Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[C:23]([C:24]#[N:25])=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[C:24]([C:23]1[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=[CH:21][N:22]=1)#[N:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nccnc3C#N)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2nccnc2C#N)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of [6-(3-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (200 mg, 0.566 mmol) in THF (5 mL) and H2O (2 mL) was added LiOH (0.120 g, 2.83 mmol). The resulting solution was stirred at 0° C. for 2 hrs. The mixture was diluted with H2O and acidified to pH 3 with 1N HCl at 0° C. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The title compound was obtained (150 mg, 82%) as a white solid. 1H NMR (CD3OD) δ8.42 (d, 1H), 8.38 (d, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 5.65 (dd, 1H), 3.20 (dd, 1H), 2.41 (s, 3H), 2.36 (dd, 1H). MS found: (M+H)+: 326.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH:27][C:28](=[O:30])[CH3:29])=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:3][CH2:2]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].N1CCC([N:44]2[C:57]3[CH:56]=CC(C4NN=NN=4)=CC=3O[C:50]3[C:45]2=CC=CC=3)CC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].C[N+:79](C)(C)C>ClCCCl.C1COCC1>[NH:44]1[CH:57]=[CH:56][N:79]=[C:45]1[CH2:50][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH:27][C:28](=[O:30])[CH3:29])=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][CH2:6]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]
Reactant: C[N+](C)(C)C
Reactant: c1ccc2c(c1)Oc1cc(-c3nnn[nH]3)ccc1N2C1CCNCC1
Reactant: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1N2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1N2C1CCN(Cc2ncc[nH]2)CC1

Procedure:
Using an adaptation of the method described in Procedure 7, substituting N-[2-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide, 2j for the TFA salt of 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, sodium triacetoxyborohydride for tetramethylammonium borohydride, and a 3:1 mixture of 1,2-dichloroethane:THF for 100% 1,2-dichloroethane, the title compound N-(2-{10-[1-(1H-imidazol-2-ylmethyl)-piperidin-4-yl]-10H-phenoxazin-3-yl}-phenyl)-acetamide, 7j was obtained as a TFA salt after purification via reverse phase HPLC (eluent: CH3CN in H2O containing 0.1% TFA). MS m/z (MH+) 479.9.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Reactant: C1CCNCC1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1N1CCCCC1
Temperature: 160 °C
Yield: 13.6 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (300 mg, 0.74 mmol) in DMSO (6 ml). Piperidine (0.024 ml, 0.25 mmol) and DIPEA (0.129 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was further purified by Mass Directed Automated Preparative HPLC (Method E) and product-containing fractions were dried under a stream of nitrogen to afford the title compound (16 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12]>COCCOC>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:23]([OH:24])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:16]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
A solution of 8.6 g (0.063 mole) of p-aminobenzoic acid in 100 ml of 1,2-dimethoxyethane was added to a suspension of 8.0 g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered. The filtrate was thereafter diluted with 200 ml of water and chilled. The resulting precipitate was collected, and was then recrystallized from a mixture of ethanol and water to give 3.6g of white needles of N-(4-carboxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 265°-266° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4; %N, 3.8; Found: %C, 71.7; %H, 7.3; %N, 3.6.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[N:6]=[C:5]([CH3:7])[CH2:4][S:3]1.[N:9]([O-])=[O:10].[Na+].C(O)(=O)C>O>[N:9](=[C:4]1[S:3][C:2]([CH3:8])([CH3:1])[N:6]=[C:5]1[CH3:7])[OH:10]
Reactant: CC1=NC(C)(C)SC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1=NC(C)(C)SC1=NO
Temperature: 45 °C

