Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[C:21]([O:25][C:26]([N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:25][C:26]([N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccn3C(=O)OC(C)(C)C)[nH]c2c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (800 mg, 2.38 mmol) obtained in the same manner as in the method described in WO03/010140 and N-tert-butoxycarbonylpyrrole-2-boronic acid (1.00 g, 4.76 mmol) in dimethoxyethane (10 ml) and water (5 ml) were added sodium carbonate (757 mg, 7.14 mmol), lithium chloride (202 mg, 4.76 mmol) and tetrakis(triphenylphosphine)palladium (275 mg, 0.238 mmol), and the mixture was heated under reflux for 9 hr. The reaction mixture was allowed to cool to room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=8:1-6:1) to give methyl 2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-cyclohexyl-1H-indole-6-carboxylate (642 mg, yield 64%).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([CH2:9][CH3:10])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5]1)=[N+]=[N-].O>C(#N)C>[NH2:1][C@H:4]1[C@@H:8]([CH2:9][CH3:10])[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:5]1
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Solvent: O
Solvent: CC#N
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N
Temperature: 60 °C
Yield: 86.9 %

Procedure:
(3S,4S)-benzyl 3-azido-4-ethylpyrrolidine-1-carboxylate (14.0 g, 51.0 mmol) was dissolved in acetonitrile (200 mL). Added water (20 mL) and stirred at RT to a clear solution. This soln. was warmed to 60° C. for 6.5 hrs. Acetonitrile was removed in vacuo and residual aqueous portion was diluted with 1N HCl (100 mL) which was washed with ethyl acetate (5×50 mL) until all Ph3P and Ph3P oxide was removed from the aqueous portion. The aqueous portion which contains HCl salt of the amine was cooled to ˜5 deg. This acidic soln was made basic (pH 12) with 1N NaOH. Extracted this basic milky suspension with DCM (5×, 50 mL), dried (Na2SO4) and concentrated. On vacuum overnight gave (3S,4S)-benzyl 3-amino-4-ethylpyrrolidine-1-carboxylate (11.01 g, 44.3 mmol, 87% yield). LCMS:M+1=249, t=1.39 min. This material was resolved using the following chiral SFC conditions [column: Chiralpak AD-H 5×25 cm, 5 μm, Column Temp. 48° C., Flow rate: 290 mL/min, Mobile Phase: CO2/MeOH=77/23 with 0.3% triethylamine, Injection Volume: 3 mL (Conc. 68.8 mg/mL), detector wavelength: 215 nm, 100 bars]. The isolated isomers were named “Pk1” and “Pk2” in the elution order. Fractions containing Pk1 were concentrated to afford 5.1 g of the desired (3S,4S)-benzyl 3-amino-4-ethylpyrrolidine-1-carboxylate (Intermediate 9). Chiral purity: >99% ee (chiral HPLC conditions: column: Chiralpak AD-H (25×0.46 cm, 5 μm), 30% MeOH in CO2 with 0.3% triethylamine, 3 mL/min, 40° C., 200-400 nm, 100 bars). 1H NMR (400 MHz, chloroform-d) δ ppm 7.33-7.42 (5 H, m), 5.12-5.17 (2 H, m), 3.51-3.67 (3H, m), 3.32-3.40 (1 H, m), 3.14-3.21 (1 H, m), 2.0-2.15 (1 H, m), 1.44-1.55 (2 H, m), 0.97-1.02 (5 H, m). LCMS: (M+1)=249, t=1.39 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][NH:27][S:28]([C:31]1[S:32][C:33](Br)=[CH:34][CH:35]=1)(=[O:30])=[O:29]>>[CH3:23][N:24]([CH3:37])[CH2:25][CH2:26][NH:27][S:28]([C:31]1[S:32][C:33]([C:21]#[C:20][C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]([F:15])[F:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:22])[CH:4]=4)=[N:9][C:10]=23)=[CH:34][CH:35]=1)(=[O:30])=[O:29]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(=O)(=O)NCCN(C)C)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (159 mg, 0.5 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 73%). MS (ISN) 548.1 [(M−H)−]; mp 149° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[Cl:40][C:41]1[CH:42]=[C:43]([S:48](Cl)(=[O:50])=[O:49])[CH:44]=[CH:45][C:46]=1[Cl:47]>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:48]([C:43]1[CH:44]=[CH:45][C:46]([Cl:47])=[C:41]([Cl:40])[CH:42]=1)(=[O:50])=[O:49])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 60 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 5, Example 1)was added 3,4-dichlorobenzenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 60% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([NH:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[Br:1][C:2]1[C:7]([NH:26][CH2:25][CH2:24][NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: NCCNc1ccccc1
Solvent: C1COCCO1
Product: Nc1nc(NCCNc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and N-phenylethylenediamine in dioxane. ES-MS m/e (%): 376 (M{81Br}+H+, 100), 374 (M{79Br}+H+, 95).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[Cl:16]C1C=C(C=CC=1)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:16])[CH:7]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1cccc(Cl)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 3-chlorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:15]2=[O:27])[CH2:10][CH2:9]1)C1C=CC=CC=1.CO.Cl.[H][H]>[Pd].O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]2=[O:27])=[CH:20][CH:21]=1
Reactant: COc1ccc(N2CCN(C3CCN(Cc4ccccc4)CC3)C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(N2CCN(C3CCNCC3)C2=O)cc1

