Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:19]([CH2:28]Cl)=[C:20]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:23][N:22]=[CH:21]2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:19]([CH2:28][NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[C:20]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:23][N:22]=[CH:21]2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)C(Cc1cc(Cl)c2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C(Cc1cc(Cl)c2[nH]ncc2c1CNCc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
To a solution of methyl 2-{[(benzyloxy)carbonyl]amino}-3-(7-chloro-4-{chloromethyl}-1H-indazol-5-yl)propanoate (4.3 g, 9.17 mmol) in acetonitrile (100 mL) was added 4-methoxybenzyl amine (2.4 mL, 2.52 g, 18.34 mmol) and the solution stirred at room temperature for several hours. The reaction was poured into a saturated aqueous solution of sodium bicarbonate (500 mL) and the mixture extracted with ethyl acetate. The combined organic extracts were washed once with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to give 4.1 g of the title compound. MS: m/z=537 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:28])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]C(=O)C)=[CH:10][CH:9]=2)=[O:5])C.CO.O.[OH-].[Li+]>C1COCC1>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:28])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)=[O:27]
Reactant: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3OC(C)=O)ccc2n1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C(=O)O)cc2cc(NC(=O)c3ccccc3O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of step (a) (2.0 g, 5.26 mM) was dissolved in THF (30 mL), methanol (10 mL), and water (10 mL). The mixture was treated with lithium hydroxide (882 mg, 21.04 mM) and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated to 15 mL and the pH was adjusted to about 3.0 with 1 N HCl. The mixture was extracted 3 times with ethyl acetate (25 mL). The ethyl acetate fractions were combined, dried over MgSO4, filtered and concentrated to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:53][C@H:54]([C:56]([O:58][CH2:59][CH2:60][O:61][C:62]1[CH:67]=[CH:66][C:65]([C:68]2[C:73]([C:74]#[N:75])=[C:72]([N:76]3[CH2:80][CH2:79][CH2:78][CH2:77]3)[N:71]=[C:70]([S:81][CH2:82][C:83]3[N:84]=[C:85]([C:88]4[CH:93]=[CH:92][C:91]([Cl:94])=[CH:90][CH:89]=4)[S:86][CH:87]=3)[C:69]=2[C:95]#[N:96])=[CH:64][CH:63]=1)=[O:57])[CH3:55]>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:53][C@H:54]([C:56]([O:58][CH2:59][CH2:60][O:61][C:62]1[CH:67]=[CH:66][C:65]([C:68]2[C:73]([C:74]#[N:75])=[C:72]([N:76]3[CH2:77][CH2:78][CH2:79][CH2:80]3)[N:71]=[C:70]([S:81][CH2:82][C:83]3[N:84]=[C:85]([C:88]4[CH:89]=[CH:90][C:91]([Cl:94])=[CH:92][CH:93]=4)[S:86][CH:87]=3)[C:69]=2[C:95]#[N:96])=[CH:64][CH:63]=1)=[O:57])[CH3:55])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](N)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
26.756 g (141.406 mmol) of N-(tert-butoxycarbonyl)-L-alanine together with 29.572 g (154.261 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 29.529 g (192.827 mmol) of 1-hydroxy-1H-benzotriazole hydrate and 55.979 ml (321.378 mmol) of N,N-diisopropylethylamine were dissolved in 10 l DMF. 97.60 g (128.551 mmol) of trifluoroacetic acid-2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl L-alaninate (1:1) were then added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was stirred into water and extracted with dichloromethane. The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether, and the solid was filtered off with suction and air-dried. This gave 95 g (91% of theory) of the desired target compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:25]([O-])=O)[CH:8]=[C:9]([O:23][CH3:24])[C:10]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]=[CH:4][CH:3]=1>[Ni]>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:25])[CH:8]=[C:9]([O:23][CH3:24])[C:10]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Agent: [Ni]
Product: COc1cc(N)c2nccc(C)c2c1Oc1cccc(C(F)(F)F)c1
Yield: 75.5 %

