Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([N:6]([CH2:31][CH3:32])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[C:14]([Cl:19])[CH:15]=[CH:16][CH:17]=2)[C:12]([N:20]2C(=O)C3=CC=CC=C3C2=O)=[N:11]1)[CH3:5].O.NN>O>[CH2:31]([N:6]([CH2:4][CH3:5])[CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[C:14]([Cl:19])[CH:15]=[CH:16][CH:17]=2)[C:12]([NH2:20])=[N:11]1)[CH3:32]
Reactant: CCN(CC)CCCn1nc(N2C(=O)c3ccccc3C2=O)c2c(Cl)cccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To 70 ml of ethyl alcohol was added 3.50 g of the 1-(3-diethylaminopropyl)-3-phthalimido-4-chloroindazole. The mixture was added with 85% hydrazine hydrate under cooling with ice and stirred for 3 hours under cooling with ice. The reaction mixture was filtered and the filtrate was removed under reduced pressure. The residue thus obtained was added with 20 m1 of water and extracted with chloroform. The chloroform layer was extracted with 2N hydrochloric acid. The pH of the hydrochloric acid layer was adjusted to 10 with potassium carbonate, and the alkali layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and filtered. The filtrate was removed under reduced pressure to give 2.03 g of 1-(3-diethylaminopropyl)-3-amino-4 -chloroindazole having the following analytical values in a yield of 85%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[Br:18]Br>C(Cl)Cl.CO>[Br:18][C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH:12]=1
Reactant: BrBr
Reactant: CCNC(=O)Nc1nc2ccc(OC)cc2s1
Solvent: ClCCl
Solvent: CO
Product: CCNC(=O)Nc1nc2cc(Br)c(OC)cc2s1
Temperature: 25 °C

Procedure:
1-Ethyl-3-(6-methoxy-1,3-benzothiazol-2-yl)urea (1.10 g, 4.38 mmol) was suspended in DCM (50 mL) and MeOH (5 mL). Bromine (0.34 mL, 6.60 mmol) was added and the mixture stirred at rt. The mixture was stirred for a total of 1.5 h then concentrated to dryness under reduced pressure. The desired compound was obtained as an orange solid, 2.17 g, and used without further purification, stating purity as 66 mass % in further reactions. m/z: 329.94/331.91 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=5[F:37])=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[F:37][C:30]1[C:31]([O:35][CH3:36])=[CH:32][CH:33]=[CH:34][C:29]=1[C:25]1[C:24]2[N:23]([N:22]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)[N:38]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c1F
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c1F

Procedure:
[8-(2-Fluoro-3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine was prepared from 4-{4-[8-(2-fluoro-3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (0.312 g, 0.603 mmol) and trifluoroacetic acid (1 mL) in a manner analogous to Example 312 to give product (0.248 g, 98%). MP=98-101° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.61 (s, 1H), 8.83 (d, 1H), 7.60 (m, 3H), 7.25 (m, 3H), 7.10 (m, 3H), 3.90 (s, 3H), 3.05 (m, 2H), 2.55 (br m, 4H), 1.65 (m, 2H), 1.45 (m, 2H). MS=418 (MH)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:6]([C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:8])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(Cc2ccccc2)CC1)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of (R)-tetrahydro-2-furoic acid (58.5 g, 504 mmol) and oxalyl chloride (86 mL, 1.0 mol) in 100 mL CH2Cl2 were refluxed for 2 hours in a flask equipped with a CaCl2 guard tube. After the solution was cooled to room temperature the solvents and excess oxalyl chloride were removed by evaporation under reduced pressure. The resulting acid chloride was dissolved in 200 mL CH2Cl2 and added dropwise to a solution of 1-benzyl-4-amino piperidine dihydrochloride (142 g, 539 mmol) and triethylamine (240 mL, 1.7 mol) in 300 mL CH2Cl2 cooled in an ice bath. The resulting mixture was stirred for 2 hours at room temperature and subsequently washed twice with 300 mL portions of 5% aq. NaHCO3 and 300 mL saturated aq. NaCl solution, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The solid residue was triturated with 500 mL heptanes, collected by filtration, and washed twice with 200 mL portions of heptanes. The solid was air-dried at 45° C. to yield (R)-tetrahydrofuran-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide (128 g, 88%) as an off-white solid. 1H-NMR (300 MHz, CDCl3): δ 7.35-7.20 (m, 5H), 6.58 (bs, 1H), 4.29 (dd, J=5.9, 8.4 Hz, 1H), 3.92-3.77 (m, 2H), 3.48 (s, 2H), 2.82-2.74 (m, 2H), 2.32-2.21 (m, 1H), 2.19-1.95 (m, 3H), 1.94-1.78 (m, 4H), 1.58-1.40 (m, 2H) ppm.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:28]=[C:24]([C:25]([NH2:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1.O>CS(C)=O>[C:25]([C:24]1[CH:28]=[C:20]([CH:21]=[CH:22][C:23]=1[OH:29])[O:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8])(=[O:26])[NH2:27]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: NCCCCOc1ccc(O)c(C(N)=O)c1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1OCC(O)CNCCCCOc1ccc(O)c(C(N)=O)c1
Reaction time: 1 h