Procedure:
A solution of 33 g of 1-benzyl-4-piperidone and 29 g of 1-(4-methoxy-phenyl)-ethylenediamine in 310 ml of methanol, with the addition of 1 g of a 5% platinum on charcoal catalyst, is hydrogenated at room temperature and under normal pressure until 1 molar equivalent of hydrogen has been taken up. The catalyst is thereafter removed by filtration and the filtrate concentrated. The residue is treated with toluene to yield the 1-benzyl-4-[2-4-methoxy-anilino)-ethylamino]-piperidine as a yellowish oil, which is used without purification. With vigorous stirring, 87 g of phosgene gas are introduced at 5° to 10° C. in the course of 21/2 hours into a mixture of 63 g of 1-benzyl-4-[2-(4-methoxy-anilino)-ethylamino]-piperidin in 570 ml of toluene and 285 ml of 2 3 N aqueous potassium hydroxide solution. Stirring is continued for a further 2 hours at room temperature and then 252 ml of a 6 N aqueous potassium hydroxide solution are added dropwise in the course of 15 minutes, when a slightly exothermic reaction occurs. The reaction mixture is stirred for a further 20 hours at room temperature. Thereafter the organic phase is separated and the alkaline aqueous phase is extracted with two 100 ml portions of toluene. The organic extracts are dried over sodium sulphate and concentrated under reduced pressure. The residue is treated with toluene and recrystallised from isopropanol to yield 1-(1-benzyl-4-piperidyl)-3-(4-methoxy-phenyl)-imidazolidin-2-one with a melting point of 144°-147° C. A mixture of 44 g of 1-(1-benzyl-4-piperidyl)-3-(4-methoxyphenyl)-imidazolidin-2-one, 320 ml of methanol, 130 ml of water and 12 g of a conc. aqueous solution of hydrochloric acid, with the addition of 10 g of a palladium on charcoal catalyst, is hydrogenated at 30° to 40° C. and under reduced pressure until 1 molar equivalent of hydrogen has been taken up. Thereafter the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is treated with toluene and recrystallised from a mixture of isopropyl alcohol and diethyl ether to yield the 1-(4-methoxyphenyl)-3-(4-piperidyl)-2-imidazolidinone with a melting point of 140° C.
Reaction SMILES: O.[OH-].[Na+].[C:4]([CH2:6][CH2:7][N:8]([CH2:48][CH2:49][C:50]#[N:51])[CH2:9][CH2:10][N:11]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])#[N:5].C(OC(OC(=O)C(C1C=CC=CC=1)=O)=O)(C)(C)C>[Ni].[OH-].[K+]>[NH2:5][CH2:4][CH2:6][CH2:7][N:8]([CH2:48][CH2:49][CH2:50][NH2:51])[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCN(CCC#N)CCC#N
Agent: [Ni]
Agent: CC(C)(C)OC(=O)OC(=O)C(=O)c1ccccc1
Agent: [K+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCN(CCCN)CCCN
Reaction time: 24 h

Procedure:
2.5 g of Raney nickel are added to 50 ml of water. With stirring, 4.5 g of sodium hydroxide are added so rapidly thereto that the water does not quite boil over, and the whole is then stirred for half an hour. 320 mg (0.48 mmol, MW 671.2) of N′,N′-bis(2-cyanoethyl)-N,N-dioctadecylethylenediamine are taken up in 500 ml of 0.5M potassium hydroxide solution (in EtOH/water 95:5 v/v). The activated Raney nickel is separated from the supernatant by decanting and is added to the starting solution. The whole is then hydrogenated for 24 hours using a hydrogenation plant. After removing the solvent by rotary evaporation, the residue is dissolved in 5 ml of methylene chloride. 500 mg (2.02 mmol, MW 246.27) of O-(tert-butoxycarbonyl)-phenylglyoxylic acid nilrile oxime (BOC-ON) are added thereto and the whole is stirred at room temperature for 24 hours. Subsequently, concentration by rotary evaporation is carried out. The crude product is purified by flash chromatography. The product is then taken up in 10 ml of a 1:3 v/v mixture of trifluoroacetic acid and methylene chloride. After 2 to 3 hours, the whole is subject to rotary evaporation and dried for 0.5 hours under a high vacuum. Finally, lyophilisation from butanol/water (1:1 v/v) is carried out
Reaction SMILES: [C:1](NC(=C)C(O)=O)(=O)C.[C:10]([NH:13][C:14](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([OH:17])=[O:16])(=[O:12])[CH3:11].[Si](C=[N+]=[N-])(C)(C)C>>[C:10]([NH:13][C:14](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([O:17][CH3:1])=[O:16])(=[O:12])[CH3:11]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Reactant: C=C(NC(C)=O)C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)C(=Cc1ccccc1)NC(C)=O