Procedure:
A solution of 4-methyl-5-(3-trifluoromethylphenoxy) -6-methoxy-8-nitroquinoline (VI, 5.9 g, 15.6 mmol) in ethanol-dioxane (4:3, v/v, 350 mL) containing wet Raney nickel (ca. 4 g) was reduced at 45 psig for 11/4 hour. The catalyst was filtered and the filtrate was concentrated to dryness. The residual solid was crystallized from ligroin (bp 60°-80°) to afford 4.1 g (76%) of the title compound mp 113°-115°. A sample recrystallized once again gave an analytical sample, mp 116°-117°.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][N:11]([CH3:28])[C:12](=[O:27])[CH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1.I[CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[Cl-].[NH4+]>O1CCCC1.CN1CCCN(C)C1=O>[CH3:9][O:10][N:11]([CH3:28])[C:12](=[O:27])[CH:13]([C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1)[CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: CON(C)C(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: ICC1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CON(C)C(=O)C(CC1CCOCC1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Lithium diisopropylamide (2M tetrahydrofuran solution, 6.9 mL) was diluted with tetrahydrofuran (20 mL), a solution of tert-butyl 4-{2-[methoxy(methyl)amino]-2-oxoethyl}benzoate (3.70 g) in a mixed solvent of tetrahydrofuran (20 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12 mL) were added at −78° C., and the mixture was stirred for 1 hr. To the reaction mixture was added a solution of 4-(iodomethyl)tetrahydro-2H-pyran (3.30 g) in tetrahydrofuran m (20 mL) at −78° C. and the mixture was stirred for 3 hr. The mixture was slowly warmed to room temperature, and stirred overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3.81 g, yield 76%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 378 (MH+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13](I)[C:12]([Cl:16])=[CH:11][N:10]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[CH:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[C:31][C:13]2[C:12]([Cl:16])=[CH:11][N:10]=[C:9]([Cl:8])[CH:14]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1cc(I)c(Cl)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Cl)ncc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Copper(I) iodide (0.50 g), bis-(triphenylphosphine)-palladium(II) chloride (0.50 g), and triethylamine (3.4 mL) are added successively to a solution of 2,5-dichloro-4-iodo-pyridine (6.54 g) in N,N-dimethylformamide (45 mL) under Ar atmosphere at room temperature. The resulting mixture is stirred at room temperature for 1 h prior to the addition of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (5.15 g). The mixture is stirred at 55° C. for 2 h. The solvent is evaporated and the residue is diluted with ethyl acetate. The resulting mixture is washed with water and brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 85:15→50:50) to give the title compound. LC (method 3): tR=1.66 min; Mass spectrum (ESI+): m/z=355/357/359 (2 Cl) [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[OH-].[Li+:8]>O>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Li+:8].[Li+:8].[Li+:8].[Li+:8]
Reactant: CC(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(O)C(=O)[O-]
Yield: 266.7 %

Procedure:
2880 g of 25% hydrolyzed synthetic lactic acid are stirred into 83.8 g of lithium hydroxide . H2O. The resulting clear solution is dried in the laboratory thin-layer evaporator according to the process described in Example 1 at 12-15 torr and 80° C. 896 g of a pourable crystalline lithium tetralactate with a melting point of 250°-255° C. are obtained.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[CH3:22][O:23][C:24]([CH:26]1[CH2:30][O:29][C:28]([CH2:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:27]1)=[O:25]>C(Cl)Cl>[CH3:22][O:23][C:24]([C:26]1[N:27]=[C:28]([CH2:31][CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[O:29][CH:30]=1)=[O:25]
Reactant: CCOC(=O)CC(CC1=NC(C(=O)OC)CO1)c1ccccc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)CC(Cc1nc(C(=O)OC)co1)c1ccccc1
Reaction time: 0.08 h
Yield: 63.7 %

Procedure:
To a suspension of CuBr2 (1.17 g, 5.26 mmole) in degassed (3×vacuum/N2) CH2Cl2 (6 mL) was added hexamethylenetetramine (737 mg, 5.26 mmole) then DBU (0.78 mL, 5.26 mmole). After 5 min, a solution of ethyl (±)-4-(4-methoxycarbonyl-1,3-oxazolin-2-yl)-3-phenylbutanoate (420 mg, 1.32 mmole) in CH2Cl2 (2 mL) was added dropwise. After 6 hr, the mixture was filtered through a pad of silica gel (EtOAc) and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel (50% EtOAc/hexanes) to give the title compound (267 mg, 64%) as a white solid: MS (ES) m/e 318 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:22]2[CH2:23][O:24][CH:25]=CC=2)[CH2:12][CH2:13][CH:14](CO)CCCCC)(=O)=O)=CC=1.[CH2:29]1[O:37][CH:30]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)C(O)CCCCC>CN(P(N(C)C)(N(C)C)=O)C>[C:31]1([CH:30]2[CH2:25][O:24][CH:23]([CH2:22][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:29][O:37]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: CCCCCC(CO)CCC(OS(=O)(=O)c1ccc(C)cc1)C1=CC=COC1
Agent: CCCCCC(O)CO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCC1COC(c2ccccc2)CO1

