Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([N:10]([N+:29]([O-:31])=[O:30])[C@H:11]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[N+:29]([NH:10][C@H:33]([C:34]([CH:6]([NH2:7])[CH2:5][CH2:4][CH2:3][C@@H:2]([C:8]([N:10]([N+:29]([O-:31])=[O:30])[C@H:11]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18])=[O:9])[NH2:1])=[O:36])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18])([O-:31])=[O:30]
Reactant: N=C(N)NCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)O)N(C(=O)[C@@H](N)CCCCN)[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)NCCC[C@H](N[N+](=O)[O-])C(=O)C(N)CCC[C@H](N)C(=O)N([C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)O)[N+](=O)[O-]

Procedure:
From compound 8, in a manner similar to the synthesis of compound 2 (except that instead of trifluoroacetic acid use is made of its mixture with methylene chloride in the volume ratio of (1:1) α-benzyloxycarbonyl, ε-(nitroarginyl)lysylnitroarginylproline trifluoroacetate (compound 9) is obtained. The yield is 96%. αD20 =-12.0° (c=1, dimethylformamide). Ehis =0.52 (1 N acetic acid), Rf ==0.16 (B), 0.52 (C), 0.54 (D).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(CCCCN=[N+]=[N-])(CCCc1cccnc1)C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(CCCCN)(CCCc1cccnc1)C(=O)OCC
Reaction time: 48 h

Procedure:
To a solution of 42.59 g (0.11 mole) of diethyl [4-azidobutyl][3-(3-pyridyl)-propyl]-malonate in 270 mL THF and 3.1 mL water is added 29 g (0.11 mole) of triphenyl phosphine and the solution is stirred well for 48 hours. Solvent is evaporated and the residue subjected to flash chromatography to give diethyl [4-aminobutyl][3-(3-pyridyl)- propyl]malonate as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([N:15]=CC2C=CC=CC=2)[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:6]=1.O.NN.O>C(O)COCCO>[NH2:15][N:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:6]=[C:2]1[NH2:1]
Reactant: COc1cccc(-c2cn(N=Cc3ccccc3)c(N)n2)c1
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: COc1cccc(-c2cn(N)c(N)n2)c1

Procedure:
A solution of 8.1 g of 2-amino-1-benzylideneamino-4-(3-methoxyphenyl)-imidazole and 5.5 ml of hydrazine hydrate in 28 ml of diethylene glycol is stirred at 170° C. for 7 hours. After cooling, 150 ml of water are added to the reaction mixture. The product that has separated out is filtered off with suction, washed with water and recrystallized from 100 ml of ethanol. In that manner there is obtained the title compound, m.p. 181°-182° C., 1H-NMR (DMSO): δ=7.17 (m, 3H); 7.06 (s, 1H); 6.64 (m, 1H); 5.52 (s, 2H); 5.35 (s, 2H); 3.74 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1COCC1>[CH2:1]([NH:8][C:18](=[O:19])[CH2:17][Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of benzylamine (60.3 mL) and triethylamine (96.3 mL) in THF (800 mL) was added chloroacetyl chloride (45.8 mL) at 0° C. The reaction mixture was allowed to warm to room temperature over night. Additional chloroacetyl chloride (4.6 mL) was added and stirring was continued until no starting material could be detected. The reaction mixture was filtered, washed with ethyl acetate and concentrated. The crude product was crystallized from dichloromethane to yield N-benzyl-2-chloro-acetamide (71.6 g) as off-white solid.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:41]([CH3:42])[C:40](=[O:43])[N:39]([CH2:44][C@H:45]3[CH2:50][CH2:49][C@H:48]([C:51]([OH:53])=O)[CH2:47][CH2:46]3)[C:38]=2[CH:54]=1.[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:57])[CH3:56]>CN(C=O)C>[C:55]([O:59][C:60]([N:62]1[CH2:67][CH2:66][N:65]([C:51]([C@H:48]2[CH2:47][CH2:46][C@H:45]([CH2:44][N:39]3[C:38]4[CH:54]=[C:34]([O:33][CH3:32])[CH:35]=[CH:36][C:37]=4[N:41]([CH3:42])[C:40]3=[O:43])[CH2:50][CH2:49]2)=[O:53])[CH2:64][CH2:63]1)=[O:61])([CH3:58])([CH3:56])[CH3:57]
Reactant: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)O)CC1)c(=O)n2C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)n(C[C@H]1CC[C@H](C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethyl amine (0.39 ml, 2.77 mmol) was added to solution of HATU (1.05 g, 2.77 mmol) and trans-4-(6-Methoxy-3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexanecarboxylic acid (0.8 g, 2.5 mmol) in DMF (15 ml). The mixture was stirred at room temperature for 20 minutes and then tert-butyl-1-piperazinecarboxylate (0.47 g, 2.52 mmol) was added. The mixture was stirred at room temperature overnight, the solvent was removed under reduced pressure and the crude product was dissolved in DCM (50 ml). The organic solution was washed with HCl 1M (2×40 ml) and then with a saturated solution of NaHCO3. The organic solution was dried over Na2SO4, filtered and the solvent removed. Purification by silica column using cyclohexane/EtOAc (8/1) as eluent gave the titled compound (960 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH3:13])[C:4]=2[S:5][CH:6]=1.[Cl:14][CH:15]=[CH:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:17]/[CH:16]=[CH:15]/[Cl:14])[CH3:13])[C:4]=2[S:5][CH:6]=1
Reactant: ClC=CCCl
Reactant: CNCc1cccc2c(Cl)csc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C/C=C/Cl)Cc1cccc2c(Cl)csc12
Temperature: 50 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
To a solution of 0.22 g (1.0 mmol) of 3-chloro-N-methylbenzo[b]thiophene-7-methanamine in 3 ml of dimethyl sulfoxide were added 0.12 ml-(1.2 mmol) of 1,3-dichloropropene (E/Z=9/1) and 0.21 g (1.5 mmol) of ground potassium carbonate.- The mixture was stirred for 17 hours at 50° C., and poured into 50 ml of ethyl acetate. The organic layer was washed with 25 ml×2 of water and 10 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-heptane→n-heptane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 0.21 g (yield: 73%) of the above identified compound as an oil.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N+:16]=1[O-:22]>OS(O)(=O)=O>[Cl:14][C:15]1[CH:20]=[C:19]([N+:10]([O-:13])=[O:11])[C:18]([Cl:21])=[CH:17][N+:16]=1[O-:22]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1cc(Cl)ccc1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1cc(Cl)[n+]([O-])cc1Cl
Temperature: 25 °C