Procedure:
2-Acetamidoacrylic acid and acetamidocinnamic acid were hydrogenated using the same general procedure, derivatised using TMS-diazomethane and analysed using the same method described for the corresponding methyl esters.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:8]1[CH2:13][NH:12][CH:11]=[N:10][CH2:9]1)[C:5]([NH2:7])=[O:6].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[C:36](Cl)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[NH2:3][CH:4]([CH:8]1[CH2:13][N:12]([C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:11]=[N:10][CH2:9]1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)C(N)C1CN=CNC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)C(N)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 71 %

Procedure:
Amino(1,4,5,6-tetrahydropyrimidine-5-yl)acetamide dihydrochloride (1.33 g, 5.8 mmol), diazabicycloundecene (DBU, 2.6 ml, 17.4 mmol), and tritylchloride (1.61 g, 5.8 mmol) are dissolved in anhydrous DMF (20 ml) with stirring under nitrogen at room temperature. After 18 hours stirring the suspension is evaporated in vacuo, and the residue chromatographed (silica, chloroform/methanol, 9:1) to yield 1.64 g (71%) white crystalline solid, identified by 300 MHz nmr and ms m/z=398.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:15])[CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[OH2:16]>>[C:1]([NH:4][C:5](=[O:15])[CH2:6][S:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)CSCc1ccccc1
Reactant: O
Product: CC(=O)NC(=O)CS(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.011 mole of NaIO4 in 25 ml. of water which has been cooled to 5° C. is added 0.01 mole of N-acetyl-2-(benzylthio) acetamide. The reaction mixture is allowed to warm to room temperature and then stirred overnight and concentrated to dryness. Chromatography of the residue on 200 g. of silica gel eluting with ethyl acetate in hexane (25-75%) gives N-acetyl-2-benzylsulfinylacetamide.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([Cl:39])[CH:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)[CH:36]=[C:37]([Cl:39])[CH:38]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2cc(Cl)cc(Cl)c2)c2cc(-c3ccccc3)ccc21
Yield: 22 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3,5-dichlorophenyl boronic acid. The title compound (34 mg) was obtained as a beige solid, (yield=22%).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=O)[C:8](=[CH:12][CH:13]=1)[C:9]([OH:11])=O.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>O>[CH3:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:2]([CH3:1])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[C:9](=[O:11])[N:22]([CH2:23][C:24]([OH:26])=[O:25])[C:14]2=[O:16]
Reactant: NCC(=O)O
Reactant: Cc1cccc(C)c1Oc1ccc(C(=O)O)c(C(=O)O)c1
Solvent: O
Product: Cc1cccc(C)c1Oc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Yield: 99 %