Procedure:
30.0 g (0.232 mol) of 2,2,4-trimethyl-3-thiazoline and 17.6 g (0.255 mol) of sodium nitrite are dissolved in 75 ml of water and 26.6 ml (0.464 mol) of acetic acid are added dropwise, with stirring at 45° C. The internal temperature of the reaction mixture is allowed to rise slowly to 10°-15° C., and the mixture is then stirred at this temperature for an additional 2 hours. The product precipitates as ochre-brown crystals and is filtered, washed with water and dried in vacuo. A single recrystallization from chloroform/n-hexane yields 5-oxo-2,2,4-trimethyl-3-thiazoline oxime, m.p. 159°-161° C.
Reaction SMILES: C(O[C:6]([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1CC[CH2:49][CH2:48][CH2:47]1>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:39][CH2:49][CH2:48][CH2:47][CH2:6]3)=[O:38])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: C1CCNCC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (137 mg) described in Example 769 and piperidine (26 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (54 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][CH2:5][N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:3]1.[O:27]1[C:36]2[CH:35]=[C:34]([NH:37]C(=O)OC(C)(C)C)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.[H-].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[O:27]1[C:36]2[CH:35]=[C:34]([NH:37][CH2:8][CH:7]3[CH2:6][CH2:5][N:4]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:3][CH:2]3[OH:1])[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)Nc1cc2c(cn1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc3c(cn2)OCCO3)C(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
A mixture of rac-(3R*,4R*)-tert-butyl 3-hydroxy-4-((tosyloxy)methyl)piperidine-1-carboxylate (prepared as described in Tetrahedron (2008), 64, 2456-2464, 0.26 g, 0.67 mmol) and tert-butyl (2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)carbamate (prepared as described in WO 2009/104159, 0.17 g, 0.67 mmol, 1 eq.) was dissolved in DMF (2.5 mL). NaH (60% dispersion in oil, 0.04 g, 0.88 mmol, 1.3 eq.) was added and the mixture was vigorously stirred at rt for 2 h. More NaH (0.03 g, 0.67 mmol, 1 eq.) was added. After two more hours, sat. aq. NaHCO3 (5 mL) was added and the mixture was extracted with EA (3×10 mL). The combined org. phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by CC (DCM/MeOH 19:1) to afford the title compound as a white solid (0.15 g, 62% yield).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:5][CH:4]=1)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[OH:28])[C:21]([NH:23][NH2:24])=[O:22]>>[OH:16][CH2:15][CH2:14][CH2:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH:1]=[N:24][NH:23][C:21](=[O:22])[C:20]2[CH:25]=[CH:26][C:27]([OH:28])=[C:18]([Cl:17])[CH:19]=2)=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(CCCO)c2ccccc12
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Product: O=C(NN=Cc1ccc(CCCO)c2ccccc12)c1ccc(O)c(Cl)c1

Procedure:
This compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones by condensation of 1-formyl-4-(3-hydroxypropyl) naphthalene from step B and 3-chloro-4-hydroxy benzoic acid hydrazide.
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7].[H][H].[CH3:13]O>>[CH3:13][O:8][C:6](=[O:7])[CH:5]([CH3:9])[CH2:4][C:3]([OH:2])=[O:10]
Reactant: C=C(CC(=O)OC)C(=O)O
Reactant: [H][H]
Reactant: CO
Product: COC(=O)C(C)CC(=O)O
Reaction time: 16 h

Procedure:
5.73 g (39.8 mmol) of 2-methylenesuccinic acid 4-monomethyl ester were introduced into 12 ml of methanol under protective gas in a 50 ml glass autoclave, and 0.12 ml of a solution of 6.6 mg of (RophosARhCOD)CF3SO3 (=precatalyst) in 3 ml of methanol was added (0.00036 mmol of precatalyst). Hydrogenation was then carried out at 60° C. under 5 bar of hydrogen. Conversion of the precursor was complete after 16 h. The enantiomeric excess of the product was 98%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[C:39]([Zn]C#N)#[N:40].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CN(C=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:39]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:26][CH2:27]3)[CH:20]=[N:19][CH:18]=1)#[N:40]
Reactant: N#C[Zn]C#N
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C#N)cc34)n2)C1
Temperature: 100 °C
Yield: 91.5 %