Procedure:
7.3 g of 2-(2,3-epoxypropoxy)benzonitrile are added to a solution of 6.7 g of 5-(4-aminobutoxy)salicylamide in 60 ml of dimethyl sulphoxide and the mixture is stirred for 1 hour in a bath at 90°. The reaction mixture is poured into 300 ml of water and extracted twice with 200 ml of ethyl acetate each time. Working up analogously to Example 23 yields crude 1-[4-(3-carbamoyl-4-hydroxyphenoxy)butylamino]-3-(2-cyanophenoxy)propan-2-ol as a viscous oil, the IR- and 1H-NMR-spectra of which are in concordance with the assumed structure and the Rf-value of which is 0,51 according to thin-layer-chromatography on silicagel using a mixture of ethylacetate-ethanol-conc. ammonia 24:12:4 as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH2:23][CH:22]([CH2:24][NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:21][C:20]3=[O:32])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[O:34]C1C=CC(C2C=CC(S(NC(CC3OC3)C(OC)=O)(=O)=O)=CC=2)=CC=1.NC1C=CC=CC=1.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:23][CH:22]([OH:34])[CH2:24][NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]([OH:21])=[O:32])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3CC(CNc4ccccc4)OC3=O)cc2)cc1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Nc1ccccc1
Solvent: O
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CNc3ccccc3)C(=O)O)cc2)cc1
Temperature: 80 °C

Procedure:
3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-5-[(phenylamino)methyl]-tetrahydrofuran: To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-4,5-epoxypentanoate 1d (0.5 g, 1.28 mmol) in aniline (0.17 mL, 1.92 mmol) is added magnesium perchlorate (2 mg, 0.009 mmol) and the resulting mixture is heated for 4 h at 80° C. The resulting mixture is cooled to room temperature, and then the mixture is diluted with water, and extracted three times with EtOAc. The combined EtOAc layer is washed with water, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with hexane/EtOAc (7:3) to give the desired product.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:46]2[CH:47]=[C:42]([Cl:41])[CH:43]=[CH:44][C:45]=2[F:48])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: OB(O)c1cc(F)ccc1Cl
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4cc(Cl)ccc4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-5-fluorophenyl)boronic acid gave 281. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.12 (dd, J=6.4, 2.7 Hz, 1H), 7.79 (s, 1H), 7.55-7.39 (m, 4H), 5.07 (dd, J=7.0, 4.5 Hz, 1H), 3.99-3.84 (m, 2H), 3.72 (s, 3H), 3.52-3.43 (m, 1H), 3.33-3.24 (m, 1H), 3.15 (s, 3H), 2.33-2.22 (m, 1H), 1.82-1.52 (m, 4H). LCMS (ES+) m/z 495 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:11]([O-])=[O:12].[Na+]>C(O)C.O>[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH3:9])[C:8]=1[N:11]=[O:12]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)cc(C)c1N=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
750 ml of concentrated HCl are added to a solution of 3,5-dimethyl phenol (80.6 g) in 750 ml of 95% ethyl alcohol. The mixture is cooled to 0° C. in an ice/methanol bath. While maintaining the temperature of the reaction mixture below 5° C., a solution of NaNO2 (69.0 g) in 150 ml of H2O is added dropwise to the reaction mixture. The mixture is stirred at 0° C. for more than an hour and then poured into 9 liters of water. The aqueous mixture is filtered to give a yellow solid which is recrystallized from hot methanol and filtered to give 71.45 grams of a yellow solid, M.P. 180°-181° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27].[OH-].[Na+]>O1CCCC1>[C:11]([C:8]1[CH:9]=[C:10]2[C:2]([NH:1][C:26](=[O:28])[CH3:27])=[N:3][NH:4][C:5]2=[N:6][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1cc2c(N)n[nH]c2nc1-c1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1n[nH]c2nc(-c3ccc(O)cc3)c(C#N)cc12
Yield: 36.2 %