Procedure:
4-(2,6-Dimethyl-phenoxy)-phthalic acid and an equimolar amount of glycine were ground thoroughly together in a mortar. The mixture was then heated at 220 to 240° C. in an oil-bath in vacuo until the formation of water ceased (ca. 30 min) to give the title compound as a dark glass (yield: 99%); MS-(−)-ion: M−1=324.5.
Reaction SMILES: [OH-].[Na+].S(OC)(O[CH3:7])(=O)=O.[C:10]([O:14][C:15]([N:17]1[CH2:21][C@@H:20]([CH2:22][OH:23])[C@H:19]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[C:10]([O:14][C:15]([N:17]1[CH2:21][C@@H:20]([CH2:22][O:23][CH3:7])[C@H:19]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@H](CO[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
Tetrabutylammonium iodide (0.110 g, 0.28 mmol), 50% aqueous NaOH (20 mL) and dimethyl sulfate (0.325 mL, 3.41 mmol) were added to a solution of trans-tert-butyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (0.982 g, 2.84 mmol) in CH2Cl2 (20 mL). The reaction was stirred at rt overnight. TLC showed some starting material remaining so additional dimethyl sulfate (0.150 mL) was added to the reaction mixture and stirred at rt for 3 hrs. Aqueous NH3OH (30 mL) was added to the reaction mixture and stirred at rt for 1 hr. The mixture was diluted with water (20 mL) and extracted with CH2Cl2 (two×30 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified via flash chromatography eluting with 10% EtOAc/heptane to give the title compound as a colorless oil (451 mg, 44% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.60-3.70 (m, 1H), 3.55 (br. s., 2H), 3.37-3.48 (m, 1H), 3.34 (m, 4H), 3.05-3.23 (m, 2H), 2.22-2.40 (m, 1H), 2.07-2.21 (m, 1H), 1.43-1.49 (m, 9H), 0.89 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].C([Li])CCC.[CH:21]([C:24]1[N:25]=[C:26]([CH2:29][CH2:30][C:31]2[CH:49]=[CH:48][N:34]3[C:35](=[O:47])[C:36]([CH:45]=O)=[C:37]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[N:38]=[C:33]3[CH:32]=2)[S:27][CH:28]=1)([CH3:23])[CH3:22]>O1CCCC1>[CH:21]([C:24]1[N:25]=[C:26]([CH2:29][CH2:30][C:31]2[CH:49]=[CH:48][N:34]3[C:35](=[O:47])[C:36](/[CH:45]=[C:6](\[CH3:7])/[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:37]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[N:38]=[C:33]3[CH:32]=2)[S:27][CH:28]=1)([CH3:23])[CH3:22]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1c(N2CCOCC2)nc2cc(CCc3nc(C(C)C)cs3)ccn2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
Under nitrogen atmosphere, triethyl 2-phosphonopropionate (155 mg, 0.65 mmol) was dissolved in tetrahydrofuran (2 ml), added with n-butyl lithium (1 M, 0.65 ml) at −78° C., and stirred at the same temperature for 20 minutes. The reaction mixture was added with a solution of 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde (50 mg) dissolved in tetrahydrofuran (1 ml). The cooling bath was removed, and the reaction mixture was warmed to room temperature and stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (14 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([OH:20])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([N:46]3[CH2:49][CH:48]([OH:50])[CH2:47]3)=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: OC1CNC1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nccc(-n2nc(C(=O)N3CC(O)C3)c3ccc(I)cc32)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2-amino-pyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (500 mg, 1.08 mmol) in DMF (5 ml) was added HATU (823.46 mg, 2.17 mmol) followed by azetidin-3-ol HCl (237.26 mg, 2.17 mmol) and triethylamine (0.45 ml, 3.25 mmol). The reaction mixture was stirred at RT for 3 hr. A white precipitate was also observed which was not soluble in EtOAc and water. The solid was filtered and washed with EtOAc and the filtrate worked up. The solid was dried and analysed by LCMS found to be clean title compound. To the filtrate water (6 ml) was added and the product extracted into EtOAc (2×10 ml). The combined organics were washed with water and brine and concentrated in vacuo. The material was then purified by column chromatography, (9:1 DCM: methanol). The combined column fractions were then triturated from acetonitrile to give the title compound; 1H NMR (500 MHz, DMSO) 3.86 (1H, dd, J=10.56, 3.94 Hz), 4.26-4.46 (2H, m), 4.52-4.64 (1H, m), 4.88 (1H, dd, J=9.77, 7.25 Hz), 5.83 (1H, d, J=6.62 Hz), 7.10 (1H, d, J=5.36 Hz), 7.17 (2H, br. s), 7.77 (1H, d, J=8.51 Hz), 8.04 (1H, d, J=8.51 Hz), 8.36 (1H, d, J=5.67 Hz), 9.34 (1 H, s). LC-MS: m/z=+436.95 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22].O>CC(C)=O>[Cl:22][CH2:21][CH2:20][CH2:19][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: ClCCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCCCCl
Yield: 5.9 %

Procedure:
A mixture of vanillin (30.4 g, 200 mmol), K2CO3 (27.6 g) and acetone (150 ml) was stirred and refluxed for 0.5 hours. Heating was removed and 1-bromo-3-chloropropane (40.8 g, 260 mmol) in acetone was added dropwise. The reaction was stirred and refluxed for 16 hours, and then it was poured into water. The aqueous mixture was extracted with diethyl ether, the extract was dried (MgSO4), and the solution was concentrated to afford an oil, which upon evacuation solidified to a white solid (50.2 g). An 8.0 g sample was flash chromatographed on silica gel with 50% ethyl acetatehexane as eluent. Concentration of appropriate fractions gave 2.7 g (37%) of 4-(3-chloropropoxy)-3-methoxybenzaldehyde as a white solid, m.p.=53°-55° C.