Procedure:
At 0° C., 30% oleum (13 mL) is added slowly to fuming HNO3 (22 mL) and the resulting mixture is added slowly to the solution of 2,5-dichloro-pyridine 1-oxide (5.2 g, 31 mmol) in concentrated H2SO4. After addition, the reaction mixture is warmed to room temperature over 1 hr, then heated to 80° C. for 2 hr. After cooling to room temperature, the mixture is poured into ice (120 g) and precipitate is formed gradually. The solid is collected by filtration and washed with water. The product is obtained as yellow solid. 1H NMR (CDCl3) δ 8.46 (s, 1H), 8.25 (s, 1H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=1)=[CH:8][CH:7]=2.C(Br)(Br)(Br)[Br:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:29][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=1)=[CH:8][CH:7]=2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCO)cc4c3)nc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCBr)cc4c3)nc2c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[2-(2-hydroxy-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-one (6.20 g, 16.9 mmol) in anhydrous DMF (25 mL) was added carbon tetrabromide (6.47 g, 19.5 mmol) and triphenylphosphine (5.11 g, 19.5 mmol). The reaction mixture was stirred at 40° C. for 16 hours. DMF was removed under vacuum and water (150 mL) was added. The separated solid was filtered and mixed with ether (150 mL) and heated for 10 minutes. The solid was filtered and dried under vacuum to give 2-[2-(2-bromo-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 6.1 g (84%).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([NH:17][C:18]([C:20]2[C:21]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH:12]=[CH:13][C:14]=1[CH2:15]O.C(N(CC)CC)C.[CH2:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH2:43]([N:50]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([NH:17][C:18]([C:20]3[C:21]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:31]=4)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[CH:10]=2)[CH2:15]1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: NCc1ccccc1
Reactant: O=C(Nc1ccc(CO)c(CCO)c1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)CCN(Cc1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 60 h
Yield: 39 %

Procedure:
Methanesulfonyl chloride (0.041 mL) was added to a 0° C. solution of 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxymethyl-phenyl]-amide (100 mg, 0.24 mmol) and triethylamine (0.084 mL) in THF (2 mL). TLC showed complete reaction after 30 min. Benzylamine (0.132 mL) was added and the contents stirred for 18 hrs at 25° C. and 60 hrs at 50° C. The solvent was removed under vacuum, the residue dissolved in methylene chloride (15 mL), washed with pH9 buffer, phases separated, and the organic phase dried with magnesium sulfate. Removal of the solvent under vacuum gave the crude product as a white solid (204 mg), which was repulsed in CDCl3 filtered off and dried to give the product as a white solid (46 mg, 39%). mp=230-32° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][C:7]=1[CH3:37].[OH-].[Na+].Cl>O1CCCC1.C(OCC)C>[CH3:37][C:7]1[CH:8]=[C:9]([S:12][CH2:13][C:14]2[S:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=3)=[N:16][C:15]=2[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:38])=[O:2]
Reactant: COC(=O)CCc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COc2ccccc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COc2ccccc2)ccc1CCC(=O)O
Temperature: 25 °C

