc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Tin chloride dihydrate (57.9 g, 0.26 mole) in ethyl alcohol (90 ml) was added to a mixture of 2-(2-methylthioethoxy)nitrobenzene (18.1g, 0.085 mole), conc. HCl (72.4 ml) and ethyl alcohol (36 ml). The reaction mixture was stirred for 24 h at room temperature. Sodium hydroxide (6M, 270 ml) was added to the reaction mixture. Extraction with methylene chloride (3×400 ml) gave after drying the organic layer over sodium sulfate and evaporation of the solvent 14.8 g (95%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C=O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: Fc1cnc2[nH]nc(Br)c2c1
Reactant: Clc1ccccc1C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cnc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine, 133a, (0.97 g, 4.49 mmol) and K2CO3 (1.86 g, 13.47 mmol) in DMF (9.7 mL) was cooled to 0° C. Chlorodiphenylmethylbenzene (1.38 g, 4.94 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted into ethyl acetate (40 mL) and water (30 mL) and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (40% ethyl acetate/hexanes) to afford 1.68 g of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.45-8.38 (m, 1H), 8.04 (dd, J=8.0, 2.7 Hz, 1H), 7.35-7.16 (m, 15H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.03 minutes (M+H) 459.46.