Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([O:61][Si](C(C)(C)C)(C)C)[CH:57]=4)[CH:52]=3)[CH:46]([OH:69])[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:60]=[CH:59][C:58]4[C:53](=[CH:54][CH:55]=[C:56]([OH:61])[CH:57]=4)[CH:52]=3)[CH:46]([OH:69])[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5cc(O)ccc5c4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 48 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (39.8 mg) in CH2Cl2 (1.5 mL) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL of a 10% w/v solution). The mixture was stirred 1.25 h at 0° C. and then 1.75 h at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted 2× with 2:1 hexanes/acetone) affording 17 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(6'"-hydroxynaphth-2-yloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:23][CH2:24][CH2:25][OH:26])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:23][CH2:24][CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCO)c2cccc(F)c2F)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCOS(C)(=O)=O)c2cccc(F)c2F)C1
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate in dry CH2Cl2 (50 mL) was added Et3N (5.2 mL, 37.6 mmol) at −5-0° C. Then a solution of MsCl (1.3 g, 11.3 mmol) in dry CH2Cl2 (20 mL) was added dropwise at the same temperature. After addition, the reaction was allowed to gradually warm to rt. Upon completion of the reaction, 50 mL of water was added, the aqueous layer was extracted with CH2Cl2, the combined organic layers were washed with 10% citric acid, sat. NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (4.2 g, 99%), which was used in the next step without purification. 1H NMR (CDCl3, 400 MHz) δ 7.12 (m, 3H), 4.52 (q, 1H), 4.31 (m, 3H), 4.09 (t, 1H), 3.57 (m, 2H), 3.06 (d, 3H), 2.70 (m, 2H), 1.93 (m, 2H), 1.44 (d, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+].O>C(O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[N:18][OH:19])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(C=NO)cc1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A solution of (4-formylphenyl)carbamic acid tert-butyl ester (1.0 g), hydroxylamine hydrochloride (0.31 g), and sodium acetate (0.37 g) in ethanol (8.5 mL)/water(1.5 mL) is heated at reflux temperature for 1 hour. The mixture is cooled to ambient temperature and partitioned between diethyl ether and water. The aqueous layer is back-extracted with diethyl ether and the combined organic extracts are washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.8 g pure white solid as the product. MS: m/z 237 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10]OCC)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[BH4-].[Li+].C[CH2:17][O:18]CC>C1COCC1>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][CH2:17][OH:18])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOCCP(=O)(OCC)OCC
Reactant: CCOCC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(CCCO)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of (2-ethoxy-ethyl)-phosphonic acid diethyl ester (0.500 g, 2.1 mmol) in ether (8.5 mL) and THF (1.5 mL) was treated with lithium borohydride. The reaction mixture stirred at room temperature for 1 hour and was then concentrated in vacuo. The crude mixture was partitioned between dichloromethane and water. The organic phase was washed with saturated NaHCO3 and brine, dried (MgSO4), then concentrated in vacuo. The residue was purified by silica gel chromatography (5/95—methanol/dichloromethane) to afford (3-hydroxy-propyl)-phosphonic acid diethyl ester 178 (0.100 g, 24%) as an oil: 1H NMR (CDCl3) δ 4.1 (m, 4H), 3.7 (m, 2H), 2.95 (bs, 1H), 1.85 (m, 4H), 1.30 (t, 3H); 31P NMR (CDCl3) δ 33.26; MS: 197 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[CH:4]=[N:3]1.[Br:22][C:23]1[CH:24]=[N:25][C:26](I)=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:22][C:23]1[CH:24]=[N:25][C:26]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:8]=2)=[N:27][CH:28]=1
Reactant: Brc1cnc(I)nc1
Reactant: Cn1cc(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(-c3ncc(Br)cn3)c2)cn1
Temperature: 100 °C
Yield: 45.3 %