Procedure:
3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionic acid methyl ester (100 mg, 0.1796 mmol) is dissolved in tetrahydrofuran (1 mL) and 5N NaOH (1 mL) is added. The mixture is heated to reflux until the conversion is complete. Upon complete conversion, the reaction is cooled to room temperature and 5N HCl (1 mL) is added. The mixture is diluted with diethyl ether and extracted with 1N HCl. The organic layer is washed with water and brine, then dried over anhydrous sodium sulfate. Concentration of the solvent reveals the pure 3-{2-Methyl-4-[4-phenoxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl]-phenyl}-propionic acid in near quantitative yield (93 mg, 0.170 mmol).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@H:13]([CH2:18][OH:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:27]>O1CCOCC1>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([CH2:18][OH:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:27]
Reactant: CSCC[C@@H](CO)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CSCC[C@@H](CO)NC(=O)[C@@H](N)Cc1ccccc1

Procedure:
A solution of 21.1 g Boc-Phe-Met-ol in 20 ml dioxane is added at 0° C. to 130 ml 5 N HCl in dioxane. After reaction for 1 hour at 0° C., 400 ml ethyl ester are added, the precipitate filtered under suction, washed with ethyl ether and dried over P2O5 and KOH under vacuum, to yield the title compound: [α]D20 =+8.8° (c=1 in DMF), decomposition at 200° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[NH3:15]>CCO>[NH2:15][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: N
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Solvent: CCO
Product: NCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 68 %

Procedure:
4-(Bromomethyl)-3-nitrobenzoic acid (3.2 g; 12.3 mmol) was dissolved in 8% NH3 in EtOH (300 mL) and the resulting solution was stirred at room temperature. After 22 h the solution was evaporated and the residue suspended in H2O (70 mL). The suspension was stirred for 15 min and filtered. The collected solid was suspended in H2O (40 mL) and dissolved by the addition of few drops of 25% aq. NH4OH (pH 12), then the pH of the solution was adjusted to 6 by addition of 6 N HCl. The precipitated solid was filtered, and washed sequentially with MeOH (3×5 mL), and Et2O (10 mL) and was vacuum dried (1.3 kPa; P2O5) to give 4-(aminomethyl)-3-nitrobenzoic acid as a pale brown solid (1.65 g; 8.4 mmol). Yield 68%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]4([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]4)[CH:5]=[CH:4][N:3]=3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: OCC1(COc2ccnc(Cl)n2)CCC1
Product: OCC1(COc2ccnc(N3CCN(c4ccccc4)CC3)n2)CCC1

Procedure:
The title compound was prepared from (1-{[(2-chloro-4-pyrimidinyl)oxy]methyl}cyclobutyl)methanol using the same experimental procedure as in example 21a using 1-phenylpiperazine. 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=6 Hz, 1H), 7.21 (m, 2H), 6.92-6.82 (m, 3H), 5.93 (d, J=6 Hz, 1H), 4.37 (s, 2H), 3.90 (m, 4H), 3.58 (s, 2H), 3.18 (m, 4H), 2.54 (br s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH2:5]([CH:7]1[O:9][CH2:8]1)[Cl:6]>>[Cl:1][CH2:2][CH:3]([OH:4])[CH2:8][O:9][CH2:7][CH2:5][Cl:6]
Reactant: OCCCl
Reactant: ClCC1CO1
Product: OC(CCl)COCCCl
Yield: 74.9 %