Procedure:
A solution of 4.06 g. 4-hydroxymethyl-3-oxa-1-phenyl-nonan-1-ol 1-mono-p-toluene sulphonate (obtainable by reaction of styrene oxide with heptane-1,2-diol and partial tosylation of the 4-hydroxymethyl-3-oxa-1-phenylnonan-1-ols obtained) in 100 ml. phosphoric acid hexamethyltriamide is heated for 24 hours to 80°. One evaporates, works up as usual and obtains 2-phenyl-5-pentyl-1,4-dioxane as an oily isomer mixture. Isomerization of 1 g. of the mixture by 2 hours heating with 0.05 g. K tert.-butylate in 10 ml. dimethyl sulphoxide to 80° leads to trans-2-phenyl-5-pentyl-1,4-dioxane.
Reaction SMILES: CO.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH3:24])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([CH:25]=[CH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:7][C:6]=2[N:5]=1>[Pd].C(O)C>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:22][O:23][CH3:24])[N:16]([CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])[C:12]=2[C:11]2[CH:10]=[CH:9][C:8]([CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:7][C:6]=2[N:5]=1
Reactant: COCc1nc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c2n1CC(C)(C)O
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: COCc1nc2c(N)nc3cc(CCS(C)(=O)=O)ccc3c2n1CC(C)(C)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (200 mg), methanol (12.5 mL), ethanol (12.5 mL) and 1-{4-amino-2-(methoxymethyl)-7-[2-(methylsulfonyl)ethenyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (750 mg, 1.85 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The mixture was shaken at 50° C. for approximately 18 hours and then cooled to ambient temperature. The reaction mixture was sequentially filtered through a 0.2 micron PTFE membrane filter, concentrated under reduced pressure, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-7% gradient of methanol in dichloromethane) to provide 195 mg of 1-{4-amino-2-(methoxymethyl)-7-[2-(methylsulfonyl)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a white solid, mp 210-212° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][O:7][C:8]([N:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:16]=2)[C@@:12]([C:30](=O)[CH2:31]Br)([CH3:29])[CH2:11]1)=[O:9]>CO>[CH3:6][O:7][C:8]([N:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH:16]=2)[C@:12]([CH3:29])([C:30]2[N:5]=[C:3]([NH:2][CH3:1])[S:4][CH:31]=2)[CH2:11]1)=[O:9]
Reactant: CNC(N)=S
Reactant: COC(=O)N1C[C@H](c2ccc(OC)c(OC3CCCC3)c2)[C@](C)(C(=O)CBr)C1
Solvent: CO
Product: CNc1nc([C@]2(C)CN(C(=O)OC)C[C@@H]2c2ccc(OC)c(OC3CCCC3)c2)cs1
Temperature: 70 °C

Procedure:
To a solution of 1-methyl-2-thiourea (0.038 g, 0.418 mmol) in methanol (1 mL), at 50° C., was added a solution of (3S,4R)-3-(2-bromoethanoyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-pyrrolidine-1-carboxylic acid methyl ester (0.19 g, 0.42 mmol) in methanol (1 mL). The temperature was raised to 70° C. and refluxed for 2 hours. The reaction mixture then was concentrated under reduced pressure and dissolved in acetonitrile-water (CH3CN—H2O) (1 mL) for purification by HPLC on a C18 column (Luna 10 μ, C18, 250×10 mm). Gradient elution of 50-100% acetonitrile-water (0.05% TFA) yielded the named product as a white powder after lyophilization (91 mg, 49%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>ClCCl>[Br:40][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(CCCOCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(CCCOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
{4-[3-(benzyloxy)propyl]benzyl alcohol (1.86 g, 7.31 mmol) was dissolved in 82 mL dichloromethane. The solution was cooled to 0° C. 3.25 g (12.41 mmol) triphenyl phosphine and 4.11 g (12.41 mmol) carbon tetrabromide were added to the solution. The ice bath was removed and the reaction was stirred for 1 h. The solution was concentrated in vacuo, to the residue was added tert-butyl methyl ether (100 mL) and the mixture was stirred at −20° C. for 30 min. The mixture was filtrated and the filtrate was concentrated in vacuo. The crude product was purified on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: CS(O)(=O)=O.C[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1.Br.[OH-].[Na+]>O>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(C(=O)CCCn2ccnn2)cc1
Agent: Br
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: O
Product: O=C(CCCn1ccnn1)c1ccc(O)cc1
Temperature: 0 °C

Procedure:
1.70 g (5.0 mmol) 1-(4-Methoxy-phenyl)-4-[1,2,3]triazol-1-yl-butan-1-one methane-sulfonate and 7 ml 47% aqueous HBr were heated to 80° C. overnight. After diluting with 10 ml water and cooling to 0° C. the mixture was alkalized (pH 12.6) by dropwise addition of 4N NaOH and extracted three times with toluene. Concentration of the toluene phase in vacuo gave 0.05 g recovered starting material. The aqueous phase was cooled and adjusted to pH=6.3 by addition of 6 N HCl. The resulting precipitate was isolated and dried in vacuo at 40° C. to give 1-(4-hydroxy-phenyl)-4-[1,2,3]triazol-1-yl-butan-1-one. Yield: 0.96 g (83%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([CH3:29])([CH3:28])[C:20]2=[O:30])=[CH:15][CH:14]=1.[CH3:31]I.[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH3:29][C:21]1([CH3:28])[C:22]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][C:4]3[N:5]([CH3:31])[C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N:3]=3)=[CH:14][CH:15]=2)[C:20]1=[O:30]
Reactant: CC1(C)C(=O)N(c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc21
Reactant: CI
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(N3C(=O)C(C)(C)c4cccnc43)cc2)nc2ccccc21