Procedure:
To a solution of 1-Methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazole (intermediate 1, 5.0 g, 17.5 mmol) in 1,4-dioxane (80 mL) was added 5-Bromo-2-iodo-pyrimidine (6.0 g, 21.0 mmol) and potassium carbonate (7.3 g, 5.25 mmol) in a sealed tube. The reaction mixture was purged with nitrogen for 30 min. Then Tetrakis(triphenyl phospine)Palladium(0) (2.02 g, 0.17 mmol) was added and the reaction mixture was heated at 100° C. O/N. It was filtered through a celite pad and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (EtOAc/hexane) afforded the title compound as a yellow solid (2.5 g, 45%). 1H NMR (400 MHz, DMSO-d6): δ 9.09 (s, 1H), 8.49 (t, J=1.64 Hz, 1H), 8.25 (s, 1H), 8.18 (dd, J=1.2, 4.74 Hz, 1H), 7.90 (d, J=1.2 Hz, 1H), 7.75-7.73 (m, 1H), 7.52 (t, J=4.0 Hz, 1H), 3.88 (s, 3H). HPLC (Condition A): Rt 4.19 min (purity 98.9%). MS (ESI+): 317.0.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]([S:13]Cl)=[O:12]>C1(C)C=CC=CC=1>[C:2]1([C:1]2[O:8][C:11](=[O:12])[S:13][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccccc2)ns1
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a solution of benzamide (66.03 mmol) in toluene (132 mL) was added chlorocarbonylsulfenyl chloride (82.4 mmol). The reaction mixture was stirred at 100° C. for 4 h. After cooling to r.t. the reaction mixture was concentrated in vacuo, and the residue was crystallized from EtOAc to give the title compound (9.43 g) as a white solid: MS (m/z) 179.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:16]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.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>[CH3:16][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: COC(=O)c1cnc(C(F)(F)F)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(C(F)(F)F)c(C)c1
Yield: 33.6 %

Procedure:
To a solution of methyl 5-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate (1173 mg, 4.13 mmol) in 1,4-dioxane (25 ml) stirred under N2 was added K2CO3 (1712 mg, 12.39 mmol), trimethylboroxine (0.866 ml, 6.19 mmol) and tetrakis(triphenylphosphine)palladium (0) (239 mg, 0.206 mmol). The reaction mixture was stirred heating under reflux for 24 h. HPLC showed starting material remaining, more tetrakis(triphenylphosphine)palladium (0) was added until starting material was not detected by HPLC. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography using a 40 g Merck silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded methyl 5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylate (304 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:15])C(=O)[NH:7]2.[OH-:16].[Na+].OO.Cl>C(O)(=O)C>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([NH2:7])[C:4](=[C:3]([O:2][CH3:1])[CH:11]=1)[C:5]([OH:15])=[O:16]
Reactant: [OH-]
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(N)c(C(=O)O)c(OC)c1
Temperature: 100 °C
Yield: 50 %

Procedure:
To a heated mixture (in an oversized flask) of 13 g (63 mmol) 4,6-dimethoxyindole-2,3-dione prepared in Example 1 and 108 ml of 33% NaOH solution was carefully added 20 ml of a 30% solution of H2O2. A vigorous exothermic reaction occurs. After all H2O2 was added, the reaction mixture was maintained at 100° C. for an additional 10 min. The pH of the solution was brought to 8 with concentrated HCl and acidified to pH 5-6 with acetic acid. The solid was filtered, washed with water and dried to yield 6.2 g of 4,6-dimethoxyanthranilic acid as a pale brown solid (50% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[OH-].[NH4+].[I-:12].[K+].II>O>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[I:12]
Reactant: N#Cc1ccc(O)cc1
Reactant: [I-]
Agent: II
Agent: [K+]
Agent: [NH4+]
Solvent: O
Product: N#Cc1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
In a 2000 mL round-bottom flask containing 10.0 g (84 mmol) of 4-cyanophenol, 450 mL conc. ammonium hydroxide was added and contents were allowed to stir at 25° C. for 15 min. Next, a solution of 67.9 g (409 mmol) potassium iodide and 21.3 g (84 mmol) iodine chips, dissolved in 100 mL water, was quickly added. The reaction mixture was allowed to stir at 25° C. for 18 h at which time contents were filtered. The filtrate was concentrated under reduced pressure and redissolved in 500 mL dichloromethane. The organic layer was then washed twice with 250 mL water, dried, and concentrated under reduced pressure to provide the title compound as a light yellow solid (14.3 g, 67% yield). 1HNMR (300 MHz, CDCl3) δ 7.03 (d, 1H), 7.66 (dd, 1H), 7.98 (s, 1H); MS DCI m/e, 263 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=O)[N:12]=2)[N:7]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:6]=1)=[O:4].[N:32]1[N:33]=[CH:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][C:36]=12.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[N:32]1[N:33]=[CH:34][N:35]2[CH2:40][CH2:39][N:38]([CH2:17][C:16]3[CH:15]=[C:14]([C:11]4[N:12]=[C:13]5[C:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:31])[CH3:30])=[CH:6][N:7]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[C:8]5=[N:9][CH:10]=4)[CH:21]=[CH:20][CH:19]=3)[CH2:37][C:36]=12
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C=O)c3)nc12
Reactant: c1nnc2n1CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CN4CCn5cnnc5C4)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 3-[7-(2,2-Dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzaldehyde (0.150 g, 0.3428 mmol) and 5,6,7,8-Tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.064 g, 0.514 mmol) in 1.2 mL of dichloroethane was added 1.2 mL acetic acid and 0.109 g of sodium triacetoxyborohydride (0.514 mmol). The reaction was stirred overnight at room temperature before quenching with saturated aqueous Na2CO3. The reaction mixture was extracted 3 times with ethyl acetate, combined organics dried over MgSO4, filtered and concentrated in vacuo. Silica gel chromatography (0→100% EtOAc/hexanes over 30 minutes, followed by a flush with 100% methanol) afforded 0.0744 g (40% yield) of 1-[2-[3-(5,6-Dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-ylmethyl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a white solid. MS (E/I): 546 (M+H)
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[CH3:22])[N:10]=[C:9]2[N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]1[CH3:33].BrB(Br)Br>ClCCl>[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[CH3:22])[N:10]=[C:9]2[N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]1[CH3:33]
Reactant: COc1cccc2c(N3CCc4ccccc4C3C)nc(Nc3ccc(F)cc3C)nc12
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(F)ccc1Nc1nc(N2CCc3ccccc3C2C)c2cccc(O)c2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.7 %