Procedure:
(4R)-tert-Butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (124 mg, 0.212 mmol), dicyanozinc (Aldrich, St. Louis, Mo.; 32.4 mg, 0.276 mmol), Pd2(dba)3 (Aldrich, St. Louis, Mo.; 9.71 mg, 10.61 μmol), and XPhos (Strem, Newburyport, Mass.; 10.11 mg, 0.021 mmol) in a mixture of DMF (2.0 mL) and water (0.020 mL) was heated at 100° C. for 19 h. The mixture was concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(5-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (102.8 mg, 0.194 mmol, 91% yield) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.04 (1 H, s), 8.74 (1 H, br. s.), 8.25 (1 H, br. s.), 8.02 (1 H, s), 7.78 (1 H, s), 7.64 (1 H, s), 5.84 (1 H, d, J=6.8 Hz), 4.63 (1 H, br. s.), 4.35-4.44 (1 H, m), 4.21-4.33 (1 H, m), 3.90-4.10 (2 H, m), 3.73-3.85 (2 H, m), 3.34 (2 H, d, J=14.1 Hz), 2.53-2.70 (2 H, m), 2.45 (1 H, m), 2.09-2.30 (2 H, m), 1.68-1.90 (4 H, m), 1.14 (9 H, br. s.). MS (ESI, pos. ion) m/z: 531.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH:23]=O)=[CH:21][N:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.N1([CH2:39][CH2:40][S:41]([NH2:44])(=[O:43])=[O:42])CCNCC1.C([N:47]([CH2:50][CH3:51])[CH2:48][CH3:49])C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH:25]2[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]2)[C:15]([NH:17][C:18]2[S:19][C:20]([CH2:23][N:47]3[CH2:48][CH2:49][N:44]([S:41]([CH2:40][CH3:39])(=[O:43])=[O:42])[CH2:51][CH2:50]3)=[CH:21][N:22]=2)=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC1CCC(N(C(=O)Nc2ncc(C=O)s2)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: NS(=O)(=O)CCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCC(C)CC3)C3CCN(C(=O)OC(C)(C)C)CC3)s2)CC1
Yield: 58 %

Procedure:
Prepared as described in general procedure (P) using 4-[3-(5-formyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.45 mmol), piperazine ethane sulfonamide hydrochloride (125 mg, 0.58 mmol), triethyl amine (80 μL, 0.58 mmol) and sodium triacetoxyborohydride (113 mg, 0.53 mmol) to afford 160 mg (58%) of the desired product after purification.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[O:9].[S:10]([O-:13])([O-:12])=[O:11].[Na+:14].[Na+]>O>[OH:9][CH:8]([S:10]([O-:13])(=[O:12])=[O:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:14]
Reactant: O=S([O-])[O-]
Reactant: C=O
Reactant: Oc1ccccc1
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])C(O)c1ccccc1
Reaction time: 5 h

Procedure:
No. 1 A one-liter three necked flask provided with a stirrer and a reflux condenser was charged with 94g of phenol, 81g of 37% formalin, 126g of sodium sulfite and 300g of water. Reaction was conducted for 5 hours under heating by a boiling water bath to obtain a water solution of sodium hydroxybenzylsulfonate. The concentration of the solution thus obtained was about 40% by weight, and the pH value thereof was 11.5. This solution was used as a water-reducing additive designated as A.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[NH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)C(C)C)C.S(=O)(=O)(O)O.N[C:39]1[CH:40]=[N:41][N:42]2CCCN[C:43]=12>C(Cl)Cl>[C:19]([O:18][C:17]([NH:16][CH2:15][CH2:14][NH:13][C:1](=[O:2])[NH:8][C:12]1[CH:40]=[N:41][N:42]2[CH2:43][CH2:39][CH2:9][NH:10][C:11]=12)=[O:23])([CH3:20])([CH3:22])[CH3:21]
Reactant: Nc1cnn2c1NCCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)Nc1cnn2c1NCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (973 mg) in methylene chloride (10 ml) was added tert-butyl N-(2-aminoethyl)carbamate (1.11 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added N-ethyldiisopropylamine (1.28 g) and 3-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine sulfuric acid salt (1.18 g), and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 5% methanol/chloroform to give 3-(3-{2-[(tert-butoxycarbonyl)amino]ethyl}ureido)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (150 mg) as a solid.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][CH2:12][OH:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][CH2:12][O:13][C:30](=[O:31])[NH:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:33])[F:32])=[CH:24][CH:25]=2)[NH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1n[nH]c(SCCO)n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1n[nH]c(SCCOC(=O)Nc2ccc(C(F)(F)F)cc2)n1

