Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH:52]12[CH2:61][CH:56]3[CH2:57][CH:58]([CH2:60][CH:54]([CH2:55]3)[CH:53]1[NH:62][CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[CH2:59]2>CN(C=O)C.O>[CH:54]12[CH2:55][CH:56]3[CH2:57][CH:58]([CH2:59][CH:52]([CH2:61]3)[CH:53]1[NH:62][CH:63]1[CH2:68][CH2:67][N:66]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:65][CH2:64]1)[CH2:60]2
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: C1CC(NC2C3CC4CC(C3)CC2C4)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(NC2C3CC4CC(C3)CC2C4)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 81.8 %

Procedure:
DIPEA (150 mg, 3.5 mmol) was added to a stirred solution [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (150 mg, 0.53 mmol) in DMF (4 mL) followed by HOBt (82 mg, 0.61 mmol) and EDCI.HCl (270 mg, 1.4 mmol). After 2 minutes of stirring, adamantan-2-yl-piperidin-4-yl-amine dihydrochloride (150 mg, 0.59 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water and the precipitate was filtered to afford 200 mg (81.63% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(adamantan-2-ylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 462.28, 91.77%. 1H NMR (300 MHz, DMSO-d6): δ8.2-8.0 (bs, 1H), 7.82-7.76 (d, 2H), 7.5-7.42 (t, 2H), 7.4-7.34 (t, 1H), 7.2-7.1 (bs, 1H), 4.3-4.1 (m, 3H), 3.8 (d, 1H), 3.1 (t, 1H), 2.9-2.7 (m, 3H), 2.1 (d, 2H), 1.9-1.6 (m, 1H), 1.4-1.3 (d, 3H), 1.2-1.1 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[NH:6][CH:5]=1.N1C=CN=C1.[CH:19]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[CH:19]([Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][NH2:1])([CH3:21])[CH3:20]
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1ccc2[nH]cc(CCN)c2c1)(C(C)C)C(C)C

Procedure:
A solution of 3-(2-amino-ethyl)-1H-indol-5-ol (3.0 g), imidazole (9.6 g), and triisopropylsilyl chloride (4.5 mL) was stirred in 20 mL N,N-dimethylformamide for 6 h. The solution was diluted with 100 mL of ethyl acetate and washed with 100 mL of sodium carbonate and 100 mL of saturated sodium chloride (3 times). The organic phase was dried over sodium sulfate and the solvent was evaporated. Silica gel chromatography (2% methyl alcohol in dichloromethane) gave 2-(5-triisopropylsilanyloxy-1H-indol-3-yl)-ethylamine (2.6 g). This compound was cyclized with formaldehyde by Procedure OO to afford 6-triisopropylsilanyloxy-2,3,4,9-tetrahydro-1H-β-carboline, which was protected with tert-butoxycarbonyl group by Procedure CC to give 6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31](OC)=[O:32])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([N:37]([CH2:41][CH3:42])[CH2:38][CH2:39][NH:40][C:31](=[O:32])[CH2:30][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=2)=[N:9]1)[CH3:36]
Reactant: CCN(CC)CCN
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: CCN(CC)CCNC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21

Procedure:
The representative procedure for amide formation was used in the reaction of methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.035 g, 0.067 mmol) with N,N-diethylethylenediamine (1 mL). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 7.12-7.98 min) afforded N1-[2-(diethylamino)ethyl]-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide as an off-white solid (0.017 g, 0.028 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.22 (s, 1H), 8.12 (br, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.44 (t, 1H), 7.31 (m, 3H); 6.95 (br, 2H), 4.96 (s, 2H), 3.35 (m, 2H), 2.82 (m, 2H), 2.50 (m, 4H), 1.05 (t, 6H); MS: (M−H)− 607.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[C:23]([C:28]([F:31])([F:30])[F:29])=[N:22]3)[CH:17]=2)[CH2:12]1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>C(Cl)Cl.O=[Si]=O.[OH-].[Pd+2].[OH-]>[NH2:10][C@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[C:23]([C:28]([F:31])([F:30])[F:29])=[N:22]3)[CH:17]=2)[CH2:12]1
Reactant: O=C(N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: O=[Si]=O
Solvent: ClCCl
Solvent: CCO
Product: N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Yield: 70.7 %