Procedure:
A mixture consisting of 100 g 2-chloroethanol (12.4 mol), 573 g epichlorohydrin (6.2 mol) and 20 g of an acidic ion exchange resin was refluxed for 24 hours. The mixture was then filtered to remove the ion exchange resin and the excess alcohol and unreacted epichlorohydrin were removed by distillation. The residue was distilled under vacuum and the product 1-chloro-3-(2-chloroethoxy)-2-propanol (804 g, 75% yield) distilled between 89 and 91° C. at 0.05mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15](OC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CC(=O)OCC>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH2:15][OH:16])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1CCCC(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(CCCc1ccccc1CO)Cc1ccccc1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
30h (1.8 g, 4.55 mmol) in THF (5 mL) was added dropwise to a stirred solution of LiAlH4 (0.35 g, 9.1 mmol) in THF (25 mL) at 0° C. Then the mixture was stirred at rt until TLC analysis indicated the total consumption of the SM. The reaction was quenched carefully by the slow addition of water (10 mL), and then the liquid was decanted away from the precipitate. The precipitate was washed with DCM (3×50 mL) and the organic layers were combined and dried over Na2SO4. The solvent was removed and the residue was purified by CC using PE:EA=5:1 as mobile phase to afford the desired product (1.3 g, 79% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][OH:39])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[OH:39][CH2:38][C@@H:34]1[CH2:35][CH2:36][CH2:37][N:33]1[S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:15][CH2:16]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31]
Reactant: Nc1cccc(S(=O)(=O)N2CCC[C@H]2CO)c1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)N2CCC[C@H]2CO)c1)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and (S)-[1-(3-amino-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (example B.13) according to general procedure II. Pale-yellow solid. Mp 180-182° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=4)[N:15](S(C4C=CC=CC=4)(=O)=O)[CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[C:21]4[C:16](=[CH:17][C:18]([F:22])=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccc(Cl)nn3)c2)c2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Fc1ccc2c(-c3cnn(-c4ccc(Cl)nn4)c3)c[nH]c2c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 28.7 %

Procedure:
A mixture of 3-(1-(6-chloropyridazin-3-yl)-1H-pyrazol-4-yl)-6-fluoro-1-(phenylsulfonyl)-1H-indole (Intermediate 44; 226 mg; 0.50 mmol) in THF (20 mL) was added NaOH (80 mg; 2.0 mmol). The reaction mixture was stirred at 75° C. for 16 hours, concentrated, and purified by preparative HPLC to afford 45 mg (28%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:16]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[Li+].[OH-]>O1CCCC1>[CH3:1][C:2]1[C:3]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:28][CH:29]=2)(=[O:17])=[O:18])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(S(=O)(=O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2c(cc1S(=O)(=O)c1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Yield: 97 %

Procedure:
To a solution of 50 mg (0.12 mmol) of ethyl 4-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthylsulfonyl)benzoate (Compound 10) in 3.0 mL of tetrahydrofuran was added 1.0 mL of LiOH (1N aqueous solution). The solution was heated at 50° C. for 3 h, cooled to room temperature and concentrated in vacuo. The residue was diluted with brine, acidified using 10% HCl and extracted with ether (2×). The combined ether layers were dried (MgSO4), filtered, and the solvents were removed in vacuo to give the title compound as a white solid (45 mg, 98%):
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([OH:20])=[O:19])=[CH:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])=[CH:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
A solution of compound 31 (2.03 g, 7.4 mmol) in DMF (50 mL) was treated with sodium bicarbonate (1.8 g, 21.4 mmol), and benzyl bromide (4 mL, 33.6 mmol). The reaction mixture was stirred for 18 h at room temperature. Water (50 mL) was added and the product was extracted with ethyl acetate (80 mL×3). The solution was dried with sodium sulfate, concentrated in vacuo to give compound 32 (2.27 g, 84% yield) as a white solid. m.p.180°-182° C. 1H NMR (DMSO-d6, ppm): 11.93 (s, 1 H, NH), 7.51-7.02 (m, 9 H, Ar--H), 5.38 (s, 2 H, CH2C6 H5), 1,48 (s, 9 H, C(CH3)3). Anal. (C21H22 N2O4 0.25H2O), C, H, N.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.Cl.[CH2:16](O)[CH:17]=C>>[OH:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH2:12][CH:16]=[CH2:17])=[O:10])=[CH:13][CH:14]=1
Reactant: C=CCO
Reactant: COC(=O)c1ccc(CO)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: C=CCOC(=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
To an alkoxide solution prepared from sodium hydride (60% in oil, 1.60 g, 40.0 mmol) and allyl alcohol (100 mL) was added methyl 4-hydroxymethylbenzoate (3.32 g, 20.0 mmol) under ice-cooling. The resulting mixture was stirred at room temperature for 6 h, adjusted with 1N hydrochloric acid to pH 3, and then concentrated under reduced pressure. To the residue was added ethyl acetate (150 mL), and the mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was separated and purified by silica gel column chromatography (hexane-ethyl acetate, 5:2) to give 3.59 g (93%) of allyl 4-hydroxymethylbenzoate as a pale-yellow oil.