Procedure:
To a mixture of 4.1 g of the compound(9.6 mM) prepared in Example 34 and 50 ml of dichloromethane, 48 ml of tribromoboran was added at 0° C. The resultant was stirred at room temperature for 14 hours and then poured into ice water. The solids produced were filtered, dissolved in dichloromethane, and neutralized by adding aqueous NaOH solution. The dichloromethane layer was separated, dried over anhydrous sodium sulfate and concentrated to give 2.4 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[N:24]1([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[Cl-].[NH4+].[OH-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:30](=[NH:31])[N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Reactant: N#CN1CCOCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=N)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
A solution of 5-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 26a (0.4 g, 1.28 mmol) in tetrahydrofuran (10 mL) under argon, was cooled to −78° C. A solution of 2.5 M n-butyllithium in hexanes (0.61 mL, 1.53 mmol) was added dropwise over 5 min. After the addition, stirring was continued for 15 min at −78° C. 4-Morpholinecarbonitrile (0.172 g, 1.53 mmol) was added all at once and reaction continued for 90 min at that temperature. A saturated ammonium chloride solution was added at −78° C. After warming to room temperature the mixture was made basic (pH 9) with concentrated ammonium hydroxide and the product was extracted with dichloromethane. The combined organics were dried with magnesium sulfate, the solvent was evaporated and the residue purified by flash chromatography eluting with 6% methanol in dichloromethane containing 0.6% of ammonium hydroxide, to yield 0.24 g of 5-(imino-morpholin-4-yl-methyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 27a.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:2]=1.[H-].[Na+].[Cl:21][C:22]1[C:23]([F:31])=[C:24]([C:27]([F:30])=[CH:28][CH:29]=1)[CH2:25]Br.O>CN(C=O)C>[Cl:21][C:22]1[C:23]([F:31])=[C:24]([C:27]([F:30])=[CH:28][CH:29]=1)[CH2:25][N:12]1[C:13]2[CH:1]=[N:2][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: Fc1ccc(Cl)c(F)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1
Reaction time: 22 h
Yield: 75 %