Procedure:
Palladium hydroxide (20% on carbon) (3.86 mmol, 0.542 g) was wetted in a hydrogenation vessel before addition of (R)-benzyl-5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-ylcarbamate (3.86 mmol, 1.72 g) and ethanol (50 mL) followed by aqueous 5N HCl solution (5.00 mL). The mixture was stirred under 2 bar of hydrogen for 35 min before diluting with DCM (100 mL) and filtration through a dicalite pad which was then washed with 10% MeOH/DCM (150 mL). Combined organics were concentrated and partitioned between ethylacetate and saturated sodium carbonate solution. The organic layer was concentrated to give (R)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.85 g, 70.7%). 1H NMR (400 MHz, CDCl3) δ 2.65 (m, 2H) 3.15 (m, 2H) 3.83 (m, 1H) 4.61 (s, 2H) 5.24 (s, 2H) 7.06 (d, 1H) 7.11 (s, 1H) 7.19 (d, 1H) 7.38 (s, 1H).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:35])[CH:6]([O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][CH2:30][CH2:29]2)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1.CO.Cl>O>[CH2:31]1[C:32]2[C:28](=[CH:27][C:26]([O:25][CH:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:9][CH:8]=3)[C:5]([OH:35])=[O:4])=[CH:34][CH:33]=2)[CH2:29][CH2:30]1
Reactant: COC(=O)C(Oc1ccc2c(c1)CCC2)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(Oc1ccc2c(c1)CCC2)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 100.2 %

Procedure:
A mixture of 5 g of potassium hydroxide, 7.0 g of methyl(5-indanyloxy){p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate, 5 ml of methanol and 50 ml of water is refluxed for 4 hours. The mixture is acidified with concentrated HCl, chilled and the aqueous layer decanted from the gum which separated. The gum is washed with water, dissolved in chloroform and the solution dried (MgSO4). The solvent is removed under reduced pressure to give 6.8 g of gum. The gum is crystallized from petroleum ether containing a small amount of ether to give 5.4 g of off-white crystals. Recrystallization from chloroform-hexane gives white crystals, mp 104°-108° C.
Reaction SMILES: CN(C)C=O.[Cl:6][CH2:7][C:8]([CH2:10]Cl)=[CH2:9].[CH:12]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[OH:24])[C:17]([O:19][CH3:20])=[O:18])=[O:13].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:6][CH2:7][C:8](=[CH2:9])[CH2:10][O:24][C:23]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH:12]=[O:13]
Reactant: C=C(CCl)CCl
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(CCl)COc1ccc(C(=O)OC)cc1C=O
Reaction time: 26 h
Yield: 52.4 %

Procedure:
45 ml of dimethylformamide and then 1.15 ml (9.95 mmol) of 2-chloromethyl-3-chloro-1-propene are added under argon to 717 mg (3.98 mmol) of methyl 3-formyl-4-hydroxybenzoate as a mixture with 1.055 g (9.95 mmol) and 440 mg (1.195 mmol) of tetrabutylammonium iodide. The solution is stirred for 26 hours and then water is added. In order to break the emulsion, the pH is brought to 7 using a 1N hydrochloric acid solution. The aqueous phase is extracted several times with ether and then the combined organic phases are washed several times with water and with brine. After drying over magnesium sulfate and concentrating under vacuum, the crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 20/80) to give 560 mg (52%) of methyl 4-{[2-(chloromethyl)-2-propenyl]oxy}-3-formylbenzoate in the form of a white solid; 1H NMR (300 MHz, CDCl3): 10.44 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.18 (dd, J=2.4 Hz and 8.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.44 and 5.39 (2s, 2H), 4.79 (s, 2H), 4.19 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:14][CH2:13][C@H:12]([N:15]=[N+:16]=[N-:17])[CH2:11][NH:10][C:9]1=[O:18])(C)(C)C.C(OC(=O)N[C@H]1CC[C@@H](OCCCCCCN=[N+]=[N-])CN(C)C1=O)(C)(C)C>>[NH2:7][C@H:8]1[CH2:14][CH2:13][C@H:12]([N:15]=[N+:16]=[N-:17])[CH2:11][NH:10][C:9]1=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N=[N+]=[N-])CNC1=O
Agent: CN1C[C@H](OCCCCCCN=[N+]=[N-])CC[C@H](NC(=O)OC(C)(C)C)C1=O
Product: [N-]=[N+]=N[C@H]1CC[C@H](N)C(=O)NC1