Procedure:
To 5 g (20 mmole) of 3-t-butyl-5-(2-hydroxyethylthio)-1H-1,2,4-triazole in 50 ml of chloroform was added 0.1 g of triethylamine and 3.8 g (20 mmole) of 4-trifluoromethylphenylisocyanate. After refluxing for three hours, the mixture was concentrated in vacuo and crystallized from ether/hexane to give 3-t-butyl-5-(2-(4-trifluoromethylphenylcarbamoyloxy)-ethylthio)-1H-1,2,4-triazole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:16]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCN
Solvent: ClCCl
Product: O=C(NCCCCCNC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
Under N2, 1,5-diaminopentane (2.86 ml., 2.5 g., 0.0245 mol) was dissolved in 50 ml. CH2Cl2 and cooled to 0°. With stirring, benzyloxycarbonyl chloride (3.67 ml., 4.17 g., 0.0245 mol) was added dropwise, maintaining the temperature near 0°. The mixture was warmed to room temperature, washed 2×50 ml. 5% HCl, 1×50 ml. saturated NaHCO3, and 1×50 ml. brine, dried (MgSO4) and stripped to yield title product as a white solid, 4 g.; 1H-nmr (CDCl3) includes delta 5.2 ppm (s, 4H, two benzyl CH2 groups). The yield is greatly enhanced by use of two molar equivalents of the acid chloride.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[C:11]([O:15][C:16](=[O:25])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])([CH3:14])([CH3:13])[CH3:12].[C:26](=[O:28])=[O:27]>O.C1COCC1>[C:11]([O:15][C:16]([NH:17][C:18]1[C:19]([F:24])=[CH:20][CH:21]=[CH:22][C:23]=1[C:26]([OH:28])=[O:27])=[O:25])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyllithium in pentane (1.7M, 34 ml, 58 mmol) was added with caution to a solution of (2-fluoro-phenyl)-carbamic acid tert-butyl ester whilst cooling to less than −50° C. The mixture was maintained at this temperature, stirred for 3 h then poured onto a slurry of THF and dry ice. The mixture was allowed to warm to room temperature, diluted with water and evaporated in vacuo. The residue was taken up in water and washed with diethyl ether. A solution of 0.3M potassium hydrogen sulphate was added until pH6 and extracted with chloroform. The chloroform extracts were combined, washed with brine, dried and reduced to give a white solid; yield 2.7 g, 37%.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:27][S:28]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[Cl:62]CCl>>[ClH:62].[ClH:62].[ClH:62].[NH2:8][C@@H:9]([CH2:27][SH:28])[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)CN1CCN(c2cccc3c2CCCC3)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H](CS)CN1CCN(c2cccc3c2CCCC3)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step E, except using 1-(2(R)- tert-butoxycarbonylamino-3-triphenylmethylthiopropyl)-4-(5,6,7,8-tetrahydronaphth-1-yl)piperazine obtained in Step B above, triethylsilane (0.71 mL, 4.48 mmol), trifluoroacetic acid (6 mL) and dichloromethane (12 mL). Purification by preparative HPLC using gradient elution (100% Solvent A to 40% Solvent A/60% Solvent B over 60 min), ion exchange and lyophilization afforded the title compound as a white powder (89 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[NH:9][C:10]([CH3:18])=[C:11]3[C:16]=2[CH:15]=[N:14][NH:13][C:12]3=[O:17])[CH:7]=1.C(N(CC)CC)C.ClCCl.[CH2:38]([S:40](Cl)(=[O:42])=[O:41])[CH3:39]>O1CCCC1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[CH:7][C:6]=1[C:8]1[NH:9][C:10]([CH3:18])=[C:11]2[C:16]=1[CH:15]=[N:14][NH:13][C:12]2=[O:17]
Reactant: Cc1[nH]c(-c2cc(N)ccc2Oc2ccc(F)cc2F)c2cn[nH]c(=O)c12
Reactant: CCS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2[nH]c(C)c3c(=O)[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
To a solution of Example 78c (40.5 mg, 0.110 mmol) and triethylamine (0.077 mL, 0.55 mmol) in the mixture of dichloromethane (2 mL) and tetrahydrofuran (2 mL) was added ethanesulfonyl chloride (0.038 mL, 0.40 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 6 hours and concentrated. The residue was diluted with dioxane (2 mL) and 1M sodium hydroxide (1.1 mL), and heated at 50° C. for 1 hour. The reaction mixture was cooled to ambient temperature, diluted with water and ethyl acetate, adjusted the pH to 7 by addition of 1M HCl and separated. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1-5% methanol in dichloromethane) to afford the title compound (20 mg, 40%). 1 H NMR (300 MHz, DMSO-d6) δ 12.45 (s, 1 H) 11.45 (s, 1 H) 9.81 (s, 1 H) 8.04 (s, 1 H) 7.36-7.50 (m, 2 H) 7.13-7.27 (m, 2 H) 7.02-7.12 (m, 1 H) 6.88 (d, J=8.73 Hz, 1 H) 3.13 (q, J=7.14 Hz, 2 H) 2.63 (s, 3 H) 1.23 (t, J=7.34 Hz, 3 H). MS (ESI+) m/z 461 (M+H)+.