Procedure:
To a mixture of 165 mg (0.66 mmol) of 3-amino-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile obtained following general procedure D1 and of 180 μL (2.16 mmol) of pyridine diluted in 1.6 ml of anhydrous tetrahydrofuran, are added dropwise at 0° C. 168 mg (2.16 mmol) of acetyl chloride. The solution is stirred under reflux for 4 h, then 655 μL (5M, 3.28 mmol) of sodium hydroxide solution are added, and the mixture is stirred for 1 h30 at 40° C. The tetrahydrofuran is concentrated and the solution is brought to acid pH (in the order of 3/4). The solid is filtered, washed with water, dried, and triturated in ethanol to yield 70 mg of N-(5-cyano-6-(4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)acetamide in the form of a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][NH:12][C:11]1=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:22][O:23][C:24](=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:12]1[CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:11]1=[O:21]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1[nH]cc(-c2ccccc2)n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(Cc2ccccc2)c1=O

Procedure:
The product is produced as described in example 1 from 1.8 g of NaH (80% suspension in mineral oil), 15 g of 1-benzyl-5-phenyl-4-imidazolin-2-one, 120 cc. of DMF, 14.2 g of 8-bromocaprylic acid methyl ester and 1.8 g of NaJ.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]3[S:35][C:34](=N)[NH:33][C:32]3=[O:37])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][C:8]2=[O:40])(=O)C.Cl.C[O:43]CCO>O>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:21])([CH3:22])[CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][CH:31]3[S:35][C:34](=[O:43])[NH:33][C:32]3=[O:37])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][C:8]2=[O:40]
Reactant: COCCO
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(CC3SC(=N)NC3=O)cc1)CC2=O
Agent: Cl
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc2c(cc1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
A mixture of 5.2 g of 5-{4-[6-acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy]-benzyl}-2-iminothiazolidin-4-one prepared as described in Preparation 26), 16 ml of 2N hydrochloric acid and 25 ml of ethylene glycol monomethyl ether was heated for 6 hours at 85°-90° C. under a nitrogen atmosphere. The reaction mixture was then poured into water and extracted with benzene. The benzene extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give the title compound as a slightly yellow foamy solid, softening at 100°-105° C.
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[F:10][C:9]([F:12])([F:11])[C:5]1[CH:4]=[C:3]([CH:2]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cccc(C(Cl)c2cccc(C(F)(F)F)c2)c1
Reactant: C1CNCCN1
Solvent: CC#N
Product: FC(F)(F)c1cccc(C(c2cccc(C(F)(F)F)c2)N2CCNCC2)c1
Temperature: 100 °C

Procedure:
To a solution of bis(3-(trifluoromethyl)phenyl)methanol (1.1 g, 3.4 mmol) in CH2Cl2 (10 mL) was added dropwise thionyl chloride (0.50 ml, 6.9 mmol) at rt. The reaction was stirred at 50° C. for 4 h, concentrated under vacuum, azeotroped with toluene, and dried under vacuum to give crude chlorobis(3-(trifluoromethyl)phenyl)methane. The crude chlorobis(3-(trifluoromethyl)-phenyl)methane was added to a solution of piperazine (0.81 ml, 10 mmol) in acetonitrile (10 mL), heated to 100° C. for 18 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3, filtered, and concentrated to give 1-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazine. The crude 1-(bis(3-(trifluoromethyl)phenyl)-methyl)piperazine was dissolved in acetonitrile (10 mL) and tert-butyl bromoacetate (0.55 mL, 3.4 mmol) and triethylamine (0.96 ml, 6.9 mmol) was added. The solution was stirred for 4 h, diluted with water, and extracted with CH2Cl2. The organic layer was washed with saturated NaCl solution, then dried over Na2SO4, and concentrated. The crude product was purified by ISCO using 0-50% EtOAc in hexanes to give tert-butyl 2-(4-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazin-1-yl)acetate (0.86 g, 50% yield). MS (ESI, pos. ion) m/z: 503.1 (M+1), which was then converted to the title compound by proceeding as described in Example 4 above.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[CH2:23]([NH3+:27])[CH2:24][CH2:25][CH3:26]>>[CH2:23]([NH:27]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH2:24][CH2:25][CH3:26]
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: CCCC[NH3+]
Agent: CC(=O)[O-]
Product: CCCCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 64 %