Procedure:
Following the procedure of example 2d) ((3S,6S)-6-azido-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester is substituted for [(3S,6R)-6-(6-azido-hexyloxy)-1-methyl-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester to give (3S,6S)-3-amino-6-azido-azepan-2-one. MS (ESI) 170 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22].C.Cl>C(#N)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([NH:35][CH2:34][CH2:33][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]3[CH2:26][N:23]([CH2:21][CH3:22])[CH2:24][CH3:25])=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Reactant: CCN(CC)CC1CCCCN1CCN
Agent: Cl
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2cc(Cl)ccc2C(=O)Nc2cccnc21
Yield: 50 %

Procedure:
Prepared analogously to Example 2 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (+)-2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 50% of theory. Colourless crystals, m.p. 169°-170° C. (from acetonitrile, using activated charcoal); [α]D20 =+11.88° (dilute hydrochloric acid).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2ccccc2NC1=O
Product: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step A) by the procedure described in Example 1, Step F. 1H NMR (300 MHz, CDCl3): 1.34 (s,6H), 1.41 (s,9H), 1.90 (m,1H), 2.45 (d,15 Hz,1H), 2.56 (d,15 Hz,1H), 2.65 (m,1H), 2.76 (m,1H), 2.92 (m,1H), 4.53 (m,1H), 5.20 (br s,1H), 6.62 (d,7 Hz,1H), 6.97 (d,8 Hz,1H), 7.10-7.25 (m,3H), 7.35 (br s,1H). FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H,45%).
Reaction SMILES: Cl[S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3].[CH:11]([C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:25])[CH3:24])[C:15]=1[OH:26])([CH3:13])[CH3:12]>C(Cl)Cl>[CH:23]([C:16]1[CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=[C:14]([CH:11]([CH3:13])[CH3:12])[C:15]=1[O:26][S:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])=[O:3])([CH3:25])[CH3:24]
Reactant: CCOC(=O)CS(=O)(=O)Cl
Reactant: CC(C)c1cc(C(C)C)c(O)c(C(C)C)c1
Solvent: ClCCl
Product: CCOC(=O)CS(=O)(=O)Oc1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1H NMR (CDCl3): δ1.35 (t, 3H), 4.1 (s, 2H), 4.25 (q, 2H). A mixture of ethyl sulfoacetate (16.82 g, 100 mM) and POCl3 (30.67 g, 200 mM) was heated at 125° C. for 5 hours. The mixture was cooled and filtered, and excess POCl3 was removed to give ethyl chlorosulfonylacetate. The ethyl chlorosulfonylacetate (18.66 g, 100 mM) was added dropwise with stirring to a solution of 2,4,6-triisopropylphenol (22.1 g, 100 mM) in 50 mL CH2Cl2 maintained at 0° C. The mixture was stirred at room temperature for an additional 18 hours. The solvent was removed and the residue was redissolved in 100 mL ethyl acetate and washed with 1 N HCl and brine. The ethyl acetate was evaporated to provide ethyl (2,4,6-triisopropylphenoxysulfonyl)acetate.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)#[N:3].[CH2:20]([OH:22])[CH3:21]>>[ClH:1].[CH2:20]([O:22][N:3]=[CH:2][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:5]=1)[CH3:21]
Reactant: CCO
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C#N)cc1
Agent: Cl
Product: CCON=Cc1ccc(NC(=O)NCC(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 30 h