Procedure:
To a stirred solution of ethyl 9H-β-carboline-3-carboxylate (440 mg, 1.83 mmol) in DMF (5 mL) under a nitrogen atmosphere was added NaH (73.3 mg, 60% in mineral oil, 1.83 mmol) portionwise, followed by 3-chloro-2,6-difluorobenzyl bromide (442 mg, 1.83 mmol). Stirring was continued for 22 hours at ambient temperature, water (30 mL) was then added to the mixture. The precipitate was filtered, washed with water and dried to give the title product (0.55 g, 68%). 1H NMR (400 MHz, CD3OD): δ 9.04 (1H, s), 8.86 (1H, s), 8.26 (1H, d, J=8 Hz), 6.98–7.69 (5H, m), 5.82 (2H, s), 4.44 (2H, q, J=8 Hz), 1.43 (3H, t, J=8 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[S:19][CH:18]=[N:17][C:16]=2[CH3:20])=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH:5]=O.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1>>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[S:19][CH:18]=[N:17][C:16]=2[CH3:20])=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH2:5][NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1
Reactant: NCCCNc1cc(=O)c2sccc2[nH]1
Reactant: CSc1cc(Br)c(OCCc2scnc2C)c(C=O)c1
Agent: Cl
Product: CSc1cc(Br)c(OCCc2scnc2C)c(CNCCCNc2cc(=O)c3sccc3[nH]2)c1

Procedure:
5-(3-{3-bromo-5-methylsulfanyl-2-[2-(4-methyl-thiazol-5-yl)-ethoxy]-benzylamino}-propylamino)-4H-thieno[3,2-b]pyridine-7-one was prepared by reductive amination of the aldehyde prepared in Example 4 with amine XVIII following method C, Scheme 1. 1H NMR (400 MHz, CD3OD) δ 8.75 (1H, s), 7.70 (1H, d), 7.41 (1H, s), 7.29 (1H, s), 6.98 (1H, d), 5.59 (1H, s), 4.13 (2H, t), 3.72 (2H, s), 3.33 (4H, m), 2.65 (2H, t), 2.46 (3H, s), 2.40 (3H, s), 1.73 (2H, d).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:17])([CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[CH3:9])(C)(C)C.Cl.O>C(O)(C)C>[NH2:7][C:8]([CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)([CH3:17])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C1CCC(O)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC(C)(N)C1CCC(O)CC1
Reaction time: 8 h
Yield: 145.3 %

Procedure:
580 mg of [1-Methyl-1-(4-hydroxy-cyclohexyl)-ethyl]-carbamic acid tert-butyl ester (21) were dissolved in 10 mL of isopropanol and 10 mL of 2N hydrochloric acid were added. The mixture was stirred overnight. Water was added and the isopropanol was removed in vacuo. The residue was taken up in water and lyophilized for another two times from water to give 515 mg of (22) as the hydrochloride. Rt=0.18 min (Method 5). Detected mass: 158.2 (M+H+).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:19](=O)(O)[O-].[Na+]>CO>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:19])=[O:11])=[CH:5][CH:6]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(CCCC(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
A solution of 4-(p-tolyl)-butyric acid (10.0 g, 56.11 mmol) in methanol (680 mL) was treated with concentrated sulfuric acid (5.4 mL). The reaction was stirred at room temperature for 18 hour. Sodium bicarbonate (≈15 g) was added and the mixture was stirred for 15 minutes, then concentrated. The residue was dissolved in ethyl acetate/water. The organic phase was separated and washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (10.8 g, 100% crude) as an oil which was used for the next reaction.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([S:35][C:36]1[N:37]([CH3:43])[C:38]([C:41]#[CH:42])=[CH:39][N:40]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:42]=[C:41]([C:38]4[N:37]([CH3:43])[C:36]([S:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[N:40][CH:39]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1cnc(SC(C)(C)C)n1C
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(SC(C)(C)C)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 30 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 2-tert-butylsulfanyl-5-ethynyl-1-methyl-1H-imidazole in the same manner as Example 15. ESI MS m/z 626 [C30H39N7O4S2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH:13]3[CH2:15][O:14]3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>O1CCOCC1.O>[N:16]([CH:13]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2)[CH2:15][OH:14])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2cccc(C3CO3)c2n1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2cccc(C(CO)N=[N+]=[N-])c2n1
Yield: 44 %

Procedure:
A solution of 2-methoxy-8-(2-oxiranyl)-quinoline (900 mg; prepared according to WO 2006/046552) in dioxane/water (5:1; 60 mL) was reacted with NaN3 at 90° C. for 5 h. The solvents were removed under reduced pressure and the residue was purified by CC (Hex/EA 2:1 to 1:1), affording a yellow oil (480 mg; 44% yield).