Procedure:
Prepared as in Example 35 from 2-benzoyl-benzo[b]thiophen-3-ol and n-butylammonium acetate with a yield of 64% of theory; m.p. 106°-107° C. (petroleum ether/ethyl acetate 1:1).
Reaction SMILES: [Li]CCCC.[Br-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:37]1([C:43]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:44]2[CH:48]=[C:47]([CH:49]=O)[N:46]=[CH:45]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[CH:49]([C:47]1[N:46]=[CH:45][N:44]([C:43]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:48]=1)=[CH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of n-BuLi (4.1 mL, 6.5 mmol, 1.6M in hexanes) was added dropwise to a suspension of n-undecyl-triphenylphosphoniumbromide (3.09 g, 6.2 mmol, obtained from triphenylphosphine and undecylbromide) in 100 mL THF at -78° C. under an atmosphere of N2. The resulting orange solution was stirred for 45 minutes before a solution of 1-(triphenylmethyl)-4-imidazolecarboxaldehyde (2.0 g, 5.9 mmol, Ref: Kelly J. L., Miller C. A., and McLean E. W., J. Med. Chem. 1977;20:721) in 75 mL THF was added dropwise. Warmed to room temperature and stirred for 16 hours. Quenched by adding 50 mL saturated NH4Cl solution and concentrating in vacuo. The residue was partitioned between water and dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give a yellow oil. Chromatography (10% EtOAc/hexanes on silica) gave the title compound (1.8 g, 64%) as a clear oil.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([CH3:14])=[CH:4][N:3]=1.C1(C2[N:25]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH:23]([CH2:29][OH:30])[O:22]2)C=CC=CC=1.[H-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[CH:26]([NH:25][CH2:24][CH:23]([OH:22])[CH2:29][O:30][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([CH3:14])=[CH:4][N:3]=1)([CH3:28])[CH3:27]
Reactant: Cc1cnc(Cl)c(N2CCOCC2)n1
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cnc(OCC(O)CNC(C)C)c(N2CCOCC2)n1
Temperature: 0 °C

Procedure:
10.7 g of 2-chloro-3-morpholinyl-5-methyl-pyrazine and 16.6 g of 2-phenyl-3-isopropyl-5-hydroxymethyloxazolidine are dissolved in 130 ml of hexamethylphosphoric acid triamide. 3.6 g of a 50% strength suspension of sodium hydride in paraffin oil are introduced into this solution over the course of 30 minutes at 0°-5° C., whilst stirring. The mixture is then stirred for 1 hour at 0°-5° C. and 24 hours at room temperature. The reaction mixture is then poured onto 500 ml of ice water and extracted by shaking with ether. The ether extracts are washed with water and evaporated in a waterpump vacuum. The residue is taken up in 200 ml of 1 N sulphuric acid and the reaction mixture is stirred for 15 hours at room temperature and then extracted by shaking with ether. The acid aqueous phase is rendered alkaline with concentrated sodium hydroxide solution and is then extracted by shaking with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue crystallises from etherpentane. 2-(3'-Isopropylamino-2'-hydroxy-propoxy)-3-morpholinyl-5-methyl-pyrazine, melting point 77°-78° C., is thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of [4-(3-amino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (30 mg, 0.079 mmol) and benzoyl chloride (16.4 mg, 0.119 mmol) in tetrahydrofuran (3 mL) was added triethylamine (16 mg, 0.158 mmol) at 0° C. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-benzoylamino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (27.4 mg, 72%) as a white solid. MS cald. for C24H26N4O5S 482, obsd. (ESI+) [(M+H)+] 483.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:22]([O:24][CH2:25][C:26](Cl)=O)[CH3:23].C(N(CC)CC)C>C(O)C>[CH2:22]([O:24][CH2:25][C:26]1[N:12]([CH2:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:23]
Reactant: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A modification of the method described in Part C of Example 5 was used to treat ethyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropanoate (15.5 g, 60.2 mmol, prepared in Parts A through D of Example 26) with ethoxyacetyl chloride (8.7 g, 71 mmol) followed by triethylamine (24.4 mL, 175 mmol). The reaction with ethoxyacetyl chloride was stirred overnight, and the reaction with triethylamine was heated at reflux in ethanol (125 mL) for four days. Following the work-up procedure, the crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 100:0 to 95:5) to provide 7.9 g of ethyl 3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropanoate as an oil.