Procedure:
Dry HCl gas is introduced with stirring and cooling (0° C.) into a suspension of 2.3 g (9.3 mmol) of ethyl 3-(4-cyanophenyl)ureidoacetate in 50 ml of anhydrous ethanol. After 30 h, the mixture is concentrated in vacuo. The residue is stirred with ether and filtered off.
Reaction SMILES: [CH2:1]=[O:2].[F:3][C:4]([F:11])(Br)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl-].[NH4+]>O1CCCC1.[Zn]>[F:3][C:4]([F:11])([CH2:1][OH:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C=O
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CO

Procedure:
A mixture of paraformaldehyde (4.5 g, 50 mmol), ethyl difluorobromoacetate (10.2 g, 50 mmol) and activated zinc dust (3.3 g, 40 mmol) in anhydrous tetrahydrofuran was heated under reflux for 0.5 h. Then the mixture was treated with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. After usual work-up the desired compound ethyl 2,2-difluoro-3-hydroxypropionate was obtained by flash chromatography on silica gel (ethyl acetate:hexane; 25:75) (4.1 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-chloro-2-oxindole (167 mg), 3-methylindole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 5-chloro-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[N+:14]([O-:16])=[O:15].Cl.[CH3:18][NH:19][O:20][CH3:21].N1C=CC=CC=1.O>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([N:19]([O:20][CH3:21])[CH3:18])=[O:13])=[C:7]2[N+:14]([O-:16])=[O:15]
Reactant: CNOC
Reactant: O=C(O)c1[nH]c2c(Cl)cccc2c1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1[N+](=O)[O-]
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution of 7-chloro-3-nitroindole-2-carboxylic acid (step 1, 400 mg, 1.7 mmol) in thionyl chloride (2 ml) was heated at 70° C. for 3 h, the mixture cooled and concentrated. The residue was dissolved in dichloromethane (20 ml). To the solution was added N,O-dimethylhydroxylamine hydrochloride (326 mg, 3.4 mmol) and pyridine (0.27 ml, 3.4 mmol). After stirring for 16 h, the mixture was poured into water (100 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with 2N aqueous HCl (100 ml), water (100 ml), saturated aqueous sodium bicabonate (100 ml), brine (100 ml), and dried (MgSO4). After removal of solvent, the residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:10˜1:1) to give 420 mg (87%) of the title compound. tlc: Rf=0.55 (25% ethyl acetate in hexanes)
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[OH:28][CH:29]([CH2:33][CH3:34])[C:30](O)=[O:31]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[CH:29]([OH:28])[CH2:33][CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: CCC(O)C(=O)O
Agent: Cl
Product: CCC(O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (15 mg, 50.1%), MS (ISP) m/z=418.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (Intermediate A) (30 mg, 68.1 mmol) and 2-hydroxybutanoic acid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]2[CH2:14][O:15][CH2:16][C@@H:9]12)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[O:11]1[CH2:12][CH2:13][NH:8][C@@H:9]2[CH2:16][O:15][CH2:14][C@@H:10]12
Reactant: c1ccc(CN2CCO[C@@H]3COC[C@H]32)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C1CO[C@@H]2COC[C@H]2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-benzylhexahydro-2H-furo[3,4-b][1,4]oxazine (600 mg, 2.73 mmol) in MeOH (10 mL) at room temperature was added Pd(OH)2/C (250 mg). Hydrogen was purged through the reaction for 10 minutes and then the reaction was stirred at room temperature under 1 atm of hydrogen for 2 hours. Concentrated HCl (0.3 mL) was added, and the solution was stirred for 15 minutes. The reaction was filtered through celite, and the solvent was evaporated to afford (trans)-hexahydro-2H-furo[3,4-b][1,4]oxazine (HCl salt, racemic). 1H NMR (400 MHz, CD3OD) δ 3.72-4.29 (m, 6H), 3.41-3.69 (m, 3H), 3.23-3.35 (m, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][CH:4]=1.[B:18](OC)([O:21]C)[O:19]C.Cl.[Cl-].[Na+]>O1CCCC1>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3]([B:18]([OH:21])[OH:19])=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COB(OC)OC
Reactant: CCCCCCCCCc1ccc(Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCc1ccc(B(O)O)cc1
Reaction time: 2.5 h
Yield: 78.4 %