Procedure:
NaH (17.28 mg) was added to a solution of 1-[4-(1H-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (40 mg) and MeI (10.13 μl) in DMF(1 mL) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3,3-dimethyl-1-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (35 mg) as white crystals.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])=[C:2]=[S:3].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[NH2:22].C(O)(=O)C>C(O)C>[SH:3][C:2]1[N:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH3:11])[C:14](=[O:13])[C:15]2[C:16](=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:22]=1
Reactant: COc1ccccc1N=C=S
Reactant: COC(=O)c1ccc(C)cc1N
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccccc1-n1c(S)nc2cc(C)ccc2c1=O
Temperature: 25 °C
Yield: 61.5 %

Procedure:
1-Isothiocyanato-2-methoxy-benzene (0.76 mL, 5.45 mmol) was added to a solution of 2-amino-4-methyl-benzoic acid methyl ester (900 mg, 5.45 mmol) and acetic acid (1.5 mL) in ethanol (10 mL), and heated at reflux for 16 hr. The reaction mixture was cooled to room temperature and diluted with ethanol. The precipitated solid was filtered, washed with ethanol and dried to afford 2-mercapto-3-(2-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (1.0 g, 62%) as white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C([N:22]=[C:23]=[S:24])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:23]([NH2:22])=[S:24])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(-c2ccncc2)cc1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 152.9 %

Procedure:
To a solution of 4-pyridin-4-yl-phenylamine (142 mg, 0.83 mmol) in tetrahydrofurane (5 mL) was added drop wise under benzoyl isothiocyanate (124 uL, 0.88 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in methanol (6 mL) and a solution of potassium carbonate (346 mg, 2.5 mmol) in water (3 mL) was added. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off, washed with water and diethyl ether to yield the title compound as a pale yellow solid (291 mg, 152%). MS ISP (m/e): 230.2 (56) [(M+H)+], 213.0 (100) [(M-NH3+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.86 (s, 1H, NH), 8.61 (d, 2H), 7.79 (d, 2H), 7.69 (d, 1H), 7.61 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH:22]2[CH2:26][CH2:25][O:24][CH2:23]2)=[C:6]([C@H:8]2[CH2:12][CH:11]([OH:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:17]([O:16][C:14]([N:9]1[CH2:10][C:11](=[O:13])[CH2:12][C@@H:8]1[C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:21][CH:22]1[CH2:26][CH2:25][O:24][CH2:23]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@@H]1c1cc(F)ccc1OC1CCOC1
Agent: O=C([O-])O
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@@H]1c1cc(F)ccc1OC1CCOC1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of (2R)-tert-butyl 2-(5-fluoro-2-((tetrahydrofuran-3-yl)oxy)phenyl)-4-hydroxypyrrolidine-1-carboxylate (18.0 g, 49 mmol) in DCM (150 mL) at −40° C. was added trichloroisocyanuric acid (12.5 g, 54 mmol) followed by 2,2,6,6-tetramethylpiperidino-1-oxy (TEMPO) (0.76 g, 4.9 mmol). After stirring 1 h at −40° C. to −10° C., the reaction mixture was poured into cold saturated aqueous NaHCO3 solution (200 ml), extracted with DCM (400 ml), combined extracts were washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated to dryness to give the corresponding ketone (17.5 g, crude yield 98%) as pale yellow oil, which was used without purification in the next step. MS (ESI): m/z 266.2 (de-Boc), (M+H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]2([S:11]([NH:14][C:15](=[O:17])[CH3:16])(=[O:13])=[O:12])[CH2:8][CH2:9][CH2:10]2)=[N:4][CH:3]=1
Reactant: NS(=O)(=O)C1(c2ncc(Br)s2)CCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)C1(c2ncc(Br)s2)CCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
1-(5-Bromo-1,3-thiazol-2-yl)cyclobutanesulfonamide (110 mg, 0.370 mmol, prepared according to Example 70, Steps 1-5) was taken up in pyridine (5 mL), and acetic anhydride (524 μL, 5.55 mmol) was added. The reaction was stirred at 70° C. overnight. The reaction was concentrated to dryness, diluted with water, acidified with 2 N HCl, and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to give N-{[1-(5-bromo-1,3-thiazol-2-yl)cyclobutyl]sulfonyl}acetamide (120 mg, 96%) as a beige solid. MS ESI: [M+H]+ 338.9/340.9.