Procedure:
A solution of the Grignard compound prepared from 0.55 mol of magnesium and 0.37 mol of 1 -bromo-4-nonylbenzene in 550 ml of dry tetrahydrofuran is added dropwise to a solution of 0.4 mol of trimethyl borate in 400 ml of dry tetrahydrofuran at 0° C. under a protective gas atmosphere. The mixture is stirred for an additional 2.5 h at this temperature. Then 600 ml of 10% stength hydrochloric acid are added and the resulting mixture is stirred at room temperature for 30 min. After addition of 120 g of sodium chloride, the reaction mixture is extracted with tert-butyl methyl ether, the combined organic extracts are washed with saturated sodium chloride solution and dried with magnesium sulfate. The solvent is removed under reduced pressure and the raw product is recrystallized from acetonitrile, giving 72 g (79%) of 4-nonylphenylboronic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:29]([N:36]1[C:48]2[C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]=[C:40](N)[C:39]=2[N:38]=[CH:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(N(CC)CC)C>[C:6]([N:8]([CH2:9][C:10]([OH:12])=[O:11])[CH3:13])([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7].[CH2:29]([N:36]1[C:48]2[C:47]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[N:41]=[C:40]([C:6]([NH2:8])=[O:5])[C:39]=2[N:38]=[CH:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1nc2ccccc2c2c1ncn2Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Product: NC(=O)c1nc2ccccc2c2c1ncn2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 134.3 %

Procedure:
18.9 g (0.1 mol) of N-t-Butyloxycarbonyl-N-methylglycine was dissolved in 300 ml of dichloromethylene. 20.6 g of N,N′-Dicyclohexylcarbodiimide was added into the reaction mixture. The mixture was stirred for 1 hour at 0° C. 32.2 g (0.1 mol) of 1-benzyl-1H-imidazo[4,5-c]quinolin-4-amine and 20 ml of triethylamine were added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solid was removed by filtration. The dichloromethylene solution was washed with water (1×100 ml), 30% citric acid (1×100 ml), water (1×100 ml), 5% NaHCO3 (2×100 ml), and water (3×100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. The organic solution was evaporated to dryness. After drying, it yielded 33 g of the desired product (74.1%). Elementary analysis: C25H27N5O3; MW: 445.51; calculated % C, 67.40; H, 6.11; N, 15.72; O: 10.77. found % C, 67.35; H, 6.14; N, 15.70; O: 10.81.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([CH:13]([OH:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)C(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of Ethyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)-2-hydroxyacetate (Compound 191), (100 mg, 0.24 mmol, 1.0 eq) in DMSO (10 mL) was added IBX (168 mg, 0.6 mmol, 2.5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, the residue was purified by silica gel column chromatography (PE:EA=2:1) to give ethyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)-2-oxoacetate (Compound 189) (90 mg, 90.8%). LC-MS (m/z): 418.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.79 (m, 2H), 0.99-1.01 (m, 2H), 1.35 (t, J=7.0 Hz, 3H), 1.93-1.97 (m, 1H), 4.37-4.42 (m, 2H), 6.43 (s, 1H), 7.89 (d, J=3.6 Hz, 1H), 8.14 (d, J=3.6 Hz, 1H), 8.51 (s, 1H), 9.50 (s, 1H), 12.35 (s, 1H).